key: cord- -toam r y authors: franquet, tomás; chung, johnathan h. title: imaging of pulmonary infection date: - - journal: diseases of the chest, breast, heart and vessels - doi: . / - - - - _ sha: doc_id: cord_uid: toam r y the spectrum of organisms known to cause respiratory infections is broad and constantly increasing as new pathogens are identified, and an increasing number of patients have impaired immunity due to disease or medications. the radiographic manifestations of a given organism may be variable depending on the immunologic status of the patient and the presence of pre- or coexisting lung disease. moreover, the clinical data and radiographic findings often fail to lead to a definitive diagnosis of pneumonia because there are an extensive number of noninfectious processes associated with febrile pneumonitis. this chapter describes and illustrates the characteristic imaging manifestations of the most common community- acquired pneumonias, nosocomial pneumonias, and the various infections seen in both immunocompetent and immunocompromised patients. community acquired pneumonia refers to an acute infection of the lung in patients who did not meet any of the criteria for hcap, presenting select clinical features (e.g., cough, fever, sputum production, and pleuritic chest pain) and accompanied by an acute infiltrate on a chest radiograph. pulmonary opacities are usually evident on the radiograph within h of the onset of symptoms [ ] . although the imaging findings do not allow a specific etiologic diagnosis, cap diagnosis and disease management most frequently involve chest radiography, and other imaging modalities are not usually required [ ] . the spectrum of causative organisms of cap includes gram-positive bacteria such as streptococcus pneumoniae (pneumococcus), haemophilus influenzae, and staphylococcus aureus, as well as atypical organisms such as mycoplasma pneumoniae, chlamydia pneumoniae, or legionella pneumophila and viral agents such as influenza a virus and respiratory syncytial viruses [ ] . however, many community-acquired pneumonias are still commonly caused by s. pneumoniae and are lobar in appearance. the radiographic patterns of cap are often related to the causative agent. infection of the lower respiratory tract, acquired by way of the airways and confined to the lung parenchyma and airways, typically presents radiologically as one of three patterns: (a) focal nonsegmental or lobar pneumonia, (b) multifocal bronchopneumonia or lobular pneumonia, and (c) focal or diffuse "interstitial" pneumonia. microorganisms responsible for vap may differ according to the population of patients in the icu, the durations of hospital and icu stays, and the specific diagnostic method(s) used. the spectrum of causative pathogens of vap in humans is staphylococcus aureus, pseudomonas aeruginosa, and enterobacteriaceae [ ] . chest radiograph is most helpful when it is normal and rules out pneumonia. however, pulmonary opacities were detected by computed tomography (ct) scan in % of cases with a normal portable chest x-ray. when infiltrates are present, the particular pattern is of limited value for differentiating among cardiogenic pulmonary edema, noncardiogenic, pulmonary edema, hemorrhage, atelectasis, and pneumonia. when pneumonia is associated with healthcare risk factors such as prior hospitalization, dialysis, residing in a nursing home, and immunocompromised state, it is now classified as a healthcare-associated pneumonia (hcap). the number of individuals receiving healthcare outside the hospital setting, including home wound care or infusion therapy, dialysis, nursing homes, and similar settings, is constantly increasing [ ] . a clinical diagnosis of pneumonia can usually be readily established on the basis of signs, symptoms, and chest radiographs, although distinguishing pneumonia from conditions such as left heart failure, pulmonary embolism, and aspiration pneumonia may sometimes be difficult. differentiation of etiologies based solely on the radiograph is not reliable, yet the pattern of abnormalities should be very useful in formulating a differential diagnosis of the nature of disease [ ] . chest radiographs are of limited value in predicting the causative pathogen but are of good use to determine the extent of pneumonia and to detect complications (i.e., cavitation, abscess formation, pneumothorax, pleural effusion), to detect additional or alternative diagnoses, and, in some cases, to guide invasive diagnostic procedures. the most common radiographic manifestations of respiratory infection are foci of consolidation, ground-glass opacities, or reticulonodular opacities. other less common radiographic findings include hilar and mediastinal lymphadenopathy, pleural effusion, cavitation, and chest wall invasion [ , ] . computed tomography, particularly high-resolution ct (hrct), has been shown to be more sensitive than the radiograph in the detection of subtle abnormalities and may show findings suggestive of pneumonia up to days earlier than chest radiographs. ct is recommended in patients with clinical suspicion of infection and normal or nonspecific radiographic findings, in the assessment of suspected complications of pneumonia or suspicion of an underlying lesion such as pulmonary carcinoma. pneumonias are usually divided according to their chest imaging appearance into lobar pneumonia, bronchopneumonia, and interstitial pneumonia. in lobar pneumonia the inflammatory exudate begins in the distal airspaces adjacent to the visceral pleura and then spreads via collateral air drift routes (pores of kohn) to produce uniform homogeneous opacification of partial or complete segments of the lung and occasionally an entire lobe. • pneumonia is the leading cause of death due to infectious disease. • a variety of organisms that may present with similar clinical symptoms result in similar radiographic manifestations. • the radiographic manifestations of a given organism may be variable depending on the immunologic status of the patient. as the airways are not primarily involved and remain patent, there is little to no volume loss, and air bronchograms are common. some pneumonias present as spherical-or nodularshaped consolidations. bronchopneumonia (lobular pneumonia) is characterized histologically by peribronchiolar inflammation manifesting radiologically as patchy airspace nodules with poorly defined margins. radiologically a bronchopneumonia is characterized by large heterogeneous, scattered opacities which only later, with worsening of disease, become more homogeneous. an air bronchogram is usually absent. the most common causative organisms of bronchopneumonia are s. aureus, h. influenzae, p. aeruginosa, and anaerobic bacteria [ ] . characteristic manifestations of bronchopneumonia on hrct include centrilobular ill-defined nodules and branching linear opacities, airspace nodules, and multifocal lobular areas of consolidation [ ] . the term atypical pneumonia (interstitial pneumonia) was initially applied to the clinical and radiographic appearance of lung infection not behaving or looking like that caused by s. pneumoniae [ ] . today, when new diagnostic techniques such as direct antigen detection, polymerase chain reaction, and serology (elisa) have moved beyond the initial diagnostic methods, a debate with regard to the appropriate use of the term "atypical pneumonia" is open [ ] . radiographically focal or diffuse small heterogeneous opacities are seen uniformly distributed in the involved lung. frequently these opacities are described as reticular or reticulonodular. the usual causes of interstitial pneumonia are viral and mycoplasma infections [ ] . streptococcus pneumoniae, a gram-positive coccus, is the most common bacterial cause of cap among patients who require hospitalization. risk factors for the development of pneumococcal pneumonia include the extremes of age, chronic heart or lung disease, immunosuppression, alcoholism, institutionalization, and prior splenectomy. the characteristic clinical presentation is abrupt in onset, with fever, chills, cough, and pleuritic chest pain. the typical radiographic appearance of acute pneumococcal pneumonia consists of a homogeneous consolidation that crosses segmental boundaries (nonsegmental) but involves only one lobe (lobar pneumonia) ( fig. . ) . occasionally, infection is manifested as a spherical focus of consolidation that simulates a mass (round pneumonia). complications, such as cavitation and pneumatocele formation, are rare. pleural effusion is common and is seen in up to half of patients. pneumonia caused by s. aureus usually follows aspiration of organisms from the upper respiratory tract. risk factors for the development of staphylococcal pneumonia include underlying pulmonary disease (e.g., copd, carcinoma), chronic illnesses (e.g., diabetes mellitus, renal failure), or viral infection. the clinical presentation of staphylococcal pneumonia is changing and of particular importance is the dramatic increase of the incidence of methicillinresistant staphylococcus aureus (mrsa) infections in recent years. increasingly, previously healthy young people without traditional risk factors for s. aureus disease are presenting with severe necrotizing infection and high mortality. fever, cough, and purulent sputum are prominent symptoms in cases of post-aspirative staphylococcal pneumonia. severe pneumonia caused by community-associated methicillin-resistant staphylococcus aureus (mrsa) carrying genes for panton-valentine leukocidin has been described in immunocompetent young adults. the characteristic pattern of presentation is as a bronchopneumonia (lobular pneumonia) that is bilateral in % of patients. the radiographic manifestations usually consist of bilateral patchy areas of consolidation. air bronchograms are uncommon. other features are cavitation, pneumatoceles, pleural effusions, and spontaneous pneumothorax ( fig. . ). pneumatoceles are seen especially in children [ ] . thoracic actinomycosis is a chronic suppurative pulmonary or endobronchial infection caused by actinomyces species, most frequently actinomyces israelii considered to be a gram-positive branching filamentous bacterium. pulmonary infection is characterized pathologically by bronchopneumonia with focal or multifocal abscess formation. actinomycosis has the ability to spread across fascial planes to contiguous tissues without regard to normal anatomic barriers. on ct, parenchymal actinomycosis is characterized by airspace consolidation with cavitation or central areas of low attenuation and adjacent pleural thickening. endobronchial actinomycosis can be associated with a foreign body (direct aspiration of a foreign body contaminated with actinomyces organisms) or a broncholith (secondary colonization of a preexisting endobronchial broncholith by aspirated actinomyces organisms). nocardia is a genus of filamentous gram-positive, weakly acid fast, aerobic bacteria that affects both immunosuppressed and immunocompetent patients. nocardia asteroides is responsible of % of infections by this organism in man. pulmonary nocardiosis can be an acute, subacute, or chronic disease. nocardiosis usually begins with a focus of pulmonary infection and may disseminate through hematogenous spread to other organs, most commonly to the cns. imaging findings are variable and consist of unifocal or multifocal consolidation and single or multiple pulmonary nodules [ ] . nocardia asteroides infection may complicate alveolar proteinosis. gram-negative pneumonias are chiefly caused by klebsiella pneumoniae, enterobacter sp., serratia marcescens, escherichia coli, proteus sp., and pseudomonas aeruginosa. patients affected are invariably debilitated by a chronic medical or pulmonary disease. the lower lobes contrast-enhanced ct image shows a mixed opacity of consolidation (arrow) and ground-glass opacity (small arrows) consistent with lobar pneumonia tend to be affected, and the radiographic pattern is similar to that seen with s. aureus infections in adults. klebsiella pneumoniae is among the most common gramnegative bacteria accounting for . - . % of all cases of pneumonia. these features are bulging fissures, sharp margins of the advancing border of the pneumonic infiltrate and early abscess formation. ct findings consist of ground-glass attenuation, consolidation, and intralobular reticular opacity, often associated with pleural effusion. complications of klebsiella pneumonia include abscess formation, parapneumonic effusion, and empyema. axial contrast-enhanced ct shows a cavitary mass within the right lower lobe (arrow) and a mass in the left upper lobe demonstrating surrounding ground-glass opacity (halo sign) (arrows) escherichia coli accounts for % of cases of cap and - % of cases of hap or hcap. it occurs most commonly in debilitated patients. the typical history is one of abrupt onset of fever, chills, dyspnea, pleuritic pain, and productive cough in a patient with preexisting chronic disease. the radiographic manifestations usually are those of bronchopneumonia; rarely a pattern of lobar pneumonia may be seen. pseudomonas aeruginosa is a gram-negative bacillus that is the most common cause of nosocomial pulmonary infection. it causes confluent bronchopneumonia that is often extensive and frequently cavitates (fig. . ) . the radiologic manifestations are nonspecific and consist most commonly of patchy areas of consolidation and widespread poorly defined nodular opacities [ ] . chlamydia pneumoniae is the most commonly occurring gram-negative intracellular bacterial pathogen. it is frequently involved in respiratory tract infections and has also been implicated in the pathogenesis of asthma in both adults and children. symptoms include sore throat, headache, and a nonproductive cough that can persist for months if treatment is not initiated early. chest radiographs tend to show less extensive abnormalities than are seen with other causes of pneumonia. on ct, c. pneumoniae pneumonia demonstrates a wide spectrum of the most common rickettsia lung infection is sporadic or epidemic q-fever pneumonia caused by coxiella burnetii, an intracellular, gram-negative bacterium. infection is acquired by inhalation from farm livestock or their products and occasionally from domestic animals. imaging findings consist of multilobar airspace consolidation, solitary or multiple nodules surrounded by a halo of "groundglass" opacity and vessel connection, and necrotizing pneumonia. tularemia is an acute, febrile, bacterial zoonosis caused by the aerobic gram-negative bacillus francisella tularensis. it is endemic in parts of europe, asia, and north america. primary pneumonic tularemia occurs in rural settings. humans become infected after introduction of the bacillus by inhalation, intradermal injection, or oral ingestion. chest radiographic findings are scattered multifocal consolidations, hilar adenopathy, and pleural effusion. haemophilus influenzae is a pleomorphic, gram-negative coccobacillus that accounts for - % of cap in patients in whom an organism can be identified successfully. factors that predispose to haemophilus pneumonia include copd, malignancy, hiv infection, and alcoholism. the typical radiographic appearance of haemophilus influenza pneumonia consists of multilobar involvement with lobar or segmental consolidation and pleural effusion. legionella is a pathogenic gram-negative bacterium with at least species. it is one of the most common causes of severe community-acquired pneumonia in immunocompetent hosts. human infection may occur when legionella contaminates water systems, such as air conditioners and condensers. risk factors for the development of l. pneumophila pneumonia include immunosuppression, posttransplantation, cigarette smoking, renal disease, and exposure to contaminated drinking water. patients with legionella pneumonia usually present with fever, cough, initially dry and later productive, malaise, myalgia, confusion, headaches, and diarrhea. thirty percent of patients develop pleuritic chest pain. imaging findings include peripheral airspace consolidation similar to that seen in acute s. pneumoniae pneumonia. in many cases, the area of consolidation rapidly progresses to occupy all or a large portion of a lobe (lobar pneumonia) or to involve contiguous lobes or to become bilateral. cavitation is uncommon in immunocompetent patients, and pleural effusion may occur in - % of cases. moraxella catarrhalis (formerly known as branhamella catarrhalis) has emerged as a significant bacterial pathogen of humans over the past two decades. it is an intracellular gram-negative coccus now recognized as one of the common respiratory pathogens [ ] . m. catarrhalis causes otitis media and sinusitis in children and mild pneumonia and acute exacerbation in older patients with copd. it is currently considered the third most common cause of community-acquired bacterial pneumonia (after s. pneumoniae and h. influenzae). the majority of patients with pneumonia ( - %) have underlying chronic pulmonary disease. chest radiographs show bronchopneumonia or lobar pneumonia that usually involves a single lobe. m. pneumoniae is one of the most common causes of community-acquired pneumonia. it accounts for up to % of cap in persons treated as outpatients. patients with copd appear to be more severely affected with m. pneumoniae than normal hosts. the radiographic findings in m. pneumoniae are variable and in some cases closely resemble those seen in viral infections of the lower respiratory tract. chest radiograph shows fine linear opacities followed by segmental airspace consolidation [ ] . • a "tree-in-bud" pattern is a characteristic ct manifestation of infectious bronchiolitis. • focal areas of consolidation secondary to infection in immunocompromised patients are most commonly due to bacterial pneumonia. • interstitial and/or mixed interstitial and airspace opacities in cap are typically due to viruses or m. pneumoniae. mycobacterium tuberculosis accounts for more than % of pulmonary mycobacterial infections. other mycobacterial species, m. kansasii and m. avium-intracellulare complex (mac), account for the remainder. factors that contribute to the large number of cases seen worldwide are human immunodeficiency virus (hiv) infection, inner city poverty, homelessness, and immigration from areas with high rates of infection. other predisposing conditions are diabetes mellitus, alcoholism, silicosis, and malignancy. this form is seen in infants and children. with improved control of tuberculosis in western societies, however, more people reach adulthood without exposure, and primary patterns of disease are being seen with increasing frequency in adulthood and represents about - % of all adult cases of tuberculosis. although primary tuberculosis typically presents with radiographic manifestations, chest radiograph may be normal in % of cases. lymphadenopathy is the most common manifestation of primary tuberculosis in children and occurs with or without pneumonia. in adults hilar or mediastinal lymphadenopathy is less common declining to about % of cases in the older population. pleural effusion occurs in children, who usually have parenchymal or nodal disease, or in teenagers and young adults, when it is frequently isolated. most cases are due to reactivation of quiescent lesions, but occasionally a new infection from an exogenous source occurs. pathologically, the ability of the host to respond immunologically results in a greater inflammatory reaction and caseous necrosis. the radiological manifestations may overlap with those of primary tuberculosis, but the absence of lymphadenopathy, more frequent cavitation, and a predilection for the upper lobes are more typical of postprimary tuberculosis. a rasmussen aneurysm is a rare life-threatening complication of cavitary tuberculosis caused by granulomatous weakening of a pulmonary arterial wall. endobronchial spread can occur with or without cavitary disease and is similar to that seen with primary tuberculosis leading to the appearance of the typical images of "tree-inbud" [ , ] . after antituberculous treatment healing results in scar formation. the fibrosis produces well-defined, upper lobe nodular and linear opacities, often with evidence of severe volume loss and pleural thickening. residual thin-walled cavities may be present in both active and inactive disease. although classically a manifestation of primary disease, miliary tuberculosis is now more commonly seen as a postprimary process in older patients. multiple small ( - mm) discrete nodules are scattered evenly throughout both lungs. a tuberculoma may occur in the setting of primary or postprimary tuberculosis and represents localized parenchymal disease that alternately activates and heals. it usually calcifies and frequently remains stable for years [ ] . as mentioned above, - % of pulmonary mycobacterial infections are caused by agents other than m. tuberculosis: usually m. avium-intracellulare complex (mac) and less commonly m. kansasii. patients are often predisposed by reason of underlying debilitating disease, immune compromise, chronic airflow obstruction, previous pulmonary tuberculosis, or silicosis and following lung transplantation [ ] . clinically, mac may be an indolent process with symptoms of cough, with or without sputum production. more commonly, mac presents with a radiological pattern that does not resemble that of postprimary tuberculosis. it consists of multiple nodules, with or without small ring opacities, showing no specific lobar predilection and bronchiectasis particularly in the lingula and right middle lobe. the most typical form of pulmonary nontuberculous mycobacteria (ntmb) infection is frequently associated to elderly men with underlying lung disease and to elderly white women without underlying lung disease (lady windermere syndrome). radiological findings consist of mild to moderate cylindrical bronchiectasis and multiple - mm diameter centrilobular nodules. fungi involved in pulmonary infections are either pathogenic fungi, which can infect any host, or saprophytic fungi, which infect only immunocompromised hosts. pathogenic fungi include coccidioidomycosis, blastomycosis, and histoplasmosis. saprophytes include pneumocystis, candidiasis, mucormycosis, and aspergillosis. pulmonary fungal infections may be difficult to diagnose, and a definitive diagnosis of pulmonary fungal infections is made by isolating the fungus from tissue specimen. aspergillosis is a fungal disease caused by aspergillus species, usually a. fumigatus that can take different forms depending on an individual's immune response to the organism. classically, pulmonary aspergillosis has been categorized into saprophytic, allergic, and invasive forms [ , ] . aspergillus mycetomas are saprophytic growths which colonize a preexisting cavity in the lung (e.g., from sarcoidosis or tuberculosis). most cavities and thus mycetomas are in the upper lobes or superior segments of the lower lobes. allergic bronchopulmonary aspergillosis (abpa) describes a hypersensitivity reaction which occurs in the major airways. it is associated with elevated serum ige, positive serum precipitins, and skin reactivity to aspergillus. the radiographic appearances consist of nonsegmental areas of opacity most common in the upper lobes, lobar collapse, branching thick tubular opacities due to bronchi distended with mucus and fungus, and occasionally pulmonary cavitation. the mucus plugs in abpa are usually hypodense, but in up to % of patients, the mucus can be hyperdense on ct (fig. . ) . angioinvasive aspergillosis is seen in immunocompromised hosts with severe neutropenia. this form is characterized by invasion and occlusion of small-to-medium pulmonary arteries, developing necrotic hemorrhagic nodules or infarcts. the most common pattern seen in ct consists of multiples nodules surrounded by a halo of ground-glass attenuation (halo sign) or pleural-based wedgeshaped areas of consolidation [ ] . candida species has been increasingly recognized as an important source of fungal pneumonia in immunocompromised patients, particularly in those with underlying malignancy (acute leukemia and lymphoma), intravenous drug abuse, and acquired immune deficiency syndrome a b c fig. . (a, b, c) allergic bronchopulmonary aspergillosis: (a) posteroanterior chest radiograph demonstrates basilar branching opacities suggestive of mucus-filled bronchiectasis (arrows). (b) axial ct image confirms the presence of left basilar bronchiectasis, mucus-filled airways (arrows). (c) hyperdensity of mucus-filled airways on axial mip image (arrows) from chest ct is diagnostic of allergic bronchopulmonary aspergillosis (aids), and following bone marrow transplantation. the most common thin-section ct findings of pulmonary candidiasis consist of multiple bilateral nodular opacities often associated with areas of consolidation and groundglass opacity [ ] . pneumocystis jiroveci a unique opportunistic fungal pathogen that causes pneumonia in immunocompromised individuals such as patients with aids, patients with organ transplants, and patients with hematologic or solid organ malignancies who are undergoing chemotherapy. in % of patients with pneumocystis jiroveci, pneumonia chest radiographs show diffuse bilateral infiltrates in a perihilar distribution ( fig. . ) . the most common high-resolution ct finding in pneumocystis jiroveci pneumonia is diffuse ground-glass opacity [ ] . mucormycosis is an opportunistic fungal infection of the order mucorales, characterized by broad, nonseptated hyphae that randomly branch at right angles. the most common radiographic findings consist of lobar or multilobar areas of consolidation and solitary or multiple pulmonary nodules and masses with associated cavitation or an air-crescent sign [ ] . viruses can result in several pathologic forms of lower respiratory tract infection including tracheobronchitis, bronchiolitis, and pneumonia. viral infections predispose to secondary bacterial pneumonia. organizing pneumonia, a nonspecific reparative reaction, may result from a variety of causes or underlying pathologic processes including viral infections [ ] . influenza type a is the most important of the respiratory viruses with respect to the morbidity and mortality in the general population. in recent years, both influenza and parainfluenza viruses have been recognized as a significant cause of respiratory illness in immunocompromised patients, including solid organ transplant recipients. the predominant high-resolution ct findings are ground-glass opacities, consolidation, centrilobular nodules, and branching linear opacities. adenovirus accounts for - % of acute respiratory infections in infants and children but for less than % of respiratory illnesses in adults. swyer-james-macleod syndrome is considered to be a post-infectious bronchiolitis obliterans (bo) secondary to adenovirus infection in childhood. respiratory syncytial virus (rsv) is the most frequent viral cause of lower respiratory tract infection in infants. the major risk factors for severe rsv disease in children are prematurity (< weeks gestation), congenital heart disease, chronic lung disease, immunocompromised status, and multiple congenital abnormalities. ct findings consist of small centrilobular nodules, airspace consolidation, ground-glass opacities, bronchial wall thickening, and "tree-in-bud" opacities ( fig. . ). primary infection with ebv occurs early in life and presents as infectious mononucleosis with the typical triad of fever, pharyngitis, and lymphadenopathy, often accompanied by splenomegaly. mild, asymptomatic pneumonitis occurs in about - % of cases of infectious mononucleosis. the ct manifestations of ebv pneumonia are similar to those of other viral pneumonias. the findings usually consist of lobar consolidation, diffuse and focal parenchymal haziness, irregular reticular opacities, and multiple miliary nodules or small nodules with associated areas of ground-glass attenuation ("halo"). varicella is a common contagious infection in childhood with increasing incidence in adults. clinically presents in two forms: varicella (chickenpox) representing a primary disseminated disease in uninfected individuals and zoster (shingles) representing reactivation of latent virus (unilateral dermatomal skin eruption). pneumonia, although rare, is the most serious complication affecting adults with chickenpox. the thin-section ct appearances in varicella pneumonia reflect the multicentric hemorrhage and necrosis centered on airways. common findings include numerous nodular opacities measuring - mm in diameter, some with a surrounding halo of ground-glass opacity, patchy ground-glass opacities, and coalescence of nodules. cytomegalovirus pneumonia is a major cause of morbidity and mortality following hematopoietic stem cell (hsct) and solid organ transplantation and in patients with aids in whom cd cells are decreased to fewer than cells/mm . this complication characteristically occurs during the post-engraftment period ( - days after transplantation) with a median time onset of - days posttransplantation. ct features of cmv pneumonia consist of lobar consolidation, diffuse and focal ground-glass opacities, irregular reticular opacities, and multiple miliary nodules or small nodules with associated areas of ground-glass attenuation ("halo"). severe acute respiratory distress syndrome (sars) caused by sars-associated coronavirus (sars-cov) is a systemic infection that clinically manifests as progressive pneumonia. severe acute respiratory distress syndrome was first detected in the guangdong province of china in late , with major outbreaks in hong kong, guangdong, singapore, and toronto and vancouver, canada. over people were affected, with a mortality rate of %. the typical clinical presentation consists of an incubation period of - days, early systemic symptoms followed within - days by dry cough or shortness of breath, the development of radiographically confirmed pneumonia by day - , and lymphocytopenia in many cases. histologically, acute diffuse alveolar damage with airspace edema is the most prominent feature. the imaging features consist of unilateral or bilateral ground-glass opacities, focal unilateral or bilateral areas of consolidation, or a mixture of both [ , ] . mers is a viral disease caused by a coronavirus (mers-cov), with most of the infections believed to have originated in saudi arabia and the middle east. most patients develop a severe acute respiratory illness. ct may depict groundglass opacities, consolidation, interlobular thickening, and pleural effusion. during the subsequent weeks, other findings may be present, such as centrilobular nodules, a "crazypaving" pattern, obliterative bronchiolitis, peribronchial air trapping, and organizing pneumonia [ ] . in the spring of , an outbreak of severe pneumonia was reported in conjunction with the concurrent isolation of a novel swine-origin influenza a (h n ) virus, widely known as swine flu, in mexico. on june , , the world health organization declared the first pandemic of the twenty-first century caused by swine-origin influenza virus a (h n ). the predominant ct findings are unilateral or bilateral ground-glass opacities with or without associated focal or multifocal areas of consolidation. on ct, the ground-glass opacities and areas of consolidation have a predominant peribronchovascular and subpleural distribution, resembling organizing pneumonia [ ] . • primary tb occurs most commonly in children. • the most typical form of pulmonary ntmb infection is frequently associated to elderly non-smoking white women without underlying lung disease (lady windermere syndrome). • with respect to the morbidity and mortality, influenza type a is the most important of the respiratory viruses in the general population. vap: the diachronic linguistics of pneumonia community-acquired pneumonia admission chest radiograph lacks sensitivity in the diagnosis of community-acquired pneumonia community-acquired pneumonia re-evaluation of the etiology and clinical and radiological features of community-acquired lobar pneumonia in adults ventilator-associated pneumonia health care-associated pneumonia (hcap): empiric antibiotics targeting methicillin-resistant staphylococcus aureus (mrsa) and pseudomonas aeruginosa predict optimal outcome imaging infection imaging of community-acquired pneumonia high resolution ct findings in community-acquired pneumonia atypical pneumonia atypical pneumonia--time to breathe new life into a useful term? radiology of bacterial pneumonia ct findings of pulmonary nocardiosis moraxella catarrhalis: from emerging to established pathogen mycoplasma pneumoniae pneumonia: radiographic and high-resolution ct features in patients ct of pulmonary tuberculosis treein-bud pattern at thin-section ct of the lungs: radiologic-pathologic overview tuberculosis: a radiologic review update on the epidemiology of pulmonary nontuberculous mycobacterial infections spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings the spectrum of pulmonary aspergillosis pulmonary candidiasis after hematopoietic stem cell transplantation: thinsection ct findings pneumocystis jiroveci pneumonia: high-resolution ct findings in patients with and without hiv infection pulmonary mucormycosis: radiologic features at presentation and over time imaging of pulmonary viral pneumonia thin-section ct of severe acute respiratory syndrome: evaluation of patients exposed to or with the disease severe acute respiratory syndrome (sars) middle east respiratory syndrome coronavirus: what does a radiologist need to know? ct utilization in the prospective diagnosis of a case of swine-origin influenza a (h n ) viral infection /), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license and indicate if changes were made. the images or other third party material in this chapter are included in the chapter's creative commons license, unless indicated otherwise in a credit line to the material. if material is not included in the chapter's creative commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use key: cord- -rzdxdzp authors: jenks, christopher l.; uysal, askin; papacostas, michael f. title: drug hypersensitivity causing organizing eosinophilic pneumonia in a pediatric patient date: - - journal: heart lung doi: . /j.hrtlng. . . sha: doc_id: cord_uid: rzdxdzp objective: to describe a relatively rare hypersentivity reaction with pulmonary manifestations in a pediatric patient. data sources: electronic medical records. study selection: patient treatment in the pediatric critical care unit. data extraction and synthesis: electronic medical records. conclusions: eosinophilic pneumonias are rare in the pediatric population. peripheral eosinophilia is not necessary to make the diagnosis. bronchoalveolar lavage is the diagnostic study of choice. lung biopsies are rarely needed to make the diagnosis. the treatment of choice is steroids. if steroids fail to improve the patient's condition, consider ivig, and cyclosporine a. a year old female with no significant past medical history presented to our emergency department for evaluation of dyspnea and fever. she is normally an active girl, with no smoking history, no second hand smoke exposure at home, and no history of illicit drug use. about weeks prior to her presentation, she was seen by her primary care physician for an abscess on her thumb. she started a course of sulfamethoxazole/trimethoprim. shortly thereafter, she developed a fever, cough, and a diffuse rash. she stopped taking the sulfamethoxazole/trimethoprim after days due to decreased oral intake. she returned to her primary care physician for re-evaluation, and was diagnosed with an acute otitis media (although no ear symptoms were present at the time). she was started on amoxicillin. she stopped the amoxicillin after one day due to nausea and vomiting. her amoxicillin was then changed to azithromycin. she promptly stopped taking it due to profuse vomiting and an urticarial type rash. she then presented to an urgent care facility. her work up included a rapid flu and strep both of which were negative. she was given a prescription for topical hydrocortisone and oral diphenhydramine. she started to improve so her mother re-started the original sulfamethoxazole/trimethoprim. shortly after re-starting the sulfamethoxazole/trimethoprim, she developed diffuse myalgias, dyspnea, and fever to . c. she then went to an emergency department. work up included another rapid flu (negative), a rapid strep (negative), wbc thousand/ mm , and a chest roentgram (cxr) which was consistent with a "viral process." she was discharged on oral prednisone mg a day. her dyspnea worsened necessitating ambulance transport to our facility. on presentation, she complained of cough, dyspnea, upper abdominal pain worse with deep inspiration, and anxiety to the point that she was afraid to go to sleep. she had no problems with confusion, seizures, emesis/diarrhea, chest pain, or swollen joints. there was no history of recent travel, tick bites, or sick contacts. her blood pressure was / , heart rate , respiratory rate , temperature . c, height cm, weight . kg, body mass index . , pulse oximetry % on l nasal cannula. physical exam was significant for a clear oropharynx, coarse breath sounds which were decreased in the bases bilaterally, tachypnea and tachycardia. she was admitted to the general pediatric floor. her oxygen was continued. cxr showed bibasilar interstitial prominence. heart & lung j o u r n a l h o m e p a g e : w w w . h e a r t a n d l u n g . o r g a cxr revealed pneumomediastinum, pneumopericardium, and bilateral pneumothoraces. oxygen saturations noted to be %. intubation, pleural decompression followed by bilateral chest tube placement helped stabilize her condition. oxygen saturations returned to normal. a peripherally inserted central catheter (picc) line was placed in her left upper extremity. the following day a computerized tomography (ct) scan of the chest with pulmonary embolism protocol revealed saddle thrombus located in the right pulmonary artery seen within the middle and lower lobe lobar, segmental, and subsegmental arteries with a probable tiny amount of thrombus within the left lower lobe segmental and subsegmental arteries, also noted to have ground glass appearance of the lower lobes bilaterally. hypercoagulable work up included homocysteine level, protein c and s, antithrombin iii, factor ii, factor v leiden, and factor viii all which were normal. lupus anticoagulant anticardiolipin antibodies, b glycoprotein were all negative. ultrasound of her left upper extremity showed an occlusive thrombus associated with the picc line involving the axillary and basilica vein. she did not have any thrombosis in her lower extremities. she was placed on a continuous heparin drip with goals to keep her anti xa levels . e . . blood and urine cultures remained negative. tests for tularensis, rickettsi, erlichia, hanta virus, human immunodeficiency virus, herpes simplex virus (hiv), pneumocystis were negative. bronchoscopy with bronchoalveolar lavage (bal) was negative for cytomegalovirus, legionella, ebstein barr virus, yeast, and acid fast bacilli. her bal showed % eosinophils. an open lung wedge biopsy was negative for mycobacterium, mycoplasma, and herpes simplex virus. the surgical pathology returned as organizing eosinophilic pneumonia consistent with a drug hypersensitivity reaction. no evidence of infectious organisms, vasculitis, or evidence of aspiration seen. we re-started her on corticosteroids after which she showed continuous improvement over the next weeks. her pneumomediastinum and pneumothoraces resolved, and her chest tubes were removed. we discharged her on enoxaparin for her pulmonary embolism. the eosinophilic pneumonias encompass a wide variety of different interstitial lung disease, but all typically have eosinophilic infiltration of the lungs. the exact role of the eosinophil is these disease processes are unknown, but may be related to tissue injury from inflammation and eosinophilic degranulation. the eosinophilic pneumonias are generally placed into two large categories: idiopathic and secondary. the idiopathic group contains eosinophilic granulomatosis with polyangiitis, idiopathic chronic eosinophilic pneumonia, and idiopathic acute eosinophilic pneumonia. the secondary group includes parasites, drugs, toxins, allergic bronchopulmonary aspergillosis and neoplasms. many drugs have an association with eosinophilic pneumonia, but not all have a proven causal relationship. some of the associated drugs include the following: antibiotics (beta lactams, tetracycline, sulfonamides, nitrofurantoin, isoniazid, ethambutol, pentamadine), antiepileptics (carbamazapine, phenytoin), illicit drugs (heroine, cocaine), non-steroidal anti-inflammatory drugs (ibuprofen, naproxen, indomethacin, diclofenac, piroxicam), antidepressants (amitriptyline, trazodone, venlafaxine), chemotherapeutic agents (bleomycin, camptothecin), cardiovascular drugs (angiotensin converting enzyme inhibitors, amiodarone, b-blockers), biologics (infliximab, interferon alpha, granulocyte e macrophage colony stimulating factor), and nutraceuticals (l-tryptophan). eosinophilic pneumonia is not common in the pediatric population. the mean age is typically in the late s. the exact incidence is unknown. there appears to be an association with hiv, smoking, and hypersensitivity to drugs or toxin exposure. our patient seemed to have a causal relationship with sulfamethoxazole/ trimethoprim. the presentation is typically rapid over the course of e days, and generally involves fever, myalgias, pleuritic chest pain, crackles on lung exam, plus or minus peripheral eosinophilia as was the case in our patient. a cxr typically shows non-specific findings but includes consolidation, hilar adenopathy, pleural effusions, and reticulonodular densities. ct scans of the chest usually show ground glass opacities, nodules, or irregular lines. the ct chest in our patient demonstrated a ground glass appearance as well as a pulmonary embolism. bronchoalveolar lavage is the diagnostic study of choice to diagnose an eosinophilic lung disease as it may be the only clue revealing a high eosinophil count (typically > % when the normal in bal fluid is < %). our patient had a slight elevation in her bal eosinophils likely due to the fact that she had been partially treated with corticosteroids prior to her hospital presentation. a recent search of the available literature has revealed only a few papers that describe an association with a pneumothorax related to an eosinophilic pneumonia (in the setting of a paragonimiasis infection). there have been very few reported cases of organizing eosinophilic pneumonia being associated with pulmonary embolism or a pneumomediastinum. our patient's condition was associated with a pneumothorax, pneumopericardium, and pneumomediastinum. the exact etiology of the pulmonary embolism is unclear. some possible etiologies could include the picc line, an undiagnosed hypercoagulable disorder, or related to the inflammation of the eosinophilic disorder. her hypercoagulable work up was negative but an undiagnosed mutation is always a possibility. eosinophilic pneumonia has no obvious association with pulmonary embolism but still could be the possible etiology. the picc line was present for less then hours, but theoretically could have been the cause. an interesting component of our patient is that she did not readily improve on her initial corticosteroid treatment, but did clinically respond to the corticosteroids later on in her hospital course. corticosteroid refractory eosinophilic lung disease has been previously reported in the pediatric literature. ronald mortan et al reported a neonate at weeks of life that had a protracted course of pneumonia, received several courses of corticosteroids with no improvement. at weeks of life the patient had a lung biopsy which showed the eosinophilic pneumonia. the patient was then treated with an empiric course of intravenous immunoglobulin (ivig). the ivig was ineffective and a trial of cyclosporine a was instituted resulting in rapid clinical improvement. eosinophilic pneumonias are rare in the pediatric population. peripheral eosinophilia is not necessary to make the diagnosis. when this diagnosis is entertained, a bal should be performed as early as possible because it is the diagnostic study of choice. lung biopsies are rarely needed to make the diagnosis, but may be necessary if the primary diagnostic study of choice is unrevealing. the treatment of choice is corticosteroids. if corticosteroids fail to improve the patient's condition, other treatment options could include ivig, and cyclosporine a. eosinophilic lung diseases. immunol allergy clin north am eosinophilic lung diseases pleuropulmonary infection by paragonimus westermani in the united states: a rare cause of eosinophilic pneumonia after ingestion of live crabs steroid-refractory neonatal eosinophilic pneumonia responsive to cyclosporin a. am j respir crit care med key: cord- -bz g a authors: davis, kailah; staes, catherine; duncan, jeff; igo, sean; facelli, julio c title: identification of pneumonia and influenza deaths using the death certificate pipeline date: - - journal: bmc med inform decis mak doi: . / - - - sha: doc_id: cord_uid: bz g a background: death records are a rich source of data, which can be used to assist with public surveillance and/or decision support. however, to use this type of data for such purposes it has to be transformed into a coded format to make it computable. because the cause of death in the certificates is reported as free text, encoding the data is currently the single largest barrier of using death certificates for surveillance. therefore, the purpose of this study was to demonstrate the feasibility of using a pipeline, composed of a detection rule and a natural language processor, for the real time encoding of death certificates using the identification of pneumonia and influenza cases as an example and demonstrating that its accuracy is comparable to existing methods. results: a death certificates pipeline (dcp) was developed to automatically code death certificates and identify pneumonia and influenza cases. the pipeline used metamap to code death certificates from the utah department of health for the year . the output of metamap was then accessed by detection rules which flagged pneumonia and influenza cases based on the centers of disease and control and prevention (cdc) case definition. the output from the dcp was compared with the current method used by the cdc and with a keyword search. recall, precision, positive predictive value and f-measure with respect to the cdc method were calculated for the two other methods considered here. the two different techniques compared here with the cdc method showed the following recall/ precision results: dcp: . / . and keyword searching: . / . . the f-measure were . and . respectively (dcp and keyword searching). both the keyword and the dcp can run in interactive form with modest computer resources, but dcp showed superior performance. conclusion: the pipeline proposed here for coding death certificates and the detection of cases is feasible and can be extended to other conditions. this method provides an alternative that allows for coding free-text death certificates in real time that may increase its utilization not only in the public health domain but also for biomedical researchers and developers. trial registration: this study did not involved any clinical trials. the ongoing monitoring of mortality is crucial to detect and estimate the magnitude of deaths during epidemics, emergence of new diseases (for example, seasonal or pandemic influenza, aids, sars), and the impact of extreme environmental conditions on a population such as heat waves or other relevant public health events or threats [ , ] . the surveillance of vital statistics is not a novel idea; mortality surveillance has played an integral part in public health since the london bills of mortality were devised in the seventeenth century [ ] . the bills served as an early warning tool against bubonic plague by monitoring deaths from the to the s. today, mortality surveillance continues to be a critical activity for public health agencies throughout the world [ ] [ ] [ ] [ ] . pneumonia and influenza are serious public health threats and are a cause of substantial morbidity and mortality worldwide; for instance, the world health organization (who) estimates seasonal influenza causes between , to , deaths worldwide each year [ ] while pneumonia kills more than million people worldwide every year [ ] . worldwide, the morbidity and mortality of influenza and pneumonia have a considerable economic impact in the form of hospital and other health care costs. each year in the united states approximately million persons acquire pneumonia and, depending on the severity of the influenza season, to million people in the us contract influenza [ ] . these numbers contribute to approximately . million hospitalizations, of which . million are pneumonia cases [ ] and the remainder for influenza [ ] . moreover, pneumonia cases and influenza together cost the american economy . billion dollars in [ ] . in the netherlands it has been estimated that influenza accounts for and days of hospitalization per , highrisk and low-risk elderly, respectively [ ] . due to the public health burden and the unpredictability of an influenza season, strong pneumonia and influenza surveillance systems are a priority for health authorities. mortality monitoring is an important tool for the surveillance of pneumonia and influenza which can aid in the rapid detection and estimates of excess deaths and inform and evaluate the effect of vaccination and control programs. traditionally, influenza mortality surveillance often uses the category of "pneumonia and influenza" (p-i) on death certificates as an indicator of the severity of an influenza season or to identify trends within a season; however, only a small proportion of these deaths are influenza related. it has been reported that only . [ ] [ ] [ ] [ ] [ ] . % of all pneumonia and influenza deaths are influenza related [ , ] . the non-influenza-related pneumonia deaths tend to be stable from year to year and fluctuations in this category are largely driven by the prevalence and severity of seasonal influenza. as a result, the p-i category is an important sentinel indicator. in the us, death certificates are the primary data source for mortality surveillance whose findings are widely used to exemplify epidemics and measure the severity of influenza seasons [ ] . currently, there are three systems to monitor influenza-related mortality; one system in particular, the cities mortality reporting system, provides a rapid assessment of pneumonia and influenza mortality [ ] . each week, this system summarizes the total number of death certificates filed in us cities, as well as the number of deaths due to pneumonia and influenza. however, even these data can be delayed by approximately - weeks from the times of death. this delay can be attributed to one of the following reasons: ) timeliness of death registration and ) reviewing of the death certificates to identify pneumonia and influenza deaths [ , , ] . the registration and reviewing of death certificates varies by states and, as a result, there is variability in length of time to report a death to cdc. for instance, states with paper-based death registration system typically perform manual reviews of the death certificates which can take up to weeks; however states with electronic death registration systems (edrs) may perform automatic reviews which can decrease this time significantly. the current cities mortality reporting system surveillance system also lacks flexibility for expanding the number of conditions and/or the geographic distribution. moreover, the unavailability of coded death records due to the complexity of the national center of health statistics (nchs) coding process results in multiple strategies to identify common outbreaks such as pneumonia and influenza deaths, which greatly vary by jurisdiction. to bypass the lengthy nchs process, a variety of approaches have been attempted that are close to 'realtime' but less than optimal. for instance, in utah keyword searching is used to identify pneumonia and influenza deaths; although this method is fast and easy to implement, it can easily result in the over or under estimation of cases. this can occur by missing cases due to misspelled terms, synonyms, variations, or the selection of strings containing the search term. other research groups [ , ] have demonstrated the feasibility of using mortality data for real time surveillance but all used "free text" search for the string "pneumonia", "flu" or "influenza." as noted earlier, although this method can provide the semi quantitative measurements for disease surveillance purposes, keyword searches can also result in an array of problems that result from complexities of human language such as causal relationships and synonyms [ ] . therefore, the lack of coded death data that may not be available for months [ ] seriously limits the use of death records in automated systems. at this time, there is little published on the automatic assignment of codes to death certificates for automatic case detection. currently the coding of death certificates is a complex process which involves many entities. in the us, where we are focusing this study, the codes on death certificates that are generated by the national center for health statistics (nchs) depend on information reported on the death certificate by the medical examiner, coroner, or another certifier, and there is substantial variation in how certifiers interpret and adhere to causeof-death definitions [ ] . the cause of death literals are coded into international classification of diseases tenth revision (icd- ) [ ] and the underlying and multiplecause-of-death codes are selected based on the world health organization coding rules. these coding rules have been automated by cdc with the development the mortality medical data system (mmds) which consists of four programs: super mortality medical indexing classification and retrieval (supermicar) data entry; mortality medical indexing classification and retrieval (micar); automated classification of medical entities (acme) and transax (translation axes). supermi-car was designed to facilitate the entry of literal text of causes of death in death certificates and convert them into standardized expressions acceptable by micar. it contains a dictionary which assigns an entity reference number (ern) to statements on the death certificate. these erns are fed into micar which transforms the erns into icd- codes by using specific mortality coding rules; the rules require look-up files and a dictionary. acme and transax then selects the underlying and multiple causes of death respectively. icd- codes from micar are fed into acme which assigns the underlying cause of death using decision tables. the decision table contains all possible pairings of diseases for which the first disease can cause the second. in the latest version of the system, acme is comprised of eight decision tables including three tables of valid and invalid codes, causal relationships (general principle and rule ), and direct sequel (rule ), and three other tables needed by modification rules. figure provides the workflow for the mmds system. of the . million deaths that occur each year - percent are automatically coded through super-micar, and the remaining records are then manually coded by nosologists, a medical classification specialist [ ] ; this is a tedious and lengthy process lasting up to months. although the automation process has decreased the time required for coding death data to - weeks, the national vital statistics data is not available for at least two years. therefore, local health department still manually code records or perform basic process techniques to quickly characterize disease patterns [ ] . records that were processed through super-micar or were manually coded are then processed through the remaining components (micar , acme and transax) of mmds. in , micar had a throughput rate of - %, while acme rate was percent. moreover, based on a reliability study, acme error rate for selecting the underlying cause is at onehalf percent, while transax, the multiple cause codes had a one-half percent error rate [ ] . due to the high processing rates and low error rates, mmds is considered by practitioners as the gold standard for the processing and coding of death certificates in the us and other countries (such as canada, the united kingdom (uk) and australia). therefore, we used the codes produced by this system as the "gold standard" when comparing with the methods developed here. in , the us steering committee to reengineer the death registration process (a task force representing federal agencies, the national center for health statistics and the social security administration, and professional organizations representing funeral directors, physicians, medical examiners, coroners, hospitals, medical records professionals, and vital records and statistics officials (naphsis) published the report "toward an electronic death registration system in the united states: report of the steering committee to reengineer the death registration process." this report explained the feasibility of developing electronic death registration in the united states [ ] and argued that these electronic death records have the potential to be an effective source of information for nation-wide tracking and detecting of disease outbreaks. however, little actions have been taken to implement such recommendations in a comprehensive manner. as of july , electronic death registration systems were operating in states, the district of colombia, and in development or planning stage in a dozen others [ ] . information representing the 'cause of death' field on the death certificates is free text. one major goal of natural language processing (nlp) is to extract and encode data from free-texts. there have been many research groups developing nlp systems to aid in clinical research, decision support, quality assurance, the automation of encoding free text data and disease surveillance [ ] [ ] [ ] . although, there have been a few nlp applications to the public health domain [ , ] , little is known about its capability to automatically code death certificates for outbreak and disease surveillance. recently, medical match master (mmm) [ ] , developed by riedl et al at the university of california davis, was used to match unstructured cause of death phrases to concepts and semantic types within the unified medical language system (umls). the system annotates each death phrase input with two types of information, the concept unique identifier, cui, and a semantic type both assigned by the umls. mmm was able to identify an exact concept identifier (cui) from the umls for over % of 'cause of death' phrases. although, the focus of this study was to use nlp techniques to process death certificates, the description of this system reported in the literature did not show how well coded data from an nlp tool along with predefined rules can detect countable cases for a specific disease or condition. the purpose of our project is to create a pipeline which automatically encodes death certificates using a nlp tool and identify deaths related to pneumonia and influenza which provides daily and/or weekly counts. we compared the new technique developed here with keyword searching and mmds as exemplars of the easiest possible approach and the current "gold standard", respectively. the comparison of the techniques was done by calculating recall, precision, f-measure, positive predictive value and agreement (cohen's kappa). we obtained , de-identified electronic death records all with multiple-cause-of-death from the utah department of health (udoh) for the period january to december . the records included a section describing the disease or condition directly leading to death, and any antecedent causes, co-morbid conditions and other significant contributing conditions. an example of a paper and electronic death certificate are shown in figures and respectively. all death certificates used in this study have been processed using the mortality medical data system (mmds) and the record axis codes were received from udoh. for our study we randomly selected , ( %) records. all death records included in the study were previously also coded by nchs into icd- , but this information was not used for our coding, it was only used as posteriori to assess to quality of the automatic coding. we chose to apply the centers of disease control and prevention case definition of pneumonia and influenza deaths defined by cdc's epidemiologist staff through personal communication. therefore, the operational definition for deaths from influenza includes deaths from all types of influenza with the exception of deaths from haemophilus influenzae infection and deaths from parainfluenzae virus infection. pneumonia deaths include deaths from all types of pneumonia including pneumonia due to h. influenza and pneumonia due to parainfluenzae virus. the exceptions include aspiration pneumonia (o . , o , o . , j .-and p .-) , pneumonitis (j . , j -j ), and pneumonia due to pneumococcal meningitis (j , g . ) . pneumonia and influenza related deaths were defined as one of the diagnoses listed in table which were reported in any cause of death field. these codes were selected through manual review of the icd- version manual [ ] . the death certificates pipeline, dcp, was developed to identify pneumonia and influenza cases. the pipeline consisted of two components. the first component of the system was the natural language processor, for which we used metamap [ ] , and the second component was the definitional rules that were applied to the output generated by metamap. the study procedures for this pipeline included: preprocessing, nlp, extraction of coded data and the detection of pneumonia and influenza cases (figure ). spelling errors are common on death certificates; therefore, the death records were first processed through a spell checker to identify misspellings. although the umls sl has a spell suggestion tool called gspell [ ] [ ] [ ] , we decided not to use it and chose to utilize aspell [ ] . our motivation for this decision was based upon an evaluation which showed aspell outperforming gspell; aspell performed better on three areas of performance which were ( ) whether the correct word was ranked in the top ten; and ( ) whether the correct word was found at all [ ] . perl (www.perl.org), a high-level computer programming language that aids in the manipulation and processing of large volume of text data was then used to prepare the cause of death free text for nlp. the preprocessing also involved the removal of non-ascii characters; this was a required technical step for metamap processing. step : natural language processing metamap was used to convert the electronic death records to coded descriptions appropriate for the rule based system. metamap [ ] , developed by the national library of medicine (nlm), is useful in identifying biomedical concepts from free-form textual input and maps them into concepts from the unified medical language system (umls) metathesaurus [ , ] . metamap works by breaking the inputted text into words or phrases, map them to standard terms, and then match the terms to concepts in the unified medical language system (umls) [ ] . for each matched phrase, metamap classifies it into a semantic type then returns the concept unique identifier (cui) and the mapping options which are ranked according to the strength of the mapping. output from metamap. text bolded in the output from nlp represent the code and its corresponding phrase. step : extraction of coded data the data produced by metamap (xml format) was processed through a perl script to extract the inputted text and its corresponding meta-mapped cuis. this extracted data was outputted to a text document. step : identification of p-i deaths the identification of pneumonia and influenza cases involved two steps: ) identifying cuis relating to pneumonia and influenza and ) use of the cuis to create a rules based algorithm to identify cases. details of each step are explained in the following paragraphs. to determine which cui codes were relevant for identifying pneumonia and influenza deaths it was necessary to create a "cui code list" that represents all the icd- codes of interest (see table ). to create this list, we generated a subset of the umls ab database [ ] using the metamorphosys [ ] tool provided by the national library of medicine, nlm. the umls database includes many vocabularies, therefore, to determine which vocabularies are relevant to our aims we used the procedure used by riedl three queries were performed on the subset described above to map pneumonia and influenza icd- codes to cuis and identify related pneumonia and influenza concepts. each query was then placed in a separate database, all duplicates were removed and a sub-query was run to ensure that only the icd- codes in table were included in this list. this produced distinct concept identifiers (cuis) relating to pneumonia or influenza. these codes were used to develop the rules to identify the cases of interest. the coded data produced by metamap was accessed by rules, aimed at identifying the presence of pneumonia and influenza based on the coded data. the rules for identifying these deaths used the cui code list described above. the rule looks at each cause of death field (underlying cause, additional causes, etc.) to flag records with relevant codes. these rules used boolean operators (and, or, not) and if-then statements to create a chain of rules ( figure ). the list of cases identified by our automated detection system was compared with those identified by two other methods: a) keyword searching and b) the reference standard: the icd- codes given by the cdc mmds method. for key-word searching we followed the process to evaluate the performance of both techniques against the reference standard, we needed to specify what constituted a match. each death record is associated to a unique number; therefore, we considered a match if the unique identifier was identified by the comparator and also found by the reference standard. three standard measures were used to evaluate the performance of one method in relation to the reference standard used in this study: precision (equivalent to positive predictive value; recall (equivalent to sensitivity or true positive rate), and f-measure. kappa statistics were used to assess agreement and mcnemar's test was used to analyze the significance between the two methods. all calculations were performed in r [ ] . to calculate these values, pneumonia and influenza related deaths were examined by comparing the reference standard output vs. the two comparators: dcp and keyword search. for both comparators, the deaths were counted and categorized as true posi-tives (cases found by the comparator-pneumonia deaths being correctly classified); false positives (incorrect cases found by the comparator-the number of pneumonia and influenza deaths incorrectly identified by the comparator); false negatives (correct cases not found by the comparator-the number of pneumonia deaths not identified by the comparator). precision, recall and f-score were calculated as follows: precision = true positives/(true positives + false positives) ( ) recall = true positives/(true positives + false negatives) ( ) f-measure = *(p r/ p + r) ( ) mcnemar's test was also calculated to evaluate the significance of the difference between the two comparators. to calculate this value a confusion matrix was created where a is the number of times both methods have correct predictions; b is the number of times method has a correct prediction and method has a wrong prediction; c is the number of times method has a correct prediction and method has a wrong prediction; d is the number of times both methods have incorrect predictions. ethics approval was not required for this study. identifying variables that could be used for re-identifying individuals were excluded from the study data. the records were processed and analyzed on a server with two opteron dual-core . ghz processors and gb ram at the center of high performance computing at the university of utah. using keyword searching the cpu processing time to identify pneumonia and influenza cases was . seconds and the wall time was . seconds. for the dcp, the total cpu processing time was . seconds. the nlp portion of the pipeline attributed to . percent of the processing time (nlp- seconds). while the dcp execution time is much longer, still it is well within the "in real time" realm. for instance, it would take , . seconds cpu time seconds for dcp to code and flag all the weekly death records of the us ( , ). recall and precision were calculated at a . confidence intervals; the f-measure was also calculated. the performance of each method is described below. of the , records analyzed keyword search identified records as pneumonia and influenza deaths, being identified as false positives. precision for keyword searching was calculated at %. of the false positives, records correctly mentioned pneumonia in the cause of death text but their corresponding icd- codes failed to provide any code related to pneumonia, while records were flagged because it included the sub-string "pneumonia" in the additional cause of death field. the death literal for these two records were "bacteremia due to streptococcus pneumonia" and "streptococcal pneumoniae septicemia", the remaining errors were due to the entry of the death literals; in all cases the negation of 'aspiration pneumonia' either due to: ) 'pneumonia' being in a separate cause of death field to 'aspiration' or ) 'pneumonia' not being directly followed by 'aspiration' in the death text (example "pneumonia due to secondary aspiration"). a total of false negatives were recorded, yielding a recall of %. the false negatives could be generalized into two categories: ) misspellings of pneumonia on the death certificated (n = ) and ) appropriate pneumonia or influenza icd- code was coded but the death literals did not mention an appropriate scanned phrase (n = ). f-measure was also calculated at %. a high level of agreement was seen among keyword searching and the reference standard (kappa . ). utilizing the death certificates pipeline (dcp), we identified records as pneumonia and influenza deaths, of which were false positives. the precision for this method was calculated at %. like the keyword searching method, of the false positives, records mentioned pneumonia in the cause of death field but their corresponding icd- codes failed to provide any code related to pneumonia and the remaining errors were due to the reporting of aspiration pneumonia on the death certificate. this method had only false negative for the death literal stating "recurrent aspiration with pneumonia", thus yielding a recall at . %, being less than keyword searching. f-measure was calculated at %. the level of agreement between the pipeline and the gold standard was almost perfect with a cohen's kappa of . . the precision and recall scores that are reported above suggest that the dcp is a better method for identifying pneumonia and influenza deaths than keywordsearching. therefore, we investigated if this observation is supported by statistical analysis. performing a fisher's exact test at α = . , significant difference was seen for both recall (p = . e- ) and precision (p = . ). the mcnemar's test result also showed dcp to be a better method with a p-value = . e- . for the pneumonia and influenza cases found by the reference standard, dcp correctly identified cases, missed one case and incorrectly flagged nine cases. most failures were due to discrepancies between the death literal and its respective icd- code. for the only case which the pipeline did not match, the phrase 'recurrent aspiration with pneumonia' was present in the death literal. metamap coded this literal as aspiration pneumonia which was excluded from the cui code list, but its respective icd- included j . for the additional cases which were not present in the reference standard, we noticed two categories of errors: )cases where the string 'pneumonia' is present in the death literal but not coded into icd- and ) the reporting of aspiration pneumonia on the death certificate. the first category of errors was not due to metamap or the rule algorithm, but perhaps due to the coding process. as described earlier, mmds produces entity axis and record axis codes. the entity axis codes would be a more appropriate reference standard for they provide the icd codes for the conditions or events reported as listed by the death certifier and maintains the order as written on the death certificate [ ] ; but as noted earlier only the record axis codes were made available for this study. the algorithm used to produce record axis codes from the entity axis data removes duplicate codes and contradictory diagnoses within the entity axis data to produce the more standardized record axis [ ] . for example, if a medical examiner reports pneumonia with chronic obstructive pulmonary disease both conditions will be shown in entity axis code data. however, in record axis code data, they will be replaced with a single condition: chronic obstructive pulmonary disease with acute lower respiratory infection (j . ). we were unable to verify that codes related to pneumonia were present in the entity axis codes for the six cases; therefore, we can only speculate the reason for this failure. the second category of errors was due to the reporting of aspiration pneumonia on the death certificate. in cases where the string "aspiration" and pneumonia" were not reported in the same text field metamap processed the string separately thus yielding two codes: one for aspiration and the other pneumonia, instead of one code for "aspiration pneumonia" [c ]. in an initial review of metamap we found metamap had difficulties processing the phrase "pneumonia secondary to acute aspiration", therefore, our rule detection algorithm excluded cases where the code for pneumonia and aspiration were present in the same text field. to our knowledge, this is the first published report on using a natural language processing tool and the umls to identify pneumonia and influenza deaths from death certificates. we found that automated coding and identification of pneumonia and influenza deaths is possible and computationally efficient. the death certificates pipeline developed here was statistically different to keyword searching and has higher recall and precision when compared to the current semi-automatic methods in use by the cdc. a good recall is required to help capture the 'true' p-i deaths and a good precision is needed to avoidoverestimating the number of p-i deaths. this study also indicated that keyword searching underestimated pneumonia and influenza deaths in utah. the simple keyword search method not only decreased recall and precision but also reduced the level of agreement. when reporting counts for surveillance purposes it's best to be as accurate as possible; however, there's a trade-off between recall and precision. for disease surveillance, increased precision enables public health officials to more accurately focus resources for control and prevention, therefore, although both methods had good precision the pipeline developed would be more advantageous to utilize. metamap did an excellent job at extracting cause of deaths from free-form text which is consistent with the results of reid et al [ ] . most of the concepts were present in the umls which attributed good recall. both recall and precision depended on the comprehensiveness of the cui code list. the performance of this system is determined largely by the coverage of terms and sources in the umls. both keyword searching and the system's weakest point is its lack of precision. most of the concepts the system did not identify had either the aspiration text in another field or pneumonia was mentioned in the cause of death text but not coded ( cases fit these criteria). the sample size was sufficient to show difference between the two methods. it is important to note that utilizing trained nosologists, who would manually code the death certificates, would have developed an absolute gold standard which may or may not be a better reference standard than icd- codes. however, our motivation for utilizing icd codes was influenced due to the fact that the use of icd codes to identify all-cause pneumonia has been examined and has showed to be a valid tool for the identification of these cases [ , ] . in terms of timing, while keyword searching is faster than the dcp, our method is also sub / second range, which implies that it is possible to process the daily utah deaths (~ ) in approximately . seconds and all deaths in the us (~ ) in approximately . seconds using current hardware. this timing would be much faster than the minimum of two weeks to receive the coded data from the current cdc process. moreover, these timings make it apparent that this system can be integrated in a real time surveillance system without introducing any additional bottlenecks. there are several potential limitations with this analysis. first, the generalizability of the findings is limited because the death records were only from one institution. although death certificates have a standardized format, the death registration process and the reviewing of death records differ by institutions. udoh utilizes keyword searching to identify pneumonia and influenza cases, other institutions may use more accurate (manual review) or less accurate methods for finding cases. second, a separate evaluation of the nlp component of the dcp was not performed. further research is needed to examine the use of nlp on electronic death records across institutions and countries which may have different documentation procedures. this study shows that it is feasible to achieve high levels of accuracy when using nlp tools to identify cases of pneumonia and influenza cases from electronic death records while still providing a system that can be used for real time coding of death certificates. identification of concept identifiers related to the cdc's case definition of pneumonia and influenza was very important in producing a highly accurate rule for the identification of these cases. future work will aim to improve the preprocessing phase of the pipeline by providing the inclusion of the spellchecker used by the cdc's mortality medical data system. future work will also involve evaluating the flexibility (e.g. identification of different diseases) of the system to deploy the pipeline tool, along with other public health related analytical tools, as a grid service to provide to real time public health surveillance tool that uses data and services under the control of different administrative domains. we have shown that it is feasible to automate the coding of electronic death records for real-time surveillance of deaths of public health concern. the performance of the pipeline outperformed the performance of current methods, keyword searching, in the identification of pneumonia and influenza related deaths from death certificates. therefore, the pipeline has the potential to aid in the encoding of death certificates and is flexible to identify deaths due to other conditions of interest as the need arises. participants of a workshop on mortality monitoring in europe: monitoring excess mortality for public health action: potential for a future european network public health surveillance: historical origins, methods and evaluation communicable disease surveillance the new automated daily mortality surveillance system in portugal description of a new all cause mortality surveillance system in sweden as a warning system using threshold detection algorithms a method for timely assessment of influenza-associated mortality in the united states mortality surveillance - , england and wales. deaths and rates by sex and age group for th revision causes, a-list and chapters. london: great britain office of population census and surveys prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices (acip) national hospital discharge survey: summary influenza-associated hospitalizations in the united states american lung association state of lung disease in diverse communities economic evaluation of influenza vaccination. assessment for the netherlands mortality associated with influenza and respiratory syncytial virus in the united states estimating seasonal influenza-associated deaths in the united states: cdc study confirms variability of flu flu activity & surveillance: reports and surveillance methods in the united states real-time surveillance of pneumonia and influenza mortalities via the national death certificate system prospective surveillance of excess mortality due to influenza in new south wales: feasibility and statistical approach medical language processing: computer management of narrative data death certificate comparability of cause of death between icd- and icd- : preliminary estimates world health organization: international statistical classification of disease and related health problems, tenth revision version for selected data editing procedures in an automated multiple cause of death coding system using the umls and simple statistical methods to semantically categorize causes of death on death certificates description of the national center for health statistics software systems and demonstrations toward an electronic death registration system in the united states: report of the steering committee to reengineer the death registration process national association for public health statistics and information systems classifying free-text triage chief complaints into syndromic categories with natural language processing automatic detection of acute bacterial pneumonia from chest x-ray reports automated encoding of clinical documents based on natural language processing using nlp on va electronic medical records to facilitate epidemiologic case investigations evaluating natural language processing applications applied to outbreak and disease surveillance a: effective mapping of biomedical text to the umls metathesaurus: the metamap program a frequency-based technique to improve the spelling suggestion rank in medical queries lexical systems: a report to the board of scientific counselors umls language and vocabulary tools metamap: mapping text to the umls metathesaurus the unified language system (umls): integrating biomedical terminology umls distribution team: r: a language and environment for statistical computing. vienna: r foundation for statistical computing entity axis codes documentation of the mortality tape file for community-acquired pneumonia: can it be defined with claims data? icd- codes are a valid tool for identification of pneumonia in hospitalized patients aged > or = years identification of pneumonia and influenza deaths using the death certificate pipeline this study has been supported in part by the grants from the national library of medicine (lm ) and from the centers of disease control and prevention center of excellence (ip hk - ). the authors declare that they have no competing interests. all the authors contributed equally to this research. all authors read and approved the final manuscript.submit your next manuscript to biomed central and take full advantage of: key: cord- -nml kqiu authors: lhommet, claire; garot, denis; grammatico-guillon, leslie; jourdannaud, cassandra; asfar, pierre; faisy, christophe; muller, grégoire; barker, kimberly a.; mercier, emmanuelle; robert, sylvie; lanotte, philippe; goudeau, alain; blasco, helene; guillon, antoine title: predicting the microbial cause of community-acquired pneumonia: can physicians or a data-driven method differentiate viral from bacterial pneumonia at patient presentation? date: - - journal: bmc pulm med doi: . /s - - -y sha: doc_id: cord_uid: nml kqiu background: community-acquired pneumonia (cap) requires urgent and specific antimicrobial therapy. however, the causal pathogen is typically unknown at the point when anti-infective therapeutics must be initiated. physicians synthesize information from diverse data streams to make appropriate decisions. artificial intelligence (ai) excels at finding complex relationships in large volumes of data. we aimed to evaluate the abilities of experienced physicians and ai to answer this question at patient admission: is it a viral or a bacterial pneumonia? methods: we included patients hospitalized for cap and recorded all data available in the first -h period of care (clinical, biological and radiological information). for this proof-of-concept investigation, we decided to study only cap caused by a singular and identified pathogen. we built a machine learning model prediction using all collected data. finally, an independent validation set of samples was used to test the pathogen prediction performance of: (i) a panel of three experts and (ii) the ai algorithm. both were blinded regarding the final microbial diagnosis. positive likelihood ratio (lr) values > and negative lr values < . were considered clinically relevant. results: we included patients with cap ( . % men; [ – ] years old; mean sapsii, [ – ]), % had viral pneumonia, % had bacterial pneumonia, % had a co-infection and % had no identified respiratory pathogen. we performed the analysis on patients as co-pathogen and no-pathogen cases were excluded. the discriminant abilities of the ai approach were low to moderate (lr+ = . for viral and . for bacterial pneumonia), and the discriminant abilities of the experts were very low to low (lr+ = . for viral and . for bacterial pneumonia). conclusion: neither experts nor an ai algorithm can predict the microbial etiology of cap within the first hours of hospitalization when there is an urgent need to define the anti-infective therapeutic strategy. the world health organization (who) estimates that due to antimicrobial resistance, bacterial infections will outcompete any cause of death by [ ] , meaning that there is an urgent need for new strategies to improve antibiotic treatments. the agency for healthcare research and quality (ahrq) safety program for improving antibiotic use recently proposed a structured approach to improve antibiotic decision making by clinicians, which emphasizes the critical time points in antibiotic prescribing [ , ] . the first time point of this organized approach requires the physician to ask: "does this patient have an infection that requires antibiotics?". this question aims to remind the clinician to synthesize all relevant patient information to determine the likelihood of an infection that requires antibiotic therapy. the questionable ability of physicians to answer this first question properly in the context of pneumonia was the impetus for this study. community-acquired pneumonia (cap) is a major global healthcare burden associated with significant morbidity, mortality and costs [ ] [ ] [ ] [ ] [ ] [ ] . identifying the etiology of cap is an utmost priority for its management and treatment decisions [ ] . although the range of pathogens that may be involved in these cases is broad, physicians must at least determine whether a bacterial or a viral pathogen (or both) is causing the pneumonia to determine if antibiotic treatment is appropriate. whether the etiology of cap is viral or bacterial should be determined based on the patient interview, clinical symptoms and signs, biological findings and radiological data from the very first hours of the patient's presentation (a time when microbiological findings are typically not yet available). physicians must use the knowledge obtained from their routine practice and medical education to make sense of these diverse data input streams, triage the resulting complex dataset, and make appropriate decisions. a growing body of research has recently suggested that difficulties in accessing, organizing, and using a substantial amount of data could be significantly ameliorated by use of emerging artificial intelligence (ai)-derived methods, which are nowadays applied in diverse fields including biology, computer science and sociology [ ] . ai excels at finding complex relationships in large volumes of data and can rapidly analyze many variables to predict outcomes of interest. in the context of cap in intensive care units (icus), where information are particularly diverse, we wondered if an ai datadriven approach to reducing the medical complexity of a patient could allow us to make a better hypothesis regarding the microbial etiology at the patient's presentation. the aim of our study was to evaluate and compare the abilities of experienced physicians and a data-driven approach to answer this simple question within the first hours of a patient's admission to the icu for cap: is it a viral or a bacterial pneumonia? this study was conducted in two steps. first, we performed prospective data collection (step ); second, we retrospectively assessed the microbial etiology prediction performances of experienced physicians (more than years' experience) and a computational data-driven approach for this dataset (step ). step : patient data collection prospective data collection was conducted in a single center over an -month period. the study complied with french law for observational studies, was approved by the ethics committee of the french intensive care society (ce srlf [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , was approved by the commission nationale de l'informatique et des libertés (cnil) for the treatment of personal health data. we gave written and oral information to patients or next-of-kin. patients or next-of-kin gave verbal informed consent, as approved by the ethic committee. eligible patients were adults hospitalized in icu for cap. pneumonia was defined as the presence of an infiltrate on a chest radiograph and one or more of the following symptoms: fever (temperature ≥ . °c) or hypothermia (temperature < . °c), cough with or without sputum production, or dyspnea or altered breath sounds on auscultation. community-acquired infection was defined as infection occurring within h of admission. cases of pneumonia due to inhalation or infection with pneumocystis, pregnant women and patients under guardianship were not included. cases with pao ≥ mmhg in ambient air or with the need for oxygen therapy ≤ l/min or without mechanical ventilation (invasive or non-invasive) were not included. baseline patient information was collected at case presentation through in-person semi-structured interviews with patients or surrogates (see supplementary table ). observations from the physical examination at presentation, including vital signs and auscultation of the lungs, were recorded. findings of biological tests done at presentation (within the first three-hour period) were also recorded (hematology and chemistry tests), as were findings from chest radiography. two physicians interpreted chest x-rays; a third physician reviewed the images in cases of disagreements in interpretation. microbiological investigations included blood cultures, pneumococcal and legionella urinary antigen tests, bacterial cultures and multiplex pcr respifinder smart ® (pathofinder b.v., oxfordlaan, netherlands) analyses on respiratory fluids (sputum and/or nasal wash and/or endotracheal aspirate and/or bronchoalveolar lavage [bal]). step : clinician and data-driven predictions of microbial etiology clinicians and a mathematical algorithm were tasked with predicting the microbial etiology of pneumonia cases based on all clinical ( items), and biological or radiological ( items) information available in the first -h period after admission except for any microbiological findings (supplementary table ). for this proof-of-concept investigation, we decided to study only cap caused by a singular and identified pathogen; cases of cap with mixed etiology or without microbiological documentation were excluded. from the initial dataset of patients, we randomly generated two groups (prior to any analysis): (i) a work dataset ( % of the initial dataset) dedicated to construction of the mathematical model and training the experts; (ii) an external validation dataset ( % of the initial dataset) dedicated to testing the prediction performances. the methodology used is summarized in fig. a . an external three member expert panel reviewed the work dataset to familiarize themselves with the dataset containing the patient characteristics. then, the experts were asked to predict the microbial etiologies in the external validation dataset (fig. a) . the clinicians had to answer the question: is it a viral or a bacterial pneumonia? they were also asked to give a confidence index regarding the accuracy of their answer: (very low), (low), (moderate), (high). agreement of at least two of the three experts was required for the final predicted etiology. the data were analyzed using an ai method (fig. b) involving a logistic regression analysis using forward stepwise inclusion. this method was employed to optimize the ability of the algorithm to distinguish viral and bacterial pneumonia based on the combination of parameters available in the work dataset. all available data were thus included in the model, regardless of the data type. qualitative data were processed as binary information (i.e. influenza immunization: present " ", absent " "). raw data were provided for quantitative values (no cut-offs defined). we built the predictive mathematical model from the work dataset using the random forest method and leave-one-out cross-validation. we started by determining the most relevant item to use through a variable selection procedure using the random forest method and the mean decrease in gini criterion (value . ). then, the population in the work dataset was randomly separated into two independent datasets: % of cases were assigned to the training set and % were assigned to the test set. n models with bootstrap resampling (with n = ) were performed on the training set and validated on the test set. the model providing the best prediction criteria was selected, and the final model was built from the entire work dataset. finally, an independent validation set of samples was used to test the pathogen prediction performance of the ai algorithm. to decipher the relative importance of clinical versus biological/radiological variables in the predictions, we generated three algorithms built from different parameters of the work dataset: (i) clinical variables only, (ii) biological and radiological variables only, and (iii) all variables. for each parameter tested, the area under the roc curve (auc) was calculated, and the best cutoff value that yielded the highest accuracy was determined along with the sensitivity and specificity. we compared the concordance between the predictions and the final microbial etiologies for the experts and for the algorithm and calculated sensitivity, specificity, positive predictive value (ppv), negative predictive value (npv) and likelihood ratios (lrs) for the predictions [ ] . given the importance of this diagnostic prediction in the patient's therapeutic management, we determined that the discriminant properties should be "high" (lr + > and/ or lr-< . ) for the prediction to be considered useful for clinical practice [ , ] . table summarizes the lr cutoff values defining the discriminant properties of the predictions [ ] . quantitative data are reported as the median value and interquartile range (iqr). statistical analyses were done with jmp software (sas, version . ). a total of patients diagnosed with cap were eligible for inclusion over an -month period; patients were included; % had viral pneumonia, % had bacterial pneumonia, % had a co-infection and % had no identified respiratory pathogen. finally, we performed the analysis on patients as co-pathogen and no-pathogen cases were excluded. the patient selection flow chart is presented in fig. . the characteristics of the patients according to microbial diagnosis are detailed in table . experts had "high" confidence in their predicted etiology only . % of the time. confidence levels were typically "moderate" ( . %) or "low" ( . %), but never "very low". all three experts agreed in . % of the cases. correct predictions were made . % of the time. the clinician predictions had a sensitivity of . , specificity of . , ppv of . and npv of . for the diagnosis of bacterial pneumonia ( table ). the lr+ for diagnosing a viral pneumonia was . , and the corresponding lr-was . . the lr+ for diagnosing a bacterial pneumonia was . , and the corresponding lr-was . . therefore, the discriminant abilities of experienced physicians to distinguish viral and bacterial etiologies for pneumonia were categorized as very low to low (according to defined cutoff values for the interpretation of likelihood ratios, see table ). predictions by the data-driven algorithms generated from clinical data alone resulted in an roc curve with a fig. schematic representation of the study methodology. a we built an initial dataset from all sources of information available in the first h of the patient's presentation in the icu for cap. we matched these presenting cases with their final identified causal respiratory pathogen. the initial dataset was randomly split into a work dataset, used for the machine learning and training the icu experts on how the data were presented, and an external validation dataset used to assess the prediction performances of the artificial intelligence (ai) algorithm and the panel of experts. b data flow to engineer the data-driven algorithm corresponding auc of . . predictions by the data-driven algorithms generated from biological and radiological variables data alone resulted in an roc curve with an auc of . . finally, predictions generated from the dataset that included all data sources outperformed the other algorithms and resulted in an roc curve with an auc of . (table , fig. ). this model based on the more inclusive dataset was considered the final model for comparison with the expert panel. the final algorithm made predictions with a sensitivity of . , specificity of . , ppv of . and npv of . for the diagnosis of bacterial pneumonia. the lr+ for diagnosing a viral pneumonia was . , and the corresponding lr-was . . the lr+ for diagnosing a bacterial pneumonia was . , and the corresponding lr-was . . consequently, the discriminant abilities of the data-driven algorithm to distinguish viral and bacterial etiologies for pneumonia were categorized as low to moderate (according to defined cutoff values for the interpretation of likelihood ratios, see table ). addressing antimicrobial resistance requires investment in several critical areas, the most pressing of which is the ability to make rapid diagnoses to promote appropriate anti-infective therapeutics and limit unnecessary antibiotic use. here, we set up a pilot study and demonstrated that neither experts nor a mathematical algorithm could accurately predict the microbial etiology of severe cap within the first hours of hospitalization when there is an urgent need to define the appropriate anti-infective therapeutic strategy. we encoded all information available in the first hours after admission for a large cohort comparable with other published cohorts in terms of the distribution of causal microbial pathogens, patient characteristics and severity of disease [ ] [ ] [ ] . we demonstrated that experienced clinicians synthesizing all this information failed to adequately answer the question: "is it a viral or a bacterial pneumonia?", as the discriminant ability between the two diagnoses was considered low. we interpreted our results mainly based on the calculation of likelihood ratios, as recommended for reports of a diagnostic test for an infectious disease [ ] . likelihood ratios incorporate both sensitivity and specificity and, unlike predictive values, do not vary with prevalence, making them good statistical tools to facilitate translation of knowledge from research to clinical practice [ ] . in parallel, we designed a data-driven approach. different ai methods were available; we selected the random forest method because it is one of the most efficient strategies for providing a predictive algorithm in this context [ ] [ ] [ ] [ ] . importantly, the final algorithm was tasked with providing predictions for a novel population independent of the dataset used for the algorithm construction. the discriminant abilities of the ai approach restricted to the binary choice "viral" or "bacterial" were superior to those of experts but still considered low or moderate and were ultimately insufficient to provide an indisputable therapeutic decision. it is important to emphasize that we chose a high cutoff value for determining the discriminant ability of the ai approach (lr+ > , lr-< . ); this choice was made for two reasons. first, in this proof-ofconcept study, we did not analyze co-infections and restricted the possible choices to a binary prediction. because we reduced the complexity of the cases, we expected high predictive performances. second, the goal of this study was not a prediction of outcomes (e.g., icu length of stay, mortality), which are informative but do not determine patient management; it was to provide a clear and immediate medical decision: whether or not to prescribe antibiotics. the immediate clinical consequences in this situation demand a high predictive performance. still, it is important to highlight that the machine learning method we developed achieved an auc of . , which is superior or at least equal to auc values usually observed for predictive mathematical models developed for the icu environment. for instance, the systemic inflammatory response syndrome (sirs) criteria, the simplified acute physiology score ii (saps ii) and the sequential organ failure assessment (sofa) have auc values of . , . and . , respectively, for identifying sepsis [ ] . an ai sepsis expert algorithm for early prediction of sepsis has been engineered and achieved auc values ranging from . - . according to the time of the prediction. an ai method for predicting prolonged mechanical ventilation achieved an auc of . [ ] . how can it be that ai or machine-learning predictive algorithms that can already automatically drive cars or successfully understand human speech failed to predict the microbial cause of pneumonia accurately? first, having data of excellent quality is critical for the success of ai predictions. the icu environment is data-rich, providing fertile soil for the development of accurate predictive models [ ] , but it is also a challenging environment with heterogeneous and complex data. in our study, the data that fueled the ai method were from a real-world data source. it is probably more difficult to create a consistent data format when merging data from interviews, patient examinations, biological and radiological information than when using datasets from the insurance or finance industries. additionally, data arising from patient examinations and interviews are still strictly dependent on the physician's skill and experience. finally, although we hypothesized that the ai capabilities would exceed human skills and make accurate predictions when physicians cannot, we must also consider the null hypothesis: viral and bacterial pneumonias share the same characteristics and cannot be distinguished based on initial clinical, biological or radiological parameters. the dividing lines between the signs and symptoms of a viral versus a bacterial infection could be too blurry to permit the two diagnoses to be discerned without microbial analyses. our results emphasize the need to use a rapid turnaround time system for the accurate identification of respiratory pathogens from patient specimens. utilizing rapid molecular respiratory panel assays may increase the likelihood of optimal treatment of acute respiratory infections [ ] [ ] [ ] [ ] [ ] . however, antibiotic consumption was not reduced by the use of a molecular point-of-care strategy in adults presenting with acute respiratory illness in a large randomized controlled trial [ ] . it seems that we are experiencing a switch in perspectives regarding microbial diagnoses of respiratory infections: physicians are used to dealing with an absence of information, but they will likely be overloaded with information in the near future [ ] . the positive detection of respiratory viruses may or may not be useful for the immediate management of a patient [ ] . thus, the development of molecular point-of-care analysis techniques will not lessen the usefulness of our ai strategy. on the contrary, we believe that ai could be a great help in dealing with information overload, which could soon be a common problem. ai methods should not be viewed as ways to replace human expertise but rather as catalysts that accelerate human expertise-based analyses of data. ai methods can assist-rather than replace-in clinical decision-making by transforming complex data into more actionable information. further studies are needed to assess if ai system integrated with point-of-care rapid molecular respiratory panel assays could be a useful addition for the clinician. ultimately, randomized controlled trial should determine the effect of this strategy on the decision making regarding antibiotic use. our study should be interpreted in the context of several limitations. first, this was a proof-of-concept study, and we excluded cases of cap with mixed etiology or without microbiological documentation. consequently, the results were obtained from artificially dichotomized situations (viral or bacterial pneumonia, patients in total) and cannot be directly extrapolated to real-life practice. moreover, we did not include cases of acute pneumonia with non-infectious origins. second, the experts were asked to make their predictions based on case reports exhaustively described in excel files. they did not have the opportunity to interview or directly examine the patients themselves. furthermore, the experts' predictions were not performed in "real-life" situation. this could have affected the experts' predictive performance. third, we cannot rule out the possibility that some bacterial or viral pneumonia cases were misdiagnosed. we relied on stateof-the-art methods for microbial discovery, but it is possible that our current technology is sometimes suboptimal for detecting respiratory microbial pathogens. neither a panel of experts nor a data-driven approach could accurately distinguish viral from bacterial pneumonia within the first hours of patient admission in icu for cap. the heterogeneous and complex data generated in the icu environment are likely difficult to use to generate an ai algorithm with a high predictive quality. the results of our pilot study at least highlight that we should not treat machine learning and data science as crystal balls for making predictions and automating decision-making; we should rather use these techniques to more critically examine all available information and enhance existing human expertise. supplementary information accompanies 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analysis. cj, hb performed the ai algorithm. pa, cf, gm, kab and lgg made substantial contribution to analysis, the conception of the study and to the draft of the manuscript. all authors read and approved the version to be published. we have no sources of support to declare. the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. the study complied with french law for observational studies, was approved by the ethics committee of the french intensive care society (ce srlf [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , was approved by the commission nationale de l'informatique et des libertés (cnil) for the treatment of personal health data. we gave written and oral information to patients or next-of-kin. patients or next-of-kin gave verbal informed consent, as approved by the ethic committee. patients or next-of-kin gave verbal informed consent for publication, as approved by the ethic committee. the authors declare that they have no competing interests.author details chru tours, service de médecine intensive réanimation, bd tonnellé, key: cord- - r j h authors: cao, bin; huang, yi; she, dan‐yang; cheng, qi‐jian; fan, hong; tian, xin‐lun; xu, jin‐fu; zhang, jing; chen, yu; shen, ning; wang, hui; jiang, mei; zhang, xiang‐yan; shi, yi; he, bei; he, li‐xian; liu, you‐ning; qu, jie‐ming title: diagnosis and treatment of community‐acquired pneumonia in adults: clinical practice guidelines by the chinese thoracic society, chinese medical association date: - - journal: clin respir j doi: . /crj. sha: doc_id: cord_uid: r j h community‐acquired pneumonia (cap) in adults is an infectious disease with high morbidity in china and the rest of the world. with the changing pattern in the etiological profile of cap and advances in medical techniques in diagnosis and treatment over time, chinese thoracic society of chinese medical association updated its cap guideline in to address the standard management of cap in chinese adults. extensive and comprehensive literature search was made to collect the data and evidence for experts to review and evaluate the level of evidence. corresponding recommendations are provided appropriately based on the level of evidence. this updated guideline covers comprehensive topics on cap, including aetiology, antimicrobial resistance profile, diagnosis, empirical and targeted treatments, adjunctive and supportive therapies, as well as prophylaxis. the recommendations may help clinicians manage cap patients more effectively and efficiently. cap in pediatric patients and immunocompromised adults is beyond the scope of this guideline. this guideline is only applicable for the immunocompetent cap patients aged years and older. the recommendations on selection of antimicrobial agents and the dosing regimens are not mandatory. the clinicians are recommended to prescribe and adjust antimicrobial therapies primarily based on their local etiological profile and results of susceptibility testing, with reference to this guideline. the revision of the guideline was initiated by chinese thoracic society (cts) and chinese medical association (cma). the overall framework and main content of the updated guideline were finalized following face-to-face work meetings and online video conferences. the experts specialized in methodology provided training on standardized literature search and grading of evidence to all the specialists contributing to the guideline. level of evidence and grading of recommendation were based on the infectious diseases society of america/american thoracic society (idsa/ats) guidelines for cap ( ) . the level of evidence represents the assessment on the quality of study evidence, and the grading of recommendation refers to the assessment on the degree to which the benefits of an intervention outweighs the risks. generally speaking, the higher the evidence level, the stronger the grade of recommendation, but they do not fully correspond to each other. the willingness and values of patients, as well as resource consumption should also be considered when making a recommendation (table ) . this guideline document is composed of sections. the core panel members are responsible for separate groups to prepare the first draft by searching and reviewing the relevant domestic and international literature, evaluating evidence level with the unified standard. the grading of recommendations is decided by vote of all members participating in the preparation of the guidelines. the principal writer was responsible for summarization and modification of the first draft. in the process, face-toface work meetings were held to discuss revision of the draft. three rounds of consultation were conducted to solicit advice and opinions from the specialists of the specialty groups within cts, cma, specialists in relevant disciplines the distribution and antimicrobial resistance profile of cap pathogens are significantly different across different countries and regions, and change over time. currently, the results of several epidemiological surveys of cap conducted in level i (high) evidence from well-designed, randomized, controlled trials (rcts), authoritative guidelines and high quality systematic reviews and meta-analyses level ii (moderate) evidence from rcts with some limitations (eg, trials without allocation concealment, nonblinded, or loss to follow-up not reported), cohort studies, case series and case-control studies level iii (low) evidence from case reports, expert opinions and in vitro antimicrobial susceptibility studies without clinical data grade of recommendation a (strong) most patients, physicians and policy makers will adopt the recommended action. the recommendation will be adopted by the majority, but not by some individuals. decisions should be made with consideration of the specific condition of the patient to reflect his/her values and willingness. c (weak) insufficient evidence; decisions must be made via mutual discussions involving the patients, physicians and policy makers. chinese adults have shown that mycoplasma pneumoniae and streptococcus pneumoniae are important pathogens of cap in adults in china. [ ] [ ] [ ] [ ] [ ] other common pathogens include haemophilus influenzae, chlamydia pneumoniae, klebsiella pneumoniae and staphylococcus aureus; but pseudomonas aeruginosa and acinetobacter baumannii are infrequently isolated. , [ ] [ ] [ ] in china, only a small number of cases of community-acquired methicillin-resistant s. aureus (ca-mrsa) pneumonia are reported in children and teenagers. [ ] [ ] [ ] [ ] ca-mrsa was not identified in the antimicrobial resistance surveillance of community-acquired respiratory tract pathogens in adults conducted in - . for special populations such as elderly patients or patients with underlying diseases (eg, congestive heart failure, cardiovascular or cerebrovascular diseases, chronic respiratory system diseases, kidney failure and diabetes mellitus), gramnegative bacteria such as k. pneumoniae and escherichia coli are more common. , , with the development and application of virus detection technology, the role of respiratory tract viruses is gradually gaining attention in the aetiology of cap in chinese adults. the results of several recently published multicenter studies showed that the detection rate of viruses was %- . % in chinese adult cap patients, of which influenza virus accounted for the largest proportion. other contributing viruses included parainfluenza virus, rhinovirus, adenovirus, human metapneumovirus (hmpv) and respiratory syncytial virus (rsv). among the patients with positive test results for viruses, . %- . % could have concomitant infection caused by bacteria or atypical pathogens. , , , considering the resistance profile of major pathogens, the high percentage of s. pneumoniae resistant to macrolides found in chinese adult cap patients is an important characteristic that differs from that in european and american countries. two nation-wide multicenter surveys on adult cap conducted in [ ] [ ] [ ] showed that . %- . % of s. pneumoniae isolates were resistant to macrolides. , recently, the results of multicenter community-acquired respiratory tract infection pathogen surveillance (car-tips) studies in adults conducted in urban tertiary hospitals in china showed that . %- . % of s. pneumoniae isolates were resistant to azithromycin, the minimum inhibitory concentration of which required to inhibit the growth of % of organisms (mic ) was - mg/l and . % of the isolates were resistant to clarithromycin. , while in european and american countries, . %- % and . %- . % of s. pneumoniae isolates were resistant to erythromycin and azithromycin, respectively. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] moreover, . %- . % of s. pneumoniae isolates were resistant to oral penicillins, and . %- . % resistant to second-generation cephalosporins in china. however, relatively low percentage of s. pneumoniae isolates were resistant to injectable penicillins and third-generation cephalosporins ( . % and . %, respectively). , the high percentage of mycoplasma pneumoniae strains resistant to macrolides is another important characteristic in the aetiology of cap in china, which is different from that in most other countries. study results showed that . %- . % of the mycoplasma strains isolated from chinese adult cap patients were resistant to erythromycin, and . %- . % resistant to azithromycin. [ ] [ ] [ ] the infections caused by antibiotic-resistant mycoplasma may prolong the duration of fever and anti-infective treatment. in addition to china, %- % of the mycoplasma strains isolated from japanese adult and teenage cap patients were resistant to macrolides. macrolides-resistant m. pneumoniae was also reported in france, canada, the united states, spain and germany. [ ] [ ] [ ] [ ] [ ] [ ] m. pneumoniae is highly resistant to macrolides in china, but it remains susceptible to doxycycline, minocycline and quinolones. , a. onset in community. b. relevant clinical manifestations of pneumonia: ( ) new onset of cough or expectoration, or aggravation of existing symptoms of respiratory tract diseases, with or without purulent sputum, chest pain, dyspnea, or hemoptysis; ( ) fever; ( ) signs of pulmonary consolidation and/or moist rales; ( ) peripheral white blood cell count (wbc) > /l or < /l, with or without a left shift. c. chest radiograph showing new patchy infiltrates, lobar or segmental consolidation, ground-glass opacities, or interstitial changes, with or without pleural effusion. clinical diagnosis can be established if a patient satisfies criterion a, criterion c and any one condition of criterion b and meanwhile, tuberculosis, pulmonary tumour, noninfectious interstitial lung disease, pulmonary edema, atelectasis, pulmonary embolism, pulmonary eosinophilia and pulmonary vasculitis are all excluded. step : determine whether a diagnosis of cap is valid or not. for patients with clinically suspected cap, the possibility of unusual infections such as tuberculosis and noninfectious causes must be considered. step : evaluate the severity of cap and select the location for treatment. step : predict the potential pathogens of cap and risks of antibiotic resistance ( table ) : considering patient age, season of onset, underlying diseases and risk factors, symptoms or signs, characteristics of chest imaging (x-ray film or ct), laboratory tests, severity of cap, prior antibacterial therapies and so on. step : arrange for reasonable etiological tests, and initiate empirical anti-infective treatment in a timely manner. step : evaluate the effectiveness of empirical antiinfective treatment on cap in a dynamic manner; investigate the cause if initial treatment fails, and adjust treatment protocol promptly. step : follow up after treatment; and provide education on health maintenance. cap s ev eri ty, c ri ter ia f or hos p i ta l adm i s s io n and di agno s ti c cr it eri a f or s the evaluation of cap severity is crucial for selection of appropriate location of treatment, initial empirical antimicrobial agents, as well as adjunctive and supportive treatments. the scoring systems of cap severity differ from each other ( table ) . they can be used as an aid for evaluation and provide support for clinical diagnosis and treatment, but physicians should take clinical experience into consideration when making judgments, and monitor disease progression in a dynamic manner (ii a). curb- , crb- (c: disturbance of consciousness, u: urea nitrogen, r: respiratory rate, b: blood pressure, : age), and pneumonia severity index (psi) scoring systems underestimate the risk of death and severity of influenza pneumonia, - while oxygenation index combined with absolute reduction of peripheral blood lymphocyte is superior to curb- and psi in predicting the risk of death due to influenza pneumonia (ii b). curb- score is recommended as a standard for deciding whether a patient should be hospitalized or not. a score of - point: theoretically, patients should receive outpatient treatment; a score of points: patients are recommended to receive inpatient treatment or extramural treatment with close follow-up; a score of - points: patients should be hospitalized (i a) . however, other factors such as patient age, underlying diseases, socioeconomic status, gastrointestinal functions and treatment compliance should also be taken into account for comprehensive evaluation (ii b). criteria for diagnosis of severe cap : patients who meet any of the major criteria or minor criteria could be diagnosed as severe pneumonia and need close monitoring and active treatment; it is also recommended that the patients should be hospitalized in icu if applicable (ii a). acute onset, high fever with potential shivers, purulent sputum, brown bloody sputum, chest pain, significant increase in peripheral wbc, increased c-reactive protein (crp), signs of pulmonary consolidation or moist rales; radiograph shows alveolar infiltrates or lobar or segmental distribution of consolidation. [ ] [ ] [ ] [ ] [ ] mycoplasma or chlamydia under years of age, with few underlying diseases; continuous cough, no sputum or no bacteria discovered in sputum smear test, few pulmonary signs, peripheral wbc < /l; radiograph may show lesions in the upper lung field of both lungs, centrilobular nodules, tree-in-bud sign, ground-glass opacities, or thickening of bronchial wall and may show signs of consolidation with disease progression. , , [ ] [ ] [ ] virus mostly seasonal, may have history of exposure to an epidemic or clustered outbreak, acute upper respiratory tract symptoms, myalgia, normal or decreased peripheral wbc, procalcitonin (pct) < . ng/ml, unresponsive to treatment with antibacterial agents; radiograph shows bilateral, interstitial exudates in multiple lobes and/or ground-glass opacities, which may be accompanied by consolidation. , [ ] [ ] [ ] iv. patients without improvement after active anti-infective therapies, who require differential diagnosis with non-infectious pulmonary lesions (such as tumour, vasculitis and interstitial lung disease) (iii b). see table for the primary testing methods for cap pathogens and their corresponding diagnostic criteria. | s ecti on . anti -i nf ect i ve ther ap i es f or c ap after clinical diagnosis of cap is established, and etiological test and sampling arranged appropriately, the most potential pathogens should be assessed in terms of patient age, underlying disease, clinical characteristics, results of laboratory and radiography tests, severity of disease, hepatic and renal functions, and history of medication and antimicrobial susceptibility profile, then evaluate the risk for antibiotic resistance, select the appropriate anti-infective agent (s) and dosing regimen ( table ). the initial empirical antibacterial therapy should be administered promptly. it is important to note that the epidemiological distribution and antimicrobial resistance profile of pathogens may be different in different regions of china. the anti-infective drugs listed in table are optional for initial empirical therapy. the treatment recommendations are only theoretical. the selection of therapies for specific patients must be based on the actual situation in local healthcare facilities. additionally, the pharmacokinetic and pharmacodynamic properties of antibacterial agents must be taken into consideration. for time-dependent antibacterial agents (such as penicillins, cephalosporins, monobactams and carbapenems), their bactericidal ability is almost saturated at - times of mic, and t > mic (time above mic) is an important determinant of efficacy. better clinical efficacy can be achieved by multiple doses per day based on half-lives. meanwhile, the bactericidal ability of concentrationdependent antibacterial agents, such as aminoglycosides and quinolones, increases with drug concentration. the effect improves with higher peak drug concentration. therefore, these drugs are usually administered once daily in order to increase drug activity and decrease the risk of drug resistance and kidney injury caused by aminoglycosides. recommendations of this guideline for empirical antiinfective treatment of cap are provided in the following. . the first dose of anti-infective agent should be used as early as possible after diagnosis of cap is established in . fluorescent smear microscopy is more sensitive than ziehl-neelsen staining , . the sensitivity of mycobacteria culture is superior to that of smear microscopy; in vitro susceptibility testing can be performed, but it is more timeconsuming and complex, and has a higher biological safety requirement for laboratories order to improve efficacy and decrease mortality and hospital stay. however, it is important to note that a correct diagnosis is a prerequisite. physicians should not ignore necessary differential diagnosis for the purpose of early diagnosis [ ] [ ] [ ] [ ] . anti-infective therapy can usually be terminated - days after fever is relieved and the primary respiratory tract symptoms are improved significantly. however, the duration of therapy should differ based on the severity of disease, treatment response, complications and pathogens. it is not necessary to use chest x-ray or ct as an indication of termination of anti-bacterial agents. generally, the duration of therapy should be - days for patients with mild or moderate cap, which could be reasonably prolonged for patients with severe cap or with extra-pulmonary complications. the duration of therapy can be prolonged to - days for patients with atypical pathogens and/or slow response to treatment. s. aureus, p. aeruginosa, klebsiella and anaerobic bacteria may cause necrosis of lung tissues, therefore, the duration of therapy may be prolonged to - days , , , - (i b). once aetiology of cap is determined, targeted therapies can be delivered according to the results of in vitro susceptibility testing. see table for common pathogens of cap, common anti-infective agents, as well as dosage and administration. cap is the primary cause of death among infectious diseases. in addition to anti-infective treatment targeting the pathogens, it is also necessary for patients with moderate or severe cap to receive adjunctive therapies such as rehydration, maintenance of fluid and electrolyte balance, nutrition support and physical therapy (ii b). for patients with concomitant low blood pressure, early fluid resuscitation is an important measure to decrease the mortality of serious cap , (ii b). for patients with hypoxemia, oxygen ( ) repeated doses of antibacterial drugs or glucocorticoids due to chronic airway disease. combination therapy is recommended for patients with severe cap or proven antimicrobial resistance i generation cephalosporins: cefazolin, cefradine, cephalexin, cefathiamidine and so on. ii generation cephalosporins: cefuroxime, cefamandole, cefotiam, cefaclor, cefprozil, and so on. iii generation cephalosporins: intravenous: ceftriaxone, cefotaxime, ceftizoxime and so on; oral: cefdinir, cefixime, cefpodoxime proxetil, cefditoren pivoxil and so on. respiratory quinolones: levofloxacin, moxifloxacin, gemifloxacin. aminopenicillins: amoxicillin, ampicillin. penicillins-b-lactamase-inhibitor combinations (not including penicillins with antipseudomonal activity, such as piperacillin, ticarcillin): amoxicillin-clavulanic acid, amoxicillin-sulbactam, ampicillinsulbactam and so on. macrolides: azithromycin, clarithromycin, erythromycin. quinolones with antipseudomonal activity: ciprofloxacin, levofloxacin. beta-lactams with antipseudomonal activity: ceftazidime, cefepime, aztreonam, piperacillin, piperacillin-tazobactam, ticarcillin, ticarcillin-clavulanic acid, cefoperazone, cefoperazone-sulbactam, imipenem-cilastatin, meropenem, panipenem-betamipron, biapenem. weeks; followed by tmp-smx for - months the duration of therapy is - months for primary pulmonary nocardiosis. ampicillin g iv q h, for - weeks, followed by penicillin v potassium - g/kg per day, oral, for piperacillin; amoxicillin-clavulanic acid; ampicillin-sulbactam; piperacillin-tazobactam; doxycycline; minocycline; ceftriaxone; clindamycin; chloramphenicol; azithromycin; erythromycin; moxifloxacin; imipenem; ertapenem penicillin g is an alternative to ampicillin: - million u/d, iv, divided into - separate doses, for - weeks. gentamicin mg/kg iv once daily doxycycline; minocycline tmp-smx can be used to prevent yersinia pestis pneumonia. chloramphenicol is effective but with high toxicity. cephalosporins and quinolones are effective in animal models. ciprofloxacin mg iv q h or levofloxacin mg iv once daily or doxycycline mg iv q h clindamycin mg iv q h rifampin mg iv q h; switch to oral therapy and reduce dosage after improvement: ciprofloxacin mg oral, twice daily; clindamycin mg oral, q h, and rifampin mg oral, twice daily. duration of therapy is d. penicillin g clindamycin can inhibit the production of toxins. rifampin can enter cerebrospinal fluid and into cells. if the isolated pathogen is susceptible to penicillin, penicillin million u iv q h should be given. if structural or inductive b-lactamase is produced, penicillin or ampicillin should not be used alone. cephalosporins or tmp-smx should not be used. erythromycin and azithromycin have borderline activity. clarithromycin is effective. moxifloxacin is effective, but without clinical data. cidofovir mg/kg iv once daily weeks, and oral probenecid g should be given every time before injection. and g oral probenecid should the drug is contraindicated when serum creatinine > . mg/dl, crcl ml/min, or urine protein mg/l. no specific drug so far ribavirin . - g/d iv q h (not recommended for regular use) therapies are mainly symptomatic treatments, including fluid replacement and oxygen therapy. no specific drug so far therapy and assisted ventilation are also important to improve the outcomes of patients. additionally, nebulization, postural drainage and chest physical therapy are also used in cap treatment [ ] [ ] [ ] (ii b) . adjunctive drugs for severe cap also include glucocorticoids, intravenous immune globulin and statins, although currently there is no conclusive evidence for their effectiveness (ii b). . | oxygen therapy and assisted respiration . the blood oxygen level of hospitalized cap patients should be evaluated in a timely manner. oxygen therapy via nasal catheter or face mask is recommended for patients with hypoxemia in order to maintain blood oxygen saturation at above %. additionally, for patients with risk of hypercapnia, oxygen saturation should be maintained at %- % before obtaining the results of blood gas analysis , (iii a). the results of recent studies showed that heated and humidified high-flow oxygen therapy via nasal catheter ( - l/min) could also be used in clinical practice , (ii b). . compared with high-concentration oxygen therapy, noninvasive ventilation (niv, including bilevel positive airway pressure or continuous positive pressure ventilation) can decrease the endotracheal intubation rate and mortality of cap patients with acute respiratory failure, [ ] [ ] [ ] [ ] [ ] improve oxygenation index faster and more significantly, , , , and decrease the incidence of multiple organ failure, and septic shock. these benefits are more significant for patients with concomitant chronic obstructive pulmonary disease (ii b). however, for cap patients with acute respiratory distress syndrome (ards), niv has shown high failure rate and it cannot improve prognosis. niv is also not appropriate for cap patients with severe hypoxemia (oxygenation index < mm hg) (ii a) . additionally, the failure of niv must be recognized timely. niv failure is indicated if niv cannot improve respiratory rate or oxygenation state within the initial - h, , , or the therapy cannot decrease the blood carbon dioxide level in a patient with initial hypercapnia. the oxygen therapy should be switched to tracheal intubation and ventilator-assisted ventilation immediately (ii a). . mechanical ventilation with low tidal volume ( ml/kg ideal body weight) should be used for cap patients with ards after tracheal intubation , (i a) . . for patients with severe cap and concomitant ards, extracorporeal membrane oxygenation (ecmo) can be used if regular mechanical ventilation cannot lead to improvement [ ] [ ] [ ] [ ] (ii b). indications of ecmo include: ( ) reversible respiratory failure associated with severe the selection of antimicrobial agents should ultimately depend on susceptibility testing results and the opinions of local microbiological specialists. the appropriate dosage of antimicrobial agents should be based on local data. crcl, creatinine clearance; mic, minimum inhibitory concentration; mrsa, methicillin-resistant s. aureus; tmp-smx, trimethoprim-sulfamethoxazole. a cefoxitin - g iv q h-q h; cefmetazole - g q h-q h; cefotetan - g iv q h (maximum dose g once daily); cefminox g iv q h. b levofloxacin, moxifloxacin, gemifloxacin (not as first-line therapy for penicillin-susceptible strains); ciprofloxacin is mainly used in treatment of gram-negative bacteria (including h. influenzae). c ticarcillin g iv q h-q h; piperacillin - g iv q h-q h; piperacillin-tazobactam . g iv q h-q h; aztreonam - g iv q h-q h; ceftazidime - g iv q h-q h; cefepime - g iv q h-q h; cefoperazone - g iv q h; cefoperazone-sulbactam ( : ) g q h-q h; imipenem-cilastatin (for p. aeruginosa) mg (based on imipenem) iv q h-q h; meropenem - g iv q h; panipenem-betamipron - g iv q h-q h; biapenem . piperacillin-tazobactam . g iv q h-q h; ticarcillin-clavulanic acid . g iv q h-q h; ampicillin-sulbactam . - g iv q h or amoxicillin-clavulanic acid . g iv q h-q h. f imipenem-cilastatin mg (based on imipenem) iv q h-q h; meropenem - g iv q h; ertapenem - g iv q h; panipenem-betamipron - g iv q h-q h; biapenem . g iv q h. glucocorticoids can decrease the mortality of cap patients complicated with septic shock. [ ] [ ] [ ] hydrocortisone succinate mg/day is suggested based on the treatment of septic shock. the drug should be stopped promptly after septic shock is corrected. the duration of therapy is normally no more than days (ii c the initial therapy is assessed as effective or failure based on the patient's response to treatment, and subsequent management is provided accordingly. assessment after initial therapy should include the following aspects: . clinical manifestations: including respiratory and systemic symptoms and signs (iii a). . vital signs: general condition, consciousness, body temperature, respiratory rate, heart rate, blood pressure and so on. (i a). . general laboratory tests: including routine blood test, blood biochemistry, blood gas analysis, c-reactive protein, procalcitonin and so on. it is recommended to repeat c-reactive protein, procalcitonin and routine blood tests after h for hospitalized patients in order to differentiate between treatment failure and slow response to therapy. patients with severe conditions should be monitored closely , - (ii b). microbiological tests: it is appropriate to repeat regular microbiological tests. molecular biological and serological assays can be used when necessary. efforts should be made to obtain etiological evidence [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] (ii b). chest radiography: it is not recommended to repeat chest radiography regularly for patients with significant improvement in clinical symptoms. when symptoms and signs persist or exacerbate, chest x-ray or chest ct should be repeated to identify the changes of lung lesions (i a). . an effective initial therapy is defined as the situation that the clinical condition of a patient is stabilized after therapy. all the criteria below must be met for clinical stability: ( ) . subsequent management is recommended after an effective initial therapy: ( ) for patients with significant improvement in symptoms after initial therapy, it is appropriate to continue the same anti-infective treatment (i a). ( ) for patients who have achieved clinical stability and are able to receive oral therapy, sequential therapy should be administered with pathogen-susceptible oral preparations of the same types of antimicrobial agents or another agent with similar antibacterial spectrum , (i a). . a failed initial therapy is defined as either of the following situations in a patient: the symptoms are not improved after initial therapy, and requiring alternative antibiotics; exacerbation and disease progression after initial improvement during initial therapy (ii a). the epidemic season is from february to may. the virus is commonly seen in adults without underlying disease. the incubation period is - d. hadv- , hadv- and hadv- are relatively common serotypes , similar to pneumonia caused by influenza virus; more common in immunocompetent adults [ ] [ ] [ ] [ ] patients with severe conditions primarily show pulmonary consolidation, which may be associated with ground-glass opacities or patchy nodule infiltrates in unilateral or bilateral lungs or multiple lobes [ ] [ ] [ ] and use of tumour necrosis factor-a antagonists. the relevant epidemiological history includes contact with contaminated air conditioners, air conditioner cooling tower, or contaminated potable water, hot recreational spa, gardening activities or plumbing repairs and the history of traveling to an area with legionella outbreak. , , , the possibility of legionella pneumonia should be suspected when an adult cap patient develops the following conditions: fever but relative bradycardia, acute onset of headache, non-drug-induced disturbance of consciousness or sleepiness, non-drug-induced diarrhoea, acute renal and/or hepatic impairment, hyponatremia, hypophosphatemia and unresponsiveness to b-lactams. , , [ ] [ ] [ ] [ ] [ ] [ ] the relatively specific manifestations of legionella pneumonia in chest radiograph is sharply demarcated consolidation intermingled with ground-glass opacities. another characteristic of legionella pneumonia is radiographic progression within a short period of time ( week) even though improvement in clinical symptoms. or it may take several weeks or even months for pulmonary infiltrates to be completely absorbed. [ ] [ ] [ ] macrolides, respiratory quinolones or doxycycline monotherapy are appropriate for immunocompetent patients with mild or moderate legionella pneumonia. quinolones combined with rifampin or macrolides are recommended for patients with severe conditions, or when monotherapy fails and those immunocompromised patient , , [ ] [ ] [ ] [ ] (i a) . when quinolones are combined with macrolides, physicians should pay close attention to the potential risk of abnormalities in cardiac electrophysiology (i a). currently, ca-mrsa pneumonia is relatively rare in mainland china. only a small number of cases are reported in children and teenagers. [ ] [ ] [ ] [ ] similarly, among the skin and soft tissue infections caused by s. aureus, mrsa only accounts for a small proportion ( / ). among the pathogens of hospitalized cap patients, the proportion of mrsa is . % in taiwan, . % in japan and . %- . % in the united states according to a survey. the estimated incidence of ca-mrsa pneumonia is . - . / , mainly pulmonary involvement in subpleural and basal segments of lungs; broad appearance of ground-glass opacities, which may be associated with consolidation. pleural effusion, interlobular septal thickening may also appear , ribavirin combined with interferon , (ii c) people. ca-mrsa pneumonia is a severe disease associated with mortality up to . %. vulnerable populations include patients or individuals with close contact with a mrsa carrier or patient, individuals affected by influenza virus, prisoners, professional athletes, individuals who serve in the army recently, men who have sex with men, intravenous drug users, regular sauna users and those using antibacterial agents before infection. ca-mrsa pneumonia progresses rapidly. the clinical symptoms include influenza-like symptoms, , fever, cough, chest pain, gastrointestinal symptoms and skin rashes. for patients with serious conditions, severe pneumonia symptoms such as hemoptysis, confusion, ards, multiple organ failure and shock may appear, as well as complications such as acidosis, disseminated intravascular coagulation, deep vein thrombosis, pneumothorax or empyema, pneumatocele, pulmonary abscess and acute necrotic pneumonia. radiographic characteristics of ca-mrsa pneumonia include extensive pulmonary consolidation and multiple cavities in bilateral lungs. ca-mrsa pneumonia should be suspected after influenza or in previously healthy young patients in case of cavitation, necrotic pneumonia associated with rapid increase of pleural effusion, massive hemoptysis, neutropenia and/or erythematous rashes. glycopeptides or linezolid are the primary choice for ca-mrsa pneumonia , (iii b). currently, the consensus definition of cap in the elderly (elderly cap) is pneumonia occurring in the population aged years. , , the incidence of elderly cap increases with age. the clinical manifestations of elderly cap can be atypical. , the manifestations may only include poor appetite, urinary incontinence, tiredness and altered mental state and so on. , typical manifestations of pneumonia such as fever, cough and increased wbc/neutrophil count may not be so evident. therefore, missed diagnosis and misdiagnosis may occur. tachypnea is a sensitive index for diagnosis of elderly cap. when fever or any of the abovementioned atypical symptoms appear, chest radiography should be done as early as possible to confirm the diagnosis. s. pneumoniae is still the main pathogen for elderly cap, but the possibility of enterobacteriaceae infection should be considered for elderly patients with underlying diseases (congestive heart failure, cardiovascular and cerebrovascular diseases, chronic respiratory system diseases, renal failure, diabetes mellitus, etc.). , , these patients should be further evaluated for risk factors of esbls-producing enterobacteriaceae. empirical treatment with cephamycins, piperacillin-tazobactam, cefoperazone-sulbactam, ertapenem or other carbapenems is recommended for patients with high risk of infections with esbls-producing enterobacteriaceae [ ] [ ] [ ] (iii b) . relevant risk factors include history of esbls-producing bacterial colonization or infection, prior use of third generation cephalosporins, history of repeated or long-term hospitalization, indwelling medical devices, renal replacement therapies. [ ] [ ] [ ] elderly patients are associated with reduced organ functions, which must be monitored during treatment to avoid side effects. reduced renal excretion may cause prolonged half-lives of drugs, so the dosage should be reasonably adjusted in terms of crcl when treating such patients (ii b). if no contraindication exists, hospitalized elderly cap patients should be evaluated for risk of deep vein thrombosis and prophylaxis with low molecular weight heparin should be administered when necessary (ii b). the treatment failure rate is %- % for elderly cap. common reasons are concomitant severe sepsis, myocardial infarction, or progression of pneumonia. cardiovascular event is common in elderly cap, which is one of the reasons for increased mortality. , aspiration pneumonia is pulmonary infectious lesions caused by aspiration of food, oropharyngeal secretion, or gastric content into the throat or lower respiratory tract, not including chemical inflammation in the lung due to aspiration of sterile gastric fluid. [ ] [ ] [ ] the majority cases of aspiration pneumonia are caused by silent aspiration, accounting for around % of elderly cap. the following points should be noted when making diagnosis of aspiration pneumonia: ( ) whether there are risk factors for aspiration (eg, disturbance of consciousness due to cerebrovascular diseases or other reasons, dysphagia, periodontal diseases, or poor oral hygiene) , , - ; ( ) whether chest radiograph shows primary lesions in the posterior segment of upper lobe and dorsal or basal segment of the lower lobe, just as in hypostatic pneumonia. , [ ] [ ] [ ] aspiration pneumonia is mostly caused by infections with anaerobic bacteria, gram-negative bacteria or s. aureus. the treatment should cover the above pathogens and based on the severity of disease using antimicrobial agents with antianaerobic activity, such as amoxicillin-clavulanic acid, ampicillin-sulbactam, moxifloxacin, carbapenems or in combination with metronidazole or clindamycin , [ ] [ ] [ ] , , (ii a). targeted treatment can be administered after the results of sputum culture and antimicrobial susceptibility testing are available. intensive care is required for the elderly patients with risk factors of aspiration in order to reduce the incidence of aspiration pneumonia, specifically: ( ) the head of bed should be elevated to - for long-term bedridden patients if there is no contraindication, and the patient should be in appropriate position when feeding the patient; ( ) oral hygiene should be maintained to reduce bacterial colonization in the oropharyngeal area; ( ) for elderly patients with severe dysphagia who have already experienced aspiration, physicians should evaluate the risks and benefits of nasal feeding via indwelling gastric tube; ( ) antipsychotic drugs, antihistamines and anticholinergic agents should be avoided or decreased , , (ii b). smoking cessation, avoid excessive alcohol drinking, adequate nutrition and good oral health are all helpful in preventing pneumonia (iii b). good hand hygiene habits should be maintained. during an episode of respiratory tract symptoms such as coughing or sneezing, wearing a mask or using tissues or elbow clothes to cover the nose and mouth can reduce the dissemination of respiratory tract pathogens (iii a). vaccination against s. pneumoniae can reduce the risk of pneumonia in specific populations. the s. pneumoniae vaccines currently in use include pneumococcal polysaccharide vaccine (ppv) and pneumococcal conjugate vaccine (pcv). in china, -valent pneumococcal polysaccharide vaccine (ppv ) has been on the market. it can effectively prevent invasive s. pneumoniae infections. ppv is recommended for the following populations (i b): ( ) age years; ( ) age < years, but with chronic pulmonary disease, chronic cardiovascular disease, diabetes mellitus, chronic renal failure, nephrotic syndrome, chronic hepatic disease (including hepatic cirrhosis), alcoholism, cochlear implant, cerebrospinal fluid leakage, immunodeficiency or functional or organic asplenia; ( ) long-term residents in nursing homes or other medical institutions; ( ) smokers. for the above patients, one dose of vaccine by intramuscular or subcutaneous injection is recommended. usually, repeat vaccination is not advised for immunocompetent individuals, although it is appropriate for individuals under years of age, but with chronic renal failure, nephrotic syndrome, functional or organic asplenia or immunodeficiency. there should be at least a -year interval between two doses of ppv . repeat vaccination is not necessary for the individuals who are at least years of age at the time of first vaccination (i b). the -valent pneumococcal conjugate vaccine (pcv ) can cover %- % of s. pneumoniae serotypes in china, , associated with excellent immunogenicity, but it has not been available in china market. pcv vaccination strategy: adults aged years who have not received s. pneumoniae vaccination should receive dose of pcv , and dose of ppv within - months afterward; adults aged years who have received one or more doses of ppv should receive dose of pcv at least one year after the latest dose of ppv ; adults who have received ppv before the age of should receive pcv after years old (at least one year after the last vaccination), and can repeat ppv vaccination at least - months later, but there should be at least a -year interval between the two doses of ppv (i b). influenza vaccines can prevent influenza or reduce influenza-associated symptoms. , they also have some protective effects against influenza pneumonia and bacterial pneumonia secondary to influenza. the target population of influenza vaccines is broader than that of s. pneumoniae vaccines. see the chinese guidelines for diagnosis and treatment of influenza and visit the website for national influenza center for details. one dose of influenza vaccine is recommended per annual influenza season (i a). combination of pneumococcal vaccines with influenza 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community-acquired pneumonia in adults: clinical practice guidelines by the chinese thoracic society, chinese medical association the following experts provided valuable opinions in the revision of these guidelines. their efforts are highly appreciated: writing group members: yusheng chen, xiangqun fang, zhancheng gao bin cao has been a speaker invited by pfizer, gsk and bayer. jie-ming qu has been a speaker on behalf of msd china, pfizer, bayer, daiichi sankyo and sanofi-aventis. all other authors declare no conflict of interests. li-xian he and you-ning liu contributed to be advisors; all authors contributed to critical revision and final approval of the manuscript. no ethics approval required. jing zhang http://orcid.org/ - - - key: cord- -j vrvqf authors: fong, i. w. title: issues in community-acquired pneumonia date: - - journal: current trends and concerns in infectious diseases doi: . / - - - - _ sha: doc_id: cord_uid: j vrvqf pneumonia is one of the most commonly diagnosed infectious diseases and is the third most frequent cause of death worldwide. accurate statistics of community-acquired pneumonia incidence globally or in countries of various regions are lacking. although the clinical diagnosis of pneumonia is not difficult, the etiology diagnosis to guide targeted specific antimicrobial therapy still poses a challenge even with novel molecular methods. this has led to different approaches and guidelines for the empiric treatment of community-acquired pneumonia, often with broad-spectrum antimicrobial agents which may play a role in fostering the worldwide development of antibiotic resistant bacteria. severe community-acquired pneumonia, seen mainly at the extremes of age and in persons with chronic underlying diseases, is associated with high mortality of – %. pneumonia severity tools, such as curb- , have been developed over the past decade to assist emergency department physicians to recognize, admit, and implement rapid antimicrobial therapy in severely ill patients. the evidence for the beneficial effects of these tools will be reviewed in this chapter. issues in the management of severe community-acquired pneumonia that are discussed include: combination with newer macrolides [irrespective of microbial etiology], value of adjunctive therapy such as corticosteroids and statins. cough reflex, and mucociliary clearance of foreign material and invaders of the tracheobronchial tree. local production of immunoglobulins [iga, igg, and ige] in the mucosa of the respiratory tract provides another layer of protection against invading microbes. the relative proportion of iga and igg in the respiratory tract changes with the location, greater ratio of iga to igg in the nasal mucosa, trachea and bronchial tree and reversed ratio in the alveoli with greater proportion of igg [ ] . iga may be more important in protecting against viral infections, as it can neutralize several respiratory viruses such as rhinovirus, influenza, and respiratory syncytial virus [ ] . but it may be involved in the mechanisms of preferential bacterial adherence. whereas, most individuals with iga deficiency do not have increased respiratory infections, those with igg or certain igg subclass deficiency have recurrent respiratory infections [ ] . igg limits the invasion of microorganisms in the epithelium by opsonization and complement fixation and the concentration can increase a hundred-fold in the respiratory tract in the presence of infection and increased vascular permeability. protection of the respiratory tract from microbial invaders is a complex process that involves many immune cells: dendritic cells, b and t-lymphocytes, neutrophils and macrophages and their secretory products [immunoglobulins, cytokines, opsonins, enzymes, and oxygen metabolites]; and nonimmune opsonins such as surfactant, fibronectin fragments, and possibly c-reactive protein [ ] . recent studies indicate that progranulin, an autocrine growth factor expressed in a variety of tissues and cell types, plays a protective role in lung immunity during bacterial pneumonia [ ] . elevated progranulin levels were observed in clinical and experimental bacterial pneumonia and it mediated host defense in both gram-positive and gram-negative bacterial pneumonia. the healthy mucosa is colonized by a complex milieu of microorganisms, not exclusively aerobic and anaerobic bacteria, that probably plays an important protective role against invading pathogens. these normal microbes prevent the establishment of invading pathogenic microbes in the respiratory epithelium, the first step to induce infection. in the past decade, there has been marked interest and research on the role of the normal microbiome of the respiratory tract in health and disease. this has been facilitated by modern sophisticated, molecular, multiomics techniques. recent studies of the human microbiome, including the respiratory tract, have demonstrated that the resident microflora is much more abundant and diverse than previously realized; including many species of nonculturable bacteria, viruses [virome], fungi, and protozoa. present data indicate that the microbiome of the gut and the lungs are linked, by immune cells and mediators, and maybe important and associated with the pathogenesis of respiratory diseases [ ] [ ] [ ] . the bronchial tract harbors a complex and dynamic microbial milieu of about species, which overlaps with the oral microbiome [ ] . the lung is also colonized by airway microbiota that resembles the microbiome of the mouth but not the nostrils at a lower density. studies [ ] [ ] [ ] have linked dysbiosis of the respiratory microbiome with asthma and chronic lung diseases such as cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease [copd] . however, there is no data as yet on association with acute pneumonia. it is generally believed, that cap occurs from aspiration of pathogenic microbes colonizing the nasopharynx in situations where there is defect of the normal airway defenses. inciting factors that may play a role in the development of pneumonia include preceding viral upper respiratory tract infections [seen in nearly % of bacterial cap]. these minor infections can result in defect in mucociliary function and clearance of aspirated bacteria and allow adherence of pathogens to the mucosa. it is quite possible that upper respiratory virus infections can result in dysbiosis of the commensal respiratory microbiome. cigarette smoking can have a similar effect on airway defense and has been associated with dysbiosis of the resident microbiota. although numerous microorganisms can cause lung involvement or pneumonia [estimated about ], only several have been associated with cap in children or adults. in clinical practice the identification of etiologic microbes in cap is usually achieved in < % of cases. sputum cultures are often nonspecific and difficult to interpret because of contamination of oral-pharyngeal commensals, and blood cultures are positive in only - % of adults and even less in children with bacterial pneumonia [ ] . urinary antigen detection of streptococcus pneumoniae may improve the sensitivity compared to culture [ - % sensitive], but can be false positive from colonization in children [ ] . in recent years studies have applied molecular assays for viruses and bacteria for microbial diagnosis. results have indicated that the etiology of cap may vary with age. in children < years of age cap is most commonly due to viruses [mainly respiratory syncytial virus or rsv], especially in the absence of lobar consolidation and effusion [ ] ; but even with extensive testing a pathogen cannot be identified in - % of children with cap [ , ] . in a recent study of children < years of age hospitalized for cap without an identifiable etiology and asymptomatic controls, metagenomics [next-generation sequencing] and pan-viral pcr were able to identify a putative pathogen in % of unidentifiable cases from nasopharyngeal and oropharyngeal swabs [ ] . putative viral pathogens included human parainfluenza virus , human bocavirus, coxsackieviruses, and rhinovirus a and c. human bocavirus was the most commonly detected virus [ %] . it is plausible that these viruses were causing upper respiratory tract disease that resulted in cap from bacterial pathogens. although cultures and pcr for bacterial pathogens were obtained, endobronchial secretions were not routinely obtained. in a meta-analysis of detection of viruses by pcr in childhood cap, the pooled incidence was . % with mixed infection in . % [ ] . rhinovirus, rsv, and bocavirus were the three most common viruses in childhood cap. respiratory viruses were detected in . % of patients aged ≤ year, . % of patients - years, and . % of children aged ≥ years [ ] . it was estimated that more than half the viral infections were probably concurrent with bacterial infections. the etiology inference of identifying viruses in the upper respiratory tract in children with cap is still unclear. although higher viral loads can . microbial etiology of community-acquired pneumonia be found in children with pneumonia compared to controls with some viruses, the utility to diagnose viral pneumonia with quantitative pcr was equivocal [ ] . it is still the opinion of experts that most cap in children with radiographic alveolar infiltrate is due to bacteria, predominantly s. pneumoniae. previous studies have reported an association of upper airway density of s. pneumoniae and pneumococcal pneumonia, and nasopharyngeal bacterial load with this pathogen is significantly higher in viral infection compared with no viral infection [ ] . in a case-control study from seven developing countries, colonization density of s. pneumoniae in the upper airway was compared in children [< years of age] with proven pneumococcal pneumonia and controls [ ] . pneumococcal colonization density > . log copies/ml was strongly associated with confirmed pneumococcal pneumonia, with a sensitivity of % and specificity of % but not sufficiently accurate for clinical diagnosis. the same group of investigators also assessed the colonization density in the upper respiratory tract and confirmed pneumonia with haemophilus influenzae, moraxella catarrhalis, staphylococcus aureus, and pneumocystis jirovecii. there was an association of colonization density [ . log copies/ml] and h. influenzae confirmed pneumonia, with a sensitivity of % and specificity of %, but not with the other respiratory pathogens [ ] . in adults, the microbial diagnosis of cap with conventional microbiology, urine antigen detection and commercial pcr for viruses in two prospective studies in the usa have had low yield [ , ] . each study failed to identify a respiratory pathogen in about - % of cases, pneumococci was found in < % of cases, respiratory viruses in - %, and atypical organisms in about % of cases in one study [ ] . a prospective study of hospitalized patients with cap in the netherlands, using similar investigative techniques but added real-time pcr for "atypical organisms" [mycoplasma pneumoniae, legionella pneumophila, coxiella burnetii, and chlamydophila sp.], identified s. pneumonia in %, c. burnetii in %, h influenzae in %, and atypical bacteria including legionella in % [ ] . some european studies have used advanced microbiological techniques with identification of pneumococcus in - % of cases and identification of a pathogen in % of cases [ , ] . in norway, bacterial etiology was found in % and viruses in %, including viral-bacterial coinfections [ ] . a prospective study from china, beside viral culture and nucleic acid amplification assessed paired sera for antibody response, and viral etiology was established in . % of cap [ ] . in a review and meta-analysis of the incidence of viral infections in adult cap, incidence ranged from . to . %; lower tract samples were associated with higher viral yield and the three main viruses were influenza virus, rhinovirus, and coronavirus [ ] . in a similar review by other investigators, the pooled proportion of patients with viral infection was similar, . %, but in studies that obtained lower respiratory samples the proportion increased to . % [ ] . more recently in britain, adult patients with confirmed pneumonia admitted to two tertiary-care hospitals had cultures and comprehensive molecular testing [multiplex real-time pcr for respiratory viruses and bacteria] from sputum [ %] and endotracheal aspirate [ % or cases] [ ] . an etiology agent was identified in % with molecular testing compared to % with culture-based methods. bacterial pathogen was detected by pcr in % and culture in % but most patients [ %] received antibiotics before admission. viruses were present in % of cases but % were co-detected with bacterial pathogens. it was surprising that h. influenzae was the most common bacteria in . %, followed by pneumococcus in . %, m. catarrhalis in . %, s. aureus in . %, klebsiella pneumoniae in %, and atypical organisms in < % [ ] . it is questionable that mere detection of a pathogen is sufficient to attribute causality, unless there is evidence of acute immune response, as most specimens were sputa and not aseptically collected endotracheal secretions. the high incidence of h. influenzae could represent oropharyngeal colonization with non-typeable strains, high prevalence of copd [about %] and high proportion of older patients above years of age [ . %] . the low prevalence of atypical organisms [mycoplasma and chlamydophila pneumoniae] is not surprising as the patients had severe pneumonia requiring hospitalization. it is likely that mildmoderate cap receiving ambulatory treatment would have a higher proportion of the atypical bacteria. a similar but smaller study in japan used conventional methods and real-time pcr for diagnosis of cap [n = ] from sputa and nasopharyngeal swabs; molecular methods detected a causative organism in % versus % with conventional methods [ ] . s. pneumoniae was most frequently identified, followed by h. influenzae and m. pneumoniae [ %] . pneumococcus is the most important bacterial cause of cap, responsible for most cap mortality in severe cases, but rates of detection have varied from to %. rapid diagnosis of pneumococcal etiology could lead to initiating treatment with a narrow-spectrum antibiotic such as penicillin, which would be cost saving, with decreased risk of superinfection with clostridium difficile and lower rate of predisposing to multiresistant bacteria. sputum gram stain at presentation is an inexpensive, rapid, easy to perform test that is underused in clinical settings to assist in the diagnosis and treatment of cap. in a prospective study of patients with pneumonia [ cap], the utility of sputum gram stain was assessed from good quality samples [ ] . the sensitivity and specificity of gram stain were . % and . % for s. pneumoniae, . % and . % for h. influenzae, . % and . % for m. catarrhalis, . % and . % for k. pneumoniae, and . % and % for s. aureus. unfortunately about % of patients with pneumonia had no or poor quality sputum, which limits the overall diagnostic value. hence, this simple test should be routinely used in the diagnosis of cap whenever purulent sputum is available. detection of pneumococcus c-polysaccharide in urine by immune chromatography is increasingly being used for evaluation of patients with cap. in a large observational, multicenter, prospective study of patients admitted to hospital for cap, pneumococcal infection was diagnosed in %, with % of the cases diagnosed exclusively by urinary antigen test [ ] . the sensitivity and specificity were % and . %, respectively. a combination of different methods, however, appears to be more sensitive. using quantitative [q] pcr on blood samples, multiplex immunoassay for urine antigen and multiplex immunoassay for serologic antibody responses against serotypes were able to detect pneumococcus in % of cases and % more patients than conventional methods [ ] . the qpcr of blood samples, however, was not more sensitive than blood culture. how can we interpret these studies utilizing comprehensive molecular methods for etiology diagnosis of cap? finding viruses or pathogenic bacteria from nasopharyngeal and sputum specimens may not prove of causality in pneumonia, as they clearly can just be causing upper tract infection or colonization without producing lower respiratory disease. however, the absence of any specific pathogens from theses assays can effectively exclude them as etiology agents, since nearly all cap is a result of aspiration of upper airway microbes. a combination of tests such as sputum gram stain and culture, blood culture, urinary antigen and antibody response to the microbe[s] may be the most specific and reliable methods of determining causality, but are not highly sensitive nor provide rapid results to affect management. future research should focus on rapid, readily available, and inexpensive tests for etiologic diagnosis of cap that could be used in emergency departments. such methods may use immunoassays that could detect various bacterial pathogens or antigens semiquantitatively from sputum, blood, and urine in the form of a dipstick, similar to that of a urinalysis test. in most cases of cap, the diagnosis should be straightforward, but since the advent of chest radiograph there has been no significant advance in diagnostic methods. typical mild cases of cap with clinical symptoms of recent cough, fever, and the presence of chest crackles may be treated empirically without a chest x-ray or blood tests. however, normal chest examination can be present in about % of cap. chest radiograph is the standard investigation to confirm pneumonia in suspected cases and should be done in moderate-severe cap even in the presence of typical chest findings, to define the extent of lung[s] involvement, assess for presence of parapneumonic effusion or possible empyema, and the presence of pulmonary cavitation or abscess. the presence of necrotizing pneumonia restricts the etiologic diagnosis to a few bacteria and usually requires a longer duration of therapy. diagnosis of cap can be difficult in some more complicated cases, often severe cases with multi-organ failure or dysfunction requiring intensive care. in these situations, the difficulty lies in the interpretation of the chest x-ray. problems arise from differentiating pneumonia from pulmonary edema, hemorrhage, atelectasis, and acute respiratory distress syndrome [ards]. computerized tomography [ct] scan may or may not be able to differentiate these conditions. bedside ultrasonography has been used for diagnosing pneumonia but is less reliable than radiography, with sensitivity ranging from % to % and specificity of % to % [ ] . ultrasound is more useful for defining the presence and severity of associated pleural effusion. investigators have also assessed the value of molecular biomarkers in severely ill patients to differentiate cap from noninfectious cause of lung infiltrates. in a study of patients admitted to the intensive care unit [icu] with suspected cap genome-wide transcription profiling of blood leucocytes was investigated. expression of proinflammatory and anti-inflammatory pathways was similar between patients with and without cap, and blood concentrations of biomarkers such as procalcitonin, interleukin [il]- , and interleukin il- were not discriminatory [ ] . further analysis revealed that the ratio of two genes, faim and plac , was best for distinguishing cap from no-cap. the faim :plac ratio provided a positive predictive value of . % and negative predictive value of . %. however, the clinical utility for management in seriously ill patients is questionable and further studies are needed. the risk of cap and invasive pneumococcal infection in adults increases with older age, number of comorbidities, cigarette smoking, and the combination of the above [ ] . proton pump inhibitors [ppi], a commonly prescribed medication, in this high-risk population also may add to the risk of cap. a systematic review of studies with , cases of cap reported a . -fold increased risk of cap, with the highest risk in the first days after initiating a ppi [ ] . cap is the most common infectious disease leading to hospitalization in the icu and the leading cause of mortality in patients with infection [ ] . severe sepsis may be present in about one-third of patients presenting with cap at a hospital. predictors of severe sepsis and assessment for these factors are important on arrival in the emergency department [ed], to facilitate rapid treatment and close monitoring to avoid high fatality. in a prospective multicenter cohort study of hospitalized cap patients, . % presented with severe sepsis [ ] . [ ] . other comorbid conditions such as cardiovascular disease may not predispose to severe sepsis but may result in higher mortality and morbidity. previous studies indicate that cap is associated with increased cardiovascular complications. in a multicenter prospective cohort of patients hospitalized for cap, [ ] . various scoring systems and biomarkers have been developed to identify severe cap, assess prognosis for mortality risk and to assist physicians in making decisions on hospital and icu admission. these scoring systems were designed for the use in non-immunosuppressed patients. the most commonly used scoring system is the curb- score, which is based on five easily measurable factors [see table . ]. the presence of each factor was given a score of to a maximum of . in the initial study of patients in the derivation cohort and a separate validation cohort, the day mortality was . - . %, . - . %, . %, . %, and % for , , , , or factors [ ] . based on these data, it was suggested that that cap patients with a score of - could be treated as outpatients, those with a score of should be admitted to hospital, and those with a score of or more should be assessed for icu care. however, another large study of patients with cap reported a mortality of . % with a curb- score of [ ] ; which suggests even score should be an indication for hospital admission. but a healthy -year-old person without other factors or significant comorbid illness could be treated with outpatient antibiotic. in a more recent study, however, curb- had very good accuracy for predicting the -day mortality among patients with cap discharged from the er [ ] . among all er encounters the curb- threshold of > was . % sensitive and . % specific for predicting mortality, with a . % negative predictive value. a simplified version without blood test to measure blood urea nitrogen [bun], designated crb- , can be used in the doctor's office to assess severity of cap. if i or more score is present then the patient is referred to the hospital for admission. the crb- score has not been extensively evaluated but was found to have good predictive value in patients with cap [ ] . the pneumonia severity index [psi] assessment is based on the presence of variables and is divided into five strata of increased risk for short-term mortality at presentation [ ] . low-risk patients with cumulative mortality of < % falls in the class i-iii, whereas patients in class iv and v have higher mortality risk of % to %. although several large studies have validated its predictive utility, it is more complex to calculate, less user friendly than curb- , and the predictive performance is similar in prospective comparison [ ] . hence, curb- is more commonly used by ed physicians to assess cap severity. the british thoracic society and the national institute for health and care excellence [nice] guidelines recommend curb- and crb- for severity assessment in cap [ , ] . bun blood urea nitrogen disposition of patient based on total score: - treat as outpatient; admit to hospital for and above for patients hospitalized for cap risk prediction can be used to assess the need for icu care, mechanical ventilation, and mortality. monitoring the c-reactive protein [crp] during hospitalization may be useful in predicting response and the risk of death. in a retrospective multicenter study of patients with cap admitted to three dutch hospitals, the highest mortality risk was seen in patients who failed to demonstrate a decline in their crp by % after days of treatment, irrespective of the actual value and initial curb- score [ ] . this study should be validated by a larger prospective study. three scoring systems have been developed to identify severe cap in hospital and the need for icu management. these include the severe community-acquired pneumonia score [scap], smart-cop, and the infectious diseases society of america/ american thoracic society [idsa/ats] severity criteria [see table . ]. all three systems utilize a combination of clinical criteria [shock, altered mental state, and respiratory failure], routine blood tests, and arterial blood gas results. a scap score of ≥ [at least one major and two minor criteria] was superior to curb- in predicting progression to more severe pneumonia [ ] . further validation study showed that the scap score was just as accurate as other prediction scoring systems for predicting icu admission, progression to severe sepsis, treatment failure and need for mechanical ventilation [ ] . the smart-cop scoring system was assessed in a prospective study of episodes of cap requiring hospitalization, with more than % of patients over years old [ ] . each factor led to accrual of one point, except low systolic blood pressure, poor oxygenation, and low arterial ph, each subscribed two points. smart-cop score of ≥ points identified % of patients who received intensive respiratory or vasopressor support [ ] . the predictability of smart-cop was less accurate in younger adults < years of age, as it failed to identify the need for these critical measures in % of patients in this age group [ ] . the idsa/ats severity system is based on two major criteria and nine minor criteria [ ] . any one of the major criteria, septic shock requiring vasopressors and requirement for mechanical ventilation, are universally accepted and are self-evident. three or more of the minor criteria indicate need for icu management. a validation study of patients with cap, not meeting the major criteria, found the minor criteria were equivalent to the smart-cop scoring system for predicting need for mechanical ventilation, vasopressor support, and icu care [ ] . recently, other investigators have modified the idsa/ats minor criteria by excluding four infrequent variables [leucopenia, hypothermia, hypotension, and thrombocytopenia] but adding age ≥ years [ ] . the modified version best-predicted mortality, but it is unclear whether it is as useful for predicting need for icu care and vasopressor/ventilation support. various blood biomarkers have been studied as prognostic predictors in cap and these include procalcitonin [pct], crp, proadrenomedullin [pro-adm], presepsin [scd -st], copeptin, and cortisol. the pct was the most extensively studied in a total of studies with pneumonia patients. although elevated pct level was a risk factor for death in cap, particularly patients with a low curb- score, the commonly used cutoff, . ng/ml, had low sensitivity in identifying patients at risk of dying [ ] . in a systematic review and meta-analysis of the prediction value of various biomarkers in , cap patients, they demonstrated moderate-good accuracy to predict mortality but had no clear advantages over cap-specific scores [ ] . curb- should be the standard prediction score applied to patients seen in hospital ed with cap, the main contentious issue is whether or not patients with a score of should be admitted or treated as outpatients. it may be reasonable to admit patients with one factor, other than age years alone. using age alone for admission has no supporting evidence for almost every medical illness. however, patients years or older with significant comorbid illness, such as underlying cardiovascular disease, should be admitted and monitored. once patients are admitted to hospital the idsa/ ats guidelines maybe the most appropriate to use on deciding on further care in the icu, although scap and smart-cop scores are suitable as well. empiric treatment of cap is designed to treat common bacterial respiratory pathogens [s. pneumoniae, h. influenzae] and atypical bacteria [m. pneumoniae, c.pneumoniae], but recent etiology studies suggest that a large proportion of cap is due to no pct threshold discriminated viral from bacterial etiology with a very high sensitivity and specificity [ ] . a contentious issue in the empiric management of cap is the routine coverage for atypical bacteria with a macrolide, as m. pneumoniae and c. pneumoniae infection are usually associated with self-limited course and recovery. whereas, north american guidelines for outpatient treatment of cap list a macrolide as first choice [ ] european guidelines do not [ ] and consider macrolides as second choice for penicillin-allergic patients. moreover, coverage for atypical bacteria routinely in the management of cap has not been proven to be beneficial. in a systematic review of trials and with randomized patients, no advantage was found for regimens covering atypical bacteria in the major outcomes tested-mortality and clinical efficacy [ ] . macrolide as a sole therapy for cap maybe inadequate to cover pneumococcus, as the prevalence of macrolide resistance has been increasing and is currently up to %, although the clinical significance is uncertain [ ] . for patients with moderate-severe cap being hospitalized, north american and european guidelines [ , , ] recommend initiating broad-spectrum therapy of a β-lactam agent [often ceftriaxone] and a macrolide or a respiratory quinolone alone. the macrolides have immunomodulatory effects and anti-inflammatory properties that may improve outcome even for pneumococcal infection. even in gram-negative sepsis and ventilator-associated pneumonia, clarithromycin has been reported to restore the immunoparalysis and improve outcome [ ] . a recent systematic review of antibiotic therapy for hospitalized adults with cap has been published [ ] . several key aspects of antibiotic therapy can be summarized: ( ) eight observational studies showed that antibiotic initiation within - h of hospital arrival was associated with decreased mortality; ( ) stepping down from intravenous to oral therapy once patients are stable shortens hospital stay without affecting outcome; ( ) choice of empiric antibiotics on outcome was mixed and inconclusive. six of eight lowquality observational studies [with up to , patients] found that the combina- . treatment of cap tion of β-lactam and macrolide was associated with reduced short-term mortality over β-lactam monotherapy. the three largest studies were all retrospective in design. three observational, mainly retrospective, studies found reduced mortality with quinolone monotherapy compared to β-lactam monotherapy [ ] . however, in prospective randomized, trials the results have not confirmed superiority of combination with a macrolide nor quinolone over β-lactam monotherapy. in the first trial in switzerland, adults with moderate-severe cap admitted to six acute care hospitals were randomized to β-lactam monotherapy or a macrolide combination [ ] . the mortality, icu admission, length of stay, and recurrence of pneumonia within months were not different between the treatments. in the second prospective multicenter dutch trial, patients with cap admitted to non-icu wards were allotted to one of three treatments by a cluster-randomized, crossover design with strategies rotated in -months period [ ] . monotherapy with a β-lactam was non-inferior to strategies with β-lactam macrolide combination or quinolone monotherapy for months mortality, length of stay, or any complications. quinolones when used can be given orally from the onset if the patients can take oral medications, since they are fully bioavailable. idsa guidelines had recommended initial intravenous therapy for severe pneumonia, but well-conducted observational study confirms that intravenous route is not necessary for severe cap [ ] . the duration of treatment for cap is not well established. idsa/ats guidelines recommend at least days treatment in patients who are stable and have been afebrile ≥ h [ ] ; the british guidelines advice days for mild-moderate and - days for moderate-severe cap [ ] ; and the nice guidelines recommend days for mild and - days for moderate-severe cap [ ]. in a recent multicenter randomized trial from four teaching hospitals in spain, the duration of antibiotic treatment was studied in hospitalized patients with cap [ ] . after days of treatment, the intervention group stopped antibiotics if they were afebrile for h and had no more than one cap-associated sign of instability, and the duration of antibiotics in the control group was determined by physicians. there was no significant difference in the outcome between the two groups. thus, the idsa/ats guideline is safe to implement in hospitalized patients with cap. current data indicates that amoxicillin for outpatient treatment of mild-moderate cap for days is the preferred therapy. macrolide monotherapy should be avoided due to high and rising resistance of s. pneumoniae. furthermore, moderate macrolide resistance in m. pneumoniae has now been reported with analysis for resistant mutation genes [ ] . amoxicillin/clavulanic acid maybe preferable to cover β-lactamase strains of h. influenzae and m. catarrhalis in the elderly and subjects with copd or chronic bronchitis. patients admitted to hospital for moderate-severe cap, not requiring icu care, can be treated with a β-lactam monotherapy [commonly ceftriaxone] but amoxicillin/clavulanic acid can be used or respiratory quinolone orally. whenever pneumococcus is shown to be the etiologic agent, penicillin should be used as there is no evidence that the outcome is adversely affected for penicillin nonsusceptible [relative resistance] strains in cap even with bacteremia. in patients with severe cap requiring icu care, a β-lactam [ceftriaxone] with a macrolide or a quinolone alone is suitable. in this setting, the macrolide is used for l. pneumophila infection until this organism can be excluded. severe cap has a high mortality [about %] despite adequate antibiotic therapy, thus adjunctive therapy has been studied and used empirically to try and improve the outcome. combination with a macrolide for macrolide-resistant bacteria is a form of adjunctive therapy. comparative studies on the inflammatory response of patients with severe and non-severe cap can be useful to guide adjunctive therapy. in one such study, the severe cap group showed higher plasma levels of pro-and anti-inflammatory cytokines but in contrast, lower sputum concentration of proinflammatory cytokines [ ] . moreover, neutrophils from severe cap patients showed reduced respiratory burst activity compared to the non-severe group. these results indicate that patients with severe cap fail to mount a robust local inflammatory response but instead produce a heightened systemic inflammatory response [ ] . it has been suggested that statins, primarily indicated for dyslipidemia and cardiovascular disease, have modulation effects on the cytokine cascade and could be useful in severe cap. in a previous review of the immunomodulatory effects of statins in cap, experimental and clinical studies were identified [ ] . statins attenuated pulmonary inflammation by reducing cytokine release and expression, modulating neutrophil function, and by protecting against disruption of lung integrity. observational studies suggested a decrease in mortality due to cap in current statin users but randomized studies are lacking [ ] . a randomized, double-blind, placebo-controlled trial of simvastatin for cap was initiated in spain but was terminated after enrolling patients because of slow enrolment [ ] . however, after h of statin, there was no difference in concentrations of cytokines compared to patients on placebo. thus, the benefit of statins in cap remains unknown. corticosteroids [steroids] have been studied for its anti-inflammatory effect in severe cap in an attempt to reduce mortality, ards and need for mechanical ventilation and icu care with inconclusive results. although steroids have been shown to improve outcome and decrease risk of respiratory failure in pneumocystis pneumonia, it failed to improve outcome in a major, definitive randomized controlled trial in patients with all cause sepsis [ ] . in a previous review of this topic in , it was concluded that steroids should not be used in cap because of insufficient evidence of the beneficial effect and potential harm [ ] . since then, two other randomized, placebo-controlled trials of adjunct steroids in cap have been reported. the first study from spain randomized patients to intravenous methylprednisolone or placebo for days. there was less early treatment failure [composite end . adjunctive therapy for severe cap points defined by the study] in the steroid treated group but no difference in mortality [ ] . the second study from switzerland randomized patients to either prednisone mg daily or placebo for days. prednisone shortened the time to clinical stability by about . days without an increase in complications but did not improve mortality [ ] . in the past - years four systematic reviews and meta-analyses of the value of steroids in cap have been published. in the first report, ten randomized controlled trials [rct] with cases of hospitalized cap were reviewed. mortality was decreased in the severe-case subgroup and patients requiring icu care. length of icu decreased by . days and length of hospital stay by day [ ] . in the second review in , trials were included with patients and concluded that steroids may reduce mortality by %, need for mechanical ventilation by %, and hospital stay by day [ ] . were included in the analysis. steroids treatment was associated with reduced ards and reduced length of icu stay but no effect on mortality [ ] . none of the four studies found significant adverse events with steroids except for hyperglycemia. in moderate-severe cap adjunctive macrolide is not beneficial. further randomized studies are still needed for the more severe cases at risk for icu management. steroids may be beneficial to reduce mortality, ards and mechanical ventilation for the severe cap but the results are not conclusive. thus, it would be premature to use steroids routinely in severe cap, pending larger rct in this subgroup of patients admitted to hospital. in the most recent review and meta-analysis of steroids in hospitalized patients with cap, with analysis of cases from six trials, steroids reduced time to clinical stability and length of hospital stay by day but did not reduce mortality and increased risk of hyperglycemia and cap-related rehospitalization [ ] . the state of the art is reminiscent of the data of steroids in sepsis/septic shock, when steroids appeared to be effective in reducing mortality based on small rcts but was proven ineffective in larger, definitive trials. at least three large trials registered on clinical trials.gov are expected to enroll a total of patients and are scheduled for completion by october will provide more definitive data on the use of steroids in cap. future trials should investigate the effect of adding nonsteroidal anti-inflammatory agents [nsaids] for the treatment of cap. in a recent open randomized trial from hong kong, patients hospitalized with severe influenza a [h n ] with pulmonary infiltrates had significantly lower -day mortality and shorter hospital stay after treatment with naproxen-clarithromycin [ days] + oseltamivir than oseltamivir, both groups received beta-lactam antibiotics [ ] . in the past - years, marked reductions in the total burden and mortality of pneumonia in children < years of age have occurred worldwide. this has been attributed to a number of factors, improved healthcare and social-economic conditions in low earning countries, and major contribution due to increased vaccination against measles, pertussis, s. pneumoniae and h. influenzae type b with conjugate vaccines. however, similar reduction in cap has not been realized in adults. smoking cessation may reduce the risk of cap in chronic smokers but permanent cessation is difficult to achieve. the world health organization estimates that > billion of the world's population smoke and smoking is a strong risk factor for invasive pneumococcal disease and bacterial pneumonia [ ] . in most temperate countries peak incidence of cap occurs in the winter during the peak influenza season. thus universal yearly influenza vaccination may decrease the incidence of cap in children and adults for influenza and bacterial pneumonia. previous studies have shown that influenza vaccination is effective in preventing hospitalization for acute respiratory illness associated with confirmed influenza. estimates ranged from % to % among children, % to % among all adults, and % to % for adults years or older [ ] [ ] [ ] [ ] . however, most of these studies did not specifically assess the effect of influenza vaccination on the prevalence of cap. in a prospective observational multicenter study of hospitalization for cap over . years in four us sites, patients were hospitalized for cap. among children and adults, only those with confirmed influenza-associated pneumonia had lower odds of having received influenza vaccine [ ] . indicating that influenza vaccination reduces cap from influenza complication, including secondary bacterial pneumonia. the introduction of the -valent and subsequent -valent s.pneumoniae conjugate vaccine [pcv ] in children in resource-rich countries has resulted in the decline of pneumococcal pneumonia in children and adults as well, through herd protection [ ] . the -valent pneumococcal polysaccharide vaccine [ppv ] has been available for > years and is recommended in many countries for high-risk patients, but its efficacy in preventing cap is debatable. three recent reviews and meta-analysis of the benefit of ppv in preventing pneumococcal cap in adults have been published with inconsistent conclusions. one review found no proof that ppv can prevent pneumococcal cap in the elderly population [ ] . another study reviewed seven randomized trials involving , subjects and concluded that the ppv vaccine provided weak protection against all cause pneumonia [ ] . the third review, however, reported that ppv vaccine effectiveness in preventing invasive pneumococcal disease was % for cohort studies and % for case-control studies [ ] . but lower for prevention of cap, % reduction in trials, % for case-control studies and % effectiveness for cohort studies. however, the conjugate vaccine appears to be more effective in adults. in a large placebo-rct involving , adults years of age and older, the community-acquired pneumonia immunization trial in adults [capita], the pcv vaccine was assessed [ ] . the vaccine efficacy in preventing vaccine-type pneumococcal cap was . % and % in preventing invasive pneumococcal disease, but not effective in preventing cap from any cause. more effective treatment is clearly needed for smoking cessation worldwide to prevent lung cancer, cardiovascular disease, copd and many associated cancers and illnesses, including possible cap. although universal annual influenza vaccination is now recommended for children and adults, the rate of vaccination in all countries 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case-control study vaccine effectiveness against laboratoryconfirmed influenza hospitalization among elderly adults during the - season association between hospitalization with community acquired laboratory-confirmed influenza pneumonia and prior receipt of influenza vaccination impact of infant -valent pneumococcal conjugate vaccine on serotypes in adult pneumonia efficacy of ppv in preventing pneumococcal pneumonia in adults at increased risk---a systematic review and meta-analysis efficacy of -valent pneumococcal polysaccharide vaccine in preventing community-acquired pneumonia among immunocompetent adults: a systematic review and meta-analysis of randomized trials the effectiveness of pneumococcal polysaccharide vaccine [ppv ] in the general population of years of age and older: a systematic review and meta-analysis polysaccharide conjugate vaccine against pneumococcal pneumonia in adults key: cord- - aotgq m authors: monard, céline; pehlivan, jonathan; auger, gabriel; alviset, sophie; tran dinh, alexy; duquaire, paul; gastli, nabil; d’humières, camille; maamar, adel; boibieux, andré; baldeyrou, marion; loubinoux, julien; dauwalder, olivier; cattoir, vincent; armand-lefèvre, laurence; kernéis, solen title: multicenter evaluation of a syndromic rapid multiplex pcr test for early adaptation of antimicrobial therapy in adult patients with pneumonia date: - - journal: crit care doi: . /s - - -y sha: doc_id: cord_uid: aotgq m background: improving timeliness of pathogen identification is crucial to allow early adaptation of antibiotic therapy and improve prognosis in patients with pneumonia. we evaluated the relevance of a new syndromic rapid multiplex pcr test (rm-pcr) on respiratory samples to guide empirical antimicrobial therapy in adult patients with community-acquired pneumonia (cap), hospital-acquired pneumonia (hap), and ventilator-acquired pneumonia (vap). methods: this retrospective multicenter study was conducted in four french university hospitals. respiratory samples were obtained from patients with clinical and radiological signs of pneumonia and simultaneously tested using conventional microbiological methods and the rm-pcr. a committee composed of an intensivist, a microbiologist, and an infectious diseases specialist retrospectively assessed all medical files and agreed on the most appropriate antimicrobial therapy for each pneumonia episode, according to the results of rm-pcr and blinded to the culture results. the rm-pcr-guided antimicrobial regimen was compared to the empirical treatment routinely administered to the patient in standard care. results: we included pneumonia episodes. most patients were hospitalized in intensive care units (n = , %), and episodes were hap (n = , %), cap (n = , %), and vap (n = , %). conventional culture isolated ≥ microorganism(s) at significant level in ( %) patients. the syndromic rm-pcr detected at least one bacteria in ( %) episodes. based on the results of the rm-pcr, the multidisciplinary committee proposed a modification of the empirical therapy in ( %) pneumonia episodes. the modification was a de-escalation in ( %), an escalation in ( %), and undetermined in ( %) patients. in microbiologically documented episodes (n = ), the rm-pcr increased appropriateness of the empirical therapy to ( %), as compared to ( %) in routine care. conclusions: use of a syndromic rm-pcr test has the potential to reduce unnecessary antimicrobial exposure and increase the appropriateness of empirical antibiotic therapy in adult patients with pneumonia. inadequate and delayed empirical treatments are strong predictors of mortality in sepsis [ , ] . therefore, in pneumonia patients, international guidelines state that an attempt should be made to obtain respiratory samples and recommend to start early empirical treatment while awaiting for the results of culture and antimicrobial susceptibility testing (ast) [ ] . for severe patients or those with risk factors of multidrug-resistant organisms (mdro), the empirical treatment should include a broad-spectrum antibiotic [ , ] . however, conventional microbiological techniques have a low sensitivity, particularly on microbiological samples collected in non-intubated patients and in case of prior exposure to antibiotics [ , ] . the lack of a reliable microbiological diagnosis thus prevents from deescalating the empirical regimen in a large proportion of patients [ ] . identification of causative microorganisms provides the potential to target antibiotic therapy, but the turnaround time from microbiological sampling to ast usually requires at least h. new molecular diagnostic tools aim at shortening this time. syndromic rapid multiplex pcr (rm-pcr) can be used for simultaneous detection of multiple organisms and resistance markers in a specific clinical context, within a few hours [ ] . alongside with antimicrobial stewardship (ams), the use of rm-pcr has been shown to significantly decrease time-to-appropriate therapy and optimize clinical and economic outcomes [ , ] . during a previous evaluation in community-acquired pneumonia, a rm-pcr assay achieved pathogen detection in % of patients compared to % using culture-based methods [ ] . in addition, in this population, molecular testing had the potential to lead to a de-escalation in the number and/or spectrum of initial empirical antibiotics in % of patients. the biofire® filmarray® pneumonia panel (biomerieux s.a., marcy-l'etoile, france) is a novel assay able to simultaneously identify of the most common pathogens involved in lower respiratory tract infections (semi-quantitative results for gram-negative and gram-positive bacteria, qualitative results for atypical bacteria and viruses) as well as antibiotic resistance genes (fig. ) . two studies have found excellent agreement between this molecular method and standard culture [ , ] . our main objective was to estimate the potential impact of this new syndromic rm-pcr assay on early adaptation of empirical antimicrobial therapy in adult patients with pneumonia. between july and december , french university hospitals participated in a pre-commercialization evaluation of the investigative-use-only (iuo) version of the rm-pcr biofire® filmarray® pneumonia panel (biomerieux s.a., marcy-l'etoile, france). a total of respiratory samples (sputa, endotracheal aspirations (eta), blind bronchial sampling (bbs), and bronchoalveolar lavages (bal)) were tested simultaneously, using conventional techniques and the rm-pcr. the syndromic rm-pcr demonstrated high agreement with conventional culture in this panel of patients [ , ] . four centers (bichat-paris, cochin-paris, rennes, and lyon) were further selected to participate in the present sub-study. criteria for patient inclusion were as follows: ( ) age ≥ years and ( ) presence of clinical and radiological criteria for pneumonia according to the idsa guidelines: new lung infiltrate on a chest x-ray and evidence that the infiltrate was of an infectious origin, i.e., at least two of three clinical features (fever greater than °c, leukocytosis or leukopenia, and purulent secretions) [ ] . criteria for pneumonia were evaluated by two clinical investigators in each center. communityacquired pneumonia (cap), hospital-acquired pneumonia (hap), and ventilator-associated pneumonia (vap) were included. hap was defined as pneumonia occurring h or more after admission, which was not incubating at the time of admission and not associated with mechanical ventilation [ ] . vap referred to pneumonia arising > h after endotracheal intubation [ , ] . cap included all episodes of pneumonia acquired outside of the hospital setting. even if not strictly included in the most recent definition of cap [ ] , we also included patients with immunocompromising conditions. respiratory specimens were routinely analyzed in each local microbiology laboratory according to current recommendations of the french standard guidelines in medical microbiology (remic) [ ] . in brief, sputum and eta samples were digested and diluted according to sample types. then, they were streaked on recommended plates according to semi-quantitative patterns and incubated for days in co and aerobic conditions. results of standard culture were expressed in colony-forming unit (cfu)/ml. the thresholds for positivity on culture were ≥ cfu/ml for bbs, ≥ cfu/ml for bal, ≥ cfu/ml for eta, and ≥ cfu/ml for sputa [ ] . diagnostic tests for viruses and atypical bacteria were conducted only if requested by the physician in charge. respiratory samples were simultaneously tested with the iuo version of the biofire® filmarray® pneumonia panel according to the manufacturer's instructions directly on native respiratory samples. the iuo version is identical to the final fda-cleared and ce-marked version. the system integrates sample preparation, nucleic acid extraction and purification, amplification, detection, and analysis, with a total run time of about h. results of the syndromic rm-pcr are expressed as semiquantitative results ( to ≥ ) in dna-copies/ml for commonly culturable bacteria and as qualitative results (presence/absence) for resistance genes, viruses, and atypical bacteria. bacteria found under the threshold of . copies/ml are not reported on the final rm-pcr report. clinical and demographical data were retrospectively obtained from the electronic medical records of each patient. investigators collected demographic characteristics (age, gender) and medical data such as medical history, classification of pneumonia (vap, hap, or cap), severity scores, and antibiotics prescribed. in each study center, a multidisciplinary committee composed of an intensivist, an infectious diseases specialist, and a clinical microbiologist was formed. during a face-to-face meeting, the local multidisciplinary committee retrospectively reviewed medical files of all pneumonia patients, including patients' medical history, previous antimicrobial treatments received, previous microbial colonization and risk factors for mdro carriage, clinical parameters (e.g., fever, hemodynamics, and respiratory parameters), results of standard biological analyses, and chest imaging. for each episode, the result of the syndromic rm-pcr was presented to the committee, blinded to ( ) the direct examination of the sample, ( ) the results of the standard culture and ast, and ( ) the empirical therapy administered in routine care. guided by the rm-pcr results, the multidisciplinary committee agreed on the most appropriate antimicrobial therapy for each pneumonia episode. the antimicrobial therapy proposed by the multidisciplinary committee based on syndromic rm-pcr results (pcr-guided therapy) was compared to the empirical therapy actually delivered to the patient in routine care (empirical therapy). the primary endpoint was the number of pneumonia episodes in which pcr-guided therapy differed from empirical therapy. the secondary endpoints were as follows: ( ) the number of de-escalations of the antibiotic regimen based on syndromic rm-pcr results and ( ) the number of episodes in which pcrguided therapy would be active on pathogens isolated at significant threshold on culture. both primary and secondary endpoints were evaluated by an independent central committee composed of an intensivist and an infectious disease specialist from two different university hospitals (sk and cm). de-escalation was defined according to previous studies as discontinuation of any companion drug and/or switch of the pivotal drug to a narrower-spectrum antibiotic [ , ] . ranking of pivotal drugs was determined according to their antibacterial spectrum and putative ecological impact and defined either within the same antibiotic family or from a family to another (e.g., vancomycin to oxacillin). β-lactams were categorized into six groups, as previously described by weiss et al. [ ] (fig. ) . in several cases (e.g., switch from piperacillin/tazobactam to a fourth-generation cephalosporin), as hierarchy of antibiotics could not be established, the antibiotic change was qualified as "undetermined." if a companion drug was stopped but a new one was started, the antibiotic change was also considered as "undetermined." definitive results of standard culture and ast were considered by the central committee to state on the susceptibility of pathogens to the pcr-guided therapy. this secondary endpoint was evaluated only in microbiologically documented pneumonia episodes. only pathogenic microorganisms cultured at significant levels on culture were considered as documentation. coagulase-negative staphylococci (cons) and enterococcus spp. were considered as non-pathogenic. all data were anonymously collected and stored on a secured database. descriptive analysis was performed using the r software ( . . , r foundation for statistical computing, vienna, austria). due to relatively small numbers and the retrospective design of our study, we did not perform a formal statistical analysis, but rather present the description of data. for each variable, when data were missing, they were excluded from the calculation of percentages. according to the french legislation, this study was approved by the ethics committee of the french society of infectious diseases (société de pathologie infectieuse de langue française), n° - , and declared to the french national data protection commission (commission nationale de l'informatique et des libertés, cnil), n° - . among pneumonia episodes included in the precommercialization evaluation in the four investigating centers, were retained for final analysis. exclusion criteria were as follows: age < years (n = ) and criteria for pneumonia not fulfilled (n = ). a total of patients ( %) were hospitalized in intensive care units (icus) at inclusion, and their median [iqr] sofa score was [ . - . ]. overall in-hospital mortality was % ( / ). pneumonia episodes were classified as hap (n = , %), cap (n = , %), and vap (n = , %). microbiological samples were as follows: eta (n = , %), sputum samples (n = , %), bal (n = , %), and bbs (n = , %). other demographic data are reported in table . conventional culture isolated ≥ microorganism(s) at significant level in episodes ( %): / ( %) in cap, / ( %) in hap, and / ( %) in vap. the syndromic rm-pcr detected at least one bacteria in ( %) episodes; a viral co-infection was detected in episodes and a virus without bacteria in episodes. among the undocumented episodes on culture, the syndromic rm-pcr identified a microorganism in episodes (bacteria in episodes and viruses in episodes). the main pathogens identified on culture were gramnegative bacilli (escherichia coli ( ), pseudomonas aeruginosa ( ), enterobacter cloacae complex ( ), klebsiella pneumoniae ( ), haemophilus influenzae ( )) and gram-positive cocci (staphylococcus aureus ( ), streptococcus pneumoniae ( )) ( table ) . results of the microbiological analyses according to sample type are described in the supplementary material (supplementary table ). multiple microorganisms were detected in % of episodes using culture and % using the syndromic rm-pcr method. no influenza virus was found, neither using standard methods nor the syndromic rm-pcr. the syndromic rm-pcr identified antibiotic resistance genes: bla ctx-m and meca/c-mrej genes. all pathogens identified as harboring an extended-spectrum β-lactamase on ast (n = ) were found positive for the bla ctx-m by the rm-pcr. the staphylococcus aureus strains resistant to methicillin on ast were detected by the rm-pcr, which detected more methicillin-resistant staphylococcus aureus strains that were not found on culture. six enterobacteriaceae probably had an overproduction of ampc β-lactamase, which could not be detected by the rm-pcr. the empirical therapy included a β-lactam in ( %) pneumonia episodes: third-generation cephalosporin (n = , %), amoxicillin/clavulanate (n = , %), piperacillin/tazobactam (n = , %), or fourth-generation cephalosporin (n = , %), and carbapenems (n = , %). a companion molecule was prescribed in ( %) episodes: mainly macrolides (n = , %), imidazoles (n = , %), and aminoglycosides (n = , %; table ). based on the results of the rm-pcr, the multidisciplinary committee proposed a modification of the routine empirical therapy in ( %) pneumonia episodes: deescalation in ( %) and escalation in ( %; table ). the proportion of antibiotic modifications was higher in vap ( / , %), as compared to hap ( / , %) and cap ( / , %). de-escalation consisted in change of the pivotal drug to a narrower spectrum antibiotic (n = , %) and/or discontinuation of a companion drug (n = , %), or discontinuation of all antibiotics (n = , %). sputum samples were associated with less antimicrobial modifications ( / , %) compared to other sample types ( / , %; / , %; / , %; for eta, bal, and bbs respectively). modifications in the sputum group were escalation and de-escalation in the same number of cases, whereas there was more de-escalation compared to escalation in the other type of samples (supplementary table ). in microbiologically documented episodes (n = ), pathogens were susceptible to the empirical therapy in ( %) episodes and to the pcr-guided therapy in ( %) episodes. the proportion of the empirical and pcr-guided therapies that were active on the documented pathogens did not statistically differ between cap, hap, and vap (data not shown). when the pcrguided therapy differed from the empirical therapy, pathogens were susceptible to pcr-guided therapy in % [ / ] of the de-escalations and % [ / ] of the escalations. for ( %) patients, the pcr-guided therapy was active against documented pathogens, whereas the empirical routine therapy was non-active. conversely, patients had an active empirical therapy, and the multidisciplinary committee proposed a non-active pcr-guided therapy. in patient, the syndromic rm-pcr was negative and the committee proposed to discontinue antibiotics, whereas standard culture grew up cfu/ml morganella morganii (not included in the panel). of note, gram-negative bacilli were identified on direct examination of the respiratory sample (bal), but this information was not considered by the multidisciplinary committee. in other patients treated with fourth-generation cephalosporin as empirical therapy, the committee proposed a treatment with piperacillintazobactam. these patients had a syndromic rm-pcr positive for enterobacter cloacae complex confirmed by culture, consequently found resistant to piperacillintazobactam due to overexpression of the naturally produced ampc β-lactamase. the fourth patient was empirically treated with ceftolozane-tazobactam, and the committee proposed to treat him with ceftazidime. both syndromic rm-pcr and conventional culture identified pseudomonas aeruginosa, which was phenotypically confirmed as resistant to ceftazidime. of note, this patient was already known to be colonized with a p. aeruginosa of this particular phenotype. details on all inadequate antibiotic therapies (either empirical or pcr-guided) are available in the supplementary material (supplementary table ). acinetobacter calcoaceticus-baumannii complex -- legionella pneumophila -- conventional techniques include culture for all pathogens presented, apart from legionella pneumophila which was detected using molecular techniques. only pathogens cultured at pre-defined levels are presented (≥ cfu/ml for blind bronchial sampling, ≥ cfu/ml for bronchoalveolar lavage, ≥ cfu/ml for endotracheal aspiration, and ≥ cfu/ml for sputum samples) a immunosuppression was defined as leucopenia < giga/l, hiv infection, history of solid organ or stem cell transplantation, and immunosuppressive treatment including corticosteroids over mg/day of equivalent prednisone for more than days b chronic pulmonary condition included patients with history of chronic obstructive pulmonary disease, severe bronchiectasis, cystic fibrosis, and chronic respiratory insufficiency overall, as described in table , compared to routine empirical therapy, the syndromic rm-pcr would have theoretically led to avoid prescriptions of β-lactams in this retrospective multicenter study, a syndromic rm-pcr approach with semi-quantitative results had the potential to lead to a change in empirical antimicrobial therapy in % of pneumonia episodes in adult patients. the most frequent intervention was a de-escalation, which occurred in almost half of the patients. using standard culture and ast as the reference method, pcr-guided antibiotic treatment was more frequently adequate when compared to the empirical treatment. as observed in previous studies, microbiological documentation was almost twice as high using the rm-pcr compared to the standard method [ ] . if this higher sensitivity is an advantage for patients treated with antibiotics prior to sampling, it also implies a very cautious interpretation of results. the test might detect nucleic acids from pseudomonas aeruginosa enterobacter cloacae complex klebsiella pneumoniae group acinetobacter calcoaceticus-baumannii complex enterobacter aerogenes serratia marcescens proteus spp. moraxella catarrhalis klebsiella oxytoca gram-positive cocci streptococcus pneumoniae streptococcus pyogenes streptococcus agalactiae legionella pneumophila mycoplasma pneumoniae chlamydophila pneumoniae resistance meca targets not included in the rm-pcr panel citrobacter sp. others* -conventional techniques include culture for all pathogens presented, apart from legionella pneumophila which was detected using molecular techniques rm-pcr real-time multiplex polymerase chain reaction *acinetobacter junii (n = ), actinomyces odontolyticus (n = ), corynebacterium sp. (n = ), coagulase-negative staphylococcus (n = ), enterococcus faecium (n = ), enterococcus faecalis (n = ), lactobacillus reuteri (n = ), streptococcus alpha (n = ), streptococcus pseudopneumoniae (n = ) in the present report, we did not evaluate the correlation between culture quantification (in cfu/ml) and molecular semi-quantification (in dna copies/ml). this question is currently under investigation [ ] . meanwhile, clinicians should be aware that molecular diagnosis is highly sensitive and the use of thresholds established for conventional culture to guide interpretation of the rm-pcr is not straightforward and may lead to misinterpretation. it should also be kept in mind that even if it detects a large panel of microorganisms, the test is not exhaustive and several important pathogens (such as morganella spp., citrobacter spp., hafnia alvei, stenotrophomonas maltophilia, or pneumocystis jirovecii) are not included. the same issue can be raised for the resistance genes, especially esbl-encoding genes for which only the most frequent ones (i.e., bla ctx-m ) are included in the panel. thus, when a pathogen is identified by the test, the absence of resistance genes does not predict with certainty its phenotypic susceptibility. when a gene encoding for a resistance marker is detected alongside with different bacteria, it is not possible to link the resistance to one of the detected microorganisms. also, overexpression of intrinsic resistance genes (such as ampc β-lactamase) is not detected by the panel. from this perspective, rm-pcr should not be considered as a sufficient diagnostic test for pneumonia but rather as a complementary tool in adjunction to standard culture and ast, to allow for an earlier pathogen-directed therapy. multidisciplinary discussion of the results is a prerequisite for optimal use. in our experience, the rare errors ( over episodes) in the choice of pcr-guided therapy were linked to ( ) amp-c overproduction in enterobacter sp. in cases, ( ) isolation of pathogens not included in the panel (i.e., morganella morganii) in case, and ( ) isolation of a multi-drug-resistant p. aeruginosa (that was previously isolated in this particular patient) in case. in this last case, it is important to note that interpretation of the rm-pcr in light of the previous microbial documentation could have prevented this error. our intervention was based on a multidisciplinary approach with physicians from different specialties interpreting the results of the rm-pcr together and agreeing on an optimal therapy. the success of this approach is concordant with previous studies where strategies combining rapid diagnostic testing and ams interventions in bloodstream infections showed a significant and synergistic impact on early antibiotic de-escalation, mortality, and costs [ ] [ ] [ ] [ ] . moreover, implementation of ams programs, led by dedicated multidisciplinary teams, is strongly encouraged to improve the quality of antibiotic prescriptions [ ] [ ] [ ] . interestingly, the use of rapid diagnostic tests without active ams intervention failed to provide the expected benefits in patients [ , [ ] [ ] [ ] . it is uncertain whether the same results would have been observed if only one clinician, non-expert of the diagnostic methods, had to choose alone a therapy guided by the rm-pcr results. another strength of the present study is its multicenter character, as it improves the generalizability of the results, but also because the multidisciplinary committees were local and therefore aware of the ecology of their hospitals. the present study presents some limitations. its retrospective and observational design did not allow comparison of clinical outcomes with the rm-pcr versus standard treatment approach. second, although we included a large panel of pneumonia patients (severe icu patients with vap or hap and non-severe cap patients from the emergency room), it remains unclear what group of patients will benefit most from the syndromic rm-pcr diagnosis. further studies should evaluate this new test in more selected groups of patients. however, most patients herein were severe patients hospitalized in icus with complicated microbiological histories, and results suggest the rm-pcr could help to choose the antimicrobial treatment even in this particular group of results are presented as n (%) cap community-acquired pneumonia, hap hospital-acquired pneumonia, vap ventilator-associated pneumonia patients. also, even if we tried to give the multidisciplinary committee as much information as needed to choose the antibiotic treatment, in some cases, important data may have been missing. as an example, this might explain why the clinician chose a ceftolozane-tazobactambased treatment for a patient with a past history of infection with piperacillin-tazobactam-resistant p. aeruginosa, whereas the committee decided to use piperacillintazobactam despite identification of p. aeruginosa by the rm-pcr. again, this reinforces the necessity to carefully interpret the rm-pcr report, in light of the clinical and historical microbiological data. in our panel of cap patients, only half had microbiological documentation on conventional culture. this is in accordance with previous studies that highlighted a low rate of documentation in cap, due to difficulties to obtain contributive microbiological samples and to previous exposure to antibiotics [ ] . in the cap patients with positive microbiology results, we identified pathogens frequently involved in cap (staphylococcus aureus, haemophilus influenzae, streptococcus pneumoniae) and gram-negative bacilli ( escherichia coli, pseudomonas aeruginosa, klebsiella pneumoniae, enterobacter sp., raoultella). the number of gram-negative bacteria isolated is likely related to the profile of patients included in our study. indeed, all participating centers were tertiary university hospitals, referral centers for specific comorbidities as highlighted in table : among cap patients, % had chronic respiratory conditions and % immune suppression. the gold standard used herein for microbiological diagnosis was culture with ast. in certain cases, the syndromic rm-pcr detected pathogens that were not detected by culture. this finding questions the choice of culture as the gold standard for microbial identification, notably in case of antibiotic treatment before sampling. because the molecular diagnostic methods are probably more sensitive than cultures, the present results would have been even more favorable for pcr-guided therapy if we had also considered as documentation the organisms identified by rm-pcr and not by culture. as an example, one patient had a staphylococcus aureus ( copies/ml), a moraxella catarrhalis ( copies/ ml), and a meca/c-mrej gene found by rm-pcr while the culture remained negative and was therefore considered as "undocumented." also, because two thirds of our samples were non-protected (eta and sputum), this could have led to an over-identification of bacteria [ ] . however, since we used the culture and validated the significance thresholds for interpretation, this bias was minimized. the high proportion of non-invasive samples reflects the heterogeneity of practices between icus and is consistent with the idsa guidelines which suggest noninvasive sampling with semi-quantitative cultures to diagnose vap, rather than invasive sampling [ ] . many questions regarding the syndromic rm-pcr still remain unanswered and should be addressed in future evaluations. the cost-effectiveness ratio of the syndromic rm-pcr needs to be evaluated in order to justify its use in particular subgroups of patients. to date, no studies addressed this medico-economic outcome in lower respiratory tract infections, but a syndromic rm-pcr developed for the higher tract respiratory infections was found to decrease the length of hospital stay, duration of antibiotic therapy, and time in isolation, therefore decreasing related costs [ , ] . as previously discussed, thresholds for interpretation of rm-pcr results cannot be directly derived from those established for culture and must be more precisely defined. because of these limits, physicians should be aware of the test's drawbacks and the present results highlight the need for a close cooperation between infectious disease specialists, clinical microbiologists, and clinicians for the interpretation of results. we also suggest that the results of the test should be included in a decision algorithm, alongside with the suspected pathogens, the history of the patient, and their personal risk factors for mdro infection. we recommend that decision regarding antibiotic treatment based on rm-pcr results should consider clinical presentation, local epidemiology, direct smear of the sample, and historical microbiological data in each patient. as a guidance for use in clinical practice and based on our experience, we may recommend to ( ) consider the semi-quantitative result regarding the type of sample, in order to discriminate between colonization and infection (future results should be available soon to precise the significance thresholds); ( ) if a microorganism is identified and thought to be pathogenic, the antimicrobial therapy should be chosen considering colonization of the patient, previous microbial documentations, and risk factors for mdro; ( ) if a pathogen of the group is detected, an amp-c overproduction cannot be excluded and therefore treatment with cefepim or meropenem should be considered; ( ) oseltamivir should not be prescribed in the absence of influenza detection; ( ) a companion molecule such as macrolide could be discontinued for community-acquired pneumonia without identification of atypical bacteria; and ( ) identification of a resistance gene should always be considered. to date, the rm-pcr should not be considered as a sufficient diagnostic test for pneumonia but rather as a complementary tool in adjunction to standard culture and ast, to allow for an earlier pathogen-directed therapy. controlled randomized trials evaluating the impact of rm-pcr on patient's outcomes are currently ongoing, and their results will be of major help to precise the impact of the rm-pcr on infection control, length of stay, and resistance selection. results suggest that early use of rm-pcr in pneumonia could reduce unnecessary antimicrobial exposure without compromising the appropriateness of the treatment. together with an expert advice, this promising diagnostic tool could improve the quality of care and participate in the reduction of broad-spectrum antimicrobial agents' use. prospective randomized controlled trials are needed to confirm these results, identify categories of patients that would most benefit from the test, and define precise guidelines to appropriately adjust the empirical therapy based on the results. supplementary information accompanies this paper at https://doi.org/ . /s - - 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pneumonia [abstract p guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia diagnosis and treatment of adults with community-acquired pneumonia. an official clinical practice guideline of the recommendations by the european committee on antimicrobial susceptibility reading eucast available at nosocomial bronchopneumonia in the critically ill. histologic and bacteriologic aspects impact of de-escalation of beta-lactam antibiotics on the emergence of antibiotic resistance in icu patients: a retrospective observational study antibiotic de-escalation for bloodstream infections and pneumonia: systematic review and meta-analysis elaboration of a consensual definition of de-escalation allowing a ranking of β-lactams randomized trial of rapid multiplex polymerase chain reaction-based blood culture identification and susceptibility testing cumulative effect of an antimicrobial stewardship and rapid diagnostic testing bundle on early streamlining of antimicrobial therapy in gramnegative bloodstream infections integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibiotic-resistant gram-negative bacteremia rapid molecular diagnostic tests in patients with bacteremia: evaluation of their impact on decision making and clinical outcomes implementing an antibiotic stewardship program: guidelines by the infectious diseases society of america and the society for healthcare epidemiology of america human resources estimates and funding for antibiotic stewardship teams are urgently needed antimicrobial resistance and antibiotic stewardship programs in the icu: insistence and persistence in the fight against resistance. a position statement from esicm/escmid/waaar round table on multi-drug resistance introduction of rapid methicillin-resistant staphylococcus aureus polymerase chain reaction testing and antibiotic selection among hospitalized patients with purulent skin infections use of pna fish for blood cultures growing gram-positive cocci in chains without a concomitant antibiotic stewardship intervention does not improve time to appropriate antibiotic therapy assessment of impact of peptide nucleic acid fluorescence in situ hybridization for rapid identification of coagulase-negative staphylococci in the absence of antimicrobial stewardship intervention impact of quantitative invasive diagnostic techniques in the management and outcome of mechanically ventilated patients with suspected pneumonia impact of a rapid respiratory panel test on patient outcomes routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (respoc): a pragmatic, open-label, randomised controlled trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank all research teams and laboratory teams that participated in the study in each center. the authors thank philip robinson/verena landel for participating in manuscript preparation. the authors thank all the members from the adapt study group: agathe becker, julien charpentier, julien textoris, claude-alexandre gustave, grégory destras, françois vandenesch, bruno lina, jean sebastien casalegno, manon lejeune, philippe montravers, claire poyart, hugo tête, jean-françois timsit, and thomas uberti. authors' contributions cm and sk elaborated the study protocol, had full access to all of the data, did the analysis, and take responsibility for the integrity of the data and the accuracy of the data analysis. cm, od, vc, lal, and sk drafted the paper. all authors critically revised the manuscript and gave final approval for the version to be published. not applicable. the datasets used during the current study are available from the corresponding author on reasonable request. according to the french legislation, this study was approved by the ethics committee of the french society of infectious diseases (société de pathologie infectieuse de langue française), n° - , and declared to the french national data protection commission (commission nationale de l'informatique et des libertés, cnil), n° - . competing interests biomerieux sa provided iuo tests for the study. biomerieux sa did not interfere with data collection and analysis, nor with manuscript preparation. dr. julien textoris participated in the elaboration of the protocol. sk declares grants from biomérieux and lecture fees and conference invitations from biomérieux, msd, and accelerate diagnostics. cm received lecture fees from biomerieux sa. atd and ng report no conflicts of interest. vc reports personal fees from accelerate diagnostics, astellas, biomérieux, correvio, curetis, eumédica, menarini, mylan, pfizer, and sanofi. la received lecture fees from pfizer, msd, biocodex, and biomerieux. all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed.author details key: cord- - lews uw authors: haas, andrew r.; marik, paul e. title: community-acquired pneumonia date: - - journal: pharmacology and therapeutics doi: . /b - - - - . - sha: doc_id: cord_uid: lews uw nan community-acquired pneumonia (cap) is an infection of the lung parenchyma acquired outside of hospitals or extended-care facilities. even with the advent of and continuing advances in antimicrobial therapy, cap remains a major health problem in the united states. it is the seventh leading cause of death in the united states, and the number one cause of death from infectious disease. nearly million hospitalizations with an estimated cost of $ billion for therapy alone can be attributed to cap. - these estimates do not factor in the associated costs of lost productivity, rehabilitation, and potential disability. therefore, the health care and economic impact of cap is readily evident. over the last years, our armamentarium to battle pneumonia has expanded dramatically. this expansion in therapeutic options for cap is driven by changes in the pathogenic organisms and the ever-evolving antimicrobial resistance acquired by these pathogens. this chapter provides an overview of cap and recommendations for the use of the various antimicrobial agents available for its treatment. cap development and prognosis is defi ned by the route of infection, host, and microbial factors. identifi cation of the offending organism in cap is important to guide therapy and predict complications and outcomes. unfortunately, even with extensive diagnostic evaluation, the etiologic agent is not identifi ed in as many as % of patients. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] for all patients presenting with cap, streptococcus pneumoniae is the most common pathogen isolated ( fig. - ) and accounts for % to % of cap patients treated on an ambulatory basis, % to % of patients requiring hospitalization, and % to % of patients requiring intensive care unit (icu) admission. , , , other "typical" pathogens that account for cap include the gram-negative coccobacillus haemophilus infl uenzae and the gram-negative diplococcus moraxella catarrhalis. the classically described "atypical" pathogens that cause cap include chlamydia pneumoniae, mycoplasma pneumoniae, and legionella species. the "atypical" moniker is an inaccurate description of the clinical features of the pneumonia associated with these organisms and is retained more as a classifi cation than a specifi c descriptor of the disease process or clinical presentation. mycoplasma pneumoniae has been shown to be the most common of the atypical pathogens and accounts for % to % of outpatient cap and % to % of cap requiring hospitalization. , , chlamydia pneumoniae is more common than legionella species; however, legionella species can lead to rapidly progressive and fatal pneumonia. although % or more of cap can be explained by the previously mentioned organisms, other organisms can be encountered. in certain patient populations, aerobic gram-negative infections (pseudomonas aeruginosa), enteric gram-negative infections, and anaerobic infections must be considered (see box - later). furthermore, it has recently been demonstrated that age greater than alone is a specifi c epidemiologic risk factor for drug-resistant s. pneumoniae (drsp), but not other organisms. , of particular interest and concern in the last several years have been several reports of methicillin-resistant staphylococcus aureus (mrsa) cap. traditionally, mrsa infection and/or pneumonia had been isolated to health care settings or high-risk groups such as intravenous drug abusers; however, since , there have been several reports of severe, fulminant necrotizing mrsa pneumonia in young, healthy individuals without typical risk factors. , in addition, the clinician must also take into consideration any unusual exposure or occupational hazards that would predispose a patient to unusual pathogens such as chlamydia psittaci (birds), coxiella burnettii (ungulates), leptospira species (rats), and francisella tularensis (rabbits). the mortality rate from cap varies dramatically depending on the patient's severity of illness at presentation and underlying comorbid conditions. in the outpatient setting, the mortality rate is less than % to %; however, once patients require hospitalization, the mortality rate approaches %. [ ] [ ] [ ] [ ] [ ] [ ] in more seriously ill patients with bacteremia who require icu admission, the mortality rate can approach more than %. , the presence of underlying comorbid conditions such as chronic obstructive pulmonary disease (copd), asthma, diabetes mellitus, renal insuffi ciency, congestive heart failure (chf), coronary artery disease, malignancy, alcoholism, age greater than years, chronic neurologic disease, and/or chronic liver disease not only can contribute signifi cantly to cap mortality, but also may alter the etiologic organisms underlying the infection (box - ). [ ] [ ] [ ] when cap is strongly suspected on the basis of history, physical examination, and chest radiography, the next critical management decision is whether the patient will require hospital admission. the american thoracic society and infectious disease society of america have defi ned four groups in their management of cap consensus statement , : . outpatients with no prior cardiopulmonary disease or modifying factors . outpatients with cardiopulmonary disease (chf or copd) and/ or other modifying factors (risk factors for specifi c organisms; see box - ) . inpatients, not admitted to the icu, with or without cardiopulmonary disease or modifying factors . icu-admitted patients with or without risk factors for p. aeruginosa these stratifi cation groups were defi ned by the expert panels in order to try to ensure adequate antimicrobial coverage of the most common organisms encountered in each group based on their risk factors and severity of illness. as discussed later in the section on treatment recommendations for cap, there are specifi c organisms of concern for each group. the diffi culty with this stratifi cation system is the lack of an objective quantifi cation of severity of illness to predict if a patient needs inpatient versus outpatient care or general medical admission versus icu admission. therefore, more recently, many groups have attempted to apply multivariate analyses to patients' objective data to predict the need for admission and to ascertain their level of care. two of the most (table - ) . interestingly, these two prediction rules are meant to serve complementary roles as they attempt to identify different patients. the bts rule aims to identify high-risk patients who require not only admission, but icu admission; therefore, it is meant to prevent underestimation of severity of illness. , in contrast, the port rule separates patients into high and low risk of death and is meant to identify patients at low risk of death so as not to overestimate their severity of illness. many investigators have studied the role of these prediction rules in various settings and support the ability of these prediction rules to assist in the triage of patients with cap, [ ] [ ] [ ] [ ] while other studies reinforce that, while these prediction rules may have a role, clinicians still need to use their clinical judgment when stratifying patient care. antimicrobial agents are the cornerstone of treatment in patients with cap. while a randomized, placebo-controlled study in patients with cap has never been performed (nor is one likely to be performed), the overwhelming preponderance of evidence suggests that the timely administration of an antibiotic(s) to which the offending pathogens(s) are sensitive reduces the complications and improves the survival of patients with cap. following its discovery and introduction into clinical medicine, penicillin g was the drug of choice for cap for almost half a century. however, with the recognition that pathogens other than s. pneumoniae may cause cap and with the emergence of drsp, penicillin g is no longer recommended in the management strategy of patients with cap. macrolides, quinolones, and second-and/or thirdgeneration cephalosporins are now considered the antimicrobial agents of fi rst choice in patients with cap. as discussed later, the treatment recommendations depend upon the patient's comorbidities, risk stratifi cation, and treatment setting. resistance to antibiotics has been an increasingly recognized problem in the therapy for cap. many factors contribute to resistance, including overutilization of antibiotics, patient comorbidities, and a higher percentage of the population residing in long-term care facilities. since s. pneumoniae is the most common etiologic agent of cap, resistance to this pathogen is a major concern and increasing problem. according to the tracking resistance in the us today study in (trust- ), % to % of s. pneumoniae has in vitro resistance to penicillin and/or macrolides, . % to ceftriaxone, and . % to levofl oxacin. the current defi nition of "intermediate-level" in vitro resistance to penicillin is a minimum inhibitory concentration (mic) value of . mcg/ ml, while "high-level" in vitro resistance is defi ned by mic values of . mcg/ml. interestingly, when high-level penicillin resistance was nursing home resident + liver disease + congestive heart failure + stroke + renal failure + altered mental status + respiratory rate > breaths/min + systolic blood pressure < mm hg + pulse rate ≥ beats/min + arterial ph < . + blood urea nitrogen > mg/dl + partial pressure of arterial oxygen < mm hg pleural effusion + present, in vitro resistance to cefotaxime ( %), meropenem ( %), erythromycin ( %), and trimethoprim-sulfamethoxazole ( %) was also present. a centers for disease control and prevention study has demonstrated that the breakpoint for clinically relevant resistance to penicillin is a mic value of . mcg/ml. signifi cant controversy exists about the clinical relevance of these in vitro resistance patterns as few clinical failures (in the absence of meningitis) are documented, especially with macrolides and fl uoroquinolones, which are commonly used to treat cap in the outpatient setting. the unanswered question is whether continued use of these antibiotic classes for outpatient management of cap will further push selection pressure and increase the virulence of these in vitro resistant organisms such that clinical treatment failures become more prevalent. although the resistance patterns of s. pneumoniae appear to have changed the greatest, increased antimicrobial resistance is a universal phenomenon of all organisms associated with cap. moreover, it should be noted that resistance patterns vary considerably among geographic areas, and clinicians should be familiar with their local resistance patterns in order to adjust their therapeutic decisions accordingly. the pulmonary vasculature and parenchyma fi lter the entire blood volume; however, not all antibiotics have the same degree of penetration into the lung parenchyma so as to achieve appropriate dose levels for adequate killing and prevention of resistance. with the development of the fl uoroquinolones, effective high levels of lung penetration have been achieved without the development of resistance to treat even those patients with severe pneumonia using a single agent once a day (except those with risk factors for p. aeruginosa). in fact, levels of fl uoroquinolones are greater in the epithelial lining fl uid and alveolar macrophages than in serum. , these agents (levofl oxacin, moxifl oxacin, gatifl oxacin) have excellent antipneumococcal activity as well as activity against gram-positive, gram-negative, and atypical pathogens; thus, they are ideal single agents for many patients, except those with severe cap requiring icu admission. macrolides are another highly effective class of antibiotics with excellent lung and alveolar macrophage penetration and good coverage for gram-positive and atypical organisms. as discussed previously, there has been increasing in vitro s. pneumoniae resistance to macrolides, which has many concerned about the clinical effectiveness of these agents in the years ahead. although vancomycin is not recommended for initial empirical therapy of cap due to adequate antibiotic coverage of drsp and methicillin-sensitive s. aureus with currently recommended agents, in the appropriate patient population (long-term care facility or young healthy individuals with aggressive pneumonia), failure of initial treatment should raise the suspicion of mrsa pneumonia. in these patients, vancomycin therapy has been considered the drug of choice, but recently the question of what constitutes adequate serum levels to provide appropriate lung penetration of vancomycin to treat mrsa has been raised. in this setting, linezolid may have better penetration into lung tissue and be more active against mrsa. , two retrospective analyses of large medicare databases identifi ed that the time between presentation to the hospital and the time to the fi rst antibiotic dose (tfad) is a predictor of patient outcome when patients require hospital admission. these studies demonstrated a % reduction in -day mortality when the tfad was either hours or a more stringent hours. , based on the fi ndings in these two retrospective studies, the national pneumonia project of the centers for medicare & medicaid services has decided that patients (age > ) who require hospitalization should receive antibiotics within hours of hospital presentation as a quality-of-care benchmark for cap. many thirdparty payers have extrapolated these data to all patients presenting to the hospital with cap and have begun to use it for hospital-level public reporting and "pay-for-performance" programs. consequently, much controversy has arisen surrounding the benchmark of hours to tfad. two recent prospective cohort studies of patients admitted to the hospital with cap demonstrated that the delay to tfda was strongly associated with altered mental status, absence of fever and/or hypoxia, lack of infi ltrates on chest radiograph, and increasing age. , since diagnostic uncertainty can be a barrier to tfad, an excessive number of patients will be treated with antibiotics in order to comply with the tfad -hour benchmark, thus leading to the potential for increased antibiotic resistance, costs, and adverse events. investigators in this fi eld believe that the benchmark should be applied to the population from which the data were derived-persons age or older with radiographic evidence of cap and no antibiotic pretreatment. with our understanding that early aggressive antibiotic therapy is one of the cornerstones in management of septic shock, it seems intuitive that early recognition and antibiotic administration for cap could improve outcomes; however, within what time frame and in what populations remain to be determined. this clearly will be an area of intense investigation and debate in the forthcoming years. the traditional therapeutic period for cap had been days of intravenous antibiotics until a study in demonstrated that hours of intravenous antibiotic therapy followed by days of oral therapy had similar outcomes to days of intravenous therapy. this study and several subsequent studies have confi rmed that the conversion from intravenous to oral antibiotics decreases hospital length of stay, costs, and incidence of phlebitis and intravenous line infection without impacting on mortality or outcomes. , the improved pharmacokinetic profi le of newer generation antibiotics due to their high degree of bioavailability, rapid gastrointestinal absorption, and equivalent blood and tissue levels regardless of oral or intravenous administration (particularly the antipneumococcal fl uoroquinolones) has enhanced the ability to treat patients with moderate to moderately severe cap with oral therapy. in fact, several studies have demonstrated that shortcourse high-dose therapy with antibiotics has equivalency to traditional antibiotic regimens with better patient compliance, less cost and fewer adverse events, and a possible reduction in selection pressure for resistance. [ ] [ ] [ ] [ ] interestingly, in a recent randomized trial in the netherlands, patients with mild to moderately severe cap were randomized to days versus days of high-dose ampicillin therapy. there was no difference in clinical success rate or radiographic success at day or day between the two groups. consequently, patients with mild to moderately severe cap requiring hospitalization can likely be treated for much shorter durations than the traditional -to -day time period without an impact on patient outcomes. these shorter durations of therapy would surely represent cost savings, reduce the number of adverse events, and decrease the selection pressure for antibiotic resistance. the conversion from the traditional -week treatment period to much shorter time frames will give some clinicians trepidation of treatment failure, but the data have not demonstrated differences in outcome. therefore, as more data become available, clinicians should strongly reconsider shorter treatment courses for cap. in this patient population without underlying cardiopulmonary disease, and no risk factors for drsp, aspiration, or enteric gramnegative organisms (see box - ), the most likely pathogens are s. pneumoniae, atypical pathogens, respiratory viruses, and possibly h. infl uenzae (especially in smokers). for these patients, initial therapy with an advanced-generation macrolide (azithromycin or clarithromycin) is optimal, with doxycycline as a second choice if patients are intolerant of or allergic to macrolides (table - ) . advancedgeneration macrolides are preferred over erythromycin due to fewer gastrointestinal side effects and less frequent dosing, which may improve patient compliance. although an antipneumococcal fl uoroquinolone would be equally effective, use of one of these agents in this chapter community-acquired pneumonia practice: therapy of infectious diseases low-risk patient population is likely unnecessary and may promote selection pressure for resistance. although these patients are at risk for the usual cap pathogens, they are at increased risk for cap due to drsp, enteric gram-negatives, and aspiration; consequently, the empirical coverage of cap in these patients must be adjusted accordingly to take these organisms into consideration (table - ). an oral β-lactam agent may be used in combination with an advanced-generation macrolide (or doxycycline if the patient is intolerant of macrolides) in these patients. the oral β-lactam agent is chosen to be effective against drsp (mic = mg/l), but should be administered at high doses to overcome drug resistance. options for β-lactam agents include cefuroxime or cefpodoxime, highdose ampicillin ( g every hours), or amoxicillin-clavulanate ( g twice daily). alternatively, a more appealing choice for these patients with risk factors for drsp is the new-generation antipneumococcal fl uoroquinolones. due to the very low incidence of resistance of these agents to drsp and their once-daily administration, patient compliance and cost may be reduced compared to the combination of a βlactam agent and a macrolide. moreover, if the patient has risks for aspiration or resides in a long-term care facility, coverage for anaerobes should be considered with amoxicillin-clavulanate or amoxicillin with a macrolide. if anaerobes are documented or a lung abscess is present, clindamycin or metronidazole should be incorporated into the regimen. this category of patients likely represents a small population as most patients without cardiopulmonary disease or modifying factors likely can be treated effectively on an outpatient basis. the most common organisms in this group are similar to those of the outpatient without cardiopulmonary disease: s. pneumoniae, atypicals, h. infl uenzae, and respiratory viruses (table - ) . if the severity of illness entails hospitalization (not to an icu), these patients are effectively treated with intravenous azithromycin alone at mg daily for to days followed by oral therapy at mg daily for a total of to days. , if the patient is intolerant of macrolides due to adverse events, then therapy should be initiated with doxycycline and a β-lactam or an antipneumococcal fl uoroquinolone. therapy for these patients should include coverage for drsp and enteric gram-negatives as this population is at risk for these pathogens. similar to outpatients with similar risk factors, therapy with a β-lactam agent and macrolide can be initiated (see table - ). the β-lactam agent should be administered at the high dose level discussed earlier to ensure adequate coverage of drsp. a macrolide is added to cover atypical pathogens and can be administered orally or intravenously depending on the severity of illness. doxycycline is the alternative if the patient is intolerant of macrolide therapy. similar to outpatients with drsp risk factors, an alternative to the β-lactam-macrolide regimen is to use an antipneumococcal fl uoroquinolone alone. once again, the fl uoroquinolones simplify the regimen to once daily and may improve compliance and decrease costs. if the patient has risk factors for aspiration or lives in a long-term care facility, coverage for anaerobes should be considered with the addition of ampicillinsulbactam, high-dose ampicillin, or other active β-lactams. the documentation of anaerobes or the presence of a lung abscess should prompt the addition of clindamycin or metronidazole to the regimen. patients with severe cap with admission to the icu should have therapy directed against s. pneumoniae, h. infl uenzae, and legionella and other atypicals, but stratifi cation based on risk factors for p. aeruginosa infection must be considered (table - ). if no p. aeruginosa risk factors are present, initial therapy with a β-lactam active against drsp in combination with either azithromycin or a fl uoroquinolone should be instituted. the β-lactam agent that is chosen should have activity against drsp (cefotaxime, ceftriaxone, ampicillin-sulbactam), but those β-lactam agents that also have antipseudomonal activity (cefepime, piperacillin-tazobactam, imipenem, meropenem) are not recommended for primary treatment when p. aeruginosa is not suspected. if p. aeruginosa risk factors are present, therapy should always include two agents with antipseudomonal activity and also cover drsp and legionella species. therapeutic options include select β-lactams (cefepime, piperacillin-tazobactam, imipenem, meropenem) plus an antipseudomonal quinolone (ciprofl oxacin), or select β-lactams with an aminoglycoside plus either azithromycin or a nonpseudomonal fl uoroquinolone. if the patient has p. aeruginosa risk factors and is βlactam allergic, aztreonam can replace the β-lactam agent and should be combined with an antipneumococcal fl uoroquinolone and an aminoglycoside. as mentioned previously, an increasing incidence of communityacquired mrsa infection has been reported throughout the country. although this clearly represents a small number of patients with cap, it tends to affect young, healthy individuals with devastating effects. therefore, in the appropriate patient population-a resident of a longterm care facility; a young, healthy person with rapidly progressive necrotizing pneumonia; or a person with a post-infl uenza syndrome pneumonia-serious consideration should be given to the addition of vancomycin or linezolid to cover mrsa, especially if there is minimal to no clinical response to initial treatment. with recent reports clearly documenting the increasing incidence of mrsa cutaneous infections, it is likely that mrsa cap will become more prevalent, and clinicians must be aware of the possibility of this organism as a community-acquired pathogen. patients who develop pneumonia in the setting of an acute or chronic health care facility must be distinguished from those who develop pneumonia in the community; the former patients are referred to as having health care-associated pneumonia, which includes hospitalacquired pneumonia and ventilator-associated pneumonia. this distinction is important as these patients are at high risk of having infection with mrsa and multidrug-resistant (mdr) bacterial pathogens. the mdr pathogens include p. aeruginosa, extended-spectrum β-lactamase-producing klebsiella pneumoniae, acinetobacter baumanii, enterobacter species, and enterococcus species. health careassociated pneumonia contributes signifi cantly to morbidity, length of hospitalization, increased health care costs, and increased mortality. early broad-spectrum antimicrobial coverage with multiple antibiotics is recommended in these patients, with de-escalation once the implicated pathogen has been identifi ed. in general, this requires the combination of an antipseudomonal cephalosporin (cefepime, ceftazidime), carbapenem (imipenem, meropenem), or penicillin (piperacillintazobactam) plus either an antipseudomonal fl uoroquinolone or an aminoglycoside. supplemental oxygen is usually required for those patients with cap admitted to a hospital. the oxygen saturation of these patients should be closely followed. patients with cap who progress to develop severe sepsis and septic shock will require resuscitation with intravenous fl uids and vasopressor agents. drotrecogin alfa activated (activated protein c) should be considered in patients with cap who develop organ failure or septic shock. the recombinant human activated protein c worldwide evaluation in severe sepsis (prowess) study demonstrated a reduction in -day all-cause mortality in patients with cap and severe sepsis who were treated with this agent. the role of corticosteroids in patients with severe cap is controversial. confalonieri and colleagues, in a small randomized, placebocontrolled study, demonstrated that hydrocortisone given as a bolus of mg followed by an infusion of mg/hr for days reduced the complication rate and mortality in patients with severe cap. additional studies are required to determine the role of corticosteroids and other immunomodulating agents in the management of patients with severe cap. community-acquired pneumonia is the leading cause of infectious mortality in the united states. recognition of the clinical syndrome consistent with pneumonia, assessing patients' risk factors for specifi c organisms, determining their medical comorbidities, and evaluating their severity of illness will allow the clinician to ascertain pertinent pathogens and choose appropriate empirical coverage for cap. clinicians should have an understanding of their local resistance patterns as this may alter the empirical coverage chosen. when and if specifi c pathogens are isolated, empirical coverage should be de-escalated as guided by microbiologic data to maximize kill and minimize the development of resistance. due to the evolution of existing infectious pathogens and newly discovered pathogens (e.g., that causing severe acute respiratory syndrome), the recommendations 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immunocompétent ? date: - - journal: reanimation doi: . /s - - - sha: doc_id: cord_uid: lx pa current diagnostic methods allow microbial identification in % of patients admitted with severe community-acquired pneumonia (cap). guidelines derived from epidemiological data help physicians to start empirical antimicrobial therapy. definitive microbial diagnosis is useful to guide further pathogen-directed therapy. blood cultures, cultures of respiratory specimens and urine antigen tests are recommended to determine the causative bacterial pathogen. positive blood cultures range from to % of cap patients according to severity. whether sputum specimens represent or not lower respiratory secretions determines its accuracy in cap microbial diagnosis. in intubated patients, endotracheal aspirates are often of interest. detection of positive pneumococcal or legionella urinary antigen is often associated with cap severity. the sensitivity of this test is not decreased in patients who have received antibiotics prior to sampling. viral pneumonia account for to % of severe cap. nasal swabs are recommended for influenza identification using polymerase chain reaction (pcr) in order to deliver oseltamivir treatment. in the emergency department, atypical pneumonia serology is less useful than respiratory specimens obtained using fiberoptic bronchoscopy. serum pcr to diagnose bacterial cap is not superior to the other usual methods. résumé grâce aux méthodes de diagnostic actuelles, l'identification microbiologique des pneumonies communautaires graves (pcg) peut être établie dans la moitié des cas. si les études épidémiologiques ont permis d'établir des recommandations préconisant l'antibiothérapie empirique à débuter, l'identification microbiologique du ou des pathogène(s) responsable(s) est nécessaire pour la conduite ultérieure du traitement. les principaux examens à effectuer pour l'identification bactérienne sont la réalisation d'hémocultures, d'un examen cytobactériologique des sécrétions respiratoires et la recherche d'une antigénurie pneumococcique ou légionnelle. les hémocultures sont positives dans à % des cas de pcg. l'examen cytobactériologique des crachats ou l'aspiration endotrachéale, chez le patient intubé, aide au diagnostic sous réserve que le prélèvement ne soit pas contaminé par la flore oropharyngée. la positivité d'une antigénurie est également fonction de la sévérité de la pneumonie. cet examen permet un diagnostic rapide et n'est pas influencé par une antibiothérapie préalable. les virus à tropisme respiratoire seraient responsables de à % des pcg. en période épidémique, des prélèvements par écouvillonnage nasal à la recherche du virus influenza sont recommandés, en raison du bénéfice attendu avec l'instauration d'un traitement par oseltamivir. les sérologies permettant de faire le diagnostic de pneumonie à germes intracellulaires ont peu d'intérêt aux urgences de même que la réalisation de prélèvements sous fibroscopie bronchique. enfin, la recherche qualitative par reverse transcriptase (pcr) sérique présente peu d'intérêt pour le diagnostic de pneumonie bactérienne par rapport aux méthodes usuelles. abstract current diagnostic methods allow microbial identification in % of patients admitted with severe community-acquired pneumonia (cap). guidelines derived from epidemiological data help physicians to start empirical antimicrobial therapy. definitive microbial diagnosis is useful to guide further pathogen-directed therapy. blood cultures, cultures of respiratory specimens and urine antigen tests are recommended to determine the causative bacterial pathogen. positive blood cultures range from to % of cap patients according to severity. whether sputum specimens represent or not lower respiratory secretions determines its accuracy in cap microbial diagnosis. in intubated patients, endotracheal aspirates are often of interest. detection of positive pneumococcal or legionella urinary antigen is often associated with cap severity. the sensitivity of this test is not decreased in patients who have received antibiotics prior to sampling. viral pneumonia account for to % of severe cap. nasal swabs are recommended for influenza identification using polymerase chain reaction (pcr) in order to deliver oseltamivir treatment. in the emergency department, atypical pneumonia serology is less useful than respiratory specimens obtained using fiberoptic bronchoscopy. serum pcr to diagnose bacterial cap is not superior to the other usual methods. keywords severe community acquired pneumonia · microbial diagnosis la pneumonie communautaire grave (pcg) est la première cause de sepsis sévère et de choc septique rencontrée aux urgences [ ] . près de la moitié des patients présentant une pcg nécessite une hospitalisation en réanimation où la mortalité varie de à % selon les séries rapportées [ ] [ ] [ ] . les études épidémiologiques permettent d'actualiser régulièrement les agents microbiologiques responsables des pcg [ ] [ ] [ ] . À partir de ces études, de nombreuses recommandations ont défini les modalités de l'antibiothérapie empirique laissant peu de place au hasard dans la prise en charge thérapeutique de ces patients [ ] [ ] [ ] . l'application de ces recommandations a d'ailleurs permis de diminuer la mortalité des patients présentant une pcg [ ] . ainsi, puisque les pathogènes responsables et l'antibiothérapie à instaurer sont connus, l'utilité de réaliser des prélèvements microbiologiques systématiques chez tous les patients admis aux urgences pour une pneumonie communautaire peut se discuter. plusieurs études ont de fait démontré l'inutilité d'effectuer des prélèvements microbiologiques initiaux chez des patients hospitalisés pour une pneumonie communautaire non sévère [ , ] . on peut considérer qu'il en va différemment chez les patients présentant une pcg. dans ce contexte, si l'antibiothérapie empirique initiale est peu influencée par les prélèvements réalisés aux urgences, son adaptation secondaire liée à l'identification du ou des pathogènes responsables peut apporter un bénéfice à titre individuel. la réduction possible du spectre antibiotique permet la diminution de la pression de sélection, des effets secondaires et du coût du traitement. la détermination de la durée du traitement est un autre avantage attendu. l'identification du ou des pathogènes responsables prend d'autant plus son importance que le patient présente un terrain associé particulier avec des comorbidités importantes, comme une bronchopneumonie chronique obstructive (bpco) ou des hospitalisations répétées, terrains où une antibiothérapie à large spectre est souvent débutée [ , ] . de même, l'antibiothérapie est modifiée ou élargie en cas de résistance du pathogène identifié, même si cette situation doit être évitée en raison d'un pronostic aggravé [ ] . enfin la positivité d'un prélèvement permet de lever un doute diagnostique dans des situations de détresse respiratoire ou de syndrome de réponse inflammatoire systémique où la présentation clinique impose d'envisager plusieurs hypothèses diagnostiques. plusieurs modèles ou sociétés savantes ont tenté d'établir ou de définir les critères de gravité d'une pneumonie communautaire [ ] [ ] [ ] . par souci de simplification nous définirons dans cette revue, une pcg comme étant une pneumonie associée à un sepsis sévère ou un choc septique. dans une première partie, nous rapporterons les dernières recommandations des sociétés savantes en analysant les données ayant permis de les établir. dans une deuxième partie, nous mentionnerons les examens à la recherche d'une étiologie virale puis ceux n'ayant pas d'utilité avant d'évoquer ceux qui pourraient se développer dans les prochaines années afin d'améliorer la prise en charge diagnostique. les recommandations récentes des sociétés savantes, qu'elles soient françaises, britanniques ou nord-américaines, sont identiques [ ] [ ] [ ] . elles préconisent pour les patients présentant une pcg nécessitant une admission en réanimation la réalisation d'hémocultures, une analyse cytobactériologique des sécrétions trachéobronchiques et la détection d'antigènes urinaires pneumocoque et légionnelle (tableau ). celles-ci sont réalisées au plus vite avant l'instauration de l'antibiothérapie que l'on sait urgente. leur nombre optimal n'est pas précisé sauf par les britanniques qui signalent qu'au moins ml de sang doit être cultivé. si l'on fait abstraction des problèmes d'interprétation liés aux résultats faussement positifs consécutifs à des souillures, l'hémoculture est usuellement reconnue comme une méthode diagnostique fiable et spécifique en pathologie infectieuse. sa sensibilité, dans les pneumonies communautaires, semble néanmoins dépendante de la gravité de l'infection. chez les patients hospitalisés pour une pneumonie communautaire, la fréquence de positivité de l'hémoculture est de % d'après le travail de metersky et al. portant sur plus de patients [ ] . pour les patients admis en réanimation, cette fréquence apparaît plus élevée puisque comprise entre , % et , % selon les séries [ ] [ ] [ ] . toutefois, cette relation entre la gravité de l'infection et la fréquence de positivité de l'hémoculture lorsqu'elle est appréciée non plus par le lieu d'admission du patient mais par un élément objectif tel que le pneumonia severity index (psi, score de fine) ou le curb- apparaît plus difficile à établir, tant les études sur le sujet rapportent des résultats discordants. au moins deux études retrouvent une augmentation de la fréquence de positivité de l'hémoculture avec celle de la classe du score psi [ ] [ ] . par contre, un tel résultat n'est pas retrouvé par campbell et al. qui notent une fréquence faible d'hémoculture positive (moins de %) quelle que soit la classe du score psi [ ] . de même, capelastegui et al. dans une étude récente ne retrouvent aucune différence du score curb- selon que les patients souffrant de pneumonie à pneumocoque aient ou n'aient pas d'hémoculture positive [ ] . de nombreux facteurs associés avec la présence d'une bactériémie au cours d'une pneumonie communautaire ont été identifiés : absence d'antibiothérapie antérieure, atteinte hépatique, douleur pleurale, polypnée > cycles/min, pression artérielle systolique < mmhg, température < ou > °c, fréquence cardiaque > /min, urée > mg/dl ( mmol/l), natrémie < mmol/l, leucocytose < à ou > à /mm , thrombopénie < /mm , albuminémie < g/l, protéine c-réactive > mg/l [ , , ] . la prise d'anti-inflammatoires non stéroïdiens (ains), fréquemment administrés chez des patients présentant une symptomatologie infectieuse du tractus respiratoire augmente la fréquence des bactériémies chez les patients présentant une pcg. voiriot et al. rapportent dans une série récente que % des patients admis pour pcg avaient reçu des ains au domicile. parmi les patients n'ayant pas reçu d'antibiotique conjointement à la prise d'ains, la fréquence des bactériémies était plus élevée ( % vs %) [ ] . examen cytobactériologique des sécrétions trachéobronchiques idéalement, celles-ci seront prélevées par aspiration simple lors de l'intubation trachéale. celle-ci n'est toutefois pas toujours nécessaire. l'échantillon est alors prélevé lors d'une expectoration. l'analyse cytobactériologique comporte un examen direct après coloration de gram et une culture sur milieux usuels. préalablement, l'échantillon bactériologique doit être validé. il faut, en effet, s'assurer qu'il s'agisse bien d'un prélèvement issu du tractus respiratoire inférieur. bien que les critères varient parfois d'une étude à l'autre, la plupart des auteurs considèrent que lorsqu'il y a moins de cellules épithéliales squameuses et plus de leucocytes par champ à faible grossissement, l'échantillon est valide. l'examen direct est primordial dans la mesure où, comme le soulignent les experts français, la pertinence diagnostique n'est présente que si l'examen direct est positif. le rôle de la quantification bactérienne dans la prise en compte du résultat de la culture doit être enfin discuté. les experts français avaient énoncé en qu'un résultat positif ne devait être pris en compte que « s'il existe une culture pure d'un microorganisme unique ou au moins cfu/ml » [ ] . ce seuil bactérien n'est toutefois pas requis dans les recommandations usuelles nord-américaines ou britanniques, ni même dans les recommandations françaises les plus récentes. les difficultés de réalisation et d'interprétation de ce prélèvement microbiologique, associées à l'absence de standard diagnostique, expliquent les variations considérables des valeurs de sensibilité et de spécificité diagnostiques rapportées dans la littérature [ ] . quoiqu'il en soit, les données de la littérature montrent que l'examen direct et la culture de l'expectoration dès lors qu'ils sont correctement effectués chez un patient sans antibiothérapie sont fréquemment positifs au cours des pneumonies à pneumocoque les plus graves, c'est-à-dire bactériémiques [ ] . un polysaccharide c de la paroi cellulaire, commun à tous les pneumocoques peut être détecté dans les urines par un test immunochromatographique (binax now ® ) dont le résultat est disponible en minutes. la sensibilité de ce test est dépendante de la sévérité de l'infection pneumococcique. en cas de pneumonie bactériémique, à % des patients ont un examen positif. en cas de pneumonie non bactériémique, seuls à % des patients ont un test positif [ ] [ ] [ ] [ ] [ ] [ ] . la spécificité du test apparaît excellente. la colonisation oropharyngée à pneumocoque ne positive pas le test. il en va de même des exacerbations de bpco au cours desquelles l'incidence des tests positifs est très faible [ ] . la durée de positivité du test urinaire est longue puisqu'en moyenne de semaines après le début des symptômes [ ] . elle est d'au moins une semaine chez les patients sous antibiothérapie [ ] . ainsi, en résumé, ce test semble pouvoir permettre un diagnostic rapide des pcg à pneumocoque, notamment celles associées avec une bactériémie. non influencé par l'antibiothérapie antérieure ou en cours, il permet également un diagnostic étiologique « rétrospectif » chez les patients ayant des prélèvements usuels, basés sur la culture, négatifs. bien que ce test demeure longtemps positif, sa spécificité globalement élevée doit être soulignée. ces données ne doivent pas toutefois faire perdre de vue que les pneumonies ayant une étiologie pluri microbienne dans plus de % des cas il n'est peutêtre pas raisonnable de focaliser l'antibiothérapie uniquement sur le pneumocoque en cas de test positif. un test immunochromatographique permet la détection dans les urines d'antigènes appartenant au sérotype de l. pneumophila, sérotype le plus fréquemment incriminé au cours de la légionellose ( % des cas). au vu des données de la littérature, il apparaît qu'environ % des patients présentant une infection à l. pneumophila du sérotype excrètent au cours de leur maladie des antigènes au niveau urinaire. cette excrétion apparaît un à trois jours après le début de la maladie et peut durer un an. il existe une corrélation entre la sévérité de l'infection et l'excrétion urinaire de l. pneumophila . en cas de forme peu sévère, seuls à % des patients ont des antigènes détectables alors qu'en cas de forme sévère, à % des patients ont une détection possible [ ] [ ] [ ] . ce test a donc une forte valeur diagnostique lorsqu'il est positif puisqu'il permet d'affirmer le diagnostic de légionellose. il a également une valeur lorsqu'il est négatif et cela à plusieurs reprises. en effet, si on fait abstraction d'une légionellose qui serait due à un autre sérotype que le , fait rare sous nos contrées, la présence d'un test négatif au e jour d'évolution d'une pcg permet raisonnablement d'exclure le diagnostic de légionellose et donc d'adapter l'antibiothérapie probabiliste en conséquence. l'arrêt de la quinolone ou du macrolide prescrits pour « couvrir » cette étiologie est donc recommandé [ ] . les virus à tropisme respiratoire, qu'ils soient seuls ou associés à une bactérie, sont responsables de à % des pcg [ ] [ ] [ ] . les principaux virus responsables sont le virus respiratoire syncytial, le rhinovirus, le métapneumovirus, l'adénovirus et le virus influenza. si les premiers d'entre eux sont rarement responsables d'infections respiratoires sévères chez le sujet immunocompétent, les récentes épidémies et pandémies de grippe a h n et h n nous ont rappelé le pouvoir pathogène potentiel du virus influenza [ ] . le virus influenza est de ce fait le plus fréquent des virus incriminés dans les pneumonies nécessitant une admission en réanimation [ ] . en france, lors de l'hiver - , parmi les patients ayant consulté aux urgences pour grippe, , % avaient été hospitalisés et patients avaient été admis en réanimation, principalement des patients porteurs de la souche h n [ ] . ainsi, en raison de la gravité potentielle des pneumonies à virus influenza et des possibilités thérapeutiques offertes par l'oseltamivir, il est fortement recommandé d'effectuer un prélèvement à la recherche d'une grippe en période épidémique. en effet, du seul point de vue radioclinique, le diagnostic de pneumonie grippale est hasardeux d'autant plus que l'interaction fréquente grippeinfection bactérienne contribue à cette difficulté [ , , ] . l'infection à virus h n était suivie d'une infection bactérienne dans à % des cas, le plus souvent à pneumocoque [ ] . le prélèvement doit donc se faire devant toute pneumonie sévère en période d'épidémie, et ce quel que soit le statut vaccinal du patient, même si un prélèvement bactérien, comme une antigénurie pneumocoque, est positif. ce prélèvement respiratoire peut également être réalisé après la mise en route du traitement antiviral. le prélèvement doit être réalisé le plus rapidement possible car l'instauration précoce du traitement antiviral réduit la sévérité des pneumonies et la durée de l'hospitalisation. une récente méta-analyse, incluant près de patients, a démontré que l'instauration d'un traitement par oseltamivir dans les heures suivant le début des symptômes diminuait de moitié la mortalité [ ] . la réduction de mortalité était toutefois de % si le traitement était instauré au delà de heures après le début des symptômes. deux institutions, la world health organization and le center for disease control and prevention recommandent ainsi l'utilisation de l'oseltamivir en cas de grippe même au-delà des heures suivant le début des symptômes [ ] [ ] . le diagnostic de pneumonie grippale va reposer sur la positivité d'un prélèvement nasal, effectué par écouvillonnage. celui-ci se pratique en position assise, tête légèrement inclinée en arrière, en maintenant le menton afin de prélever dans la fosse nasale et non au bord de la narine. l'écouvillon stérile est placé dans un tube contenant un milieu de transport pour virus. l'écouvillonnage se fait au niveau nasal car il a une sensibilité supérieure au prélèvement pharyngé [ ] . plusieurs tests de détection du virus sont alors à disposition. le test à privilégier est la recherche par reverse transcriptase (pcr). ce test disponible dans la plupart des laboratoires de microbiologie en france est l'examen le plus sensible et le plus spécifique avec un rendu évalué entre deux et quatre heures. cette méthode doit être privilégiée sur la réalisation de tests rapides comme la recherche des antigènes du virus influenza par immunochromatographie. le délai de rendu de cet examen est certes plus court, évalué à minutes, mais sa spécificité varie de à % et sa sensibilité de à %. en plus des prélèvements microbiologiques usuels, le dosage de la procalcitonine pourrait être une aide au diagnostic. dans une étude observationnelle, multicentrique, réalisée pendant l'épidémie de grippe h n , il est rapporté qu'une concentration de procalcitonine ≥ , μg/l évoque une co-infection bactérienne avec une sensibilité de % et une spécificité de % [ ] . par ailleurs, les cliniciens doivent avoir connaissance de l'existence d'infections virales sporadiques, importées, responsables de pneumonies à l'évolution souvent fatale, telles que les récentes infections à coronavirus de type syndrome respiratoire aigu sévère (sras) ou syndrome respiratoire du moyen-orient (mers cov) [ ] [ ] . des prélèvements spécifiques à la recherche de ces virus doivent être réalisés, bien souvent après information et demande des autorités sanitaires, lorsque le contexte clinique et épidémique le justifie. techniques invasives l'examen cytobactériologique des sécrétions trachéobronchiques peut aider au diagnostic microbiologique, il a pour principale limite la contamination des prélèvements par la flore oropharyngée. pour éviter cette contamination, il existe des techniques de prélèvement protégé telles que le prélèvement bronchique distal protégé, réalisé le plus souvent à l'aveugle, et le brossage bronchique distal protégé, réalisé sous contrôle fibroscopique. contrairement aux pneumonies acquises sous ventilation mécanique, ces deux techniques ont été peu évaluées dans les pneumonies communautaires. les résultats sont contradictoires avec soit un rendement diagnostique supérieur à l'examen des expectorations soit un résultat superposable [ , , ] . ces études sont en fait assez hétérogènes avec des prélèvements réalisés dans les heures suivant l'admission en réanimation que l'antibiothérapie probabiliste ait été débutée ou non. de plus, la valeur diagnostique de ces examens réalisés majoritairement dans une structure de soins intensifs ou de réanimation n'a pas été comparée aux prélèvements microbiologiques réalisés à l'heure actuelle. de même, le lavage broncho-alvéolaire (lba) a été peu évalué dans les pneumonies communautaires, avec un rendement diagnostic variable selon les études [ , ] . sa réalisation expose également à un risque de dégradation respiratoire. dans leur étude, rodriguez et al. [ ] ont étudié l'impact thérapeutique de la réalisation d'un lba aux urgences. les modifications thérapeutiques ont été plus fréquentes dans le groupe avec lba, sans réduction significative du spectre antibactérien, ni impact sur la mortalité ( % dans le groupe lba contre , %). son indication reste bien précise : le lba est réservé au diagnostic des pneumonies chez le patient immunodéprimé. il n'est donc pas indiqué chez le patient immunocompétent. la ponction transtrachéale a, quant à elle, été abandonnée du fait de son caractère invasif. certains centres pratiquent néanmoins encore la ponction transpariétale. du fait d'un nombre non négligeable de complications (pneumothorax environ , %, hémorragies pulmonaires < , % voire décès < , %), elle semble réservée aux patients en échec d'un traitement médical bien conduit [ ] . réalisables pour mycoplasma pneumoniae, chlamydia pneumoniae, chlamydia psittaci et legionella pneumophila, elles n'ont aucun intérêt à la phase initiale de la prise en charge des pcg. le diagnostic positif nécessite une séroconversion, c'est-à-dire une ascension significative du taux d'anticorps entre deux sérologies réalisées à deux semaines d'intervalle au minimum [ ] . affirmer le diagnostic et adapter les thérapeutiques sur une sérologie réalisée à l'entrée n'a donc pas de sens. de même, le contrôle sérologique, réalisé après au minimum deux semaines d'évolution, le sera dans la majorité des cas lorsque le traitement antibiotique sera terminé. elles ne permettent donc, au mieux, qu'un diagnostic rétrospectif et n'influencent en rien la prise en charge. si, pour les pneumonies d'origine bactérienne, l'utilisation de la pcr qualitative comme méthode diagnostique apporte peu d'avantages par rapport aux méthodes usuelles, il pourrait en aller différemment lorsque avec les méthodes quantitatives permettant de déterminer la charge bactérienne. d'un point de vue diagnostique, la pcr a été évaluée dans les pneumonies à legionella pneumoniae, mycoplasma pneumoniae, chlamydia sp. et s. pneumoniae. si pour les infections à m. pneumoniae et à l. pneumophila les tests diagnostiques sont plus performants que respectivement des prélèvements pharyngés et respiratoires, il en va différemment pour les infections à pneumocoque où la recherche par pcr est plus sensible lorsqu'elle est effectuée sur des prélèvements sériques plutôt que sur des prélèvements respiratoires [ ] [ ] [ ] . les avantages de la pcr tels que l'obtention rapide du résultat et l'absence d'influence d'une l'administration préalable d'une antibiothérapie sont contre balancés par l'impossibilité d'effectuer un antibiogramme et une sensibilité diminuée par rapport aux méthodes conventionnelles [ ] . des sensibilités de à % ont été rapportées [ ] [ ] . la pcr quantitative permet d'évaluer la charge bactérienne sanguine à l'image des mesures réalisées pour certaines infections virales comme l'infection par le virus de l'immunodéficience humaine (vih) ou l'hépatite c. par le passé, quelques études avaient établi un lien entre charge bactérienne sérique et le pronostic chez des enfants présentant une bactériémie à pneumocoque ou à haemophilus influenzae [ , ] . la charge bactérienne était déterminée dans les hémocultures. un pronostic défavorable était démontré au-delà d'un seuil de ou /ml. cette technique était toutefois très consommatrice de temps et n'est plus d'actualité. plusieurs études récentes, utilisant cette fois la pcr, ont établi une corrélation entre charge bactérienne et pronostic. dans leur travail, rello et al. ont évalué la relation entre la charge bactérienne sérique et le développement d'un choc septique dans les infections sévères à pneumocoque [ ] . le dosage quantitatif de l'autolysine a, spécifique de s. pneumoniae, était la méthode utilisée pour quantifier la charge bactérienne. quatre-vingt treize patients présentant une pneumonie à pneumocoque ont été analysés. la pcr était positive pour d'entre eux. le nombre de copies d'acide désoxyribonucléique (adn) de s. pneumoniae variait de à copies/ml. un seuil supérieur à copies/ml était associé à la survenue d'un choc septique avec une spécificité de %, chaque augmentation de log multipliant par et , les risques respectifs de choc septique et de ventilation mécanique. chez l'enfant présentant une pneumonie à pneumocoque avec bactériémie, l'importance de la charge bactérienne était associée à la présence d'un empyème [ ] . de la même manière, la présence d'une charge bactérienne élevée, déterminée par pcr quantitative dans les sécrétions respiratoires, était associée à la nécessité d'une hospitalisation en réanimation chez des patients hospitalisés pour légionellose [ ] . ainsi, il n'est pas impossible de penser que la généralisation de cette technique permettrait d'améliorer la prise en charge des patients porteurs de pcg. cela permettrait de classer les patients en fonction de la sévérité attendue de la pneumonie et de d'instaurer précocement des thérapeutiques adjuvantes appropriées, le délai de rendu de l'examen étant de à heures. la connaissance de la charge bactérienne pourrait également avoir un impact sur la durée de l'antibiothérapie ainsi que sur le choix et les modalités d'administration de l'antibiothérapie. une lyse bactérienne importante, attendue en cas de charge bactérienne élevée, associée à une production excessive d'interleukine (il)- , il- ou de tumor necrosis factor (tnf)-alpha pourrait être modulé par des traitements immunomodulateurs comme les macrolides ou une corticothérapie adjuvante. epidemiology of severe sepsis in the united states: analysis of incidence, outcome and associated costs of care antibiotic prescription for community-acquired pneumonia in the intensive care unit: impact of adherence to infectious diseases society of america guidelines on survival. community-acquired pneumonia intensive care units (capuci) study investigators idsa/ats minor criteria aid pre-intensive care unit resuscitation 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bacteremia prediction model using a common clinical test in patients with communityacquired pneumonia nonsteroidal antiinflammatory drugs may affect the presentation and course of communityacquired pneumonia conduite à tenir devant une infection respiratoire basse communautaire de l'adulte detection of streptococcus pneumoniae antigen by a rapid immunochromatographic assay in urine samples evaluation of a rapid immunochromatographic test for detection of streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia evaluation of the immunochromatographic binax now assay for detection of streptococcus pneumoniae urinary antigen in a prospective study of community-acquired pneumonia in spain rapid urinary antigen test for diagnosis of pneumococcal community-acquired pneumonia in adults rapid diagnosis of bacteremic pneumococcal infections in adults by using the binax now streptococcus pneumoniae urinary antigen test: a prospective, controlled clinical 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adults with community-acquired pneumonia diagnosis of streptococcus pneumoniae infections in adults with bacteremia and community-acquired pneumonia: clinical comparison of pneumococcal pcr and urinary antigen detection diagnosis of invasive pneumococcal infection by pcr amplification of streptococcus pneumoniae genomic fragments in blood: a multicentre comparative study detection and quantitation of bacteremia in childhood relationship between the magnitude of bacteraemia in children and the clinical disease severity of pneumococcal pneumonia associated with genomic bacterial load dna bacterial load in children with bacteremic pneumococcal communityacquired pneumonia quantitative realtime pcr tests for diagnostic and prognostic purposes in cases of legionellosis key: cord- -kb eagd authors: park, ji young; kim, bong-joon; lee, eun jung; park, kwi sung; park, hee sun; jung, sung soo; kim, ju ock title: clinical features and courses of adenovirus pneumonia in healthy young adults during an outbreak among korean military personnel date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: kb eagd background: the number of pneumonia patients increased suddenly in korean military hospitals in late december , indicating the urgent need for an epidemic outbreak investigation. methods: we conducted a prospective study of pneumonia etiology among immunocompetent young adults admitted to daejeon armed forces hospital. patient blood and sputum samples were subjected to conventional culture, serology, and polymerase chain reaction tests for respiratory viruses and atypical pathogens. results: from january to may , we enrolled ( male) adults with pneumonia; the mean age was . ± . years. five patients had severe pneumonia, and one died. pathogenic human adenoviruses were most common (hadv, / [ . %]), indicating a hadv pneumonia outbreak. genotyping of isolates indicated that matched hadv- and one matched hadv- . hadv pneumonia infected recruit trainees most frequently. high and prolonged fever, nasal congestion, sore throat, and pharyngeal inflammation were significantly more common in the hadv pneumonia group, compared to patients with other or unknown causes of pneumonia. only % of hadv pneumonia patients displayed leukocytosis, whereas febrile leukopenia ( . %) and thrombocytopenia ( %) were commonly observed. hadv pneumonia patient chest ct scans displayed ground glass opacity (with or without septal thickness) with consolidation in . % of patients. conclusions: an outbreak of hadv respiratory infection occurred at the korean military training center. hadv pneumonia exhibited specific laboratory and clinical features, and although most patients were cured without complication, some progressed to respiratory failure and fatality. therefore, hadv vaccine should be provided to military trainees in korea. introduction viral respiratory infection is particularly important in military populations who experience overexertion, psychological stress, and crowding within confined spaces [ ] . there are many reports of respiratory virus outbreaks in the military [ ] [ ] [ ] . in many settings, human adenovirus (hadv) was the main causative pathogen and occasionally led to death [ , ] . hadvs are also important in the pathogenesis of community acquired pneumonia (cap) among both immunocompetent and immunocompromised individuals [ , ] . although despite reports of a low prevalence in previous studies ( . - %), adenovirus-related cap was recently ranked in the top etiologies of cap by larger studies [ , ] . moreover, hadv is easily transmittable and can be highly contagious [ ] . the clinical features of respiratory adenoviral infection among military personnel were described previously; however, hadv pneumonia in immunocompetent individuals and risk factors of disease progression to severe pneumonia or acute respiratory failure have not been well studied. in december , a sudden increase in patients with febrile respiratory illness and pneumonia occurred among military hospitals of the south korean army, including our institution. medical staff noted that the rates of hadv-positive respiratory specimens had also increased. therefore, we deduced an emergent hadv outbreak and aimed primarily to identify the pathogenic agent(s) causing the sudden increase in pneumonia cases. we also aimed to describe the clinical features and radiological findings of hadv pneumonia in immunocompetent individuals. we conducted a prospective study of cap in immunocompetent military trainees or active duty soldiers admitted for pneumonia to daejeon armed forces hospital, south korea from january to may . patients are referred to this -bed hospital by basic and advanced military training centers and other military hospitals. in south korea, military service is mandatory for all healthy men ! years old. trainees spend weeks on basic military training, and then proceed to advanced training centers or active duty [ ] . all military trainees or active duty members, but not officers, were eligible for enrollment if they were ! years old and had been admitted to the study hospital for pneumonia, defined by acute respiratory symptoms (fever, cough, sputum, dyspnea, and pleuritic chest pain) and pulmonary infiltrates on chest x-rays or computed tomography (ct) scans. patients diagnosed with other pulmonary diseases were excluded. command (afmc -irb- - ), and informed consent was obtained from all patients. consent was verbal in nature because an etiological evaluation of pneumonia is considered routine care. the verbal consent procedure was approved by the ethics committee of the armed forces medical command. the study medical officer maintained a register of patients who consented verbally to participate in the cohort. patient sputum samples for conventional culture and polymerase chain reaction (pcr) tests and blood samples for culture and serologic tests were collected before prescribing medications, which were chosen at the physicians' discretion. outpatient clinic or emergency room investigating physicians collected clinical information. sputum specimens were collected from all patients at enrollment. these were acceptable for culture if they satisfied murray-washington classification degrees iv or v [ ] . sputum specimens were cultured routinely and tested by pcr. severe pneumonia was defined by one or more of the following criteria: ) invasive mechanical ventilation, ) use of vasopressors, ) > % of lung parenchymal involvement. all cases were scored according to the pneumonia severity index (psi) and curb- [ , ] . we performed multiplex pcr for human respiratory viruses using the advansure™ rv realtime pcr kit (lg life sciences, korea; supplementary methods). this assay targets types of pathogenic rna viruses: rhinoviruses a/b/c, influenza viruses a/b, coronaviruses e/ nl /oc , respiratory syncytial viruses a/b, parainfluenza viruses / / , and metapneumovirus; and two types of dna viruses: adenovirus and bocavirus [ ] . we performed multiplex pcr for the respiratory bacterial pathogens mycoplasma pneumoniae, chlamydophila pneumoniae, legionella pneumophila, and bordetella pertussis, using the seeplex pneumobacter ace detection assay (seegene, seoul, korea; supplementary methods). streptococcus pneumoniae and haemophilus influenzae were not analyzed because we could not differentiate true infection from colonization of these pathogens [ ] . we performed nested pcr in the hypervariable region of the hexon gene for genotyping using previously described nested pcr conditions and primer sequences for hexon gene amplification [ ] . pcr products were purified with the qia quick pcr purification kit (qiagen, valencia, ca, usa) prior to their use as nucleotide sequencing templates. the genotype of each isolate was determined according to the serotype of the highest scoring strain in genbank, using the basic local alignment search tool (blast). categorical variables were analyzed by the chi-squared or fisher's exact test. continuous variables were compared by the student's t-test or mann-whitney u-test. a p-value < . was considered statistically significant. all analyses were performed using spss for windows ver. table ). typical bacteria (klebsiella pneumoniae) were cultured by conventional culture in only one patient. cases involving co-infection with multiple pathogens are listed in s table. hadv pneumonia outbreak epidemiology the number of weekly hadv-positive cases was plotted (fig a) . hadv cases peaked at week (early march ). a secondary peak occurred at week . hadv pneumonia cases occurred throughout the training period but were most common around the end of basic training (week , fig b) . most hadv pneumonia patients were basic military trainees or personnel who had recently completed training; active duty service personnel were not usually affected, even during outbreak peaks. there were no significant differences in the mean age, smoking status, and influenza vaccination rate ( table ). the median military service period (including training period) was shorter in the hadv-positive pneumonia group than in the negative group ( . vs. . , p = . ). we compared clinical characteristics according to the hadv pcr test results (tables and ) . fever, high fever (! . ˚c), nasal congestion, sore throat, throat clearing, headache, and pharyngeal inflammation were more common among hadv pneumonia patients than in others. many hematologic findings of the hadv pneumonia group differed significantly from those of the negative group (table ) , including leukocytosis, febrile leukopenia, thrombocytopenia, and hematocrit. the mean serum levels of c-reactive protein (crp) and procalcitonin were not significantly different between the two groups. pleural fluid analysis was available for three hadv pneumonia patients, and their samples were found to be lymphocyte dominant (mean, . %) with a mean adenosine deaminase level was . iu/l. the mean psi score was higher among the hadv-positive group than the negative group ( . vs. . p = . ) and psi class rates tended to be higher among the hadv-positive group (p = . , table ). chest ct images were obtained from all patients except one. ground-glass opacity (ggo; an area of increased opacity without obscuration of the underlying vessels) and septal thickening were more common in the hadv-positive group than in the negative group (p = . and p = . , respectively). nodules and bronchial wall thickening were less common in the hadv pneumonia group. the parenchymal opacities in hadv-positive pneumonia patients among hadv pneumonias, severe pneumonia was observed in five patients. severe pneumonia patients and others did not differ significantly with respect to demographic characteristics and most symptoms (s table) . however, high fever, dyspnea, and chest discomfort were more frequent and febrile periods were significantly longer among patients with severe hadv pneumonia, compared to others ( . ± . vs. . ± . days; p = . ). the time from fever onset to the greatest radiologic aggravation (increased opacity on follow-up chest x-ray) was also longer in the severe group ( . ± . vs. . ± . , p = . ). severe hadv pneumonia was associated with a lower white blood cell count (wbc) and platelet count on admission day (p < . and p = . , respectively). although the mean crp value was higher in the severe group (p = . ), the mean serum procalcitonin concentration did not differ significantly between patients with severe pneumonia and others (p = . ; s table) . there were some complications among hadv pneumonia patients. acute heart failure occurred in two patients. delirium occurred in one patient. one patient developed upperextremity deep vein thrombosis, possibly resulting from a central line catheter. two patients required mechanical ventilation. of these latter patients, one expired from respiratory and heart failure ( table ). our results show that an outbreak of hadv pneumonia occurred in korean military training centers and indicate that emergent-type hadv- infections might have caused the outbreak. in this outbreak, hadv pneumonia was associated with specific clinical symptoms, laboratory results, and chest ct scan findings. recently, multiple outbreaks of acute respiratory disease have been associated with an emergent variant, hadv- (formerly named hadv- a). whole-genome sequencing of this variant indicates potential hexon gene recombination between the hadv- and hadv- strains [ ] . such outbreaks occurred in the military forces of turkey in [ ] and singapore in [ ] . in china, several outbreaks of hadv- respiratory disease have been reported not only in the military, but also in the community (e.g., a senior high school in [ ] , beijing in [ ] , military in [ ] , and a physical training facility in [ ] ). since , hadv- has also been identified among severe pneumonia patients at a korean military hospital [ ] . most hadv pneumonia patients were basic trainees or personnel who finished their training recently. these results were similar to those of previous studies [ ] . it is well documented that the most significant factor leading to hadv infection and disease is a lack of preexisting, type-specific immunity against hadv- and hadv- . moreover, anti-hadv immunity provided % protection from adenovirus-related hospitalization and % protection from infection [ , ] . in the korean military, it is not certain why active duty service personnel were infected less frequently than trainees. one possibility is that the former group may have had preexisting hadv- antibodies from previous exposure. another possibility is that the former group had other cross-protective hadv antibodies. in , hadv- was the dominant type of hadv in the korea military [ ] . hadv- is in the same species group as hadv- (hadv- / / / are in species group b) [ ] . when a hadv- outbreak occurred at u.s. military training facilities, preexisting hadv- neutralizing antibodies provided cross-protection against hadv- in recruits [ ] . other predisposing factors that might be associated with selective infection of newly recruited trainees include overcrowding and physical or emotional stress [ , ] . hadv pneumonia diagnoses began in the nd week of training and peaked at week , in close accordance with previous u.s. army studies. kolavic-gray et al. [ ] found that hadv- -related acute respiratory diseases among military trainees peaked during week of training, and tate et al. [ ] reported that hadv- -associated febrile respiratory illness peaked during weeks - . one possible reason for this timing pattern is that sufficient numbers of infected or colonized trainees may be required to cause an outbreak [ ] . moreover, the -week training period is epidemiologically important because trainees usually move to advanced training centers or into active duty after completing basic training, possibly creating a secondary outbreak. our prospective analysis demonstrated that this hadv pneumonia was associated with specific clinical features that differed from other pneumonias. although the mean fever duration in hadv pneumonia patients was similar to those in previous studies ( - days) [ , , ] , patients with hadv pneumonia had higher and longer fevers than the hadv-negative group. moreover, the fever duration associated with severe hadv pneumonia was prolonged relative to that of mild-moderate pneumonia, again corroborating previous reports [ ] . patients with hadv pneumonia also had more upper respiratory tract symptoms than those in the negative group, suggesting that hadv infected or colonized the upper respiratory tract first, then progressed to a lower respiratory tract infection. the most typical laboratory findings of hadv pneumonia were febrile leukopenia and thrombocytopenia. in agreement with our results, vento et al. [ ] demonstrated lower wbc and platelet counts in a hadv- pneumonia among u.s. military trainees. patients with severe pneumonia had fewer wbc and lower platelet counts than those with mild to moderate pneumonia. moreover, the mean times from fever onset to the nadir of wbc and to the greatest radiologic aggravation were similar and correlated (r = . , p < . ). these findings suggest that hematologic parameters might be used to monitor hadv pneumonia and to index risk factors for disease progression. finally, although the crp levels were moderately elevated in our study, the mean procalcitonin level was only . μg/l, confirming that a bacterial infection was unlikely [ ] . in fact, bacterial coinfection was rare. among the / adenovirus-positive patients, only . % ( / ) exhibited evidence of bacterial infection (typical: ; atypical: ). in contrast, among the / adenovirus-negative patients, . % ( / ) had bacterial infections (p < . ). this further confirms the hadv infection findings in our cohort. very few case studies of the ct findings of hadv pneumonia exist in the literature [ ] . the most common pattern in our study was ggo with or without septal thickness and central consolidation, a finding specific to hadv pneumonia that was not observed with hadv-negative pneumonia. our ct scans also demonstrated that single lobe involvement was more common than multi-lobe involvement, in contrast to a previous case report that suggested such cases usually manifested as bilateral involvement [ ] . these observations might be useful during the differential diagnosis of young adults presenting with pneumonia symptoms during an outbreak; however, further radiological studies are needed. no antiviral agents have been approved to treat hadv pneumonia, and only limited data on the clinical responses of immunocompromised patients to cidofovir are available. however, kim et al. [ ] , in another study of severe hadv infection in the korean military, suggested that early treatment with cidofovir should be considered for respiratory failure due to hadv pneumonia. most patients in our study were treated empirically with antibiotics, and most hadv pneumonia cases were self-limiting without an antiviral agent. however, cidofovir was administered at a -mg/kg weekly dose to two severe hadv pneumonia patients. one patient recovered without sequelae, whereas the other patient died. it would be unsafe to offer cidofovir to all hadv pneumonia patients because of the risk of renal toxicity. moreover, this drug is expensive and is not stocked regularly in hospitals. in this respect, the early identification of patients who might develop severe pneumonia is most important when selecting cases that will receive antiviral treatment [ ] . interestingly, the psi scores and curb- values were higher in the severe pneumonia group, whereas the absolute scores in this group did not indicate high risk. notably, age is an important factor in these pneumonia severity score systems; accordingly, the lower scores obtained in our study might be partly attributable to the young ages of our adult patients. in addition, that these scoring systems were validated in communities where the main pathogens were bacterial, rather than viral [ ] . similar results were observed in pandemic h n influenza pneumonia studies in which psi and curb- failed to predict admissions to intensive care or the need for mechanical ventilation [ , ] . our study has one limitation. because pneumonia increased abruptly in our patients, we were uncertain of which pathogen(s) caused the outbreak and did not plan to conduct hadv genotyping at the study outset. we only sent partially banked sputum specimens for hadv genotyping confirmation after realizing that there a hadv outbreak was occurring in the korean military. it is uncertain whether vaccines against types and , which are currently only available in the u.s. army, will effectively protect against hadv type . therefore, new, more suitable vaccines should be developed for subtypes responsible for current outbreaks. in conclusion, this hadv pneumonia exhibited specific clinical and laboratory features and chest ct findings. although the pneumonia severity varied, this infection can induce morbidity and fatality. a respiratory virus surveillance system and epidemiological expertise are urgently needed and hadv vaccination should be considered in korean military training centers. the current smoking rate was . %, and . % of patients had received the seasonal ( - ) influenza vaccine. excepting one patient who was incidentally diagnosed with gitelman's syndrome, none had systemic disease respiratory infections in the u.s. military: recent experience and control outbreak of acute respiratory disease caused by human adenovirus type in a military training camp in shaanxi vaccine-preventable adenoviral respiratory illness in us military recruits adenovirus-associated deaths in us military during postvaccination period outbreak of adenovirus type severe pneumonia in a french intensive care unit outbreak of pneumonia associated with emergent human adenovirus serotype -southeast alaska korean adenovirus pneumonia outbreak of community-acquired pneumonia requiring hospitalization among u.s. adults incidence and characteristics of viral community-acquired pneumonia in adults adenovirus infections in immunocompetent and immunocompromised patients acute lower respiratory tract infections in soldiers microscopic and baceriologic analysis of expectorated sputum a prediction rule to identify low-risk patients with community-acquired pneumonia defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study evaluation of a multiplex real-time pcr assay for the detection of respiratory viruses in clinical specimens. annals of laboratory medicine clinical evaluation of the multiplex pcr assay for the detection of bacterial pathogens in respiratory specimens from patients with pneumonia detection and sequence-based typing of human adenoviruses using sensitive universal primer sets for the hexon gene epidemiology of human adenovirus and molecular characterization of human adenovirus in china respiratory disease caused by a species b adenovirus in a military camp in turkey outbreak of febrile respiratory illness associated with adenovirus a infection in a singapore military training camp outbreak of acute respiratory disease in china caused by b species of adenovirus type emergence of community-acquired adenovirus type as a cause of community-onset pneumonia an outbreak of acute respiratory disease in china caused by human adenovirus type b in a physical training facility outcomes of early administration of cidofovir in non-immunocompromised patients with severe adenovirus pneumonia spread of adenovirus to geographically dispersed military installations large epidemic of adenovirus type infection among military trainees: epidemiological, clinical, and laboratory studies high isolation rate of adenovirus serotype from south korean military recruits with mild acute respiratory disease computational analysis identifies human adenovirus type as a re-emergent acute respiratory disease pathogen outbreak of severe respiratory disease associated with emergent human adenovirus serotype at a us air force training facility in exploration of the effectiveness of social distancing on respiratory pathogen transmission implicates environmental contributions psychological stress and susceptibility to the common cold clinical features of radiologically confirmed pneumonia due to adenovirus in children severe community-acquired pneumonia caused by adenovirus type in immunocompetent adults in beijing pneumonia in military trainees: a comparison study based on adenovirus serotype infection viral pneumonia adenovirus pneumonia in adults: radiographic and high-resolution ct findings in five patients the pneumonia severity index: a decade after the initial derivation and validation severity assessment tools in icu patients with influenza a (h n ) pneumonia severity of influenza a (h n ) pneumonia is underestimated by routine prediction rules. results from a prospective, population-based study the authors thank bong joon kim conceptualization: jyp jok. key: cord- -y il hyb authors: nan title: pandemic flu: clinical management of patients with an influenza-like illness during an influenza pandemic date: - - journal: j infect doi: . /s - ( ) - sha: doc_id: cord_uid: y il hyb nan • this document is intended for use in the uk in the event that the world health organisation declares that an influenza pandemic has started , and the department of health in england (uk-wide lead agency on pandemic influenza, including the devolved administrations) has declared uk pandemic alert level (cases of pandemic influenza identified within the uk). • these guidelines are not relevant for the management of patients affected by seasonal/interpandemic influenza, lower respiratory tract infections, community-acquired pneumonia or exacerbations of chronic obstructive pulmonary disease (copd). • once an influenza pandemic is under way, users are strongly urged to ensure that they refer to the most up-todate version of these guidelines (from web-based access points). synopsis . clinical management of adults referred to hospitals s . . severity assessment in hospital • patients with uncomplicated influenza infection would be expected to make a full recovery and do not require hospital care. • in uncomplicated infection, the illness usually resolves in seven days although cough, malaise and lassitude may persist for weeks. • patients with worsening of pre-existing co-morbid medical conditions should be managed according to best practice for that condition with reference to published disease-specific guidelines, if available, for example, the national institute of clinical excellence's copd guideline. • in hospital, patients with influenza-related pneumonia and who have a curb- score of , or (see box a) are at high risk of death and should be managed as having severe pneumonia. • patients with bilateral lung infiltrates on chest radiography consistent with primary viral pneumonia should be managed as having severe pneumonia regardless of curb- score. • patients who have a curb- score of are at increased risk of death. they should be considered for short stay inpatient treatment or hospital supervised outpatient treatment. this decision is a matter of clinical judgment. • patients who have a curb- score of or are at low risk of death. they can be treated as having non-severe pneumonia and may be suitable for home treatment. • patients with primary viral pneumonia or a curb- score of or should be considered for hdu/icu transfer. • general indications for hdu/icu transfer include: ( ) persisting hypoxia with pao < kpa despite maximal oxygen administration ( ) progressive hypercapnia ( ) severe acidosis (ph < . ) ( ) septic shock • patients with influenza admitted to intensive care unit should be managed by specialists with appropriate training in intensive care, respiratory medicine and/or infectious diseases. pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s s . . general investigations • the following investigations are recommended in patients referred to hospital: who this applies to full blood count all patients urea and electrolytes all patients liver function tests all patients chest x-ray all patients pulse oximetry all patients. if < % on air, then arterial blood gases. patients with cardiac and respiratory complications or co-morbid illnesses. c-reactive protein if influenza-related pneumonia is suspected • in those patients who are subsequently followed up in a hospital outpatient clinic or by a general practitioner a repeat chest x-ray should be obtained at around six weeks if respiratory symptoms or signs persist or where there is a higher risk of underlying malignancy (especially smokers and those over years of age). • further investigations including a ct thoracic scan and bronchoscopy should be considered if the chest x-ray remains abnormal at follow up. s . . microbiological investigations s . . . early in a pandemic (uk alert levels , and ) • virology all patients ( ) nose and throat swabs in virus transport medium. ( ) if presentation is more than seven days after onset of illness, an 'acute' serum ( ml clotted blood) should be collected and a 'convalescent' sample ( ml clotted blood) obtained after an interval of not less than seven days. • bacteriology patients with influenza-related pneumonia ( ) blood culture (preferably before antibiotic treatment is commenced) ( ) pneumococcal urine antigen ( ml urine sample) ( ) legionella urine antigen ( ml urine sample) ( ) sputum gram stain, culture and antimicrobial susceptibility tests on samples obtained from patients who: (i) are able to expectorate purulent samples, and (ii) have not received prior antibiotic treatment. ( ) paired serological examination for influenza/other agents. acute serum should be collected and a 'convalescent' sample obtained after an interval not less than seven days (both ml clotted blood). • virology not routinely recommended • bacteriology patients with influenza-related pneumonia in accordance to the severity of illness. (a) non-severe pneumonia (curb- score , or ) no routine testing. in patients who do not respond to empirical antibiotic therapy, sputum samples should be sent for gram stain culture and antimicrobial susceptibility tests. b severe pneumonia (curb- score , or , or bilateral cxr changes) blood culture, preferably before antibiotic treatment is commenced pneumococcal urine antigen ( ml urine) sputum gram stain, culture and antimicrobial susceptibility tests on samples obtained from patients who are able to expectorate purulent samples, and have not received prior antibiotic treatment. paired serological examination for influenza/other agents. 'acute' serum should be collected and a 'convalescent' sample obtained after an interval not less than seven days (both ml clotted blood). tracheal or endotracheal aspirate samples, if available, should be sent for gram stain, culture and antimicrobial susceptibility testing. s . . general management s . • hypoxic patients should receive appropriate oxygen therapy with monitoring of oxygen saturations and inspired oxygen concentration with the aim to maintain pao kpa and sao ges; %. high concentrations of oxygen can safely be given in uncomplicated pneumonia. • oxygen therapy in patients with pre-existing chronic obstructive pulmonary disease complicated by ventilatory failure should be guided by repeated arterial blood gas measurements. non-invasive ventilation may be helpful. • in patients without pre-existing copd who develop respiratory failure, niv may be of value as a bridge to invasive ventilation in specific circumstances when level beds are in high demand. respiratory and/or critical care units experienced in the use of niv are best placed to ensure the appropriate infection control measures are adopted at all times. • patients should be assessed for cardiac complications and also volume depletion and their need for additional intravenous fluids. • nutritional support should be given in severe or prolonged illness. • temperature, respiratory rate, pulse, blood pressure, mental status, oxygen saturation and inspired oxygen concentration should be monitored and recorded initially at least twice daily and more frequently in those with severe illness or requiring regular oxygen therapy. an early warning score system is a convenient way to perform this. • in patients who are not progressing satisfactorily a full clinical reassessment and a repeat chest radiograph are recommended. • patients should be reviewed hours prior to discharge home. those with two or more of the following unstable clinical factors should consider remaining in hospital: ( ) temperature > . ºc ( ) heart rate > /min ( ) respiratory rate > /min ( ) systolic blood pressure < mmhg ( ) oxygen saturation < % ( ) inability to maintain oral intake ( ) abnormal mental status • follow up clinical review should be considered for all patients who suffered significant complications or who had significant worsening of their underlying disease, either with their general practitioner or in a hospital clinic. • at discharge or at follow up, patients should be offered access to information about their illness, take home medication and any follow up arrangements. • it is the responsibility of the hospital team to arrange the follow up plan with the patient and the general practitioner. • individuals should only be considered for treatment with antivirals (neuraminidase inhibitors) if they have all of the following: ( ) an acute influenza-like illness ( ) fever (> ºc) and ( ) been symptomatic for two days or less. • treatment schedule: adults oseltamivir mg every hours for five days. (dose to be reduced by % if creatinine clearance is less than ml/minute, i.e. mg od). • patients who are unable to mount an adequate febrile response, e.g. the immunocompromised or very elderly, may still be eligible for antiviral treatment despite lack of documented fever. • hospitalised patients who are severely ill, particularly if also immunocompromised, may benefit from antiviral treatment started more than hours from disease onset, although there is no evidence to demonstrate benefit, or lack of it, in such circumstances. s . . antibiotic management s . . . influenza • previously well adults with acute bronchitis complicating influenza, in the absence of pneumonia, do not routinely require antibiotics. • antibiotics should be considered in those previously well adults who develop worsening symptoms (recrudescent fever or increasing dyspnoea). • patients at high risk of complications or secondary infection (appendix ) should be considered for antibiotics in the presence of lower respiratory features. • most patients can be adequately treated with oral antibiotics. • the preferred choice includes co-amoxiclav or a tetracycline. • a macrolide such as clarithromycin (or erythromycin) or a fluoroquinolone active against streptococcus pneumoniae and staphylococcus aureus is an alternative choice in certain circumstances. • most patients can be adequately treated with oral antibiotics. • oral therapy with co-amoxiclav or a tetracycline is preferred. • when oral therapy is contra-indicated, recommended parenteral choices include intravenous co-amoxiclav, or a second or third generation cephalosporin (cefuroxime or cefotaxime). • a macrolide (erythromycin or clarithromycin) or a fluoroquinolone active against s. pneumoniae and staph. aureus is an alternative regimen where required eg. for those intolerant of penicillins. currently levofloxacin and moxifloxacin are the only recommended fluoroquinolones licensed in the uk. • antibiotics should be administered within four hours of admission. • patients with severe pneumonia should be treated immediately after diagnosis with parenteral antibiotics. • an intravenous combination of a broad spectrum b-lactamase stable antibiotic such as co-amoxiclav or a second (e.g. cefuroxime) or third (e.g. cefotaxime) generation cephalosporin together with a macrolide (e.g. clarithromycin or erythromycin) is preferred. • an alternative regimen includes a fluoroquinolone with enhanced activity against pneumococci together with a broad spectrum b-lactamase stable antibiotic or a macrolide. currently levofloxacin is the only fluoroquinolone with an intravenous formulation licensed in the uk. • patients treated initially with parenteral antibiotics should be transferred to an oral regimen as soon as clinical improvement occurs and the temperature has been normal for hours, providing there is no contra-indication to the oral route. • for most patients admitted to hospital with non severe and uncomplicated pneumonia, seven days of appropriate antibiotics is recommended. • for those with severe, microbiologically undefined pneumonia, ten days treatment is proposed. this should synopsis . clinical management of adults referred to hospitals synopsis of main recommendations pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s be extended to to days where staph aureus or gram negative enteric bacilli pneumonia is suspected or confirmed. • for those with non-severe pneumonia in hospital on combination therapy, changing to a fluoroquinolone with effective pneumococcal and staphylococcal cover is an option. • adding further antibiotics effective against mrsa is an option for those with severe pneumonia not responding to combination antibiotic therapy. • high fever (> . ºc) and cough or influenza-like symptoms. these children should seek advice from a community health professional. if there are no features that put them at high risk of complications they should be treated with oseltamivir, and given advice on antipyretics and fluids. children aged < year and those at risk of complications (appendix ) should be seen by a gp. • high fever (> . ºc) and cough or influenza-like symptoms, plus at risk group. these children should be seen by a gp or in a&e. children may be considered at increased risk of complications if they have cough and fever (or influenza-like illness) and temperature > . ºc, plus either chronic co-morbid disease or one of following features: breathing difficulties severe earache vomiting > hours drowsiness these patients should be offered an antibiotic as well as oseltamivir (in those > year of age) and advice on antipyretics and fluids. children aged < year with none of the above features should be treated with antipyretics and fluids with a low threshold for antibiotics if they become more unwell. • indicators for hospital admission are: ( ) signs of respiratory distress. markedly raised respiratory rate grunting intercostal recession breathlessness with chest signs ( ) cyanosis ( ) severe dehydration ( ) altered conscious level ( ) complicated or prolonged seizure ( ) signs of septicaemia extreme pallor, hypotension, floppy infant • most children admitted to hospital are likely to need oxygen therapy and/or intravenous support as well as antibiotics and oseltamivir. • indications for transfer to high dependency or intensive care are: ( ) failure to maintain sao > % in fio > % ( ) the child is shocked ( ) severe respiratory distress and a raised paco (> . kpa) ( ) rising respiratory rate and pulse rate with clinical evidence of severe respiratory distress with or without a raised paco ( ) recurrent apnoea or slow irregular breathing ( ) evidence of encephalopathy • when there are no picu beds available, children will have to be triaged on the basis of the severity of their acute and co-existing disease, and the likelihood of their achieving full recovery. • a full blood count with differential, urea, creatinine and electrolytes, liver enzymes and a blood culture should be done in all severely ill children. • a cxr should be performed in children who are hypoxic, have severe illness or who are deteriorating despite treatment. • pulse oximetry should be performed in every child being assessed for admission to hospital with pneumonia. • virology all children ( ) nasopharyngeal aspirate or nose and throat swabs ( ) if presentation is more than days after onset of illness, an 'acute' serum ( ml clotted blood) should be collected and a 'convalescent' sample ( ml clotted blood) obtained after an interval of not less than days. • bacteriology children with influenza-related pneumonia ( ) blood culture (before antibiotic treatment is commenced) ( ) sputum samples obtained from older children ( ) paired serological examination for influenza/other agents. • virology not routinely recommended • bacteriology children with influenza-related pneumonia ( ) blood culture (before antibiotic treatment is commenced) ( ) sputum samples obtained from older children • patients whose oxygen saturation is % or less while breathing air should be treated with oxygen given by nasal cannulae, head box, or face mask to maintain oxygen saturation above %. • when children are unable to maintain oral intake, supplementary fluids should, when possible, be given by the enteral route. intravenous fluids in those with severe pneumonia should be given at % basal levels. • children can be safely discharged from hospital when they: ( ) are clearly improving ( ) are physiologically stable ( ) can tolerate oral feeds ( ) have a respiratory rate < /min (< /min in infants) ( ) have an awake oxygen saturation of > % in air. • in the setting of a pandemic, children should only be considered for treatment with antivirals if they have all of the following: ( ) an acute influenza-like illness ( ) fever (> . ºc) and ( ) been symptomatic for two days or less • oseltamivir is the antiviral agent of choice. • in children who are severely ill in hospital oseltamivir may be used if the child has been symptomatic for < days (but there is no evidence to demonstrate benefit, or lack of it, in such circumstances). • children (a) who are at risk of complications of influenza or (b) with disease severe enough to merit hospital admission during an influenza pandemic should be treated with an antibiotic that will provide cover against s. pneumoniae, staph. aureus and h. influenzae. • for children under years co-amoxiclav is the drug of choice. clarithromycin or cefuroxime should be used in children allergic to penicillin. for children over years doxycycline is an alternative. • oral antibiotics should be given provided oral fluids are tolerated. • children who are severely ill with pneumonia complicating influenza should have a second agent added to the regime (e.g. clarithromycin or cefuroxime) and the drugs should be given intravenously to ensure high serum and tissue antibiotic levels. to facilitate preparedness planning, this document has been written in advance of the emergence of the next influenza pandemic, at a time when the identity of the causative virus remains unknown. these guidelines are based on the best evidence available from previous pandemic and interpandemic influenza periods. the guidance may evolve as clinicopathological information on the eventual pandemic virus emerges. once an influenza pandemic is under way, users are strongly urged to refer to the most up-todate version of these guidelines (from web-based access points). seasonal influenza is a familiar infection in the uk, especially during winter. every year strains of influenza (type a or b) circulate, giving rise to clinical consultations in primary care (age-specific impact varies by season), episodes of hospital treatment (mainly in older persons and young children, but occasionally in working age adults), and deaths (mainly in the elderly). treatment in primary care and hospital may be required due to the direct effects of influenza virus infection or its possible complications, most commonly secondary bacterial pneumonia. increases in gp consultations for influenza-like illness and winter bed pressures are frequently associated with periods of known community influenza activity . pandemic influenza occurs when a new influenza a virus subtype emerges which is markedly different from recently circulating subtypes and strains, and is able to: • infect humans; • spread efficiently from person to person; • cause significant clinical illness in a high proportion of those infected. because the virus is novel in humans, a high proportion of the population will have little or no immunity, producing a large pool of susceptible persons; accordingly the disease spreads widely and rapidly. influenza pandemics occur sporadically and unpredictably. in , a devastating and unusual pandemic caused by influenza a/h n ('spanish flu') killed between and million people worldwide. other pandemics that followed had a less devastating impact but were nevertheless severe. influenza a/h n ('asian flu') emerged in , and h n ('hong kong flu') in ; both produced roughly million excess deaths worldwide . the circumstances still exist for a new influenza virus with pandemic potential to emerge and spread, and the longest interval so far recorded between pandemics is years ( ) . the unpredictability of the timing of the next pandemic is underlined by the occurrence of several large outbreaks of highly pathogenic avian influenza associated with epizootic transmission to humans . by far the most serious has been the massive and unprecedented outbreak of highly pathogenic influenza (a/h n ) affecting poultry in east and south east asia in late , which is still continuing. this outbreak has so far been associated with a small number of human cases but a high proportion of deaths. recently, epidemiological and virological changes have been reported from northern vietnam which may indicate that the virus is beginning to adapt to humans . although the emergence of an a/h n strain with capacity to spread efficiently between humans is neither inevitable nor imminent, international concern has increased regarding the possibility that avian influenza a/h n may evolve to produce the next pandemic. other events and developments that inform the creation of this guidance are the development and licensing of a new class of drug (neuraminidase inhibitors) active against influenza, and uk government's announcement of plans to procure . million treatment courses of oseltamivir (tamiflu ® ) for use in the uk in the event of a pandemic. be involved in the management of patients with influenza. it is intended that these guidelines also be of value to health-care practitioners who do not usually manage patients with influenza but may be called upon to do so in a pandemic situation. modification of some recommendations at a local level may be necessary in specific instances. these guidelines are not relevant for the management of patients affected by seasonal influenza, sporadic acute exacerbations of chronic obstructive pulmonary disease (aecopd), lower respiratory tract infections (lrtis) or community-acquired pneumonia (cap). at the primary care level, a national operational plan including the following three broad areas is deemed important: (a) clinical management of patients with influenza (b) management of patient demand, including patients who do not have influenza (c) health service delivery plans these guidelines cover the first of these areas and will serve as the source document for the primary care operational plan. the primary care operational plan will incorporate all three areas within a single reference and is being developed by the dh in collaboration with the rcgp and the bma. even though it is impossible to predict with certainty the impact of the next pandemic, based upon the available epidemiological and modelling information, it is clear that it will generate demands for health care which may saturate or overwhelm normal nhs acute services for a period of time, perhaps several weeks or months. accordingly, it should be anticipated that the nhs (in common with all health systems around the world) will need to revert to emergency arrangements. these are laid out in further detail in operational guidance for health service planners , the uk operational framework for stockpiling, distributing and using antiviral drugs in the event of pandemic influenza and in the primary care operational plan. with regard to the delivery of medical care for patients with influenza this is normally achieved through: • gp treatment of community patients 'well' enough to be managed in the community • hospital care in acute medicine for persons considered too ill to be managed at home. in the event of a pandemic, the following additional care settings may have to be considered as the threshold for hospital admission rises: • treatment of patients in the community (who would normally receive care from a gp) by other health-care professionals (nurses, paramedics, pharmacists etc.) following treatment guidance laid out in this publication and using prescription-only medicines according to patient group directives (pgds). • treatment of patients in their own homes or in temporary intermediate care facilities by a gp, following treatment guidance laid out in this publication when, under normal circumstances, such patients would have been admitted for hospital care. • treatment of severely ill patients in hospital by medical and nursing teams who do not normally manage patients with influenza or community-acquired pneumonia, in areas of the hospital not normally used for providing medical care (for example, surgical teams and bed space diverted from routine elective work towards pandemic response). the recommendations offered in the current guidelines are based on a matrix of evidence centred mainly around seasonal influenza, expert opinion and group consensus. grading of these recommendations based on the strength of the evidence base was deemed inappropriate. section . epidemiology and health impact projections ( ) the scale and severity of illness (and hence consequences) caused by pandemic influenza generally exceed those of even the most severe winter epidemics. ( ) mortality in the uk is likely to exceed , deaths, possibly appreciably higher. ( ) besides the elderly, excess mortality is also likely in younger adults and children. ( ) modelling studies suggest that after a case occurs in hong kong, because of international travel, it will take less than one month for the virus to reach the uk. ( ) once cases begin to occur in the uk it will take only two to three weeks before activity is widespread and roughly a further three weeks (six weeks after initial cases in uk) until activity peaks. ( ) it is possible that there will be more than one epidemic wave (with an interval of several months) and, if a second wave occurs, it may be more severe than the first. ( ) cumulative clinical and serological attack rates across all waves together may be in the order of % and % respectively. ( ) increases in demand for health-care services are likely to be very substantial in both primary care and hospital settings. when an influenza pandemic occurs, a substantial proportion (possibly all) of the population is likely to be non-immune, producing a large pool of susceptible persons. in past pandemics, the scale and severity of illness (and hence consequences) have been variable but broadly of a § . epidemiology and health impact projections introductory observations higher order than even the most severe winter epidemics. it is reasonable to expect this to be the case with the next pandemic as well. excess mortality due to influenza occurs in most winter seasons but is especially marked during epidemics. the average annual excess mortality attributable to influenza in recent years is around , deaths per annum in england and wales , although there is considerable yearly variation and some years are notably much higher than the average (est. , in / epidemic). excess mortality in england and wales associated with the three pandemics of the twentieth century has also varied widely; this was estimated at , civilians in / , and , in / . in / and / (both seasons considered to be associated with the influenza a/h n pandemic), there were an estimated , and , deaths respectively . therefore the extent of mortality associated with the next pandemic cannot be reliably predicted although it is reasonable to plan for a scenario worse than a severe winter epidemic of normal influenza. typically, there are changes in the age-distribution of cases compared with seasonal influenza. mortality, which in typical seasonal influenza is usually confined to age groups over years, tends to be increased in younger age groups. the size of any increase in morbidity and mortality and the extent to which a shift in age distribution occurs depend on a variety of factors including the nature of the pandemic virus and pre-existing immunity but appears to be a consistent phenomenon . therefore, clinicians can expect to see relatively larger amounts of influenza-related illness in younger adults compared with normal winter activity. at least one third of all excess deaths may be expected in persons under years of age. virological and clinical surveillance of influenza have improved markedly since the last pandemic in . however, the extent of international travel has also grown. modelling studies using transmission characteristics based on the / pandemic and international air-traffic data from indicate that the approximate delay between a first case in hong kong and first introduction to uk will be less than one month . in terms of the spread within the uk, it will probably take only two to three weeks from the initial introduction(s) until activity is widespread and a further three weeks (six weeks from initial uk cases) until activity peaks. the temporal and spatial spread of a pandemic strain is important, particularly in terms of the demand placed on health-care services. pandemic activity taking the form of a brief but severe peak in cases will be more difficult for all services to cope with, compared with an identical number of cases distributed over a longer time course. for example, during the a/h n pandemic a long first wave occurred in the winter of / with morbidity and mortality approximately at the same level as the previous seasonal influenza; but in the following winter of / a short and more severe epidemic occurred with a threefold higher peak in general practice consultation rates and a four-fold higher peak in mortality attributed to influenza, bronchitis and pneumonia. the high peak in consultation rates is well illustrated in fig. . . in / , the a/h n pandemic occurred in three distinct epidemic waves: early spring , autumn introductory observations § . epidemiology and health impact projections s provisional guidelines from bis/bts/hpa in collaboration with the department of health, version ( october ) and late winter . the second wave was by far the largest and case-fatality rates were also higher than in the first wave. the a/h n pandemic caused an epidemic wave in the winter of / but a more severe one in / . in contrast, the second wave of the / pandemic in the uk was very small in comparison to the first . thus it should be considered a possibility that more than one wave of influenza will occur within a few months of the emergence of a pandemic virus and a subsequent wave could be worse than the first. it is impossible to predict reliably with precision the level of excess mortality that will be experienced in the next pandemic. however, table . illustrates the broad range of excess mortality that it is reasonable to consider, based on various realistic combinations of case fatality rate and clinical attack rates derived from previous pandemics and epidemics. a case fatality rate of . % corresponds to the aggregate rate observed in recent epidemic seasons ( / , / , / , / , / , / and / ) and the pandemic, although the overall case-fatality rate observed in the pandemic was in the region of %. a clinical attack rate of around % corresponds to the approximate clinical attack rate seen in all three previous pandemics of the twentieth century. thus, a figure of at least , excess deaths is likely. using mathematical projections, it is possible to illustrate the potential impact of the next pandemic, but these do not amount to accurate predictions. table . summarises the number of events that might be expected by a gp with patients on his/her list and by a pct serving a population of , persons. using the same assumptions, table . illustrates the number of events by week over an assumed -week (single wave) pandemic period in a typical pct population of , . most major acute trusts receive patients from a catchment area spanning several pcts and the figures below require pro-rata adjustment before applying to individual hospitals. section . clinical features in adults ( ) influenza is clinically defined as the presence of fever and new (or, in those with chronic lung disease, worsening) cough of acute onset in the context of influenza circulating in the community. this clinical definition may be modified once a pandemic occurs. ( ) the spectrum of clinical disease associated with a pandemic strain cannot be forecast. ( ) pneumonia, either primary viral or secondary bacterial, is the commonest complication of influenza in adults. ( ) neurological complications are rare in adults. the clinical manifestations of infection by influenza viruses are diverse, ranging from asymptomatic infection to fulminant respiratory distress leading to respiratory failure and death. furthermore, the presence of an influenza-like illness (ili) comprising of a combination of fever, cough, sore throat, myalgia and headache is not specific for influenza infection. other respiratory pathogens that may present with an ili include viruses such as respiratory syncytial virus (rsv), adenovirus, rhinovirus and parainfluenza virus, as well as bacterial pathogens such as chlamydia pneumoniae, legionella sp., mycoplasma pneumoniae and streptococcus pneumoniae [ ] [ ] [ ] . studies that have examined the value of a clinical definition of ili in the diagnosis of influenza infection have not always used the same clinical definition for an ili and have included different study populations, making comparison between studies complicated. a systematic review of the literature in this area identified the threefold combination of the presence of fever, cough and acute onset to be the most predictive clinical features. the accuracy of this clinical definition was higher in persons aged years and above compared to patient groups without age restrictions [positive likelihood ratio ( % ci) . ( . . ) vs . ( . . )] . the probability of influenza infection also increases with increasing level of fever , . importantly, the predictive value of clinical definitions based on an ili increases when influenza virus is known to be circulating in the community , , . in cohort studies, correlation of ili with laboratory-confirmed influenza infection ranges from % to % while in clinical trials, rates of % have been consistently reported , [ ] [ ] [ ] .. these findings relate to influenza infections during interpandemic periods. during a global influenza pandemic, when a pandemic strain is known to be circulating locally in an immunologically susceptible population, the presence of an ili would be expected to be highly predictive for influenza infection. (however, the extent to which a clinical diagnosis of ili becomes predictive during a pandemic will also be determined by the behaviour of the public. if many who would not normally present to a health professional are prompted to present, then the predictive value of a clinical diagnosis of ili will be reduced.) the following description will relate mainly to interpandemic influenza a infections. influenza b and c are not considered pandemic threats. different strains may be associated with different clinical presentations and disease severity. for instance, there is evidence to suggest that the h n subtype causes more severe disease than h n subtype . the spectrum of clinical disease associated with a new influenza a subtype (eg. a pandemic strain) cannot be determined currently and may differ from that described for interpandemic influenza. the incubation period prior to the onset of symptoms is commonly two to four days (range days). in adults, the illness typically presents as an abrupt onset of fever accompanied by a range of other symptoms as listed in box . [ ] [ ] [ ] [ ] [ ] . fever is the paramount symptom and may reach ºc although more usually it ranges between ºc and ºc. the peak occurs within hours of onset and lasts typically for three days (range days) [ ] [ ] [ ] [ ] [ ] . the cough is generally dry although in up to % of cases it may be productive. a productive cough together with chest tightness and substernal soreness is more common in patients with underlying chronic lung disease. myalgia affects mainly the back and limbs. gastrointestinal symptoms such as vomiting and diarrhoea are uncommon (< %) in adults. abdominal pain is rare. clinical findings include a toxic appearance in the initial stages, hot and moist skin, a flushed face, injected eyes and hyperaemic mucous membranes around the nose and pharynx. tender cervical lymphadenopathy is found in a minority (~ %) of cases. wheezing or lung crackles are recognised findings (~ %) more commonly noted in patients with coexisting chronic lung disease. although the overall clinical picture of uncomplicated influenza in any specific age group is similar for different influenza a subtypes, the frequency of certain symptoms may vary. for instance, during the 'asian' pandemic of (h n ), headache and sore throat were frequent initial symptoms . in uncomplicated infection, the illness usually resolves in seven days although cough, malaise and lassitude may persist for weeks. influenza virus infection has been associated with worsening in the clinical condition of patients with a range of existing medical conditions, such as, heart failure, diabetes, coronary heart disease, asthma and chronic obstructive airways disease (copd). in addition, specific complications associated with influenza infection regardless of co-existing medical conditions are recognised (table . ). based on data from interpandemic influenza, certain persons are identified as being at high risk from influenza-related complications. such patients are similar to the group currently recommended for influenza vaccination by the department of health. these include those of all ages with chronic respiratory disease including asthma, chronic heart disease, chronic renal disease, chronic liver disease, immunosuppression due to disease or treatment, or diabetes mellitus, and all those aged years or older, or those in long stay residential care (see appendix ). in the course of a pandemic, it may emerge that the patient group at high risk of complications differs from the group currently identified. in such circumstance, details of the 'high risk' patient group will be altered according to relevant clinico-epidemiological data. the incidence of pneumonia (defined as a combination of respiratory symptoms and signs supported by chest radiographic changes consistent with infection) complicating influenza infection varies widely, from % to %, and is dependent on viral and host factors [ ] [ ] [ ] . pneumonia generally occurs more frequently and with greater severity in patients with pre-existing chronic cardiac and respiratory conditions. patients who develop pneumonia may present with symptoms and signs indistinguishable from pneumonia related to other viral and bacterial pathogens. in the context of an influenza pandemic, the presence of an ili and new or worsening dyspnoea should prompt a careful examination for the presence of complicating pneumonia. two main types of influenza-related pneumonia are recognised: primary viral pneumonia and secondary bacterial pneumonia [ ] [ ] [ ] [ ] . patients with primary viral pneumonia typically become breathless within the first hours of onset of fever. an initially dry cough may become productive of blood-stained sputum. cyanosis, tachypnoea, bilateral crepitations and wheeze on chest examination and leucocytosis are usual. the commonest chest radiographic abnormality is of bilateral interstitial infiltrates predominantly in the mid-zones, although focal consolidation is also well recognised. rapid clinical deterioration with respiratory failure may ensue . the mortality in hospitalised patients is high (> %) despite maximum supportive treatment on intensive care [ ] [ ] [ ] [ ] . in the majority of fatal cases, death occurs within seven days of hospital admission. secondary bacterial pneumonia is more common (up to four times) than primary viral pneumonia. typically, symptoms and signs of pneumonia develop during the early convalescent period (four to five days from onset of initial symptoms). in others, symptoms of pneumonia blend in with the initial symptoms of influenza. chest radiography usually demonstrates a lobar pattern of consolidation. mortality rate ranges from % to % [ ] [ ] [ ] [ ] [ ] , although some small studies report higher mortality rates. the spectrum of pathogens implicated is similar to that observed in cap and includes streptococcus pneumoniae, staphylococcus aureus, haemophilus influenzae and groups a, c and g b-haemolytic streptococci , , [ ] [ ] [ ] . different pathogens have predominated at different times. for instance, in the pandemic, h. influenzae, b-haemolytic streptococci and s. pneumoniae were the predominant pathogens isolated. in , s. pneumoniae was the predominant pathogen ( %) followed by staph. aureus ( %) and non-typeable h. influenzae ( %) . notably, staph. aureus was identified two and a half times more frequently during the pandemic compared to pneumonia occurring in the interpandemic period , . secondary staphylococcal pneumonia is associated with a higher incidence of lung abscess formation ( % vs %) and carries a poorer prognosis compared to non-staphylococcal pneumonias (mortality % vs %) , , , . during the pandemic, staph. aureus was the predominant bacterial pathogen isolated in fatal cases of influenzarelated pneumonia (up to % of cases in some series) . bacterial and viral pneumonia can occur concurrently. in these instances, the chest radiograph may demonstrate lobar consolidation superimposed on bilateral diffuse lung infiltrates. the mortality rate in mixed viral bacterial pneumonia is high (> %), as for primary viral pneumonia [ ] [ ] [ ] [ ] . minor abnormalities on ecg such as st segment deviation, t wave changes and rhythm disturbances have been described in uncomplicated influenza illness. they have been reported in up to % of patients hospitalised with influenza . most do not have cardiac symptoms. myocarditis and pericarditis are occasionally encountered in severe illness , . post mortem evidence of necrotising myocarditis has been reported in patients without clinically significant myocarditis in the antemortem period. in contrast with myalgia affecting the back and limbs which is common on initial presentation, myositis generally develops after the subsidence of the acute upper respiratory tract symptoms. the gastrocnemius and soleus muscles are typically involved with pain and tenderness to palpation. complete recovery usually occurs in three days. elevation in serum creatine phosphokinase is recognised , . rarely, this is associated with myoglobinuria and renal failure , . myositis is more commonly described in children than in adults. central nervous system (cns) involvement in adults is uncommon. most reports originate from japan and occur in children , . the main clinical syndrome is an encephalitis or encephalopathy manifesting in the form of decreased consciousness and seizures about three days (range days) following the onset of upper respiratory tract symptoms. focal neurological signs such as paresis, aphasia, choreoathetosis and cranial nerve palsies are less common. cerebrospinal fluid (csf) examination may be normal or reveal an elevation in protein or white cell count. imaging by ct or mri may be normal and if so, is indicative of a good prognosis and full recovery may be anticipated . young age and abnormal ct/mri findings are associated with a poor outcome including death or recovery with severe neurological sequelae. [a fuller description is given in section . . .] acute necrotising encephalopathy is a rare fulminant syndrome associated with multifocal brain lesions that is described mainly in japan . other rare manifestations include transverse myelitis and guillain barré syndrome , . reye's syndrome, characterised by an encephalopathy, acute fatty liver, association with aspirin use and high mortality (~ %), is a special situation that is almost exclusively seen in children and adolescents . nevertheless, physicians managing adults are advised to be aware of this complication. [a fuller description is given in section . . . .] other complications rarely encountered in adults with influenza a infection include toxic shock syndrome in conjunction with secondary staph. aureus infection , and parotitis . otitis media is more commonly encountered in children than adults. human infections have been caused by different avian influenza a viruses in the past, including h n , h n , h n and h n . in recent years, outbreaks of human infections by a novel strain of avian influenza a (h n ) have raised particular concerns globally regarding the risk of a human pandemic . these concerns have been due in part to recognition that (a) avian influenza a (h n ) can pass directly from birds to humans and (b) once in humans, avian influenza a (h n ) causes severe disease with a high mortality. the full spectrum of human illness associated with avian influenza a (h n ) infection is not completely known. descriptions of the clinical features of influenza a (h n ) infection in humans are based largely on case series of hospitalised patients. subclinical infections, mild illnesses and atypical presentations of influenza a (h n ) infections in humans have been reported, but the frequency of such infections is difficult to determine [ ] [ ] [ ] . in hospitalised patients, an ili similar to that associated with seasonal influenza a (h n or h n ) infection is recognised. gastrointestinal symptoms are present in a relatively large proportion of both adult and paediatric cases, in contrast to the relatively low incidence of gastrointestinal symptoms in seasonal influenza. the majority of patients develop a severe primary viral pneumonia usually associated with lymphopenia, thrombocytopenia and deranged liver function tests. renal failure and multiorgan failure may develop subsequently. mortality is high. a more detailed description is given in appendix . should influenza a (h n ) acquire efficient humanto-human transmission capabilities, it may result in an influenza pandemic. in such an event, the clinical features of human h n disease may alter. ( ) the commonest presenting features of influenza during an epidemic are fever, cough and rhinorrhoea. in infants, fever with non-specific symptoms or diarrhoea and vomiting is common; in older children pharyngitis and headache are frequent. ( ) the clinical features of influenza in children during a pandemic cannot be forecast. ( ) children with underlying respiratory or cardiac disease, immune compromise or who are nonambulant are more likely to be severely affected. ( ) the younger the child the more likely hospital admission will be needed. the clinical features of influenza presenting in a pandemic cannot be predicted as they appear to be dependent on the strain of influenza and, in some respects, the host. a new strain of influenza a responsible for an epidemic or pandemic may result in a different spectrum of clinical features than previous strains , . common features during previous epidemics have been described and depend on the age of the child. the studies of clinical features are hospital based and are therefore likely to reflect more severe illness. these are nevertheless informative as one of the main issues in a pandemic is which patients require hospital admission. in young children presenting to primary care in a non-pandemic influenza season there are no specific clinical features that distinguish influenza from other winter viruses . neonates may present with non-specific signs of sepsis such as pallor, floppiness, (poor peripheral circulation, poor tone), lethargy, poor feeding, episodes of apnoea . fever may be the only presenting feature. a north american study identified influenza as the most common reason for children aged days being admitted to hospital during an epidemic with fever as the only clinical feature . fever may be the only presenting feature in this age group too. they may also be irritable and toxic and are more likely than older children to present with gastrointestinal symptoms such as diarrhoea and vomiting. febrile convulsions, particularly repeated convulsions, are positively associated with influenza a . otitis media is also a common complication in children . admission rates for under two year olds are times higher than for children aged years . the presentation does not differ significantly from adults. common features are sudden onset of high fever, chills ( %), cough, headache, sore throat, fatigue ( %), nasal stuffiness and conjunctivitis ( %) . fever tends to settle two to four days later though a dry cough and clear nasal discharge last for one to two weeks . a clinical prediction model from north america for influenza in children has shown that the triad of cough, headache and pharyngitis had a sensitivity of % and a specificity of % for a positive viral culture for influenza . the subjects, mean age six years, presented during an epidemic to a suburban emergency department with a febrile respiratory illness and one or more symptoms of influenza. a finnish retrospective study of children referred to hospital from to with influenza confirmed by antigen testing reported that the median age for those with influenza a was two years. the most common features were cough, fever and rhinorrhoea . these were also the commonest features reported in a chinese study where the mean age of the subjects with influenza a was four years . conditions these children (table . ) and those who are not ambulant experience substantial morbidity during influenza seasons, with a disproportionate number requiring inpatient care and ventilatory support. of the % of (table . ) as in adults, influenza can present with either primary viral pneumonia or bacterial pneumonia most commonly caused by s. pneumoniae or staph. aureus. there is much less published about pneumonia complicating influenza in children. an outbreak of severe pneumococcal pneumonia in children occurred in iowa in the winter of . this was coincident with an epidemic of influenza (h n ). compared with controls, patients were times more likely to have rare experienced a recent influenza-like illness. they were also more likely to have family members with the illness and to have positive serology in the convalescent period. many of these patients required chest drainage . another study in of children with proven influenza reported that who had chest radiographs had either radiographic evidence of viral pneumonia or normal radiographs. no child had lobar pneumonia reported . evidence from recent outbreaks of avian influenza (h n ) in hong kong and vietnam suggests that while some children had mild disease , others appeared to have multi-organ disease including acute respiratory distress syndrome (ards) . all children who developed progressive pneumonia with ards died. there were no reports of bacterial pneumonia. there is no reason to believe that, apart from ards, pneumonia complicating influenza presents differently from community-acquired pneumonia in children . the general clinical indicators for severity assessment of lower respiratory tract infection are summarised in the bts guidelines (appendix ). failure to improve following hours of antibiotics, or deterioration including a new, distinct spike of fever, should also be treated as severe and further complicating factors sought. the clinical course of croup caused by influenza appears to be more severe than croup caused by the more common parainfluenza virus . it is more likely to be complicated by bacterial tracheitis . influenza is a well recognised cause of otitis media . it is the commonest bacterial superinfection of influenza and is reported in approximately % of patients aged < years . influenza ranks second only to respiratory syncytial virus as a cause of bronchiolitis . the clinical features are the same . children with influenza may present with febrile convulsions. in a community study in the netherlands, recurrent febrile seizures were positively related to influenza a. it was recommended that children who have had a previous febrile convulsion should be immunised against influenza a . these complications are described in small case series. this is defined as depressed or altered level of consciousness including lethargy and/or extreme irritability in younger children or significant change in personality or behaviour persisting beyond hrs or confusion (older children). encephalopathy usually presents as seizures within several days of the onset of fever . seizures at this point are usually the first symptom of involvement of the central nervous system. febrile convulsions, which are more likely to be repeated with influenza than with other causes of fever, generally occur with the onset of fever. disturbances of behaviour and neurological deficit have been reported. a rapid and severe clinical course is usual with encephalopathy and is thought to be due to brain oedema mediated by cytokines rather than by direct invasion of the brain. steroids are therefore considered. children with encephalopathy were recognised in japan between and . death occurred in %, residual neurological deficit in % and full recovery in % . this is a rare childhood acute encephalopathy associated with liver dysfunction. the cause is unknown but it typically follows viral illness and there is a clear association with aspirin therapy: thus an innate susceptibility coupled with aspirin taken for relief of viral symptoms. influenza (particularly influenza b) is commonly implicated . there was a dramatic fall in incidence following warnings about aspirin use in children . it is possible that children on long term aspirin treatment for medical conditions may be at increased risk if they develop influenza infection. reye's syndrome is characterised by protracted vomiting and encephalopathy in afebrile patients with minimal or absent jaundice, and hepatomegaly in % of patients. it comprises: • acute non-inflammatory encephalopathy with an altered level of consciousness • elevation of ammonia levels hours after the onset of mental status changes (the most frequent laboratory abnormality) • hepatic dysfunction with a liver biopsy showing fatty metamorphosis or a more than three-fold increase in alanine aminotransferase (alt), aspartate aminotransferase (ast) neurological symptoms usually occur hours after the onset of vomiting. lethargy is usually the first neurological manifestation. diarrhoea and hyperventilation may be the first signs in children younger than two years. other investigations: head ct scanning may reveal cerebral oedema but results are usually normal. an electroencephalogram (eeg) may reveal slow wave activity in the early stages and flattened waves in advanced stages. cerebrospinal fluid may or may not have increased opening pressure with white blood cells (wbcs) fewer than /ml (usually lymphocytes). there is no specific treatment for reye's syndrome. key aspects of management are correction of metabolic imbalance and reduction of intracranial pressure. advice should be requested from a specialist in metabolic medicine. many children have an underlying inborn error of metabolism. mortality has fallen from % to less than % as a result of earlier diagnosis and more aggressive therapy. acute necrotising encephalopathy (ane): this occurs mainly in japan where it was first described in . an estimated deaths per annum are related to central nervous system complications of influenza in japan . this suggests either a genetic predisposition for this complication or a variation in the strains of influenza circulating in japan. ane is characterised by high fever, convulsions and coma in children aged one to five years. the onset is two to four days after the respiratory symptoms, and fewer than % of patients survive . there are no specific markers although some patients have raised liver transaminases. in many, the csf is normal. symmetrical multi-focal brain lesions are seen and bilateral thalamic involvement is characteristic and may be demonstrated on mri . this is defined as encephalopathy plus two of the following: fever of ºc or higher, seizures, focal neurological findings, wbc > cells/ml in csf, eeg findings consistent with encephalitis, abnormal neuro-imaging . these must be considered when a child presents with altered level of consciousness or irritability. there is good evidence of an increased risk of meningococcal disease following influenza infection . during a pandemic, the focus will be on diagnosing influenza-related illness. other neurological conditions or drug toxicity, for example, may be missed. a literature review of cases of myositis suggested that this was a complication mainly of schoolchildren. the calf muscles are predominantly affected. rhabdomyolysis and renal failure are rare. these are also rare complications but have been described in children with underlying medical conditions . section . general management and investigations in primary care with widespread concern during a pandemic, a significantly increased demand for advice and consultation should be anticipated. there are likely to be significantly higher consultation rates for all types of respiratory tract infections including those which are normally managed well at home using over-the-counter remedies (e.g. febrile colds, sore throat with temperatures). consequently, demand management in both the practice and the pct will be crucial to avoid the service's capacity to triage care being overwhelmed. guidance on demand management and health service delivery is given in the primary care operational plan (see section . ) . management decisions of patients with influenza should be based primarily on: • an assessment of illness severity • identification of whether the individual is in an 'at risk' group • current advice from doh/local public health officials based on the epidemiology of the pandemic patients who are not considered to be at high risk and who have no features suggesting severe disease or complications may not need to be seen in face to face consultations by a primary care clinician. all patients presenting in general practice with symptoms suggestive of influenza (except perhaps those in whom urgent admission is required) should be given general advice and advice on symptomatic treatment. it is important that clinicians identify and address individual concerns and expectations, provide information about the illness, and provide information about what patients can do to help themselves and when they should seek further help. some useful facts that can be provided to the patient are included in box . . there is little scientific evidence for most symptomatic and self-help treatment, but experience suggests that some of the following may help, and are unlikely to cause harm: • treat fever, myalgias and headache with paracetamol or ibuprofen • rest • drink plenty of fluids • avoid smoking • consider: short course of topical decongestants, throat lozenges, saline nose drops many infants and children will have coughs and mild fevers which may be due to other infections such as respiratory syncytial virus, especially over the winter months. these children should be managed in the usual way at home by parents with antipyretics and fluids. (note: aspirin should not be used in children.) management of these children is determined by disease severity (see appendix ). the principles of symptomatic management are similar to those for adults. box . . information about influenza to provide to patients • influenza is caused by a number different types of 'influenza' viruses. • the incubation period is typically one to four days and infected adults are usually contagious from the day of illness onset to five days after. children are typically contagious for seven days, although sometimes for longer. • fever usually declines after two to three days and normally disappears by the sixth day. • cough, weakness and fatigue can persist for one to two weeks and up to six weeks. • antibiotics do not benefit most people with influenza but are sometimes needed to treat secondary infections. (important note: this information may be modified once a pandemic occurs) • fever for four to five days and not starting to get better (or getting worse) • started to feel better then developing high fever and feeling unwell again • if taking antiviral drugs (eg. oseltamivir), symptoms should start to improve within two days. lack of any improvement after two days from starting antiviral drugs is an indication to re-consult. (important note: this information may be modified once a pandemic occurs) • children under one year of age year and those at high risk of complications (see appendix ) should be seen and assessed by a gp or at the a&e department. • children over one but under seven years of age may be seen by a nurse or a gp and those aged seven years and above may be seen by a member of the community health team (e.g. community pharmacist). • all children (and parents) should be given advice on antipyretics and fluids. • aspirin is contraindicated in children (aged under years). examples of what should prompt a patient to re-consult are given in box . . patients who are started on antiviral agents (see section for indications for antiviral use) would be expected to begin to improve within hours of starting treatment. failure to improve two days after starting an antiviral agent is an indication to re-consult. at the time of re-consultation, an alternative diagnosis should be considered as well as the occurrence of any influenzarelated complications. • any rapid deterioration following first consultation should prompt a patient to re-consult. • failure to improve two days after starting an antiviral agent is an indication to re-consult. • if the first consultation did not involve contact with a physician, re-consultation should preferably involve a physician, usually a gp. . . what general investigations should be done in the community? • general investigations, including a chest x-ray, are not necessary for the majority of patients managed in the community. the aim of microbiological investigations early in a pandemic (uk alert levels , and ) will be to confirm that influenza a is circulating in the local community. once a pandemic is established (uk alert level ), microbiological investigations are not recommended routinely or likely to be available readily. routine testing for bacterial pathogens is not recommended at any stage. • where possible, early in a pandemic (uk alert levels , and ), nose and throat swabs, or nasopharyngeal swabs (in children), in virus transport medium should be submitted to the local laboratory. • once a pandemic is established (uk alert level ), microbiological investigations are not recommended. section . criteria for hospital referral . . which adults require hospital referral? adults with uncomplicated influenza infection usually do not require hospital referral. patients who might require hospital admission fall into two main groups: those with worsening of a pre-existing medical condition and those with an influenza-related complication. patients who experience a worsening or clinical deterioration of pre-existing medical problems due to influenza infection should be managed according to recommended best practice for the medical condition in question. for instance, a patient with an acute exacerbation of copd triggered by influenza infection should be managed according to current nice guidelines for copd . those with a worsening of a pre-existing condition are likely to be in a group at 'high risk' of influenzarelated respiratory complications and consequently at risk § . criteria for hospital referral part . clinical management in primary care pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s . this group should be promptly reassessed if the illness is getting worse to consider hospital referral. pneumonia is the commonest influenza-related complication requiring hospital admission. patients complaining of new or worsening dyspnoea should be carefully assessed for signs of pneumonia. if pneumonia is diagnosed, disease severity assessment is recommended and hospital referral made accordingly. there is no validated severity assessment tool developed specifically for influenza-related pneumonia. the crb- score (table . ) is a well validated severity assessment tool developed for patients with community-acquired pneumonia (cap) , and recommended in the british thoracic society cap guidelines for use in the community setting . it is offered as an example of an assessment tool for influenza-related pneumonia. the use of any severity assessment tool does not replace clinical judgement. a patient's social circumstances should also always be taken into account. in view of the rapid and fulminant course of primary viral pneumonia, patients with pneumonia who have bilateral chest signs (crackles) should be considered for hospital referral. other influenza-related complications are uncommon. there are no specific recommendations relating to criteria for hospital admission or disease severity assessment in these cases. • patients with clinically defined uncomplicated influenza infection would be expected to make a full recovery. they require good symptomatic management, access to antiviral treatment, information about the natural history, and advice as to when to re-consult. • patients with new or worsening symptoms particularly shortness or breath or recrudescent fever not responding to treatment should be examined to assess the presence and severity of influenza-related pneumonia. • patients with worsening of pre-existing co-morbid medical conditions should be managed according to best practice for that condition with reference to published disease-specific guidelines, if available. • in patients with influenza-related pneumonia clinically, hospital referral and assessment should be considered for patients with a crb- score of or (particularly score ) and urgent admission for those with crb- score of or more. • patients with bilateral chest signs of pneumonia should be referred to hospital for further assessment regardless of crb- score. • the crb- score does not replace clinical judgment. • the antiviral treatment of choice is oseltamivir (tamiflu tm ). this is given as a five-day course of oral tablets; mg twice daily for adults. liquid suspension is available for children from the age of one year upwards. (see table . .) from clinical trial data accrued to date and based on seasonal, interpandemic influenza, the anticipated positive effect of antivirals in a pandemic will be: (a) a reduction of illness duration by hours, and therefore more rapid mobilisation of affected individuals including essential workers (b) a possible reduction in hospitalisation of infected individuals (c) a reduction of subsequent antibiotic use by infected individuals the evidence accrued to date does not suggest there will be a reduction of overall mortality, nor does it rule it out. . . who should receive antiviral drugs? • ideally, antiviral treatment should be offered to every patient who is over one year of age who (a) has an acute influenza-like illness (b) has fever ( ºc in adults, or . ºc in children) and (c) presents within hours of the onset of symptoms. • exceptions: (i) patients who are unable to mount an adequate febrile response, e.g. the immunocompromised or very elderly, may still be eligible for antiviral treatment despite the lack of documented fever. (ii) immunosuppressed patients, including those on long-term corticosteroid therapy, may suffer more prolonged viraemia, and could possibly benefit from antiviral therapy commenced later than hours after the onset of ili. (iii) patients who are severely ill, but who have not been hospitalised due to non-clinical reasons, may benefit from antiviral therapy commenced later than hours after the onset of ili. there is no strong evidence to support antiviral use in these exceptional situations. the commonest adverse effect of oseltamivir is nausea in about % of patients. this can be managed with mild anti-emetic medication. other side-effects are listed in appendix . national distribution arrangements are laid out in the uk operational framework for stockpiling, distributing and using antiviral drugs in the event of pandemic influenza and the primary care operational plan. the drug will be made available through these arrangements to pharmacies, pcts and/or gp surgeries. • pcts are encouraged to plan for the delivery of antivirals to the large numbers of previously healthy persons with an ili via community health professionals, including community pharmacists. • gps should focus their efforts on assessment and management of those persons at high risk of complications (see appendix ) and patients developing complications. section . antibiotic use in primary care the use of antibiotics in adults with influenza not complicated by pneumonia is determined by (a) the presence of any co-morbid illnesses and (b) the timing of first consultation with respect to the onset of symptoms. features of an acute bronchitis, with cough, retrosternal discomfort, wheeze and sputum production are an integral part of the influenzal illness. in previously well individuals who do not have pneumonia or new focal chest signs, antibiotics are not indicated. if the patient is seen later in the course of the illness and the illness is worsening, for instance with recrudescent fever or increasing breathlessness, a worsening bacterial bronchitis § . antibiotic use in primary care part . clinical management in primary care pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s or developing pneumonia is possible and the use of antibiotics should be considered. in selected patients, a delayed antibiotic prescription may be offered at first consultation. the antibiotic prescription should come with clear instructions that the antibiotics should be used if the illness is not starting to settle after two days or if there is worsening of symptoms. the potential advantage of this approach of delayed antibiotic prescription is to minimise rates of reconsultation . there are no robust data regarding the effect of such an approach on the incidence of influenzarelated complications. those at high risk of influenza-related complications because of (a) chronic obstructive pulmonary disease (copd) and/or (b) other severe co-morbid diseases should be strongly considered for antibiotics at first consultation. if, having started antibiotics, patients do not begin to improve over the next hours of antibiotic treatment (or if they get worse) they should be advised to re-contact their gp for assessment of pneumonia and its severity (see sections and ). antibiotics should cover the likely bacterial pathogens including s. pneumoniae, h. influenzae, m. catarrhalis and staph. aureus. the preferred first choice of antibiotic for nonpneumonic bronchial infections, including those patients with copd, should include an effective oral b-lactamase stable agent such as a tetracycline (e.g. doxycycline) or co-amoxiclav. a macrolide (e.g. erythromycin or clarithromycin) is an alternative for those intolerant of the preferred first choices, whilst remembering the possibility of antimicrobial resistance. clarithromycin has better activity against h. influenzae than azithromycin. further details regarding the principles of antibiotic use including antibiotic resistance patterns are given in section . • patients without severe pre-existing illnesses and who have uncomplicated influenza, or simple bronchitis, do not routinely require antibiotics. • patients without severe pre-existing illnesses who are seen later in the course of illness and who have developed significant worsening of symptoms (particularly recrudescent fever or increasing breathlessness) should be considered for antibiotics. • patients with copd and/or other severe pre-existing illnesses, and who are therefore at high risk of influenzarelated complications, should be strongly considered for antibiotics at first consultation. • most patients can be adequately treated with a week's course of oral antibiotics. • the preferred choice of antibiotic needs also to cover infection with staph. aureus for example either doxycycline or co-amoxiclav (see table . ). • a macrolide (e.g. erythromycin or clarithromycin) is an alternative choice in certain circumstances. the principles of antibiotic selection for patients with influenza-related pneumonia who can be managed in the community are similar to those for the management of sporadic community-acquired pneumonia in general except that adequate cover for staph. aureus, in addition to cover for s. pneumoniae, should be included in any empirical regimen. for this reason a tetracycline, such as doxycycline or oral co-amoxiclav, is the preferred regimen (table . ). a macrolide (e.g. erythromycin or clarithromycin) is an alternative for those intolerant of the preferred first choices. macrolide (erythromycin mg qds po or clarithromycin mg bd b po) a an alternative regimen is provided for those intolerant of or hypersensitive to the preferred regimen. b clarithromycin may be substituted for those with gastrointestinal intolerance to oral erythromycin and also has the benefit of twice daily dosage and better cover against h. influenzae. abbreviations: od, once daily; bd, twice; tds, times; qds, times. secondary bacterial infections particularly pneumonia and otitis media are common in children with influenza. s. pneumoniae, staph. aureus and h. influenzae are the most common pathogens encountered during influenza outbreaks. • children in any one of the following groups should be treated with an antibiotic that will provide cover against s. pneumoniae, staph. aureus and h. influenzae: ( ) those at risk of complications of influenza (see appendix ). ( ) those with one or more of the following adverse features: (a) breathing difficulties (b) severe earache (c) vomiting for more than hours (d) drowsiness. part . clinical management of adults referred to hospital section . severity assessment of adults referred to hospital . . what severity assessment strategy is recommended for patients referred to hospital with influenzarelated pneumonia? there is no validated severity assessment tool developed specifically for influenza-related pneumonia. the curb- severity assessment tool as described in the bts cap guidelines is recommended for the stratification of hospitalised patients with influenza-related pneumonia into disease severity groups (table . ). in addition, the presence of diffuse bilateral lung infiltrates on chest radiography consistent with primary viral pneumonia is an adverse prognostic feature. such patients should be treated as for severe pneumonia. in all instances, clinical judgement is essential when assessing disease severity. • patients with bilateral lung infiltrates on chest radiography consistent with primary viral pneumonia should be managed as having severe pneumonia regardless of curb- score. • in hospital, patients with influenza-related pneumonia who have a curb- score of or more are at high risk of death and should be managed as having severe pneumonia. • patients who have a curb- score of are at increased risk of death. they should be considered for short stay inpatient treatment or hospital-supervised outpatient treatment. this decision is a matter of clinical judgement. • patients who have a curb- score of or are at low risk of death. they can be treated as having non-severe pneumonia and may be suitable for home treatment. . . when should transfer to a high dependency unit (hdu) or intensive care unit (icu) be considered? the indications for transfer to hdu or icu are no different in patients with influenza infection compared to other patients. most patients who might require hdu/icu care will have influenza-related pneumonia or a severe exacerbation of underlying comorbid illness, e.g. exacerbation of copd. in a pandemic situation when hdu/icu beds may not be readily available, prioritisation of patients on an individual basis matched against available resources will be expected. • patients with primary viral pneumonia or a curb- score of or should be considered for hdu/icu transfer. • general indications for hdu/icu transfer include: ( ) persisting hypoxia with pao < kpa despite maximal oxygen administration ( ) progressive hypercapnia ( ) severe acidosis (ph < . ) ( ) septic shock • patients with influenza admitted to an intensive care unit should be managed by specialists with appropriate training in intensive care, respiratory medicine and/or infectious diseases. in acute uncomplicated influenza the chest x-ray is usually normal. when primary viral pneumonia occurs as a complication, particularly in elderly adults the chest x-ray often shows multiple infiltrates or consolidation. cavitations or pleural changes suggest bacterial superinfection. in combined viral-bacterial pneumonia, the clinical features typically appear later than primary viral pneumonia and the chest x-ray often shows cavitation or pleural effusions. secondary bacterial pneumonia usually occurs after apparent improvement from the viral infection; the chest x-ray may show consolidation. • a chest x-ray should be obtained during assessment of a suspected case of influenza seen in the hospital setting (accident and emergency department or acute admissions ward). • in those patients who are subsequently followed up in a hospital outpatient clinic or by a general practitioner a repeat chest x-ray should be obtained at around six weeks if respiratory symptoms or signs persist or where there is a higher risk of underlying malignancy (especially smokers and those over years of age). • further investigations including a ct thoracic scan, and bronchoscopy should be considered if the chest x-ray remains abnormal at follow up . in those patients with illness severe enough to present to secondary care the following tests may be useful: full blood count: a leucocytosis with left shift may occur in those with primary viral pneumonia, mixed viralbacterial pneumonia or secondary bacterial pneumonia. (lymphopenia has been noted in human cases of severe avian h n influenza.) urea and electrolytes may reveal evidence of hypo or hypernatraemia or renal impairment. liver function tests are usually normal. creatine kinase (ck) may be elevated in those with severe myalgia. c-reactive protein (crp) is unlikely to be helpful except where superimposed bacterial infection is suspected . however, the diagnostic value of crp in lower respiratory tract infections remains controversial . • the following blood tests should be obtained in patients admitted to hospital: ( ) full blood count; ( ) urea, creatinine and electrolytes; ( ) liver function tests; ( ) creatine kinase (if myositis is suspected). • in patients with suspected secondary bacterial infection, the c-reactive protein (crp) level may aid diagnosis. in acute uncomplicated influenza larger airway function remains normal. however, there is often an increase in bronchial reactivity which may persist for many weeks after resolution of the infection . lung function tests are unnecessary in most patients. section . microbiological investigations for adults in hospital . . introduction the guidelines provided below are based on the assumption that when cases are first occurring in the uk as part of a global pandemic, it will be possible to perform full microbiological investigations in all new cases of influenzalike illness and influenza-related pneumonia. as case numbers rise, possibly to pandemic levels, full or indeed any microbiological investigation will become increasingly difficult. thus, data on the relative frequency of different bacterial causes of influenza-related pneumonia and their antimicrobial susceptibilities amongst investigated cases gathered earlier in the pandemic should be available to guide and refine empirical antimicrobial therapy choices for cases occurring later in the pandemic. the most likely pathogens implicated in influenzarelated pneumonia are streptococcus pneumoniae, staphylococcus aureus, haemophilus influenzae and to a lesser extent b-haemolytic streptococci (see section . ). in the early phases (uk alert levels , and see appendix ) of a pandemic, microbiological diagnostic approaches should focus on confirming influenza as the primary illness, defining bacterial causes of influenza-related pneumonia, and optimizing both specific (for individual patients) and general (for populations) antimicrobial treatment recommendations. in later pandemic phases (uk alert level ) with the much higher caseloads anticipated, microbiological investigation should be focused on patients with severe influenza-related pneumonia unresponsive to empirical antimicrobial therapy. actual and practical local level transition to less intense microbiological investigation may occur at uk alert level in some regions as the number of local cases is likely to vary between regions. § . microbiological investigations for adults in hospital part . clinical management of adults referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s it will be necessary to perform full microbiological investigations on all hospitalised cases, including patients with severe and non-severe influenza-related pneumonia, in order to: confirm influenza as the primary infection, optimize treatment options for the patients investigated and define the most common bacterial causes of influenzarelated pneumonia and their antimicrobial susceptibility patterns. the latter data will help to inform empirical antimicrobial therapy of subsequent cases for which microbiological investigation may not be undertaken fully, or at all. in influenza, rapid virological tests, viral culture and pcr of respiratory samples will yield positive results between one and seven days after illness onset. however, if presentation is more than seven days after the onset of influenzalike illness then such sampling and testing is unhelpful. instead, serum samples for serological testing for evidence of recent influenza infection are recommended. specific detailed microbiological guidance for taking and handling specimens from individuals at risk of avian influenza prepared by prof maria zambon of health protection agency (hpa) centre for infections is available at: www.hpa.org.uk/infections/topics_az/avianinfluenza/ guidance/microbiological_guidance.htm bacteriological investigations are only recommended in patients with influenza-related pneumonia. legionella pneumophila infection is not normally associated with influenza-related pneumonia. despite this, legionella urine antigen tests should be performed on severe cap cases in the early stages of an outbreak/incident in order to confirm legionella infection is not the reason for a local increase in pneumonia admissions. these recommendations are modified from those contained in the british thoracic society community acquired pneumonia (bts cap) guidelines [thorax ; (suppl iv), see sections . , . and . (pp. iv iv )] and the update (see pages ), both available at: www.brit-thoracic.org.uk/ iqs/bts_#guidelines_pneumonia_html. sputum investigative efforts must be focused on quality samples (i.e. those from patients who are able to expectorate purulent samples, and have not received prior antibiotic treatment) and not dissipated on large numbers of poor quality samples. it is important to acknowledge that the criteria for quality samples may only be met for a minority of admissions. laboratories should offer a reliable sputum gram stain for appropriate samples, as on occasions this can give immediate indication of likely pathogens. the most likely influenzarelated pneumonia pathogens are s. pneumoniae, staph. aureus and h. influenzae, all of which may present a characteristic appearance on gram stain of purulent sputum. laboratories performing sputum gram stains should adhere to strict and locally agreed criteria for interpretation and reporting of results. a. virology all patients: • nose and throat swabs in virus transport medium should be collected from all patients and submitted to the local laboratory. the relevant laboratory should be notified of the suspected diagnosis and there should be close liaison over sample collection, handling and transport. • rapid testing by direct immunofluorescence or rapid eia test, virus culture and/or pcr should be undertaken according to local availability and/or referred to an appropriate laboratory • during uk alert level , when the uk is on high alert for the first cases of pandemic influenza, suspected cases are likely to be investigated by local health protection teams from the health protection agency and its partner organisations in the devolved administrations. • during uk alert levels and , clinicians dealing with suspected cases of pandemic influenza should ensure that the local health protection team is informed and involved from the outset. • the health protection agency and its partner organisations in the devolved administrations have established a network of more than laboratories across the uk which have been proficiency tested in molecular diagnosis of influenza a/h n . access to this service should be via local health protection teams. • if presentation is more than seven days after onset of illness, an 'acute' serum ( ml clotted blood) should be collected and a 'convalescent' sample ( ml clotted blood) obtained after an interval of not less than seven days. the two sera should be examined serologically for evidence of recent influenza infection. b. bacteriology patients with influenza-related pneumonia: • the following bacteriological tests should be performed: ( ) blood culture (preferably before antibiotic treatment is commenced) ( ) pneumococcal urine antigen ( ml urine sample). agents. acute serum should be collected and a 'convalescent' sample obtained after an interval not less than seven days (both ml clotted blood) and the two sera stored for subsequent testing. once a pandemic is established, virological investigations are not recommended routinely and in a pandemic situation may not be readily available. the diagnosis of influenza will be based on clinical findings. if influenza-related pneumonia is present, the degree of microbiological investigation will be directed by disease severity and the presence of co-morbidities. in influenza-related pneumonia, examination of sputum should be considered for patients who do not respond to empirical antibiotic therapy. this will be particularly relevant if staph. aureus is identified as a common influenza-related pneumonia pathogen during the early phase of the pandemic as, in contrast to s. pneumoniae and h. influenzae, antimicrobial susceptibilities of this organism are less predictable and empirical choices more speculative. a. virology not routinely recommended. b. bacteriology patients with influenza-related pneumonia: (i) non-severe pneumonia (curb- score , or ) • sputum samples should be sent for gram stain culture and antimicrobial susceptibility tests in patients who do not respond to empirical antibiotic therapy. (ii) severe pneumonia (curb- score , or ) • specific investigations should include: ( ) blood culture, preferably before antibiotic treatment is commenced. ( ) pneumococcal urine antigen ( ml urine). ( ) sputum gram stain, culture and antimicrobial susceptibility tests on samples obtained from patients who: (i) are able to expectorate purulent samples, and (ii) have not received prior antibiotic treatment. sputum specimens should be transported rapidly to the laboratory. ( ) paired serological examination for influenza/ other agents. 'acute' serum should be collected and a 'convalescent' sample obtained after an interval not less than seven days (both ml clotted blood) and the two sera stored for subsequent testing. ( ) tracheal or endotracheal aspirate samples, if available, should be sent for gram stain, culture and antimicrobial susceptibility testing. section . general management of adults admitted to hospital initial management will depend on the assessment of the reason for admission, the presence of complications, and the impact of the influenza on any pre-existing disease, or psychosocial factors. for instance, some elderly patients may require admission for social reasons. in broad terms, the most likely clinical reasons for admission will be (in order of frequency): • lower respiratory tract complications: non pneumonic bacterial exacerbation of chronic lung disease such as copd (possibly with a mixed viral infection) secondary bacterial pneumonia mixed bacterial and viral pneumonia primary viral pneumonia • cardiac complications: exacerbation of pre-existing cardiac disease with cardiac failure and/or arrhythmia primary myocarditis • other complications: exacerbation of other pre-existing disease, such as diabetes mellitus neurological complications rhabdomyolysis severe sinusitis the initial management is likely to most usually involve that of respiratory and cardiac complications, especially pneumonia and these are discussed below. management of other less common primary influenzal complications (such as rhabdomyolysis, encephalopathy) is not covered. all influenza patients admitted to hospital with abnormal cardiorespiratory symptoms and signs, including influenzarelated pneumonia, should have a chest radiograph and an electrocardiogram and should have oxygenation assessed by pulse oximetry, preferably whilst breathing air (see section ). those with sao < % should have arterial blood gas measurements, as should all patients with features of severe illness. knowledge of the inspired oxygen concentration is essential to the interpretation of blood gas measurements and should be clearly recorded with the blood gas result. continuous oxygen therapy is indicated for those patients with pao < kpa, hypotension with systolic bp < mmhg, metabolic acidosis with bicarbonate < mmol/l or respiratory distress with respiratory rate > /min . the aim of oxygen therapy should be to maintain pao at > kpa or sao > %. unless complicated by severe chronic obstructive pulmonary disease with ventilatory failure, high concentrations of oxygen of % or greater are indicated and can be safely used. high concentration oxygen therapy given to patients with pre-existing chronic obstructive pulmonary disease § . general management of adults admitted to hospital part . clinical management of adults referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s who may have co retention can reduce hypoxic drive and increase ventilation-perfusion mismatching. in such patients initial treatment with low oxygen concentrations ( %) should be progressively increased on the basis of repeated arterial blood gas measurements, the aim being to keep sao > % without causing a fall in arterial ph below . , in line with the management strategy recommended in the nice copd guidelines . non-invasive ventilation (niv) may be of value in patients with copd who are in acute hypercapnic respiratory failure , . the use of niv in patients with respiratory failure due to severe pneumonia but without co-existing copd has not been shown to influence mortality , . nevertheless, during an influenza pandemic when critical care level beds are in high demand, niv may be of value as a bridge to invasive ventilation in specific circumstances. in all instances, the risks of infection due to the dissemination of respiratory droplets related to the use of niv must be taken into account when deciding on management strategies. respiratory and/or critical care units experienced in the use of niv are best placed to ensure the appropriate infection control measures are adopted and observed at all times, including the use of personal protection equipment (ppe) (see uk infection control guidance for pandemic influenza) . all patients should be assessed for volume depletion and may require iv fluids. the potential for influenza to cause cardiac decompensation, either through exacerbation of pre-existing cardiac disease or from a primary myocarditis, should be borne in mind, with any complicating heart failure and arrhythmias being managed in the usual way. physiotherapy may be of benefit in selected patients with excess bronchial secretions, particularly those with concurrent chronic obstructive pulmonary disease. in cases of severe illness requiring prolonged hospital admission, increased nutritional support whether enteral, parenteral or via naso-gastric feeding should be arranged. • hypoxic patients should receive appropriate oxygen therapy with monitoring of oxygen saturations and inspired oxygen concentration with the aim to maintain pao > kpa and sao > %. high concentrations of oxygen can safely be given in uncomplicated pneumonia. • oxygen therapy in patients with pre-existing copd complicated by ventilatory failure should be guided by repeated arterial blood gas measurements. non-invasive ventilation may be helpful. • in patients without pre-existing copd who develop respiratory failure, niv may be of value as a bridge to invasive ventilation in specific circumstances when critical care level beds are in high demand. respiratory and/or critical care units experienced in the use of niv are best placed to ensure the appropriate infection control measures are adopted at all times. • patients should be assessed for cardiac complications and also volume depletion and their need for additional intravenous fluids. • nutritional support should be given in severe or prolonged illness. . . what monitoring should be conducted during a hospital stay? pulse, blood pressure, respiratory rate, temperature, oxygen saturation (with a recording of the inspired oxygen concentration at the same time) and mental status should be measured initially at least twice daily. this is most conveniently performed using an early warning score (ews) chart, which all ward staff should be familiar with. those with severe illness, requiring continuous oxygen or cardiovascular support, should be monitored more frequently. failure to improve clinically within hours should result in a full clinical reassessment and failure to improve over days is an indication to repeat the chest radiograph. • temperature, respiratory rate, pulse, blood pressure, mental status, oxygen saturation and inspired oxygen concentration should be monitored and recorded initially at least twice daily and more frequently in those with severe illness or requiring regular oxygen therapy. • an early warning score system is a convenient way to perform this. • in addition to a full clinical reassessment, a chest radiograph should be repeated in patients who are not progressing satisfactorily. there will be considerable pressure to discharge patients early during a pandemic. the type and availability of out-of-hospital facilities will dictate hospital discharge decisions. some guidance regarding simple parameters to review when considering hospital discharge can be obtained from a recent us prospective, multi-centre, observational cohort study of patients admitted to hospital with cap , and is offered as advice for all patients admitted with influenza-related respiratory complications. • patients should be reviewed before hours of discharge home. those with two or more of the following unstable clinical factors should be considered for continued hospital management: ( ) temperature > . ºc, ( ) heart rate > /min, ( ) respiratory rate > /min, ( ) systolic blood pressure < mmhg, ( ) oxygen saturation < %, ( ) inability to maintain oral intake, it is usual practice to arrange 'routine' hospital clinic follow up and repeat the chest radiograph at around six weeks after discharge for acute respiratory illness such as pneumonia. however, there is no evidence on which to base a recommendation regarding the value of this practice in patients who have otherwise recovered satisfactorily. it is also not known whether there is any value in arranging clinical follow up in a hospital clinic rather than with the patient's general practitioner. during an influenza pandemic situation, it is likely that only patients who developed complications or who had significant worsening of their underlying disease will be offered clinical review at one or other venue. at discharge, patients should be offered access to information about their take-home medication, smoking and lifestyle advice as appropriate, potential future complications and action to take in the event of a relapse of symptoms. • follow-up clinical review should be considered for all patients who suffered significant complications or who had significant worsening of their underlying disease, either with their general practitioner or in a hospital clinic. • at discharge or at follow up, patients should be offered access to information about their illness, take-home medication and any follow-up arrangements. • it is the responsibility of the hospital team to arrange the follow-up plan with the patient and the general practitioner. section . use of antivirals in hospitalised adults . . what drugs should be used for antiviral treatment during a pandemic? oseltamivir (neuraminidase inhibitor) will be the mainstay for therapy in the pandemic. the m inhibitors, amantadine and rimantadine, are unsuitable for use for treatment due to the rapid emergence of resistance together with sideeffects. from clinical trial data accrued to date and based on seasonal, interpandemic influenza, the anticipated positive effect of antivirals in a pandemic will be: (a) a reduction of illness duration by hours, and therefore more rapid mobilisation of affected individuals including essential workers; (b) a possible reduction in hospitalisation of infected individuals; (c) a reduction of subsequent antibiotic use by infected individuals. there is insufficient evidence accrued to date to determine the effect of antivirals, if any, on overall mortality. therefore the major utility of antivirals will be to maintain the essential workforce, and reduce hospitalisation and antibiotic treatment of complications. (neuraminidase inhibitors) during a pandemic? • individuals should only be considered for treatment with neuraminidase inhibitors if they have all of the following: ( ) an acute influenza-like illness ( ) fever (> ºc) and ( ) been symptomatic for two days or less • treatment schedule: adults: oseltamivir mg every hours for days. dose to be reduced by % if creatinine clearance is less than ml/minute. • exceptions: (i) patients who are unable to mount an adequate febrile response, e.g. the immunocompromised or very elderly, make still be eligible despite lack of documented fever. (ii) hospitalised patients who are severely ill, particularly if also immunocompromised, may benefit from antiviral treatment started more than hours from disease onset. this advice reflects the lack of robust evidence to guide the use of antivirals in these exceptional circumstances and places a high value on the potential benefits of antiviral therapy. drugs available for treatment and prevention of infection by influenza are summarised in table . . there are four drugs available, the older agents amantadine and rimantadine and the neuraminidase inhibitors oseltamivir and zanamivir. older agents: the older agents, amantadine and rimantadine (rimantadine is not currently licensed in the uk), are related substances that act by blocking the ion-channel function of the influenza virus m protein. this protein, although a minor surface constituent of the influenza virus particles, is essential for virus replication. these agents are only active against influenza type a. amantadine is not recommended by nice for treatment and/or prophylaxis of interpandemic influenza, so in the absence of national stockpiling, supplies of amantadine can be expected to be very low. h viruses in south east asia are resistant to amantadine, so this agent may play no role at all depending on the nature of the pandemic strain. two neuraminidase inhibitors so far have been developed to the level of entry into the formulary: zanamivir is a modification of neu ac en, a dehydrated neuraminic acid derivative. oseltamivir is a similar molecule except it has a cyclohexene ring and replaces a polyglycerol moiety with lipophilic sidechains. oseltamivir can be taken by mouth, whereas zanamivir must be inhaled, using a diskhaler device. an intravenous formulation of zanamivir has been developed but its efficacy has not been established. this may be relevant for the management of ventilator cases. both drugs are active against influenza type a as well as type b viruses. older agents. both amantadine and rimantadine are effective for the treatment of type a influenza virus infection if treatment is begun within hours of the onset of illness . historical data show that they can shorten the illness by approximately one day but their efficacy in preventing complications, hospitalisations, or deaths has never been established. although these drugs are effective, their use in clinical influenza treatment has been limited as a result of their proclivity to induce viral resistance, and their side-effect profile. several large clinical trials have demonstrated the utility of zanamivir and oseltamivir in treatment of adults with influenza in the community ( virtually all studies on the efficacy of neuraminidase inhibitors to reduce complications have been conducted with oseltamivir, and this drug has been shown to have some effect on outcomes other than time to recovery. in a meta-analysis of adults and adolescents with a virologically proven influenza illness, oseltamivir treatment reduced overall antibiotic use for any reason by . so far, the neuraminidase inhibitors have not been extensively investigated in patients who are at the highest risk of serious complications of influenza. such patients include the elderly and those with serious cardiopulmonary illness, such as chronic obstructive pulmonary disease. the neuraminidase inhibitors have not been associated with a reduction in mortality, but the clinical trials conducted so far have not been appropriate to measure this. it is not known for certain whether the neuraminidase inhibitors will be effective in pandemic influenza because their use has only been assessed in inter-pandemic influenza, where the virulence is moderate and there is some degree of host immunity. the antiviral activity is likely to be adequate; in vitro, all neuraminidase inhibitors have been demonstrated to have a broad spectrum of activity against multiple avian influenza viruses . the older agents, rimantadine and amantadine, were studied in both the hong kong pandemic and again when h n influenza appeared in a pandemic in . their efficacy has been reviewed by hayden . when the older agents were given for four to eight week periods as prophylaxis in a community setting, their protective efficacy against influenza illness averaged % compared with placebo. this compares with % efficacy observed with the same agents in studies during the interpandemic period. when amantadine or rimantadine are used to treat patients, resistant viruses emerge rapidly and approximately % of treated children or adults will shed resistant variants starting two to five days after the onset of treatment . the resistant viruses shed from these patients retain full virulence, infectivity and transmission potential. when contacts of cases treated with amantadine or rimantadine are given post-exposure prophylaxis with these older agents, the reduction in secondary cases is minimal . in contrast, the frequency of emergence of resistance during treatment with the neuraminidase inhibitors is reported to be low. however, during studies of experimentally induced influenza a/h n infection in healthy adults, % of participants shed viruses with a histidine to tyrosine substitution at position within the binding site of oseltamivir . in these cases the volunteers had increased influenza viral load within the nasopharynx but there was no deterioration of symptoms. so far, there have been no proven instances of transmission of oseltamivir or zanamivir-resistant variants in field clinical trials, but the experience is relatively small currently. sequence analysis of h n human isolates from north vietnam have revealed virus with a y (resistant) sequence. although the isolate was not fully resistant, its ic for oseltamivir was shifted upwards and it is therefore less susceptible to oseltamivir than other h n isolates that had been tested from the region. the patient from whom the virus was isolated was concurrently being treated with oseltamivir. both amantadine and rimantadine can cause nausea and vomiting in a small percentage of individuals receiving them (table . ). unfortunately amantadine is also associated with very unpleasant central nervous system side-effects including anxiety, depression, insomnia and hallucinations. the side-effects are dose-related and do resolve with discontinuation of the drug. in the case of the neuraminidase inhibitors, both drugs appear relatively safe. zanamivir has very few side-effects, but can result in bronchospasm which might be potentially serious in patients with asthma. oseltamivir requires dose-reduction in patients with low creatinine clearance (< ml/min). nausea occurs in % of oseltamivir recipients but is seldom severe enough to lead to drug discontinuation (see table . ). antimicrobial chemotherapy will be indicated primarily for respiratory complications due to secondary bacterial infections, principally influenza-related pneumonia. the majority of patients with exacerbations of chronic obstructive pulmonary disease (copd) and other chronic lung conditions due to secondary bacterial infections, such as bronchiectasis, will also require antimicrobial chemotherapy, as will some patients with severe sinusitis. few pneumonias and lower respiratory tract infections are defined microbiologically at initial assessment and hence most prescribing is empirical. in broad terms the antimicrobial management of these patients should follow the guidance offered in relevant national guidelines for the management of community-acquired pneumonia and copd, but modified in the light of the different range of pathogenic bacteria that may be implicated, specifically staph. aureus infection. in the minority of cases, the aetiology may be determined after hospital admission, thereby permitting modification of the initial empirical regimen. although the pathogens responsible for communityacquired pneumonia are diverse, in the case of bacterial pneumonia complicating influenza the principal pathogens which should be covered by any initial empirical antimicrobial therapy include s. pneumoniae, h. influenzae and staph. aureus. the latter is said to be more common with combined viral bacterial pneumonia, as some strains of staphylococci have synergistic effect with the virus. gram-negative enteric bacillary infection is also sometimes seen. exacerbations of copd will be largely associated with s. pneumoniae, h. influenzae, and moraxella catarrhalis. severity assessment and the association of pre-existing co-morbid disease is essential in predicting prognosis and in turn determines management, choice of antibiotic therapy and its method of administration (see section ). during an influenza pandemic this will be principally related to concerns about the local pattern of antimicrobial resistance of staph. aureus, and assessing the possibility of methicillin-resistant s. aureus (mrsa) being present locally. clinicians should be kept closely informed of any local shift in antimicrobial resistance patterns, both at the start and during a pandemic. staphylococcus aureus is widely resistant to penicillin and an increasing number are now methicillin-resistant (mrsa); when occurring in the community this generally reflects hospitalisation within the recent past or residence within a nursing home . hence, b-lactamase unstable penicillins (penicillin g, aminopenicillins) and, in the case of mrsa, isoxazolyl penicillins (flucloxacillin, cloxacillin) and cephalosporins, are inappropriate for such infections. the true incidence of resistance among pathogens in the community is difficult to estimate since most laboratory samples come from selected populations. with this limitation in mind, the presence of b-lactamase production among h. influenzae varies geographically but ranges from % to % , in various parts of the uk. m. catarrhalis has a high rate of b-lactamase production. antibiotic resistance among s. pneumoniae is of concern world wide, owing to the dominance of this organism as a cause of community-acquired pneumonia and because penicillin and macrolide resistance are frequently linked , . however, to date it is not a common enough problem in the uk to influence initial antimicrobial management decisions. recent data provided by the hpa of antimicrobial sensitivities of respiratory pathogens isolated from blood and respiratory samples during the last three to four years (robert george, personal communication) found macrolide resistance amongst about % methicillinsensitive staphylococcus aureus (mssa) isolates and % of s. pneumoniae. macrolides, apart from clarithromycin, have poor in vivo activity against h. influenzae. by contrast, tetracycline resistance was around % for s. pneumoniae, % for h. influenzae and % for mssa. fluoroquinolones have activity against methicillinsensitive staphylococcus aureus (mssa), with mic figures of . mg/l for ciprofloxacin, . mg/l for levofloxacin and . mg/l for moxifloxacin . modern fluoroquinolones (oral moxifloxacin and oral and iv levofloxacin currently licensed in the uk) are therefore a possible choice for secondary bacterial infections following influenza where mssa is a likely pathogen. a recent pharmacokinetic and pharmacodynamic in vitro study indicated that moxifloxacin mg od had advantages over ciprofloxacin mg bd or levofloxacin mg od in antimicrobial effects against staph. aureus . the quinolones, levofloxacin or moxifloxacin, also provide cover against s. pneumoniae and h. influenzae. mrsa is an unlikely pathogen in the uk in the context of community-acquired respiratory bacterial infection following influenza, and fluoroquinolones are not sufficiently active against mrsa. there are no robust research studies available to provide evidence-based guidance on the best empirical choice of antimicrobial therapy for bacterial complications of influenza. for these reasons the recommendations for treatment have been made on the basis of assessing a matrix of laboratory, clinical, pharmacokinetic and safety data, interpreted in an informed manner and taking account of other published guidelines . in those with chronic lung disease, particularly copd, bacterial exacerbation will be the commonest cause of admission. it is likely that all such patients sufficiently ill to require hospital admission with an exacerbation will require antibiotics. management of their underlying macrolide (erythromycin mg qds po or clarithromycin mg bd b po) or fluoroquinolone with enhanced pneumococcal activity (e.g. levofloxacin mg od po or moxifloxacin mg od po c ) if iv needed: co-amoxiclav . g tds iv or cefuroxime . g tds iv or cefotaxime g tds iv macrolide (erythromycin mg qds iv or clarithromycin mg bd b iv) or levofloxacin mg od iv c . hospital-treated, severe pneumonia co-amoxiclav . g tds iv or cefuroxime . g tds iv or cefotaxime g tds iv plus macrolide (erythromycin mg qds iv or clarithromycin mg bd b iv) fluoroquinolone with some enhanced pneumococcal activity (e.g. levofloxacin mg bd iv, po c plus, either macrolide (erythromycin mg qds iv or clarithromycin mg bd b iv) or b-lactamase stable antibiotic (co-amoxiclav . g tds iv or cefuroxime . g tds iv or cefotaxime g tds iv) a an alternative regimen is provided for those intolerant of or hypersensitive to the preferred regimen. b clarithromycin may be substituted for those with gastrointestinal intolerance to oral erythromycin and also has the benefit of twice daily dosage and better cover against h. influenzae. c levofloxacin and moxifloxacin are the only currently uk-licensed fluoroquinolones with enhanced activity against s. pneumoniae, in addition to cover for staph. aureus. levofloxacin comes in an oral and a parenteral formulation and is licensed for severe pneumonia. moxifloxacin comes in an oral formulation only in the uk and is not licensed for severe pneumonia. in the future, other fluoroquinolones such as gemifloxacin and gatifloxacin are likely to extend this choice, when licensed in the uk. abbreviations: od, once daily; bd, twice; tds, times; qds, times: iv, intravenous; po, oral. switch from parenteral drug to the equivalent oral preparation should be made as soon as clinically appropriate, in the absence of microbiologically confirmed infection. in the case of the parenteral cephalosporins, the oral switch to co-amoxiclav mg tds is recommended rather than to oral cephalosporins. condition, such as copd, should follow standard guidelines, including the use of corticosteroids if indicated. antibiotics should cover the likely bacterial pathogens, including s. pneumoniae, h. influenzae, m. catarrhalis and staph. aureus. oral therapy should be sufficient for those without adverse severity features and who are able to take oral medication. the preferred first choice of antibiotic for nonpneumonic bronchial infections should include an effective oral b-lactamase stable agent such as co-amoxiclav, or a tetracycline, such as doxycycline. a macrolide is an alternative for those intolerant of the preferred first choices, whilst remembering the possibility of antimicrobial resistance. clarithromycin has better activity against h. influenzae than azithromycin. a newer-generation fluroquinolone (e.g. levofloxacin or moxifloxacin) with enhanced activity against s. pneumoniae is an alternative choice if there is increased likelihood of resistance or local issues that dictate such a choice. • previously well adults with acute bronchitis complicating influenza, in the absence of pneumonia, do not routinely require antibiotics. • antibiotics should be considered in those previously well adults who develop worsening symptoms (recrudescent fever or increasing dyspnoea). • patients at high risk of complications or secondary infection (appendix ) should be considered for antibiotics in the presence of lower respiratory features. • most patients can be adequately treated with oral antibiotics. • the preferred choice includes co-amoxiclav or a tetracycline. • a macrolide such as clarithromycin (or erythromycin) or a fluoroquinolone active against s. pneumoniae and staph. aureus is an alternative choice in certain circumstances. patients will be suffering from primary viral pneumonia, or combined viral bacterial pneumonia, or secondary bacterial pneumonia. the features of each of these are covered in section . all patients with pneumonic involvement should receive antibiotics. the principles of antibiotic selection for nonsevere influenza-related pneumonia is similar to those for the management of sporadic community-acquired pneumonia in general , except that adequate cover for staph. aureus should be included in any empirical regimen. it is also not felt necessary to routinely provide cover for atypical pathogens (mycoplasma pneumoniae, chlamydia sp., coxiella burnetti, legionella sp.) during a pandemic as the large majority of patients will be hospitalised as a direct result of influenza and its complications caused by bacterial infection. for these reasons oral co-amoxiclav or a tetracycline such as doxycycline is the preferred regimen (table . ). when oral therapy is inappropriate, parenteral coamoxiclav or a second-or third-generation cephalosporin is offered as an alternative. based on in-vitro data, the activity of selected cephalosporins against mssa in the uk in descending rank order is cefuroxime (mic mg/l) > cefotaxime (mic mg/l) > ceftriaxone (mic mg/l) [robert george, personal communication]. only cefuroxime and cefotaxime are recommended as cephalosporins offering adequate mssa cover within an empirical regimen. a macrolide or one or the new fluoroquinolones are identified as alternatives in hospitalised patients, in specific circumstances. these include those intolerant of penicillins or where local microbiological surveillance suggests they are better choices. at the time of completing these guidelines, only levofloxacin and moxifloxacin are licensed and available in the uk for pneumonia. flucloxacillin is not recommended as part of an empirical regimen because its activity against a narrow spectrum of pathogens (predominantly staph. aureus) would require it to be used in combination with more than one other antibiotic. it is offered as the antibiotic of choice in confirmed methicillin-sensitive staph. aureus (mssa) infection. regardless of the regimen selected it is critical that the antibiotics be administered promptly (within four hours of admission), and in the case of the patient with severe pneumonia without delay, by the admitting doctor in the admissions ward or by the general practitioner if delays are expected in the hospital admission process. delays in administration of antibiotics are related adversely to mortality in some studies, particularly when managing elderly patients , . following initial assessment and empirical therapy, progress should be monitored carefully. the route and choice of antibiotic treatment will require adjustment, either by stepping up and broadening the spectrum of microbiological activity in the light of clinical deterioration or as a result of positive microbiological information, or stepping down with improvement as discussed below. • most patients can be adequately treated with oral antibiotics. • oral therapy with co-amoxiclav or a tetracycline is preferred. • when oral therapy is contra-indicated, recommended parenteral choices include intravenous co-amoxiclav, or a second or third generation cephalosporin (cefuroxime or cefotaxime respectively). • a macrolide (erythromycin or clarithromycin) or a fluoroquinolone active against s. pneumoniae and staph. aureus is an alternative regimen for those intolerant of penicillins. currently levofloxacin and moxifloxacin are the only recommended fluoroquinolones licensed in the uk. • antibiotics should be administered within four hours of admission. mortality is greatly increased in those with severe pneumonia (section ). the illness may progress before microbiological information is available. preferred and alternative initial treatment regimens are summarised in table . . the recommendation of broadspectrum b-lactam regimens plus a macrolide in those with severe influenza-related pneumonia is based on the following rationale: (a) while s. pneumoniae and staph. aureus remain the predominant pathogens, gram-negative enteric bacilli, although uncommon, carry a high mortality . (b) the recommended empirical regimen will offer double cover for the likely pathogens implicated in influenzarelated pneumonia and there is some evidence to indicate that combination therapy is associated with better outcomes in severe pneumonia . (c) although there is no evidence of an increased incidence of infection by atypical pathogens in influenzarelated pneumonia, in severe pneumonia it is felt necessary to include cover for atypical pathogens, particularly legionella sp. as it may not be possible at the outset to distinguish between patients with sporadic severe community-acquired pneumonia in whom legionella infection is important, and influenzarelated pneumonia. parenteral administration of antibiotic is recommended in those with severe community-acquired pneumonia regardless of the patient's ability or otherwise to take oral medication. this is to ensure prompt, high blood and lung concentrations of antibiotic. a fluoroquinolone is offered as an alternative, despite limited data on their use in severe pneumonia . at the time of writing, levofloxacin is the only licensed and available agent in the uk for severe pneumonia. it is marketed in parenteral and oral formulations. however, until more clinical experience is available we recommend combining it with another agent active against s. pneumoniae and staph. aureus such as a broad-spectrum b-lactam or macrolide when managing severe influenzarelated pneumonia. • patients with severe pneumonia should be treated immediately after diagnosis with parenteral antibiotics. • an intravenous combination of a broad-spectrum b-lactamase stable antibiotic such as co-amoxiclav or a second-(e.g. cefuroxime) or third-(e.g. cefotaxime) generation cephalosporin together with a macrolide (clarithromycin or erythromycin) is preferred. • an alternative regimen includes a fluoroquinolone with enhanced activity against pneumococci together with a broad-spectrum b-lactamase stable antibiotic or a macrolide. currently levofloxacin is the only such fluoroquinolone licenced in the uk. • patients who have been in hospital within the last few months have a higher chance of carrying mrsa as opposed to patients who have not been hospitalised recently. therefore due consideration should be given to the possibility of mrsa if they are known or suspected to have a staphylococcal pneumonia and/or are not responding to empirical therapy. . . when should the iv route be changed to oral? there can be no rigid recommendation concerning the timing of transfer to oral therapy and further studies of this area are needed . any decision must be individualised on the basis of assessing all factors, including the absence of any contraindications to oral administration, the availability of any microbiological information regarding aetiology of the infection and clear evidence that the patient is responding to initial therapy. the recommended guideline is that oral therapy be considered in a patient who has shown clear evidence of improvement and whose temperature has resolved for a period of hours. • patients treated initially with parenteral antibiotics should be transferred to an oral regimen as soon as clinical improvement occurs and the temperature has been normal for hours, providing there is no contraindication to the oral route. . . for how long should antibiotics be given? until there are more precise methods to reliably identify microbiological and clinical end-points, the duration of therapy will remain subject to clinical judgement and custom. for these reasons the duration of therapy will vary by individual patient, disease severity and speed of resolution. • for most patients admitted to hospital with nonsevere and uncomplicated pneumonia, seven days of appropriate antibiotics is recommended. • for those with severe, microbiologically undefined pneumonia, ten days treatment is proposed. this should be extended to days where s. aureus or gramnegative enteric bacilli pneumonia is suspected or confirmed. . . failure of initial empirical therapy in those patients who fail to respond to initial empirical therapy, several possibilities need to be considered, the first of which is whether the correct diagnosis has been made. radiographic review is recommended for the community-and hospital-managed patient. this may also indicate complications of pneumonia such as pleural effusion/empyema, lung abscess or worsening pneumonic shadowing, which will be more common in the presence of staphylococcal infection. the initial empirical antibiotic regimen may need to be reassessed. however, compliance with, and adequate absorption of an oral regimen should first be considered. microbiological data should be reviewed and further specimens examined, with a view to excluding staph. aureus and gram-negative bacillary infection. in the hospital-managed, non-severely ill patient, changing to a new fluoroquinolone such as levofloxacin provides a second alternative. in the severely ill patient already receiving a b-lactam/ clarithromycin regimen, it is recommended that further staphylococcal cover is added to include cover for mrsa . in addition, urgent referral to a respiratory physician should be made for clinical assessment including the possible need for bronchoscopic sampling. other rapid mrsa diagnostic techniques are in the evaluation stage. • for those with non-severe pneumonia in hospital on combination therapy, changing to a fluoroquinolone with effective pneumococcal and staphylococcal cover is an option. • adding further antibiotics effective against mrsa is an option for those with severe pneumonia not responding to combination antibiotic therapy. specific pathogen-directed antibiotic therapy . . what are the optimum antibiotic choices when specific pathogens have been identified? when a pathogen has been identified, specific therapy as summarised in table . is proposed. in transferring patients from empirical to pathogen-targeted therapy, the regimen and route of administration will be determined by the continued need for parenteral therapy and known drug intolerance. these recommendations are again based on a synthesis of information, which includes in vitro activity of the drugs, appropriate pharmacokinetics and clinical evidence of efficacy gleaned from a variety of studies. the choice of agent may be modified following the availability of sensitivity testing or following consultation with a specialist in microbiology, infectious disease or respiratory medicine. close liaison with the local microbiology service will be essential during a pandemic. currently s. pneumoniae highly resistant to penicillin (mic mg/l) is uncommon in the uk. however, it is important that the situation is monitored and in future § . use of antibiotics in hospitalised adults part . clinical management of adults referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s either ciprofloxacin mg bd iv or piperacillin g tds iv ± gentamicin or tobramycin (dose monitoring) higher doses of penicillins or alternative regimens may need to be considered. staphylooccus aureus is an uncommon cause of sporadic community-acquired pneumonia in the uk, but will assume much greater potential importance during a pandemic. most community isolates are methicillin-sensitive although the recent increase in mrsa in hospitalised patients may result in subsequent readmission with an mrsa infection, secondary to influenza. options for methicillin-sensitive and -resistant infections are based on parenteral administration in view of the serious nature of staphylococcal pneumonia. • if a specific pathogen has been identified, the antibiotic recommendations are summarised in children with high fever (> . ºc) and cough or influenzalike symptoms will be seen by a community health professional (a nurse or doctor if under seven years of age). if there are no features that put them at high risk of complications they should be treated with oseltamivir, and given advice on antipyretics and fluids. children under one year of age and those at risk of complications (appendix ) should be seen by a gp. children may be considered at increased risk of complications if they have: cough and fever (or influenza-like illness) and temperature > . ºc and either (i) chronic co-morbid disease (see appendix ) or (ii) one of the following features • breathing difficulties • severe earache • vomiting > hours • drowsiness these patients should be offered an antibiotic as well as oseltamivir (in those over one year of age) and advice on antipyretics and fluids. children under one year of age with none of the above features should be treated with antipyretics and fluids with a low threshold for antibiotics if they become more unwell. the most severely ill children should be referred for assessment for admission. in a pandemic situation, paediatric high dependency and intensive care beds are likely to fill quickly and will be insufficient to meet demand. children will have to be triaged by the senior paediatrician on duty in consultation with tertiary specialists in respiratory medicine, paediatric intensive care or paediatric infectious diseases. triage will be on the basis of the severity of the child's (a) acute and (b) co-existing disease and the likelihood of the child achieving full recovery. where admission is not possible § . general investigations for children in hospital part . clinical management of children referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s the tertiary specialists will provide advice and support on management to the general paediatrician. in the h n cases reported from vietnam all seven children had wbc < . (mean . ) and / had a lymphopenia < . (mean . ). six of the seven children died. in contrast, only two of the seven children reported from hong kong died but they were both leukopenic and lymphopenic. the survivors had a mean wbc of . and lymphocyte count of . . four of five cases reported from thailand were lymphopenic . in influenza a thrombocytopenia (< ) is found in % , . thrombocytopenia was found in four out of seven cases of h n infection in vietnamese children . liver transaminases are raised in % of influenza a patients and were raised in six out of six of those measured in the hong kong h n outbreak and five out of six in those measured in vietnam . c-reactive protein (crp) is unhelpful in influenza with values < in % ; < in % and > in only % . the cd /cd ratio was inverted in the two children and three adults in whom it was measured in the vietnam outbreak (mean . ; range . . ). two of these patients survived . • a full blood count with differential, urea, creatinine and electrolytes and liver enzymes and a blood culture should be done in all severely ill children. one of the largest studies of the value of chest radiography was undertaken in children aged between two months and five years with community-acquired pneumonia managed as outpatients with time to recovery as the main outcome . chest radiography did not affect the clinical outcome in these children with acute lower respiratory infection. this lack of effect was independent of clinicians' experience. there are no clinically identifiable subgroups of children within the who case definition of pneumonia who are likely to benefit from a chest radiograph. the authors concluded that routine use of chest radiography was not beneficial in ambulatory children aged over two months with acute lower respiratory tract infection (lrti). clinicians basing the diagnosis of lower respiratory infections in young infants on radiographic diagnosis should be aware that there is variation in intraobserver and interobserver agreement among radiologists on the radiographic features used for diagnosis. there is also variation in how specific radiological features are used in interpreting the radiograph. a recent study on standardization of cxr interpretation in paediatric pneumonia illustrates the importance of standardised training . the cardinal finding of consolidation for the diagnosis of pneumonia appears to be highly reliable and reasonably specific for bacterial pneumonia ( % of patients with alveolar shadowing had bacterial proven pneumonia) but overall chest radiography is too insensitive to be useful in differentiating between patients with bacterial pneumonia and those whose pneumonia is nonbacterial , . in the context of an influenza pandemic, a cxr will not distinguish viral pneumonia from viral illness with bacterial superinfection, and all children with signs of pneumonia should be treated with antibiotics. • a cxr should be performed in children who are hypoxic, have severe illness or who are deteriorating despite treatment. oxygen saturation (sao ) measurements provide a noninvasive estimate of arterial oxygenation. pulse oximetry will be a key tool in assessment and management and it is essential that it is used correctly and that users are aware of the possibility of artefactually low readings. the oximeter appears easy to use and requires no calibration. however, it requires a pulsatile signal from the patient. it is also highly subject to motion artefacts. to obtain a reliable reading: ( ) the child should be still and quiet. ( ) when using paediatric wrap around probes, the emitting and receiving diodes need to be carefully opposed. ( ) a good pulse signal (plethysmograph) should be obtained. ( ) once a signal is obtained, the saturation reading should be watched over at least seconds and a value recorded once an adequate stable trace is obtained. • pulse oximetry should be performed in every child being assessed for admission to hospital with pneumonia. to be read in conjunction with the corresponding section for adults (section in part ). as with adults, the extent of virological and microbiological investigations undertaken in children should vary according to the stage of the pandemic and additionally according to the severity of an individual case. it should be noted however, that the clinical features of influenza in children are less characteristic than in adults (see section ) and the need for special diagnostic tests is therefore greater , , the utility of rapid influenza tests has been demonstrated in studies where rapid knowledge of a diagnosis of influenza (within ten minutes) has been shown to have an impact on clinicians' behaviour with respect to antibiotic use, performance of other tests and admission to hospital , . it may be imagined that in a pandemic situation such a test could result in earlier use of antiviral therapy and a more rational approach to hospital admission and to prophylaxis of contacts. however, using a molecular reference standard, one test was shown to have low sensitivity ( %) but high specificity ( %) suggesting that its role might better be to 'rule in' influenza rather than 'ruling it out' . similar conclusions have been made with other commercial rapid tests , . as a reflection of this, rapid antigen tests were positive in only two of six patients with avian influenza a (h n ) . the need for bacteriological tests in cases of influenza with pneumonia is also logical and the range of pathogens similar to adults , , - except that legionella infection is extremely unlikely to occur in a previously healthy child and legionella-specific antigen testing is therefore unnecessary. the urinary pneumococcal antigen tests in children may lack both sensitivity and specificity and should be interpreted with care , . sputum collection in children is also unreliable although in older children (e.g. over years of age) it may be possible and should be handled as indicated for adults. a. virology all children: during an influenza pandemic children are likely to be admitted to hospital because of the severity of their disease and its complications or because of the impact of influenza on pre-existing disorders such as cardiac, respiratory or neurological disease. management of preexisting disorders is outside this guideline. • the most common reason for admission is likely to be: ( ) lower respiratory tract disease with either a viral or bacterial or mixed pneumonia. • other reasons for admission include: ( ) severe gastroenteritis ( ) cardiac disease viral myocarditis ( ) encephalitis children should be triaged to ward or hdu/picu after severity assessment (section ). an influenza pandemic is likely to occur in the winter months when other winter viruses responsible for paediatric morbidity and hospital admission are circulating (such as rsv and adenovirus). particularly in the early stages of a pandemic (uk alert levels ) it will be important to use rapid virological tests in an attempt to cohort influenzapositive and rsv-positive infants separately and to separate from other patients (see uk infection control guidance for pandemic influenza) . hypoxic infants and children may not appear cyanosed. agitation may be an indication of hypoxia. patients whose oxygen saturation is less than % while breathing air should be treated with oxygen given by nasal cannulae, head box, or face mask to maintain oxygen saturation above %. nasal cannulae do not deliver a fio more than around % even at flow rates of l/min in infants and l/min in older children. alternative methods of delivering higher concentrations of humidified oxygen such as a head box or a venturi face mask may be necessary. if sao > % cannot be maintained with an fio of % then additional support such as cpap, bipap or intubation and ventilation should be considered. • patients whose oxygen saturation is % or less while breathing air should be treated with oxygen given by nasal cannulae, head box, or face mask to maintain oxygen saturation above %. children who are unable to maintain their fluid intake due to breathlessness, fatigue or gastroenteritis need fluid therapy. where possible additional fluid should be by the enteral route, and where nasogastric tube feeds are used, the smallest tube should be passed down the smallest nostril to minimize effects on respiratory status. severely ill children may need intravenous fluids, and if the child is in oxygen therapy intravenous fluids should be given at % basal levels (to avoid complications of inappropriate adh secretion) and serum electrolytes should be monitored. the monitoring will depend on the child's condition. severely ill children will need continuous monitoring of heart rate, respiratory rate, oxygen saturation and neurological status. all children on oxygen therapy should have four-hourly monitoring including oxygen saturation. chest physiotherapy is not beneficial in previously healthy children with pneumonia. children with underlying conditions such as cystic fibrosis or neuromuscular weakness will benefit from intensive physiotherapy. children with influenza are generally pyrexial and may have some pain, including headache, chest pain, arthralgia, abdominal pain, and earache from associated otitis media. pleural pain may interfere with depth of breathing and may impair the ability to cough. antipyretics and analgesics can be used to keep the child comfortable and to help coughing. . . when can children be safely discharged from hospital? in a pandemic situation there will be great pressure on hospital beds. all children should be assessed for discharge at least twice daily. children should not remain in hospital if they are receiving therapy that could be given in the community. in previously healthy children suitable discharge criteria would be: ( ) child is clearly improving ( ) child is physiologically stable ( ) child can tolerate oral feeds ( ) respiratory rate is < /min (< /min in infants) ( ) awake oxygen saturation is > % on air. most children will make an uneventful recovery and not require follow up. those with a prolonged illness may be followed up by their general practitioner. only children with severe disease and/or at high risk of sequelae need hospital follow up. children with lobar collapse should have a follow-up cxr. follow-up cxrs after acute uncomplicated pneumonia are of no value where the patient is asymptomatic , . to be read in conjunction with the corresponding section for adults (section in part ) five antiviral agents are theoretically available for the therapy of influenza in children: the m ion channel inhibitors amantadine and rimantadine (both administered orally and for influenza a only), the neuraminidase inhibitors oseltamivir (administered orally) and zanamavir (administered through an inhaler), and ribavirin (aerosolised). the limitations of amantadine and rimantadine are detailed in section , particularly in the context of a pandemic where resistance may already be present . both have been shown to be effective in the treatment of influenza a in children . concerns exist about the development of resistance during therapy for both agents , . a household study showed that treatment and prophylaxis with rimantadine resulted in rapid selection and transmission of drug resistant virus . in a double-blind randomised, placebo controlled study, children ( years of age) received oseltamivir with a resultant reduction in the median duration of illness, incidence of otitis media as a complication of influenza ( % vs %) and the need for antibiotic prescriptions in those with influenza ( of , % vs of , %; p = . ) compared to placebo . the most common sideeffect was vomiting ( . %). a systematic review and meta-analyses published in , which included studies up to december , included only two studies of zanamivir and one study of oseltamivir in which these drugs were administered for treatment of influenza a or b in children under years of age . the reduction in the median time to alleviation of symptoms for influenza-positive children when compared with placebo was . day ( % ci: . . ) for zanamivir and . days ( . . ) for oseltamivir. across all ages a % ( %) relative reduction in complications requiring antibiotics was observed for zanamivir, and for children specifically a % relative reduction was observed for oseltamivir. this was updated through to december in a cochrane review . using its search criteria it identified two trials of oseltamivir (one in healthy children and one in children with asthma which was later published and only one with zanamivir. its conclusions were therefore the same with respect to median illness duration in healthy children. a significant reduction in complications (otitis media) was noted for oseltamivir while a trend to benefit was seen for zanamivir . vomiting was significantly more common among oseltamivir recipients than placebo recipients ( % vs. %). the review noted that there may be a difference in efficacy according to serotype, with oseltamivir showing a significant reduction in time to resolution for influenza a ( %) but not b ( . %) . with respect to children with asthma there was a trend to reduction in time to freedom from illness for oseltamivir recipients but this did not reach statistical significance. oseltamivir appeared to result in a more rapid improvement in pulmonary function, and was well tolerated in children with asthma , . the cochrane review concluded that oseltamivir was the preferred drug as it has shown a benefit with regard to secondary complications. it also concluded that there was no evidence of benefit in at-risk children (i.e. asthma). from the perspective of pandemic use however, it should be noted that there was no evidence of harm in this group. with regard to dosing of oseltamivir, pharmacokinetic studies have suggested that young children clear the drug faster than older children, adolescents and adults and therefore need higher doses , . the major practical issue with regard to zanamivir is its mode of administration limiting its use to children over the age of five years (fda guidance: over seven years of age) . the development of resistance to oseltamivir in children may be more common than appreciated and more common than seen in adults. in one study resistance mutations were documented in % of children . this has implications for widespread use in a pandemic situation. one particular issue with regard to paediatric use of oseltamivir is the apparent age limitation on its license (i.e. not for children under one year of age). this is particularly important because during epidemic years, of all children with influenza, it is children under six months of age who are most likely to be hospitalised . the basis for this exclusion appears to be that rat data have shown high mortality in infant rats at seven days of age when given a dose of mg/kg together with high brain levels of oseltamivir, assumed to reflect the immature blood brain barrier at this age. this is reflected in product literature and an fda alert although there are no published data. as a result, there are few human data in this age group as it was felt that it would be difficult to monitor cns toxicity in this age group. however, because of a fear of encephalopathy due to influenza in young children, japanese paediatricians § . use of antivirals in hospitalised children part . clinical management of children referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s have been using it in infants and data on consecutive infants from japan revealed no encephalopathy or mortality in recipients . a second japanese report where children under one year were treated ( mg/kg/day) showed similar efficacy for fever to a group of older children and no serious adverse effects . there are no data on the effectiveness of oseltamivir if given more than two days from onset of illness. it is likely to be less effective and in particular to have little or no effect after five to six days of illness unless the child is immunosuppressed. giving oseltamivir to sick hospitalised patients is theoretically likely to decrease their infectivity and so may be useful but there are no data to support this. in a double blind placebo controlled study children hospitalized with influenza who had been ill for hours or less and who had a temperature of . ºc or more were randomised to receive either ribavirin or placebo. sixtytwo patients ( in the placebo group, in the ribavirin group) had a confirmed diagnosis of influenza. the time to reduction of temperature to . ºc or less for the ribavirin group was . hours compared with . hours for the placebo group (p = . ). there were no other differences detected between groups . there have been no further published studies in the years since this report, thus ribavirin cannot be recommended at this time. • in the setting of a pandemic, children in the community should only be considered for treatment with antivirals if they have all of the following: ( ) an acute influenza-like illness ( ) fever (> . ºc) and ( ) been symptomatic for two days or less. • oseltamivir is the antiviral agent of choice. • treatment schedule for children over one year: body weight kg, i.e. < years: mg every h body weight > kg, i.e. years: mg every h body weight kg, i.e. > years: mg every h • in children who are severely ill in hospital oseltamivir may be used if the child has been symptomatic for less than six days. • oseltamivir may be considered for the treatment of infants under one year of age, especially those with severe influenza. this would need to be done following appropriate discussion with the parents highlighting the concerns from the animal data and the relative paucity of human data in this age group. section . use of antibiotics in hospitalised children . . who should get antibiotics? secondary bacterial infections, particularly pneumonia and otitis media, are common in children with influenza. a case control study during an outbreak of severe pneumococcal pneumonia demonstrated that patients with severe pneumonia were times more likely to have had an influenza-like illness and four times more likely to have positive influenza serology than controls . infections with staph. aureus and h. influenzae are also more common during influenza outbreaks. a randomized controlled trial of antibiotics in children aged four months to years presenting with influenzalike symptoms during an influenza epidemic showed a decreased incidence of pneumonia in the antibiotictreated group ( . % vs . %, p = . ) . there was no change in duration of fever or incidence of acute otitis media. interestingly only one out of seven of the cases of pneumonia in the placebo group was thought to be bacterial. the authors postulated that as bacterial proteases facilitate propogation and pathogenesis of influenza in a mouse model, decreasing bacterial numbers and hence protease levels in the lung may decrease viral pneumonia. another randomized trial of cephalosporins vs macrolides in japanese children with influenza-like symptoms showed faster alleviation of fever ( . ± . vs . ± . days, p = . ) in the macrolide group and a decrease in number with cxr evidence of pneumonia ( vs cases, p = . ; / had interstitial changes) . the authors postulate that anti-inflammatory effects of macrolides may be responsible. • children who (a) are at risk of complications of influenza or (b) have disease severe enough to merit hospital admission during an influenza pandemic should be treated with an antibiotic that will provide cover against s. pneumoniae, staph. aureus and h. influenzae. the antibiotics of choice must cover the likely pathogens as above. rarely a blood culture or pleural tap will provide the pathogen. the antibiotics should then be specifically tailored, e.g. iv benzylpenicillin or oral amoxicillin for s. pneumoniae and flucloxacillin or clindamycin for staph. aureus. part . clinical management of children referred to hospital § . use of antibiotics in hospitalised children s provisional guidelines from bis/bts/hpa in collaboration with the department of health, version ( october ) a recent randomized controlled trial of the equivalence of oral amoxicillin vs iv benzylpenicillin in children admitted to hospital with community-acquired pneumonia showed no difference in duration of illness or complications . oral antibiotics should be given provided oral fluids are tolerated. . . antibiotic choice for severe or complicated pneumonia? children who are severely ill with pneumonia complicating influenza should have a second agent which provides good cover for gram positive organisms added to the regime (e.g. clarithromycin or cefuroxime) and the drugs should be given intravenously to ensure high serum and tissue antibiotic levels. section . acknowledgements, committee members and affiliations chronic obstructive pulmonary disease (copd) including chronic bronchitis and emphysema, and such conditions as bronchiectasis, cystic fibrosis, interstitial lung fibrosis, pneumoconiosis and bronchopulmonary dysplasia (bpd). asthma requiring continuous or repeated use of inhaled or systemic steroids or with previous exacerbations requiring hospital admission. children who have previously been admitted to hospital for lower respiratory tract disease. chronic heart disease congenital heart disease, hypertension with cardiac complications, chronic heart failure and individuals requiring regular medication and/or follow-up for ischaemic heart disease. chronic renal disease nephrotic syndrome, chronic renal failure, renal transplantation. chronic liver disease cirrhosis, inflammatory bowel disease diabetes and chronic metabolic disorders diabetes mellitus requiring insulin or oral hypoglycaemic drugs. immunosuppression and malignancy due to disease or treatment: asplenia or splenic dysfunction, hiv infection at all stages, malignancy. patients undergoing chemotherapy leading to immunosuppression. individuals on or likely to be on systemic steroids for more than a month at a dose equivalent to prednisolone at mg or more per day (any age) or for children under kg a dose of mg or more per kg per day. long-stay residential care homes residents this does not include prisons, young offender institutions, university halls of residence. others doctors retain discretion in identifying additional individual patients who they recognise as at high risk of serious complications should they develop influenza; for example patients with haemoglobinopathies, neurological 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trial of clinical outcome after chest radiograph in ambulatory acute lower-respiratory infection in children standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies reliability of the chest radiograph in the diagnosis of lower respiratory infections in young children comparison of radiological findings and microbial aetiology of childhood pneumonia accuracy of radiographic differentiation of bacterial from nonbacterial pneumonia rationalised prescribing for community acquired pneumonia: a closed loop audit comparison of clinical characteristics of influenza and respiratory syncytial virus infection in hospitalised children and adolescents influenzalike illness criteria were poorly related to laboratoryconfirmed influenza in a sentinel surveillance study effect of a rapid influenza diagnosis effect of rapid diagnosis of influenza virus type a on the emergency department management of febrile infants and toddlers near patient testing for influenza in children in primary care: comparison with laboratory test comparison of binax now and directigen for rapid detection of influenza a and b new point of care test is highly specific but less sensitive for influenza virus a and b in children and adults association of invasive pneumococcal disease with season, atmospheric conditions, air pollution, and the isolation of respiratory viruses fatal influenza a virus infection in a child vaccinated against influenza toxic shock syndrome. a newly recognized complication of influenza and influenzalike illness fulminant pneumonia caused by concomitant infection with influenza b virus and staphylococcus aureus preceding respiratory infection predisposing for primary and secondary invasive haemophilus influenzae type b disease performance of the binax now streptococcus pneumoniae urinary antigen assay for diagnosis of pneumonia in children with underlying pulmonary diseases in the absence of acute pneumococcal infection evaluation of rapid assay for detection of streptococcus pneumoniae urinary antigen among infants and young children with possible invasive pneumococcal disease the utility of chest radiography in the follow-up of pneumonia references s provisional guidelines from bis/bts/hpa in collaboration with the department of health value of radiological follow up of childhood pneumonia re-emergence of fatal human influenza a subtype h n disease recovery of drug-resistant influenza a virus during therapeutic use of rimantadine high frequency of resistant viruses harboring different mutations in amantadine-treated children with influenza emergence and apparent transmission of rimantadine-resistant influenza a virus in families effectiveness of neuraminidase inhibitors in treatment and prevention of influenza a and b: systematic review and meta-analyses of randomised controlled trials neuraminidase inhibitors for preventing and treating influenza in children oral oseltamivir improves pulmonary function and reduces exacerbation frequency for influenza-infected children with asthma pharmacokinetics of anti-influenza prodrug oseltamivir in children aged years resistant influenza a viruses in children treated with oseltamivir: descriptive study burden of interpandemic influenza in children younger than years: a -year prospective study experience with oseltamivir for infants younger than year old in japan oseltamivir phosphate in infants under year of age with influenza infection efficacy and safety of aerosolized ribavirin in young children hospitalized with influenza: a double-blind, multicenter, placebo-controlled trial efficacy of antibiotics against influenza-like illness in an influenza epidemic effect of maclorides on duration and resolution of symptoms and complication of pneumonia in children with influenza a randomised controlled equilanence trial to compare oral and intravenous treatment and the direct and indirect costs of treating children with community acquired pneumonia: pivot trial human influenza a h n virus related to a highly pathogenic avian influenza virus outbreak of avian influenza a (h n ) virus infection in hong kong in avian influenza a challenge to global health care structures in addition, antivirals may be considered in the following exceptional situations:(i) patients who are unable to mount an adequate febrile response, e.g. the immunocompromised or very elderly, may still be eligible for antiviral treatment despite the lack of documented fever. (ii) severely ill and immunosuppressed patients, including those on long-term corticosteroid therapy, may benefit from antiviral therapy commenced later than hours after the onset of ili. (iii) severely ill children < year old. (parents must be informed that oseltamivir is not licensed for children < year old.) the first recorded instance of human infection by avian influenza h n occurred in may in hong kong. the first patient was a -year old child who presented initially with symptoms of fever, sore throat and abdominal pain. he later developed reye's syndrome, ards, multi-organ failure and eventually died . a total of persons were subsequently infected before the outbreak ended in december , . half the patients were aged years and below and only two were aged over years. abdominal symptoms, such as diarrhoea, vomiting and abdominal pain, were described in ten ( %) patients. eleven ( %) had a severe illness characterised by pneumonia occurring within days of symptom onset, lymphopenia, deranged liver function tests and a high mortality [six ( %) of patients with pneumonia]. secondary bacterial infections were not identified as the cause of the pneumonias.the most recent human outbreak of influenza a (h n ) infection began in december . the clinical features of hospitalised patients infected by the re-emergent avian influenza a (h n ) in were similar to those described in patients in (table a . ). children and young adults were the main groups affected. gastrointestinal symptoms were common. the presence of lymphopenia and deranged liver function tests was again associated with a poorer prognosis .since december , over cases had been reported to the who . the mortality rate among hospitalised patients has been generally high (> %). death has occurred an average of ten days after the onset of illness and most patients have died of progressive respiratory failure.there has been a review of avian influenza a (h n ) infection in humans up until september . updated information can be found at www.who.int/csr/disease/avian_influenza/en/. key: cord- -tglvxelu authors: liam, chong‐kin; pang, yong‐kek; poosparajah, shyamala; chua, keong‐tiong title: community‐acquired pneumonia: an asia pacific perspective date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: tglvxelu nan community-acquired pneumonia (cap) is a common illness that is potentially life-threatening especially in older adults and those with comorbid disease. although many microorganisms can cause cap, it is a small number of key pathogens that cause most cases. streptococcus pneumoniae is the most frequently identified pathogen, with the highest incidence of this organism reported in studies that used urinary antigen detection. haemophilus influenzae, atypical pathogens (mycoplasma pneumoniae, chlamydophila pneumoniae and legionella pneumophila) and viruses are the other commonly identified pathogens of cap. , gram-negative bacilli (enterobacteriaceae and pseudomonas aeruginosa) are the causative agents in patients who have had previous antimicrobial treatment or who have pulmonary comorbidities such as bronchiectasis or copd. even when carefully sought for in prospective studies, the causative organism remains unknown in about half of the patients. reasons for failure to identify the aetiological organism include previous antibiotic treatment, unusual pathogens that go unrecognized, viral infections and pathogens that are currently not recognized. studies conducted in japan, korea and thailand showed that the aetiology of cap is similar to that reported in the west except for the low incidence of legionella pneumonia. [ ] [ ] [ ] [ ] the low incidence of legionella infection, also reported in the other asian countries, could have been due to limitations of laboratory tests used. in a recent surveillance study conducted in urban tertiary medical centres in asia involving ambulatory and inpatients, infection rates based on a ≥ -fold rise in antibody titre between acute and convalescent sera, were found to be . % for m. pneumoniae, . % for c. pneumoniae and . % for l. pneumophila. the overall infection rate for these atypical pathogens was . %. in our recent study on hospitalized patients, l. pneumophila was identified in . % of the cases. m. pneumoniae and c. pneumoniae often cause a mild clinical disease, therefore patients are more likely to treated as outpatients. similar to reports from the west, c. pneumoniae, m. pneumoniae and s. pneumoniae were identified to be the most common aetiological agents in ambulatory patients in a thai study, accounting for %, % and % of the cases, respectively. a study in japan showed almost similar findings. a number of studies in asia where the prevalence of tuberculosis is high have shown that infection due to mycobacterium tuberculosis can commonly present as cap. , [ ] [ ] [ ] melioidosis is endemic in south-east asia and northern australia. burkholderia pseudomallei should be considered a causative organism in patients with cap in rural south-east asia particularly if the patient has diabetes mellitus. this organism was identified in . % of hospitalized cap patients in khon kaen in north-eastern thailand while in urban bangkok, it was identified in . % of the cases. similarly, in urban parts of malaysia, melioidosis is uncommon. , however, in patients admitted with severe cap in south-east asia, b. pseudomallei is a common causative organism especially if the patient is diabetic as shown by studies in singapore and khon kaen. [ ] [ ] [ ] in the asia pacific region, gram-negative bacilli other than h. influenzae such as klebsiella pneumoniae are more frequently isolated. , , , , [ ] [ ] [ ] these geographical differences in the microbiology of cap must be taken into consideration when selecting the appropriate antibiotics for initial empirical practice guidelines normally categorize cap patients based on the site of treatment (outpatient, general ward or intensive care unit), the presence of comorbidity and modifying factors (e.g. risk for penicillinresistant s. pneumoniae). , each patient group is assigned a list of likely pathogens and suggested antimicrobial therapy that provide coverage of both the likely pathogens and resistant strains. severity assessment, made on the basis of prognostic criteria which include the patients' age, comorbidities, and physical, laboratory and radiographical findings, is the key to deciding the initial site of care. the use of the pneumonia severity index (psi) for initial risk assessment has been endorsed by the infectious disease society of america, canadian infectious disease society and canadian thoracic society, and australia therapeutic guidelines. , , there is a clear correlation between mortality and risk class. the risk of death is low for risk classes i-iii ( . - . %), intermediate for class iv ( . - . %), and high for class v ( - %). however, the psi may not be practical for routine use in busy hospital emergency departments or primary care settings because of its complicated requirement for calculation of a score based on variables of patient demographics (gender, age), residence, comorbid illnesses, initial vital signs and investigation results. because the psi gives high weighting to patient age and past history but lower weighting to potentially important clinical features such as hypoxia, young, previously well patients may be classified as having mild cap (psi classes i-iii), despite being hypoxaemic and having clinically severe disease. furthermore, the psi is more useful for identifying low-risk patients who may be safely treated as outpatients rather than those with severe cap. the 'curb- score' (confusion, elevated blood urea nitrogen, elevated respiratory rate, low systolic or diastolic bp and age ≥ years) is an alternative severity assessment tool which is simpler. patients are stratified into groups according to increasing risk of mortality or need for admission for intensive care. curb- is more focused on the severity of the episode of cap rather than the patient's past history. the recently updated japanese respiratory society guidelines recommend the use of a modified version of the curb- score which include oxygen saturation by pulse oximetry as an additional parameter. however, this new severity scoring system needs to be evaluated by prospective studies. neither the psi nor curb- appears particularly useful for predicting accurately whether an individual patient will require intensive care unit admission. a recent australian study suggests a modified version of curb- as being more accurate for this purpose, but this is yet to be validated. in recent years, the proportion of penicillin nonsusceptible strains of s. pneumoniae and the level of penicillin resistance have increased in many asian countries. resistance of s. pneumoniae to other β-lactams and macrolide is also prevalent in many asia pacific countries. in fact, the prevalence rates of erythromycin resistance exceed % in several of these countries. however, most investigators found no increase in mortality for patients infected with antibiotic-resistant s. pneumoniae, after controlling for comorbid illness, although patients infected by resistant organisms may have more severe disease and suppurative complications as well as a more prolonged hospital stay. [ ] [ ] [ ] despite the widespread emergence of in vitro resistance, current antimicrobial regimens are mostly effective in the treatment of s. pneumoniae cap. chong guidelines from the infectious diseases society of america. practice guidelines for the management of community-acquired pneumonia in adults guidelines for the management of community-acquired pneumonia in adults etiology of community-acquired pneumonia in hospitalized patients: a -year prospective study in japan etiology of community-acquired pneumonia requiring hospitalization in japan a prospective multicenter study of community-acquired pneumonia in adults with emphasis on bacterial etiology. korean communityacquired pneumonia in southeast asia an asian study on the prevalence of atypical respiratory pathogens in community-acquired pneumonia pulmonary tuberculosis presenting as community-acquired pneumonia community-acquired pneumonia in japan: a prospective ambulatory and hospitalized patient study a prospective study of community-acquired pneumonia in hong kong prospective study of the aetiology of adult community acquired bacterial pneumonia needing hospitalisation in singapore a study on community acquired pneumonia in adults requiring hospital admission in penang clinical features of community-acquired pneumonia treated at srinagarind hospital community acquired pneumonia in patients requiring hospitalisation severe communityacquired pneumonia in singapore aetiology and outcome of severe community-acquired pneumonia in singapore severe communityacquired pneumonia (cap) treated at srinagarind hospital h n influenza pandemic: contingency plans update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the canadian infectious diseases society and the canadian thoracic society a prediction rule to identify low-risk patients with community-acquired pneumonia therapeutic guidelines: antibiotic, version .therapeutic guidelines limited defining community-acquired pneumonia severity on presentation to hospital: an international derivation and validation study the japanese respiratory society guidelines for the management of community-acquired pneumonia in adults a prospective comparison of severity scores for identifying patients with severe community acquired pneumonia: reconsidering what is meant by severe pneumonia high prevalence of antimicrobial resistance among clinical streptococcus pneumoniae isolates in asia (an ansorp study) resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in clinical outcomes of pneumococcal pneumonia caused by antibiotic-resistant strains in asian countries: a study by the asian network for surveillance of resistant pathogens impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia key: cord- - rhgmtbo authors: bajpai, vijeta; gupta, ekta; mitra, lalita gauri; kumar, hemant; maiwall, rakhi; soni, kapil dev; gupta, amit title: spectrum of respiratory viral infections in liver disease patients with cirrhosis admitted in critical care unit date: journal: j lab physicians doi: . /jlp.jlp_ _ sha: doc_id: cord_uid: rhgmtbo background: clinical significance of respiratory viruses (rvs) as an etiology of pneumonia in liver disease patients with cirrhosis is usually underestimated. therefore, the aim of this study was to evaluate the spectrum of rvs in cirrhotic patients with pneumonia admitted in critical care units (ccus) and its impact on the clinical outcome of cirrhotic patients. material and method: a prospective study was conducted in a tertiary care ccu, and consecutive cirrhotic patients with pneumonia were included. bronchoalveolar lavage or throat swab/nasal swab was collected in viral transport medium for analysis of rvs by multiplex real-time polymerase chain reaction. a total of cirrhotic patients were included, viral and bacterial etiology of pneumonia was identified, and analysis was done with the clinical outcome. results: overall, rvs were detected in ( . %) cirrhotic patients and viral–bacterial coinfection in ( . %) cirrhotic patients. the most common virus detected was rhinovirus in ( %) patients. mortality in cirrhotic patients with rv infection was significantly higher in comparison to cirrhotic patients with no rv infection ( [ . %] and [ . %], respectively, p < . ). conclusion: respiratory viruses in cirrhotic patients with pneumonia are associated with poor clinical outcome. i nfectious diseases are common in liver disease patients with cirrhosis and exert one of the most important reasons for morbidity and mortality in critical care units (ccus). pneumonia is one of the most common infections in liver disease patients with cirrhosis admitted in ccu. [ , ] the prevalence of pneumonia is reported in about . % of cirrhotic patients with mortality rates as high as %- %. [ ] there are several consequences of pneumonia in cirrhotic patients which include acute on chronic liver failure, multiple organ failure, sepsis, prolonged hospitalization, and mortality. [ ] although pneumonia exhibits higher mortality in patients with cirrhosis, majority of the studies focused on bacterial pneumonia as the most common cause of pneumonia in cirrhotic patients; other pathogens especially are usually underestimated in such patients and are often not underreported. [ , ] there are very few studies which have shown the influence of respiratory viruses (rvs) in clinical outcome of cirrhotic patients in ccu. [ ] [ ] [ ] till now, there is no published study showing the prevalence of rvs and their bacterial coinfections in cirrhotic patients admitted in ccu care. with this background, the purpose of the current study is to investigate the prevalence of rvs in cirrhotic patients with pneumonia and its impact on the clinical outcome of cirrhotic patients with pneumonia admitted in ccus. this is a prospective study, done over a period of year from january to december , in ccus in liver center, and all consecutive cirrhotic patients who had developed clinical signs and symptoms of pneumonia were included. pneumonia was defined as a new infiltrate focus on chest radiological examination and one or more symptoms as follows: respiratory symptoms (i.e. cough, chest pain, and dyspnea), sign of infection (fever > °c, and/or white blood cell count > , /mm or < /mm . [ ] the exclusion criteria included: ( ) under years; ( ) pregnancy; ( ) patients with immunosuppression (including patients with chemotherapy and radiotherapy and patients with drug-induced immunosuppression as a result of cytotoxic or corticosteroids [defined as > mg/kg prednisone for > month]); ( ) bone marrow or solid organ transplantation; ( ) patients with hepatocellular carcinoma or with other types of carcinoma; and ( ) hiv infection. bronchoalveolar lavage (bal) or throat swab/ nasal swab (ts/ns) was collected from cirrhotic patients with pneumonia. bal sample was collected by trained pulmonologist patients on mechanical ventilator because the ts/ns could not be from them. ts and ns were collected from nonventilated patients with pneumonia. all samples were transported in viral transport media immediately to the virology laboratory on ice. all the samples were stored at − °c till further processing. complete clinical characteristics of the patient and other biochemical parameters were recorded from the hospital information system. the study was approved by the ethical committee (irb reference no: f. / / /ilbs/ ac/ / ) of the institute. a patient admitted to the intensive care unit (icu) with the diagnosis of pneumonia without prior contact of health settings was considered as having community-acquired pneumonia (cap).infection in a patient who developed clinical features of pneumonia after h of admission was considered as hospital-acquired pneumonia (hap). impact of clinical outcome due to viral pneumonia was assessed if there was a requirement for either invasive mechanical ventilation, extended duration of stay in icu (> days), or mortality of patients. in all the samples, nucleic acids (dna/rna) were extracted using commercial kit (rtp dna/rna virus mini kit, stratec molecular, birkenfeld, germany) according to the manufacturer's instructions. multiplex quantitative real-time polymerase chain reaction was done using commercially available kit capable of detection and quantification of different pathogens ( viruses and bacteria; ftd-rp , fast-track diagnostics, luxembourg) as per the manufacturer's protocol [ table ]. results were expressed as copies/ ml, and the linear range of the assay is - copies/ ml. data were presented as mean ± standard deviation or an absolute number and percentage. to compare categorical variables, chi-square test was used, and for continuous variables, student's t-test was used. p < . was considered statistically significant. data were recorded and analyzed using spss (version . ; spss). (ibm, armonk, ny, united states of america). a total of liver disease patients with cirrhosis were admitted in icu during the study period. diagnosis of pneumonia was made in ( . %) cirrhotic patients. eighty-six ( . %) patients had hap and ( . %) patients had cap. the baseline characteristics of the study population are depicted in table . a total of patients ( . %) underwent bronchoscopy bal for etiologic diagnosis of pneumonia, and ts/nss were collected from ( . %) patients. figure shows the workflow and distribution of respiratory pathogens in all patients. the overall prevalence of rvs was found in ( . %) cirrhotic patients with pneumonia, and both viral and bacterial coinfections were seen in ( . %) cirrhotic patients with pneumonia. the proportion of rv infections were little higher in hap group than in the cap group though not significant ( [ . %] and [ . %], respectively, p = . ). the comparison of various parameters of cirrhotic patients with and without rv infection is shown in table . overall, rhinovirus (rhv) was the most common identified virus in ( . %) cirrhotic patients, followed by influenza a (flu a) in ( . %) patients, human coronavirus (hcov) in ( . %) patients, respiratory syncytial virus (rsv) in ( . %) patients, human parainfluenza virus (hpiv) in ( . %) patients, and human metapneumovirus and human adenovirus (hadv) in one each of the patients. dual viral infections such as hadv + hpiv, hcov + rsv, and hadv + rhv were found in one each of the patients, respectively [ table ]. the seasonal distribution of various rvs is described in figure . rhv was present throughout the year. flu a virus and rsv were mainly present in winter months. hcov, hadv, and hpiv were mainly present in summer and early winter seasons. overall, mortality was seen in ( . %) cirrhotic patients with pneumonia in icu. mortality in cirrhotic patients with rv infection was higher than patients with viral-bacterial coinfection ( [ . %] to the best of our knowledge, this is the first prospective study representing the investigation of viral pneumonia in cirrhotic patients in ccus. in the present study, we evaluated the epidemiology, clinical characteristics, and prognosis of cirrhotic patients with viral pneumonia in ccus. specimens obtained from the upper airway as ts/ns are often used for rv testing in pneumonia patients due to ease of specimen collection in comparison to bronchoscopy collected bal sample. [ ] however, in the current study, the proportion of rvs detected from bal samples were more than ts/ns though not significant. therefore, here comes the importance to perform bronchoscopy and collection of bal sample in the most affected lung segment according to the radiographic signs to recover the responsible respiratory pathogen in patients with pneumonia, especially in patients having chronic liver disease. over the past decade, several studies have consistently demonstrated rvs to be the second most common etiological factor of cap, accounting for %- % of diagnosed cases of pneumonia in noncirrhotic patients in ccus. [ ] our study has demonstrated that the proportion of rv infections was little higher in the hcap group than in the cap group in cirrhotic patients, which is similar to one recent study done in nonliver adult patients. [ , ] a high index of suspicion of viral pneumonia is always necessary in patients with cirrhosis because there are no distinctive clinical features to differentiate between viral and bacterial pneumonia.; hence, a high index of suspicion is necessary for this infection. none of the previously done studies have shown the spectrum of different rvs in liver disease patients. only a few studies done in our center have shown the prevalence of influenza virus and its impact on the clinical outcome of cirrhotic patients. [ , , ] the current study has found that respiratory viral infections other than influenza virus infection are also an important etiology of pneumonia in liver disease patients with cirrhosis admitted in ccus. transmission dynamics and seasonal distribution of rvs are key importance in understanding and limiting burden of morbidity and mortality of pneumonia patients in ccus. [ ] in the current study, no clear seasonality is seen for human rhv. flu a virus and rsv were mainly present in winter months. this finding can inform the timing of flu a and rsv vaccination and the judicious use of antibiotics in cirrhotic patients admitted in ccus. mixed viral and bacterial infections are widely described in pneumonia patients in ccus; however, the presence of these coinfections on the cirrhotic patients' clinical outcome remains poorly studied. [ ] various studies suggest that viral and bacterial coinfections lead to a higher severity ongoing disease, especially in patients with chronic disease. [ , ] we did not find any significant correlation in mortality and median length of stay in ccus in patients with only rv infection and viral-bacterial confection which is not in concordance of previous done studies. [ ] our study had some limitations. first of all, our study was a single-center cohort and done in a small duration period. considering small number of patients, our observations should be confirmed in larger sample size with more detailed subgroup in future study. second, our study excluded cirrhotic patients with cancer and immunosuppression. therefore, exclusions may result in statistic bias and inexact conclusion. nevertheless, our investigation provided the first comprehensive study of the prevalence of rvs and its epidemiology in cirrhotic patients with pneumonia in ccus. with the high morbidity and mortality rates associated with rv infections and the lack of directed antiviral therapy for most of these infections, prevention remains the mainstay for reducing their incidence and controlling transmission of rvs, especially in ccus settings. rvs may contribute to significant cause of pneumonia in cirrhotic patients. therefore, there should be a high index of suspicion, and early diagnosis by rapid molecular test for rvs should be instituted in cirrhotic patients with pneumonia in ccus. pneumonia in patients with cirrhosis: risk factors associated with mortality and predictive value of prognostic models community-acquired pneumonia in patients with liver cirrhosis: clinical features, outcomes, and usefulness of severity scores high mortality of pneumonia in cirrhotic patients with ascites bacterial infections in cirrhosis: a position statement based on the easl special conference bacterial infections in end-stage liver disease: current challenges and future directions bacterial infections in patients with liver cirrhosis influenza a/ h n pdm infection in liver disease patients requiring icu care a/h n / influenza is associated with high mortality in liver cirrhosis clinical impact of a/h /n / influenza in patients with cirrhosis: experience from a nosocomial cluster of infection management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the american thoracic society predictive value of testing nasopharyngeal samples for respiratory viruses in the setting of lower respiratory tract disease comparison of viral infection in healthcare-associated pneumonia (hcap) and community-acquired pneumonia (cap) incidence of respiratory viruses in patients with community-acquired pneumonia admitted to the intensive care unit: results from the severe influenza pneumonia surveillance (sips) project influenza a/h /n / infection in patients with cirrhosis has a poor outcome: a case series seasonality of respiratory viruses causing hospitalizations for acute respiratory infections in children in nha trang viral and bacterial co-infection in severe pneumonia triggers innate immune responses and specifically enhances ip- : a translational study viral-bacterial interactions in the respiratory tract secondary bacterial infections associated with influenza pandemics we would like to thank all the innocent patients for agreeing in the study and for donating their clinical samples. we feel privileged to offer the deepest sense of gratitude and respect to our teacher, dr. sk sarin, director of ilbs, for his invaluable guidance, supervision, and blessings, without which these works would not have seen the light of the day. nil. there are no conflicts of interest. key: cord- - yxmaihl authors: katsurada, naoko; suzuki, motoi; aoshima, masahiro; yaegashi, makito; ishifuji, tomoko; asoh, norichika; hamashige, naohisa; abe, masahiko; ariyoshi, koya; morimoto, konosuke title: the impact of virus infections on pneumonia mortality is complex in adults: a prospective multicentre observational study date: - - journal: bmc infect dis doi: . /s - - -y sha: doc_id: cord_uid: yxmaihl background: various viruses are known to be associated with pneumonia. however, the impact of viral infections on adult pneumonia mortality remains unclear. this study aimed to clarify the effect of virus infection on pneumonia mortality among adults stratified by virus type and patient comorbidities. methods: this multicentre prospective study enrolled pneumonia patients aged ≥ years from september to august . sputum samples were tested by in-house multiplex polymerase chain reaction assays to identify respiratory viruses. viral infection status and its effect on in-hospital mortality were examined by age group and comorbidity status. results: a total of patients were enrolled in the study and . % was aged ≥ years. ( . %) did not have comorbidities, ( . %) had chronic respiratory disease, and ( . %) had other comorbidities. viruses were detected in ( . %) patients. human rhinovirus ( . %) was the most frequently identified virus, followed by influenza a ( . %) and respiratory syncytial virus ( . %). respiratory syncytial virus was more frequently identified in patients with chronic respiratory disease ( . %) than those with other comorbidities ( . %) and without comorbidities ( . %) (p = . ). the frequencies of other viruses were almost identical between the three groups. virus detection overall was not associated with increased mortality (adjusted risk ratio (arr) . , % ci . – . ). however, influenza virus a and b were associated with three-fold higher mortality in patients with chronic respiratory disease but not with other comorbidities (arr . , % ci . – . ). intriguingly, paramyxoviruses were associated with dramatically lower mortality in patients with other comorbidities (arr . , % ci . – . ) but not with chronic respiratory disease. these effects were not affected by age group. conclusions: the impact of virus infections on pneumonia mortality varies by virus type and comorbidity status in adults. electronic supplementary material: the online version of this article ( . /s - - -y) contains supplementary material, which is available to authorized users. pneumonia is the major cause of morbidity and mortality among adults, especially in the elderly. management of pneumonia is a critical problem in an ageing society like japan. streptococcus pneumoniae and haemophilus influenzae are the leading bacterial causes of adult pneumonia, while viruses also play important roles in disease development. recent advances in molecular diagnostic techniques have enabled us to detect multiple viruses simultaneously [ ] . studies have shown that viral infection is common in pneumonia patients [ , ] . according to a recent systematic review and meta-analysis, viruses were detected in . % of respiratory samples from community-acquired pneumonia (cap) patients [ ] . various viruses are known to be associated with respiratory infections, including pneumonia. according to the systematic review, influenza is the most commonly detected virus in cap, followed by human rhinovirus (hrv), respiratory syncytial virus (rsv), and human coronavirus (hcov) [ ] . in addition to these endemic respiratory viruses, emerging respiratory viruses, such as severe acute respiratory syndrome coronavirus, middle east respiratory syndrome coronavirus, and avian influenza, are posing a particularly serious threat to global health security [ ] . studies have suggested that these emerging viral infections are associated with an increased risk of severe conditions and mortality among pneumonia patients [ , ] . it must be noted that pneumonia mortality varies substantially according to patient characteristics, such as comorbidities, aspiration risk factors, and physical functional status [ , ] . to establish effective control measures, high-priority viruses and patient groups must be identified. however, the prevalence of viruses in adult pneumonia and their virus-specific effects on clinical outcome remain largely unknown. to the best of our knowledge, no large-scale study has investigated the different effects of viruses on pneumonia mortality by patient characteristics. we conducted this prospective multicentre study to determine the distribution of viruses associated with pneumonia in adults and to establish their virus-specific effects on pneumonia mortality stratified by age group and comorbidity status. the adult pneumonia study group-japan (apsg-j) conducted multicentre prospective hospital-based surveillance for community-onset pneumonia at four community-based hospitals in japan. in our previous paper, the burden and aetiology of adult pneumonia were reported based on the data and clinical samples collected during the st phase of the study (september to january ) [ ] . the current study included all data and samples collected during the whole study period (september to august ). details of the study settings and enrolment criteria were described previously [ ] . in brief, all outpatients and inpatients were screened by hospital physicians, and eligible patients were identified using a standardized case definition: patients aged ≥ years with respiratory symptoms compatible with pneumonia and new infiltrative shadows on chest xrays or computed tomography scans. clinical information was collected from patients and medical charts using a standardized data collection form. sputum, blood, and urine samples were collected at the time of diagnosis. gram staining, sputum culture, and blood culture were performed on site. sputum samples were further tested by in-house multiplex polymerase chain reaction (pcr) assays to identify viral and bacterial pathogens at the institute of tropical medicine, nagasaki university. and legionella pneumophila) were tested using multiplex pcr assays. details about the primers and pcr methods used have been described previously [ , ] . urinary antigen testing was performed for the detection of s. pneumoniae and l. pneumophila (binax now streptococcus pneumoniae, binax now legionella; alere inc., waltham, ma, usa). diagnosis of viral infection was made according to pcr results. bacterial infection was diagnosed when any of the following criteria were fulfilled: ) culture yielded pathogenic bacteria from microscopically purulent sputum samples (i.e., geckler's classification groups and ) or normally sterile site samples; ) pcr assays were positive for bacterial dna in microscopically purulent sputum samples; or ) urinary antigen tests showed a positive result. patients were categorized into four age groups: - years, - years, - years, and ≥ years. patients' disability status was evaluated using the eastern cooperative oncology group performance status (ps) score [ ] . pneumonia severity was assessed using the curb scoring system [ ] . to estimate the effect on pneumonia mortality, viruses were categorized into four groups: ) hrv; ) influenza a and b viruses; ) paramyxoviruses (rsv, hmpv, and piv type - ); and ) other viruses (hadv, hbov, and hcov). we divided patients into three groups according to comorbidity status: ) patients without comorbidity; ) patients with chronic respiratory disease; and ) patients with comorbidities other than chronic respiratory disease (i.e., other comorbidities). chronic respiratory disease included bronchial asthma, chronic obstructive pulmonary disease (copd), interstitial pneumonia, pneumoconiosis, and bronchiectasis. other comorbidities included diabetes mellitus, cerebrovascular disease, dementia, neuromuscular disease, cardiac failure, ischaemic heart disease, collagen disease, malignancy, renal disease, and liver disease. patients were considered to have aspiration risk factors when they had any of the following factors: episodes of aspiration, the presence of dysphagia, consciousness disturbances, neuromuscular diseases, cerebrovascular diseases, tube feeding, and bedridden status [ ] . the in-hospital death was defined as any death occurred during the hospitalization. during the first year of study, we followed up our patients after the enrolment and confirmed that no outpatient had died within days of enrolment. we therefore considered the in-hospital death as a good marker of short-term mortality in pneumonia patients regardless of their hospitalization status. patients were categorized according to their comorbidity status (i.e., patients without comorbidity, with chronic respiratory disease, or with other comorbidities) and compared using chi-squared tests. viral and bacterial infection status were compared by age group and comorbidity status using chi-squared tests, fisher's exact tests, and chi-squared tests for trend. in-hospital mortality rates were calculated by viral and bacterial infection status and compared with those of the virus-negative group. the effects of viral infection on in-hospital mortality were expressed as risk ratios with % confidence intervals (ci) and estimated using poisson regression models with robust standard errors. age, study site, comorbidity status, duration of symptoms, month of diagnosis, antibiotic use, and presence of bacteria were considered potential confounders based on prior knowledge and were included in the multiple regression models. for patients whose onset of symptoms were unknown (< %), we coded those missing values as "unknown" and included all patients in our analysis. the data were analysed using stata version (stata corp., college station, tx, usa). this study was approved by the institutional review boards (irbs) of the institute of tropical medicine, nagasaki university, ebetsu city hospital, kameda medical center, chikamori hospital, and juzenkai hospital. the requirement for obtaining written consent from all participants was waived by all irbs because of the study's observational nature without any deviation from the current medical practice. anonymized data were used for the analyses. during the study period, patients were enrolled in the study. of these, were excluded because of refusal to participate in the study (n = ), absence of pulmonary infiltrates (n = ), and non-pneumonia diagnosis (n = ). after excluding ( . %) patients whose sputum samples for pcr assays were unavailable, patients were eligible for analysis ( fig. ). table shows the clinical characteristics of pneumonia patients by comorbidity status. approximately % of patients were male, and the median age was . years (interquartile range, to years). the proportions of patients aged ≥ years and ≥ years were . and . %, respectively; . % of patients had aspiration risk factors. of all patients, ( . %) did not have comorbidities, ( . %) had chronic respiratory disease, and ( . %) had other comorbidities. patients with comorbidities were more likely to be male, older, more frequently required hospitalization, more frequently developed severe disease, more frequently had aspiration risk factors, had higher ps scores, and visited the hospital earlier than those without comorbidities. the proportion of patients with aspiration risk factors was particularly high ( . %) among patients with other comorbidities. multiple symptoms were most frequently observed in patients with chronic respiratory disease ( . %), followed by those without comorbidities ( . %) and those with other comorbidities ( . %). in total, ( . %) patients tested positive for at least one virus (table ) . hrv was the most common virus identified (n = [ . %]), followed by influenza a (n = [ . %]) and rsv (n = [ . %]). two or more viruses were detected in patients ( . %). the most frequent combinations of viruses were hrv plus influenza a (n = ), followed by hrv plus rsv (n = ), and hrv plus hmpv (n = ). three viruses (hrv, hmpv, and piv type ) were detected in one patient. bacterial pathogens were detected in ( . %) patients, and both viral and bacterial pathogens were detected in ( . %) patients (i.e., viral-bacterial co-infection). viral and bacterial infection status were compared by age group (table ) and comorbidity status ( table ). the proportion of overall virus-positive pneumonia did not differ by age group. rsv was more frequently identified in older age groups, while hcov was more frequently identified in younger age groups. the proportion of influenza- other comorbidities include diabetes mellitus, cerebrovascular disease, dementia, neuromuscular disease, cardiac failure, ischaemic heart disease, collagen disease, malignancy, renal disease, and liver disease positive pneumonia was similar across all age groups. bacterial pathogens were more frequently identified in younger patients. for patients' comorbidity status, rsv was most frequently identified in patients with chronic respiratory disease ( . %), followed by those with other comorbidities ( . %) and without comorbidities ( . %) (p = . ); the frequencies of other viruses were almost identical between the three groups (table ) . bacterial pathogens were more frequently identified in patients without comorbidities than in those with comorbidities. we explored symptoms of patients with each respiratory virus groups (additional file : table s ). the proportion of patients with multiple symptoms (i.e., the number of symptoms ≥ ) was higher in patients with paramyxovirus infection than those without viral infection ( . % vs . %, p < . ). in the group of patients with aspiration risk factors, those with paramyxovirus were more likely to have a cough than patients without virus ( . % vs . %, p < . ). among patients, patients died before discharge, with an overall in-hospital mortality of . %. the mortalities among virus-positive and -negative groups were . and . %, respectively, and the overall effect (adjusted risk ratio [arr]) of viruses on mortality was . ( % ci . - . , p = . ). intriguingly, when the effect of specific virus type was analysed, paramyxoviruses, including rsv, hmpv, and piv type - , were associated with a dramatically lower mortality (arr . , % ci . - . , p = . ). among paramyxovirus-positive pneumonia, five died: three were rsv-positive, one was hmpvpositive, and one was hmpv-positive at the enrolment. rsv alone was also associated with a lower mortality (arr . , % ci . - . , p = . ), but the association did not reach a statistically significant level. none of the other virus types were associated with mortality. the virus type-specific effects were further investigated after patients were stratified by age group and comorbidity status (tables and ). similar effects of viruses were seen across all age groups. however, influenza virus a and b were strongly associated with higher mortality in patients with chronic respiratory disease (arr . , % ci . - . , p = . ), while no influenza-related death was observed in those without comorbidity. intriguingly, paramyxoviruses were associated with markedly lower mortality in patients with other comorbidities (arr . , % ci . - . , p = . ), but this association was not observed in other groups. hrv was not associated with mortality in the three groups. virus only, bacteria only, and both virusand bacteria-positive pneumonia demonstrated higher mortality than virus-and bacteria-negative pneumonia in patients with chronic respiratory disease, but these associations did not reach statistically significant levels. we explored the association between viruses and inhospital mortality in patients with aspiration risk factors (additional file : table s ). paramyxovirus was the only virus type significantly associated with reduced mortality in this category of patients (arr . , % ci . - . , p = . ). influenza a and b were not associated with mortality (arr . , % ci . - . , p = . ). the mortality was higher among patients with cough than those without cough ( . % vs . %, p < . ). in this multicentre prospective study, . % of adult pneumonias were associated with viruses. hrv was the leading virus identified, followed by influenza a and rsv. this pattern was almost identical across all age groups. influenza was strongly associated with higher mortality in patients with chronic respiratory disease but not in other groups. paramyxoviruses, including rsv, hmpv, and piv type - , were associated with improved survival in patients with other comorbidities, especially in those with aspiration risk factors. to the best of our knowledge, this study is the first to systematically investigate virus-specific effects on pneumonia mortality by age group and comorbidity status among adults. viruses are frequently observed in pneumonia patients. according to previous studies, viruses were positive in , , and % of cap patents in the us [ ] , norway [ ] , uk [ ] , and china [ ] , respectively, and hrv, influenza a, and rsv were the leading viruses identified; these findings were confirmed in our study. however, the role of viruses in pneumonia development and progression has not been fully established. a systematic review showed that the risk of death was higher in patients with viral infection, although the association did not reach a statistically significant level (odds ratio . , % ci . - . ) [ ] . the major limitation of previous studies is that all viruses and patient groups were pooled, which may have overlooked their intergroup differences. in fact, in the current study, viruses overall were not associated with increased mortality among all pneumonia patients (arr . , % ci . - . ), but the effects were different by viruses and patient characteristics. influenza increased pneumonia mortality by . -fold ( % ci . - . ) in our patients with chronic respiratory disease but did not change the mortality in other patients. although influenza is known to be an important cause of pneumonia and death, only a few studies have formally compared the mortality of influenza pneumonia with that of non-influenza pneumonia, and the findings have been inconsistent [ , ] . on the other hand, previous studies have demonstrated that chronic respiratory disease increases the risk of severe outcome among influenza patients [ , ] . bronchial epithelial cells of copd are susceptible to replication of influenza virus because of their impaired antiviral immunity [ ] ; thus, the effect of influenza on disease progression may be stronger in patients with this condition. according to the cochrane review, influenza vaccination reduces exacerbations in patients with copd [ ] . seasonal influenza vaccination campaigns must therefore pay special attention to this patient group. interestingly, paramyxoviruses including rsv were associated with improved survival in our patients with other comorbidities. inconsistent findings have been reported about the effect of paramyxoviruses on pneumonia severity. a multinational study showed that older patients who had been infected with rsv were more likely to be hospitalized than those with other respiratory viruses [ ] , while a study conducted in the us demonstrated that patients with rsv infection were less frequently hospitalized than those with influenza infection [ ] . a retrospective cohort study conducted in hong kong showed that the -day and -day mortality rates were similar between adult patients hospitalized with rsv and those with seasonal influenza [ ] . these inconsistent findings suggest that the effects of paramyxovirus infection substantially vary by patients' conditions. in fact, in the current study, compared with virus-negative pneumonia, the mortality of paramyxovirus-associated pneumonia was substantially lower among patients with other comorbidities but this finding was not observed among patients without comorbidities and patients with chronic respiratory disease. the low mortality of paramyxovirus-associated pneumonia in this groups may be associated with its high prevalence of multiple symptoms. in our study, the proportion of patients with multiple symptoms (i.e., the number of symptoms ≥ ) was higher in patients with paramyxovirus infection than those without viral infection. patients with paramyxovirus-associated pneumonia are more likely to develop symptoms and are probably more likely to visit hospitals, and this benefit may be observed in patients with comorbidities. in the group of patients with aspiration risk factors, those with paramyxovirus-associated pneumonia were more likely to have a cough than patients without virus ( . % vs . %, p < . ), and the mortality was higher among patients with cough than those without cough ( . % vs . %, p < . ). the low mortality of paramyxovirus-associated pneumonia in patients with aspiration risk factors also suggests that these viruses may stimulate the cough reflex and improve patients' survival; however, our study does not provide conclusive evidence. further studies are needed to unveil the mechanisms of potential benefits of paramyxovirus infection on pneumonia mortality. in our study, multiple viruses were identified in . % of virus-associated pneumonia and were associated with higher mortality than single viral infection in patients with chronic respiratory disease and other comorbidities. the association between multiple viral infections and pneumonia mortality remains uncertain [ ] . systematic reviews have shown that multiple viral infections in patients with respiratory disease are not associated with disease severity [ , ] ; however, the majority of previous studies included young children but not adults. the effect of multiple viruses on disease progression may be different in children and adults. consistent with previous studies [ , , ] , half of the viral pneumonia patients were co-infected with bacterial pathogens. a systematic review showed that viral-bacterial co-infection increased mortality [ ] ; however, this association was not observed in our study. viral infections of the lower respiratory tract may increase the risk of secondary bacterial infection, which may increase the risk of pneumonia and mortality [ ] . however, sputum samples were collected once in our study; thus, we were unable to determine the time course of viral and bacterial infections. a cohort study with sequential respiratory sampling may be a preferable design to establish a causal association between viral-bacterial co-infection and pneumonia mortality. advances in molecular diagnostic techniques have enabled virus detection in clinical settings. our findings raise the question of whether all pneumonia patients should be tested for viruses. the increased mortality of influenzaassociated pneumonia in patients with chronic respiratory disease suggests the importance of early diagnosis of influenza and initiation of antivirals for this patient group. on the other hand, no substantial increase of mortality was found for other viruses. screening for viruses in all pneumonia patients may be unnecessary in clinical settings. our study has limitations. first, sputum samples were not available for % of the enrolled patients. however, the clinical characteristics of patients without sputum samples did not differ from those of patients with sputum samples. exclusion of this group did not affect our findings. second, we used pcr to detect viruses. the detection of viral rna and dna in respiratory samples does not always indicate the presence of a causal pathogen; particularly, the detection of viruses in nasopharyngeal swabs may not be reflecting lower respiratory infections in pneumonia patients. we, therefore, used sputum samples from pneumonia patients, and the presence of viruses in the lower respiratory tract must be very likely causative [ ] . third, due to the nature of an observational study design, unmeasured confounding factors may have remained in our risk factor analyses for pneumonia mortality. viral infections are common in adult pneumonia, and their impact on pneumonia mortality varies by viruses and comorbidities. variable impacts of viruses by population characteristics must be considered in the development of antiviral drugs and vaccines. division of respiratory medicine - - sakamoto, nagasaki - , japan. department of general internal medicine etiology of community-acquired pneumonia: increased microbiological yield with new diagnostic methods community-acquired pneumonia requiring hospitalization among u.s. adults etiology of community-acquired pneumonia and diagnostic yields of microbiological methods: a -year prospective study in norway viral infection in community-acquired pneumonia: a systematic review and meta-analysis identification of new respiratory viruses in the new millennium middle east respiratory syndrome predictors of in-hospital mortality of older patients admitted for community-acquired pneumonia prognostic implications of aspiration pneumonia in patients with community acquired pneumonia: a systematic review with meta-analysis the burden and etiology of community-onset pneumonia in the aging japanese population: a multicenter prospective study viral pathogens associated with acute respiratory infections in central vietnamese children association between nasopharyngeal load of streptococcus pneumoniae, viral coinfection, and radiologically confirmed pneumonia in vietnamese children toxicity and response criteria of the eastern cooperative oncology group defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study differences in the features of aspiration pneumonia according to site of acquisition: community or continuing care facility comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia viral etiology of communityacquired pneumonia among adolescents and adults with mild or moderate severity and its relation to age and severity clinical and laboratory features distinguishing pandemic h n influenza-related pneumonia from interpandemic community-acquired pneumonia in adults comparison of clinical features and outcomes of hospitalized adult patients with novel influenza a (h n ) pneumonia and other pneumonia factors associated with poor outcomes among adults hospitalized for influenza in france: a three-year prospective multicenter study pneumonia among adults hospitalized with laboratory-confirmed seasonal influenza virus infection-united states targeting pi k-p alpha suppresses influenza virus infection in chronic obstructive pulmonary disease influenza vaccine for patients with chronic obstructive pulmonary disease respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness medically attended respiratory syncytial virus infections in adults aged >/= years: clinical characteristics and outcomes high morbidity and mortality in adults hospitalized for respiratory syncytial virus infections viral pneumonia single and multiple respiratory virus infections and severity of respiratory disease: a systematic review clinical disease severity of respiratory viral co-infection versus single viral infection: a systematic review and meta-analysis incidence and characteristics of viral community-acquired pneumonia in adults high incidence of community-acquired pneumonia among rapidly aging population in japan: a prospective hospital-based surveillance yield of sputum for viral detection by reverse transcriptase pcr in adults hospitalized with respiratory illness we are grateful to all the laboratory staff at the participating hospitals. we would like to thank rina shiramizu (institute of tropical medicine, nagasaki university, nagasaki, japan) and kyoko uchibori (institute of tropical medicine, nagasaki university, nagasaki, japan) for performing pcr and yumi araki (institute of tropical medicine, nagasaki university, nagasaki, japan) for administrative work. adult pneumonia study group-japan (apsg-j) are: takao wakabayashi , naoto hosokawa , norihiro kaneko , kei nakashima , yoshihito otsuka , eiichiro sando , kaori shibui , daisuke suzuki , kenzo tanaka , kentaro tochitani , masayuki chikamori , masayuki ishida , hiroshi nakaoka , hiroyuki ito , kei matsuki , yoshiko tsuchihashi , bhim g dhoubhadel , akitsugu furumoto , sugihiro hamaguchi , , shungo katoh , , satoshi kakiuchi , emi kitashoji , takaharu shimazaki , masahiro takaki , additional file : table s . proportion of patients with multiple symptoms (number of symptoms ≥ ) by virus. ethics approval and consent to participate this study was approved by the institutional review boards of the institute of tropical medicine, nagasaki university, ebetsu city hospital, kameda medical center, chikamori hospital, and juzenkai hospital. the requirement for obtaining written consent from all participants was waived by all irbs because of the study's observational nature without any deviation from the current medical practice. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. submit your next manuscript to biomed central and we will help you at every step: key: cord- -twwa djm authors: tomashefski, joseph f.; dail, david h. title: aspiration, bronchial obstruction, bronchiectasis, and related disorders date: journal: dail and hammar&#x ;s pulmonary pathology doi: . / - - - - _ sha: doc_id: cord_uid: twwa djm the conducting airways play a pivotal role in the spectrum of pulmonary pathology, not only as conduits for injurious agents to enter the lung, but also as an anatomic compartment that is affected by a diverse array of primary or secondary bronchocentric diseases. this chapter discusses aspiration and bronchial obstruction in detail, with emphasis on the aspiration of toxic, infective, or particulate matter. lung abscess, a frequent complication of obstruction or aspiration, is also reviewed. both aspiration and lung abscess are reconsidered within the context of pulmonary infectious disease mainly in chapter on bacterial infections, and to some extent in the chapters on mycobacterial (chapter ), fungal (chapter ), and parasitic diseases (chapter ). the conducting airways playa pivotal role in the spectrum of pulmonary pathology, not only as conduits for injurious agents to enter the lung, but also as an anatomic compartment that is affected by a diverse array of primary or secondary bronchocentric diseases. this chapter discusses aspiration and bronchial obstruction in detail, with emphasis on the aspiration of toxic, infective, or particulate matter. lung abscess, a frequent complication of obstruction or aspiration, is also reviewed. both aspiration and lung abscess are reconsidered within the context of pulmonary infectious disease mainly in chapter on bacterial infections, and to some extent in the chapters on mycobacterial (chapter ), fungal (chapter ), and parasitic diseases (chapter ) . bronchiectasis, which is frequently grouped with other forms of obstructive lung disease (see chapter ) , is discussed in this chapter as a major pathway of airway remodeling that may be of inflammatory, postobstructive, or congenital etiology, and is, itself, an important sequela of aspiration. the topic of bronchiectasis cannot be considered without reference to inflammatory lesions of the small airways, which may follow or precede the development of bronchiectasis (see chapter ) . the present chapter also discusses a variety of pulmonary disorders that may simulate, initiate, or complicate bronchiectasis. involvement of the large airways in systemic diseases such as amyloidosis (chapter ), sarcoidosis (chapter ), collagen vascular diseases, including relapsing polychondritis (chapter ), connective tissue disorders such as marfan's syndrome (chapter ), or as a complication of environmental dust exposures (chapter ) is reviewed in each of their respective chapters. an excellent review of bronchiectasis in systemic diseases is that by cohen and sahn.l a discussion of asthma and its related conditions of mucoid impaction, bronchocentric granulomatosis, and allergic bronchopulmonary aspergillosis can be found in chapter . unique congenital lesions of the airways in addition to the enigmatic intralobar sequestration are discussed respectively in chapters and on pediatric lung pathology. a variety of degenerative or so-called metabolic disorders that affect the large airways, such as tracheobronchopathia osteoplastica, are reviewed in chapter . finally, bronchial tumors are extensively covered throughout volume , which is devoted to pulmonary neoplasia. aspiration is the inhalation of liquid or solid materials into the lower respiratory tract, usually from the oral or nasal cavities, oropharynx, esophagus, or stomach. logically, the course of aspiration is determined by such laws of physics as inertia and gravity. larger, more solid materials, and finer more liquid materials, all follow the straightest and most dependent course after they enter the trachea. as explained in chapter , the right mainstem bronchus continues on a more direct course than the left ( to degrees compared to to degrees for the left mainstem bronchus); the wider angle of the left bronchus allows it to extend around the heart. larger, more solid objects that pass the larynx often lodge in the right mainstem bronchus, while smaller solid objects most frequently continue into the right lower lobe bronchus. this has been well demonstrated in the aspiration of foreign objects by children, generally in the age group of to years. , during this age range, children examine almost everything by placing items into their mouths. in both children and adults, larger objects are sometimes stopped at the larynx and may be expelled by strong coughing. in adults, sudden death due to laryngeal obstruction by aspirated food (most frequently meat) has been termed the cafe coronary.s more than % of aspirated foreign bodies occur in children, and among all age groups only % are spontaneously expectorated. , sharper objects may perforate a bronchus and cause bleeding, or even penetrate the pleural cavity and cause pneumothorax. a foreign body may migrate within the bronchi and cause wandering infiltra tes. young children most frequently aspirate peanuts, beads, and other fragments of wooden or plastic toys. peanuts and sunflower seeds lead the list in western countries, whereas in arabic countries children most often aspirate melon seeds. older children may inhale flowering grass fragments, which wedge themselves into more distal bronchi and resist expectoration. in any age group, teeth, fragments of bone ( fig. . ) , food, blood clots, tissue fragments, nasal pack components, lipids from oily nose drops or orally administered cathartics, bacterial fragments, and gastric content most commonly enter the lung. noguchi et a . reported a subacute reaction to mud aspiration in a victim of near-drowning, while aspiration of sand in children has been reported to cause a radiographic "sand bronchogram.,, drowning, often thought of as occurring in fresh or salt water, has also occurred in large vats of beer, wine, liquid chocolate, and other interesting concoctions. a literary example of this is shakespeare's richard iii, in which the duke of clarence is finally dispatched in a large vat of wine (the "malmsey butt,,). brock . in , beautifully illustrated the mechanics of aspiration with abscess formation, which most often followed the dependent course described. once within the lung, finer and more fluid ingredients flow into the first dependent orifices that are encountered. in the supine position, these are most often the posterior segment of the upper lobe and superior segment of the lower lobe ( fig. . ). in the more upright position, material flows preferentially into the basilar segments of the lower lobes. the basilar segments divide rather evenly, and localization within these segments is not as discrete as in other areas of the lung. when a person is in the lateral decubitus position, the axillary branches of the subsegments of apical and posterior upper lobe bronchi are favored. the more anterior portions of the lung are usually spared the effects of aspiration, unless aspiration occurs in the prone position, as in near-drowning. aspiration need not only be from external sources. rupture of large fluid-filled abscess cavities, tuberculous cavities, or other cysts might be followed by intrabronchial aspiration of infective or other types of material into dependent zones (see fig. . in chapter ). the most common conditions predisposing to aspiration include impaired consciousness, most frequently from alcohol, drugs, or anesthesia, followed by central nervous system disorders (e.g., epilepsy, stroke, dementia) or neuromuscular diseases. next in frequency is aspiration secondary to obstructing masses or other functional defects of the esophagus or stomach. episodes of aspiration are eventually confirmed in about % of children, but in only about % of adults. ,ls the difference in documentation is probably related to the altered level of consciousness in adults causing temporary amnesia. the common clinical manifestations of an aspirated foreign body constitute a triad of cough, wheezing or rhonchi, and decreased air entry. the wheezing that is sometimes associated with aspirated foreign bodies in children may be ameliorated with theophylline, leading to diagnostic confusion with asthma. early experimental animal studies showed that aspiration of material into the lungs regularly occurs when materials are placed in the nares or accessory sinuses during anesthesia. , myerson found blood immediately postoperatively in the tracheobronchial tree in % to % of humans who underwent tonsillectomy, including those under general or local anesthesia. several experimental studies have also proven that normal adults aspirate with some regularity. quinn and meyer in introduced lipiodal (iodinated poppy seed oil) into the noses of sleeping subjects and found the material often entered the lungs. amberson in reported placing barium in the mouths of normal subjects during sleep, with similar results. radiologists sometimes observe aspiration while performing upper gastrointestinal tract barium studies (see below). as reviewed by bartlett, various markers placed in the stomach the night prior to surgery have been identified in lungs sampled during surgery the next day in % to % of patients. • huxley and associates s refined these techniques by placing indium-ll chloride in the posterior nasopharynx periodically during sleep. on lung scanning, this tracer was found in the lungs of % of normal individuals and in % of those with some alteration of the central nervous system. those in the normal group who did not aspirate were fitful sleepers who tended not to enter deep sleep. the implication is that most normal people who enter deep sleep, aspirate. nasogastric and oropharyngeal tubes, including endoscopes and tracheostomy tubes, increase the risk of aspiration. normal individuals tend to clear such occult aspirations without difficulty or sequelae. an acute cough reflex is most important, but also valuable are intact mucociliary activity and alveolar macrophage response (see chapter ) . the pathologic effects of aspiration are dependent on the character, volume, and frequency of the aspirated components. in this chapter, food and medicinals, gastric acid, lighter hydrocarbons, and heavier oils are separately considered. aspirated bacteria are covered in the section on abscess formation. retained squamous if. tomashefski, jr. , and d.h. dail cells from meconium in newborns are a sign of in utero distress. squamous cells in the lungs of adults are an indicator of oral, oropharyngeal, or esophageal aspiration ( fig. . ). in the absence of other evidence of aspiration, finding mixed bacteria in lung tissue is very suggestive of aspiration of oral content. lung injury following aspiration has been subdivided by marik into aspiration pneumonitis and aspiration pneumonia. aspiration pneumonitis refers to acute chemical lung injury due to inhaled gastric acid with or without injury due to aspirated particulate matter, whereas aspiration pneumonia is an infectious process resulting from the inhalation of oropharyngeal secretions colonized by pathogenic bacteriay aspiration of gastric acid, a major cause of acute respiratory distress syndrome (ards), has been well studied in humans and in experimental animals. in experimental models, it has been suggested that a ph of . or lower and a significant quantity of acid (estimated to be to ml in an adult human or to mllkg in an experimental animal) are necessary to induce a chemical pneumonitis. when gastric acid with methylene blue was put into anesthetized dog tracheas, dye was visible on the pleural surface to seconds later. atelectasis oflung tissue was noted in minutes. human studies date from the classic study of mendelson in , and acute gastric acid aspiration is sometimes called the mendelson syndrome. mendelson studied cases of massive gastric aspiration in obstetric patients ( . % incidence) under ether anesthesia. respiratory distress occurred soon after aspiration, with accompanying cyanosis, tachypnea, and tachycardia. bronchospasm occurred in most of his patients. chest radiographs initially showed rather widespread mottled densities, most of which cleared by to days. only eight of patients became infected. this study was conducted before antibiotics were readily available, but other studies in humans with or without antibiotics or steroids have confirmed his findings. in general, later studies have found a lower incidence (about %) of bronchospasm, more frequent early temperature elevation, and increased mortality (in the range of % to %) despite therapy. hypotension and hypoxemia occurred more commonly than in mendelson's series. the combination of acid and particulate aspiration exacerbates alveolar capillary injury. bynum and pierce ! studied patients with welldocumented gastric acid aspiration. in their series, all these events followed altered consciousness, most often by a sedative drug overdose or a general anesthesia. as in mendelson's experience, respiratory symptoms developed rapidly and were very similar in all patients despite eventual outcome. three clinical outcomes were described: % died shortly after aspiration; % had rapid clinical and radiographic clearing on the average of . days; and % had rapid improvement followed by deterioration relating to bacterial infection. of this latter group % died, whereas % of the whole group died; death occurred between day and , averaging . days. these authors found initial steroid or antibiotic therapy did not affect eventual outcome. in both humans and animals, edema, congestion, hemorrhage, and degeneration of bronchiolar lining cells and alveolar type i and ii cells follows early in the course (fig. . ) . after hours alveoli are filled with polymorphonuclear neutrophils (pmns) and fibrin. hyaline membranes are formed by hours, providing a histologic picture of diffuse alveolar damage (dad) (see chapter ) . resolution begins at about hours and may either lead to figure . . gastric acid aspiration. acute effects show hemorrhagic necrosis of lung parenchyma. complete restoration of alveoli or leave some residual scarring. of course repeated aspiration may lead to combined acute, subacute, and chronic appearances. in his review, bartlett referred to this rapid and irreversible type of injury as comparable to a "flash burn," and noted that little can be done to prevent injury once acid has made contact with the lung (fig. . ). the reactions just described plus fluid extravasation help to dilute the acid, as do buffering components from serum and cell breakdown products, but these only occur after injury. more recent studies have indicated that the mechanism of lung injury following acid aspiration extends beyond the direct chemical effects of acid to involve various inflammatory mediators including tumor necrosis factora (tnf-a), interleukin- (il- ), adhesion molecules, and cyclooxygenase and lipoxygenase products. - the role of reactive oxygen species, and the adverse effect of oxygen administration after an episode of aspiration were demonstrated experimentally by nader-djalal et al. a primary role is currently placed on neutrophils and complement in mediating lung injury in this setting. , , . thus, aspiration pneumonitis represents a biphasic response composed of early-onset direct pulmonary injury due to acid, followed by delayed injury due to acute inflammation. , low-grade chronic aspiration of gastric content may escape easy detection. these occult aspirations may lead to interstitial fibrosis, and perhaps account for the % to % incidence of associated and unexplained pulmonary fibrosis in patients with esophageal abnormalities, most commonly hiatal hernia or simple reflux, , the role of reflux in asthma, chronic bronchitis, chronic cough, recurrent pneumonia, cystic fibrosis, and sudden infant death syndrome has been reviewed by allen et al. [see also section on cholesterol (endogenous lipid) pneumonia in this chapter]. children, particularly those aged to years, are likely to ingest various lighter hydrocarbons, mostly lighter volatile petroleum distillates. these products include kerosene, turpentine, and other paint thinners; furniture or shoe polish; lighter fluid; gasoline; dry cleaning fluids; and some insecticides. the toxicity is greater with those products that disperse most easily, specifically those that cause the greatest decrease in surface tension, or have the least viscosity or the highest volatility. although ingestion precedes aspiration, eade and associates nicely reviewed the reasons that aspiration is the most important toxic pathway of injury. symptoms develop rapidly and radiographs often show localized pulmonary infiltrates, often in the aspiration zones mentioned earlier. experimentally, the lethal dose by figure . . lentil bean. a. at top is thick outer coat; below, cotyledon compartments with starch cells. b. cellulose framework of legume cotyledon compartments is birefringent under ingestion alone is much higher than that usually ingested by persons who subsequently aspirate. sizable doses of distillates have been placed in the stomachs of experimental animals whose esophagi were ligated, and these animals did not suffer pulmonary toxicity. the pulmonary changes, almost identical to those of gastric acid aspiration, include diffuse congestion, hemorrhage, edema, hyaline membrane formation, and bronchopneumonia. atelectasis occurs early, apparently by direct toxic effect of these light hydrocarbons on s urfactan t. about % of affected children have abnormal chest radiographs, but only % to % have pulmonary signs or symptoms. , in the past, death has been reported in about % to % of cases, but in two large series death occurred in . % and %, respectively. a death usually occurs within hours of exposure. most survivors experience few sequelae. various food particles, such as skeletal muscle, fat tissue, or fragments of bone, may be aspirated and identified histologically in lung tissue. cooking or digestion may result in poorly defined particles that appear foreign but defy further definition. as was well demonstrated by knoblich and others, - portions of legume seeds are one of the better markers of food aspiration. the legumes most commonly eaten are various peas, beans, and peanuts; because they are relatively inexpensive and nutritious, they occur in many products. (the word lentil is sometimes used in these references, but it is also j.f. tomashefski, jr., and d.h. dail polarized light. c. degenerated aspirated vegetable material retains compartmental structure and stains strongly with gomori methenamine silver. the name of a specific type of bean). the legume seed ( fig. . ) consists of a thick cellulose outer coat, the cellulose walls of the inner food storage compartments, and the starch cells contained within these food compartments. cooking softens the outer shell and cell walls of the beans or peas and allows easy disruption of the content, with a resultant jelling effect of the starch particles (called "thickening" in cooking). the cellulose walls of the outer coat and starch compartments are more difficult to totally disrupt or digest, and therefore act as both a chronic irritant and a good marker of aspiration. aspiration of these fragments in both experimental animals and humans produces an acute exudative response within hours (fig. . ), followed by a foreignbody giant cell reaction ( fig. . ) . these cell wall fragments are gomori methenamine silver (gms) positive, and usually birefringent under polarized light (fig. . ). the glycogen compartments, when intact, are vividly periodic acid-schiff (pas) positive ( fig. . a) . starch cells may be mistaken histologically for parasite larvae (fig. . b ). at about days (experimentally) an organized granulomatous reaction occurs around the aspirated particles, and eventually the starch cells disappear, leaving only the cellulose fragments. the walls of carrots, onions, and most nonlegumes digest more readily and do not give rise to as much exuberant chronic reactions as seen with legumes. they do, however, undergo the same type of early changes if aspirated, and initiate acute and subacute pneumonia during digestion of the starch cells. some of the most offensive aspirated food fragments have undergone alterations in preparation, and some of the worst combinations are cooking oils and salts, as, for example, an aspirated potato chip ( fig. . b). eventually these areas become small fibrotic or fibrocalcific nodules, which may appear almost as degenerated parasites or as sclerosed blood vessels ( fig. . ). they may appear as small hyalinized granulomas or possibly as entrapped calcospherites, usually within a fibrous stroma. at times the conditions for aspiration are chronic, and recurrent aspiration leads to the acute and chronic changes together or in close proximity in the same specimen. respiratory bronchioles exhibit marked remodeling associated with proliferative bronchiolitis obliterans, foreign-body granulomas, and entrapped food particles. the macroscopic appearance is that of scattered yellow miliary nodules that are reminiscent of miliary figure . . chronic reaction from aspirated lentil beans. two hyalinized starch cells may be mistaken for fibrosed, obliterated blood vessels. matsuse and colleagues have designated this condition as diffuse aspiration bronchiolitis, which they observed in of consecutive autopsies ( . %). the mean age of patients with this condition was . years. affected individuals frequently were bed-ridden or had dysphagia due to underlying neurologic disorders. high-resolution computed tomography (hrct) may show a striking pattern of centrilobular miliary opacities. in chronically ill or hospitalized patients, aspirated medicinal products, such as intact or partially digested pharmaceutical tablets, may be associated with aspiration pneumonitis. inert tablet components such as microcrystalline cellulose, talc, and crospovidone may be identified histologically in conjunction with aspirated food, pneumonia, and foreign-body reaction (see chapter ) microcrystalline cellulose, like legume components, is brightly birefringent on polarization, and also positive with gms stain. it can be distinguished from vegetable particles, however, by its fiber-like, or "matchstick-like" appearance. aspirated tablet filler components, which reside within alveoli and bronchioles, usually can be discriminated from identical particles introduced by illicit intravenous injection of aqueous tablet suspensions, which localize within small pulmonary arteries or in a perivascular, interstitial distribution (see chapter ) . aspirated sodium (or calcium) polystyrene sulfonate (kayexalate), a potassium-binding cation exchange resin, has a distinctive histologic appearance characterized by large dark eosinophilic or basophilic, angulated, "glassy" particles, that sometimes appear striated ( fig. . ). [ ] [ ] [ ] [ ] duct. b. angulated, "glassy" kayexalate particles have elicited a foreign-body giant cell reaction. kayexalate particles are weakly birefringent, and positive with pas, acid-fast, and gram stains, but negative with von kossa stain. kayexalate has also been identified in tissue sections by infrared microspectrophotometry. l in humans and experimental animals, kayexalate has been shown to produce a necrotizing or organizing pneumonia. l , more frequently, kayexalate is a cause of mucosal ulcers of the gastrointestinal tract. , kayexalate histologically closely resembles the less frequently encountered material cholestyramine. cholestyramine, however, is more opaque and pink rather than red on acid-fast staining. the aspiration of an intact ferrous sulfate tablet may induce severe, potentially fatal, bronchial mucosal ulceration and hemoptysis. - the endoscopic appearance of the ulcerated bronchus typically is of a golden-brown discoloration ( fig. . a ). histologically, ulceration, necrosis, foreign-body reaction, and brown or yellow pigment that stains blue with prussian blue stain may be seen ( fig. . b ). the pathogenesis of this syndrome, colorfully termed "iron lung," is thought to be a chemical burn induced by oxidation of iron from the ferrous to the ferric form. the radiographic contrast material barium sulfate (bas ) is also readily visualized by chest x-ray in patients who aspirate this material. barium is a fairly inert white powder that tends to produce minimal functional lung impairment. grossly, following barium aspiration, lung parenchyma is chalky, tan-gray, and slightly indurated ( fig. . a ). histologically, fine, golden-tan, refractile, weakly birefringent particles of barium sulfate are present within the cytoplasm of alveolar macrophages. with chronicity, or upon repeated aspiration, barium-laden macrophages migrate into the interstitium (fig. . b ). inhalation of barium in the industrial setting (barytosis) is discussed in chapter . activated charcoal is sometimes given therapeutically for oral drug overdose. however, if the airway is not protected, charcoal may be aspirated in copious amounts, causing "charcoal lung," in which coarse black carbon particles obstruct small airways. oils that may be aspirated include mineral oils such as used in nose drops and cathartics, vegetable oils used in cooking, and animal oils such as cod liver oil or fat-soluble vitamin preparations. mineral oil, derived from petroleum products, is the most common agent of exogenous lipid pneumonia. oil aspiration was first described by laughlen in in a child who received oily oral and pharyngeal preparations for diphtheria; it was confirmed by him experimentally. the role of oil-based contrast media used for bronchoscopy was well reviewed by spencer. animal oils cause a more severe inflammatory reaction than mineral or vegetable oils, and this difference appears related to the number of free fatty acids and increased viscosity of animal oi . , . mineral oils are fairly inert, as they have no fatty acids, and are rapidly emulsified and consumed by pulmonary macrophages. vegetable oil droplets may remain in alveoli for months without eliciting significant reaction, but eventually, due to low-grade chronic irritation, they cause scarring. animal and mineral oils, but only rarely vegetable oils, may be seen in regional lymph nodes. aspiration of oils commonly occurs in older individuals, who may take oily nose drops or cathartics at bedtime. aspiration most frequently gravitates to the basilar segments of the lower lobes suggesting these patients usually sleep in a more upright position or experience aspiration before reclining. because of its weakly irritative nature, mineral oil can enter the tracheobronchial tree without stimulating glottic closure or cough reflex. only two of cases documenting exogenous lipid pneumonia at autopsy had reported significant clinical symptoms during life. because these oils float in the stomach, it is possible they also are aspirated via reflux from the stomach,z . in unselected autopsy series, oil aspiration has been documented in . % to . % of adults. . other oily products that have been incriminated as being aspirated in the lung include fragments of lip balm, burning fats (an occupational exposure), a rapid drying agent in spray enamel paint, oils applied to tobacco products (blackfat tobacco), and possibly hair spray. - children may aspirate oily medications if they are force-fed these while resisting and crying violently. atypical mycobacteria, particularly rapid growers such as mycobacterium jortuitum or m. chelonae, have been reported associated with oil aspiration pneumonia (see chapter ) . [ ] [ ] [ ] [ ] [ ] symptoms of lipid aspiration include fever ( % of patients), weight loss ( %), cough ( %), and dyspnea ( %), although in one large study lipid pneumonia was an incidental finding, without associated symptoms, in % of patients. lung function tests may indicate either obstructive or restrictive changes. computed tomography (ct) scans usually show alveolar consolidation or groundglass opacities in the lower lobes. subfissural clear zones may be interposed between densities, creating a "sandwich effect" on ct scan. grossly, lungs affected by oil aspiration are often gray to yellow and rather solid (fig. . a ). dense localized fibrotic lesions (paraffinomas) may grossly mimic cancer or complicated pneumoconiosis. , occasionally oily droplets exude from the cut surface. microscopically the lipid droplets are often dissolved by tissue processing. one exception is cod liver oil, which remains as salmoncolored droplets on hematoxylin and eosin stain after tissue processing. fats may be seen with rapid watersoluble or oil red stains on frozen section ( fig. . d); variably sized fat droplets and varying numbers of multinucleate giant cells are present ( fig. . a-c). when only a small amount of fat has been aspirated, the reaction may be contained in alveolar macrophages. this is most commonly seen in mild degrees of aspiration with a diluted fatty substance, as might be seen with milk aspiration. when larger doses of thicker and more toxic oils are aspirated or when oil aspiration is repeated, the areas become densely fibrotic with reduction of the background lung architecture ( fig. . a ). occasionally, cor pulmonale results, . transbronchial biopsies may provide enough tissue to make this diagnosis. precise identification of specific lipids can be determined by infrared spectrophotometry. in the differential diagnosis is artifactual collapse of lung around remnant air bubbles (see fig. . c in chapter ). exogenous lipid pneumonia can usually be distinguished histologically from endogenous lipid chronically ingested mineral oil as a laxative. note yellow oil layered on the surface of fluid. (cholesterol) pneumonia by subdivisions within fat droplets, coarse cytoplasmic vacuoles in macrophages, multinucleated foreign-body giant cell response, and, in more chronic cases, a greater degree of chronic inflammation and fibrosis with destruction of background lung parenchyma in exogenous lipid pneumonia ( fig. . ). at times some lipid is incorporated/entrapped in the interstitium ( fig. . c ), resembling a similar appearance in diffuse pan bronchiolitis and xanthomatous bronchiolitis obliterans (see below and chapter ). diffuse panbronchiolitis is centered more on terminalrespiratory bronchioles and is composed mostly of finely vacuolated fat. sputum cytology or cytologic aspiration specimens have been used to confirm lipid pneumonia. on bronchoalveolar lavage an oily layer is sometimes present on the surface of the collection tube ( fig. . b ). in , losner et al., using oil stains, found lipid-rich macrophages in of suspected cases in contrast to two of control patients. more recently, corwin and irwin restudied this situation using bronchoalveolar lavage in various lung diseases including aspiration, hemoptysis, cancer in the lung (either primary or secondary), bronchiectasis, interstitial fibrosis, and sarcoidosis. when compared to normal lungs, samples from diseased lungs in general contained increased fat-filled macrophages. these authors warned that the simple presence of fatty macrophages in cytology preparations is not diagnostic of lipid pneumonia; however, the quantity of lipid was more abundant in aspirators than in these other groups. their figure . . oil aspiration. a. subacute effects of oil aspiration show varyingly sized fat droplets, inflammation, lymphoid aggregates, and fibrosis. most of the lung architecture has been obliterated. b. higher power view shows foamy lipid-filled macrophages and multinucleate foreign-body cells. c. in the chronic state, oil droplets are still seen within the interstitium with "aspirator" group consisted mainly of patients with a history of upper gastrointestinal tract disease, including reflux in most. in young children the presence of numerous (> ) oil red o-positive lipid-laden macrophages on tracheal aspirate is highly specific for aspiration. corwin and irwin emphasized that the size of the fat droplets in lavage fluid cannot be used to distinguish endogenous from exogenous lipid pneumonia. wherever it occurs, an abscess is a localized accumulation of inflammatory cells, initially having abundant neutrophils, that is usually accompanied by tissue destruction. in the lungs, "cross-country" necrosis occurs during the formation of an abscess (figs. . bronchi, and arteries. in contrast, cavities that are more chronic and more slowly formed, such as tuberculous cavities, often leave remnants of fibrotic bronchopulmonary rays coursing through the cavity itself (see chapter ) . some more slowly forming nontuberculous abscesses can do this, but most of the abscesses in the lung have an acute initial phase that destroys most of the tissue in the area ( fig. . b ). bronchi frequently connect with abscess cavities, allowing drainage of the necrotic material, leaving an empty or partially empty cavity with or without an air/fluid level on chest radiograph (figs. . and . ). occasionally, inflammation seals off all such bronchial connections, resulting in a solid mass that may be suspected of being a tumor. adjacent organization in acute and subacute abscesses often accounts for an enlarged surrounding radiographic density (figs. . and . ). there are many etiologies for cavity formation in the lung, and abscess formation is but one of them. other pulmonary abscess formation, which were already well known by , were summarized in this review. by , a total of cases had been published. aspiration is the most common cause of lung abscess. other instigators of this type of damage include b. gross specimen. note cavity is mostly drained, with freshappearing, thin lining without fibrous wall. note also persistence of some trabeculae, presumed bronchopulmonary rays, and variable but narrow surrounding inflammatory reaction. penetrating trauma, postoperative states, obstruction, hemorrhage or infarction, necrotizing pneumonia, infected emboli, infection of a preexistent cyst or bulla, or extension from nearby infected areas in the mediastinum, chest wall, diaphragm, or infradiaphragmatic loca- tions. nonaspiration types of pulmonary abscesses of course do not follow the aspiration patterns of distribution, but occur as their coexistent factors dictate. for example, if there is an infarct or an obstructing tumor, infection would occur in the affected areas. septic emboli are hematogenously spread, and resultant abscesses are often multiple, small, and peripherally distributed (see fig. . in chapter ). as aspiration is the principal cause of pulmonary abscess formation, it is reasonable that conditions that favor abscess formation are identical to those favoring aspiration. the locations are similar; men are more frequently affected than women; and the right lung is involved twice as often as the left. - the posterior segments of the right upper lobe and superior segments of the right lower lobe are involved most frequently, followed by the corresponding segments on the left side. the single most commonly associated event is an alteration of consciousness; the second most frequent association is poor dental hygiene; and the third is an immunodeficient status. poor dental hygiene was noted in cases without other apparent causes of pulmonary abscess in the early studies between and . - the spectrum of bacteria involved in abscess formation is almost identical to that of endogenous oral flora. - moreover children and edentulous older people do not often develop lung abscesses.ll in children cases caused by aspiration must be separated from other cases of cavitary necrosis, such as pneumatoceles in primary staphylococcal pneumonia. - l anaerobic bacteria are the only organisms cultured in about one half to two thirds of lung abscesses; in the remaining cases either aerobic or facultative aerobic bacteria are isolated, or no bacteria are culturedys the anaerobic bacteria most frequently found are peptostreptococci (i.e., gram-positive anaerobic cocci), pigmented gram-negative bacilli (including bacteroides), and the fusobacteria. . l . spirochetes were described morphologically in earlier studies and seemed to be significant, as they were present in the growing rims of necrosis; however, they have not been mentioned much recently, perhaps because they are difficult to culture.los. about half of cultures with anaerobes also contained aerobic bacteria capable of necrosis, specifically staphylococcus, streptococcus, haemophilus, pseudomonas, klebsiella, and escherichia spp. patients with predominantly anaerobic pulmonary abscesses often present with indolent symptoms, in contrast to those with necrotizing aerobic abscesses. the latter may be more common in nosocomial-acquired lung abscess. s - immunocompromised patients often acquire gram-negative necrotizing pneumonias and vasoinvasive necrotizing fungal pneumonias, both of which may lead to cavitation. one clue to aspirated bacteria in lung abscesses is finding mixed-type organisms on smear gram stain, tissue gram stain, or culture. the oral cavity abounds with mixed bacteria and is estimated to contain some different types of organisms. this is one reason sputum cultures are notoriously difficult to interpret, and why even oral contamination of a bronchoscope interferes with most lung cultures. transtracheal and transthoracic needle aspirations, however, correlate well with blood culture results. i . the third most frequent factor in abscess formation is host response. factors that compromise normal host defenses include alcohol ingestion, diabetes mellitus, renal failure, malnutrition, malignancy, and other debilitations, along with treatment with immunosuppressive agents for any reason. patients with these factors do more poorly with pulmonary abscesses (and most other insults) than those without. [ ] [ ] [ ] pathologically, acute cavities have only a thin transition zone into the reactive adjacent lung parenchyma (see numbers of neutrophils and macrophages, along with tissue necrosis. the nearby lung parenchyma has variable findings depending on the rapidity of spread. rapidly growing cavities necrose nearby lung parenchyma, destroying any early attempts at organization. there may be adjacent hemorrhage, exudate, and fibrin extravasation. in those that are slightly more stable, beginning organization occurs in the surrounding lung parenchyma, sometimes chronic cavities heal with a thin fibrous border and may retain a coagulum of necrotic debris in their lumen. this apparently indicates that the nearby bronchi have been sealed off. chronic cavities may resolve by collapse and fibrosis, or may remain open. in the open variety they may become reepithelialized, first with a squamous lining and then with ciliated respiratory lining. in the latter case, the distinction from bronchiectasis or bronchocele may be somewhat confusing, but multiple bronchial connections in a chronic abscess cavity distinguish these entities. spontaneous healing may occur, but healing is greatly aided by appropriate antibiotic dosage. weiss l noted in appropriately treated and monitored cavities that % of cavities disappeared by weeks of therapy, % by weeks, % by weeks, and % by months. surgery is sometimes indicated for nonhealing cavities or when complications develop, such as hemoptysis, persistent sepsis, bronchopleural fistulas, or empyema. the incidence of abscess formation has greatly decreased during the past years, partly because antibiotics are available and frequently used early in pulmonary infections, and partly because factors leading to of fibrin ( ) resting on cellular granulation tissue ( ). b. wall of chronic abscess cavity composed of dense, fibrotic, mature granulation tissue. abscess formation are better understood; for example, surgery is avoided with the patient in the upright position or on patients with food in the stomach. in the pre antibiotic era approximately % of the patients treated either conservatively or by surgery died, and another one third had chronic residual lung disease. more recently the prognosis is much better, but the mortality associated with established abscess formation remains in the range of % ? although the term gangrene of the lung has been applied to necrotizing, sometimes putrid, pneumonia in any location, it has more recently been used more specifically to indicate massive necrosis and sloughing of lung associated with severe infection. this entity almost always involves the upper lobes, usually on the right side, and radiographically evolves through typical changes of diffuse infiltrate into multiple cystic spaces that become confluent, leaving a crescent of lung density compressed medially, or occasionally laterally, with a final walled-off area of pus and necrotic lung in an otherwise empty structureless space. curry and colleagues l and penner et a . attribute the first description of pulmonary gangrene to laennec in the s. phillips and rao,l l who reported four cases, refer to sir william osler's description of diseased lung "converted into a horribly offensive greenish, black mass, torn and ragged in the centre" (fig. . ) . the patients may cough up large pieces of necrotic lung, which in one case was therapeutic. these fragments histologically show ghosts of lung parenchyma and thrombosed vessels. vasculitis has been described in some reports. , assorted microorganisms cultured from these cases include klebsiella pneumoniae, pseudomonas aeruginosa, haemophilus injluenzae, staphylococcus aureus, streptococcus pneumoniae, and mucor species, anaerobic bacteria probably also playa significant role. in their reviews, phillips and rao l l and penner and colleagues note that similar predisposing factors as those with community-acquired pneumonia, such as aspiration and abscess formation, pertain to this entity, but the location helps distinguish it from the other typical sites of aspiration, when in the upper lobes, it appears to progress through necrotizing pneumonia with thrombosis of arteries (pulmonary and bronchial) and veins, [ ] [ ] [ ] although not strictly abiding by the foregoing definition (of localization in upper lobe), in one case total unilateral lung gangrene was attributed to hilar vessel involvement following treatment of a massive hilar recurrence of hodgkin's disease. pulmonary gangrene is life threatening, and surgical removal of necrotic lung tissue if. tomashefski, jr. , and d.h. dail figu re . . pulmonary gangrene, lung parenchyma is greenish-black, necrotic, and cavitated in this specimen from a patient with central bronchogenic carcinoma, bronchial obstruction, pulmonary artery invasion, and thrombotic occlusion. note hyperemic rim between necrotic lung and apical lung parenchyma. proteus, e coli, and enterococcus cultured, is often indicated since only a few patients survive with antibiotic therapy alone, an entire lung, or even one lobe, may rotate around the hilar structures and cause congestion, hemorrhage, or infarction, cases of torsion involving only single lobes most commonly occur postoperatively when a portion of ipsilateral lung has been removed, , torsion is an infrequent event. a review of the literature in by schamaun documented cases of postoperative torsion, five posttraumatic occurrences, and four spontaneous events. in a poll of british thoracic surgeons, however, of responders ( % ) had encountered at least one instance of torsion, torsion has also been documented to occur in transplanted lungs or as a result of pneumothorax or mass lesions. , due to the simultaneous compromise of pulmonary and bronchial arteries and the pulmonary vein, fatal gangrene may occur (see above), the entity of obstructive, golden, or endogenous lipid pneumonia is most commonly seen secondary to tumor obstruction of large airways, but any of the causes of obstruction can lead to obstructive pneumonia. the obstructive effect accounts for a much larger infiltrate on the usual chest radiograph than is caused by tumor alone. the involved area is primarily supplied by the affected bronchus, and the larger the obstructed bronchus, the greater the area involved. however, even when obstruction occurs in the smallest bronchioles, there may be secondary effects in the centriacinar regions. cholesterol pneumonia may also spread into the adjacent nonobstructed segment, and occasionally throughout the lobe. the latter pattern of disseminated spread is often associated with more poorly differentiated or cavitated carcinomas. the involved lung is reduced in size, but not to the extent expected in simple atelectasis. the difference is due to the infiltration by abundant inflammatory cells. the microscopic hallmark of obstructive pneumonia is flooding of air spaces initially by edema followed by fat-filled, finely vacuolated, so-called foamy alveolar macrophages (fig. . a golden-yellow color, hence the term golden pneumonia. obstructed secretions, increased cell breakdown products, and possibly leakage from vessels and interstitium, may give rise to the fat seen in this characteristic reaction. as these products are derived from the lung, this is called endogenous lipid pneumonia. early in its course the alveolar outlines are well defined though distended with foamy macrophages. if the pneumonia is rapidly reversed, lung function may return. gradually, permanent damage ensues, including fibrosis and vascular sclerosis, and it is then difficult to restore lung function even though the obstruction may eventually be reversed. some degree of intraalveolar organization may also be present in approximately % of cases. l features of superimposed infection, such as acute inflammation, necrosis, or abscesses are seen in a minority of cases. in contrast to exogenous (aspiration) lipid pneumonia, endogenous lipid pneumonia is characterized by finely vacuolated fat, absence of a foreign-body response, and minimal inflammation and fibrosis of the underlying lung architecture (figs. . and . b,c). sometimes there are changes that suggest pulmonary alveolar lipoproteinosis (see below). . at times parenchymal changes very similar to those just described may be present, although no obstruction of bronchus can be identified, so-called idiopathic cholesterol pneumonia. , in , robbins and sniffen described cases of chronic nonobstructive cholesterol pneumonia, of which ( %) occurred in men aged to years, the only female being a -year-old girl. in extent, five of their cases involved most of the lobe and six cases included a portion of one or more segments, often with pleural adhesions; some had small abscess cavities. the involved areas were wedge-shaped with their bases on the pleura and were described as bright yellow; they were accounted for histologically by abundant, finely vacuolated foamy macrophages, but otherwise these areas presented as mass effects. mucoid or mucopurulent exudate filled some bronchioles and bronchi, but no other cause of obstruction was present. bronchiectasis was absent, although focal necrotizing bronchitis was noted. the lobar distribution was not documented. these authors argued against aspiration as they noted the usual aspiration to be more diffuse, often multifocal, and more often seen in lower lobes. lawler able foreign material in ( %) and strongly suspected aspiration in another six for a total of % in this series. all except two cases ( %) of confirmed aspiration were solitary lesions. it seems reasonable that at least some of both chronic organizing pneumonia and idiopathic cholesterol pneumonia, even when not so confirmed, may be the result of aspiration, usually involving ingredients other than exogenous lipid. secondary chronic organizing pneumonia, involving large portions of a lobe or presenting as a mass lesion, is not to be confused with the distinctive form of interstitial lung disease termed cryptogenic organizing pneumonia (bronchiolitis obliteransorganizing pneumonia), which is further discussed in chapter . fisher et al. have described a series of patients (six children [< years of age] and two adults) with progressive diffuse interstitial lung disease having a combination of histologic features including endogenous lipid pneumonia, interstitial cholesterol granulomas, and patchy alveolar proteinosis (fig. . ). three patients in this study had severe combined immunodeficiency, two had pulmonary hypertension, and one each had cystic fibrosis (cf), trisomy q, and ventricular septal defect (vsd), or lysin uric protein intolerance. all patients exhibited delayed growth, five had digital clubbing, six had depressed appetite or anorexia, five were anemic, and three experienced hemoptysis. six of eight patients also had evidence of gastroesophageal reflux, which the authors suggest is important in the pathogenesis of this condition. pulmonary function tests in four patients showed either restrictive or mixed restrictive and obstructive physiology. chest x-rays predominantly showed nodular pulmonary opacities, while bronchiectasis and perihilar or mild hazy parenchymal infiltrates occurred in one patient each. the mechanism whereby gastroesophageal reflux might elicit this interesting triad of histologic findings is through recurrent micro aspiration of gastric content with associated bronchospasm (see discussion of alveolar proteinosis in chapter ). the differential diagnosis of cholesterol pneumonia also includes drug reactions, notably reactions to amiodarone. the clinical history and documentation of amiodarone therapy should facilitate the correct diagnosis (see chapter and fig. . ) . while the foamy macrophages in both of these disorders resemble each other histologically, electron microscopy demonstrates more abundant osmiophilic dense bodies and giant lamellar bodies in many different cell types in amiodarone toxicity compared to similar but smaller inclusions within macrophages in endogenous lipid pneumonia. . ~ compared to endogenous lipid pneumonia, amiodarone toxicity also encompasses a prominent inflammatory response that may include fibrosis, organizing pneumonia and diffuse alveolar damage (see chapter ) . other drugs that have been implicated as a cause of endogenous lipid cholesterol granulomas not only are associated with endogenous lipid pneumonia and pulmonary alveolar proteinosis, but also have been attributed to pulmonary hypertension, organizing hemorrhage, and a unique case of excessive consumption of apples. - kay and colleagues suggest that cholesterol granulomas in patients with pulmonary hypertension are more likely due to other concomitant processes characterized by type ii pneumocyte hyperplasia and degeneration. atelectasis is the collapse of aerated lung. most often it is caused by internal bronchial obstruction of the air flow (absorption atelectasis) (see fig. . in chapter ), but it may result from external compression of the lung, such as by empyema, mesothelioma, constrictive pleural fibrosis, or tumors, or by internal compression, secondary to a bulla, tumor, or other space-occupying lesions (compressive atelectasis). pneumothorax is an important cause of atelectasis in the ipsilateral lung. atelectasis may also be caused by a change in metabolism or surface-wetting balance such as with hyaline membrane disease, ards, infection, or gastric acid or other aspiration with loss of pulmonary surfactant. it may also have vascular causes as with embolism, postoperative splinting, obesity (e.g., pickwickian syndrome), or secondary to nerve or muscle dysfunction of diaphragm or chest wall. following complete airway obstruction, atelectasis occurs when alveolar oxygen and nitrogen are absorbed. atelectasis is also commonly seen around chronic inflammatory reactions such as bronchiectasis, and may be part of the sequence of events leading to bronchiectasis (see below). pathologists must be cautious, however, because most often, when observed histologically, atelectasis is artifactual. upon the release of negative pressure, air escapes from the lung when the thorax is opened or when lung tissue is excised, and this collapse may cause confusion with preexisting atelectasis (see fig. when bronchial obstruction is partial, it may easily lead to air trapping, as discussed in chapter (see asthma). obstruction of segmental bronchi usually does not cause atelectasis because of preserved collateral ventilation. a collapsed lung may be an isolated cause of fever, but is also a frequent site for superinfections, such as in postoperative patients. chronic atelectasis may lead to irreversible scarring. the special situation of rounded atelectasis is discussed in chapter on asbestos-related pathology. bronchiectasis simply defined refers to dilatation of bronchi. included in this broad definition are conditions such as traction bronchiectasis secondary to parenchymal scarring; airway dilatation accompanying parenchymal loss as in emphysema; or reversible dilatation, which may be seen radiographically in atelectasis or pneumonia. - a more selective definition of bronchiectasis, and the type usually understood by pathologists, is irreversible fixed airway dilatation associated with inflammation and destruction of bronchial matrix components. • bronchiectasis can be further categorized as localized or diffuse/multifocal. causes of localized bronchiectasis, the most important of which is airway obstruction, are listed in table . . localized bronchiectasis may also have an infectious etiology, most notably pulmonary tuberculosis (see fig. . in chapter ). obstructive bronchiectasis is most commonly seen beyond endobronchial tumors (fig. . ), but foreign bodies, concretions such as broncholiths, secretions such as inspissated mucus in mucoid impaction and allergic bronchopulmonary aspergillosis (see chapter ), strictures, or compression as by tumor or enlarged nodes may play a role. rarely, lack of cartilaginous support with airway collapse, bronchial atresia, or mucosal webs may be associated with bronchiectasis. obstructive bronchiectasis occurs anywhere obstruction occurs, but there are some localizing factors in a few of these conditions: the upper lobe in allergic aspergillosis or with primary epithelial tumors, which are more common in this site; the middle lobe with its tendency toward airway compression (middle lobe syndrome); and localized bronchiectasis governed by the usual routes of aspiration (covered earlier in this chapter). there are many exceptions, and bronchoscopy is usually indicated in both children and adults to diagnose the type of obstruction. localized bronchiectasis is often successfully treated by surgical resection or elimination of the cause of bronchial obstruction. diffuse or multi focal bronchiectasis is usually of the nonobstructive type, the major causes of which are listed in table . . it is this type that is more frequently a cause of significant chronic obstructive pulmonary disease (copd) and respiratory failure. nonobstructive bronchiectasis occurs most frequently in the basal segments of the lower lobes, often sparing the superior segment and the anterior basal segment. it is found more than twice as frequently in the left lower lobe as in the right. s -j next in frequency are the right middle lobe and its counterpart, the lingula. these areas of the lung may have the poorest drainage. the upper lobes may be involved but are usually not solely involved by nonobstructive bronchiectasis. tuberculosis more selectively causes bronchiectasis in the upper lobes, and cystic fibrosis should be considered in cases of upper lobe involvement without a definitive etiology. about one third of the cases of nonobstructive bronchiectasis have bilateral involvement. . , macroscopically bronchiectasis typically involves the second to the eighth order of segmental bronchi, sparing the larger, more proximal airways, which are protected by a firmly supporting cartilaginous network. - more distal airways are often obliterated or effaced as the number of bronchial divisions is reduced (fig. . ). , within a bronchopulmonary segment there may be patchy involvement (see fig. . in chapter ). there is also apparent loss of more distal lung parenchyma as the dilated airways approach the visceral pleura ( fig. . ) . , bronchiectasis has been divided into many different patterns grossly and radiographically. the most widely applied classification is that suggested by reid l : ( ) saccular (cystic), ( ) cylindrical (fusiform or tubular), and ( ) varicose. in the saccular form, the distal extensions of the bronchi are more dilated than proximal portions, described by reid as "globular ballooning." usually, the second-to fourth-order bronchi are involved. cylindrical bronchiectasis consists of evenly enlarged tubular dilatation of bronchi, usually involving the sixth-to eighthorder bronchi. is i on bronchograms dilated bronchi come to an abrupt, square-ended termination thought to be caused by impacted endobronchial secretion. the varicose type describes focal dilatation separated by more narrow areas (see fig. . in chapter ). these various gross patterns were previously best visualized by bronchography, and are not specific for any given etiology, although certain clinical-pathologic correlations have been made (see below). whitwell integrated histologic features into his classification of follicular, saccular, and atelectatic bronchiectasis. follicular bronchiectasis most frequently begins in childhood as the sequela of viral infections, most notably adenovirus. saccular bronchiectasis, in whitwell's series, was often found to be postinfective or idiopathic. the pathogenesis of atelectatic bronchiectasis was linked to lobar bronchial obstruction, often by enlarged lymph nodes. congenital bronchiectasis, purportedly due to cartilage deficiency in the bronchial walls, is a controversial entity discussed elsewhere in this chapter under the williams-campbell syndrome. , s , not to be confused with congenital bronchiectasis are those hereditary conditions, such as cystic fibrosis or primary ciliary dyskinesia, that predispose to the subsequent development of progressi ve bronchiectasis (see below). , patients with bronchiectasis typically present clinically with forceful cough, purulent sputum production, wheezing, and recurrent pneumonia in the bronchiectatic zones. wet bronchiectasis refers to abundant inflammation and mucus hypersecretion, whereas dry bronchiectasis refers to minimal sputum production. dry bronchiectasis is most common in the upper lobes, is often of the cylindrical type, and probably relates to better drainage in this zone. hemoptysis commonly presents as blood-streaked sputum, but may be massive and life-threatening. frequently purulent sinusitis accompanies bronchiectasis and may contribute to its development. the chest radiograph is usually abnormal in bronchiectasis, including specific features of ring-like shadows due to dilated airways seen on end, or of tram lines when the airways are visualized longitudinally. iss high-resolution ct scan is the best current modality for diagnosing bronchiectasis, revealing airways that are dilated relative to the adjacent blood vessels, lack of airway tapering, constrictions along the path of the airway, and terminal balloon-like cysts. is ,is pulmonary function tests show obstructive changes with reduced forced expiratory volume in second (fev )/ forced vital capacity (fvc) and frequently airway hyperresponsiveness. various theories have been proposed to explain nonobstructive bronchiectasis. inflammation seems to best account for the changes that are observed, including the fact that the involved zones of lung are those most difficult to drain. it was known even in the s and confirmed in subsequent decades that respiratory infection often preceded bronchiectasis. , , - usually older children and young adults have the well-developed disease pattern, but also have a history of infections before the age of or years, with recurrent respiratory problems dating from this time. many patients may appear stable and do well for some time, and then develop a progressive course of recurrent infections and systemic toxicity. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in approximately % of cases of bronchiectasis, however, a specific inciting factor is not identified-so-called idiopathic bronchiectasis . in these patients, childhood respiratory infections especially those likely to have produced bronchiolitis obliterans, are presumed to have initiated the process of bronchiectasis. , , viral infections may be important in many cases. , , - glauser and associates noted in an extensive review that measles and pertussis immunizations probably have played a significant role in decreasing the incidence of bronchiectasis. bacteria also playa significant role, both in primary infections (see following) and in superinfections or reinfections in areas of previous injury. aggressive treatment of pediatric pulmonary infections with antibiotics has helped to make bronchiectasis a disappearing disease. historically, the impact of immunizations and antibiotics on the declining incidence of bronchiectasis occurred at about the same time, and it is difficult to differentiate their effects; nonetheless, this association supports the role of early infection in initiating bronchiectasis. excluding cases of kartagener's syndrome, the concurrence of sinusitis and bronchiectasis is greater than expected. as early as , quinn and meyer noted a % incidence of chronic sinusitis in cases of bronchiectasis. aspiration of infective material from the sinuses may playa role. however, another study noted a % incidence of sinusitis in cases with less than years of symptoms of bronchiectasis compared to the % incidence in all cases of bronchiectasis. h. infiuenzae, a common pathogen of the upper respiratory tract, is also found with some regularity in lung cultures from patients with bronchiectasis. anaerobic bacteria, reflecting endogenous oral flora , may also be cultured from bronchial secretions. long-term antimicrobial treatment may be required for complete eradication of these organisms. the role of recurrent infection in perpetuating and aggravating bronchiectasis cannot be overemphasized. this has been documented in children and adults. the dilatations of the bronchial contours, their irregularities, their relative stenosis at the proximal end, altered secretions and exudate, surface mucosal ulcerations, and metaplasia all playa role in hampering adequate drainage. a vicious cycle ensues as the injured area perpetuates further injury, leading to increased damage and progressive bronchiectasis. necrotizing inflammation involves bronchial walls and adjacent parenchyma (fig. . ) . some scarring probably takes place in healing, with retraction of surrounding tissue. retraction occurs circumferentially, and bronchial dilatation results. as noted, the more distal bronchi and bronchioles are often destroyed. there is also general lung contracture due to atelectasis of involved zones, while nonaffected lobes may undergo compensatory hyperinflation (fig. . ) . the basic principles of fibrosis and contraction also apply to traction bronchiectasis seen in interstitial fibrosis and honeycombing. traction bronchiectasis is usually not as marked as primary bronchiectasis, and is localized and most severe in the peripheral subpleural zones where fibrosis is often most prominent (see chapter ) . grossly, the involved lung tissue is usually atelectatic, gray-blue, shrunken, and rubbery. there may be zones of golden or obstructive pneumonia, and sometimes these zones form layers around the dilated bronchial tubes. it may be difficult or impossible to adequately inflate such a chronically contracted specimen. the involved bronchi are dilated instead of following their smoothly contoured courses as they extend peripherally. these dilated bronchi almost reach the pleural surface and run in a somewhat parallel or radial fashion without interbronchial connections (figs. . and . ). partially or totally circumferential thin folds in the mucosa extend internally from the wall and are seen as transverse infolded pleats on the bronchial cast (see fig. . in chapter ). these give the appearance of webs or bands of mucosa. there are variably sized outpouchings, larger ones between the remnant bronchial cartilages, and dilated smaller pits that appear to be dilated submucosal glands. grossly, elastic fibers can be seen still running through the wall, but these are more widely separated than is normal because of the stretched diameter of the bronchus. in wet bronchiectasis there is thickening of the wall, and mucinous, granular, semisolid material accumulates within the lumen (fig. . ). occasionally this material hardens and even calcifies (see broncholithiasis, below). in dry bronchiectasis the wall is thin, almost translucent, and gray-pink without mural thickening. microscopically the respiratory mucosa may be intact, show squamous metaplasia, or be ulcerated or inflamed (fig. . ). the bronchial walls are usually chronically inflamed. submucosal glands and surface goblet cells are not prominent and may decrease, although they may occasionally increase. elastic tissue is preserved except in areas of necrosis (fig. . ). smooth muscle is usually present and often shows some degree of hypertrophy; occasionally this is atrophic. cartilage seems less obvious and occasionally is eroded, but most often appears normal histologically. in advanced saccular bronchiectasis cartilage is markedly reduced or absent. , , neutrophils, macrophages, and desquamated and mucinous debris are present in the bronchial lumen in wet bronchiectasis. acute inflammatory cells may infiltrate the bronchial wall or the adjacent lung parenchyma depending on the status of inflammation and active infection at the time of lung removal. as these patients are subject to recurrent infections, acute pneumonia may also be present. lymphocytes and plasma cells usually predominate in bronchial wall and surrounding lung tissue. in follicular bronchiectasis, hyperplastic lymphoid follicles may appear to constrict the bronchial lumens (fig. . ). there may be a degree of obstructive pneumonia correlating with the gross yellow color. small granulomas are present in a few cases, apparently as a reaction to inspissated material within the bronchi. if granulomas are extensive or present in the adjacent lung parenchyma, in more normally contoured segmental and subsegmental bronchi, or in lymph nodes, one must consider fungal or mycobacterial infections. if granulomas are confined to the injured areas, one must also consider aspiration. bronchioles are often constricted or obliterated beyond the dilated bronchi (fig. . ). other small airways may be dilated and sometimes mucus-filled probably because of their obstruction at the junction with the larger bronchi. foci of carcinoid atypical proliferation (tumorlets) occur with some frequency in bronchiectasis (see chapter ) . bronchial arteries respond to sustained inflammation, and may exceed mm in diameter. ulceration of these systemic arteries accounts for the bright-red appearance of hemoptysis. the right middle lobe and occasionally its left-sided counterpart the lingula, have lobar bronchi that branch from their parent supply at a more acute angle than most other dividing bronchi (see chapter ) . the middle lobe bronchus is relatively narrow, and there are frequently moderately prominent nodes in the angle of bifurcation that may compress and further constrict the bronchus. the subcarinal node may even approach this angle. several authors have also suggested there is less effective collateral ventilation in the middle, compared to the adjacent upper lobe. . because of these anatomic characteristics there is a greater tendency toward middle lobe and lingular atelectasis, inflammation, nonspecific scarring, broncholith formation, and bronchiectasis-collectively termed middle lobe syndrome (mls) . io in addition to peribronchial lymphadenopathy, mls can result from numerous disorders including asthma, tuberculosis, foreign bodies, cf, broncholiths, endobronchial silicosis, cardiovascular and of bronchiolar wall. white arrow indicates cross section of separate, obliterated airway (patient with cf) (elastic van gieson stain). bronchopulmonary malformations, and allergic bronchopulmonary aspergillosis. - the pathologic findings in resected lung specimens of patients with middle lobe syndrome have been comprehensively described most recently by kwon and colleagues, and are delineated in table . . although the histologic findings are nonspecific, a combination of bronchiectasis, bronchiolitis, and atelectasis is typical. in this series, a mechanical obstruction (broncholith) was identified in only one patient. as early as , culiner also recognized bronchial patency in most cases of middle lobe syndrome. the current understanding suggests that mls is due to recurrent infection related to poor lung drainage, possibly associated with intermittent obstruction of the precariously situated bronchi in the setting of reduced collateral ventilation of the middle lobe. . broncholiths represent calcified material in the airways. - they most commonly are calcified lymph nodes that compress bronchi and either partially or completely erode through the bronchial walls (fig. . ). . they then may be expectorated (lithopytsis) (fig. . ) calculus (scale equals cm). c. rare yeast-like organisms, consistent with histoplasma, were identified in the necrotic center of the broncholith (gomori methenamine silver stain). or aspirated and cause hemorrhage or obstructive changes, including cough, atelectasis, pneumonia, abscess formation, bronchiectasis, or air trapping. broncholiths form less often from chronic reaction to retained aspirated material or eroded fragments of calcified or ossified bronchial cartilage. o they may also occur with retained mucus as in bronchiectasis. historically, "spitting stones" dates back to descriptions by aretaeus, galen, and aristotle. although usually less than cm in diameter, a record-sized calculus of g c/ ib) occurred in a patient who also had produced multiple sand-like or melon-seed-sized calcified particles. the pathognomonic finding of lithoptysis is fairly rare and was seen in only two of ( %) cases by faber et al. and six of ( %) cases by schmidt et au the regional nodes usually calcify from old granulomatous disease, and tuberculosis is the most common etiology worldwide while histoplasmosis is the most common etiology in the united states. other infectious agents include coccidioides, cryptococcus, actinomyces, or no cardia. , o, , the latter two organisms probably represent superinfections of necrotic debris. silicotic lymph nodes may also cause a similar reaction. , men and women are about equally affected, and although calcified nodes may occur at any junction of the bronchial tree, they are to . times as common on the right side, and favor the anterior superior segment of the upper lobe and the bronchus intermedius, along with the right middle lobe bronchus, where they may produce the middle lobe syndrome. , , the superior segment of the lower lobe is also a site of occurrence. occasionally, erosive calcified nodes may cause bronchopleural fistulas and are the most common cause of bronchoesophageal fistulas, [ ] [ ] [ ] retraction diverticula of the esophagus may also occur secondary to peribronchial fibrosis and calcified mediastinallymph nodes associated with broncholiths. , calcified nodes have also been studied with ct scans. in the retrospective series by conces et al., of patients with ct-proven broncholiths, ( % ) had juxtabronchial calcified nodes identified on chest radiographs. calcified intraparenchymal nodules were seen radiographically in only four ( %) patients. bronchoscopy is less accurate in detecting calcifications, ranging from % to % of cases. rarely, calcifying tumors such as an ossifying bronchial carcinoid or endobronchial hamartoma can cause confusion (see chapters and ) . , histologically broncholiths appear similar to calcified fibrocaseous lymph node lesions. the outer surface of the often sharp-edged calculus may be coated with inflammatory exudate or, in cases of actinomyces superinfection, eosinophilic rays (splendore-hoeppli phenomenon). , the gms stain may disclose histoplasma yeast forms in the centrally necrotic area of the calculus (fig. . b) . , , the airway in which the calculus is lodged is typically stenotic, with mural fibrosis and chronic inflammation. within the chest, fistulas may be bronchopleural, bronchocutaneous, bronchomediastinal, or bronchoesophageal in their connections. an aortobronchial fistula is a rare (and often fatal) complication of previous aortic or cardiac surgery, bronchopleural fistulas are the most common form and often are secondary to surgery, such as from a leaking postoperative bronchial stump. other causes include necrotizing pneumonia or abscess, penetrating wounds, eroding granulomatous disease, penetrating broncholiths, or malignancies. see chapter for congenital causes. extrathoracic bronchial fistulas include connections with bile ducts, pancreas, and other assorted sites. bronchocele means one or more dilated bronchi filled with fluid, which may be mucinous (bronchomucele) or purulent (bronchopyocele ). this condition is caused by stenosis or occlusion of the proximal end of dilated sac(s), and therefore differs from bronchiectasis and mucoid impaction, in which proximal ends are generally still patent. it may be either congenital, or early or late acquired, usually of postinflammatory nature but sometimes of malignant nature. localized emphysema, which occurs around the bronchocele, may be caused either by inflammation early in lung growth with continued traction-type effects on nearby lung, or by sustained air-trapping due to airway obstruction. , . o many cases are reported as bronchial atresia. - bronchocele/ atresia may present in adults or children and typically affects the left upper lobe. a characteristic ct appearance is that of a branching mass surrounded by hyperlucency. an irregularly cylindrical (sometimes branched) thin-walled cyst (fig. , a) grossly and histologically resembles a bronchocele lined by respiratory or squamous epithelium. , o, occasionally a scar or intrabronchial web proximal to the lesion represents the remnant atretic or occluded bronchus. the adjacent bronchial arteries may appear hypertrophic, especially if there have been recurrent infections (fig. . b) , bronchocele may be a relative of saccular bronchiectasis and may be the etiology for some so-called intraparenchymal bronchogenic cysts (see below and chapter ). mucoid impaction may also be related to an allergic effect, often to noninvasive aspergillus (see chapter ), usually does not have proximal bronchial stenosisocclusion, and has more eosinophils and cellular debris in the mucus, in addition to intraluminal hyphae. bronchocele/atresia is distinguished from intralobar seques- bronchogenic cysts are closed sacs lined by respiratory mucosa, usually with bronchial glands, smooth muscle, and cartilage in their walls. they often represent congenital fragments that drop off or are remnants of the original budding of the lungs from the primitive endodermal canal. they are most common in the middle mediastinum where they account for % to % of all primary mediastinal masses but can be seen as isolated masse es) in the lung. within the lung, some may form as bronchoceles as discussed previously. a series of cases of bronchogenic cyst, with ( %) in the mediastinum and ( %) in the lung, was presented by st. georges et al. from montreal. a similar distribution was recorded in adult patients by patel and colleagues. of interest, % to % of those in the lung were symptomatic at the time of operation, most often because of infection or bronchial obstruction,z , although suspected, a preoperative diagnosis was not correctly made in any case in the large montreal series. the presence of bronchial epithelial cells on trans bronchial fine-needle aspiration (fna) was found not to be specific for the diagnosis of bronchogenic cyst. most occur in the lower lobes, but all lobes may be affected. -z the ct appearance is that of a well-defined hypertrophic bronchial arteries (ba). lumen of cyst is at top (movat stain). ovoid lesion, with surrounding mosaic and band-like linear attenuation consistent with emphysema and bronchiolar metaplasia/fibrosis. a bronchioloalveolar cell carcinoma arising in a bronchogenic cyst in a -year-old woman has been reported as a rare association. bronchogenic cysts are uncommon in adults and are further discussed in children in chapter . bronchorrhea is arbitrarily defined as production of more than ml of sputum per day. although it is a clinical symptom, pathologists may ponder the differential diagnosis if faced with this history on a specimen request card. bronchorrhea may be idiopathic, or secondary to chronic bronchitis, bronchiectasis, scleroderma, asthma, mucinous bronchioloalveolar carcinoma, metastatic mucinous adenocarcinoma, tuberculosis, or relapsing polychondritis. - cytology exams, cultures, or trans bronchial biopsies may help evaluate at least some of these possibilities. cystic fibrosis is a prototypic example of bronchocentric inflammation and bronchiectasis and the most common lethal genetic disease among caucasians, having a frequency of approximately in live births. - the molecular defect of this autosomal recessive disorder was discovered in to involve mutations in a amino acid polypeptide, the cystic fibrosis transmembrane conductance regulator (cftr), encoded by a gene on the long arm of chromosome . , over different mutations of the cftr gene have so far been identified, but the most frequent mutation worldwide and the most severe genetic lesion, is the deletion of phenylalanine at position of cftr (af ), accounting for over % of affected patients. o , cystic fibrosis transmembrane conductance regulator functions as a cell membrane-associated, cyclic adenosine monophosphate (camp)-regulated chloride channel, which also has regulatory activity on the absorption of sodium through a separate epithelial channel (enac). - the structure of cftr is schematically depicted in figure . . mutations in cftr have been grouped into six major types, each of which may present phenotypically as cf: ( ) lack of synthesis of cftr; ( ) defective processing of cftr such that it does not reach the cell membrane; ( ) aberrant regulation of ion transport due to dysfunctional cftr; ( ) abnormal conductance of chloride ions; ( ) partly defective production and processing; or ( ) accelerated turnover at the cell surface ( fig. . ) . , , , the af mutation is a type defect in which abnormal cftr is sequestered within cellular organelles leading to reduced insertion into the cell membrane, markedly limiting the ability of chloride to cross the membrane. in epithelial cells of bronchi, biliary tract, and intestine, impaired transport of intracellular chloride and its accompanying water molecules leads to dehydration of ductal and lumen secretions. o in bronchial epithelium there is also enhanced intracellular absorption of sodium ions, which further dehydrates secretions within the airway lumen. o , , in contrast, the uptake of extracellular chloride is inhibited in sweat ducts, causing an elevation of sweat chloride concentration, a key diagnostic indicator of cf. , the manifestations of cf are protean, involving nearly every organ system either directly or secondarily. the correlation between genotype and phenotypic expression is best exhibited for pancreatic function and is relatively poor for pulmonary manifestations. , , however, certain mutations such as a e or the ivs t allele are associated with relatively mild lung disease that may initially present in adults.m- a unifying feature of the pathophysiology of cf is impaction of viscid secretions in exocrine gland ducts leading to cardinal manifestations such as intestinal obstruction (e.g., meconium ileus); pancreatic acinar atrophy and fibrosis with consequent metabolic insufficiency (due to intestinal malabsorption); organ maldevelopment (e.g., congenital bilateral absence of the vas deferens); hepatic fibrosis (focal biliary cirrhosis); and infection associated with mucus stasis (e.g., infective bronchitis). o, pulmonary involvement is usually the lungs in cf are structurally normal at birth. dilatation of mucous gland ducts followed by intrabronchial mucus stasis are the earliest pulmonary lesions seen in infants. , , o it has long been recognized that patients with cf are predisposed to lung infection. . current hypotheses suggest that susceptibility to infection may be related not only to entrapment of bacteria in thick bronchial secretions, but also possibly to abnormal binding and reduced uptake of bacteria by epithelial cells, or impaired epithelial antimicrobial protection provided by defensins (natural antibiotics of the innate immunity system). . - even in infants without apparent infection, however, bronchoalveolar lavage studies document ongoing bronchial inflammation associated with increased levels of endobronchial il- , a potent cytokine that recruits neutrophils into the inflammatory response, and relatively decreased levels of il-lo, an inhibitor of proinflammatory cytokines. g- it is as yet undetermined whether or not intrinsically exaggerated inflammatory responses are the direct result of mutations in cftr. infection and inflammation stimulate bronchial mucus secretion leading to a vicious cycle of worsening airway infection and obstruction, progressing to chronic bronchitis, bronchiolitis obliterans, and bronchiectasis. the chronic pulmonary complications of cf evolve from the airway disease. hyperinflation or collapse is the direct result of bronchial obstruction. air trapping and postinflammatory cystic lesions underlie an increased susceptibility to recurrent pneumothorax. pulmonary hypertension and cor pulmonale derive from sustained hypoxia, while hemoptysis is a direct effect of bronchiectasis and bronchial artery hypertrophy. endobronchial infection tends to occur in sequential fashion, initiated by s. aureus, followed by h. injluenzae, and finally by p. aeruginosa (mucoid strains). . submucosal glands are enlarged and chronically inflamed behind ducts that are obstructed by dense, inspissated, eosinophilic secretion (a characteristic, but not pathognomonic feature of cf) (fig. . ). - although bronchial smooth muscle in individual patients may appear hypertrophic, its mean volume density is within the normal range. in patients with cf-associated lung disease, saccular bronchiectasis is usually present beyond months of age. r although all bronchopulmonary segments may be affected, bronchiectasis tends to be more severe in the upper lobes (fig. . ). . . blind-ended ectatic airways, devoid of cartilage, are surrounded by atelectatic, chronically inflamed, and fibrotic parenchyma (see fig. . ). bronchial mucosa is frequently denuded or ulcerated leaving the bronchial surface lined by highly vascular granulation tissue that is rich in histiocytes (see fig. . ). in severe disease, bronchi terminate in large, juxtapleural, thin-walled cavities that present radiographically as contiguous, bubble-like cysts. intrapleural blebs or emphysematous bullae are less common forms of cystic lesions, which contribute to an increased incidence of pneumothorax. . extensive acute and chronic bronchiolitis and bronchiolar mucoid impaction impart a finely nodular texture to the parenchymal surface and account for a micronodular radiographic appearance ( fig. . ). bronchiolitis obliterans, predominantly of the constrictive type, contributes importantly to airway obstruction, and likely precedes the development of bronchiectasis (see fig. . ). . occasionally, occlusion of respiratory bronchioles by polypoidal protrusions of fibroblastic tissue accompanies interstitial and organizing pneumonia? small airway density decreases with age and is most significantly reduced in patients with hypercapnia. . the lung parenchyma is grossly indurated by multifocal, bronchocentric chronic pneumonia and fibrosis, with features of both organizing pneumonia and endogenous lipid (cholesterol) pneumonia. a variable degree of acute bronchopneumonia may also be seen at autopsy. some patients who are colonized by burkholderia cepacia undergo an accelerated decline due to acute necrotizing pneumonia (see figs. . and . in chapter ). other patients colonized by burkholderia follow a more protracted course, similar to those colonized by p aeruginosa. [ ] [ ] [ ] fungi and nontuberculous mycobacteria may also colonize cf airways and contribute to lung destruction. , , bhargava and colleagues identified fungal organisms histologically in % of cf patients retrospectively studied at autopsy. the dilated, obstructed airways of cf patients are predisposed to fungal colonization, accounting for an increased prevalence of allergic bronchopulmonary aspergillosis (abpa) of approximately . %. infrequently the pathologic features of abpa, including bronchocentric granulomatosis, are superimposed on chronic cf-associated airways disease (see fig. . in chapter ). in cf patients with non tuberculous mycobacterial infections (often due to mycobacterium avium or rapidly growing strains like m. chelonae or m. abscessus), necrotizing fibrocaseous granulomas may be present. , , , pulmonary lesions are most likely to be found in patients with repeatedly positive sputum cultures for mycobacteria (see chapter ) . the pulmonary vascular changes of cf-associated lung disease are usually pronounced, chronic hypoxia and inflammatory changes contribute to pulmonary artery medial hypertrophy and intimal fibrosis of muscular pulmonary arteries and medial myxoid degeneration of elastic arteries. - postmortem arteriograms often show abnormally tapered arteries with a reduced background haze (see fig. . in chapter ). morphometric studies provide evidence of a decreased density of arteries, which correlates inversely with the degree of right ventricular cardiac hypertrophy, the dropout of arteries may be related to impaired postnatal growth or to vascular destruction secondary to chronic hypoxia or sustained inflammation. right ventricular cardiac hypertrophy, seen at autopsy in approximately % of cf patients older than years of age, is a direct consequence of pulmonary artery remodeling and associated pulmonary hypertension. bronchial arteries also undergo significant hypertrophy as a response to sustained bronchial inflammation, bronchiectasis, and bronchocentric abscesses (fig. . ). - the source of hemoptysis in cf patients is most frequently the delicate capillaries within airway granulation tissue (see fig. . ), , occasionally, mucosal ulcers erode into hypertrophied bronchial vessels leading to life-threatening massive hemoptysis (fig. . ). interventional bronchial artery embolization of metal coils, polyvinyl alcohol (ivalon), or gelfoam particles is undertaken to induce thrombosis and control bronchial artery bleeding. , degenerated remnants of embolized polyvinyl alcohol may surround stenotic or occluded bronchial arteries in patients who have undergone this procedure. bronchopulmonary arterial anastomoses may further allow the paradoxical entry of small embolized particles into the pulmonary arterial circuit (see fig. . in chapter ). other less frequently reported complications of cystic fibrosis include systemic amyloidosis, intralobar sequestration, and anaerobic lung abscess. - emphysema is usually a minor feature, localized to bronchiolocentric scars or as paraseptal emphysema in the upper lung zonesys, s, cystic fibrosis patients with indwelling venous access devices may surreptitiously inject aqueous suspensions of psychoactive pharmaceutical tablets leading to pulmonary artery obstruction due to embolized tablet filler materials (see chapter ). primary ciliary dyskinesia (pcd) is an autosomal recessive disorder, occurring in approximately of , to , persons, characterized by the absence or dysregulation of ciliary movement mainly due to ultrastructural defects in the ciliary axoneme. (see chapter )? - cilia on the respiratory epithelial surface play an important role in propelling mucus, bacteria, and inhaled particulate debris out of the lung (see chapter ). as a result of impaired clearance due to ciliary malfunction, patients with pcd are predisposed to chronic sinusitis, serous otitis, and recurrent bronchopulmonary infections beginning in early childhood. , primary ciliary dyskinesia has also been implicated as a cause of neonatal respiratory distress syndrome. , male patients are usually infertile due to poor flagellar motility of sperm. approximately % of patients with pcd also have situs inversus secondary to abnormal rotation of embryonic epithelia consequent to the lack of ciliary movement. the syndromic triad of situs inversus, sinusitis and bronchiectasis was first proposed by kartagener in , and is now designated kartagener's syndrome (fig. . ). . while pcd is an important cause of bronchiectasis, the prognosis is generally more favorable than that of cf. in afzelius and pedersen and mygind were among the first to recognize that ultrastructural abnormalities of ciliary dyne in arms were associated with kartagener's syndrome. originally termed immotile cilia syndrome by afzelius, it is now recognized that there are numerous structural variations that may contribute to if. tomashefski, jr., and d.h. dail pcd, and that cilia are not always immotile? when compared to normal (fig. . a) , the most commonly observed ultrastructural defects are the complete absence of dyne in arms or the selective absence of either inner or outer arms (fig. . b ). other derangements of the axoneme contributing to pcd include defective or absent radial spokes (fig. . d ), transposition of microtubules (fig. . c ) (well seen in longitudinal sections of cilia), central microtubular agenesis, absence of nexin links, agenesis of cilia, or rarely, bizarre cystic dilatation of ciliary shafts. - nonspecific findings such as ciliary blebs, megacilia, compound cilia, and displaced microtubules may accompany the more specific defects, but are also frequently present in inflammatory airway disease of diverse causes including infectious bronchitis, cf, or air pollution. - some patients with structurally normal cilia and a normal ciliary beat frequency may develop the clinical manifestations of pcd due to ciliary disorientation, resulting in uncoordinated ciliary motion (fig. . e ). , ciliary disorientation has also been described in individuals with infectious bronchitis (including cf), but the degree of disorientation is usually not as great as in those in whom the defect is primary, and the disorientation secondary to infection typically resolves after effective antibiotic treatment. the diagnosis of pcd is established by ultrastructural analysis of respiratory epithelium in conjunction with typical clinical manifestations, exclusion of other causes of chronic airway inflammation, and documentation of abnormal ciliary motion by phase contrast microscopy. . , mucosal samples obtained by endoscopic biopsy or brushing are examined by transmission electron microscopy. in patients with pcd, nasal mucosal samples are reflective of bronchial changes when most cilia are abnormal. when only few cilia are structurally abnormal in a patient in whom the diagnosis of pcd is highly suspected, a bronchial sample is required. abnormalities in sperm flagella may differ in type and quantity from those of respiratory cilia within the same patient, suggesting separate genetic control of axone mal structures at differing loci? the lung pathology in pcd is postinfective in appearance. both saccular and cylindrical bronchiectasis may be present with the predominant histologic pattern of follicular bronchiectasis. , , neither bronchial mucus stasis nor squamous metaplasia is prominent chronic interstitial pneumonitis, peribronchial fibrosis, and atelectasis accompany the bronchiectatic changes. , , studies to date suggest that pcd is a genetically heterogeneous disorder. the molecular basis of pcd has been localized in a few instances to mutations in the human dyne in axonemal heavy chain (dnah ) located on chromosome , or in the intermediate dynein chain gene (dnail) on chromosome , - a mutation in the dyne in axonemal heavy chain type (dnahll) has been associated with pcd and situs inversus, without evident ultrastructural ciliary changes, ongoing studies on genetically engineered knockout mice may uncover other genetic defects associated with pcn, , in donald young, a urologist, reported a series of patients with obstructive azoospermia, % of whom had associated respiratory conditions including bronchitis and bronchiectasis, this condition was initially designated as berry-perkins-young syndrome and later shortened to young's syndrome. patients, nearly all had chronic cough, sputum production, and recurrent pulmonary infections. bronchiectasis and chronic sinusitis were each present in about two thirds of patients. in one study it was estimated that young's syndrome accounted for approximately % of all patients who presented with bronchiectasis of unknown etiology (equivalent to the prevalence of cf and slightly greater than that of pcd). azoospermia in young's syndrome is the result of retention of semen in an enlarged epididymal head. motility studies have demonstrated impaired upper airway mucociliary transport; however, ciliary beat frequency and ultrastructure are normal. , , , in patients with young's syndrome, sweat chloride concentration and the electrical potential difference across the nasal epithelium are normal. the respiratory symptoms in young's syndrome have been suggested to be the result of altered viscoelastic properties of airway secretions, but the basic molecular defect is unknown. an association with mercury toxicity has been hypothesized. friedman and colleagues evaluated mutations of cftr in a cohort of patients with young's syndrome and found that the prevalence of mutations did not differ significantly from the expected carrier frequency in the general population. pulmonary involvement is generally less severe than in cf. bronchiectasis tends to occur at an early age and predominantly involves the lower lobes. pulmonary function tests indicate mild obstruction with decreased fev and increased residual volume, although a number of patients have undergone lung resections for bronchiectasis, the pathologic features of bronchiectasis in young's syndrome have not been well described, and it is uncertain if there are any distinctive histopathologic changes. from a diagnostic standpoint it is important to exclude cf and pcd, each of which may be clinically misclassified as young's syndrome? , the distinguishing characteristics among these three conditions are presented in table sa . williams-campbell syndrome is a rare disorder in which extensive loss of bronchial cartilage is associated with diffuse cystic bronchiectasis without other recognized predisposing factors. , the clinical presentation that commences in infancy may include cough, dyspnea on exertion, cyanosis, and clubbing. on chest radiograph large thin-walled cysts reside in hyperinflated lungs. highresolution ct scan characteristically shows central, cystic, thin-walled airways that collapse upon expiration. . the clinical course is one of recurrent pulmonary infections leading to respiratory failure. patients may survive into adulthood and require lung transplantation. as described in the original report by williams and campbell and substantiated in subsequent morphologic studies, the lungs grossly exhibit extreme saccular and cystic bronchiectasis (fig. . a ). - microscopically, dilated airways have very thin walls with minimal inflammation (fig. . b ). cartilage is absent or markedly deficient from the fourth to the eighth divisions of subsegmental bronchi. first-and second-order bronchi usually have a normal cartilage investment. pan acinar emphysema or emphysema localized to the peribronchial zone is usually also present. . bronchiolitis obliterans has also been reported. . the williams-campbell syndrome has been considered to be the result of a congenital absence of cartilage in the subsegmental airways. morphologic studies documenting absent cartilage and insignificant inflammation, and rare reports of familial occurrence have been used to support this view. . . however, given the propensity for cartilage loss in acquired saccular bronchiectasis of diverse etiologies, the williams-campbell syndrome remains a controversial entity, and its congenital origins have yet to be proven beyond question. . . . the williams-campbell syndrome has not been associated, nor is it to be confused, with congenital lobar emphysema, in which cartilage is focally deficient, usually in upper lobe bronchi, leading to bronchial collapse and air trapping (see also chapter ). tracheobronchomegaly (tbm) is a condition of marked dilatation of the trachea and major bronchi, often associated with recurrent respiratory infections. tbm can be congenital, or at least evident in early life, in which it is termed mounier-kuhn syndrome (see chapter ) . it has occurred in several cases of ehlers-danlos syndrome, suggesting it may be related to poor elastic support, or perhaps to loss of other matrix components as in chondromalacia. tracheobronchomegaly occurs in adults, mostly in men in their fourth and fifth decades, and can be an acquired condition secondary to sustained inflammation affecting the trachea, such as in chronic tracheo- bronchitis secondary to tobacco abuse, cystic fibrosis, trauma, emphysema, or pulmonary fibrosis. , a comprehensive review and an intriguing study of various pulmonary fibrotic reactions associated with this entity was reported by woodring et al. these investigators evaluated the tracheal diameter on plain chest radiography in a series of cases of fibrotic lung reactions, and found enlargement of the trachea in ( %). the associated lung diseases were idiopathic pulmonary fibrosis and sarcoidosis in four patients each, and progressive histoplasmosis in two patients. in seven of these patients as well as in nine of patients ( %) who did not meet initial radiographic criteria for tracheal dilatation, tracheomegaly developed or progressed over time, tracheobronchomegaly was usually associated with moderate-to-severe restrictive pulmonary defects, and it was proposed that shrinkage of the lung tissue retracts all adjacent spaces including the trachea in a manner similar to traction bronchiectasis. regardless of the cause oftbm, airway dilatation may extend distally, bronchomegaly simulates bronchiectasis, probably impairs lung clearance, and promotes recurrent bronchopulmonary infection, which paradoxically may induce secondary bronchiectasis. roditi and weir identified tracheobronchomegaly in % of patients with evidence of bronchiectasis on ct scan, thereby emphasizing the frequent association and possible causal connections between these two conditions. tracheobronchomegaly is predominantly a radiologic diagnosis, and its pathologic features have not been well characterized. associated radiographic features include marked tracheal wall thinning, scalloping due to mural infolding, bronchial diverticula, and collapse on expiration. . the diagnostic criteria of tbm by ct scan are a tracheal diameter of greater than cm (measured cm above the aortic arch) and diameters of . and . cm for the right and left main bronchi, respectively. al? tracheobronchomegaly must be distinguished from saber-sheath trachea, seen in some patients with emphysema, in which there is a decrease in tracheal coronal diameter and increased sagittal diameter. . patients with immune deficiency, especially hypogammaglobulinemia due to x-linked agammaglobulinemia or common variable immunodeficiency (cvid), are predisposed to develop bronchiectasis secondary to recurrent pulmonary infections. - chronic pulmonary disease is the most common long-term complication in patients with hypogammaglobulinemia. common variable immunodeficiency, a heterogeneous immunodeficiency syndrome characterized by depressed levels of serum immunoglobulin g (igg) and defective antibody response to antigen challenge, is associated with sinusitis, recurrent pneumonia, and chronic sputum production in up to % of patients. patients with cvid also have an increased incidence of autoimmune diseases, and as with other primary immunodeficiency syndromes, a tendency toward lymphoproliferative disorders (see chapter ) . , in this population there is a spectrum of lung abnormalities including interstitial fibrosis (> % of patients), pneumonia, lymphoid interstitial pneumonia (lip), sarcoidosis-like granulomatous disease ( %), lung abscess, and bronchiectasis. , bronchiectasis is the most common radiologic finding and may be identified in over % of patients by chest x-ray, and in up to % of patients by hrct. , by hrct bronchiectasis may be either focal or multilobar, and is of the cylindrical or rarely cystic type. , the lower and middle lobes tend to be predominantly involved. . although mucociliary clearance is impaired in these patients, ciliary ultrastructure is normal. there is little information on the histopathology of bronchiectasis in cvid. . hill and colleagues noted severe bronchiectasis, emphysema, fibrosis, and granulomas in the lung explant of a -year-old man with cvid. no unique features of bronchiectasis were described. patients with cvid are treated with immunoglobulin replacement therapy, which reduces the severity and frequency of respiratory infections. symptomatic bronchiectasis, identified by hrct scan, has also been reported in patients with hiv disease in whom it is associated with rapidly progressive airways obstruction. o , king and colleagues correlated airway dilatation on ct scan with increased neutrophils on bronchoalveolar lavage. a single report of a transbronchial biopsy showed only nonspecific lymphocytic peribronchiolitis. the pathogenesis of bronchiectasis in hiv patients is likely consequent to bronchial damage from recurrent pneumonia and bacterial bronchitis in this immunosuppressed population. . frequently cultured microorganisms include h. injluenzae, p. aeruginosa, and s. pneumoniae. , bronchiectasis also occurs as a complication of lung transplant-associated immunosuppression and bronchiolitis obliterans and is further discussed in chapter . . rheumatoid arthritis symptomatic bronchiectasis is estimated to occur in % to % of patients with rheumatoid arthritis (ra), although with hrct scan, up to % of patients with ra can be shown to have cylindrical bronchiectasis. . , early autopsy studies of patients with ra provided a prevalence of bronchiectasis of % to %. [ ] [ ] [ ] [ ] in some studies bronchiectasis typically preceded the development of arthritis, leading to the interesting hypothesis that chronic suppurative airway disease is involved in the pathogenesis of ra. - shadick and colleagues, however, reported patients with bronchiectasis and ra, of whom developed bronchiectasis as a late complication of severe ra. bronchiectasis may also be more frequent in patients with ra-associated sjogren's syndrome. a bronchiectasis associated with ra cannot be adequately ascribed to either traction bronchiectasis or therapeutic immunosuppression. , the morphologic features of ra-associated bronchiectasis are not well documented. by ct scan, cylindrical bronchiectasis primarily involves the middle and lower lung zones. a , bronchiectasis is part of the spectrum of lung involvement in patients with inflammatory bowel disease (ibd), ulcerative colitis more so than crohn's disease (see also chapter ) . , suppurative bronchiectasis may also develop after proctocolectomy for either of these conditions. , in the literature review of camus et al., bronchiectasis was identified in six patients with ulcerative colitis out of patients ( %) with ibd-associated lung disease histologically a dense cuff of lymphocytes typically occupies the submucosa, and squamous metaplasia replaces the overlying epithelium (fig. . ). the chronic inflammatory infiltrate involves bronchial glands and ducts; however, lymphoid germinal centers are usually absent, distinguishing ulcerative colitis-associated bronchiectasis from the usual pattern of follicular bronchiectasis (fig. . b). , neutrophils infiltrating the mucosa and spilling into the dilated bronchial lumen impart a suppurative appearance in some cases. -- direct immunofluorescence staining of bronchial biopsies in three patients with ulcerative colitis showed deposits of immunoglobulin and complement in bronchial structures. lung biopsy in patients with crohn's disease and bronchiectasis may show features of either granulomatous bronchiolitis or suppurative-appearing acute bronchiolitis (see fig. . in chapter ). inhaled steroids were of durable benefit in patients with ibd-associated chronic bronchitis, but less so in patients with bronchiectasis. speculations on the pathogenesis of bronchiectasis in ibd are presented in a provocative editorial by stockley. bronchiectasis is reported as a late sequela of heroinassociated pulmonary edema. the bronchographic features include diffuse or localized cylindrical and varicose bronchiectasis. itis are etiologic factors in some patients, and bronchial ulceration and foreign-body giant cells have been observed at autopsy. other cases of diffuse bronchiectasis in heroin users appear to be unrelated to aspiration. see chapter for other pathologic features of heroin toxicity. in adults, severe direct chemical injury such as ammonia gas inhalation or aspiration can cause bronchiectasis. - delayed-onset bronchiectasis has also been described 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immunoglobulin deficiency respiratory dysfunction in patients with common variable hypogammaglobulinemia heart lung transplantation in a patient with end stage lung disease due to common variable immunodeficiency bronchiectasis in hiv disease accelerated obstructive pulmonary disease in hiv infected patients with bronchiectasis bronchial dilatation in patients with hiv infection: ct assessment and correlation with pulmonary function tests and findings at bronchoalveolar lavage bacterial bronchitis and bronchiectasis in human immunodeficiency virus infection pathologic pulmonary alterations in long-term human heart-lung transplantation postmortem findings in lung transplant recipients use of high resolution computed tomography of the lungs in patients with rheumatoid arthritis airways involvement in rheumatoid arthritis. clinical, functional, and hrct findings visceral lesions associated with chronic infectious (rheumatoid) arthritis lung lesions in rheumatoid arthritis pulmonary 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fatal anhydrous ammonia inhalation bronchiectasis following pulmonary ammonia burn said sl bronchiectasis and progressive respiratory failure following smoke inhalation acknowledgments. the authors are deeply appreciative to diane gillihan for expert secretarial assistance, vince messina for photography, and the staff of the brittingham memorial library for bibliographic support. key: cord- - zz kaw authors: chen, feng; ren, meiji; li, hongjun title: influenza date: - - journal: radiology of influenza doi: . / - - - - _ sha: doc_id: cord_uid: zz kaw influenza, abbreviated as flu, is an acute respiratory infectious disease caused by influenza virus, which is mainly spread along with droplets with strong infectivity. the influenza virus may cause epidemics or pandemics of influenza and its incidence ranks the first among legally listed infectious diseases. the prevalence of influenza peaks in autumns and winters, with short illness course and self limitation. however, influenza can be complicated by pneumonia or other serious complications that may cause death in populations of infants, young children, the elderly, those with underlying heart and lung disease and those with compromised immunity. influenza, abbreviated as flu, is an acute respiratory infectious disease caused by influenza virus, which is mainly spread along with droplets with strong infectivity. the influenza virus may cause epidemics or pandemics of influenza and its incidence ranks the first among legally listed infectious diseases. the prevalence of influenza peaks in autumns and winters, with short illness course and self limitation. however, influenza can be complicated by pneumonia or other serious complications that may cause death in populations of infants, young children, the elderly, those with underlying heart and lung disease and those with compromised immunity. in the year of , who officially issued the nomenclature system of influenza virus, and the influenza virus is divided into types based on the antigenic properties of the virus nuclear protein since then, type a, type b and type c. influenza virus is an rna virus, which is the most stable in an environment with a ph value of . - . and is intolerant to high temperature. it loses its pathogenicity after heated to a temperature of °c for several minutes, and can be inactivated at a temperature of °c for min. in an environment with a low temperature, the virus is more stable, being capable of surviving for more than months at a temperature of °c, and more than months at a temperature of − °c. the influenza virus is sensitive to dryness, ultraviolet radiation, and commonly used disinfectants such as ethanol and iodophor. the patients with influenza and persons with asymptomatic infection are the main sources of its infection. the infectivity persists from the terminal incubation period to the terminal acute period after onset, and the infectivity is the strongest in the initial - days after onset. influenza virus exists in the respiratory secretions of the patients or persons with asymptomatic infection and spreads via airborne transmission. by talking, coughing or sneezing, the virus spreads into air along with droplets or aerosols, and causes infection after their being inhaled into susceptible individuals. the virus can also spread via direct or indirect contacts to the mucosa in the oral cavity, nasal cavity, and eyes. populations are generally susceptible to influenza, which is not related to the gender and occupation. after infection, individuals acquire certain immunity. among influenza virus a, b and c as well as different subtypes of influenza a virus, no cross immunity exists. and influenza virus can be repeatedly infected. after infection, the acquired immunity only persists for a short period of time. despite of antibodies in the blood, the person can be infected by the same virus again. the incubation period of influenza lasts for about days, and several hours in some cases. its onset is sudden and acute and the patients mainly experience systemic toxic symptoms but inapparant respiratory symptoms. according to the clini-f. chen • m. ren • h. li (*) beijing youan hospital, capital medical university, beijing, china e-mail: lihongjun @ .com cal manifestations, influenza can be divided into the following types. the simplex type is the most common, and is often characterized by sudden onset of aversion to cold and high fever with a body temperature of up to - °c. fever is the most important initial sign, often accompanied by headache, systemic muscle and joint soreness and pain, fatigue, poor appetite, and other toxic symptoms. some patients may experience such symptoms as photophobia and tears. other symptoms, such as nasal obstruction, runny nose, sore throat, voice hoarseness and other respiratory symptoms also show at the onset. pneumonia type may be secondary to the simplex type or occurs as primary influenza virus pneumonia, which is caused by spread of influenza virus from upper respiratory tract to lower respiratory tract. the pneumonia type commonly occurs in the elderly, children, patients with underlying heart and/or lung disease, pregnancies, and individuals with compromised immunity. the main manifestations include persistent high fever, difficulty breathing, cynosis, severe cough, expectoration of foamy mucous sputum or purulent sputum, expectoration of sputum with blood. the toxic type of influenza is extremely rare in clinical practice, which is caused by invasion of influenza virus into the central nervous system and cardiovascular system, with manifestations of toxic symptoms. clinically, the patients experience symptoms of encephalitis or meningitis, with high fever, coma, delirium, convulsions, and even meningeal irritation sign and diffuse intravascular coagulation that indicate serious condition. the gastrointestinal type of influenza is common in children, and is mainly characterized by nausea, vomiting, diarrhea, and abdominal pain. chest x-ray demonstrates mainly interstitial pneumonia and bronchial pneumonia, initially with poorly defined thickening of the lung markings, predominantly both lower lung field significantly; increased density of the lung markings resembling to ggo. during the progressive stage, the lung fields are demonstrated with grid like opacity and network like nodular opacity, with the nodules smaller than mm. such signs may be concurrently shown with thickened and blurry lung markings, with a distribution in both lower lung fields and around the hilum. in the late stage, cystic changes are shown in different sizes due to bronchiolar inflammatory occlusion in honeycomb like lungs, in addition to shrinkage of lungs, elevated diaphragm and shift of interlobar fissure. ct scan demonstrates small nodular opacity, ggo, tree-bud sign and mosaic like perfusion as well as interlobular septal thickening, subpleural line, adjacent pleural thickening, and pleural effusion. chest x-ray shows alveolar pneumonia (lobar pneumonia) or bronchial pneumonia (lobular pneumonia). alveolar pneumonia is mainly demonstrated as lobar consolidation opacity with high homogeneous density or consolidation opacity with high homogeneous density occupying part of lung lobe, possibly with air bronchogram. due to the different location of the lung lesions, the radiological demonstrations are accordingly different, with one or multiple lung lobes involved. bronchial pneumonia is demonstrated as thickened lung markings, with poorly defined nodular opacity in diameters of - mm or poorly defined flakes of opacity. large poorly defined patch of opacity with uneven density is the result of overlapping lesions of lobular alveolitis. bronchial obstruction by mucus is demonstrated as lobular atelectasis or focal emphysema in the diseased area. bronchiolar occlusion may cause a small triangular shaped lesion of atelectasis. the lesions are commonly located in the medial parts of both lower lung fields, with more lesions in the posterior lung lobe than in the anterior lung lobe. and the lesions distribute along bronchi, with smooth air flow in the segmental and lobar bronchi. terminal bronchiolar mucosa may be subject to congestion, edema and inflammatory exudation to cause obstructive emphysema, which is demonstrated as increased transparency of both lungs, thoracic extension, widened intercostal space, lowered and flat diaphragmatic muscle. ct scan demonstrates consolidation with uniform shape, lobar distribution and inner air bronchogram as well as poorly defined nodular and patches of opacity in different sizes that distributes along bronchial bundles. in addition, lobular pulmonary atelectasis and focal emphysema are also shown by ct scan. enhanced lung markings. the lesions are commonly located in both lower lung fields and around the hilum. chest ct scan demonstrates small nodular opacity in lungs, ggo, tree-buds sign and mosaic like perfusion, interlobular septal thickening, subpleural line, adjacent pleural thickening and pleural effusion. by radiology, the condition of this case was mild, present difficulty for the diagnosis, which depended on rich experience of the radiological clinician. in this case, influenza virus pneumonia manifested as interstitial pneumonia should be differentiated from other viral pneumonia, such as hand-foot-mouth virus pneumonia and measles virus pneumonia. the initial lesions of hand-foot-mouth virus pneumonia are mainly interstitial changes with an extensive distribution and possible involvement of each lung lobe. the lesions commonly distribute bilaterally, with enhanced and deranged lung markings in both lungs as well as common grid like and cords like opacity. along with the progression of the lesions, chest x-ray demonstrates changes of the lesions, with peripheral spread of the lobular lesions along bronchi and inflammatory consolidation of alveoli and adjacent lung tissue. the lesion may also invade alveolar duct, alveolar sac and alveoli in the lung lobule to cause lobular inflammatory exudation, demonstrated as small patches of increased density opacity confined within lung lobe or segment. there are more exudation opacities in the upper lung lobes than in the lower lung lobes and more in the right lung lobes than in the left lung lobes. chest x-ray demonstrates measles virus pneumonia as flakes or diffuse ground glass opacity and/or thickened bronchovascular bundles. ct scan demonstrates poorly defined centrilobular nodules, ground glass opacities, interlobular septal thickening as well as lobular or segmental consolidations. adenovirus pneumonia is demonstrated as thickened and blurry lung markings as well as small nodular opacities along lung markings in the middle and medial parts of bilateral middle and lower lung fields, possibly with fused lesions. the radiological demonstrations of influenza virus pneumonia resemble to those of other viral pneumonia, and the radiological diagnosis of the primary disease is, therefore, challenging. the diagnosis can be defined based on laboratory tests. a -years-old boy complained of fever and cough for days, with the highest body temperature of . °c. laboratory tests revealed wbc count . × /l, and nucleic acid of influenza virus positive. [radiological demonstration] fig. . this is a case of influenza virus pneumonia, demonstrated by chest x-ray as interstitial inflammation in both lungs. chest x-ray demonstrates primary influenza virus pneumonia mainly as interstitial pneumonia and bronchial pneumonia, early with poorly defined but enhanced lung markings, predominantly in bilateral lower lung fields. in addition, the lung markings show an increased density, resembling to ggo. during the progressive stage, the lung fields are demonstrated with reticular opacity and reticular nodular opacity, with nodules smaller than mm. such opacities may be concurrently demonstrated with poorly defined but the disease should be mainly differentiated from measles virus pneumonia, pulmonary alveolar pneumonia and allergic pneumonia. chest x-ray demonstrates measles virus pneumonia as flakes or diffusely distributed ggo and/or thickened bronchovascular bundles. by ct scan, measles virus pneumonia is demonstrated as poorly defined centrilobular nodules, ground glass opacity, interlobular septal thickening as well as lobular or segmental consolidation opacities. bacterial pneumonia is mainly demonstrated as alveolar pneumonia or bronchial pneumonia. alveolar pneumonia is mainly demonstrated as lobar consolidation opacity with high uniform density or consolidation opacity occupying part of lung lobe, with air bronchogram inside. bronchial pneumonia is demonstrated as thickened lung markings, with poorly defined nodular opacity or poorly defined flakes of opacity. allergic pneumonitis is a non-asthmatic allergic lung disease caused by a group of different allergens. chest x-ray may show no abnormalities or diffuse interstitial fibrosis, commonly with bilateral patches or nodular infiltration, thickening of the bronchial lung markings or small acinar like changes. ct scan shows thickened bronchovascular thickening, poorly defined small patches of and ground glass opacities along the bronchovascular bundles. the demonstrations by ct scan are irregular, possibly with inconsistencies between radiological findings and clinical symptoms. unlike bacterial pneumonia, the radiological signs of viral pneumonia may be inconsistent with the clinical symptoms. therefore, radiological diagnosis of primary virus pneumonia is challenging and the diagnosis can be defined based on the laboratory tests. a -years-old boy complained of fever and cough with skin rashes for days, with the highest body temperature of . °c. laboratory tests revealed wbc count . × /l, pco . mmhg, and po . mmhg; the nucleic acid of influenza virus positive. [radiological demonstration] fig. . [diagnosis] influenza virus pneumonia. [discussion] this case of influenza virus pneumonia is typically as virus pneumonia. chest x-ray demonstrates primary influenza virus pneumonia as interstitial pneumonia and bronchial pneumonia, with initial radiological signs of enhanced but poorly defined lung markings, predominantly in bilateral lower lungs. the lung markings also show increased density resembling to ground glass opacity. during the progressive stage, the lung fields are demonstrated with reticular and reticular nodular opacities, with nodules smaller than mm. such opacities can be concurrently demonstrated with enhanced but poorly defined lung markings. the lesions commonly distribute in both lower lung fields and around the hilum. the demonstrations by ct scan are diversifying and overlapping, including small nodules in lungs, tree-buds sign with sporadic and centrilobular distribution, ground glass opacity with lobar distribution, diffuse ground glass opacities accompanied by thick interstitial change as well as interlobular septal thickening, subpleural line, adjacent pleural thickening, and pleural effusion. the radiological findings are in consistency with the histopathological demonstrations. a -years-old boy complained of fever and cough for days, with aversion to cold and the highest temperature of . °c. laboratory tests revealed wbc count . × /l; the nucleic acid of influenza virus positive. [radiological demonstration] fig. . [diagnosis] influenza complicated by bacterial pneumonia. [discussion] this is a case of influenza complicated by bacterial pneumonia, with typical signs of lobar pneumonia. lobar pneumonia is commonly caused by streptococcus pneumoniae, with sudden and acute onset and a short course of illness. chest x-ray demonstrates bacterial pneumonia as alveolar pneumonia (lobar pneumonia) or bronchial pneumonia (lobular pneumonia). alveolar pneumonia is mainly demonstrated as lobar consolidation with high uniform density or consolidation with high uniform density occupying a part lung lobe, with air bronchogram inside. the lesions at different sites show different radiological signs, with lesions involving one lung lobe or multiple lung lobes. bronchial pneumonia is demonstrated as thickened lung markings, with poorly defined nodular or flakes of opacity in a diameter of - mm. and the large poorly defined patches of opacity with uneven density is actually overlapping opacities of multiple lobular alveolitis. occlusion of bronchi by mucus is demonstrated as lobular atelectasis or focal emphysema, while occlusion of bronchiole causes radiological sign of a small triangle shaped lung atelectasis. the lesions are commonly located in the medial parts of both lower lung fields, with more lesions in the posterior lung lobe than in the anterior lung lobe, which distribute along bronchial branches with smooth air flow in the segmental and lobar bronchi. congestion, edema and inflammatory exudation of terminal bronchiolar mucosa may cause obstructive emphysema, which is demonstrated as increased transparency of both lung fields, extended thorax, widened intercostal space, and lowered flat diaphragm. ct scan demonstrates uniform shaped consolidations with lobar distribution, with air bronchogram inside, and poorly defined nodular and patches of opacity in different sizes along bronchical bundle as well as lobular atelectasis or focal emphysema. it should be mainly differentiated from viral pneumonia, klebsiella pneumonia and mycoplasma pneumonia. chest x-ray demonstrates viral pneumonia mainly as interstitial pneumonia and bronchial pneumonia. during its early stage, chest x-ray demonstrates enhanced but poorly defined lung markings, predominantly in the both lower lung fields, with increased density like ggo. during the progressive stage, the lung fields are demonstrated with reticular opacity and reticular nodules, which mainly distribute in both lower lung fields and around the hilum, with a diameter of less than mm. during the advanced stage, bronchiolar inflammatory occlusion causes cystic changes in different sizes, with honeycomb like lung. the lung is demonstrated with shrinkage, elevated diaphragm and shift of interlobar fissure. ct scan demonstrates small nodules, ground glass opacity, tree-buds sign and mosaic like perfusion. klebsiella pneumonia is an acute lung inflammation caused by klebsiella pneumoniae, which commonly occurs in populations of those with chronic alcoholism or malnutrition and the elderly. chest x-ray demonstrations can be classified into types: increased lung markings type; lobular type or diffuse pneumonia type; and lobar consolidation type or lung abscess type. compared to chest x-ray, ct scan can more favorably display the lesions. in its early stage, klebsiellar pneumonia is demonstrated with lobular sporadic distribution of patches or irregular dense opacities, which involve multiple lung segments and fuse rapidly to show lobar consolidation in the right upper lung lobe. due to the thick exudated fluid from the lesion, the interlobar fissure is demonstrated to drop. the lesions are susceptible to necrosis, followed by formation of lung abscess, which is commonly multiple small cavities with a diameter of less than cm. the healing proce ss of these cavities is long, commonly with residual extensive fibrosis. mycoplasma pneumonia is an acute respiratory infection and pneumonia caused by mycoplasma pneumonia, with common occurrence in both children and adults. most of the patients show cold agglutination test positive. in its early stage, chest x-ray demonstrates increased poorly defined lung markings and blurry cloud like or homogenous opacities, commonly in the middle and lower lung fields. such opacities adjacent to the hilum are dense, and its density gradually lightens along with its distance from the hilum, with poorly defined boundary and involvement of partial lung lobe. mycoplasma pneumonia with lobar lesion can not be differentiated from lobar pneumonia induced by other pathogenic bacteria. chest ct scan mainly shows ground glass like opacity in lungs, nodular or small patches of consolidation with air cavity, thickened bronchovascular bundle, buds-in-tree sign, large consolidation as well as accompanying mediastinal lymphadenectasis and pleural effusion. a -years-old woman, pregnant for weeks, complained of fever and aversion to cold for days with the highest body temperature of . °c. laboratory test revealed wbc count . × /l, pco . mmhg, po . mmhg, sao . %; the nucleic acid of influenza virus positive. [radiological demonstration] fig. . [diagnosis] influenza complicated by ards. [discussion] different populations with influenza, show different clinical manifestations, and the special populations include children, the elderly, the pregnancy and those with compromised immunity. in the middle or late stage of pregnancy, women, after infected by influenza virus, experience the symptoms of fever and cough, with vulnerability to pneumonia. the condition rapidly progresses into dyspnea, hypoxemia and even ards, with outcomes of miscarriage, premature delivery, fetal distress and intrauterine fetal death. in addition, it may induce aggravation of the underlying diseases, with occurrence of death in severe cases. in this case, the patient was a young woman during her pregnancy, who was diagnosed with influenza complicated by ards and death occurred after active treatment due to multiple organs failure. ards is the typical manifestation of advanced stage acute lung damage, which is basically diffuse capillary damage of lung with increased permeability due to intrapulmonary or extrapulmonary serious disease. its pathological changes include pulmonary edema, hyaline membrane formation and pulmonary atelectasis, with clinical manifestations of acute respiratory failure syndrome characterized by progressive respiratory distress and intractable hypoxemia. the radiological abnormalities of ards are related to leakage of edema fluid containing a large amount of protein and its filling into the alveolar cavity after damage to the alveolar epithelium or diffuse damage to alveolar wall. and its staging by radiology is closely related to the pathological changes, including the exudative stage, the proliferative stage and the fibrosis stage, with intercorrelationship and overlapping. chest x-ray commonly demonstrates diffuse opacity in both lungs, and detectable lesions of the underlying disease, e.g. severe pneumonia induced by a variety of pathogens. ct scan demonstrates uneven distribution of the lesions: ( ) with almost no abnormality in the gravity independent region (e.g. supine, anterior thoracic cavity); ( ) with ggo in the anterior and middle thoracic cavity; and ( ) with consolidation in the gravity dependent region. chest x-ray demonstrated thickened lung markings in both lungs, decreased transparency of the right lower lung field, and poorly defined flakes of opacities in the right lower lung (a). ct scan demon-strated wedge shaped consolidation opacity in the right lower lung lobe, with its sharp end pointing to the hilum, air bronchogram inside and surrounding poorly defined small patches of opacities (b) in the cases with no capillary damage in lung, the patches of opacities evenly distribute in both lungs, with no gravity dependent lesions and no gravity dependent changes of the lesions. such a phenomenon facilitates its differential diagnosis from other lung infections. in the advanced stage of ards, radiology demonstrates twisted and stretching of the bronchi, shrinkage of lung segment or lobe, grid like opacity, cords like opacity, honeycomb like opacity, and even honeycomb like lung in severe cases. it should be mainly differentiated from viral pneumonia, bacterial pneumonia and pulmonary edema. chest x-ray demonstrates viral pneumonia mainly as interstitial pneumonia and bronchial pneumonia. in its early stage, chest x-ray demonstrates enhanced but poorly defined lung markings, predominantly both lower lung fields, with increased density like ggo. in its progressive stage, the lung fields are demonstrated with reticular opacity or reticular nodules and the nodules commonly distribute in the both lower lung fields and around the hilum, with a diameter of less than mm. it its advanced stage, bronchiolar inflammatory occlusion causes cystic changes in different sizes to show honeycomb like lung, with shrinkage of lung, elevated diaphragm and shift of interlobar fissure. ct scan demonstrates small nodular opacity, ground glass opacity, tree-buds sign and mosaic like perfusion in lungs. chest x-ray demonstrates bacterial pneumonia mainly as alveolar pneumonia or bronchial pneumonia. alveolar pneumonia is demonstrated as lobar consolidation with high uniform density or consolidation with high uniform density occupying part of lung lobe, with air bronchogram inside and one or multiple lung lobes involved. bronchial pneumonia is demonstrated as thickened lung markings, poorly defined nodular or flakes of opacity in a diameter of - mm. bronchial occlusion by mucus can be demonstrated as lobular atelectasis or focal emphysema in the diseased area. the lesions are commonly located in the medial part of both lower lung fields, with more in the posterior lung lobe than in the anterior lung lobe, that distribute along bronchial branches. and the segmental and lobar bronchi show smooth air flow. ct scan demonstrates consolidations with uniform shape and lobar distribution, with air bronchogram inside, and poorly defined nodular or patches of opacities of different sizes along bronchial bundles as well as lobular atelectasis and focal emphysema. pulmonary edema and acute or chronic systolic or diastolic heart dysfunction due to various etiological factors can lead to increased pressure in the pulmonary vein and pulmonary capillaries as well as pulmonary congestion. the liquid firstly accumulates in the perivascular sheath in lungs and interlobular space to cause pulmonary interstitial edema, which then flow into the alveolar cavity to cause pulmonary parenchyma edema. chest x-ray demonstrates interstitial edema as thickened, deranged and re-ranged lung markings, thickened but poorly defined vascular markings in both upper lung fields, enlarged and dense hilar opacities in both lungs, thickened and dilated but poorly defined vascular markings in the middle and medial parts of both lung fields. however, chest x-ray demonstrates interstitial edema with fine vascular markings in peripheral lung field and well defined peripheral lung field. its further progression can be demonstrated with flakes of opacity in both lungs with butterfly wing like shape and concentric distribution. chest x-ray demonstrates alveolar edema as initially poorly defined flakes of opacities in different sizes with sporadic distribution in both lungs. along with its progression, chest x-ray demonstrates large flakes of high density opacity after fusion, which extends from the hilum to the peripheral lung with gradually light density, in typical butterfly wing like sign. a b fig. . chest x-ray demonstrated decreased transparency of both lung fields and large consolidation opacity in both lungs, with air bronchogram inside (a). reexamination after treatment for days showed that absence of lung markings in both lungs, further decreased transparency of both lung fields, and diffuse high density in both lungs (b) diagnostic criteria of acute lung injury and acute respiratory distress syndrome what has computed tomography taught us about the acute respiratory distress syndrome? imaging diagnosis of interstitial pneumonia chest x-ray demonstrations of pediatric hand-footmouth disease complicated by pneumonia imaging of communityacquired pneumonia: roles of imaging examinations, imaging diagnosis of specific pathogens and discrimination from noninfectious diseases pneumonia: high-resolution ct findings in patients key: cord- -t dtabi authors: bousbia, sabri; papazian, laurent; saux, pierre; forel, jean marie; auffray, jean-pierre; martin, claude; raoult, didier; la scola, bernard title: repertoire of intensive care unit pneumonia microbiota date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: t dtabi despite the considerable number of studies reported to date, the causative agents of pneumonia are not completely identified. we comprehensively applied modern and traditional laboratory diagnostic techniques to identify microbiota in patients who were admitted to or developed pneumonia in intensive care units (icus). during a three-year period, we tested the bronchoalveolar lavage (bal) of patients with ventilator-associated pneumonia, community-acquired pneumonia, non-ventilator icu pneumonia and aspiration pneumonia, and compared the results with those from patients without pneumonia (controls). samples were tested by amplification of s rdna, s rdna genes followed by cloning and sequencing and by pcr to target specific pathogens. we also included culture, amoeba co-culture, detection of antibodies to selected agents and urinary antigen tests. based on molecular testing, we identified a wide repertoire of bacterial species of which have not been previously reported in pneumonia. moreover, we found putative new bacterial phylotypes with a s rdna gene divergence ≥ % from known phylotypes. we also identified fungal species of which have not been previously reported in pneumonia and viruses. patients can present up to different microorganisms in a single bal (mean ± sd; . ± . ). some pathogens considered to be typical for icu pneumonia such as pseudomonas aeruginosa and streptococcus species can be detected as commonly in controls as in pneumonia patients which strikingly highlights the existence of a core pulmonary microbiota. differences in the microbiota of different forms of pneumonia were documented. the cause of pneumonia in intensive care units (icus) remains unknown in nearly % of cases despite extensive microbiological investigations [ , ] . microbial communities previously identified, in deep respiratory samples, include bacteria, fungi and viruses for which the role in the observed pathology is not clear. microorganisms frequently identified in respiratory samples from icupneumonia patients included pseudomonas aeruginosa, staphylococci, enterobacteria, candida albicans, influenza virus, herpes simplex virus (hsv) and cytomegalovirus (cmv) [ ] [ ] [ ] [ ] [ ] . in some investigations, a pathogenic bacterium is isolated, whereas in other cases, the number of colony forming units (cfu) is considered to determine the pathogenic character [ ] . recently, the bacterial microbiota of patients with cystic fibrosis and ventilator-associated pneumonia (vap) were studied using s rdna gene amplification followed by clone libraries sequencing [ ] [ ] [ ] . our laboratory has contributed to this work and has shown, by different sequencing approaches, that the microbial population of patients with cystic fibrosis was more diverse than expected [ , ] . here, we use a comparable approach in order to study episodes of icu pneumonia and control cases. these patients were studied using broad-range primer amplification of the s rdna gene of bacteria and the intergenic spacer of s rdna gene of fungi followed by cloning and sequencing. we also used specific quantitative pcr (qpcr) to target fastidious bacteria and a spectrum of viruses. moreover, we tested samples from our patients by standardized routine culture, amoebal co-culture, blood culture, elisa targeted antibody detection, immunofluorescent assay antigenemia and antigenuria testing as routinely performed in such cases to compare these routine tests with molecular approaches. in preliminary results, we have reported the likely frequency of tropheryma whipplei and the occurrence of vegetable dna in pneumonia patients [ , ] . in this work, we highlight the different compositions of microbiota in patients with four different types of icu-pneumonia. bacterial microbiota as evaluated by s rdna molecular assays were positive for at least one bacterium for out of bronchoalveolar lavage (bal) samples from patients with pneumonia as well as from out of from control individuals (p = . ). bacterial clone libraries from amplified s rdna genes (nearly , clones that contained exploitable sequences were included) identified different bacteria at the species level. detailed data about the relative abundance and richness of each species in their corresponding library are summarized in data s and s in supplementary informations. bacterial clone libraries of patients showed that libraries were characterized by the presence of only one bacterium, libraries were polybacterial but dominated by one bacterium ( % of the clones in the library), whereas libraries were polybacterial without any dominant bacterium (fig. ) . bacterial clone libraries of controls showed that libraries were characterized by the presence of only one bacterium, libraries were polybacterial but dominated by one bacterium ( % of the clones in the library), whereas libraries were polybacterial but without any dominant bacterium (fig. ) . patients exhibited up to bacteria in their bal fluids (mean sd; . . ) (tables and ). overall, patients exhibited different species belonging to different phyla ( classes, orders, families and genera) of which had not been previously observed in bal from pneumonia, whereas bacterial clone libraries of controls identified species belonging to different phyla ( classes, orders, families and genera). in patients, aerobic gram-negative bacilli, gram-positive cocci, and anaerobic bacteria from oropharyngeal flora were the most frequent bacteria identified (tables s ,s ,s ,s , fig. ) . surprisingly, bacteria that are usually associated with other diseases such as the gram-positive anaerobe atopobium vaginae, or from unexpected animal origins, such as enterococcus canintestini, were alsoc found. moreover, strictly anaerobic bacteria ( %) were found in patients versus anaerobic bacteria ( %) found in controls (p = . ). among those bacteria which were identified in controls, bacteria were also identified in patients (fig. s , tables s ,s ,s ), including pseudomonas aeruginosa sequences respectively identified in % and % from different clones libraries from immunocompromised controls. in the second clone library, the % of the remaining sequences included achromobacter xylosoxidans, which also is a typical bacterium of nosocomial pneumonia. stenotrophomonas maltophilia sequences were found in % of clone library of another immunocompromised control, along with other bacteria. similarly, sequences of streptococcus mitis ( % of the clone library) was identified along with other bacteria in a control with acute respiratory distress syndrome (ards) and a history of aspiration pneumonia (ap) days before bal sampling. additionally, arcobacter cryaerophilus, atopobium parvulum, lachnospiraceae bacterium, prevotella melaninogenica, and prevotella pallens were significantly more frequent in controls than in patients (p = . , . , . , . and . respectively) (table s ) . bacterial clone libraries surprisingly showed new phylotypes with s rdna sequence similarity lower than % to known bacteria available in the genbank database (data s and s ). among them, novel bacterial phylotypes were identified in bal from patients, whereas novel phylotypes were identified in bal from controls (fig. ) . novel bacterial phylotypes identified in patients were more diversified, as they belonged to different phyla including bacteroidetes ( phylotypes), firmicutes ( phylotypes), proteobacteria ( phylotypes), actinobacteria (one phylotypes), acidobacteria (one phylotype) and spirochaetes (one phylotype). novel species identified in controls belong to bacteroidetes ( phylotypes), firmicutes ( phylotypes) and actinobacteria (one phylotype). prevotellaceae phylotypes represent % of all novel phylotypes identified and they were exhibited in patients with pneumonia as well as in control subjects (fig. ) . results obtained using routine bal and blood culture are available text s . fungal microbiota as evaluated by the intergenic spacer of s rdna at least one fungus was found in bal patient samples and in from controls (p = . ). positive patients exhibit up to fungi in their bal fluids (mean sd; . . ) (tables and ) . detailed data about the relative abundance and richness of each species in their corresponding library are also summarized in summary files (data s and s ) in supplementary informations. fungal microbiota obtained from patients showed the presence of different species belonging to phyla ( orders, families and genera) among which phylotypes had not been previously identified in bal fluids from pneumonia. clone libraries from controls, identified fungi belonging to one phylum ( orders, families and genera) among which fungi were also identified in patients. candida species were the most common fungal species identified (tables s ,s ,s and s ). environmental fungi, which usually colonize water, food debris and humid building surfaces, were more notably identified in our study than in previous pneumonia studies. furthermore, tree fungi belonging to basidiomycota phylum, sporidiobolales sp., cryptococcus victoriae and hyphoderma praetermissum, were found for the first time in pneumonia bal samples in the present study, while candida utilis and periconia macrospinosa were identified only in controls. additionally, candida utilis was significantly more frequent in controls than in patients (p = . ). results of fungi obtained using a routine bal culture are available in text s . four pneumonia patients were found to be positive for fastidious bacteria chlamydia pscitacii ( case), mycobacterium sp. ( cases) and mycoplasma pneumoniae ( cases) by qpcr. in addition, qpcr enabled the detection of different viruses. quantitative data of microorganisms identified by qpcr (loads or cycle threshold) are also provided and summarized in supplementary information (data s and s ). our study showed that at least one virus was identified in bal samples from patients, and from controls (p = . ). hsv and cmv were the most commonly identified viruses. while the prevalence of these two viruses in patients was not significantly different from that of controls (table s ) , cmv was more frequently identified in pneumonia patients than in controls. hsv and cmv coinfection was found in bal samples from vap patients, community-acquired pneumonia (cap) patients and non-ventilator icu pneumonia (nv icu-p) patients and one control subject. coinfection with cmv and respiratory syncytial virus type a was detected in a bal from one nv-icu-p patient, and both hsv and vzv were identified in a bal from a cap patient. rhinovirus was identified in a control with ards, urinary infection and sinusitis. parainfluenza virus- was detected in vap patients and an immunocompetent control with a pulmonary contusion. results obtained using routine serology and antigenemia for viruses and fastidious pathogens are available in text s overall, bacterial difference between patients and controls showed that bacteria belonging to bacilli and gammaproteobacteria were dominant in patients, whereas anaerobic bacteria related to bacteroidia (represented essentially by prevotella species) and clostridia were dominant in controls ( fig. ) (p, . ). mollicutes, which are represented by the mycoplasma genus, were only detected in patients with cap and vap (fig. ) . as for fungal species, members of saccharomycetes were ubiquitously identified in all cohorts. eurotiomycetes, which are represented by aspergillus, penicillium and cladophialophora genera, were dominant in the cap cohort (fig. ) . tremellomycetes, represented by the cryptococcus genus, was only identified in the nv-icu-p cohort, whereas figure . a phylogenetic tree inferred from s rdna sequences of novel bacterial phylotypes. these novel phylotypes exhibited sequence similarities of less than % to known bacteria available in the genbank database, and they were classified in silico using ''classifier'' program. phylotypes are reported according to their genus or by the last possible classification determined by the program. when possible, phylotypes with the same classification are clustered together. the frequency of phylotypes in each cohort is shown on the right.. bacteroidetes are shown in purple, firmicutes in red, proteobacteria in blue, actinobacteria in yellow, acidobacteria in orange and spirochaetes in green. cap, community-acquired pneumonia; vap, ventilator-associated pneumonia; nv icu-p, non-ventilator icu pneumonia; ap, aspiration pneumonia; and cs, control subjects. doi: . /journal.pone. .g agaricomycetes and an unclassified ascomycota (melanized limestone ascomycetes) were only identified in the vap cohort. in addition, sordariomycetes, which is represented by the periconia genus, was only identified in controls. at the specie-level, bacteria, fungi and viruses were common to at least two cohorts, among which pseudomonas aeruginosa, streptococcus mitis, prevotella melaninogenica, peptostreptococcus stomatis, candida albicans and hsv were commonly identified irrespective of cohorts, whereas haemophilus influenzae, staphylococcus aureus, streptococcus genomosp. c , streptococcus parasanguinis and streptococcus pneumoniae were commonly identified in patients regardless of pneumonia type (fig. s ) . additionally, bacteria, fungi and viruses were common to controls and at least one pneumonia cohort, whereas bacteria, fungi and viruses were common to at least two pneumonia cohorts (fig. s ). in contrast, many microorganisms ( bacteria, fungi and viruses) were restricted to one of cohorts ( bacteria and fungi only were identified in the cap cohort; bacteria and fungi only were identified in the vap cohort; bacteria, fungi and one virus only were identified in the nv icu-p cohort; bacteria only were identified in the ap cohort; bacteria, fungi and one virus only were identified in controls) (fig. s ). microbial profiles of positive pneumonia bal fluids showed that ( %) were characterized by the presence of one microorganism, whereas ( %) were polymicrobial. in controls, ( %) of bal fluids were characterized by the presence of one microorganism, whereas ( %) were polymicrobial (data s and s ). available clinical data for patients and controls showed that monobacterial patients were more frequently, but statistically insignificant, subjected to initial antibiotic therapy than polymicrobial ones (p = . ; table and table s ). in ventilated subjects, monomicrobial patients have a slightly shorter period of mechanical ventilation prior to the pneumonia episode as compared to polymicrobials. monomicrobial controls have a remarkably shorter period of mechanical ventilation before sampling compared to polymicrobials (p = . ; table ). the same observation was showed for length of icu stay prior to sampling and for total length of hospital stay. according to these observations, the polymicrobial profiles of controls seem to be partially related to the high duration of icu stay before sampling. however, the icu mortality was higher in monomicrobial patients than in polymicrobial ones (p = . ). the icu mortality rate was higher in pneumonia patients for whom bal fluids exhibited only viruses or fungi, or both than in monobacterial or polybacterial patients (p = . ; table s ). a higher but not statistically significant icu mortality was also observed in pneumonia patients for whom bal fluids exhibited only viruses or fungi, or both than in controls with the same profile (p = . ; table s ). we next compared the bacterial communities found in our study to those found in lung specimens in five previous studies which were based on s rdna amplification [ , , [ ] [ ] [ ] . comparative analyses of lung microbiota between these studies showed that different genera were found in all of them. among these genera, genera are widely distributed within the studies including gemella, haemophilus, megasphaera, neisseria, porphyromonas, prevotella, pseudomonas, staphylococcus and streptococcus genera which have commonly been found irrespective of study. in contrast, genera were restrictively identified across the studies (table ) . however, at the species level (only the studies that determined bacterial species were included [ , , ] ), comparative analyses showed that from bacteria commonly distributed within the studies, escherichia coli, haemophilus influenzae, prevotella oris, pseudomonas aeruginosa, staphylococcus aureus and streptococcus mitis were commonly found in the four studies. in contrast, bacteria were restrictively identified across the studies (fig. s ) . consequently, comparative analysis at the specie-level showed that some bacteria, such as pseudomonas aeruginosa and staphylococci, are commonly found in pulmonary specimens. however, the pattern of distribution of many other species is distinctly heterogeneous and depending on the specific study and disease. variation of lung microbiota, from one individual to another and from one study to another, suggests that the repertoire of microorganisms associated with respiratory infections still remains incompletely understood. previous studies performed on respiratory specimens showed that unexpected bacteria are increasingly identified, as well as studies describing isolated cases of respiratory infection due to an unexpected bacterium that was detected using molecular techniques [ , , , [ ] [ ] [ ] [ ] . this study extends the analyses to bacteria, fungi and viruses in a large population of icu pneumonia using comprehensive molecular testing. our results demonstrate that nearly % of the microbial species found had not been previously reported in lung samples from pneumonia. therefore, the composition of icu-pneumonia microbiota is more complex, more extensive and more diverse than originally expected. however, we raise the question on the actual role of these microorganisms in pneumonia. indeed, our study reveals that some pathogens that till now had been considered typical for icu pneumonia, such as pseudomonas aeruginosa and streptococcus species, or viruses, such cmv and hsv, can be detected as commonly in controls as in patients (fig. s and s ). this result is emphasized by more recent studies by erb-downward et al. and hilty et al. who showed that a community of lung-resident bacteria including pseudomonas and streptococcus genera can be identified in patients with chronic obstructive disease or asthma, as well as in healthy people [ , ] . our study agrees with the recent literature and highlights the existence of a core pulmonary microbiota, confirming the non-sterility of the lung [ , ] . more interestingly, we showed that pulmonary microbiota heterogeneity can be observed between patients and controls, among pneumonia cohorts and among patients within the same cohort. high pulmonary microbiota heterogeneity was also observed between our study and other previous works performed on cystic fibrosis or vap [ , , ] (fig. s ) . we found that some bacteria were commonly identified in all studies, whereas many others were only identified in one study, and most of these were unexpected. consequently, lung microbiota can vary greatly between individuals, depending on underlying diseases, habits and geographic origin. additionally, these unexpected microorganisms may explain a lack of response to drug therapies in some pneumonia patients. therefore, the possible extension of empiric treatments to cover a large spectrum of microorganisms, especially for patients who do not respond adequately to initial treatment, is questionable. another interesting observation was that mixed infection was observed in many bal fluids from pneumonia patients. interestingly, recent works report that probable interactions between parasitic species can occur in their host, and these reports also show that infection with a given microorganism may increase or decrease susceptibility to infection by another one or can create a cross-immunity response [ ] [ ] [ ] [ ] [ ] [ ] [ ] . such interaction remains to be investigated. moreover, by comparing molecular testing to standard routine methods, this study reveals that many pneumonia-associated pathogens are fastidious or uncultured and highlights a wide discrepancy between culture and molecular microorganism repertoire. our study also shows that the molecular assay remains a more efficient method to detect microorganisms in the pneumonia samples, independently of atmospheric conditions and medium nutrient supplements, which are particularly important for culture, especially for fastidious microorganisms. in addition, microorganism diagnosis was obtained for ( %) episodes of pneumonia by molecular tools compared with ( %) pneumonia episodes for which microorganism diagnosis was successfully done by culture (table s ). in particular, molecular tools seem to be far more sensitive than culture for bacterial detection. this observation is based on the high number of microorganisms, especially bacteria which were identified by molecular methods compared with those detected by culture. in fact, standard and special bal cultures identified few, essentially easily-grown and strictly aerobic or facultative anaerobic bacteria ( species) compared to molecular tools which identified bacterial species (p, . ) (fig s and s ). molecular tools enabled the identification of unexpected bacteria which usually colonize vaginal tracts, such as atopobium vaginae and peptoniphilus lacrimalis, or of other bacteria coming from unexpected animal origins, such as chlamydia pscittasi, enterococcus canintestini and streptococcus bovis, or of potentially known to be associated with other diseases, such as tropheryma whipplei, which were not identified by culture. furthermore molecular tools allowed the detection of pathogenic bacteria such as mycobacterium sp. and mycoplasma pneumoneae, for which identification attempts by culture using specific media were failed due to culture biases. moreover, all bacteria that were first associated with pneumonia in the present study were exclusively identified by molecular methods. these findings are coherent to results from previous studies on bacterial communities of respiratory diseases, including pneumonia, which showed that molecular assays are more sensitive than culture [ , , ] . however, although molecular approaches identified more fungal species than culture, fungal diagnoses were positive for ( %) episodes of pneumonia by culture compared with ( %) pneumonia episodes for which fungal diagnosis was successfully obtained using molecular tools. thus, fungal bal culture was more sensitive to detect some cultured fungi, such as candida species, than molecular approaches. another important finding was the high number of novel bacterial species never previously described to date (bacteria with blastn similarity less than %). this result is concordant with similar studies of pneumonia and cystic fibrosis subjects [ , ] and shows that in respiratory infections, more complex bacteria populations can exist, among which novel bacteria had never been previously identified. moreover, this finding was also supported by other studies performed on endodontic infections, demonstrating that many novel bacteria essentially resident in the oropharyngeal and dental plaque flora can be detected in these infections [ , ] . the oropharyngeal and dental plaque flora is potentially suspected to be a reservoir and, thus, the source of icu pneumonia pathogens, which could suggest that these novel bacteria were inhaled through oropharyngeal tracts [ , ] . nevertheless, molecular tools alone cannot give positive results in some cases, or they could just identify microorganisms known to be commensal or less pathogenic, where it may be useful to perform other tests, such as serology. this was the situation for pneumonia patients for whom serology provided evidence for influenza a virus infection, whereas qpcr performed on their bal fluids was negative. moreover, by combining culture-based methods, blood culture and serology to molecular approaches we significantly increase the probability to detect microorganisms in the pneumonia episodes. in fact, by using these exhaustive laboratory diagnostic tools, we failed to identify a microbial agent in only % of the pneumonia episodes, which is significant when compared to previous studies where the microbial agent was not found in more than % of episodes of pneumonia (p, . ) [ ] . however, the clinical significance of these microorganisms and their role in the etiology of pneumonia remain difficult to be cleared as their correlation with the disease causation remains to be studied and confirmed in the future. nevertheless, our findings suggest that it would be highly recommended to develop a rapid molecular test to target, besides typical pathogens, potential pathogens known to be fastidious or uncultured (such as anaerobic ones), and that it would be useful to add it to existing routine standard techniques. in summary, our study reveals that the respiratory microbiota is more complex than expected. a large study was implemented in our laboratory over a threeyear period (january through december ) to perform an exhaustive etiologic diagnosis of pneumonia. the study involved three icus in the public hospitals of marseille, france (one medical icu and two medico-surgical icus). a total of bal fluids, blood samples and urinary samples from icu pneumonia patients were studied. a diagnosis of community-acquired pneumonia, ventilator-associated pneumonia and aspiration pneumonia was defined as previously described [ ] [ ] [ ] . bal and blood sampling were performed as previously described [ ] . a cohort of icu patients without pneumonia was studied as controls. pneumonia patients exhibited episodes of community-associated table . comparison of lung microbiota between different studies. harris et al. [ ] bittar et al. [ ] bahranimougeot et al. [ ] erb-downward et al. [ ] hilty et al. [ ] studied nucleic acid extraction, pcr amplification, cloning and sequencing bacterial and fungal dna extraction from bal samples was performed on a magnapure lc workstation (roche diagnostics, meylan, france), using a magna pure lc dna isolation kit ii (roche diagnostics) as previously described [ ] . viral nucleic acids were extracted from ml of bal fluids using an mdx workstation and the qiaamp virus biorobot mdx kit according to the manufacturer's instructions. dna was tested by pcr for bacteria using broad-range primers targeting the s rdna gene; pcr was also used to test for universal fungi using broad-range primers targeting intergenic spacer of s rdna gene (eurogentec, seraing, belgium) ( table ). pcr product was cloned and approximately clones were screened per library. pcr, cloning and sequencing were performed as previously described [ ] . the obtained sequences were assembled and analyzed by chromaspro software and then blasted against those available in the genbank database (www.ncbi.nlm.nih.gov) for species identification. chimeric sequence search was performed with black box chimera check (b c ) program [ ] and by examining the blast profile of each sequence. suspected chimeric sequences were discarded from the study. sequences showing a similarity of . % were considered to be known species, whereas sequences showing a similarity of , % were considered to be novel species. legionella sp., afipia sp.,bradyrhizobium sp., azorhizobium sp., mesorhizobium sp., balneatrix alpaca and pneumocystis carinii were tested by pcr using specific primers followed by sequencing of pcr products ( table ). the sequences have been deposited in the genbank database (accession nu jf -jf ). standard bacteriological bal culture and blood culture as phenotypic identification of isolated bacteria were performed as previously described [ , ] . a cfu cut-off defined a positive bal culture. blood culture were processed as previously described [ ] . identification of fungi present in bal or blood samples was performed using a standard culture as previously described [ , ] . viral culture for cytomegalovirus, herpes simplex virus, parainfluenza viruses (types and ), respiratory syncytial virus, varicella-zoster virus, influenza viruses (type a and b), and enterovirus was performed using shell-vial culture as previously described [ , ] . amoeba co-culture were performed in microplates on acanthamoeba polyphaga as previously described [ ] . tentative isolations of mycobacterium sp., legionella sp. and mycoplasma pneumoniae were performed by using bactec mb automate, bcye agar plates and sp medium as previously described [ ] [ ] [ ] . results obtained using routine culture are available in table s ,s ,s ). mycobacterium sp., m. tuberculosis, m. avium group, bosea sp, parachlamydia sp., coxiella burnetii, chlamedia pneumoniae, chlamedia psittaci, mycoplasma pneumoniae, aspergillus sp., mimivirus, cmv, hsv, parainfluenza viruses and , respiratory syncytial virus, rhinovirus, metapneumovirus, varicella-zoster virus, influenza viruses a and b, enterovirus, and coronaviruses oc- , -e and nl- were detected using quantitative pcr. quantitative pcr was performed using a lightcyclerh instrument (roche diagnostics, meylan, france) in conjunction with the quantitect probe pcr kit. primers and probes used to identify these microorganisms are reported in table . the reaction was performed as previously described [ ] . for rna viruses, rna was first reverse transcribed using multiscribe tm reverse transcriptase (applied biosystems, courtaboeuf, france) as previously described [ ] . sera from patients were tested by immunofluorescent assay (ifa) for coxiella burnetii, bartonella quintana, bartonella henselae, legionella pneumophila, legionella anisa [ , , ] . viral serologies for adenovirus, cytomegalovirus, herpes simplex, parainfluenza viruses and , varicella-zoster virus and, influenza viruses a and b were performed using standard serologic methods (immunofluorescent assay or enzyme linked immunosorbent assay) [ ] . hemagglutination inhibition, immunoperoxidase staining and elisa techniques were used in-house to identify aspergillosis. l. pneumophila antigenuria and cmv pp antigenemia were tested for as previously reported [ , ] . results obtained using routine serology and antigenemia for viruses and fastidious pathogens are available in table s . bacterial and fungal nucleic acid sequences obtained from broad-range primer pcr were aligned with bioedit program (http://www.mbio.ncsu.edu/bioedit/bioedit.html) and phylogenetic trees were create with mega software version . using the neighbor-joining method and the kimura- parameter [ ] . species having sequence similarities , % with those available in genbank databases were also blasted and classified in silico using ''classifier'' program in the ribosomal database project (http:// rdp.cme.msu.edu/) [ ] . statistical analyses were performed using chi square test, fisher's exact test, students t-test or mantel-haenszel's chi square test when appropriate. p values that were less than or equal to . were considered significant. the pubmed database (www.ncbi.nlm.nih.gov/pubmed/) and google website (http://www.google.fr/) were used to search whether species identified in our study had been previously reported in cases of pneumonia for articles published between and march , with the combined search term ''species name'' and ''pneumonia'', ''lung'' or ''infection.'' additional articles were identified by hand-searching the references of selected papers. additional search terms included ''microbiology'', ''diagnosis'', '' s'' and ''molecular detection'' were used. only publications in english were considered. papers in languages other than english were considered only when their abstracts in english were available. figure s schematic representation of microorganisms commonly identified in pneumonia and control cohorts, and those only detected in one cohort. fungi are shown in rectangles, viruses in octagons, and bacteria in circles. the name of each microorganism is indicated. (tif) figure s schematic representation of microorganisms that were commonly identified between each pneumonia form and controls, and those which were detected in only one cohort. fungi are shown in rectangles, viruses in octagons, and bacteria in circles. actinobacteria are shown in red, bacteroidetes in yellow, chlamydiae in orange, firmicutes in green, fusobacteria in purple, proteobacteria in blue and tenericutes in sky blue. cap, community-acquired pneumonia; vap, ventilatorassociated pneumonia; nv icu-p, non-ventilator icu pneumonia; ap, aspiration pneumonia; and cs, control subjects. (tif) figure s comparison of the bacterial communities found in our study with those found in lung specimens in three previous studies. novel phylotypes are not shown. actinobacteria are shown in red, bacteroidetes in yellow, chlamydiae in orange, firmicutes in green, fusobacteria in purple, proteobacteria in blue and tenericutes in sky blue. the name of the first author of each study and the name of each bacterium are indicated. the comparative analysis was conducted using cytoscape software. vap, ventilator-associated pneumonia; cf, cystic fibrosis. (tif) figure s molecular methods compared to standard routine culture for bacteria identification. text s bal culture, blood culture and serology results. data s detailed data about the relative abundance and richness of each species in their corresponding library. data s schematic data about the relative abundance and richness of each species in the corresponding library. table s species only detected in bal from pneumonia patients by molecular assays. (docx) nosocomial pneumonia in the intensive care unit acquired during mechanical ventilation or not etiology and diagnosis of pneumonia requiring icu admission guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia active cytomegalovirus infection is common in mechanically ventilated medical intensive care unit patients cytomegalovirus. an unexpected cause of ventilator-associated pneumonia viral infections in the icu herpes simplex virus: a marker of severity in bacterial ventilator-associated pneumonia bronchoscopic bal in the diagnosis of ventilatorassociated pneumonia molecular identification of bacteria in bronchoalveolar lavage fluid from children with cystic fibrosis microbial diversity in the sputum of a cystic fibrosis patient studied with s rdna pyrosequencing molecular detection of multiple emerging pathogens in sputa from cystic fibrosis patients tropheryma whipplei in patients with pneumonia detection of plant dna in the bronchoalveolar lavage of patients with ventilator-associated pneumonia molecular analysis of oral and respiratory bacterial species associated with ventilator-associated pneumonia analysis of the lung microbiome in the ''healthy'' smoker and in copd disordered microbial communities in asthmatic airways chlamydia-like bacteria in respiratory samples of community-acquired pneumonia patients acetobacter indonesiensis pneumonia after lung transplant francisella philomiragia adenitis and pulmonary nodules in a child with chronic granulomatous disease severe pneumonia with leptotrichia sp. detected predominantly in bronchoalveolar lavage fluid by use of s rrna gene sequencing analysis human polymicrobial infections selection for staphylococcus aureus small-colony variants due to growth in the presence of pseudomonas aeruginosa burkholderia pseudomallei, b. thailandensis, and b. ambifaria produce -hydroxy- -alkylquinoline analogues with a methyl group at the position that is required for quorum-sensing regulation pseudomonas aeruginosa extracellular products inhibit staphylococcal growth, and disrupt established biofilms produced by staphylococcus epidermidis analysis of pseudomonas aeruginosa -hydroxy- -alkylquinolines (haqs) reveals a role for -hydroxy- -heptylquinoline in cell-to-cell communication prokaryote-eukaryote interactions identified by using caenorhabditis elegans candida albicans impairs macrophage function and facilitates pseudomonas aeruginosa pneumonia in rat molecular analysis of bacteria in asymptomatic and symptomatic endodontic infections molecular and cultural analysis of the microflora associated with endodontic infections colonization of dental plaque: a source of nosocomial infections in intensive care unit patients genetic relationships between respiratory pathogens isolated from dental plaque and bronchoalveolar lavage fluid from patients in the intensive care unit undergoing mechanical ventilation infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults amoebaresisting bacteria and ventilator-associated pneumonia aspiration pneumonitis and aspiration pneumonia clinical significance of a positive serology for mimivirus in patients presenting a suspicion of ventilator-associated pneumonia black box chimera check (b c ): a windows-based software for batch depletion of chimeras from bacterial s rrna gene datasets direct identification of bacteria in positive blood culture bottles by matrix-assisted laser desorption ionisation time-of-flight mass spectrometry evaluation of nested and real-time pcr assays in the diagnosis of candidaemia quantification of leishmania infantum dna by a real-time pcr assay with high sensitivity ameba-associated microorganisms and diagnosis of nosocomial pneumonia isolation of new fastidious alpha proteobacteria and afipia felis from hospital water supplies by direct plating and amoebal co-culture procedures cost-effectiveness of blood agar for isolation of mycobacteria diagnosis of legionnaires' disease. an update of laboratory methods with new emphasis on isolation by culture mycoplasma and ureaplasma. - q fever serology: cutoff determination for microimmunofluorescence value of microimmunofluorescence for diagnosis and follow-up of bartonella endocarditis detection of legionella pneumonophila antigen in urine by enzyme-linked immunospecific assay mega : molecular evolutionary genetics analysis (mega) software version . naive bayesian classifier for rapid assignment of rrna sequences into the new bacterial taxonomy key: cord- - ure authors: lim, tow keang; siow, wen ting title: pneumonia in the tropics date: - - journal: respirology doi: . /resp. sha: doc_id: cord_uid: ure pneumonia in the tropics poses a heavy disease burden. the complex interplay of climate change, human migration influences and socio‐economic factors lead to changing patterns of respiratory infections in tropical climate but also increasingly in temperate countries. tropical and poorer countries, especially south east asia, also bear the brunt of the global tuberculosis (tb) pandemic, accounting for almost one‐third of the burden. but, as human migration patterns evolve, we expect to see more tb cases in higher income as well as temperate countries, and rise in infections like scrub typhus from ecotourism activities. fuelled by the ease of air travel, novel zoonotic infections originating from the tropics have led to global respiratory pandemics. as such, clinicians worldwide should be aware of these new conditions as well as classical tropical bacterial pneumonias such as melioidosis. rarer entities such as co‐infections of leptospirosis and chikungunya or dengue will need careful consideration as well. in this review, we highlight aetiologies of pneumonia seen more commonly in the tropics compared with temperate regions, their disease burden, variable clinical presentations as well as impact on healthcare delivery. pneumonia continues to be an important cause of death and accounts for % of all deaths in children under the age of . the disease burden, especially in children, is heaviest in south asia and sub-saharan africa. these regions have tropical climates, which are characterized by a hot climate present all year round, whilst large volumes of rainfall each year result in the spread of zoonotic diseases. besides environmental influences, socio-economic factors also impact heavily on the epidemiology of tropical diseases. the tropics, which is the geographical region of the earth centred on the equator and limited by the tropic of cancer on the north and the tropic of capricorn on the south, is also home to some of the poorest nations. together with the movement of people triggered by globalization, mass migrations and climate change, these dynamics have a profound effect upon the patterns of respiratory tract infections in the tropics. global temperatures have risen through the past decades due to greenhouse gas emissions, and we have also seen a rise in a number of extreme meteorological events such as tropical super typhoon haiyan in . warmer temperatures and altered rainfall patterns are anticipated to promote outbreaks of infectious diseases due to more hospitable environments for pathogens and lack of ready access to health care. prevalence and mortality from pneumonia in children are the highest during rainy months in tropical and subtropical regions of asia and africa, which again highlights the pattern of pneumonia against climate. global warming and climate change also result in an increase in average as well as nadir temperatures, even in temperate regions. , hence, areas that were previously free from tropical diseases may now encounter such entities. this is shown by an emergence of tropical diseases in temperate regions, such as an outbreak of leptospirosis in in springfield, illinois in the united states, and an outbreak of human pneumonic plague in colorado in . natural disasters have been linked to disease outbreaks including pneumonia, due to an increased risk of water-, air-and vector-borne diseases. in the post-disaster period, phase is the impact phase ( - days) where victims are rescued and immediate treatment is provided for disaster-related injuries. phase which is the postimpact phase ( days to weeks post-disaster) is the period when the first surge of infectious diseases may surface, and phase the recovery phase (after weeks) when symptoms of diseases with longer incubation periods may declare. examples of such diseases are influenza and leptospirosis. a tertiary hospital reported an increase in patient admissions for pneumonia and tuberculosis (tb) in the aftermath of typhoon haiyan especially in the impact and post-impact phases, and the entity 'tsunami lung' has been described in victims who have pneumonia following a near-drowning episode after surviving a tsunami event. victims described by inoue et al. were rescued immediately after the tsunami and were in respiratory distress. the term tsunami lung describes both pneumonia from various organisms (such as stenotrophomonas maltophilia, burkholderia cepacia and pseudomonas aeruginosa), as well as severe systemic after-effects such as disseminated aspergillosis. there are no clear differences in viral aetiologies of pneumonia when comparing tropical with temperate climates. [ ] [ ] [ ] [ ] [ ] different authors have found varying impacts of precipitation on viral pneumonias. [ ] [ ] [ ] respiratory syncytial virus respiratory syncytial virus (rsv) is a common causative pathogen in respiratory tract infections and was the most commonly isolated virus in children with respiratory tract infections in a malaysian study, accounting for . % of patients. in adults, most manifestations are in the upper respiratory tract, although about % will develop pneumonia. the virus is detected using polymerase chain reaction methods, immunofluorescent or immunoassay antigen detection, cultures or serology analysis. treatment is mainly supportive. aerosolized ribavirin can be used as a specific antiviral therapy for rsv, but this is less well studied in adults compared with infants. influenza a influenza, which remains a global health burden, displays seasonality. a recent study of viral infectious patterns according to time of the year in a singaporean medical intensive care unit by siow et al. showed peaking of influenza cases around the start and middle of the year. in this study, the most common viral isolate was the influenza a h n / virus, followed by human rhinovirus. the seasonal distribution of influenza a in this study echoes the results of tang et al. who found the incidence of influenza a in singapore to peak during january and june to july period, as well as chew et al. who noted two peaks during the november to january and june to july period. in singapore, months with heaviest rainfall are clustered around year-end (october to december), and drier months are clustered around mid-year, in june and july. pharmacological treatments include antivirals such as oseltamivir and zanamivir to help shorten the duration of illness if administered within h of onset of illness. the seasonality of influenza therefore cannot be fully explained by rainfall alone. multiple contributory reasons have been hypothesized, including host behaviour such as spending more time indoors during adverse weather conditions, and altered host defences, but uncertainties remain. we must consider the complex relationship of climate and human behaviour when determining patterns, not just for influenza, but for other respiratory viruses as well. the h n strain of avian influenza was the causative agent of an influenza pandemic in asia in . prevalent in poultry and wild birds, animal-to-human transmission occurs to cause a spectrum of pneumonia/ pneumonitis, culminating in acute respiratory distress syndrome (ards). as of april , the world health organization (who) recorded a total of confirmed human cases of h n with deaths with a % mortality rate. as recently as october , who was notified of the influenza a (h n ) virus outbreak in china. since then, it has been noted to have an increased number of cases in december and january. , the major risk factor of infection was live poultry exposure. as live poultry markets are commonplace in china, and with chinese new year festivities the consumption of poultry in the populace will increase, there will be a higher risk of continued exposure leading to sporadic infections or small clusters of human cases. hantavirus is associated with the hantavirus pulmonary syndrome (hps). its manifestation is as a rapidly progressing non-cardiogenic pulmonary oedema and can mimic that of a severe pneumonia clinically and radiologically. hps was first discovered in in the southwestern united states, and since then has been described in latin america as well. risk factors are exposure to rural activities and rodents, and treatment is largely supportive. other viruses associated with pneumonias are the corona viruses, such as the middle eastern respiratory syndrome corona virus (mers-cov) and severe acute respiratory syndrome corona virus (sars-cov). these entities are beyond the scope of discussion of this paper, but suffice to say their impact on global health has been daunting given confirmed deaths out of confirmed mers-cov infections and more than cases of sars-cov, of which a large proportion were concentrated within asia (in particular, china, hong kong and taiwan). there are differences between causative organisms encountered in the tropics compared with temperate climates. due to both environmental and socioeconomic factors, diseases such as melioidosis, leptospirosis and tb are more widespread in the tropics-these will be discussed later. observation of the aetiologies of community-acquired pneumonia (cap) in an asian outpatient setting showed that the most common isolates were chlamydophila pneumoniae, followed by mycoplasma pneumoniae and streptococcus pneumoniae. that same systematic review by peto et al. identified s. pneumoniae as the most common pathogen in hospitalized patients with cap. although there was great variation in terms of proportion between countries in this study, frequency was similar to the trends observed in european studies quoted in the review and also comparable to findings by siow et al. interestingly, the most common gram-negative bacillus isolated in the studies was klebsiella, with higher proportions being reported in india and southeast asia. the authors found that asian patients with cap requiring hospitalization yielded a larger proportion of gramnegative bacilli ( . % vs . %) and staphylococcus aureus ( . % vs . %) isolates compared with referenced european studies. however, there was no comparison made between the asian countries, as certain countries such as korea and japan experience a temperate climate compared with the tropical climates of thailand and malaysia. siow et al. found the top two causative pathogens to be s. pneumoniae and klebsiella pneumoniae in a recent study looking at bacterial isolates from severe cap patients in a singaporean medical intensive care unit. streptococcus pneumoniae was the main grampositive bacterium isolate, and s. aureus was the next common gram-positive organism. otherwise, gramnegative organisms such as k. pneumoniae, escherichia coli and p. aeruginosa represented the majority of cases detected. similarly, lin et al. described k. pneumoniae not only as a prevailing cause of cap with bacteraemia in a taiwanese tertiary hospital, but also showed that it was associated with a more fulminant clinical course and worse prognosis when compared with patients with s. pneumoniae cap with bacteraemia. in a series of severe cap cases in singapore, patients who had gram-negative organisms isolated tended to have a worse outcome including a higher mortality, especially for patients with pseudomonas and burkholderia pseudomallei infections. this has changed the way local clinicians initiate their empiric treatment for patients admitted for severe cap, with antibiotics deliberately chosen to cover gram-negative organisms, melioidosis as well as gram-positive pathogens. a systematic review by goyet et al. looking at resistance patterns of cap pathogens in cambodia and neighbouring countries showed that up to % of s. pneumoniae and . % of k. pneumoniae were resistant to amoxicillin-clavulanic acid. streptococcus pneumoniae also displayed a high resistance to trimethoprim/sulfamethoxazole (average of . %) and wide range of resistance patterns to cephalosporins: between . % and . % to ceftriaxone, and up to . % to cefuroxime. there was also a mean high-level resistance rate to penicillin g of . %. burkholderia pseudomallei did not show resistance to first-line treatments ceftazidime, carbapenems and trimethoprim/sulfamethoxazole. as a result of this study, the authors have advocated the preservation of fluoroquinolones as they are not warranted as first-line therapy, and they are also used to treat tb, which importantly is endemic in this region. this highlights the importance of continued surveillance of regional resistance patterns and revision of therapeutic guidelines. melioidosis was first described by krishnaswami and whitmore in , when they noticed a 'glanders-like' disease afflicting opiate addicts in rangoon. today, melioidosis still poses a threat to public health due to mortality rates up to % if early treatment is not instituted. in an endemic country like thailand, it can account for up to % of the pathogens identified in adult patients with pneumonia. currie and kaestli estimated global mortality from melioidosis in to be , comparable with deaths from measles, and higher than those from dengue and leptospiral disease. the causative pathogen, b. pseudomallei, is a gramnegative rod that is found in soil and fresh water. it occurs mainly in northern australia, southeast asia, china and south asia with increased incidences during rainy seasons. this is in contrast to temperate countries where melioidosis is extremely rare and almost always encountered in migrants or travellers. presentation of melioidosis can be either acute or subacute. acute illnesses usually present with pneumonia which can be associated with ards and shock. subacute presentations may take a more insidious course, mimicking tb. there is also a propensity for the pathogen to spread haematogenously, and patients may present with extrapulmonary manifestations such as solid organ and skin abscesses, and even septic arthritis and encephalomyelitis. diagnosis of melioidosis is confirmed on positive cultures. with potential mortality rates approaching %, a clinician's suspicion must be high when faced with a patient with severe cap coupled with an appropriate travel history. in the local context, because of being in an endemic region, intensive care units including those in singapore have adopted empirical antibiotic treatment to include specific coverage for melioidosis (ceftazidime and meropenem would be appropriate) for patients admitted with severe cap. , indeed, in a prospective study over years in darwin, mortality rates have improved over time ( % described by the authors) with better recognition of the disease as well as early treatment with appropriate antibiotics. leptospirosis is a zoonotic disease prevalent in the tropics, with a much higher incidence than in temperate regions. within the asia pacific region, high-incidence countries include thailand, bangladesh and cambodia. there are also certain regions such as korea and china where leptospirosis incidences, although low, are increasing. leptospira are aerobic spirochetes. both feral and domesticated animals can host the diseasecommonly, dogs, cattle, rodents, swine, but interestingly, and rarely in cats. human infection typically occurs after contact with contaminated urine, animal tissue, water or soil. in the tropics, it especially affects low-income regions with poor sanitation, low education and poor housing, where outbreaks are common and morbidity is high. even in higher income regions, heavy rainfall leading to flooding increase the risk of both humans and livestock exposure to contaminated water. for example, there was an outbreak in anuradhapura, sri lanka. anuradhapura is a region with abundant paddy fields for rice farming and was not previously known as an endemic area, so the diagnosis and outbreak of leptospirosis which followed flooding was initially challenged by local clinician. recreational events such as caving, canoeing and freshwater swimming could expose humans to contaminated sources. an example highlighting the impact of these activities would be the leptospirosis outbreak in springfield, illinois, involving triathletes who were exposed to lake water. clinical features are variable. it can take a subclinical, self-limited course, or can progress to severe and potentially life-threatening illness complicated by jaundice, renal failure and ards, with reported mortality rates up to %. typical presenting complaints include fever, myalgia, headaches and conjunctival insufflation. cough, nausea, vomiting and diarrhoea are common. dall'antonia et al. described cough and haemoptysis in patients with serologically proven leptospirosis. severe forms of the disease with multiorgan dysfunction and ards-like syndromes may be fatal. chest roentgenogram findings are non-specific; they commonly show non-segmental patchy or even nodular infiltrates with poorly defined margins usually in the lower lobes, which can be unilateral or bilateral. interestingly, leptospirosis and chikungunya coinfection can potentially lead to a delayed diagnosis and subsequent deleterious outcomes. nhan et al. described a fatal case of leptospirosis and chikungunya co-infection in a french-polynesian outbreak during the rainy season, where diagnosis was delayed due to overlapping symptoms. co-infections with dengue have also been described by pan et al., where three cases of co-infection were detected during a dengue outbreak. again, diagnosis was challenging because of nonspecific symptoms such as fever, chills and myalgia. adding on to the diagnostic challenge, sathiyakumar et al. described a case of haemorrhagic pneumonitis secondary to leptospirosis, which showcases the spectrum of clinical presentation. the diagnosis of leptospirosis is both clinical and microbiological, but the gold standard is the microscopic agglutination test (mat). cumberland et al. found the mat to have a sensitivity of between % and % (depending on when samples were taken in the disease's time course), and % specificity. leptospira can be grown in vitro from blood, cerebrospinal fluid and urine from infected hosts. however, the laboratory needs to be notified if leptospira needs to be isolated as it requires specialized culture media, and time to positive cultures can take between week and months. should the clinician strongly suspect leptospirosis clinically, empiric antibiotics such as doxycycline or ceftriaxone should be started. the strain of rickettsial illness encountered in the tropics is scrub typhus-a mite-borne disease caused by orientia tsutsugamushi, a gram-negative coccobacillus. it is predominantly found in the asia pacific rim, with larval mites ('chiggers', from the genus leptotrombidium) that live on vegetation and rodents. wu et al. have described a rise in the incidence of scrub typhus in mainland china between and with a . times increase. on top of seasonal peaks, the authors postulated that the increase of popularity in ecotourism have exposed more people to vector habitats. clinical manifestations typically include myalgia, high fevers, headaches, as well as a rash and eschar at the chigger bite. scrub typhus is usually self-limiting over - weeks but is sometimes associated with severe illness and multiorgan failure leading to death, although this is rare. [ ] [ ] [ ] pneumonia can occur in the late phase of the disease , , as well as in an ardslike picture. pulmonary involvement is well described. chest roentgenograms may be abnormal in - % of patients, and may show bilateral diffuse reticulonodular opacities, septal lines and hilar lymphadenopathy. consolidation is not common, and would tend to appear in the lower zones. pleural effusions can be found in up to . % of patients. , the diagnosis is confirmed on serological testing or eschar biopsy, but there should be a suspicion of scrub typhus infection if there is an appropriate exposure history. patients who have been started on appropriate antibiotics (such as doxycycline, chloramphenicol and azithromycin) usually have defervescence of the fever within h. countries in the tropics bear the brunt of tb, and south east asia holds approximately one-third of the global burden of tb. peto et al. found more than % of cases of cap in asia were attributable to mycobacterium tuberculosis. however, with the rise in tourism and immigration, tb is now seen in higher income countries, with a substantial proportion of cases diagnosed in immigrants in the united states and england. , people at risk include those with poor nutrition, immunocompromised and those living in poorly ventilated and overcrowded environments. the american thoracic society and infectious diseases society of america recommends repeat examinations of expectorated sputum for acid fast bacilli (afb) augmented by a nucleic acid amplification test such as the xpert mtb/rif assay (cepheid, sunnyvale, ca, usa) in the rapid diagnosis of pulmonary tb. in smear-negative cases, they suggest the testing of induced sputum instead of proceeding to bronchoscopy and lavage which seems to be a very popular option. sputum induction is more cost effective than bronchoscopic examination and should be the test of choice if smear-negative pulmonary tb is the most likely diagnosis. we must also consider that in certain settings, it is common to lack access to high-quality chest roentgenograms and people who can reliably interpret them, and there may not be access to the xpert mtb/rif assay. who has an alternative algorithm to reference in settings where chest roentgenograms and/or xpert mtb/rif assays are not available, and it is largely based upon careful history taking, clinical examination and sputum smear analysis. treatment regimens using first-line drugs include rifampicin, isoniazid, ethambutol and pyrazinamide. directly observed therapy (dot) has been utilized in some countries to ensure compliance as this is the crux of treatment success, but a cochrane review of trials in found no significant differences in cure rates, treatment completion when comparing dot and selfadministered therapy. the authors have stated that given the costs and personnel involved in dot, policymakers may wish to have alternative strategies to help improve adherence to treatment. multidrug-resistant tb and extensively drug-resistant strains are beyond the scope of this review and will not be examined. helminthic and protozoal parasitic diseases are common in the tropics. pulmonary disease typically presents as an eosinophilic lung disease, with or without peripheral blood eosinophilia. lung infiltrates may be fleeting on radiology-this was famously described by loffler in . lymphatic filariasis lymphatic filariasis can manifest as a syndrome known as tropical pulmonary eosinophilia (tpe). the disease is seen mainly in south asia, southeast asia and the south pacific islands. three species of filarial nematodes cause tpe: wuchereria bancrofti, brugia malayi and brugia timori. , mosquitoes transmit the disease and humans are the definitive hosts. microfilariae trapped in the lungs lead to an immune hyper-responsiveness, leading to symptoms of cough, fever, night sweats, wheezing and weight loss. pulmonary radiology can appear miliary or nodular, mimicking tb. however, imaging can be normal in up to % of patients. spirometry tends to demonstrate a restrictive pattern with airways obstruction, and airway obstruction is usually reversed by bronchodilators. treatment with diethylcarbamazine is associated with rapid improvement in signs and symptoms, as well as a gradual trend towards normal in spirometric values, although permanent impairment in lung function can occur. the causative pathogen, paragonimus westermani, is endemic in much of asia and south america. a foodborne trematode, infection is cause by ingestion of raw of improperly cooked freshwater crabs. patients may be asymptomatic although can also experience a chronic cough, chest pain and haemoptysis which can be recurrent. radiological findings include pleural effusions, pneumothorax, ring shadows and consolidation on chest roentgenograms. , computer tomography scanning can reveal cysts within the consolidated lung. paragonimiasis is treated with triclabendazole or praziquantel. strongyloides infection is common in the tropics, sub tropics and warmer temperate climates. nematode larva spread haematogenously as well as via the lymphatics to the heart and lungs. patients can present with loeffler's syndrome and peripheral eosinophilia during larval migration through the lungs. respiratory signs and symptoms include cough, bronchospasm and in some cases haemoptysis. chest roentography can be normal. during larval migration, miliary nodules or ill-defined patchy consolidation may be present. in an overwhelming infection especially in the immunocompromised host, a marked bilateral alveolar pattern similar to that of pulmonary oedema can be seen, and clinically the patient would be in ards. , , diagnosis of strongyloides can be strengthened with examination of several stool samples on several days. larvae may also be demonstrated on duodenal aspirates, sputum and bronchoalveolar lavage fluid. ivermectin and albendazole can be used for effective treatment. , additionally, clinicians need to be aware of gut translocation of enteric organisms especially in immunocompromised hosts, leading to further complications of sepsis. malaria is caused by the intraerythrocytic protozoa plasmodium. it is transmitted to humans by the bite of the female anopheles mosquito, and falciparum malariae is the most severe of all malarial infections. the symptoms leading to a suspicion of malarial infection are fever which can be cyclical, breathing difficulties and anaemia. once the disease is suspected, light microscopy is the standard tool used to detect parasites on blood smears. rapid diagnostic tests utilize antigen detection technology as an alternative when reliable light microscopy is unavailable, and the who is recommending its use as a field alternative when rapid diagnosis is paramount. there is a wide range of pulmonary manifestations, from a non-productive cough to ards, occurring in up to % of adults with severe falciparum malaria infection although any strain of plasmodium can lead to ards. the development of ards portends an extremely grave prognosis , -gachot et al. described a % mortality rate in patients with malaria and acute lung injury despite admission to an intensive care unit. chest roentgenogram findings are non-specific and can range from confluent nodules to basal and/or bilateral pulmonary infiltrates, mimicking pulmonary oedema, although this is usually non-cardiogenic. resistance to antimalarial drugs especially chloroquine and sulfadoxine-pyrimethamine has become widespread. who now recommends artemisinin-based combination therapy (act) as the firstline treatment in uncomplicated falciparum malaria. for uncomplicated, non-falciparum malaria in regions with low choroquine resistance, chloroquine can be used. we have summarized the common pathogens causing pneumonia in tropical regions in table . other differentials of pneumonia in the tropics would be tpe, pulmonary plague, histoplasmosis, cryptococcosis, thoracic actinomycosis, nocardiosis and pulmonary anthrax. however, these are beyond the scope of this review, and we would urge clinicians to practice careful history taking including a travel and exposure history, and conscientious examination to lead them towards the correct diagnosis. the burdens of pneumonia in tropical and subtropical regions remain high, especially when coupled with global warming and climate change. with the advances in air travel, immigration patterns and international tourism would mean tropical diseases including pneumonias would be encountered in the temperate countries as well. it is important for clinicians to recognize these relations and conditions so that correct treatment can be instituted early, as some of the tropical diseases such as leptospirosis, melioidosis and malaria with ards herald a poor prognosis if treatment is delayed. clinicians will need to be cognizant of co-infections with overlapping symptoms such as chikungunya or dengue co-infection with leptospirosis, as late diagnosis would potentially lead to deadly consequences. t.k.l. is professor of medicine and senior consultant in the department of medicine, national university hospital singapore. his research interests include effective implementation of clinical evidence and improving clinical reasoning expertise by deliberate practice and structured reflection. w.t.s. is an associate consultant in the department of respiratory and critical care medicine, national university hospital singapore. her clinical interests include critical care medicine and biomedical technology. world health organization. pneumonia factsheet climate change and respiratory infections characterizing hospital admissions to a tertiary care hospital after typhoon haiyan human health: impacts, adaptation, and co-benefits childhood pneumonia: a neglected, climate-sensitive disease? diurnal temperature range and daily mortality in shanghai leptospirosis working group. outbreak of leptospirosis among triathlon participants and community 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doc_id: cord_uid: ja b vy the widespread introduction of penicillin in the s resulted in a substantial reduction in mortality from community-acquired pneumonia (cap). however, despite significant advances in medical science, only a small improvement has occurred since, particularly in patients with bacteremic pneumococcal pneumonia [ , ]. even modern intensive care has only made a small difference to the mortality in patients with severe pneumonia [ , ]. while the aging population, increased number of patients with severe co-morbid illnesses, and the human immunodeficiency virus (hiv) epidemic have certainly contributed to the persistently high mortality rate [ , , ], apparently healthy, immunocompetent patients continue to die from cap. disturbingly, a recent british thoracic society study concluded that no available therapy could substantially reduce the mortality rate from severe cap in young adults [ ]. the widespread introduction of penicillin in the s resulted in a substantial reduction in mortality from community-acquired pneumonia (cap). however, despite significant advances in medical science, only a small improvement has occurred since, particularly in patients with bacteremic pneumococcal pneumonia [ , ] . even modern intensive care has only made a small difference to the mortality in patients with severe pneumonia [ , ] . while the aging population, increased number of patients with severe co-morbid illnesses, and the human immunodeficiency virus (hiv) epidemic have certainly contributed to the persistently high mortality rate [ , , ] , apparently healthy, immunocompetent patients continue to die from cap. disturbingly, a recent british thoracic society study concluded that no available therapy could substantially reduce the mortality rate from severe cap in young adults [ ] . while some causative microorganisms, such as pseudomonas, and some strains of common causative microorganisms appear to be more virulent, the majority of cap patients who die are infected with organisms sensitive to commonly prescribed antibiotics. even the recent emergence of high level penicillin-resistant strains of s. pneumoniae has not significantly increased the mortality of cap. given that most cap patients die despite microbiological confirmation that they received appropriate antibiotic therapy, the introduction of new antibiotic classes is unlikely to reduce mortality further. for this reason, research has been directed into non-antibiotic therapeutic measures. generally, supportive measures for cap can be separated into two categories -( ) immunomodulatory therapy for the systemic inflammatory response induced by pneumonia and ( ) support for the gas exchange abnormalities unique to a pulmonary source of sepsis. chapter focuses on potential immunomodulatory therapies in patients with sepsis, including pneumonia. this chapter will focus on a few pneumoniaspecific immunomodulatory therapies and other advances in the intensive care management of patients with severe cap. although discussed in chapter , a more detailed discussion of the recent controversy over high dose corticosteroids in patients with cap is warranted. the best evidence of benefit for corticosteroids comes from studies in specific, narrowly defined groups of cap patients caused by less common agents. randomized, controlled trials have shown corticosteroids reduce mortality in aids patients with pneumocystis carinii pneumonia and significant hypoxia, if instituted at or prior to the onset of anti-pneumocystis therapy [ , ] . based on a small, retrospective study of subjects, corticosteroids may also improve the outcome of severe varicella pneumonia [ ] . anecdotally, corticosteroids are frequently used in the setting of severe fungal pneumonia, particularly due to histoplasmosis [ , ] , and a small controlled trial of patients supported their use in miliary tuberculosis [ ] . following the success of pre-antibiotic corticosteroids in children with meningitis [ ] , marik and colleagues [ ] studied the effect of a single dose of hydrocortisone ( mg/kg) min prior to antibiotic therapy in a small randomized placebo controlled trial of adult patients with severe cap (scap). hydrocortisone had no detectable effect on tumor necrosis factor alpha (tnf) production in the following h, mortality (only four deaths) or length of stay in the icu. while not encouraging, the small number of subjects studied ( received hydrocortisone), the use of only a single dose and the measurement of only a single pro-inflammatory cytokine for only h does not qualify this study to be a definitive statement on the role of corticosteroids in cap. an important finding of this study was that beta-lactam antibiotics did not result in a significant increase in serum tnf levels, as rapid antigen release due to bacterial lysis has been postulated as a potential cause of deterioration in patients with severe cap [ ] . also supporting a possible role for corticosteroids in severe cap, montón and co-workers [ ] studied the effect of intravenous methylprednisolone on bronchoalveolar lavage fluid (balf) and serum cytokines in patients with severe nosocomial pneumonia or cap. the patients who received methylprednisolone had significantly lower serum and balf tnf, interleukin (il)- q , il- and c-reactive protein. there was also a non-significant trend to lower mortality in the steroid treated group ( % vs. %). recently, confalonieri and colleagues compared intravenous hydrocortisone ( mg bolus followed by mg/h for days) with placebo in patients with severe cap admitted to the icu [ ] . the trial was stopped early after an interim analysis showed a significant mortality benefit in the steroid group ( % vs %, p = . ). however, the mortality difference was driven by deaths after day and a high incidence of "delayed septic shock". the marked incidence of this scenario has not been seen in any other scap study. significant differences in the percent of patients who received noninvasive ventilation rather than intubation and mechanical ventilation also compromise the data regarding a beneficial effect of steroids on gas exchange. noninvasive ventilation has been shown by the same group to decrease mortality compared to invasive ventilation [ ] . the statistical design of the study led to an early closure of the study, limiting the ability to exclude the possibility that other factors explain the mortality difference. the complete absence of any mortality in the corticosteroid group has also raised significant concerns about potential bias in patient selection and whether either the control or case cohort were truly representative of the general group of patients with severe cap. despite the reservations, all three pilot studies suggested a trend toward benefit with steroids so further clinical studies clearly need to be conducted. prostaglandin antagonists are worth special comment as they have been studied in animal and human patients with pneumonia. ibuprofen reduced the intrapulmonary shunt fraction from % to % in dogs with lobar pneumonia [ ] , with a corresponding decrease in the consolidated area of lung. acetylsalicylic acid had a similar effect, reducing the shunt fraction from % to % [ ] . the mechanism is unclear but may be due to reversal of prostaglandin inhibition of the hypoxia-induced pulmonary vasoconstriction. in a small study of ten subjects with pneumonia requiring mechanical ventilation, hanley et al. [ ] studied the effect of indomethacin ( mg/kg oral or rectal) on arterial oxygenation. five subjects had substantial improvement in oxygenation with a small improvement in three additional patients. improvement tended to occur in the patients with the greatest degree of hypoxemia. as ibuprofen administration appears to be relatively safe, even in the setting of sepsis [ ] , further studies are warranted. in contrast, ferrer et al. found a g infusion of acetylsalicylic acid (asa) had no effect on arterial oxygenation in seven patients with severe unilateral pneumonia [ ] . although intrapulmonary shunting did reduce by a small amount ( ± % vs. . ± %), the lack of clinically apparent benefit was discouraging. several possible explanations were advanced to explain the discrepancy between this study and that of hanley et al. clearly, a difference in efficacy between asa and indomethacin may be the cause. however, the subjects in the study by hanley et al. were also more severely hypoxic, with a mean pa /fi of compared to . in any event, it would seem reasonable for future studies to use indomethacin in preference to asa. before the advent of antibiotic therapy, passive immunization with serum was used with some success in patients with pneumonia [ ] . mortality was reduced by approximately % in most age groups with a diminishing effect in patients over the age of . with the exception of patients with specific immunoglobulin deficiencies, this therapy has largely been abandoned due to the much greater efficacy of antibiotics in addition to the difficulty, and cost, of obtaining sufficient serum. the development of new antiviral drugs has also largely obviated the anecdotal use of hyper-immune serum in cytomegalovirus and varicella pneumonitis. while the overall efficacy of pneumococcal immunization is unclear, especially in the elderly with some comorbid illnesses, several studies and a meta-analysis have suggested that even if pneumococcal pneumonia is not prevented, the incidence of invasive pneumococcal disease is decreased. the use of specific anti-pseudomonal exotoxin antibodies has been tried as an adjunct to antibiotics with some success in mice [ ] and guinea pigs [ ] , and pseudomonas specific vaccines have enhanced antibiotic response in guinea pigs [ ] . anti-pseudomonal antibodies appeared safe in human subjects with evidence of increased opsonophagocytic activity in a small phase i study of subjects [ ] , but further studies are required to determine whether they have any clinically relevant effect. in human sepsis studies, generic anti-endotoxin strategies have so far been disappointing [ , ] . although they have not specifically been studied in pneumonia, the primary site of sepsis in many of the patients in these studies was the lung, indicating a low likelihood of benefit. legionella pneumophila is consistently identified as a leading cause of cap, particularly in patients with severe cap [ - ] . unlike pneumococcal pneumonia, the immune response to legionella infection is predominantly of a th type [ ] and bacterial killing is predominantly by macrophages [ ] . skerrett and martin studied the effect of interferon gamma (ifn * ), a potent stimulator of macrophage function [ , ] , given as an intratracheal bolus in rats with experimental l. pneumophila pneumonia [ ] . intratracheal ifn * markedly reduced the replication of l. pneumophila in corticosteroid treated rats, but had no detectable effect in immunocompetent rats or when given intraperitoneally. the ability to give ifn * by aerosol is particularly appealing since not only are systemic side effects avoided, but also a much greater effect on intrapulmonary macrophage function is seen compared to systemic administration [ ] . aerosolized ifn * has also been shown to be safe in patients with drug resistant tuberculosis [ ] , and may have a role in treatment of this condition. further studies of nebulized ifn * , especially in patients with pulmonary legionellosis, are awaited. after many unsuccessful trials of non-antibiotic agents designed to disrupt or ameliorate the pro-inflammatory process driving septic shock and associated organ failure, activated protein c (drotrecogin alpha activated) was the first successful agent to reduce mortality in a large randomized, double blind, placebo controlled trial [ ] . while -day mortality was clearly better in sub-groups of patients who received drotrecogin alpha activated [ ] , the subgroup with community-acquired pneumonia drove most of the benefit of the drug [ ] , with the greatest reduction in mortality seen with streptococcus pneumoniae infection (rr= . ; % ci . - . ). the availability of rapid urinary antigen detection for s. pneumoniae allows this association to enter clinical decision-making (several references for urinary antigen). drotrecogin alpha activated appeared to have a greater effect in single organ failure than waiting for multiple ( & two) organ failure but clearly has its greatest benefit in patients who have the highest acuity of illness. worsening thrombocytopenia, suggestive of early disseminated intravascular coagulation, appears to be another important indicator for patients likely to respond to drotrecogin alpha activated [ ] . while different criteria for the administration of drotrecogin alpha activated have been established in different institutions around the world, the presence of pneumonia and shock should prompt physicians to consider its use as early as is possible. the main additional supportive therapy unique to cap is improved oxygenation and secretion clearance. the remainder of supportive care is not different than that of other critically ill patients with infection. cap is one of the more common causes of severe hypoxic respiratory failure. a common method to improve oxygenation, the addition of positive end expiratory pressure, may actually make oxygenation worse in patients with severe asymmetrical lung disease like cap. the peep will tend to overdistend the unaffected lung, increasing pulmonary vascular resistance on the local area. this overdistension may then direct greater blood flow to the pneumonic area, especially if hypoxic vasoconstriction has been blocked by some bacterial product. with extensive unilateral pneumonia, positioning the ventilated patient in the lateral decubitus position with the affected lung up has been demonstrated to improve oxygenation [ ] . positioning increases perfusion to the dependent, non-involved lung, increases secretion clearance from the affected lung, and may allow addition of peep without increasing shunt because the dependent lung is now less compliant and less likely to become overdistended. the combination of positioning and prostaglandin inhibitors is usually adequate to temporarily improve oxygenation until hypoxic vasoconstriction is restored. differentially ventilating each lung by means of a dual lumen endotracheal tube may also be beneficial [ , ] . this allows the use of higher levels of peep in the affected, less compliant, lung and lower levels of peep in the normal lung, thus reducing the risk of barotrauma. a study by ranieri et al. showing a correlation between the level of peep and pro-inflammatory cytokine production further supports this approach to protect the 'normal' lung [ ] . the point at which differential ventilation is worth commencing is not clear, but carlon and colleagues [ ] suggest optimal benefit occurs when there is a ml or greater difference in distribution of tidal volume between each lung. ecmo, a modification of cardiopulmonary bypass, was designed to provide oxygenation in patients with severe respiratory failure. although available since the s, initial poor results from a national institutes of health sponsored prospective, multicenter randomized trial [ ] limited the use of ecmo to research centers. however, a significant reduction in complications has led to resurgence in interest in ecmo as a means of providing oxygenation when all other means have failed. the role of ecmo has most extensively been studied in neonates. in newborn infants with respiratory failure unresponsive to other therapy it has proven highly effective, having an overall survival of % in over , neonates where nearly % mortality would be expected [ ] . modification of the neonatal ecmo technique has also been effective in some pediatric patients with respiratory failure [ ] , including those with pneumonia from both bacterial [ ] and viral [ ] pathogens. as would be expected, as the duration of ecmo required increases, the prognosis decreases [ ] . in the nih-sponsored ecmo trial, adults with viral pneumonia did particularly poorly. in a retrospective review of adults with severe acute respiratory failure supported with ecmo by kolla and colleagues [ ] , a % survival rate was found in the patients with a primary diagnosis of pneumonia. although this mortality seems high, patients selected for ecmo had an expected mortality in excess of %. predictors of poor response to ecmo were increasing age, days of ventilation prior to commencement of ecmo and the degree of respiratory failure as measured by the pa /fi ratio. cases of successful intervention in adults with severe legionella [ , ] , pneumococcal [ ] and varicella pneumonia [ ] have all been reported. the clearest indication for ecmo in adults may be the hantavirus pulmonary syndrome (hps). with no effective antiviral therapy, care is entirely supportive. in a small series, the dramatic but time-limited cardiovascular and pulmonary hemorrhagic manifestations of hps appeared to be well supported by ecmo [ ] . ecmo would appear to have a role in some patients with severe respiratory failure secondary to pneumonia. the timing, duration and patient selection for what is an expensive, labor intensive therapy remain to be determined by prospective studies. liquid ventilation with volatile hydrocarbons has been studied in the management of ards. little data is currently published on its use specifically in human sub-jects with pneumonia. in rats given lethal doses of pneumococci, partial liquid ventilation in combination with perfluorocarbon doubled survival compared to antibiotics alone [ ] . nitric oxide (no) inhalation has also been studied as adjunctive therapy of ards, as well as some other forms of severe pulmonary hypertension. while no studies specifically address human patients with pneumonia, in dogs with escherichia coli pneumonia, inhaled no had a minimal effect on oxygenation and no effect on sepsis induced pulmonary hypertension [ ] . since no is one of the effector molecules released by macrophages to kill bacteria [ ] , inhaled no has a potential antibacterial effect. hoehn and colleagues studied the bacteriostatic effect of no on bacterial cultures from neonates [ ] . at ppm (greater than the usual dose range of - ppm) no inhibited the growth group b streptococcus, staphylococcus epidermidis and e. coli but not pseudomonas aeruginosa or staphylococcus aureus. further studies will be required to determine whether inhaled no has any real bacteriostatic effect in vivo, particularly as it may have deleterious effects on the function of neutrophils [ ] . aerosolized prostacyclin has also been shown by walmrath et al. to improve oxygenation by reducing shunt and pulmonary hypertension in patients with pneumonia [ ] . twelve patients with severe pneumonia (pa /fi < ), six of whom had interstitial lung disease (ild), received varying doses of prostacyclin. patients with ild required substantially larger doses of prostacyclin to produce a clinical effect. although its efficacy has not been compared to no in patients with pneumonia, its greater cost is a significant disadvantage. significant accumulation of mucopurulent secretions can occur in cap, particularly in patients on mechanical ventilation. mucus impaction can lead to obstruction, ranging in severity from linear atelectasis to lobar collapse. clearly the most effective secretion clearance is a spontaneous cough. however, the respiratory compromise often attendant to severe cap may prevent an effective cough. support with noninvasive ventilation (niv) may benefit the patient by both improving respiratory mechanics while allowing the patient to spontaneously expectorate [ ] . however, retained secretions is also one of the causes of failure of niv. an important strategy to avoid this complication is to avoid continuous ap-plication of niv and actively encourage the patient to cough during periods off niv. in mechanically ventilated cap patients, removal of secretions by regular suctioning is essential. the use of percussion or vibration in ventilated patients has been associated with worsening of gas exchange and the benefit in cap patients in general is unclear. the benefit of bronchoscopy for secretion removal is also poorly supported. bronchoscopy for secretion removal has been associated with an increased risk of development of subsequent nosocomial pneumonia [ ] . therefore its therapeutic use should be limited. one of the few studies on this area has suggested that if lobar atelectasis is accompanied by an air bronchogram, bronchoscopy is unlikely to find a mucus plug or benefit the patient. changing the rheologic properties of thick tenacious mucus is often attempted with little scientific support. avoidance of dessication and inspissation of secretions does appear to be important. adequate hydration may be the most effective therapy. intubated cap patients with significant secretions are poor candidates for heat and moisture exchangers and should usually have ventilation initiated with heated humidification. the pharmacologic intervention most often ordered is n-acetylcysteine. most support for this therapy is an extension of results in some cystic fibrosis patients. whether the same benefit can be achieved in cap patients is unclear as there is no published data of n-acetylcysteine use in this setting. the potential benefit is also partially offset by induction of bronchial irritation and bronchospasm in some patients. preliminary data on agents with more physiologic support, such as utp [ ] , are encouraging but need further study. guaifenesin has limited data in non-pneumonia patients and is unlikely to have a major benefit in intubated cap patients. although a variety of other mucolytic agents are available, including bromhexine, rhdnase and polymyxin b, there is no data to support their use in patients with pneumonia. cap remains a significant health problem and patients continue to die despite receiving appropriate antibiotic therapy. modification of the host immune response, both anti-and pro-inflammatory approaches, has yet to live up to the promise of improved outcome. despite this, there is significant reason for optimism. some immunomodulatory therapies clearly have efficacy in some patients. as our understanding of the immune response to pneumonia improves, our ability to tailor specific therapies for individual patients will also improve, hopefully avoiding the deleterious effects that have so far prevented the development of an effective immune based therapy. the possibility of delivering cytokines directly to the lung, such as with nebulized ifn * , is a particularly promising way of achieving the desired pulmonary effect without systemic side effects. corticosteroids are currently unique in that they have a proven role in the therapy of pneumonia due to p. carinii. recent research suggests there may be a much wider therapeutic indication for corticosteroids in severe cap and further research is awaited. once respiratory failure has ensued, supportive measures such as patient positioning and differential lung ventilation can improve oxygenation at no additional risk in some patients, particularly those with severe unilateral pneumonia. in facilities where ecmo is available it may be beneficial in selected patients when all 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liquid ventilation with perfluorocarbon in the treatment of rats with lethal pneumococcal pneumonia cardiopulmonary effects of inhaled nitric oxide in normal dogs and during e. coli pneumonia and sepsis nitric oxide: mediator, murderer, and medicine effect of therapeutic concentrations of nitric oxide on bacterial growth in vitro alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation effects of aerosolized prostacyclin in severe pneumonia acute respiratory failure in patients with severe community-acquired pneumonia. a prospective randomized evaluation of noninvasive ventilation a predictive risk index for nosocomial pneumonia in the intensive care unit acute safety and effects on mucociliary clearance of aerosolized uridine '-triphospate ± amiloride in normal human adults key: cord- -oorac he authors: nair, girish b.; niederman, michael s. title: community-acquired pneumonia: an unfinished battle date: - - journal: med clin north am doi: . /j.mcna. . . sha: doc_id: cord_uid: oorac he community-acquired pneumonia remains a common illness with substantial morbidity and mortality. current management challenges focus on identifying the likely etiologic pathogens based on an assessment of host risk factors, while attempting to make a specific etiologic diagnosis, which is often not possible. therapy is necessarily empiric and focuses on pneumococcus and atypical pathogens for all patients, with consideration of other pathogens based on specific patient risk factors. it is important to understand the expected response to effective therapy, and to identify and manage clinical failure at the earliest possible time point. prevention is focused on smoking cessation and vaccination against pneumococcus and influenza. have shown that patients with cap in a medicare population have a -year mortality of more than %, suggesting that pneumonia may be a surrogate marker of severe underlying comorbidity, or that it initiates a series of adverse consequences for some patients that leads to their eventual death. despite the availability of different guidelines and treatment options, the economic burden associated with cap remains high at more than $ billion annually in united states alone. although most patients with cap are outpatients, the greatest portion of the cost for this illness is borne by those admitted to hospital, making the decision about admission an important one for several reasons. a recent study noted that decreasing the length of stay by day in a patient with cap had a potential economic benefit of $ . with new health care reforms imminent and the emphasis on better health care delivery, cost-effective treatment of pneumonia will assume greater significance. there are several challenges with the management of cap, from the accurate diagnosis of lung infiltrates, decisions about the site of care, and the choice of appropriate antibiotics. the infectious disease society of america (idsa)/american thoracic society (ats) guideline from provides a summary of the approach to the treatment of cap directed mainly towards primary care physicians, hospitalists, and emergency medicine physicians. multiple validated severity assessment scores have been developed that stratify patients according to the risk of death and can be used as decision support tools to guide site-of-care decisions. , the emergence of drugresistant organisms, particularly drug-resistant streptococcus pneumoniae (drsp), is another challenge in disease management. biomarkers are increasingly being used to distinguish bacterial pneumonia from other causes and to help reduce the duration of antibiotic therapy. this article reviews the recent advances in the diagnosis, management, and potential complications associated with cap. in cap, the major route of infection is microaspiration from a previously colonized oropharynx, but inhalation of suspended aerosolized microorganisms is the mechanism of infection for viruses, legionella, and tuberculosis. interactions between the host immune response, the virulence of the infecting organism, and the size of the inoculums determine whether a patient develops pneumonia. defective cough, mucociliary clearance, and impaired local and humoral immunity predispose to severe pneumonia. alcohol consumption and smoking are independent risk factors for the development of pneumonia. medical comorbidities such as chronic obstructive pulmonary disease (copd), congestive heart failure, chronic kidney disease, liver disease, and immune deficiency states have an increased predisposition for the development of cap. recent use of proton pump inhibitor therapy started within days has been identified as a risk factor for cap. elderly patients are at increased risk for development of pneumonia and, when it occurs, they are more likely to die than younger individuals. although many patients develop severe pneumonia because of immune impairment, others develop acute lung injury (acute respiratory distress syndrome [ards]) as a consequence of unilateral pneumonia because of an inability to localize the immune response to the initial site of infection, possibly because of the presence of a genetic variation in their immune responsiveness. , the most common organism causing cap, in all patient populations, is s pneumoniae, or pneumococcus. other pathogens include hemophilus influenzae (particularly in cigarette smokers), moraxella catarrhalis, staphylococcus aureus (after influenza and recently in the form of methicillin-resistant s aureus [mrsa]), viruses (including influenza, respiratory syncytial virus, parainfluenza, and epidemic viruses), and atypical pathogens such as mycoplasma pneumoniae, chlamydophila pneumoniae, and legionella pneumophila. in most series, atypical pathogens are common, including in those admitted to the icu, where they can account for up to % of the identified pathogens. in addition, many investigators have documented that atypical pathogens may coexist with bacterial pathogens, accounting for their presence in up to % of patients with cap, when serologic testing is used. gram-negative bacteria (pseudomonas aeruginosa, klebsiella pneumoniae, escherichia coli, enterobacter spp, serratia spp, proteus spp) are the causal agents in up to % of patients with cap, but may be more common in patients who develop pneumonia out of the hospital and have hcap risk factors. gram-negative bacteria have been associated with severe cap, and k pneumoniae was noted to be an independent risk factor for mortality in severe cap. in one study from korea, in a multivariate analysis, the risk factors associated with gram-negative cap were septic shock (with an odds ratio of . ), cardiac disease, smoking, hyponatremia, and dyspnea, emphasizing the association of these organisms with severe illness. enterobacter cap behaves more like hospital-acquired pneumonia and is associated with prolonged mechanical ventilation, delay in initiation of antibiotics, and longer icu stay. risk factors for community-acquired p aeruginosa pneumonia include bronchiectasis, immunocompromised state, use of multiple courses of antibiotics, prolonged glucocorticoids in patients with copd, and recent hospitalization. anaerobic organisms should be considered when aspiration is suspected. influenza is a common viral cause of cap, with a seasonal variation in frequency. primary influenza pneumonia tends to cause severe pneumonia, which can be either caused by the virus itself or a result of secondary bacterial infection with pneumococcus, s aureus, or h influenzae. high-risk patients include those with chronic heart or lung disease, diabetes, immunosuppression, hemoglobinopathy, renal disease, and otherwise healthy individuals more than years of age. other viruses that cause cap include parainfluenza virus, respiratory syncytial virus (rsv), human metapneumovirus, severe acute respiratory syndrome virus, varicella, hantavirus, and adenovirus. many of these patients have viral infection as part of a mixed infection, often with bacterial pathogens. emergence of drsp and community-acquired mrsa is a matter of concern that has complicated the empiric therapy choices for patients with cap. drsp is seen most often in patients older than years of age, and in those with a history of alcoholism, antibiotic therapy within months, multiple medical comorbid conditions, exposure to children in day care, or those with immune-compromised states. community-associated mrsa (ca-mrsa) pneumonia occurs in patients with no prior health care exposure, usually after influenza, and may lead to a severe necrotizing pneumonia, although milder forms of illness have also been reported. in patients with severe illness, the organism may produce a variety of exotoxins, including the panton-valentine leukocidin (pvl), which may contribute to lung necrosis. multidrug resistance has been reported with ca-mrsa strains but, in general, these organisms are more drug sensitive than their hospital-acquired counterparts. other less common causes of cap include mycobacterium tuberculosis, coxiella burnetii (q fever), burkholderia pseudomallei (melioidosis), chlamydophila psittaci (psittacosis), endemic fungi (histoplasmosis, coccidioidomycosis, blastomycosis), pasteurella multocida, bacillus anthracis, actinomyces israeli, francisella tularensis (tularemia), and nocardia spp. these organisms should be included in the differential diagnosis when evaluating a patient with cap, depending on the presence of specific risk factors that are noted in the clinical history. patients with cap usually present with an acute illness of to days duration. in those with intact immune response, systemic and respiratory symptoms such as cough, dyspnea, fever, and pleuritic chest pain predominate. fever and chills have a sensitivity of % to %, and dyspnea a sensitivity of % for the diagnosis of cap, whereas purulent sputum has a sensitivity of only %. hemoptysis suggests necrotizing infection, such as lung abscess, tuberculosis, or gram-negative pneumonia, but is also a common finding, even in patients with bronchitis. in patients with disease and age-associated impairments in the immune response, the clinical presentation may be subtle, and involve primarily nonrespiratory findings. in the elderly, chest pain and cough may be absent in the early course of the disease, and fever and confusion may be the only symptoms. other complaints such as lethargy, falling, poor oral intake, and decompensation of a chronic illness could also occur in patients with comorbid conditions and among the elderly. a good history and physical examination are essential for determining the possible causal agent and assessing the severity of illness, which in turn helps with management. risk factors for hcap, such as hospitalization or antibiotic therapy in the past days, residence in a long-term care facility, chronic dialysis, outpatient wound care, or home infusion therapy, needs to be identified, because these patients are at risk for drug-resistant gram-negative organisms and s aureus. the history should identify risk factors for drsp and gram-negative organisms, as discussed earlier. it is also important to elicit recent travel history and exposure to birds, bats, farm animals, and rabbits ( table ) . on physical examination, patients may have tachypnea, tachycardia, crackles, bronchial breath sounds, and findings of pleural effusion. clinicians should pay attention to other clues, such as relative bradycardia in relation to fever, which can be seen in infections caused by agents like legionella, chlamydophila, and mycoplasma. mycoplasma can also cause cervical lymphadenopathy, arthralgia, and bullous myringitis. poor outcomes are noted in patients with a respiratory rate greater than breaths/min, diastolic blood pressure less than mm hg, systolic blood pressure less than mm hg, heart rate greater than beats/min, and temperature less than c or greater than c. these clinical findings can be used to determine the risk of death, by incorporating them into prognostic scoring, using the pneumonia severity index (psi), the curb- criteria (a modification of the british thoracic society scoring system), or other tools (discussed later). other than raising clinical suspicion, no combination of symptoms and signs can accurately diagnose pneumonia in the clinical setting, and the definitive diagnosis requires a chest radiograph. the clinical diagnosis has an overall sensitivity ranging from % to % and specificity between % and %. therefore, whenever there is suspicion of cap, a chest radiograph should be obtained for corroboration of the physical findings. certain chest radiographic findings can also suggest more severe illness, including the presence of multilobar infiltrates, rapid progression of infiltrates, pleural effusion, and findings of necrotizing pneumonia. in the outpatient setting, extensive diagnostic testing is not routinely performed, because results are nonspecific, and antibiotic treatment should be initiated nair & niederman empirically. even for inpatients, the value of diagnostic testing is limited and, when outcomes were compared using pathogen-directed therapy, compared with empiric therapy, there was limited benefit of testing. in one prospective study of patients from the netherlands, a pathogen was identified in % of cases. adequate sputum samples were obtained from only patients, gram stain was diagnostic and confirmed by a positive sputum in %, urine pneumococcal antigen was positive in % of cases, blood cultures were positive in %, and bronchoscopic samples added benefit to diagnostic yield when sputum could not be expectorated. in most studies, a specific causal diagnosis is obtained in less than % of patients with cap, even with extensive diagnostic testing, and the major focus of laboratory testing should be to assess severity of illness and allow early identification of the presence of pneumonic complications. white blood cell count may be normal on admission, and leukopenia is seen in patients with overwhelming pneumococcal pneumonia with sepsis and pneumonia caused by gram-negative organisms. thrombocytosis and thrombocytopenia are associated with worse -day mortality in patients admitted with cap. hyponatremia (< meq/l) is also associated with a poor outcome, if present on admission, in patients with cap. the idsa/ats guidelines recommended testing for patients with pneumonia ( table ) . radiographic evidence of lung infiltration provides a sensitive, but not specific, confirmation of community-acquired pneumonia. chest radiograph may show areas of consolidation, pleural effusion, lung abscess, necrotizing pneumonia, or multilobar illness. it may help in pattern recognition of the disease process: h influenzae has a peribronchial distribution of bronchopneumonia; s pneumoniae infection can have either lobar consolidation or bronchopneumonia; atypical pathogens may have an alveolar and interstitial pattern; aspiration most commonly involves the superior segment of the right lower lobe or the posterior segment of the right upper lobe; hematogenous dissemination follows the distribution of blood flow and may lead to bilateral nodular infiltrates. cavitation or necrotizing pneumonia suggests infection with anaerobes, gram-negative bacteria, or s aureus, including mrsa. loculated effusion can be ruled out by decubitus film or computed tomography (ct). chest ultrasound is increasingly being used to assess the size, and to identify a safe site for sampling of pleural fluid. the usefulness of chest radiography is suboptimal in patients with very early infection, dehydration, severe granulocytopenia, structural changes such as with bullous emphysema, and in obese patients. it is reasonable to repeat a follow-up radiograph in to hours in patients who have had a negative initial finding, but have clinical signs of pneumonia. there may be interobserver variability in chest radiographic interpretation of pneumonia. in a study that compared the readings of at least radiologists, positive agreement ( %) was less frequent than negative agreement ( %). ct has better sensitivity in diagnosing an infiltrate than chest radiography, but it is not routinely used, because there is a lack of evidence that use of ct scan improves outcomes. sputum should be sent for gram stain and culture before starting therapy, but primarily in patients suspected of infection with drug-resistant or unusual pathogens. a good specimen contains no more than squamous epithelial cells and more than polymorphonuclear cells per low per field. the gram stain pattern on sputum can help with tailoring of antibiotics, particularly if it shows a pathogen that would not be treated routinely (such as clumps of gram-positive cocci, suggesting s aureus). the sensitivity of identifying s pneumonia is only % to % and specificity is greater than %. it is less likely to have s aureus or gram-negative pneumonia in the absence of these organisms on gram stain of a good sputum sample, but this test is more valuable if positive than if negative. routine culture of expectorated sputum is not useful in the absence of an informative gram stain. the usefulness of realtime polymerase chain reaction testing of sputum samples has not been shown. culture can be obtained from intubated patients by collecting an endotracheal aspirate. a positive blood or pleural culture is seen in less than % of patients with pneumonia but, if present, helps with establishing the diagnosis. most positive cultures are of s pneumoniae. the idsa/ats guidelines recommend blood culture testing in patients admitted to icu, and in those with multiple other risk factors, including active alcohol abuse, liver disease, cavitatory lung disease, asplenia, leukopenia, and pleural effusion. these recommendations are based, in part, on the data from , medicare patients who showed that a true-positive blood culture was associated with no previous antibiotics, underlying liver disease, systolic blood pressure less than mm hg, fever less than c or greater than c, pulse greater than beats/ min, blood urea nitrogen greater than . mmol/l ( mg/dl), serum sodium less than mmol, and leukocyte count less than or greater than , cells/ ml. the diagnostic yield of blood cultures increased in patients with or more risk factor and in those who had not received antibiotics before blood was collected. urinary antigen testing (uat) is commercially available for detection of capsular polysaccharide of s pneumoniae and l pneumophilia serogroup . pneumococcal urinary antigen tests have a sensitivity of % to % and specificity of more than %. the degree of positivity is correlated with the psi for s pneumoniae. false-positive tests occur in patients who have had cap from pneumococcus within the previous months. uat for legionella has a sensitivity of % to % and a specificity of up to % for detection of infection with serogroup , by far the commonest species to infect humans. however, it does not detect other types of legionella, so a negative finding cannot rule out this infection. in one study, the use of uat for legionella had increased with time, leading to more diagnoses of serogroup infection, but a decreased mortality from legionella, suggesting that urinary antigen testing was finding milder illness than had been recognized previously. although one prospective study of episodes of cap from spain found that s pneumoniae was diagnosed by urinary antigen test in . % and helped physicians optimize antibiotic choice, in general, it remains uncertain whether a positive result of any urinary antigen test changes cap management, or whether it is primarily of epidemiologic interest. serologic tests are of questionable importance in the initial setting, but are useful for the epidemiologic diagnosis of agents that are not readily cultured, although results are generally not available for weeks, and require the collection of both acute and convalescent serum samples. the diagnosis of most pathogens is based on acute and convalescent blood serologies showing a fourfold increase in immunoglobulin (ig) g obtained to weeks apart, which applies to c pneumoniae, c psittaci, q fever, and m pneumoniae. ig m antibodies start to increase in the acute phase and are useful in the early course of the disease. cold agglutinins are sometimes present in patients with m pneumoniae. nucleic acid amplification tests provide rapid test results in cap for atypical agents such as viruses, mycoplasma, chlamydophila, and legionella. polymerase chain reaction (pcr) assays were widely used for detecting influenza virus in the recent h n epidemic. direct immunofluorescence or enzyme immunoassay are available for detection of viral antigens like influenza, rsv, adenovirus and parainfluenza viruses. the usefulness of pcr assays in managing cap has not been proven, and the concern with this method is that it is so sensitive that, if a respiratory sample is positive, it cannot distinguish colonization from infection unless the presence of a specific pathogen is itself diagnostic of infection (such as m tuberculosis). however, the test may be valuable if negative, because the absence of a suspected pathogen by pcr may permit a more focused antibiotic therapy approach. several newer biomarkers have been developed (midregional proadrenomedullin, midregional proatrial natriuretic peptide, proarginin-vasopressin, proendothelin- , procalcitonin [pct], c-reactive protein [crp]) to identify patients with bacterial infection and to define the prognosis of cap. in one recent study, cardiac biomarkers, such as midregional proadrenomedullin, were better predictors of -day and -day mortality than inflammatory biomarkers such as pct. in that study, biomarkers correlated with disease severity and mortality, but did not help with causal diagnosis. in another prospective study evaluating the relationship between biomarkers and icu admission, inflammatory biomarkers helped identify patients needing intensive care monitoring, including those requiring delayed icu admission. the inflammatory biomarkers that have been studied most extensively are crp and pct, both of which are acute-phase reactants primarily produced by the liver in the presence of bacterial infection, but not viral illness. crp may identify which patients with acute respiratory symptoms have infectious pneumonia; levels are higher in patients who require hospitalization and in those with pneumococcal and legionella infection. pct is a hormokine, produced in response to microbial toxins and certain host responses associated with bacterial infection, but inhibited by viral-related cytokines. serum levels tend to be high in patients with cap, who benefit from antibiotic therapy, and in those with an increased risk of death from cap. serial measurements of serum levels have also been used to define when antibiotics can be safely stopped in the presence of cap. , , in one study of patients with radiographic infiltrates and suspected cap, initiation of antibiotics and duration of therapy were determined by randomizing patients to management by an algorithm dictated by serial pct measurements versus management by clinical assessment. the pct-guided group had significantly fewer antibiotic prescriptions on admission and less antibiotic usage, and the duration of therapy was reduced from to days with similar clinical success. one of the most important decisions in the management of pneumonia is to assess the severity of the disease, which can be used to predict mortality risk and may be nair & niederman a surrogate measure to define the site of care (outpatient, hospital ward, or icu). proper site-of-care decisions can have an impact on mortality, with several studies showing that delayed admission to the icu leads to a poor outcome. , the most widely used prognostic scoring systems are the psi and the curb- score. in clinical practice, the psi is not widely used because it is complex and difficult to calculate a score. in addition to these general scoring tools, some evaluations are designed to identify the need for icu admission, including the idsa/ats criteria for severe cap, and an australian method called the smart-cop, which is designed to predict the need for intensive respiratory or vasopressor support. other prediction rules are available and their clinical application varies widely. the psi was developed to identify patients with a low risk of dying who could be safely discharged home and receive outpatient treatment. the psi stratifies patients into categories based on -day mortality, by using a scoring system based on factors. it includes demographic characteristics, coexisting illnesses, physical examination findings, laboratory measurements, and radiographic finding. patients in classes iv ( -day mortality risk of %- %) and v ( % risk of death at days) are usually admitted to the hospital and often to the icu. those in low-risk classes i and ii are often treated as outpatients, whereas it is a clinical judgment whether those in class iii should be hospitalized. the psi score includes age as an important determinant of point scoring and hence can overestimate the severity of illness in the elderly and in those with comorbidity. in one study of patients in psi class v, only approximately % needed icu admission, and these tended to be individuals who scored points based on acute illness features, and not on age and comorbid illness factors. in contrast, the psi may underestimate severity of illness in young patients without comorbid illness, especially if their vital sign abnormalities are slightly less than the cutoffs used in the scoring system. this was a particular problem during recent influenza epidemics that have involved primarily younger populations, in which psi scoring was not valuable for defining the need for icu admission. the curb- score from the british thoracic society is an easy scoring system to use, with the score ( - ) being defined ( point each) by the presence of confusion, blood urea nitrogen greater than . mol/l ( . mg/dl), respiratory rate of breaths/min or greater, systolic blood pressure less than mm hg or diastolic blood pressure no greater than mm hg, and age years or older. patients with of these criteria have a high enough risk of death that they should probably be admitted to the hospital, while those with or more points should be considered for icu admission. modifications of this tool, without the laboratory measurement of blood urea nitrogen (crb- ) have also been found to be similarly accurate. the limitation of this approach is its focus on assessment of only clinical parameters, such as vital signs, but without measurement of oxygenation or serial measurement of severity of illness after the initial hospital admission, and that it does not evaluate the presence of comorbid illness and its decompensation from baseline. serum biomarkers can be used to supplement data obtained by prognostic scoring. data from the german competence network for the study of community acquired pneumonia (capnetz) study group, showed that all new biomarkers were good predictors of short-term and long-term all-cause mortality and correlated with crb- score. in other studies, low levels of pct were able to define patients at low risk of death regardless of findings using severity scoring. huang and colleagues as well as kruger and colleagues found, that even in patients identified as high risk using curb- or psi, a low pct value predicted a low chance of dying. , severe cap scoring systems can also be used to help define which patients need icu care, identifying those with severe illness. the idsa/ats guidelines and the piro (predisposition, insult, response, and organ dysfunction) scoring system were developed to help define mortality risk in patients with severe pneumonia. according to the idsa/ats guidelines, severe cap is present if a patient needs invasive mechanical ventilation or requires vasopressors or has any of from the minor criteria listed later. liapakou and colleagues found that patients meeting the major criteria needed icu admission, but those patients who had only minor criteria present had no increased mortality risk, regardless of how many criteria were met. more recently, brown and colleagues found that both the positive and negative predictive value of minor criteria exceeded % if criteria were used to define the need for icu admission rather than just criteria. the piro score is calculated within hours of icu admission, with point given for each variable: comorbidities (copd, immunocompromise), age greater than years, multilobar opacities on chest radiograph, shock, severe hypoxemia, acute renal failure, bacteremia, and acute respiratory distress syndrome. the maximum score that can be achieved is . patients are stratified into levels of risk: (a) low, to points; (b) mild, points; (c) high, points; and (d) very high, to points. the piro score performed well as a -day mortality prediction tool in patients with cap requiring icu admission, with a better performance than apache ii and idsa/ ats criteria. the smart-cop tool was developed to identify the need for intensive respiratory or vasopressor support (irvs), rather than a specific site-of-care decision. this tool uses a complex scoring system with the following values: low systolic blood pressure (< mm hg) ( points), multilobar pneumonia ( point), low albumin level (< . g/dl) ( point), high respiratory rate ( - breaths/min) ( point), tachycardia (> beats/min) ( point), confusion ( point), poor oxygenation ( points), and low arterial ph (< . ) ( points). when this method was used, the finding of a patient with a score of more than points identified % of those needing irvs, with a specificity of . %, whereas the psi and curb- did not perform as well for this an algorithm for decision on site of care based on scoring system and treatment strategy is provided later (fig. ) . early diagnosis and timely administration of antibiotics are associated with improved outcomes in patients with cap. , although administration of therapy within to hours of arrival at the hospital can reduce mortality, it is important to only use antibiotics when the diagnosis is certain, because indiscriminate use of antibiotics in the absence of radiographic pneumonia has limited benefit and a real risk of community-acquired pneumonia antibiotic-associated adverse events, including drug-induced infectious diarrhea. according to idsa/ats guidelines, the first dose of antibiotic should be given in the emergency department, preferably within to hours of arrival, but no time period is specified. because no diagnostic testing can rapidly identify the causal pathogens in a patient with cap, initial therapy is empiric, based on an epidemiologic assessment of patient risk factors for specific pathogens. this assessment requires a careful history of patient comorbidity, recent antibiotic therapy history (within the past months), and identification of pathogen-specific risk factors (see table ; box ). the idsa/ats guidelines recommend outpatient treatment with a macrolide or doxycycline for previously healthy adult patients with no risk factors for drsp. in patients with risk factors for drsp, a respiratory fluoroquinolone or a b-lactam antibiotic plus a macrolide or doxycycline is recommended. in choosing between these options, it is important to take a history about antibiotic usage in the past months and to use an agent that is different from what has recently been used, because recent therapy may predispose to pneumococcal resistance to the agent used, rendering that therapy less effective. for patients admitted to the hospital, but not to the icu, an intravenous respiratory fluoroquinolone or a b-lactam plus a macrolide should be used. as mentioned earlier, the choice should be influenced by a history of which antibiotics have been used in the past months, using agents from a different class, if possible. doxycycline is an in patients allergic to penicillin -respiratory fluoroquinolone plus aztreonam. if community-acquired mrsa is suspected vancomycin (and possibly clindamycin) or linezolid alone added to above regimen. if pseudomonas is suspected a b-lactam with activity against p aeruginosa (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin, or a b-lactam with activity against pseudomonas plus an aminoglycoside and azithromycin or a nonpseudomonal respiratory fluoroquinolone (moxifloxacin) alternative to a macrolide. ertapenem is an alternative to b-lactam agents such as cefotaxime, ceftriaxone, or ampicillin-sulbactam, and should be considered for patients with risk factors for infection with gram-negative pathogens other than p aeruginosa. all patients with cap should have routine therapy directed at pneumococcus and atypical pathogens, plus other organisms, as dictated by specific risk factors. the routine coverage for atypical pathogens is based on outcome studies that show that the addition of a macrolide to a b-lactam, or the use of a quinolone alone, leads to better outcome than b-lactam monotherapy. in addition, some studies have shown a high frequency of atypical pathogen coinfection in patients with bacterial cap. current cap guidelines do not recommend monotherapy with any agent, including a quinolone, for patients with severe cap who are admitted to the icu. in patients with bacteremia (pneumococcal and other), atypical pathogen coverage with a macrolide (monotherapy or combination) improves mortality compared with treatment regimens with a quinolone, particularly quinolone monotherapy. , combination therapy with a b-lactam and a macrolide has a survival advantage compared with quinolones alone in patients in the icu, and in the prospective study that compared quinolone monotherapy with a b-lactam/quinolone combination therapy the monotherapy arm was not as effective. in addition, in patients with pneumococcal bacteremia, especially in those with severe illness, the use of dual therapy (usually by adding a macrolide to a b-lactam) is associated with better outcome than with monotherapy, implying benefit from atypical pathogen coverage or from the antiinflammatory effect of the macrolide. in a prospective study by rodriguez and colleagues on patients with cap and shock requiring vasopressors, combination therapy with either a b-lactam and a macrolide or a b-lactam and a quinolone had a -day survival advantage compared with monotherapy with a b-lactam or a quinolone alone. based on these data, in patients in the icu, an intravenous b-lactam plus either a macrolide or respiratory fluoroquinolone is recommended for patients without pseudomonal risk factors. in patients with risk factors for pseudomonal infection, an antipseudomonal b-lactam should be combined with either levofloxacin or ciprofloxacin, or the antipseudomonal b-lactam can be combined with both an aminoglycoside and either azithromycin or a respiratory quinolone. in patients allergic to penicillin, a respiratory fluoroquinolone should be used with aztreonam as an alternative regimen. when ca-mrsa is suspected, vancomycin or linezolid should be added to the other recommended agents. however, it may be necessary to add an anti-toxin producing agent, because part of the illness caused by ca-mrsa is mediated by bacterial exotoxin production. to stop toxin production, it may be necessary to add clindamycin to vancomycin, or to use linezolid alone. outpatients with mild-to-moderate cap are treated for days or fewer with oral antibiotics, and therapy is stopped if they are afebrile and clinical features of pneumonia are resolving (cough, dyspnea, and sputum production). for inpatients, antibiotics are switched from intravenous to oral once the patient is afebrile for at least occasions hours apart, is able to take food by mouth, and there are clinical signs of improvement (in parameters such as cough, dyspnea, sputum production, oxygenation, and vital sign abnormalities), and this usually happens by the second or third hospital day. the switch to oral antibiotics can also be done for bacteremic patients, although it may take longer for these patients to reach clinical stability compared with nonbacteremic patients. use of pct as a guide to decide on the duration of antibiotic use is supported by clinical trial data. the duration of therapy should be a minimum of days, providing that the patient is afebrile for to hours, there is no sign of community-acquired pneumonia extrapulmonary infection, the correct therapy was used initially, and the organism identified is not s aureus or p aeruginosa. with appropriate antibiotic treatment, most cases of cap resolve without complications. however, the treating physician should be alert to potential complications that, if not detected early, can lead to adverse outcomes. if the patient is responding well to therapy, no immediate follow-up radiograph is needed, and imaging is only done to weeks after discharge to define a new radiographic baseline. in most patients, the chest radiograph usually clears within weeks, especially in patients younger than years without underlying pulmonary disease or bacteremia. however, resolution may be delayed for weeks or longer in older individuals and those with underlying lung disease and bacteremia. in about % of patients, there is a lack of response or clinical deterioration despite antibiotic therapy. the idsa/ats guidelines define early failure as progressive pneumonia or clinical deterioration, occurring in the first hours of therapy, usually with respiratory failure or septic shock, and is a consequence of inappropriate antibiotic therapy or an incorrect initial diagnosis. later failure or nonresponse is often caused by a nosocomial infection, a disease-related or therapy complication, or a noninfectious process (eg, pulmonary embolism, inflammatory lung disease). if the patient has persistent fever, worsening dyspnea, unresolving pneumonia symptoms, and continued debility, a repeat radiograph should be done focusing on a broad differential diagnosis, including therapy for an unusual or drug-resistant pathogen (tuberculosis, endemic fungus, or a zoonosis), a pneumonic complication (empyema), an antibiotic complication (drug-induced colitis) or a nonpneumonic diagnosis (inflammatory lung disease, malignancy). diagnostic testing can include a chest ct scan, bronchoscopy, and, in some cases, open lung biopsy. organizing pneumonia is a complication of viral lung infection and other processes, and is characterized by fibroblast proliferation and diagnosed by a combination of radiographic findings, bronchoscopic lung biopsy, and the absence of ongoing infection. it is often managed with a therapeutic trial of steroids. the definitive investigation is an open lung biopsy. parapneumonic effusion and empyema are complications that can lead to apparent treatment failure. the chest radiograph shows an effusion, which should be sampled, and, if a low pleural fluid ph is present (< . if previously healthy, but < . if chronically ill) or if organisms are present, chest tube drainage and prolonged antibiotic therapy is required. a connection between the pleural space and the lung can develop and result in a bronchopleural fistula, which can be caused by erosion of the lung infection to the pleural surface. bronchopleural fistula is initially treated conservatively with antibiotics and a chest tube, but sometimes requires surgical repair. localized bronchiectasis can be a long-term sequela of cap, as a result of injury and dilation of the bronchus, and can be seen on ct scan of the chest. patients present with chronic productive sputum and recurrent infection on the same area. treatment is with postural drainage, antibiotics for exacerbation, and bronchodilators for coexisting airflow obstruction. recurrent pneumonia can occur after clinical and radiographic resolution of pneumonia. if it is present, whether it is in the same or a different area as the original infection should be determined. if it is in the same area, an anatomic problem (obstruction by tumor or foreign body) needs to be considered, whereas, if it is at another site, it may be the consequence of general immune impairment. the risk of this problem is higher in the elderly, those with a history of alcoholism, and in smokers. an underlying systemic immune deficiency should be ruled out by measuring quantitative ig levels. a detailed discussion of prevention is beyond the scope of this article. in the idsa/ats guidelines, the mainstay of prevention is pneumococcal and influenza vaccination for at-risk individuals, and provision of smoking cessation information to those smoking cigarettes at the time of pneumonia onset. influenza vaccine is recommended during the appropriate season, for all persons aged years or older, and for those with specific risk factors, including pregnant women and those with chronic heart, lung, metabolic, hematologic, or immune-compromising illnesses. pneumococcal polysaccharide vaccine should be given to all patients aged years or older, and to younger patients with chronic heart or lung disease, asplenia, diabetes mellitus, and to residents of long-term care facilities. one revaccination after years should be given to those with either a poor immune response or after age years for those first immunized before the age of years. in guidelines, and also in performance measures for hospitalized patients, vaccination should be given before discharge for all patients admitted with cap. infectious diseases society of america/american thoracic society consensus guidelines on the management of 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validation of the infectious diseases society of america/american thoracic society guidelines to predict an intensive care unit admission validation of the infectious disease society of america/american thoracic society guidelines for severe community-acquired pneumonia piro score for community-acquired pneumonia: a new prediction rule for assessment of severity in intensive care unit patients with community-acquired pneumonia smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia timing of antibiotic administration and outcomes for medicare patients hospitalized with community-acquired pneumonia quality of care, process, and outcomes in elderly patients with pneumonia antibiotics for bacteremic pneumonia: improved outcomes with macrolides but not fluoroquinolones combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia comparison of levofloxacin and cefotaxime combined with ofloxacin for icu patients with community-acquired pneumonia who do not require vasopressors combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock early switch from intravenous to oral antibiotics in hospitalized patients with bacteremic community-acquired streptococcus pneumoniae pneumonia key: cord- -mticfoic authors: guan, xuhua; silk, benjamin j.; li, wenkai; fleischauer, aaron t.; xing, xuesen; jiang, xiaoqing; yu, hongjie; olsen, sonja j.; cohen, adam l. title: pneumonia incidence and mortality in mainland china: systematic review of chinese and english literature, – date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: mticfoic background: pneumonia is a leading infectious disease killer worldwide, yet the burden in china is not well understood as much of the data is published in the non-english literature. methodology/principal findings: we systematically reviewed the chinese- and english-language literature for studies with primary data on pneumonia incidence and mortality in mainland china. between and , studies met the inclusion criteria. the quality of the studies was highly variable. for children < years, incidence ranged from . – . episodes per person-year and mortality ranged from – , deaths per , population. overall incidence and mortality were stable or decreased over the study period and were higher in rural compared to urban areas. conclusions/significance: pneumonia continues to be a major public health challenge in young children in china, and estimates of pneumonia incidence and mortality vary widely. reliable surveillance data and new prevention efforts may be needed to achieve and document additional declines, especially in areas with higher incidence and mortality such as rural settings. despite the availability of safe and effective antibiotics and vaccines for treatment and prevention, pneumonia is a leading cause of death worldwide and the leading infectious disease killer [ , ] . pneumonia is the single leading cause of death globally among children under years of age accounting for approximately million deaths annually [ , ] . children in developing countries have an estimated . episodes of pneumonia per person-year, compared with . episodes per person-year in developed countries [ ] . pneumonia is one of the leading causes of death in adults and children in china [ ] . in urban areas, pneumonia is the fourth leading cause of death, and in rural areas pneumonia is the leading cause of death [ , ] . a recent article in the chinese literature estimated that each year in china there are . million patients with pneumonia and that , ( %) of these patients die of pneumonia-related illness [ ] . a global review by rudan and colleagues estimated that there were . million new cases of clinical pneumonia annually in china in children under years of age ( . episodes/person-year), which is second only to india in burden ( . million new cases, . episodes/person-year) [ ] . available estimates of the burden of childhood pneumonia in china vary widely, and pneumonia accounts for an estimated % of all child deaths in china and % of all childhood pneumonia deaths in the western pacific region [ , , ] . although the global community recognizes that pneumonia is an important public health issue in china, the disease burden is not well studied nor necessarily reported in the english language and these data have not been systematically reviewed for english-or chinese-language readers [ ] . complicating an assessment of the pneumonia incidence and mortality in china is the lack of ongoing and systematic surveillance. with the exception of human avian influenza and severe acute respiratory syndrome (sars), pneumonia and other respiratory diseases are not included in the nationally notifiable infectious diseases in china [ ] . however, in the wake of the sars outbreak, enhanced surveillance using pneumonia of unknown etiology for early detection of suspected sars was initiated in (case definition given in table s ). we conducted a systematic review of the chinese-and englishlanguage literature in order to describe pneumonia incidence and mortality in china, evaluate the quality of published studies, and identify gaps in the literature that can be addressed through surveillance and epidemiologic research projects in the future. no ethical review was required since all results are from the published literature. using pubmed, we searched the national library of medicine database for manuscripts published before october , . the reference terms``pneumonia,''``acute respiratory infection,'' and`l ower respiratory tract infection'' were each combined with`c hina'' and``mainland china.'' using equivalent terms, we performed additional searches for publications in the chinese medical literature using the wanfang (http://www.wanfangdata. com/) and chongqingvip (www.cqvip.com) databases [ , ] . in these databases, publications were available since and , respectively. the english search terms were translated into chinese (by author x.g.) for use in the chinese-language searches [º, %'| sÓ, | sÓ (p-ý-ý' f)]. in addition, journal articles cited in the identified manuscripts were collected and added to the review. clinical and community-based studies with primary data collection in humans were identified through a literature search conducted in november ( figure ). studies conducted exclusively in hong kong special administrative region (sar), macao sar or taiwan, china, were excluded. we also excluded studies focusing exclusively on sars and avian influenza, outbreak reports, diagnostic studies of pneumonia etiologies, and studies that did not include population-based estimates of incidence or mortality. two coauthors who read chinese as a first language (x.g., w. l.) abstracted from these references the year of publication; province, prefecture, and city; study population (e.g., age group); study design; site of case detection (i.e., inpatient, outpatient, or both); pneumonia case definition; and estimates of pneumoniarelated incidence and mortality. english data abstraction was each checked by a native english and mandarin speaker. data abstractions were validated during direct discussions with english-speaking epidemiologists (b.j.s., a.t.f., s.j.o., a.l.c.). incidence is reported as the annual number of pneumonia episodes per year (i.e., person-years). for manuscripts presenting incidence per , population, data were converted to personyears to be comparable. for example, if there were cases in a year in a population of , , the incidence would be converted from , per , per year to . person-years. when incidence was reported on an annual basis during a multi-year study period within a single study, a simple mean was calculated to report overall incidence during the study period. for mortality measures, when possible, we calculated case fatality rate (i.e., the percentage of pneumonia cases that died), mortality per , population, and mortality per , live births annually. we evaluated trends in incidence and mortality and made comparisons across studies by using studies with similar study methods and case definitions when possible. there were three pneumonia case definitions used in the studies: i. the world health organization (who) case definition of pneumonia for integrated management of childhood illness [ ] , ii. chinese medical association guidelines (iia: communityacquired pneumonia (cap) [ ] or iib: hospital-acquired pneumonia (hap) [ ] ), and iii. physician assessment (iiia: acute lower respiratory infection; iiib: newborn pneumonia; or iiic: pneumonia as a cause of death in children under years of age). the specific signs and symptoms for each case definition are detailed in table s . for each study that we identified through the systematic review, we critically reviewed the quality of each manuscript. based on published recommendations for measuring quality of epidemiologic studies of pneumonia [ ] , we assessed quality using the following six criteria: ( ) geographic location was reported, ( ) study was conducted for a period of at least one year or multiples of one year to account for seasonal factors, ( ) site of case detection or surveillance location was reported, ( ) age and population size of cohort of at least cases were reported, ( ) quality assurance and monitoring methods were employed to assure that data was complete and high quality, and ( ) a clearly defined case definition (e.g., not based solely on clinical diagnosis) was used and reported. these six criteria were selected to represent basic and essential indicators of epidemiologic study quality. each criteria was dichotomous ( = reported and = not reported); the sum of all reported criteria yielded the manuscript's overall quality criteria score ( to ; tables s and s ). at least one coauthor who read chinese as a first language (x.g., w.l.) reviewed each of the studies to evaluate these six criteria; evaluations were then validated during direct discussions with an english-speaking epidemiologists (b.j.s., a.t.f., s.j.o., a.l.c.). we included all studies in this review to report the differences in study quality. thirty-seven published studies met the inclusion criteria ( figure ); publications included data on pneumonia incidence and publications reported pneumonia mortality estimates. at least three studies were conducted in beijing, guangxi ar, hubei, jiangsu, shanghai, shanxi, and sichuan each ( figure ). five ( %) of the incidence articles and ( %) of the mortality articles were identified using pubmed [ , , , , , , , ] . the studies were each evaluated on six quality indicator criteria (tables s and s ) . first, all studies reported the geographic location of the study, but few, if any, reported more specific information on setting such as altitude and annual rainfall, prevalence of malnutrition and aids, or immunization coverage against pneumonia vaccines and access to health care [ ] . second, all but studies ( [ %] of ) reported at least one year of data. third, all studies reported the site of case detection and the age of the cases. fourth, the population size was not given for ( %) of the mortality studies; when population was reported, at least cases were reported. fifth, four ( %) of studies of incidence and ( %) of studies of mortality reported quality assurance and monitoring. the sixth quality criteria evaluated the case definition used. of the studies that reported incidence, ( %) used the who case definition for pneumonia and ( %) used the chinese medical association guidelines case definition; ( %) used physician diagnosis, which was considered less reliable than the other case definitions. the incidence estimates using the who case definition were generally higher than those using a physician diagnosis, so we report incidence estimates separately by case definition; there was no clear trend in mortality estimates based on case definition, so we did not separate these estimates by case definition. five ( %) of incidence studies and only ( %) mortality study included chest x-ray in their case definition. most of the mortality data relied on physician diagnosis ( [ %] of studies). one quarter ( of ) of the mortality studies were reports of deaths for children under years of age collected through the national death surveillance program. in summary, all of the studies met at least four of the six quality criteria. only ( %) of the mortality studies and none of the incidence studies met all six quality criteria. age. based on studies, the age-specific incidence of pneumonia in children , year of age ranged from . ± . episodes per person-year using either clinical or who case definitions [ , , , , , ] . based on studies of children , years, the incidence ranged from . ± . episodes per personyear using clinical case definition and from . ± . using the who case definition (table s ) [ , , , , , , , , ] . incidence was lower in older children [ , ] , and one study presented a pneumonia incidence for adults: . episodes per person-year for people $ years of age [ ] . time trends. a study conducted in two provinces in the west found that pneumonia incidence in children , years of age decreased from to by % in yunnan province ( . in versus . episodes per person-year in ) and by % in qinghai province ( . in versus . in ) [ ] . rural vs. urban areas. seven incidence studies were performed in urban areas ( %), five in rural areas ( %), and two ( %) in both urban and rural areas. pneumonia incidence rates were generally higher in rural areas compared with urban areas (table s ) . for example, a study in guangdong that compared pneumonia rates in both rural and urban settings found that rates in rural areas were more than four times higher than urban rates in children , year of age ( . vs. . episodes per person-year, respectively) and more than six times higher in children , years of age ( . vs. . episodes per person-year, respectively) [ ] . regions. most ( . %) studies on pneumonia incidence were conducted in northeast and southeast china. the incidence of pneumonia in children , years of age in northeastern china (range: . ± . episodes per person-year) [ , , , ] , was lower than southern china (range: . ± . episodes per personyear), which includes the southeast, south central, and southwest regions (table s ) [ , , ] . there were no studies exclusively in the north central or northwest regions. one multi-site study showed that pneumonia incidence among children , years of age was higher in southern than in northern provinces ( . versus . episodes per person-year in southern yunnan and northern qinghai, respectively) [ ] . a multi-site study in reported that pneumonia incidence in children , years of age in eastern china (range . ± . episodes per person-year) was higher than in western and central china (range . ± . episodes per person-year) [ ] . age. twelve ( %) of studies that evaluated pneumoniarelated mortality presented estimates for children , year of age; ( %) presented estimates for children aged , years; most ( studies, %) presented mortality as deaths per , live births per year (table s ) . mortality rates ranged from to deaths from pneumonia per , population for children , year of age [ , , ] , and from to deaths from pneumonia per , population for children , years of age [ , , , , ] . when mortality was measured per , live births, the estimates ranged from . to . deaths for children , year of age [ , , , , , , , , ] and from . to for children , years of age [ , , , , , , , , , , , , , , , , , , ] (table s ). case fatality rates were higher in children , year of age ( . ± . %) than in children , years of age ( . ± . %). one study in adults, which included older adults up to age years, found a case fatality rate of . % [ ] . time trends. nine ( %) of studies that examined multiple years of data reported decreasing mortality trends during their study periods [ , , , , , , , , ] . for example, a seven-year study in shandong province found that the case fatality rate for pneumonia decreased from . % to . % from to , mortality decreased from to deaths from pneumonia per , population, and mortality per live births decreased from . to . [ ] . however, another nine studies did not show a clear declining trend [ , , , , , , , , ] . for example, a separate study in shandong province found that while the mortality rate was lowest in the most recent year of the -year study ( . deaths per live births in children , years in ), there was no clear decrease in mortality over the previous decade [ ] . no studies showed increasing mortality. rural vs. urban areas. nineteen ( %) of mortality studies were conducted in both urban and rural areas, while ( %) were conducted in rural areas and ( %) were conducted in urban areas only. as with incidence, pneumonia mortality in rural areas was generally higher than in urban areas. in one study conducted in zhejiang from to , mortality for infants , year old ranged from . to . cases per , live births in rural areas compared with . to . cases per , live births in urban areas; for children , years, pneumonia mortality ranged from . to . in rural areas compared with . to . in urban areas [ ] . a study in jiangsu province found . and . deaths per live births in rural and urban areas, respectively [ ] . regions. studies on pneumonia mortality were more geographically representative than studies of pneumonia incidence, and there was at least one study of mortality from each of the six regions (table s ). estimates of mortality from pneumonia in infants , year old were consistent in four of the six studies conducted in southern china ( . ± . deaths from pneumonia per , live births) [ , , , ] ; only one study in northern china reported mortality rates from pneumonia in infants ( . deaths from pneumonia per , live births) [ ] . in children aged , years, the highest mortality rates were reported by four studies that were each conducted in multiple regions throughout mainland china ( . ± . deaths from pneumonia per , live births; table s ) [ , , , ] . relatively high mortality rates in this age group were also reported in the northwest [ , , ] and the southwest [ , ] ( . ± . and . ± . deaths from pneumonia per , live births, respectively). three studies evaluated hospital-acquired pneumonia [ , , ] . in shanghai where the studies were performed, the hospital-acquired pneumonia rate ranged from . % to . % of hospitalized patients. given the population size of china ( . billion persons) [ ] , the varied health utilization and economic development, the diverse climate (tropical to subarctic), and the range of population densities, the burden of pneumonia in china would be expected to be large and highly variable across regions. despite overall trends from these studies suggesting that pneumonia incidence and mortality are stable or decreasing, pneumonia continues to be a major public health concern in china [ ] . the studies in this review found incidence of pneumonia in children , years of age that were as low as what has been estimated for the developed world globally ( . episodes per person-year) and that were as high as what has been estimated for the developing world ( . episodes per person-year) [ ] . the studies included in this review reported pneumonia incidence for children , years of age ( . ± . episodes per person-year from to ) that was similar or less than what has been estimated for china ( . episodes per person-year in ) [ ] . although the studies reported a wide range of pneumonia mortality estimates ( ± , deaths per , population), these are consistent with pneumonia remaining the leading cause of childhood mortality in china [ ] . while the data summarized here provide insights into pneumonia in china, they also serve as a reminder that reliable and high quality national and regional data on pneumonia incidence and etiology are needed to adequately direct prevention and control efforts. perhaps the largest limitation to this study is that study comparisons of morbidity and mortality rates were constrained by the wide variation and quality of the study designs. this is particularly evident in the wide range of mortality estimates among the different studies. in general, the incidence estimates were higher when the more standardized who case definition was used compared with estimates obtained from physician diagnosis; however, there was significant variability even among studies that used similar case definitions. the use of a standard pneumonia case definition that is designed for surveillance and epidemiologic research would improve generalizability and could allow for direct comparisons of incidence and mortality estimates in china and elsewhere [ , ] . most studies spanned multiple years, which would account for differences in seasonality of pneumonia, but a few were conducted for one year or less. although a few of the studies reported large surveillance populations, many calculated incidence based on relatively small populations or did not report the population under surveillance. most of these studies were conducted in large, urban centers primarily serving residents of densely-populated areas; few included adults or populations from rural western china. although many of the studies were conducted prospectively, none calculated incidence using active, population-based surveillance and population denominators were not reliably measured in each study. until standardized case definitions and appropriate surveillance methodology are applied, pneumo-nia incidence and mortality estimates should be interpreted cautiously. in regions for which we identified published data, pneumonia incidence in china appears to be declining and mortality is stable or declining from the s to the s. there are several factors that could have contributed to these changes over time. china experienced substantial economic growth during these years, a trend that was more pronounced in the coastal (eastern) areas. from the beginning of economic reforms in to , china's gross domestic product (gdp) increased , % from . billion rmb to , . billion rmb [ ] . the income of the average chinese person also improved during this time period; gdp per capita rose by , % from rmb to , rmb [ ] . economic development may have led to improvements in healthcare quality and access to health services. in addition to economic development, china is undergoing dramatic healthcare reform, including government-sponsored healthcare in rural areas [ , ] . declines in the incidence of pneumonia are likely attributable to the implementation of pneumonia intervention measures, such as technical training for village doctors, health education to parents, improved pneumonia surveillance and case management, and the use of vaccines against pneumonia in the routine immunization program (namely measles and pertussis). the improved detection and recognition of pneumonias following the sars, avian influenza and influenza h n epidemics could lead to more cases of pneumonia being promptly identified and treated. large scale programs to introduce less polluting cookstoves in china have led to decreases in lung cancer and chronic obstructive pulmonary disease [ , ] ; studies from other countries suggest that reductions in exposure to indoor air pollution from solid fuels used for cooking can also lead to fewer cases of pneumonia [ ] . other strategies, including better access to care, improved hygiene, and better nutrition may need strengthening to effectively reduce the incidence of pneumonia in china [ ] . for many chinese, adequate healthcare remains difficult to access; this review revealed a disparate incidence and mortality of pneumonia across different regions of china [ , ] , some of which is likely due to inequalities in health care. for example, respirators and ventilators for children are not currently available in many county hospitals. eastern china is more developed, whereas western china is more rural. according to a report on national maternal and child health endorsed by the china ministry of health, unicef, and who, pneumonia is the leading cause of death in children under years of age in some rural areas, and comprises a larger proportion of deaths in children under years of age as the area becomes more rural [ ] . this report also demonstrated the decreasing trends in pneumonia mortality across china, especially in areas where few clinical studies have been completed. better access to proven public health interventions, including vaccines, is needed in the public sector in china. vaccines against haemophilus influenzae type b (hib), streptococcus pneumoniae, and influenza are not part of routine childhood vaccination programs in many countries worldwide [ , ] ; none of these vaccines are included in the routine childhood immunization schedule in mainland china. however, hib and influenza vaccines are commonly available in many parts of china through vaccination clinics, and hong kong sar is the first region in china, as well as asia, where pneumococcal conjugate vaccine will be included in their routine childhood immunization program starting september [ ] . in addition, hong kong sar recommends seasonal influenza vaccine use in high risk groups. vaccine clinical trials in other countries have estimated that % of radiologically confirmed pneumonia is caused by hib [ ] and % by pneumococcus [ , ] ; over % of hospitalized pneumonia in children in nearby thailand are due to influenza [ ] . studies within china have suggested that hib and pneumococcus are common causes of pneumonia in children [ , , ] , suggesting that widespread use of these two vaccines, as well as influenza vaccine, could reduce the incidence and mortality of pneumonia in china. this paper has several strengths, particularly the inclusion of papers published in both the english and chinese literature. a recent global review on childhood pneumonia incidence included only two of the articles presented here, suggesting that articles not published in english are usually overlooked and difficult to obtain [ , , ] . we did not search three of the five major chinese-language literature databases (the china national knowledge infrastructure china academic journals full-text database, chinese biomedical literature database, and chinese medical current content), so we may not have captured all relevant manuscripts; however, the two databases that we did search include some of the greatest number of journals and articles of the five major databases [ , , ] . in addition, this review includes information on all ages, although only two studies included adults. while global pneumonia prevention efforts often focus on children, the burden of pneumonia in adults and the elderly is also substantial. importantly, interventions aimed at children may have underappreciated benefits on adults. for example, the introduction of universal childhood pneumococcal vaccination in the united states in resulted in significant declines in pneumococcal incidence in both children and adults. in , the indirect effect of preventing invasive pneumococcal disease in adults was over twice the direct effect of preventing cases in children [ ] . comprehensive data on pneumonia incidence and mortality are essential for monitoring disease trends, guiding policy decisions, and prioritizing disease prevention and control strategies. for china, accurate information on the incidence and mortality of pneumonia, as well as data on cost, will be central for planning the addition of new vaccines to routine childhood immunization programs. also, seasonal and pandemic influenza remain ever present global threats. continued surveillance and consideration of influenza vaccination and other control measures are needed. in collaboration with the u.s. centers for disease control and prevention (cdc), china's cdc is implementing active, population-based surveillance for pneumonia in certain areas using a standard approach and case definitions. the surveillance system will aim to better define pneumonia incidence, identify etiologies, and guide important clinical and public health decisions. increased laboratory capacity needs to be built to ensure continued rigorous surveillance and quick response to emerging threats. together these improved surveillance and laboratory data should help improve detection, prevention and control of pneumonia throughout china. the top causes of death global, regional, and national causes of child mortality in : a systematic analysis epidemiology and etiology of childhood pnemonia major causes of death among men and women in china contentions on the pathogenic spectrum of communityacquired pneumonia and the first experimental application of antibiotic agents people's republic of china national bureau of statistics ( ) china statistical yearbook causes of deaths in children younger than years in china gaps in policy-relevant information on burden of disease in children: a systematic review emergence and control of infectious diseases in china chinese journals: a guide for epidemiologists five large chinese biomedical bibliographic databases: accessibility and coverage world health organization who recommended surveillance standards community-acquired pneumonia diagnosis and treatment guidelines hospitalacquired pneumonia diagnosis and treatment guidelines methodological and quality issues in epidemiological studies of acute lower respiratory infections in children in developing countries acute respiratory infections in beijing children. epidemiological studies at dongguan brigade the incidence of neonatal pneumonia in urban and rural areas of beijing surveillance and control of ari among urban nurseries in beijing inspection on the one-month attack rate of community acquired pneumonia among old persons in analysis the effect of maternity and child health services project on reducing the mortality and morbidity rate in the poorest areas in china. maternal and child health care of china beijing da xue xue bao effectiveness of control programs for pneumonia among children in china and fiji seasonal analysis of the morbidity of pneumonia in children under years of age in guangzhou area epidemiologic surveillance of pneumonia among children in the mch model counties in establishing a surveillance network for children respiratory infection to reduce pneumonia mortality. (úË?å| Ñkq § tºmnº{¡v). maternal and child health care of china countermeasures for death-pneumonia of children under age in hubei province an analysis of the acute infection of respiratory tracts monitored in the children under the trend of changes in the rate of mortality of children with pneumonia in the rural area of guangxi from effect evaluation of child pneumonia case management. (?åºÅ¡aehÄ÷). maternal and child health care of china mortality analysis of children under years of age in weihai over an -year period. (Áw te å?å{¡Åµae) approach to indicators of avoidable causes of death among children under five in jiangsu proivnce the surveillance analysis for years on causes of death for the children aged under years in fujian study on avoidable causes of death among children under years of age in guangdong province. (Á å?åÑ ïm{àv) death causes analysis of the children under years of age in hengyang city from to . (a  , t å ?å{¡àae) death causes analysis of children under years of age. (ù å?å{¡àae) mortality investigation and analysis of children under years of age in mao county from surveillance of pneumonia mortality in children under years of age in china from to . ( , t-ý å?åº {¡ÑkÓ) mortality analysis of children under years of age in dalian city from mortality analysis of children under years of age in taigu county. (*u¿ å?å{¡ae) analysis of the death monitoring of children under years old in xiaodian area taiyuan city from the change tendency of the children's death under age in weinan city from to . maternal and child health care of china mortality analysis of children under years of age in nanzheng county from to . (wÑ¿ , t å?å{¡ae). maternal and child health care of china mortality and death causes analysis of children under years of age in jinghe county from to . (¾³¿ , t å?å {¡Ê{àae). maternal and child health care of china death causes analysis of children under years of age in changxing county from to . (t¿ , t å ?å{¡àae) mortality analysis of children under years of age in yunhe county from changing trend and interventions on mortality of children under years of age in zigong city from analysis of under years old children mortality and the leading death cause in china from pathogens and prognosis of nosocomial lower respiratory tract infection cohort study of hospital acquired lower respiratory tract infections in shanghai cohort study of incidence and related factors of nosocomial lower respiratory tract infection in hospitals in shanghai global estimate of the incidence of clinical pneumonia among children under five years of age standardizing surveillance of pneumococcal disease gdp growth ± . . ( ) health-system reform in china china's barefoot doctor: past, present, and future household stove improvement and risk of lung cancer in xuanwei improvement in household stoves and risk of chronic obstructive pulmonary disease in xuanwei, china: retrospective cohort study indoor air pollution from unprocessed solid fuel use and pneumonia risk in children aged under five years: a systematic review and meta-analysis global action plan for the prevention and control of pneumonia: report of an informal consultation tackling the challenges to health equity in china ministry of health china, unicef, world health organization, unfpa ( ) joint review of maternal and child survival strategies in china progress introducing haemophilus influenzae type b vaccine in low-income countries prevenar vaccination: review of the global data bravo for hong kong as tots get free jabs. the standard burden of disease caused by haemophilus influenzae type b in children younger than years: global estimates burden of disease caused by streptococcus pneumoniae in children younger than years: global estimates incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in thailand the role of haemophilus influenzae type b in fatal community-acquired pneumonia in chinese children streptococcus pneumoniae as a frequent cause of severe community-acquired pneumonia among children in beijing haemophilus influenzae type b and streptococcus pneumoniae as causes of pneumonia among children in beijing harnessing the wealth of chinese scientific literature: schistosomiasis research and control in china direct and indirect effects of routine vaccination of children with -valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease±united states technical bases for the who recommendations on the management of pneumonia in children at first-level health facilities retrospective analysis of pneumonia incidence and mortality among newborn inpatients for years. ( tob°?ºÑÅ Ê{¡Þ~ae). health vocational education key: cord- -gk rwyq authors: weinberger, steven e.; cockrill, barbara a.; mandel, jess title: pneumonia date: - - journal: principles of pulmonary medicine doi: . /b - - - - . -x sha: doc_id: cord_uid: gk rwyq by nearly any criteria, pneumonia (infection of the pulmonary parenchyma) must be considered one of the most important categories of disease affecting the respiratory system. this chapter is organized primarily as a general discussion of the clinical problem of pneumonia. as appropriate, the focus on individual etiologic agents highlights some characteristic features of each that are particularly useful to the physician. also covered is a commonly used categorization of pneumonia based on the clinical setting: community-acquired versus nosocomial (hospital-acquired) pneumonia. in current clinical practice, the approach to evaluation and management of these two types of pneumonia is often quite different. the chapter concludes with a brief discussion of several infections that were uncommon or primarily of historical interest until recently, as the threat of bioterrorism emerged. in addition to reviewing inhalational anthrax, the chapter briefly describes two other organisms considered to be of concern as potential weapons of bioterrorism: yersinia pestis (the cause of plague) and francisella tularensis (the cause of tularemia). by nearly any criteria, pneumonia (infection of the pulmonary parenchyma) must be considered one of the most important categories of disease affecting the respiratory system. of note: • pneumonia is extraordinarily common; it is the most common reason for hospital admission in the united states other than women giving birth. • mortality is higher with an admitting diagnosis of pneumonia for adults years of age in the united states than for any of the other top admitting diagnoses. • in , pneumonia had an aggregate cost of nearly $ . billion for . million hospital stays in the united states. • it is the world's leading cause of death among children under years of age, and it is the most common reason for children to be hospitalized in the united states. • worldwide, pneumonia afflicts an estimated million people per year and results in million deaths. it is no wonder that sir william osler referred to pneumonia as "the captain of the men of death," particularly as he spoke before the era of effective antibiotic therapy. for many types of pneumonia, medical therapy with antibiotics (along with supportive care) has great impact on the duration and outcome of the illness. because of the effectiveness of treatment, the diseases discussed in this chapter are typically gratifying to treat for all involved medical personnel. unfortunately, the emerging trend during the past years has been the acquisition of antibiotic resistance by some of the organisms causing pneumonia, and treatment of pneumonia has had to evolve to keep pace. although many of the specific agents causing pneumonia are considered here, this chapter is organized primarily as a general discussion of the clinical problem of pneumonia. as appropriate, the focus on individual etiologic agents highlights some characteristic features of each that are particularly useful to the physician. also covered is a commonly used categorization of pneumonia based on the clinical setting: community-acquired versus nosocomial (hospital-acquired) pneumonia. in current clinical practice, the approach to evaluation and management of these two types of pneumonia is often quite different. the chapter concludes with a brief discussion of several infections that were uncommon or primarily of historical interest until recently, as the threat of bioterrorism emerged. in addition to reviewing inhalational anthrax, the chapter briefly describes two other organisms considered to be of concern as potential weapons of bioterrorism: yersinia pestis (the cause of plague) and francisella tularensis (the cause of tularemia). the host defenses of the lung are constantly challenged by a variety of organisms, including both viruses and bacteria (see chapter ) . viruses in particular are likely to avoid or overwhelm some of the upper respiratory tract defenses, causing a transient, relatively mild, clinical illness with symptoms limited to the upper respiratory tract. when host defense mechanisms of the upper and lower respiratory tracts are overwhelmed, microorganisms may establish residence, proliferate, and cause a frank infectious process within the pulmonary parenchyma. with particularly virulent organisms, no major impairment of host defense mechanisms is needed; pneumonia may occur even in normal and otherwise healthy individuals. at the other extreme, if host defense mechanisms are quite impaired, microorganisms that are not particularly virulent and are unlikely to cause disease in a healthy host may produce a life-threatening pneumonia. in practice, several factors frequently cause enough impairment of host defenses to contribute to the development of pneumonia, even though individuals with such impairment are not considered "immunosuppressed." viral upper respiratory tract infections, ethanol abuse, cigarette smoking, heart failure, and preexisting chronic obstructive pulmonary disease (copd) are a few of the contributing factors. more severe impairment of host defenses is caused by diseases associated with immunosuppression (e.g., advanced aids), various underlying malignancies (particularly leukemia and lymphoma), and the use of corticosteroids and other immunosuppressive drugs. in these cases associated with impairment of host defenses, individuals are susceptible to both bacterial and more unusual nonbacterial infections (see chapters to ). microorganisms, especially bacteria, find their way to the lower respiratory tract in two major ways. the first is by inhalation, whereby organisms are usually carried in small droplet particles inhaled into the tracheobronchial tree. the second is by aspiration, whereby secretions from the oropharynx pass through the larynx and into the tracheobronchial tree. aspiration is usually thought of as a process occurring in individuals unable to protect their airways from secretions by glottic closure and coughing. although clinically significant aspiration is more likely to occur in such individuals, everyone is subject to aspirating small amounts of oropharyngeal secretions, particularly during sleep. defense mechanisms seem able to cope with this nightly onslaught of bacteria, and frequent bouts of aspiration pneumonia are not experienced. less commonly, bacteria reach the pulmonary parenchyma through the bloodstream rather than by the airways. this route is important for the spread of certain organisms, particularly staphylococcus. when pneumonia results in this way from bacteremia, the implication is that a distant primary source of bacterial infection is present or that bacteria were introduced directly into the bloodstream (e.g., with intravenous drug use). many individual infectious agents are associated with the development of pneumonia. the frequency with which each agent is involved is difficult to assess and depends to a large extent on the specific population studied. the largest single category of agents is probably bacteria. the other two major categories are viruses and mycoplasma. of the bacteria, the organism most frequently associated with pneumonia is streptococcus pneumoniae; in common parlance, it is often called pneumococcus. it has been estimated that in adults, approximately one-half of all pneumonias serious enough to require hospitalization are caused by s. pneumoniae. s. pneumoniae, a normal inhabitant of the oropharynx in a large proportion of adults, is a gram-positive coccus typically seen in pairs, or diplococci. pneumococcal pneumonia is commonly acquired in the community (i.e., in nonhospitalized patients) and frequently occurs following a viral upper respiratory tract infection. the organism has a polysaccharide capsule that interferes with immune recognition and phagocytosis, and therefore is an important factor in its virulence. there are many different antigenic types of capsular polysaccharide, and for host defense cells to phagocytize the organism, the antibody against the particular capsular type must be present. antibodies contributing in this way to the phagocytic process are called opsonins (see chapter ). staphylococcus aureus is another gram-positive coccus, but usually appears in clusters when examined microscopically. three major settings in which this organism is seen as a cause of pneumonia are ( ) as a secondary complication of respiratory tract infection with the influenza virus; ( ) in the hospitalized patient, who often has some impairment of host defense mechanisms and whose oropharynx has been colonized by staphylococcus; and ( ) as a complication of widespread dissemination of staphylococcal organisms through the bloodstream. a variety of gram-negative organisms are potential causes of pneumonia, but only a few of the most important examples from this group of organisms are mentioned here. haemophilus influenzae, a small coccobacillary gram-negative organism, is often found in the nasopharynx of normal individuals and in the lower airways of patients with copd. it can cause pneumonia in children and adults-the latter often with underlying copd as a predisposing factor. klebsiella pneumoniae, a relatively large gram-negative rod normally found in the gastrointestinal tract, has been best described as a cause of pneumonia in the setting of underlying alcoholism. pseudomonas aeruginosa, found in a variety of environmental sources (including the hospital environment), is seen primarily in patients who are debilitated, hospitalized, and often previously treated with antibiotics. p. aeruginosa is also a very common cause of respiratory tract infections in patients with underlying bronchiectasis or cystic fibrosis. the bacterial flora normally present in the mouth are potential etiologic agents in the development of pneumonia. a multitude of organisms (both gram-positive and gram-negative) that favor or require anaerobic conditions for growth are the major organisms comprising mouth flora. the most common predisposing factor for anaerobic pneumonia is the aspiration of secretions from the oropharynx into the tracheobronchial tree. patients with impaired consciousness (e.g., as a result of coma, alcohol or drug ingestion, or seizures) and those with difficulty swallowing (e.g., as a result of stroke or diseases causing muscle weakness) are prone to aspirate and are at greatest risk for pneumonia caused by anaerobic or mixed mouth organisms. in addition, patients with poor dentition or gum disease are more likely to develop aspiration pneumonia because of the larger burden of organisms in their oral cavity. in some settings, such as prolonged hospitalization or recent use of antibiotics, the type of bacteria residing in the oropharynx may change. specifically, aerobic gram-negative bacilli and s. aureus are more likely to colonize the oropharynx, and any subsequent pneumonia resulting from aspiration of oropharyngeal contents may include these aerobic organisms as part of the process. the two final types of bacteria mentioned here are more recent additions to the list of etiologic agents. the first of these organisms, legionella pneumophila, was identified as the cause of a mysterious outbreak of pneumonia in affecting american legion members at a convention in philadelphia. since then it has been recognized as an important cause of pneumonia occurring in epidemics, as well as in isolated sporadic cases, and seems to affect both previously healthy individuals and those with prior impairment of respiratory defense mechanisms. retrospectively, several prior outbreaks of unexplained pneumonia have been shown to be due to this organism. although the organism technically is a gram-negative bacillus, it is poorly visualized by conventional staining methods. the other organism, chlamydophila pneumoniae, has been recognized in epidemiologic studies as the cause of approximately % to % of cases of pneumonia. it appears related to gram-negative bacteria, and for part of its life cycle it is an obligate intracellular parasite. diagnosis is rarely made clinically because of the lack of distinguishing clinical and radiographic features, and the organism is not readily cultured. as a result, serologic studies serve as the primary means of diagnosis, although they are infrequently obtained and may be difficult to interpret. many other types of bacteria can cause pneumonia. because all of them cannot be covered in this chapter, the interested reader should consult some of the more detailed publications listed in the references at the end of this chapter. although viruses are extremely common causes of upper respiratory tract infections, they are diagnosed relatively infrequently as a cause of frank pneumonia, except in children. in adults, the influenza virus is the most commonly diagnosed agent. the h n influenza pandemic fortunately caused fewer deaths than originally anticipated and raised the profile of best practices for prevention, diagnosis, and treatment of this virus. in contrast, the influenza pandemic is estimated to have resulted in to million deaths, or % to % of the world's population. outbreaks of pneumonia caused by adenovirus also are well described, particularly among military recruits. a relatively rare cause of a fulminant and often lethal pneumonia was described in the southwest united states, but cases in other locations have also been recognized. species of hantavirus, the genus of viruses responsible for this pneumonia, are found in rodents and were previously described as a cause of fever, hemorrhage, and acute renal failure in other parts of the world. several other viruses have caused limited epidemics of severe viral pneumonia in recent years. an outbreak of a novel, highly contagious, and highly lethal pneumonia was reported in in east asia and canada. the outbreak, termed severe acute respiratory syndrome (sars), was attributed to a novel coronavirus that may have evolved from a type normally found in the civet (a weasel-like mammal found in chinese markets). in , middle east respiratory syndrome (mers) coronavirus caused an outbreak of severe pneumonia with a nearly % mortality rate. the causative agent is related to a virus that normally infects camels, and most cases have been traced to initial exposures in the arabian peninsula. mycoplasma appears to be a class of organisms that is intermediate between viruses and bacteria. unlike bacteria, they have no rigid cell wall. unlike viruses, they do not require the intracellular machinery of a host cell to replicate and are capable of free-living growth. similar in size to large viruses, mycoplasmas are the smallest fully free-living organisms that have been identified thus far. these organisms are now recognized as a common cause of pneumonia, and are perhaps responsible for a minimum of % to % of all cases. mycoplasmal pneumonia occurs most frequently in young adults but is not limited to this age group. the pneumonia is generally acquired in the community-that is, by previously healthy, non-hospitalized individuals-and may occur in either isolated cases or localized outbreaks. the pathologic process common to all pneumonias is infection and inflammation of the distal pulmonary parenchyma. an influx of polymorphonuclear leukocytes (pmns), edema fluid, erythrocytes, mononuclear cells, and fibrin develops to a variable extent in all cases. bacterial pneumonias in particular are characterized by an exuberant outpouring of pmns into alveolar spaces as they attempt to limit proliferation of the invading bacteria. individual types of pneumonia may differ in exact location and mode of spread of the infection. in the past, a distinction was often made between pneumonias that follow a "lobar" distribution, those that behave more like a "bronchopneumonia," and those with the pattern of an "interstitial pneumonia." however, these distinctions are often difficult to make because individual cases of pneumonia frequently do not adhere to any one particular pattern, but have mixtures of the three patterns in varying proportions. given this limitation, a brief mention of the three major types follows. lobar pneumonia. lobar pneumonia has classically been described as a process not limited to segmental boundaries but rather tending to spread throughout an entire lobe of the lung. spread of the infection is believed to occur from alveolus to alveolus and from acinus to acinus through interalveolar pores known as the pores of kohn. the classic example of a lobar pneumonia is that due to s. pneumoniae, although many cases of pneumonia documented as being due to pneumococcus do not necessarily follow this typical pattern. bronchopneumonia. in bronchopneumonia, distal airway inflammation is prominent along with alveolar disease, and spread of the infection and the inflammatory process tends to occur through airways rather than through adjacent alveoli and acini. whereas lobar pneumonias appear as dense consolidations involving part or all of a lobe, bronchopneumonias are more patchy in distribution, depending on where spread by airways has occurred. many bacteria, such as staphylococci and a variety of gramnegative bacilli, may produce this patchy pattern. interstitial pneumonia. interstitial pneumonias are characterized by an inflammatory process within the interstitial walls rather than alveolar spaces. although viral pneumonias classically start as interstitial pneumonias, severe cases generally show extension of the inflammatory process to alveolar spaces as well. in some cases of pneumonia, the organisms are not highly destructive to lung tissue even though an exuberant inflammatory process may be seen. pneumococcal pneumonia classically (although not always) behaves in this way, and the healing process is associated with restoration of relatively normal parenchymal architecture. in other cases, when the organisms are more destructive, tissue necrosis may occur, with resulting cavity formation or scarring of the parenchyma. many cases of staphylococcal and anaerobic pneumonias follow this more destructive course. infections of the pulmonary parenchyma produce their clinical sequelae not only by altering the normal functioning of the lung parenchyma but also by inducing a more generalized systemic response to invading microorganisms. the major pathophysiologic consequence of inflammation and infection involving the distal air spaces is decreased ventilation to affected areas. if perfusion is relatively maintained, as it often is because of the vasodilatory effects of inflammatory mediators, ventilation-perfusion mismatch results, with low ventilation-perfusion ratios in diseased regions. when alveoli are totally filled with inflammatory exudate, there may be no ventilation to these regions, and extreme ventilation-perfusion inequality (i.e., shunt) results. ventilation-perfusion inequality generally manifests as hypoxemia. although shunt may explain part of the hypoxemia, ventilation-perfusion mismatch with areas of low ventilation-perfusion ratio is usually a more important factor. carbon dioxide retention is not a feature of pneumonia unless the patient already has an extremely limited reserve, especially from underlying copd. in fact, patients with pneumonia frequently hyperventilate and have a pco less than mm hg. the systemic response to pneumonia is not unique but rather is a reflection of the body's response to serious infection. perhaps the most apparent aspects of this response are fever, an outpouring of pmns into the circulation (particularly with bacterial pneumonia), and often a "toxic" appearance of the patient. these indirect systemic responses can be clues that an infectious process is the cause of a new pulmonary infiltrate. in many ways the clinical manifestations of pneumonia are similar, even when different infectious agents are involved. in other ways, the presentations and manifestations are quite different. although recognition of subtle clinical differences sometimes allows the astute clinician to suggest an etiologic diagnosis, methods for identifying a specific infectious agent are required for a definitive final diagnosis. however, in many cases, a specific agent cannot be clearly identified, and patients often are managed in an empirical way based on the setting in which they present. perhaps the most important constellation of symptoms in almost any type of pneumonia consists of fever, cough, and often shortness of breath. the cough is nonproductive in some cases, particularly in pneumonias due to viruses or mycoplasma; in others, especially bacterial pneumonias, sputum production is a prominent feature. when the inflammatory process in the pulmonary parenchyma extends out to the pleural surface, the patient often reports pleuritic chest pain. if the fever is high and "spiking," patients frequently experience shaking chills associated with the rapid rise in body temperature. physical examination reflects the systemic response to infection and the ongoing inflammatory process in the lung. patients often have tachycardia, tachypnea, and fever. examination of the chest typically reveals crackles or rales overlying the region of the pneumonia. if dense consolidation is present and the bronchus supplying the area is patent, sound transmission is greatly increased through the consolidated pneumonic area. as a result, breath sounds may be increased and bronchial in quality, fremitus is increased, and egophony is present. the consolidated area is characteristically dull to percussion of the overlying chest wall. examination of peripheral blood generally shows an increase in white blood cell count (leukocytosis). especially in patients with bacterial pneumonia, the leukocytosis is composed primarily of pmns, and a shift toward greater numbers of immature neutrophils such as band forms may be seen. in pneumococcal pneumonia, the onset of the clinical illness often is relatively abrupt, with the sudden development of shaking chills and high fever. the cough may be productive of yellow, green, or blood-tinged (rusty-colored) sputum. before the development of pneumonia, patients often have experienced a viral upper respiratory tract infection, which can be an important predisposing feature. mycoplasmal pneumonia, in contrast to pneumococcal pneumonia, characteristically has a somewhat slower, more insidious onset. cough is a particularly prominent symptom, but it often is non-productive. fever is not as high, and shaking chills are uncommon. young adults are the individuals most likely to have mycoplasmal pneumonia, although the disease is not limited to this age group. patients with either staphylococcal or gram-negative bacillary pneumonias are often quite ill. frequently these patients have complex underlying medical problems and have already been hospitalized. many have impaired defense mechanisms or have recently received antibiotics. staphylococcal pneumonia classically may be seen as a secondary complication of influenza infection or as a result of dissemination of the organism through the bloodstream. pneumonia with anaerobic organisms generally occurs in patients with impaired consciousness or difficulty swallowing who cannot adequately protect the airway from aspiration of oropharyngeal secretions. dentition often is poor, and patients frequently have gingivitis or periodontal abscesses. clinical onset of the pneumonia tends to be gradual, and sputum may have a particularly foul odor, suggesting anaerobic infection. successful culture of causative organisms may be difficult. while generally slow growing, anaerobic organisms can cause substantial tissue destruction, and necrosis of affected tissue and abscess formation are relatively common sequelae. pneumonia caused by l. pneumophila, commonly called legionnaires' disease, can be seen as isolated cases or localized outbreaks. otherwise healthy hosts may be affected, but patients with impaired respiratory defense mechanisms appear to be predisposed. patients are often extremely ill, not only with respiratory compromise and even respiratory failure but also with nonrespiratory manifestations; specifically, gastrointestinal, central nervous system, hepatic, and renal abnormalities may accompany the pneumonia. as with other disorders affecting the pulmonary parenchyma, the single most useful tool for assessing pneumonia at the macroscopic level is the chest radiograph in both posteroanterior and lateral views. the radiograph not only confirms the presence of a pneumonia but also shows the distribution and extent of disease and sometimes give clues about the nature of the etiologic agent. the classic pattern for s. pneumoniae (pneumococcus) and k. pneumoniae is a lobar pneumonia (fig. . ). staphylococcal and many of the gram-negative pneumonias may be localized or extensive and often follow a patchy distribution (fig. . ) . mycoplasma organisms can produce a variety of radiographic presentations, which are classically described as being more impressive than the clinical picture would suggest. pneumonias caused by aspiration of oropharyngeal secretions characteristically involve the dependent regions of lung: the lower lobe in the upright patient or the posterior segment of the upper lobe or superior segment of the lower lobe in the supine patient (fig. . ) . legionella pneumonia most commonly presents with a patchy or consolidated unilobar infiltrate, although all patterns have been described. chest radiographs also are useful for demonstrating the presence of pleural fluid, which frequently accompanies pneumonia, particularly of bacterial origin. the pleural fluid can be either thin and serous or thick and purulent; in the latter case, the term empyema is used (discussed later under empyema). microscopic examination of sputum may play an important role in evaluating patients with pneumonia. however, the importance of obtaining a sputum specimen and using it as a guide to treatment, as opposed to treating the patient empirically without a sputum specimen, is an issue of substantial controversy. for patients who do not require hospitalization, most authorities now recommend basing initial treatment on clinical presentation, without substantial efforts at identifying a causative organism. in contrast, patients who are sick enough to be admitted to the hospital are still treated empirically, but attempts are made to identify the organism in order to further guide therapy. when a sputum specimen is obtained, it is important to evaluate the quality of the specimen because a poor quality specimen may provide inadequate or inaccurate information. in an appropriate sputum specimen (i.e., one that contains few squamous epithelial cells picked up in transit through the oropharynx), inflammatory cells and bacteria can be seen. in most bacterial pneumonias, large numbers of pmns are seen in the sputum. in contrast, mycoplasmal and viral pneumonias have fewer pmns and more mononuclear inflammatory cells. pneumococcal, staphylococcal, and gram-negative bacillary pneumonias commonly demonstrate a relatively homogeneous population of the infecting bacteria. anaerobic aspiration pneumonias, caused by a mixture of organisms from the oropharynx, show a mixed population of bacteria of many different morphologies. in legionnaires' disease, the bacterium does not stain well with the usual gram stain reagent and generally requires special stains to appreciate its presence. in mycoplasmal and viral pneumonia, the infecting agent is not visualized by light microscopy, and only the predominantly mononuclear cell inflammatory response is seen. in conjunction with the initial gram stain and microscopic examination of sputum, the specimen is cultured for bacteria. however, some bacteria are relatively difficult to grow, and in many if not most cases the initial gram stain is just as important in making the etiologic diagnosis. special culture media are available to facilitate the growth of legionella species. when sputum is not spontaneously expectorated by the patient, other methods for obtaining respiratory secretions (or even material directly from the lung parenchyma) may be necessary. techniques that have been used-flexible bronchoscopy, needle aspiration of the lung, and occasionally surgical lung biopsy-are described in greater detail in chapter . techniques for testing urine for the presence of antigens related to s. pneumoniae and legionella (see below) are becoming increasingly useful. routine stains and cultures of sputum are not useful for three of the important causes of pneumonia: mycoplasma, chlamydophila, and legionella. sometimes the diagnosis can be confirmed by a variety of serologic techniques that demonstrate a rise in antibody titer against the organism, but these techniques provide a retrospective diagnosis and are not clinically useful. several newer methods are seeing increasing clinical usefulness over time. for example, direct fluorescent antibody staining can be performed for legionella, especially on tissue specimens, but more recent methods include culture on special supplemented media and a commonly used urinary antigen radioimmunoassay (only for certain l. pneumophila serotypes). nucleic acid amplification methods, including polymerase chain reaction, are now widely used to detect mycoplasma, chlamydophila, and specific respiratory viruses, such as influenza or coronaviruses. functional assessment of patients with acute infectious pneumonia is usually limited to evaluating gas exchange. arterial blood gas values characteristically demonstrate hypoxemia accompanied by normal or decreased pco , as well as a widened alveolararterial (a-a) oxygen gradient. pulmonary function tests have little usefulness in this setting. the cornerstone of treatment of bacterial pneumonia is prompt, effective, antibiotic therapy directed at the infecting organism. however, because the causative organism often is not known when the pneumonia is first diagnosed and, in fact, frequently is not identified at any point during the clinical course, initial treatment strategies have been developed on the basis of the clinical setting (e.g., community-acquired vs. hospital-acquired pneumonia). these initial treatment strategies are outlined later under initial management strategies based on clinical setting of pneumonia. if and when an organism is identified, the regimen may be changed to allow for more focused or more effective antibiotic coverage. because knowledge of antibiotic susceptibility of specific organisms helps with understanding the rationale behind initial treatment strategies, this section first considers some of the general patterns of antibiotic susceptibility for the major organisms causing pneumonia. in the case of pneumococcal pneumonia, penicillin has been the most appropriate agent traditionally, assuming the patient is not allergic to penicillin, although cases with various degrees of resistance to penicillin are encountered with increasing frequency. in addition, because penicillin is not effective against some of the other common causes of community-acquired pneumonia (e.g., mycoplasma pneumoniae, c. pneumoniae), other classes of antibiotics with a broader spectrum against agents causing communityacquired pneumonia are typically used when antibiotics are initiated. they include macrolides (erythromycin or a derivative, such as azithromycin) and quinolones (e.g., moxifloxacin). when high-level resistance of pneumococcus to penicillin is found, either a quinolone or vancomycin is typically necessary. intermediately resistant strains can often be treated with ceftriaxone. staphylococci generally produce penicillinase, which requires the use of a penicillinaseresistant semisynthetic derivative of penicillin, such as oxacillin or nafcillin. many staphylococci are also resistant to these derivatives, in which case vancomycin is the antibiotic of choice. h. influenzae may be sensitive to ampicillin, but the high frequency of organisms resistant to this antibiotic generally justifies alternative coverage, such as a second-or third-generation cephalosporin, an extended-spectrum macrolide, trimethoprim-sulfamethoxazole, a quinolone, or a β-lactam/β-lactamase inhibitor combination. many of the other gram-negative bacillary pneumonias often display resistance to a variety of antibiotics. aminoglycosides (e.g., gentamicin and tobramycin), third-or fourth-generation cephalosporins, quinolones, carbapenems (e.g., meropenem), or an extended-spectrum penicillin with a β-lactamase inhibitor (e.g., piperacillin/ tazobactam) may be used initially while antibiotic sensitivity testing is performed. pneumonia caused by anaerobes is treated most commonly with either penicillin or clindamycin. a macrolide or a quinolone is the antibiotic of choice for pneumonias caused by either legionella or mycoplasma. no definitive forms of therapy are available for most viral pneumonias, although rapid advances in this field may lead to the development of more clinically useful therapeutic agents. the influenza vaccine (see chapter ) is effective in preventing influenza in the majority of individuals who receive it, whereas antiviral agents (amantadine or rimantadine for influenza a, a neuraminidase inhibitor, such as zanamivir or oseltamivir, for influenza a or b) may reduce the duration or severity of the illness if given soon after the onset of clinical symptoms. other modalities of therapy are mainly supportive. chest physical therapy and other measures to assist the clearance of respiratory secretions are useful for some patients with pneumonia, particularly if neuromuscular disease or other factors impair the effectiveness of the patient's cough. if patients have inadequate gas exchange, as demonstrated by significant hypoxemia, administration of supplemental o is beneficial. occasionally, frank respiratory failure develops, and appropriate supportive measures are instituted (see chapter ). during the past two decades, greater emphasis on the cost-effective use of medical resources has spurred development of algorithms and guidelines for the clinician approaching common clinical problems. pneumonia is a particularly good example of an important clinical problem for which such management strategies have been developed, relating to both diagnostic evaluation and initiation of therapy. separate strategies are being promulgated for two distinct groups of patients with pneumonia, depending on the setting where the pneumonia developed: community-acquired or nosocomial (hospital-acquired). guidelines apply to patients who do not have a significant underlying impairment of systemic host defense mechanisms, such as patients with aids or those receiving immunosuppressive drugs or cancer chemotherapy. community-acquired pneumonia refers to pneumonia that develops in the community setting (i.e., in an individual not hospitalized). although this category is not meant to include patients with significant impairment of systemic host defense mechanisms, it can include patients with other coexisting illnesses or risk factors that alter the profile of organisms likely to be responsible for pneumonia. surprisingly, the cause of community-acquired pneumonia is never identified in a high proportion of patients, estimated to be up to %. the likelihood of particular agents is believed to be influenced by a number of modifying factors: the presence of coexisting illness, recent treatment with antibiotics, residence in a nursing home, and the severity of illness at the initial presentation. one issue that has sparked controversy is whether an attempt should be made to identify a specific etiologic agent, using gram stain and culture, in patients with community-acquired pneumonia, or whether empirical therapy should be used based on the patient's risk factors, clinical characteristics, and local bacterial resistance patterns. if a specific pathogen is identified, modification of the initial antibiotic regimen is often appropriate, particularly to avoid an overly broad spectrum of coverage. table . summarizes the etiology and initial management of four broad subcategories of patients with community-acquired pneumonia. the first group comprises patients who do not have coexisting cardiopulmonary disease or other modifying risk factors, who have not used antibiotics in the previous months, and who do not require hospitalization. the most common pathogens in this group of patients include s. pneumoniae, m. pneumoniae, c. pneumoniae, respiratory viruses, and in smokers, h. influenzae. the preferred therapeutic regimen is one of the advanced-generation macrolide antibiotics, such as azithromycin or clarithromycin, but this recommendation is subject to local differences in rates of bacterial resistance. for example, in some regions of the united states, up to % of s. pneumoniae isolates are resistant to macrolides. the second group includes patients who have coexisting cardiopulmonary disease or other modifying risk factors but still can be treated in an outpatient setting. important comorbidities that place a patient in this category include chronic heart, lung, hepatic, or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressive conditions or drugs; or the use of antibiotics within the prior months (in which case, antibiotics from a different class should be used). again, local resistance patterns of s. pneumoniae should be taken into account, and residence in a nursing home should be considered a factor that increases the risk of pneumonia caused by a gram-negative organism. poor dentition (leading to an increased burden of anaerobic organisms in the mouth), problems with swallowing, or impaired consciousness increase the risk of an anaerobic aspiration pneumonia. recommended options for the management of this group have included either an oral quinolone (used as a single agent) or a β-lactam antibiotic (e.g., second-or third-generation cephalosporin) given in combination with a macrolide (particularly an advanced-generation macrolide, such as azithromycin or clarithromycin). the third and fourth groups differ from the first two on the basis of severity of the pneumonia. the third group is defined by a need for hospitalization. the fourth group includes patients with the most severe disease, which necessitates admission to an intensive care unit (icu). these patients still commonly have pneumonia caused by s. pneumoniae or the other organisms found in outpatients, but with the additional concern for gram-negative bacilli, legionella, and sometimes s. aureus. therapy for these patients is adjusted accordingly (see table . ). antibiotics, such as a quinolone or an advanced-generation macrolide, plus a β-lactam (particularly a third-generation cephalosporin), a carbapenem, or an extended-spectrum penicillin with β-lactamase inhibitor, are typically used in these settings, frequently in combination with vancomycin. there are increasing data to suggest that adjunctive treatment with corticosteroids may be beneficial in many patients with severe pneumonia. however, the practice has not been uniformly adopted, and some data suggest that patients with pulmonary infection due to influenza or aspergillus may have worse outcomes if corticosteroids are used. a number of scoring systems have been developed to assess the need for hospitalization or icu admission for an individual patient based upon the demographic characteristics and the severity of the illness at presentation. a detailed discussion of these algorithms is beyond the scope of this chapter, but references to the most common clinical prediction rules are provided. in contrast to community-acquired pneumonia, nosocomial pneumonia is acquired by hospitalized patients, generally after more than hours of hospitalization. patients in icus, especially those receiving mechanical ventilation, are at particularly high risk for developing this category of pneumonia. perhaps the most common problem leading to nosocomial pneumonia is colonization of the oropharynx by organisms not usually present in this site, which is followed by microaspiration of oropharyngeal secretions into the tracheobronchial tree. patients at risk often have other underlying medical problems, have been receiving antibiotics, or have an endotracheal tube in their airway that bypasses some of the normal protective mechanisms of the respiratory tract. gastric acid-reducing medications, particularly proton-pump inhibitors, have been implicated as a risk factor for nosocomial pneumonia in some studies. an increase in gastric ph allowing increased bacterial growth is the presumed mechanism. organisms of particular concern in patients who develop hospital-acquired pneumonia are enteric gram-negative bacilli and s. aureus, but other organisms such as pseudomonas aeruginosa and legionella can be involved. diagnostic evaluation is difficult and often complicated by the need to distinguish bacterial colonization of the tracheobronchial tree from true bacterial pneumonia. the clinical issues involved with diagnostic testing and optimal forms of therapy are beyond the scope of this discussion but can be found in the references at the end of this chapter. organisms of particular concern in nosocomial pneumonia include legionella. as part of the discussion of pneumonia, two specific intrathoracic complications of pneumonia-lung abscess and empyema-are briefly considered because they represent important clinical sequelae. a lung abscess, like an abscess elsewhere, represents a localized collection of pus. in the lung, abscesses generally result from tissue destruction complicating a pneumonia. the abscess contents are primarily pmns, often with collections of bacterial organisms. when antibiotics have been administered, organisms may no longer be culturable from the abscess cavity. etiologic agents associated with formation of a lung abscess are generally those bacteria that cause significant tissue necrosis. most commonly, anaerobic organisms are responsible, suggesting that aspiration of oropharyngeal contents is the predisposing event. however, aerobic organisms, such as staphylococcus or enteric gram-negative rods, can also cause significant tissue destruction with cavitation of a region of lung parenchyma and abscess formation. treatment of a lung abscess involves antibiotic therapy, often given for longer than for an uncomplicated pneumonia. although abscesses elsewhere in the body are drained by surgical incision, lung abscesses generally drain through the tracheobronchial tree, and surgical intervention or placement of a drainage catheter is needed only rarely. when pneumonia extends to the pleural surface, the inflammatory process eventually may lead to empyema, another intrathoracic complication of pneumonia. the term empyema (or more properly, empyema thoracis) refers to pus in the pleural space. in its most florid form, an empyema represents thick, creamy, or yellow fluid within the pleural space. the fluid contains enormous numbers of leukocytes, primarily pmns, often accompanied by bacterial organisms. with a true empyema or often even with other grossly inflammatory pleural effusions accompanying pneumonia (parapneumonic effusions), pleural inflammation can result in formation of localized pockets of fluid or substantial scarring and limited mobility of the underlying lung. several different bacterial organisms may be associated with development of an empyema. anaerobes are particularly common, but staphylococci and other aerobic organisms are also potential causes. after an empyema has been documented, usually by thoracentesis and sampling of pleural fluid, drainage of the fluid is required. in many cases thoracoscopic surgery is performed to completely drain the pleural space. alternative techniques are used in some specific clinical situations and can include open surgical procedures or placement of large-bore chest tubes with repeated instillation of fibrinolytic agents (e.g., alteplase and dnase) into the pleural space. the magnitude of society's concerns about bioterrorism has increased abruptly in recent years. in , recognition of cases of both cutaneous and inhalational anthrax contracted by handling mail containing anthrax spores in the united states illustrated all too vividly not only the danger posed by some previously uncommon biological agents but also the widespread fear elicited by the threat of bioterrorism. this section briefly discusses three biological agents with life-threatening effects that can be mediated by infection involving the respiratory system: bacillus anthracis, yersinia pestis, and francisella tularensis. bacillus anthracis, a gram-positive spore-forming rod found in soil, causes infection in farm stock and wild animals. human cases have occurred as a result of exposure to infected animals, contaminated animal products, and inhalation of aerosolized spores. the virulence and potential lethality of the organism are related to elaboration of a toxin that causes prominent edema, inhibits neutrophil function, and alters production of a number of cytokines. whereas cutaneous anthrax results from spores introduced through a break in the skin, inhalational anthrax follows the inhalation of spores into alveolar spaces and the transport of viable spores via lymphatics to the mediastinal lymph nodes. germination of the spores in the mediastinum is associated with toxin release and a hemorrhagic lymphadenitis and mediastinitis. clinically, patients with inhalational anthrax typically present with a flulike illness with symptoms of mild fever, myalgias, nonproductive cough, malaise, and chest discomfort. several days later, they become acutely and severely ill with fever, dyspnea, cyanosis, septic shock, and often findings of meningitis. the most prominent abnormality on chest radiograph is mediastinal widening from hemorrhagic lymphadenitis and mediastinitis. because viable spores are present in the mediastinum and not the alveoli, anthrax is generally not transmitted from person to person via droplet nuclei. despite treatment with ciprofloxacin or doxycycline, mortality is extremely high after the onset of clinical illness, and public health guidelines have focused on prophylaxis (with either of these antibiotics) to prevent inhalational anthrax following confirmed or suspected exposure to aerosolized spores. an anthrax vaccine is available but requires a complex administration schedule and annual booster injections. despite its association with epidemics of devastating proportions, such as the black death of the th century, plague is now an uncommon disease. however, plague is one of the conditions thought to be of major concern as a possible weapon of bioterrorism. the causative organism, yersinia pestis, a gram-negative rod transmitted by fleas from rodents to humans, is still endemic in many parts of the world, including the southwest and pacific coastal regions of the united states, the former soviet union, and focused areas in africa, asia, and south america. infection through the skin disseminates to regional lymph nodes, leading to the clinical syndrome of bubonic plague. infection of the lungs (pneumonic plague) can occur either secondary to bacteremic spread from skin or lymph nodes or via airborne transmission of the organism from person to person. pneumonic plague is highly contagious through aerosolization of the organisms during cough. pulmonary involvement is characterized by widespread bronchopneumonia that can have regions of homogeneous consolidation. clinically, patients become acutely ill with high fever, malaise, myalgias, rigors, dyspnea, and cyanosis. chest radiography shows widespread bronchopneumonia with a diffuse pattern that can resemble acute respiratory distress syndrome (ards). mortality is high unless antibiotic treatment is initiated soon after the onset of symptoms. streptomycin and doxycycline are the treatments of choice. tularemia is caused by francisella tularensis, a gram-negative coccobacillary organism that infects small mammals and is transmitted to humans by insect vectors (e.g., ticks), exposure to contaminated animals, or the inhalation of aerosolized organisms. although several different forms of clinical presentation may occur with tularemia, depending on the mechanism of transmission and the site of entry, pulmonary tularemia secondary to inhalation of f. tularensis is the primary concern for the use of this organism as a bioterrorist weapon. pulmonary tularemia is characterized by patchy inflammation and consolidation of the lung parenchyma, sometimes with the enlargement of hilar lymph nodes and the development of pleural effusions. patients develop fever, chills, malaise, and headache. chest radiography shows patchy consolidation that may be accompanied by hilar lymphadenopathy and pleural effusions. treatment consists of streptomycin, and mortality is estimated to be approximately % without treatment. ventilator-associated pneumonia towards an ecology of the lung: new conceptual models of pulmonary microbiology and pneumonia pathogenesis community acquired pneumonia in children appropriate antibiotic use for acute respiratory tract infection in adults: advice for high-value care from the american college of physicians and the centers for disease control and prevention acid-suppressive medication use and the risk for hospital-acquired pneumonia executive summary: management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the antibiotic therapy for adults hospitalized with community-acquired pneumonia: a systematic review bts guidelines for the management of community acquired pneumonia in adults: update infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics the role of influenza in the severity and transmission of respiratory bacterial disease community-acquired pneumonia ventilator-associated pneumonia: present understanding and ongoing debates in the clinic: community-acquired pneumonia community-acquired pneumonia intrapleural use of tissue plasminogen activator and dnase in pleural infection corticosteroid therapy for patients hospitalized with community-acquired pneumonia: a systematic review and meta-analysis laboratory diagnosis of pneumonia in the molecular age international ers/esicm/escmid/alat guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia clinical practice. community-acquired pneumonia middle east respiratory syndrome atypical pneumonia treatment of mycoplasma pneumonia: a systematic review legionnaires' disease pneumococcal pneumonia. mechanisms of infection and resolution respiratory syncytial virus and parainfluenza virus hantaviruses-globally emerging pathogens aspiration pneumonitis and aspiration pneumonia the severe acute respiratory syndrome management of parapneumonic effusions and empyema viral pneumonia atypical pneumonia: updates on legionella, chlamydophila, and mycoplasma pneumonia pathogenesis, treatment, and prevention of pneumococcal pneumonia diagnosing viral and atypical pathogens in the setting of community-acquired pneumonia writing committee of the who consultation on clinical aspects of pandemic (h n ) influenza. clinical aspects of pandemic influenza a (h n ) virus infection other community respiratory viruses middle east respiratory syndrome clinical management of potential bioterrorism-related conditions index case of fatal inhalational anthrax due to bioterrorism in the united states anthrax infection key: cord- -qt a pxs authors: virkki, r.; juven, t.; mertsola, j.; ruuskanen, o. title: radiographic follow‐up of pneumonia in children date: - - journal: pediatr pulmonol doi: . /ppul. sha: doc_id: cord_uid: qt a pxs this study assessed the clinical value of routine follow‐up chest radiographs in hospitalized children with community‐acquired pneumonia. the study population consisted of children hospitalized for community‐acquired pneumonia diagnosed between – . seventeen infective agents ( viruses and bacteria) were sought. chest radiographs were taken on admission and – weeks later. all children were treated with antibiotics. data on the course of illness over the following – years were obtained from patient files and questionnaires sent to parents. a potential causative agent was found in ( %) of cases. on follow‐up chest radiographs, residual or new changes were seen in % of cases. the residual changes tended to be more common after mixed viral‐bacterial infection ( %) than after sole viral ( %) or sole bacterial ( %) infection. interstitial infiltrates ( %), atelectasis ( %), and enlarged lymph nodes were the most common sequelae seen on follow‐up. residual findings on follow‐up radiographs did not affect the treatment of the children. no further chest radiographs were taken. during the – ‐year follow‐up of children, no illnesses appeared that were associated with previous pneumonia. twenty‐six children had a new episode of pneumonia, of them had asthma, and had different underlying illnesses. in conclusion, routine follow‐up chest radiographs are not needed in childhood community‐acquired pneumonia if the child has a clinically uneventful recovery. pediatr pulmonol. © wiley‐liss, inc. childhood community-acquired pneumonia is a common illness. its incidence is - episodes/ , children/year in those < years of age. , many organisms may cause childhood community-acquired pneumonia. recent observations suggest that % of patients have a viral infection alone, % have a bacterial infection alone, % have a mixed viral-bacterial infection, and % have an etiology that cannot be defined. streptococcus pneumoniae, respiratory syncytial virus, and mycoplasma pneumoniae are the most common causative agents. [ ] [ ] [ ] the clinical diagnosis of pneumonia is difficult, because the symptoms of illness are often nonspecific: fever, cough, rhinorrhea, dyspnea, and malaise/lethargy. , the clinical signs (decreased breath sounds, tachypnea, and crackles) are sensitive but low in specificity. thus the presentation of pneumonia in children can be very nonspecific, and a high index of suspicion is required. chest radiography is suggested as a tool for the confirmation of clinical suspicion or for ruling out pneumonia. , , , children usually recover from community-acquired pneumonia rapidly and without sequelae. the role of follow-up chest radiographs is not clear. only a few studies with a limited number of patients addressed the value of radiologic follow-up in children with communityacquired pneumonia. this prospective study was undertaken to investigate the resolution of chest radiographic changes in children with viral and bacterial pneumonia, and to assess the clinical value of information obtained from follow-up radiographs taken - weeks after a diagnosis of pneumonia. for a long-term perspective, - years later, the medical records of patients were reviewed, and a questionnaire was sent to the parents to elicit the illness history after the time of follow-up chest radiograph. as part of a -year prospective study of the etiology and clinical profile of childhood community-acquired pneumonia, , , , we studied follow-up chest radiographs. in addition, the illness history of the following - years was recorded. between january , -december , , consecutive hospitalized children with community-acquired pneumonia were enrolled in the study. the diagnosis was based on a simultaneous finding of an infiltrate (opacity in the lung) on chest radiograph and fever (> . c), and/or respiratory symptoms. the radiologic diagnosis was made by either a pediatric radiologist (during office hours) or a resident on call. one hundred children were excluded. the exclusion criteria were unavailability of a convalescent serum for viral and bacterial studies ( cases), unavailability of initial chest radiographs for review or absence of infiltrate found on the radiograph on review ( cases), or unavailability of followup chest radiographs taken within - days after the initial radiographs or their unavailability for review ( cases). the remaining cases were the material of this study. posteroanterior and lateral chest radiographs were obtained on admission. they were reviewed retrospectively and separately by three pediatric radiologists. the radiographic findings at time of diagnosis in the original cases were reported earlier. findings were classified according to alveolar (dense fluffy opacity/consolidation) and/or interstitial (ill-defined diffuse opacity of interstitium) pneumonic changes, hyperaeration, hilar enlargement, atelectasis (a dense streak or a triangular shape opacity), pleural fluid, and location in one lung or both lungs. the follow-up posteroanterior and lateral chest radiographs were reviewed in the same manner by one (r.v.) of the original three pediatric radiologists. the role of microbes ( viruses and bacteria) as causative agent was studied. details of the methods were reported earlier. in brief, antibody tests in acute and convalescent serum samples were used for bacterial diagnosis. for viral diagnosis, we used virus culture, sensitive immunoassay for seven viruses, a polymerase chain reaction assay for rhinovirus from nasopharyngeal aspirates, and serologic tests from acute and convalescent sera. the antibiotic treatment was chosen by the attending physician. total white blood cell count (wbc), erythrocyte sedimentation rate (esr), and serum c-reactive protein (crp) were determined on admission, using routine laboratory methods. the follow-up examination was made - weeks after discharge, when in addition to a history of the time after discharge and clinical examination, blood samples for viral and bacterial serology and a chest radiograph were taken. between june -august , , - years after the initial pneumonia episode, we studied the medical records of these children. one child had died of myocarditis, and families had relocated from our hospital district. thus, the medical records of of ( %) children were studied for illness history during the - -year follow-up. in addition, a questionnaire was sent to the parents of patients, asking the illness history of the child after the occurrence of pneumonia. the questions were: ) has the child had bouts of pneumonia? ) if so, where was the diagnosis made and was it based on a chest radiograph? ) was the child treated after the occurrence of pneumonia in a hospital for a respiratory illness? ) has the child had asthma diagnosed by a physician? ) has the child received any asthma treatment for difficulty in breathing during the past months? ) has the child coughed for longer than weeks at any time? pearson's standard chi-square test was used to compare proportions between groups (or fisher's exact test when the expected count was less than ). the median age of children with pneumonia was . years (range, . - . years; aged < year, aged - years, aged - years, and > years of age). of the patients, % were boys. a probable etiology was found in % of cases. evidence of a bacterial infection was documented in ( %) cases, viral infection in ( %) cases, and mixed viral-bacterial infection in ( %) cases, whereas no etiologic agent was found in ( %) cases. the causative agents were s. pneumoniae ( %), respiratory syncytial virus (rsv) ( %), rhinovirus ( %), adenovirus ( %), parainfluenza type , , or viruses ( %), nontypable haemophilus influenzae ( %), m. pneumoniae ( %), coronavirus ( %), chlamydia pneumoniae ( %), influenza a or b viruses ( %), human herpesvirus ( %), and epstein-barr virus ( %). table shows the laboratory findings. in % of patients, fever ! . c was recorded. of the patients, % had wbc >  /l, % had esr > mm/hr, and % had serum crp > mg/l. all patients were treated with antibiotics, usually with penicillin g ( %), cefuroxime ( %), or erythromycin ( %). table shows the radiographic findings at time of diagnosis and at follow-up. at time of diagnosis, sole alveolar changes were seen in %, sole interstitial changes in %, and mixed alveolar-interstitial changes in % of patients. one patient had empyema, and in her case, several chest radiographs were taken during recovery. on follow-up, % of patients had radiographic abnormalities. sole interstitial infiltrates ( %), atelectasis ( %), and enlarged lymph nodes ( %) were the most frequent findings. in % of patients with original sole alveolar changes and in % of patients with original sole interstitial changes, the infiltrates were still detectable at follow-up (chi-square p ¼ . ; fisher's exact p ¼ . ). hyperaeration disappeared in all cases, while enlarged lymph nodes remained in of and atelectasis in of original cases. in % of patients, new radiographic changes developed after the original chest radiograph: most commonly, small atelectasis (in cases), enlarged lymph nodes, and interstitial infiltrates ( table ) . no single etiologic agent predicted the persistence of radiographic changes (data not shown), and the numbers of viral and bacterial infections showed no significant differences between the original patient population and those with residual findings on follow-up radiograph ( table ). the age of the patient, increased wbc (> .  /l), increased serum crp (> mg/l), or increased esr (> mm/hr) did not predict the persistence of inflammatory changes on chest radiograph (data not shown). the radiographic findings at the follow-up visit did not change the treatment in any patient, and further follow-up radiographs were not taken in spite of residual changes. information about medical events during the following - years was obtained from medical records of of ( %) children and from (answer rate, %) questionnaires. the parents of two families who relocated could not be reached, and follow-up information was thus available on children. in the questionnaire, the parents of children reported new episodes of pneumonia during the follow-up. eight of these diagnoses had been made in a hospital. in addition, from the hospital records, we found patients with pneumonia that the parents had not reported. of these patients with recurrent pneumonia, had an underlying illness predisposing to pneumonia, including down syndrome ( cases), large brain cysts with tetraplegia ( case), postoperative status after resection of astrocytoma of pons ( case), complement system deficiency ( case), and left upper lobe bronchiectasis ( case; after lobectomy, this patient has been well). thus, ( %) of children without any known predisposing illness had recurrent pneumonia during follow-up. one including patients with alveolar changes on follow-up but not on initial radiograph. including patients with interstitial changes on follow-up but not on initial radiograph. including one patient who had interstitial and alveolar changes on follow-up but only interstitial changes on initial radiograph. including patients with enlarged lymph nodes on follow-up but not on initial radiograph. including patients with atelectasis on follow-up but not on initial radiograph. including patient with pleural fluid on follow-up but not on initial radiograph. follow-up of pneumonia patient had three pneumonia episodes. of these patients, only one had changes on follow-up chest radiograph - weeks after the initial pneumonia. eleven of these recurrent pneumonias had been diagnosed at our hospital, and at a health center or a private practice. in ( %) cases, the diagnosis of pneumonia had been based on chest radiograph, and children were hospitalized due to pneumonia. a further children had been hospitalized for a respiratory illness during the - -year follow-up: for asthma, for wheezy bronchitis, and for laryngitis. twenty-six of ( %) patients without pneumonia and ( %) of patients with pneumonia during follow-up had asthma (p ¼ . ). twenty-five ( %) of patients had received asthma medication during the past months. cough had occurred in patients ! weeks, and of them were among patients with changes on the follow-up radiograph. our results confirm that a routine repeat chest radiograph is not necessary in children with communityacquired pneumonia. in uncomplicated cases, % of patients become afebrile within hr after onset of antibiotic treatment, and only a short hospital stay may be needed. it is well-known that infiltrates seen on chest radiograph lag behind clinical recovery. in this study, one third of the fully recovered patients still had changes on chest radiograph, mainly interstitial infiltrates and atelectasis. interestingly, in % of patients, new changes had developed, showing that the diagnostic chest radiograph is only one illustration of the dynamic inflammatory process. the radiographic findings at follow-up resulted in no changes in the treatment of the children. most important, during the following - years, no illnesses appeared that were associated with previous pneumonia and that had gone undetected at time of diagnosis. three earlier studies addressed the value of a follow-up chest radiograph in community-acquired childhood pneumonia. in their prospective investigation, grossman et al. studied children with radiologically confirmed pneumonia, and of them had a repeat chest radiograph - weeks after the initial diagnosis. only two of the obtained blood cultures showed significant pathogens. no further etiologic investigations were carried out. of the patients, ( %) did not have complete radiologic resolution. nine of these patients had a second follow-up between weeks and months later, all of them showing complete radiologic resolution. gibson et al. studied consecutive pneumonias. nine of them showed microbiological evidence of etiology, but no detailed information was given. the investigators reported residual pulmonary infiltrates in ( %) of the repeat chest radiographs of children returning for a follow-up visit - weeks after discharge. of these patients, had complete clinical resolution, and they had only minor resolving radiologic changes. seven of the children with symptoms or signs at follow-up showed an improved appearance, and only one remained unchanged. in the study by heaton and arthur of children with pneumonia, a nasopharyngeal aspirate was positive for respiratory syncytial virus in children. no other information on the etiology of pneumonia was given. of patients with follow-up chest radiographs, had a follow-up visit between - weeks, at less than weeks, and more than weeks after discharge. the follow-up chest radiograph was normal in ( %) children, showed residual shadowing, and had an unchanged appearance. the conclusion of these three studies on patients with community-acquired pneumonia was that a follow-up chest radiography is not necessary if symptoms and signs are absent. if a follow-up chest radiograph is indicated, it should be put off till at least weeks after discharge. [ ] [ ] [ ] our study differs from previous studies in several important respects. we included patients during years to be able to have a higher number of patients and all major causative agents. the etiology of pneumonia was detected in % of cases. this permitted a comparison between bacterial and viral infections. patients were followed for - years after follow-up chest radiographs to find out long-term outcomes of the illness. radiological resolution of pneumonia was seen equally after sole viral (most often rsv) and sole bacterial (most often s. pneumoniae) pneumonia. however, after mixed viral-bacterial infection, the children tended to have more residual changes on follow-up chest radiograph than after viral and bacterial pneumonia. the duration of fever after onset of antibiotic treatment was reported to be longer in mixed viral-bacterial pneumonia than in viral and bacterial pneumonia. mixed viral-bacterial infections are probably more common than previously recognized, and may induce a more severe inflammatory process in pneumonia than sole viral or sole bacterial infection. , several studies suggest that the relative frequency of empyema as a complication of pneumonia in children is increasing. [ ] [ ] [ ] in the first study of tan et al. during - , . % of hospitalized children had empyema, and in their second study during - , % of patients had a complicated pneumonia. empyema may not be seen on the first chest radiograph. slow response to antibiotic treatment is an indication for a repeat radiograph. children with empyema are usually > years of age, with a history of ! days of fever. they often have antibiotic treatment before diagnosis, and have immature polymorphonuclear leukocytes in peripheral blood and high crp levels. [ ] [ ] [ ] only one of our patients developed empyema. however, during the following years, cases of empyema were diagnosed at our center (r. virkki, unpublished findings). it is of interest that every tenth child without a chronic underlying illness had a second episode of communityacquired pneumonia. only one child had at least two recurrent episodes of pneumonia. children with recurrent pneumonia tended to have asthma more often than children without recurrent pneumonia. this finding is in agreement with the study of lodha et al., showing that % of children with recurrent pneumonia had asthma. in adults, the radiographic resolution of communityacquired pneumonia is comparable to that in children. mittl et al. prospectively assessed resolution in patients. complete resolution occurred in % of patients after weeks, and in % after weeks. faster clearance occurred in younger patients and in patients with only one lobe involved. a follow-up chest radiography is necessary in adults to exclude noninfectious diseases such as partially obstructing tumors or pulmonary embolism, which may become diagnosed only after pneumonic changes have resolved. , in children, pulmonary tumors are very rare, and repeat chest radiographs are thus not needed to exclude them. in conclusion, routine follow-up chest radiographs are not needed in childhood community-acquired pneumonia if the child has an uneventful recovery. however, the frequency of complicated pneumonia is increasing, and a repeat chest radiograph should be taken in case of a poor response to treatment. childhood community-acquired pneumonia community-acquired pneumonia in children etiology of community-acquired pneumonia in hospitalized children etiology of childhood pneumonia: serologic results of a prospective, population-based study epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children symptoms and signs of community-acquired pneumonia in children can we predict which children with clinically suspected pneumonia will have the presence of focal infiltrates on chest radiographs? bts guidelines for the management of community acquired pneumonia in childhood clinical response to antibiotic therapy for community-acquired pneumonia differentiation of bacterial and viral pneumonia in children roentgenographic followup of acute pneumonia in children value of radiological follow up of childhood pneumonia the utility of chest radiography in the followup of pneumonia mixed microbial aetiology of community-acquired pneumonia in children severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection an epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations clinical characteristics of children with complicated pneumonia caused by streptococcus pneumoniae clinical manifestations and molecular epidemiology of necrotizing pneumonia and empyema caused by streptococcus pneumoniae in children in taiwan clinical characteristics and outcome of children with pneumonia attributable to penicillin-susceptible and penicillin-nonsusceptible streptococcus pneumoniae recurrent pneumonia in children: clinical profile and underlying causes radiographic resolution of community-acquired pneumonia practice guidelines for the management of communityacquired pneumonia in adults canadian guidelines for the initial management of communityacquired pneumonia: an evidence-based update by the canadian infectious diseases society and the canadian thoracic society key: cord- - p qutc authors: le roux, david m.; zar, heather j. title: community-acquired pneumonia in children — a changing spectrum of disease date: - - journal: pediatr radiol doi: . /s - - - sha: doc_id: cord_uid: p qutc pneumonia remains the leading cause of death in children outside the neonatal period, despite advances in prevention and management. over the last years, there has been a substantial decrease in the incidence of childhood pneumonia and pneumonia-associated mortality. new conjugate vaccines against haemophilus influenzae type b and streptococcus pneumoniae have contributed to decreases in radiologic, clinical and complicated pneumonia cases and have reduced hospitalization and mortality. the importance of co-infections with multiple pathogens and the predominance of viral-associated disease are emerging. better access to effective preventative and management strategies is needed in low- and middle-income countries, while new strategies are needed to address the residual burden of disease once these have been implemented. pneumonia has been the leading cause of death in children younger than years for decades. although there have been substantial decreases in overall child mortality and in pneumonia-specific mortality, pneumonia remains the major single cause of death in children outside the neonatal period, causing approximately , of the estimated . million child deaths in [ ] . substantial advances have occurred in the understanding of risk factors and etiology of pneumonia, in development of standardized case definitions, and in prevention with the production of improved vaccines and in treatment. such advances have led to changes in the epidemiology, etiology and mortality from childhood pneumonia. however in many areas access to these interventions remains sub-optimal, with large inequities between and within countries and regions. in this paper we review the impact of recent preventative and management advances in pneumonia epidemiology, etiology, radiologic presentation and outcome in children. the overall burden of childhood pneumonia has been reduced substantially over the last decade, despite an increase in the global childhood population from million in to million in [ ] . recent data suggest that there has been a % decrease in the incidence of pneumonia, from . episodes per child year in low-and middle-income countries in , to . episodes per child year in [ ] . this is substantiated by a % decrease in pneumonia-associated disability-adjusted life years between and , from million to million as estimated in the global burden of disease study [ ] . pneumonia deaths decreased from . million in to , in [ ] . these data do not reflect the full impact of increasingly widespread use of pneumococcal conjugate vaccine in low-and middle-income countries because the incidence of pneumonia and number of deaths are likely to decrease still further as a result of this widespread intervention [ ] . notwithstanding this progress, there remains a disproportionate burden of disease in low-and middle-income countries, where more than % of pneumonia cases and deaths occur. the incidence in high-income countries is estimated at . episodes per child year, compared to . episodes per child year in low-and middle-income countries [ ] . on average, in children in high-income countries is affected by pneumonia per year, compared to in children in low-and middle-income countries. even within low-and middleincome countries there are regional inequities and challenges with access to health care services: up to % of severe pneumonia deaths occur outside a hospital [ ] . in addition to a higher incidence of pneumonia, the case fatality rate is estimated to be almost -fold higher in low-and middle-income countries as compared to high-income countries [ , ] . childhood pneumonia can also lead to significant morbidity and chronic disease. early life pneumonia can impair longterm lung health by decreasing lung function [ ] . severe or recurrent pneumonia can have a worse effect on lung function; increasing evidence suggests that chronic obstructive pulmonary disease might be related to early childhood pneumonia [ , ] . a meta-analysis of the risk of long-term outcomes after childhood pneumonia categorized chronic respiratory sequelae into major (restrictive lung disease, obstructive lung disease, bronchiectasis) and minor (chronic bronchitis, asthma, abnormal pulmonary function) groups [ ] . the risk of developing at least one of the major sequelae was estimated as % after an ambulatory pneumonia event and % after an episode of hospitalized pneumonia. because respiratory diseases affect almost billion people globally and are a major cause of mortality and morbidity [ ] , childhood pneumonia might contribute to substantial morbidity across the life course. chest radiologic changes have been considered the gold standard for defining a pneumonia event [ ] because clinical findings can be subjective and clinical definitions of pneumonia can be nonspecific. in , to aid in defining outcomes of pneumococcal vaccine studies, the world health organization's (who) standardized chest radiograph description defined a group of children who were considered most likely to have pneumococcal pneumonia [ ] . the term "end-point consolidation" was described as a dense or fluffy opacity that occupies a portion or whole of a lobe, or the entire lung. "other infiltrate" included linear and patchy densities, peribronchial thickening, minor patchy infiltrates that are not of sufficient magnitude to constitute primary end-point consolidation, and small areas of atelectasis that in children can be difficult to distinguish from consolidation. "primary end-point pneumonia" included either end-point consolidation or a pleural effusion associated with a pulmonary parenchymal infiltrate (including "other" infiltrate). widespread use of pneumococcal conjugate vaccination and haemophilus influenzae type b conjugate vaccination has decreased the incidence of radiologic pneumonia. in a review of four randomized controlled trials and two case-control studies of haemophilus influenzae type b conjugate vaccination in high-burden communities, the vaccination was associated with an % decrease in radiologic pneumonia [ ] . introduction of pneumococcal conjugate vaccination was associated with a % decrease in radiologic pneumonia in california between and [ ] . in vaccine efficacy trials in low-and middle-income countries, pneumococcal conjugate vaccination reduced radiologic pneumonia by % in the gambia [ ] , % in south africa [ ] and % in the philippines [ ] . the who radiologic case definition was not intended to distinguish bacterial from viral etiology but rather to define a sub-set of pneumonia cases in which pneumococcal infection was considered more likely and to provide a set of standardized definitions through which researchers could achieve broad agreement in reporting chest radiographs. however, despite widespread field utilization, there are concerns regarding inter-observer repeatability. there has been good consensus for the description of lobar consolidation but significant disagreement on the description of patchy and perihilar infiltrates [ , ] . in addition, many children with clinically severe lung disease do not have primary end-point pneumonia: in one pre-pneumococcal conjugate vaccination study, only % of children hospitalized with pneumonia had primary end-point pneumonia [ ] . a revised case definition of "presumed bacterial pneumonia" has been introduced, and this definition includes pneumonia cases with who-defined alveolar consolidation, as well as those with other abnormal chest radiograph infiltrates and a serum c-reactive protein of at least mg/l [ , ] . this definition has been shown to have greater sensitivity than the original who radiologic definition of primary end-point pneumonia for detecting the burden of pneumonia prevented by pneumococcal conjugate vaccination [ ] . using the revised definition, the -valent pneumococcal conjugate vaccine (pneumococcal conjugate vaccination- ), had a vaccine efficacy of % in preventing presumed bacterial pneumonia in young children in south america [ ] , and pneumococcal conjugate vaccination- had a vaccine efficacy of % in preventing presumed bacterial pneumonia in children older than weeks who were not infected with human immunodeficiency virus (hiv) in south africa [ ] . thus there is convincing evidence that pneumococcal conjugate vaccination decreases the incidence of radiologic pneumonia; however there is no evidence to suggest that pneumococcal conjugate vaccination modifies the radiologic appearance of pneumococcal pneumonia. empyema is a rare complication of pneumonia. an increased incidence of empyema in children was noted in some high-income countries following pneumococcal conjugate vaccination- introduction, and this was attributed to pneumococcal serotypes not included in pneumococcal conjugate vaccination- , especially and a [ ] . in the united states, evidence from a national hospital database suggests that the incidence of empyema increased . -fold between and [ ] . in australia, the incidence rate ratio increased by . times when comparing the pre-pneumococcal conjugate vaccination- period ( to ) to the post-pneumococcal conjugate vaccination- period ( to ) [ ] . in scotland, incidence of empyema in children rose from . per million between and , to per million in [ ] . these trends have been reversed since the introduction of pneumococcal conjugate vaccination- . data from the united states suggest that empyema decreased by % in children younger than years [ ] ; similarly, data from the united kingdom and scotland showed substantial reduction in pediatric empyema following pneumococcal conjugate vaccination- introduction [ , ] . several national guidelines from high-income countries, as well as the who recommendations for low-and middleincome countries, recommend that chest radiography should not be routinely performed in children with ambulatory pneumonia [ ] [ ] [ ] . indications for chest radiography include hospitalization, severe hypoxemia or respiratory distress, failed initial antibiotic therapy, or suspicion for other diseases (tuberculosis, inhaled foreign body) or complications. however, point-of-care lung ultrasound is emerging as a promising modality for diagnosing childhood pneumonia [ ] . in addition to the effect on radiologic pneumonia, pneumococcal conjugate vaccination reduces the risk of hospitalization from viral-associated pneumonia, probably by reducing bacterial-viral co-infections resulting in severe disease and hospitalization [ ] . an analysis of ecological and observational studies of pneumonia incidence in different age groups soon after introduction of pneumococcal conjugate vaccination- in canada, italy, australia, poland and the united states showed decreases in all-cause pneumonia hospitalizations ranging from % to % [ ] . in the united states after pneumococcal conjugate vaccination- replaced pneumococcal conjugate vaccination- , there was a further % decrease in hospitalizations for pneumonia among children eligible for the vaccination, and a further % decrease among unvaccinated adults [ ] . a systematic review of etiology studies prior to availability of new conjugate vaccines confirmed s. pneumoniae and h. influenzae type b as the most important bacterial causes of pneumonia, with staphylococcus aureus and klebsiella pneumoniae associated with some severe cases. respiratory syncytial virus was the leading viral cause, identified in - % of pneumonia cases, followed by influenza a and b, parainfluenza, human metapneumovirus and adenovirus [ ] . more recent meta-analyses of etiology data suggest a changing pathogen profile, with increasing recognition that clinical pneumonia is caused by the sequential or concurrent interaction of more than one organism. severe disease in particular is often caused by multiple pathogens. with high coverage of pneumococcal conjugate vaccination and haemophilus influenzae type b conjugate vaccination, viral pathogens increasingly predominate [ ] . in recent case-control studies, at least one virus was detected in % of clinical pneumonia cases in south africa [ ] , while viruses were detected in % of radiologic pneumonia cases in sweden [ ] . in a large multi-center study in the united states, viral pathogens were detected in % of children hospitalized with radiologic pneumonia, while bacteria were detected in only % of cases [ ] . a meta-analysis of case-control studies of viral etiology in radiologically confirmed pneumonia in children, completed up to , reported good evidence of causal attribution for respiratory syncytial virus, influenza, metapneumovirus and parainfluenza virus [ ] . however there was no consistent evidence that many other commonly described viruses, including rhinovirus, adenovirus, bocavirus and coronavirus, were more commonly isolated from cases than from controls. further attribution of bacterial etiology is difficult because it is often not possible to distinguish colonizing from pathogenic bacteria when they are isolated from nasal specimens [ ] . another etiology is pertussis. in the last decade there has also been a resurgence in pertussis cases, especially in highincome countries [ ] . because pertussis immunity after acellular pertussis vaccination is less long-lasting than immunity after wild-type infection or whole-cell vaccination, many women of child-bearing age have waning pertussis antibody levels. their infants might therefore be born with low transplacental anti-pertussis immunoglobulin g levels, making them susceptible to pertussis infection before completion of the primary vaccination series [ ] . in , more than , pertussis cases were reported to the centers for disease control and prevention in the united states; in some states, population-based incidence rates are higher than at any time in the last years [ ] . in contrast, most low-and middleincome countries use whole-cell pertussis vaccines and the numbers of pertussis cases in those countries were stable or decreasing until [ ] . however recent evidence from south africa (where the acellular vaccine is used) shows an appreciable incidence of pertussis among infants presenting with acute pneumonia: % of clinical pneumonia cases among infants enrolled in a birth cohort were caused by pertussis [ ] , and . % of infants and young children presenting to a tertiary academic hospital had evidence of pertussis infection [ ] . similarly, childhood tuberculosis is a major cause of morbidity and mortality in many low-and middle-income countries, and mycobacterium tuberculosis has increasingly been recognized as a pathogen in acute pneumonia in children living in high tuberculosis-prevalence settings. postmortem studies of children dying from acute respiratory illness have commonly reported m. tuberculosis [ , ] . a recent systematic review of tuberculosis as a comorbidity of childhood pneumonia reported culture-confirmed disease in about % of cases [ ] . because intrathoracic tuberculosis disease is only culture-confirmed in a minority of cases, the true burden could be even higher; tuberculosis could therefore be an important contributor to childhood pneumonia incidence and mortality in high-prevalence areas. childhood pneumonia and clinically severe disease result from a complex interaction of host and environmental risk factors [ ] . because of the effectiveness of pneumococcal conjugate vaccination and haemophilus influenzae type b conjugate vaccination for prevention of radiologic and clinical pneumonia, incomplete or inadequate vaccination must be considered as a major preventable risk factor for childhood pneumonia. other risk factors include low birth weight, which is associated with . times increased odds of severe pneumonia in low-and middle-income countries, and . times increased odds in high-income countries [ ] . similarly, lack of exclusive breastfeeding for the first months of life increases odds of severe pneumonia by . times in low-and middle-income countries and . times in highincome countries. markers of undernutrition are strong risk factors for pneumonia in low-and middle-income countries only, with highly significant odds ratios for underweight for age ( . ), stunting ( . ) and wasting ( . ) . household crowding has uniform risk, with odds ratios between . and . in both low-and middle-income countries and high-income countries. indoor air pollution from use of solid or biomass fuels increases odds of pneumonia by . times; lack of measles vaccination by the end of the first year of age increases odds of pneumonia by . times [ ] . it is estimated that the prevalence of these critical risk factors in low-and middle-income countries decreased by % between and , contributing to reductions in pneumonia incidence and mortality in low-and middle-income countries, even in countries where conjugate vaccines have not been available [ ] . the single strongest risk factor for pneumonia is hiv infection, which is especially prevalent in children in sub-saharan africa. hiv-infected children have times increased odds of developing severe pneumonia or of death compared to hiv-uninfected children [ ] . since the effective prevention of mother-to-child transmission of hiv, there is a growing population of hiv-exposed children who are uninfected; their excess risk of pneumonia, compared to hiv unexposed children, has been described as . -to . -fold higher [ ] [ ] [ ] [ ] [ ] . the pneumococcal conjugate vaccination and haemophilus influenzae type b conjugate vaccination have been effective tools to decrease pneumonia incidence, severity and mortality [ , ] . however, equitable coverage and access to vaccines remains sub-optimal. by the end of , haemophilus influenzae type b conjugate vaccination had been introduced in countries, with global coverage estimated at %. however, inequities are still apparent among regions: in the americas coverage is estimated at %, while in the western pacific it is only %. by , pneumococcal conjugate vaccination had been introduced into countries, with global coverage of % for three doses of pneumococcal conjugate vaccination for infant populations [ ] . to address this issue, the who's global vaccine access plan initiative was launched to make life-saving vaccines more equitably available. in addition to securing guarantees for financing of vaccines, the program objectives include building political will in low-and middle-income countries to commit to immunization as a priority, social marketing to individuals and communities, strengthening health systems and promoting relevant local research and development innovations [ ] . maternal vaccination to prevent disease in the youngest infants has been shown to be effective for tetanus, influenza and pertussis [ ] . influenza vaccination during pregnancy is safe, provides reasonable maternal protection against influenza, and also protects infants for a limited period from confirmed influenza infection (vaccine efficacy % in bangladesh [ ] and . % in south africa [ ] ). however as antibody levels drop sharply after birth, infant protection does not persist much beyond weeks [ ] . recently respiratory syncytial virus vaccination in pregnancy has been shown to be safe and immunogenic, and a phase- clinical trial of efficacy at preventing respiratory syncytial virus disease in infants is under way [ ] . within a decade, respiratory syncytial virus in infancy might be vaccine-preventable, with further decreases in pneumonia incidence, morbidity and mortality [ ] . improved access to health care, better nutrition and improved living conditions might contribute to further decreases in childhood pneumonia burden. the who integrated global action plan for diarrhea and pneumonia highlights many opportunities to protect, prevent and treat children [ ] . breastfeeding rates can be improved by programs that combine education and counseling interventions in homes, communities and health facilities, and by promotion of baby-friendly hospitals [ ] . improved home ventilation, cleaner cooking fuels and reduction in exposure to cigarette smoke are essential interventions to reduce the incidence and severity of pneumonia [ , ] . prevention of pediatric hiv is possible by providing interventions to prevent mother-to-child transmission [ ] . early infant hiv testing and early initiation of antiretroviral therapy and cotrimoxazole prophylaxis can substantially reduce the incidence of community-acquired pneumonia among hiv-infected children [ ] . community-based interventions reduce pneumonia mortality and have the indirect effect of improved-careseeking behavior [ ] . if these cost-effective interventions were scaled up, it is estimated that % of pneumonia deaths in lowand middle-income countries could be prevented by [ ] . case management of pneumonia is a strategy by which severity of disease is classified as severe or non-severe. all children receive early, appropriate oral antibiotics, and severe cases are referred for parenteral antibiotics. when implemented in highburden areas before the availability of conjugate vaccines, case management as part of integrated management of childhood illness was associated with a % decrease in overall child mortality, and % decrease in pneumonia-specific mortality [ ] . however the predominance of viral causes of pneumonia and low case fatality have prompted concern about overuse of antibiotics. several randomized controlled trials comparing oral antibiotics to placebo for non-severe pneumonia have been performed [ ] [ ] [ ] and others are ongoing [ ] . in two studies, performed in denmark and in india, outcomes of antibiotic and placebo treatments were equivalent [ , ] . in the third study, in pakistan, there was a non-significant % vs. % rate of failure in the placebo group, which was deemed to be non-equivalent to the antibiotic group [ ] . furthermore, because who-classified non-severe pneumonia and bronchiolitis might be considered within a spectrum of lower respiratory disease, many children with clinical pneumonia could actually have viral bronchiolitis, for which antibiotics are not beneficial [ ] . this has been reflected in british [ ] and spanish [ ] national pneumonia guidelines, which do not recommend routine antibiotic treatment for children younger than years with evidence of pneumococcal conjugate vaccination who present with non-severe pneumonia. the united states' national guidelines recommend withholding antibiotics in children up to age years presenting with non-severe pneumonia [ ] . however, given the high mortality from pneumonia in low-and middle-income countries, the lack of easy access to care, and the high prevalence of risk factors for severe disease, revised world health organization pneumonia guidelines still recommend antibiotic treatment for all children who meet the who pneumonia case definitions [ ] . use of supplemental oxygen is life-saving, but this is not universally available in low-and middle-income countries; it is estimated that use of supplemental oxygen systems could reduce mortality of children with hypoxic pneumonia by % [ ] . identifying systems capacity to increase availability of oxygen in health facilities, and identifying barriers to further implementation are among the top priorities for future childhood pneumonia research [ ] . however, up to % of pneumonia deaths in occurred outside health facilities [ ] , so there are major challenges with access to health services and health-seeking behavior of vulnerable populations. identifying and changing the barriers to accessing health care is an important area with the potential to impact the survival and health of the most vulnerable children [ ] . much progress has been made in decreasing deaths caused by childhood pneumonia. improved socioeconomic status and vaccinations, primarily the conjugate vaccines (against haemophilus influenzae and pneumococcus), have led to substantial reductions in the incidence and severity of childhood pneumonia. stronger strategies to prevent and manage hiv have reduced hiv-associated pneumonia deaths. however, despite the substantial changes in incidence, etiology and radiology globally, there remain inequities in access to care and availability of effective interventions, especially in low-and middle-income countries. effective interventions need to be more widely available and new interventions developed for the residual burden of childhood pneumonia. global and national 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an -valent pneumococcal conjugate vaccine against radiologically confirmed pneumonia among children less than years of age in the philippines: a randomized, double-blind, placebo-controlled trial accuracy of the interpretation of chest radiographs for the diagnosis of paediatric pneumonia variability in the interpretation of chest radiographs for the diagnosis of pneumonia in children chest x-rayconfirmed pneumonia in children in fiji effectiveness of pneumococcal conjugate vaccine against presumed bacterial pneumonia hospitalisation in hiv-uninfected south african children: a casecontrol study efficacy of pneumococcal nontypable haemophilus influenzae protein d conjugate vaccine (phid-cv) in young latin american children: a double-blind randomized controlled trial usefulness of creactive protein to define pneumococcal conjugate vaccine efficacy in the prevention of pneumonia five-fold increase in pediatric parapneumonic empyema since introduction of pneumococcal conjugate vaccine 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immunology and evolution incidence and diagnosis of pertussis in south african children hospitalized with lower respiratory tract infection burden of respiratory tract infections at post mortem in zambian children lung diseases at necropsy in african children dying from respiratory illnesses: a descriptive necropsy study tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosisendemic areas: a systematic review risk factors for severe acute lower respiratory infections in children: a systematic review and meta-analysis global, regional, and national estimates of pneumonia burden in hiv-infected children in : a meta-analysis and modelling study epidemiology of acute lower respiratory tract infection in hiv-exposed uninfected infants incidence and severity of childhood pneumonia in the first year of life in a south african birth cohort: the drakenstein child health study clinical outcomes of hiv-exposed, hiv-uninfected children in sub-saharan africa infant morbidity, mortality, and breast milk immunologic profiles among breastfeeding hiv-infected and hiv-uninfected women in botswana risk factors for presumed bacterial pneumonia among hiv-uninfected children hospitalized in soweto interventions to address deaths from childhood pneumonia and diarrhoea equitably: what works and at what cost? impacts of the -valent pneumococcal conjugate vaccine in children keeping children healthy: the vaccine alliance progress report . gavi, the vaccine alliance world health organization perspectives on the contribution of the global alliance for vaccines and immunization on reducing child mortality maternal immunization effectiveness of maternal influenza immunization in mothers and infants influenza vaccination of pregnant women and protection of their infants duration of infant protection against influenza illness conferred by maternal immunization: secondary analysis of a randomized clinical trial vaccination against respiratory syncytial virus in pregnancy: a suitable tool to combat global infant morbidity and mortality? lower respiratory tract infection caused by respiratory syncytial virus: current management and new therapeutics ending preventable child deaths from pneumonia and diarrhoea by . development of the integrated global action plan for the prevention and control of pneumonia and diarrhoea interventions to improve breastfeeding outcomes: a systematic review and metaanalysis population-wide preventive interventions for reducing the burden of chronic respiratory disease respiratory effects of air pollution on children consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection: recommendations for a public health approach. world health organization community-acquired pneumonia in hivinfected children: a global perspective effect of pneumonia case management on mortality in neonates, infants, and preschool children: a metaanalysis of community-based trials does -day course of oral amoxicillin benefit children of non-severe pneumonia with wheeze: a multicentric randomised controlled trial antibiotic treatment of pneumonia and bronchiolitis. a prospective randomised study comparison of oral amoxicillin with placebo for the treatment of world health organizationdefined nonsevere pneumonia in children aged - months: a multicenter, double-blind, randomized, placebo-controlled trial in pakistan a double blind communitybased randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged - months in karachi, pakistan (retapp) antibiotics for bronchiolitis in children under two years of age integrated management of childhood illness: chart booklet. world health organization an evaluation of oxygen systems for treatment of childhood pneumonia setting research priorities to reduce global mortality from childhood pneumonia by acknowledgments h.j.z. acknowledges grants for studies on childhood pneumonia from the bill and melinda gates foundation (opp ); from the national institutes of health, united states (h africa u ai - a ); from the mrc south africa; and from the national research foundation, south africa. key: cord- -kg dmgq authors: darden, dijoia b.; hawkins, russell b.; larson, shawn d.; iovine, nicole m.; prough, donald s.; efron, philip a. title: the clinical presentation and immunology of viral pneumonia and implications for management of coronavirus disease date: - - journal: crit care explor doi: . /cce. sha: doc_id: cord_uid: kg dmgq this review will briefly examine the clinical presentation and important immunology of viral pneumonia with a focus on severe acute respiratory syndrome coronavirus (coronavirus disease ). data sources, study selection, data extraction, and data synthesis: the most relevant, original and review literature were assessed for inclusion in this review. sources included the centers for disease control and prevention, world health organization, and pubmed. conclusions: pneumonia is a leading cause of hospitalization and death worldwide, with viral etiologies being very common. given the rapidly emerging pandemic associated with the novel severe acute respiratory syndrome coronavirus causing coronavirus disease , it is important to review the clinical presentation and immunologic changes associated with viral pneumonia. symptoms of viral pneumonia include common respiratory tract infection symptoms of cough, fever, and shortness of breath. immunologic changes include up-regulation of airway pro-inflammatory cytokines and pathogen- and damage-associated molecular patterns contributing to cytokine and genomic changes. coronavirus disease clinical presentation is typical of viral pneumonia with an increased prevalence of early pulmonary infiltrates and lymphopenia. principles of early coronavirus disease management and isolation as well as potential therapeutic approaches to the emerging pandemic are discussed. objectives: this review will briefly examine the clinical presentation and important immunology of viral pneumonia with a focus on severe acute respiratory syndrome coronavirus (coronavirus disease ). data sources, study selection, data extraction, and data synthesis: the most relevant, original and review literature were assessed for inclusion in this review. sources included the centers for disease control and prevention, world health organization, and pubmed. conclusions: pneumonia is a leading cause of hospitalization and death worldwide, with viral etiologies being very common. given the rapidly emerging pandemic associated with the novel severe acute respiratory syndrome coronavirus causing coronavirus disease , it is important to review the clinical presentation and immunologic changes associated with viral pneumonia. symptoms of viral pneumonia include common respiratory tract infection symptoms of cough, fever, and shortness of breath. immunologic changes include up-regulation of airway pro-inflammatory cytokines and pathogenand damage-associated molecular patterns contributing to cytokine and genomic changes. coronavirus disease clinical presentation is typical of viral pneumonia with an increased prevalence of early pulmonary infiltrates and lymphopenia. principles of early coronavirus disease management and isolation as well as potential therapeutic approaches to the emerging pandemic are discussed. key words: coronavirus; immunology; influenza virus; severe acute respiratory syndrome; viral pneumonia p neumonia is the leading infectious cause of hospitalization among adults and children in the united states ( ) . according to the world health organization (who), lower respiratory tract infection is among the top causes of death globally ( ) . the centers for disease control and prevention (cdc) etiology of pneumonia in the community study estimated prevalence of pneumonia-related hospitalizations among adults older than to be - times higher than those to years old ( ) . viral infections are the leading cause of community-acquired pneumonia (cap) and are an important source of morbidity and mortality. severe acute respiratory syndrome coronavirus (sars-cov- ) is a newly discovered virus causing coronavirus disease (covid- ) that is responsible for an emerging pandemic. given the rapid spread of this virus and its association with severe pulmonary disease, the purpose of this review is to provide an overview of the presentation and immunology of viral pneumonia, principles of early management, and application to covid- . according to the cdc, the prevalence of cap is highest among adults to years old ( ) . hospitalization among adults is highest in elderly patients (≥ yr) and those with preexisting obstructive lung disease or other cardiopulmonary disorders ( , ) . the most common cause of community-or hospital-acquired pneumonia in adults is viral with the most frequently detected pathogen being human rhinovirus, followed by influenza ( - % and - %, respectively) ( ) ( ) ( ) ( ) ( ) . other commonly detected causes of viral pneumonia include adenovirus, conventional coronaviruses, human metapneumovirus (hmpv), respiratory syncytial virus (rsv), and parainfluenza. the prevalence of viral respiratory illness is temporal in north america, with peaks of influenza, hmpv, and rsv normally seen in the winter months ( table ) ( ) . the clinical presentation of viral pneumonia does not differentiate between the specific viral causes of respiratory infection. the common clinical presentation of acute viral respiratory infection includes cough, dyspnea, fever, and pleuritic chest pain. viral etiologies of lower respiratory infection are less likely to cause sputum production, and if present, tends to be watery or scant. in contrast, sputum production tends to be mucopurulent when due to bacterial pneumonia ( , ) . clinical signs of viral respiratory illness include fever, rales (crackles) on auscultation, hypoxemia, and tachycardia. these four signs together have a positive predictive value of . %, with fever as the strongest clinically predictive sign of a viral respiratory infection versus that of bacterial etiology ( ) . typically, patients with viral pneumonia also will present with a normal leukocyte count and bilateral pulmonary infiltrates on chest radiograph ( ) . severe viral pneumonia can manifest as sepsis and respiratory distress requiring intensive care ( ) . in many moderate to severe cases of pneumonia, hypoxemia occurs from impaired alveolar gas exchange ( ) , often necessitating mechanical ventilation. biopsies in pneumonia are not routinely performed due to the lack of diagnostic, prognostic, and treatment value. however, since influenza has caused the most viral respiratory epidemics to date, a number of studies have examined infected patient's lung biopsy specimens ( ) . biopsies obtained during influenza infection reveal a wide range of pathologies, including alveolar edema and exudate, interstitial inflammatory infiltration, and ulceration of bronchial mucosa to type ii cell metaplasia ( , ) . in autopsy specimens from h n influenza patients, the respiratory tract exhibited tracheitis, bronchitis, diffuse hemorrhagic alveolar damage, and inflammatory infiltration of alveolar ducts and alveoli ( , ) . the host response to severe viral lung infection occurs secondary to immune dysregulation leading to lung injury and the systemic inflammatory response. there have been many studies on the immunologic changes associated with influenza a virus (iav). however, little is known about other respiratory viral illnesses in adults. therefore, much of our discussion on the immunology of viral pneumonia will focus on iav studies. during a respiratory infection, airway epithelial cells, natural killer (nk), and cd t-cells release interferon-gamma (inf-γ) to limit viral replication ( , ) . there is additional release of interleukin (il)- and il- , important mediators of tissue damage and associated with disease progression, respectively ( ) . high levels of il- , tumor necrosis factor (tnf)-α, inf-γ, and il- have been found in postmortem human lung tissue after severe iav ( ) . although there seems to be a difference in cytokine response based on the cause of respiratory infection, there are mixed results in the utility of plasma cytokine levels for prediction of pneumonia etiology ( , ) . in a recent single-center study, differences in admission plasma levels of il- , il- , il- a, and inf-γ were observed between different etiologies of cap, with inf-γ most elevated in viral cap ( ) . conversely, a similar study demonstrated, admission plasma cytokine levels were not statistically different based on etiology (bacterial vs viral vs mixed bacterialviral vs unknown etiology) ( ) . other studies noted that serum transforming growth factor-beta (tgf-β) levels predicted viral pneumonia, as opposed to other etiologies of cap, where tgfβ had negative correlations with the sequential organ failure assessment score in patients that progressed to sepsis ( , ) . therefore, although the specific cytokine profile elicited by particular viruses is unknown, it is clear that, as with most etiologies of sepsis, an elevation of both pro-and anti-inflammatory cytokines are responsible for the host septic and systemic inflammatory response syndrome response in all severe viral cases of pneumonia ( , ( ) ( ) ( ) . as with many other responses to infection, it is pertinent to recognize the role of pathogen-associated molecular patterns (pamps) and damage-associated molecular patterns (damps) in viral respiratory infection. pattern recognition receptors on respiratory epithelial cells, such as toll-like receptors (tlrs), detect evolutionarily conserved microbial ligands, or pamps ( , ) . viral pamps are typically viral envelope proteins or nucleic acids motifs within the dna or rna genomes of the virus, which are critical for structure and function ( ) . the recognition of viral pamps leads to transcription and release of type i interferons ( ) which effect decreased expression of viral proteins and replication, enhance antigen presentation and nk cell function, and augment adaptive immune responses. additional recognition of host cell constituents from damaged or dying cells, recognized as damps, are thought to control the magnitude of the immune response ( ) ( ) ( ) . together, pamps and damps play a major role in the initiation of both the innate and adaptive immune response to viral lung infection ( , , ( ) ( ) ( ) ( ) . viruses can be the primary cause of pneumonia, present in conjunction with bacterial pneumonia, and/or contribute to increased susceptibility to secondary bacterial infection. in addition to influenza, other viruses, such as rhinovirus, can cause severe pneumonia requiring mechanical ventilation, however, this usually occurs in the elderly and immunocompromised ( , ) . severe pneumonia associated with noninfluenza viruses is also significantly associated with bacterial coinfection ( , ( ) ( ) ( ) , most commonly due to staphylococcus aureus, streptococcus pneumoniae, or haemophilus influenzae ( , ) . a pattern of dysregulated inflammation caused by viral respiratory infection leads to this increased susceptibility to secondary bacterial pneumonia or coinfection. most research on viral-bacterial respiratory coinfection has been focused on elucidating the pathophysiology of influenza viruses given its high propensity to cause pandemics and higher mortality when compared with the other viruses ( ) . influenza a causes a reduction in murine alveolar macrophages and dysregulation of remaining macrophages and neutrophils, one of the body's primary defense mechanisms against bacterial pathogens ( ) ( ) ( ) . additionally, prior infection with influenza virus attenuates bacterial induced release of il- leading to decreased innate t cell-mediated bacterial clearance ( ) . replication of iav in respiratory epithelium impairs mucociliary clearance, allowing for increased bacterial colonization ( , , ) . additionally, there is evidence of sustained desensitization of tlr ligands following viral infection, leading to decreased chemokine release and nuclear factor kappa b activation in macrophages ( , ) . this in turn results in attenuated neutrophil recruitment, further decreasing the ability to reduce bacterial load in secondary bacterial infection ( , ) . although cap remains a significant source of morbidity and mortality, very little work has been done establishing genomic, epigenetic, or transcriptomic changes specifically associated with viral pneumonia ( ) . in particular, no clear polymorphism definitively raises the risk of viral pneumonia, limiting personalized medicine for predictive models. in one of the few studies of transcriptomics in viral pneumonia, microarray analysis and ingenuity pathway analysis (qiagen, redwood city, ca) was performed on critically ill patients with h n influenza a pneumonia. the most severely ill group of patients demonstrated impaired expression of numerous genes participating in adaptive immune responses (e.g., diminished antigen presentation, b-cell development, t-helper cell differentiation, and apoptosis), suggesting impaired adaptive immunity in severe viral pneumonia ( ) . in terms of epigenetics, many postulate that longterm epigenetic changes following severe pneumonia are responsible an increased likelihood of later infections and death, although specific epigenetic changes are yet to be identified ( ) . natural infection with viral causes of pneumonia does not induce long-term protective immunity due to an evolutionary advantage allowing viruses to evade host immune defenses via antigenic shift and drift. antigenic drift occurs with small point mutations in the viral genome leading to minor changes in key viral epitopes, while antigenic shift is a major change in a key gene leading to a complete exchange of a key epitope ( ) . antigenic shift often leads to influenza epidemics secondary to vaccine strain-circulating strain mismatches. antigenic shift is the molecular mechanism by which novel influenza strains emerge and is the cause of pandemics such as the h n pandemic ( ) ( ) ( ) ( ) ( ) . influenza vaccines rely on conserved antigens such as ectodomain of influenza m protein, m e, or hemagglutinin stalk domains. hemagglutinin globular head specific antibodies confer immunity since it interferes with virus attachment to host cell receptors; however, they are also one of the most variable viral antigens ( ) . additional adjuvants are important in vaccine formulations to induce desired immune responses that would not be triggered with the antigen alone ( ) . the need for adjuvants in vaccinations confers an additional important role for damps and pamps in viral immunity. one recent study used pamp tlr agonist and commonly used pharmaceutical additive to induce the release of damps to improve immunogenic response to the seasonal influenza vaccine ( ) . prevention of viral pneumonia is mainly limited to influenza vaccines since the formalin-inactivated rsv vaccine in the s failed secondary to adverse events ( ) . however, oral adenovirus vaccination has been used in military populations with -fold reduction of respiratory illnesses ( , ) . production of this vaccine was stopped in but was reintroduced in , leading to a dramatic and sustained decrease of acute respiratory distress outbreaks among u.s. army trainees ( , ) . additionally, there is still ongoing work to develop a vaccine to prevent rsv infection. recently, one study reported protective immunity against rsv with a molecularly adjuvanted adenovirus serotype based rsv oral vaccine in a rat model ( ) . however, two recent randomized control failed to establish an effect of anti-rsv monoclonal antibodies and recurrent wheeze of early childhood or asthma ( ) ( ) ( ) ( ) . since the covid- caused by the novel coronavirus known as sars-cov- began its rapid spread in wuhan, china, in november , researchers have responded swiftly to help thwart the pandemic by quickly establishing studies to better understand the virus. sars-cov- is a novel beta-coronavirus that likely originated in bats. the virus uses a glycosylated spike protein to bind to and enter the human host cell predominantly via angiotensin-converting enzyme receptors that are highly expressed in type alveolar cells ( ) . the clinical presentation of covid- can be indistinguishable from other viral causes of pneumonia and include fever ( - %), dry cough ( - %), and fatigue or myalgia ( - %) ( , ) . the median age of confirmed covid- cases is in the th decade of life with a slight male predominance. twenty-five percent of patients have severe symptoms requiring intensive care treatment of which % develop respiratory failure requiring mechanical ventilation. chest radiograph imaging of these patients reveals bilateral patchy infiltrates and ct imaging shows ground-glass infiltrates. patients typically present with laboratory findings of prolonged prothrombin time, elevated lactate dehydrogenase, and lymphopenia ( % of patients) ( ) . however, it is unclear if the lymphopenia is related to direct cytotoxic effect of the virus or underlying chronic conditions ( , ) . there are limited publications on the autopsy results of patients who have died from covid- . however, pathologic samples show hyaline membrane formation, interstitial mononuclear inflammatory infiltrates, and multinucleated giant cells. there are also high levels of pro-inflammatory cytokines, such as il- and tnf-α. as with other causes of severe viral pneumonia, a "cytokine storm" occurs which also contributes to the high morbidity and mortality ( , ) . the most important aspect of early management of viral spread has been early isolation of those presenting with concerning symptoms, history, and high likelihood of exposure to prevent spread of the disease to those in immunocompromised states, the elderly, and/or those with comorbid conditions. a chest radiograph along with throat and mid-turbinate nasal swabs for respiratory viral panel (reverse transcriptase-polymerase chain reaction) are needed for proper diagnosis of covid- . among hospitalized patients, negative pressure rooms and airborne-droplet-contact precautions are important for prevention and further spread between patients and hospital care-workers ( ) . currently, there is no approved drug or vaccination for the treatment or prevention of sars-cov- viral pneumonia. there are many trials underway attempting to attenuate the disease with remdesivir, il- receptor blockers, il- , and antiretrovirals such as lopinavir-ritonavir ( ) . the new england journal of medicine recently published a randomized controlled trial evaluating the efficacy of lopinavirritonavir versus standard care alone in the treatment of adult hospitalized patients with severe covid- . there were no differences in hospital mortality, time to clinical improvement, or viral rna levels. although the median time to improvement was day shorter with lopinavir-ritonavir on intention-to-treat analysis, % of patients had adverse events requiring treatment discontinuation. therefore, it was concluded that there was no benefit observed with lopinavir-ritonavir treatment versus standard treatment of severe covid- patients ( ) . historically, hydroxychloroquine, an anti-malarial and antiinflammatory agent, has shown some promise in reducing mortality from sars and, therefore, is currently being studied for covid- ( ) . in one very limited study from france (n = per group, nonrandomized), hydroxychloroquine was associated with reduced viral load and reduced duration of viral detection which was further attenuated by the addition of azithromycin ( ) . research is already underway to create a vaccine to protect against sars-cov- . taking advantage of the similarities in structure between sars-cov (responsible for the sars epidemic) and sars-cov- (responsible for covid- ), studies have mapped several epitopes to be targeted for a potential vaccine ( , ) . who estimates an approximately -month timeframe for covid- vaccine availability. until such time that effective therapies and vaccines become available, public health efforts should continue to focus on mitigating the spread of sars-cov- through well-established infection control strategies ( ) . this can be aided in the hospital with admission of sars-cov- positive patients into negative pressure rooms with contact precaution protocols requiring personal protective equipment such as gowns, gloves, fit-tested n respirators, and face shields. additionally, rules limiting the people entering the isolation room and requiring logging of healthcare workers involved in covid- patient care should be followed to effectively monitor patient contact and limit spread. all equipment (monitors, etc.) in the isolation room should be designated for the case patient only. physicians 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pneumonia with influenza -pathogenesis and clinical implications marked improvement of severe lung immunopathology by influenza-associated pneumococcal superinfection requires the control of both bacterial replication and host immune responses depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections influenza a inhibits th -mediated host defense against bacterial pneumonia in mice influenza virus infection decreases tracheal mucociliary velocity and clearance of streptococcus pneumoniae adherence of type i streptococcus pneumoniae to tracheal epithelium of mice infected with influenza a/pr virus toll-like receptor agonistic antibody promotes innate immunity against severe pneumonia induced by coinfection with influenza virus and streptococcus pneumoniae sustained desensitization to bacterial toll-like receptor ligands after resolution of respiratory influenza infection community-acquired pneumonia: genomics, epigenomics, transcriptomics, proteomics, and metabolomics host adaptive immunity deficiency in severe pandemic influenza influenza virus: dealing with a drifting and shifting pathogen changes in and shortcomings of control strategies, drug stockpiles, and vaccine development during outbreaks of avian influenza a h n , h n , and h n among humans human infection with a novel avian-origin influenza a (h n ) virus writing committee of the whococaopi: clinical aspects of pandemic influenza a (h n ) virus infection global epidemiology of influenza: past and present influenza vaccine effectiveness in the united states during the - season nucleic acid sensing at the interface between innate and adaptive immunity in vaccination damp-inducing adjuvant and pamp adjuvants parallelly enhance protective type- and type- immune responses to influenza split vaccination viral pneumonia follow-up analysis of the incidence of acute respiratory infections among enlisted service members during their first year of military service before and after the resumption of adenovirus vaccination of basic trainees dramatic decline of respiratory illness among us military recruits after the renewed use of adenovirus vaccines acute respiratory disease in us army trainees years after reintroduction of adenovirus vaccine ( ) oral adenoviral-based vaccines: historical perspective and future opportunity orally administered adenoviral-based vaccine induces respiratory mucosal memory and protection against rsv infection in cotton rats respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial respiratory syncytial virus and recurrent wheeze interactions between human and carp (cyprimus carpio) low density lipoproteins (ldl) and ldl receptors does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? critical review of the evidence and guidance for future studies from a world health organization-sponsored meeting covid- -new insights on a rapidly changing epidemic china medical treatment expert group for covid- : clinical characteristics of coronavirus disease in china lymphopenic community acquired pneumonia as signature of severe covid- infection clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study shared features of endothelial dysfunction between sepsis and its preceding risk factors (aging and chronic disease) immune responses in covid- and potential vaccines: lessons learned from sars and mers epidemic clinical features of patients infected with novel coronavirus in wuhan, china diagnosis and management of first case of covid- in canada: lessons applied from sars chinese clinical trial register: a randomized, controlled open-label trial to evaluate the efficacy and safety of lopinavir-ritonavir in hospitalized patients with novel coronavirus pneumonia (covid- ) a trial of lopinavir-ritonavir in adults hospitalized with severe covid- covid- -navigating the uncharted hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial preliminary identification of potential vaccine targets for the covid- coronavirus (sars-cov- ) based on sars-cov immunological studies receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of sars coronavirus review of the clinical characteristics of coronavirus disease (covid- ) world health organization: coronavirus disease (covid- ) technical guidance: infection prevention and control/wash. key: cord- - yt fzo authors: mcloud, theresa c.; boiselle, phillip m. title: pulmonary infections in the normal host date: - - journal: thoracic radiology doi: . /b - - - - . - sha: doc_id: cord_uid: yt fzo nan the computed tomography (ct) features of lobar pneumonia are similar to those seen on standard radiography ( fig. - ). there is usually evidence of confluent opacification with air bronchograms. the air bronchograms are often more easily visualized with ct examination. table - summarizes the radiographic clues to the cause of pneumonia. bronchopneumonia (i.e., lobular pneumonia) results when organisms are deposited in the epithelium of peripheral airways (i.e., distal bronchi or bronchioles), resulting in epithelial ulcerations and formation of a peribronchiolar exudate. the inflammatory process spreads through the airway to involve the peribronchiolar alveoli, which become filled with edema and pus. lobules may be affected in a patchy pattern initially, and further spread results in involvement of contiguous pulmonary lobules. eventually, a confluent bronchopneumonia may resemble lobar pneumonia. offending organisms that produce this type of pathologic response include s. aureus, gram-negative organisms, anaerobic bacteria, and l. pneumophila. the radiographic appearance of bronchopneumonia pneumonia is most frequently that of multiple, ill-defined nodular opacities that are patchy but that may eventually become confluent and produce consolidation with airspace opacification (fig. - ) . the opacification may be multifocal and involve several lobes, or it may be diffuse. as the disease progresses, segmental and lobar opacification develops, similar to the pattern of a lobar pneumonia. early necrosis and cavitation can occur. the nodular opaci- ties of bronchopneumonia can be identified with facility on ct scans. the small nodules, usually less than cm in diameter, represent peribronchiolar areas of consolidation or ground-glass opacity. they are called acinar or airspace nodules, but these nodules histologically are found in a peribronchiolar location. they are ill-defined and may be of homogenous soft tissue opacity and obscuring vessels, or they may be hazy and less dense so that adjacent vessels are clearly seen (i.e., ground-glass opacity). these nodules usually have a centrilobular location because of their proximity to small bronchioles. this type of pneumonia is usually produced by viral organisms, which result in edema and mononuclear cell infiltration around the bronchi and bronchiolar walls and extend into the interstitium of the alveolar walls. bronchopneumonia or an acute interstitial pneumonia may be seen with viral infections . the early radiographic appearance is that of thickening of end-on bronchi and tram lines. however, this often evolves into a reticular pattern that may be seen extending outward from the hila. hematogenous spread to the lungs from bacterial infection may occur, although this is unusual. one of the most frequent manifestations is septic infarcts. they usually originate from right-sided tricuspid endocarditis or infected thrombi within major systemic veins. this phenomenon is seen in intravenous drug abusers and patients with longstanding indwelling central catheters. septic infarcts tend to be multiple and peripheral and to abut the pleural surface. they occur more frequently in the lower lobes. these nodules or wedge-shaped opacities may show evidence of cavitation ( fig. - ) . ct often demonstrates a vessel connected to the area of infarction. on ct, the septic infarcts appear as wedge-shaped, peripheral opacities abutting the pleura. they may contain air bronchograms or rounded lucencies of air, sometimes referred to as pseudocavitation. true cavitation is common. occasionally, septic bacterial infection may result in diffuse massive seeding of the lungs with a miliary pattern (i.e., very small nodular pattern), although this is much more common with hematogenous dissemination of granulomatous infections. box - outlines the complications of pneumonia. necrosis of lung parenchyma with cavitation ( fig. - ) may occur in pneumonia, particularly that produced by virulent bacteria, including s. aureus, streptococci, gram-negative bacilli, and anaerobic bacteria. if the inflammatory process is localized, a lung abscess will form. it is usually rounded and focal, and it appears to be a mass ( fig. - ) . with liquefaction of the central inflammatory process, a communication may develop with the bronchus; air enters the abscess, forming a cavity, which often contains an air-fluid level. the walls of the cavity may be smooth, but more often, they are thick and irregular. multiple, small cavities or microabscesses may develop in necrotizing pneumonia ( fig. - ). they are recognized as multiple areas of lucency within a consolidated lobe or segment. a similar appearance may be produced by consolidation superimposed on areas of preexisting emphysema. if the necrosis is extensive, arteritis and vascular thrombosis may occur in an area of intense inflammation, causing ischemic necrosis and death of a portion of lung. this is a particular complication of klebsiella pneumonia and other pneumonias producing lobar enlargement. the radiographic features include multiple areas of cavitation, often with air-fluid levels. portions of dead lung may slough and form intracavitary masses. coned-down view of the right lung demonstrates a fine reticulonodular pattern, which is more prominent centrally. pneumatoceles are usually associated with pneumonia caused by virulent organisms; the classic offender is s. aureus (fig. - ) . they usually form subpleural collections of air, which result from alveolar rupture. radiographically, they appear as single or multiple, cystic lesions with thin and smooth walls. they may show rapid change in size and location on serial radiographs. intrathoracic lymphadenopathy that can be recognized on standard radiographs is uncommon in most bacterial and viral infections; some notable exceptions include mycobacterium tuberculosis, pasteurella tularensis, and yersinia pestis. adenopathy may be associated with fungal infections or bacterial infections that are long-standing or virulent, as in lung abscesses. ct may show slightly enlarged nodes (> cm) in patients with common bacterial infections that are not visible on standard radiography. pleural effusion is a common complication of pneumonia, occurring in about % of cases ( fig. - ). most effusions are parapneumonic, but infection of the pleural space with empyema requiring drainage is an important but uncommon complication of some pneumonias. empyemas can be recognized by the presence of gross pus within the pleural space, by a white blood cell count in the pleural fluid of greater than , cells/mm , by the presence of bacteria within the pleural fluid, or by a ph less than . . chapter provides more detail on the pleural complications of pneumonia. parenchymal necrosis in an underlying pneumonia may produce a fistula between the bronchus and the pleural space (i.e., bronchopleural fistula), and this results in an empyema with an air-fluid level. further discussion of these entities can be found in chapter . rapidly progressive and fulminant bacterial or viral pneumonia may result in the acute respiratory distress syndrome (ards). in the preantibiotic era, bronchiectasis was an extremely common complication of bacterial pneumonia, but the incidence of bronchiectasis has declined with the advent of antibiotics. most pneumonias clear within or weeks, but in elderly patients, resolution may take to months. necrotizing pneumonias also tend to resolve slowly. recurrent pneumonias are frequently found in patients with predisposing factors such as chronic obstructive lung disease, bronchiectasis, alcoholism, and diabetes. although recurrent or persistent pneumonia in the same location raises the possibility of an obstructing endobronchial lesion due to lung carcinoma, cancer accounts for less than % of such cases. the most common gram-positive bacteria causing pneumonia include s. pneumoniae (pneumococcus), s. aureus, and streptococcus pyogenes. s. pneumoniae (box - ) is responsible for one third to one half of community-acquired pneumonias in adults. these infections occur more frequently in the winter and early spring. pneumococcal pneumonia occurs in healthy people, but it is much more common in alcoholic, debilitated, and other immunocompromised individuals. the radiographic features include consolidation that is usually unilateral, although it may be bilateral, and it typically affects the lower lobes (see fig. - ) . although it is a lobar pneumonia, it is uncommon for the lobe to be completely consolidated. cavitation is rare, and large pleural effusions are uncommon. when present, they suggest the development of empyema. sometimes, especially in children, the pneumonia may have a rounded, masslike appearance ( fig. - ) . this is called a round pneumonia; it results from centrifugal spread of the rapidly replicating bacteria by way of the pores of kohn and canals of lambert from a single primary focus in the lung. s. aureus (box - ) is a gram-positive coccus, and the spherical organisms occur in pairs and clusters. this pneumonia rarely develops in healthy adults, but it is sometimes a complication of viral infections and is much more common in infants and children. in infants, unilateral or bilat-eral consolidation involving the lower lungs is the most frequent radiographic presentation. pneumatoceles, thinwalled cysts filled with air or partially filled with fluid, may develop and occasionally rupture into the pleural space, resulting in pneumothorax. in adults, the disease is usually bilateral and is preceded by an atypical pneumonia such as influenza. cavitation is a common feature, and the cavities may be multiple, thick walled, and irregular ( fig. - ). there is a high incidence of large pleural effusions, and empyema resulting from bronchopleural fistula is a common complication. methicillin resistant staphylococcus aureus (mrsa) pneumonia usually occurs as a nosocomial infection in health care centers particularly in older, immunocompromised or intensive care unit patients. staphylococcal infection in the lungs may occur by way of the hematogenous route. this is usually the result of septic emboli, which arise in the central veins or as vegetations on cardiac valves, particularly in intravenous drug abusers and patients with indwelling intravenous catheters. the radiographic appearance is that of multiple nodular masses with or without cavitation, as previously described. streptococci (box - ) are gram-positive cocci that occur in pairs and chains. the pneumonia occasionally occurs in epidemic proportions. this form of pneumonia is much less common than that caused by staphylococcus or s. pneumoniae (pneumococcus). the radiographic features include lower lobe consolidation, often occurring with a segmental distribution. pleural effusions occur frequently, but localized empyema is unusual. pneumonias caused by gram-negative organisms usually are nosocomial pneumonias that affect hospitalized patients. these pneumonias tend to occur in patients maintained on artificial ventilators or in those who have intravenous catheters or a variety of other ancillary support systems. the incidence of gram-negative pneumonia acquired in the community is increasing, which may be related to the a b c klebsiella pneumonia (box - ) usually occurs in middle-aged or elderly patients, in those with underlying chronic lung disease, and in alcoholic individuals. radiographic features consist of an upper lobe consolidation. cavitation is common, and the lobar consolidation may lead to an expanded lobe with bulging interlobar fissures (see fig. - ). if necrosis is extensive, pulmonary gangrene may develop. e. coli pneumonia (box - ) may be caused by direct extension from the gastrointestinal or genitourinary tract across the diaphragm or result from bacteremia. as is true of most of the gram-negative pneumonias, it is frequently characterized by the development of necrosis and multiple cavities. the lower lobes are more frequently involved. p. aeruginosa pneumonia (box - ) usually occurs in hospitalized patients, particularly those with debilitating disease (see fig. - ). organisms that affect the lungs often result from contamination of suction and tracheostomy devices. radiographic features include a lower lobe predilection. however, the consolidation may spread rapidly to affect both lungs. pleural effusions are uncommon. multiple, irregular nodules may develop and are usually associated with bacteremia. these nodules may cavitate. h. influenzae pneumonia (box - ) usually develops in patients with copd. the appearance is typically that of a bronchopneumonia with homogeneous segmental opacities, usually in the lower lobes. cavitation and pleural effusions are rare. chemical pneumonitis and acute lung injury diffuse consolidation resembling pulmonary edema aspiration of particulate matter or foreign bodies may produce different clinical syndromes, depending on the size of the aspirated material and the level of airway obstruction. large food particles or foreign bodies may be aspirated into the larynx and upper trachea, resulting in the so-called café coronary syndrome, which is caused by acute upper airway obstruction. these patients exhibit respiratory distress and aphonia. results of chest radiographs are usually normal for patients who have aspirated foreign bodies. if the foreign body is opaque, it may be visible in the airways. air trapping may occur if the foreign body causes airway obstruction of one of the major bronchi. this can be demonstrated by inspiratory and expiratory radiographs, decubitus views, or chest fluoroscopy. occasionally, complete obstruction of the bronchus results in atelectasis and, if the foreign body is unrecognized, in the development of distal pneumonitis or bronchiectasis. ninety percent of aspiration pneumonias and lung abscesses are caused by anaerobic organisms. the pathogens include prevotella, bacteroides, fusobacterium, and peptostreptococcus. because of the presence of oxygen in the lung, the progression of anaerobic infection is slow, beginning in the dependent lung zones. if the patient is in a supine position when the aspiration occurs, the superior segments of the lower lobes are most commonly affected, with the right side affected more frequently than the left (fig. - ) . aspiration can also affect the posterior segments of both upper lobes. chronic or recurrent aspiration, particularly in patients who are in the upright position, usually results in consolidation involving the basilar segments of the lower lobes. the middle lobe and lingula are uncommon sites for aspiration pneumonia. aspiration is the most common cause of a primary lung abscess (see fig. - ) . a primary lung abscess refers to a focal, walled-off area of anaerobic pneumonia with central liquefaction necrosis. it is most commonly identified in the superior segments of either lower lobe. lung abscesses have a fairly thick wall and may or may not have an air-fluid level. a rounded, masslike lesion may precede the development of cavitation. occasionally, aspiration of nontoxic material that contains insufficient bacteria to produce an infection or insufficient volume to produce atelectasis may occur. the radiographic appearance usually consists of basilar patchy opacities resembling atelectasis, and these areas clear within several days. mendelson's syndrome is a specific form of aspiration that results from the aspiration of gastric acid. this event produces a chemical pneumonitis and acute lung injury. the radiographic manifestations of gastric aspiration are similar to those of noncardiogenic pulmonary edema. the distribution is usually diffuse. atypical pneumonia syndrome (box - ) describes pneumonias that do not respond to usual empiric antimicrobial therapy or do not have clinical features distinctive from the usual bacterial pathogens responsible for communityacquired pneumonias. originally, these atypical pneumonias were thought to be caused by viruses. however, other treatable organisms have emerged as important causes of atypical pneumonia, including m. pneumoniae, l. pneumophila, and chlamydia. these nonviral, atypical pneumonias are for the most part readily treatable with antibiotics. most patients with atypical pneumonia present with a nonspecific syndrome consisting of fever, usually without shaking chills, and nonproductive cough, headache, myalgias, and some degree of dyspnea. this contrasts with the classic presentation of bacterial pneumonia, which is characterized by abrupt onset with fever, shaking chills, and purulent sputum, often with chest pain. patients with the latter signs and symptoms usually have a bacterial pneumonia attributable to pneumococci, group a streptococci, klebsiella, s. aureus, or h. influenzae. many of the atypical pneumonias are associated with extrapulmonary manifestations. for example, diarrhea is a prominent part of legionella and mycoplasma infection. m. pneumoniae (box - ) accounts for approximately % of all cases of pneumonia. it usually occurs during the winter months in enclosed populations, such as students in college dormitories. the incubation period is to weeks, and the onset is often insidious, with low-grade fever and nonproductive cough. extrapulmonary manifestations may include otitis, nonexudative pharyngitis, and diarrhea. the radiographic features are usually those of a fairly diffuse, interstitial, fine reticulonodular pattern. this may evolve to patchy airspace consolidation, particularly in the lower lobes ( fig. - ). hilar adenopathy is seen in approximately % to % of patients. the radiographic appearance is very similar to that of many viral infections. the diagnosis is made by serologic evaluation. the first outbreak of legionnaires' disease was recognized in philadelphia at a legionnaires' convention (box - ). clinical features include acute febrile illness without pneumonia; systemic disease with primarily pulmonary manifestations; a peak incidence in patients older than years; a predisposition in smokers and those with alcoholic liver disease; high fever, shaking chills, and cough with small amounts of mucoid sputum; pleuritic chest pain; watery diarrhea in about one half of patients; and headache. the organism is spread by airborne transmission, usually through moist air exhaust or cooling towers. the radiographic features of legionnaires' disease often consist of segmental opacification and consolidation, particularly of an upper lobe. rapid development of coalescence with complete consolidation of an involved lobe and rapid extension to adjacent lobes are common features ( fig. - ). parenchymal changes are extensive, but pleural effusions are uncommon. the diagnosis of legionnaires' disease is usually made by serology using indirect fluorescent antibody. direct identification of the organism may be confirmed by direct fluorescent antibody (dfa) techniques using properly collected specimens. chlamydia, a long recognized cause of pneumonia in neonates, is an increasingly frequent cause of communityacquired atypical pneumonia in adult patients (box - ). it is caused by the twar agent (chlamydia pneumoniae). chlamydia pneumonia may occur in compromised and noncompromised adults as an atypical pneumonia. the disease is characterized by fever and nonproductive cough. it is often preceded by pharyngitis. radiographic features may be similar to those of mycoplasma pneumonia. however, more commonly there is a localized area of consolidation in the middle or lower lobes, which may be patchy or homogeneous ( fig. - ). atypical nonviral pneumonias are rare. they include psittacosis; q fever, a rickettsial disease; and tularemia. chlamydia psittaci is the etiologic agent of psittacosis, which may be transmitted by any avian species, and it is contracted by inhalation of infected aerosol material. the clue to the diagnosis is the history, which should include information about any contact with birds. psittacosis usually mimics a standard bacterial pneumonia on chest radiography. coxiella burnetii is the etiologic agent of q fever, which is a rickettsial disease. it is most common in the western and southwestern parts of the united states, and it can be transmitted by infected dust from animals. the radiographic features vary, but the most specific pattern simulates mycoplasma or viral pneumonia and usually consists of bilateral, diffuse reticulonodular opacities. tularemia, another animal-associated, atypical pneumo nia, is transmitted by ticks in summer and rabbits in winter. there is an ulceroglandular form, which produces a skin papule that eventually ulcerates at the port of entry. regional lymph nodes may become enlarged and eventually drain and ulcerate. in the typhoidal form, no portal of entry is apparent, but patients are characteristically extremely ill with gastrointestinal symptoms. pneumonia may occur in patients with either of these presentations. the most common radiographic feature is that of a localized and homogenous opacity, but lobar consolidation has also been reported. occasionally, multiple lobes are involved. bilateral hilar adenopathy may occur. primary respiratory viruses (box - ) include the parainfluenza and influenza group of viruses, respiratory syncytial virus (rsv), adenovirus, and picornavirus. the incidence of these infections varies with the age of the patient. for example, in children, rsv is responsible for up to % of epidemic lower respiratory tract infections and up to % of all pneumonias; in adults, the influenza and parainfluenza groups are responsible for most of the epidemic viral pneumonias. they usually occur during late winter. adenovirus and picornavirus cause nonepidemic respiratory infections. other viruses (e.g., cytomegalovirus) produce pneumonia as part of a systemic infection. in all cases, the infection usually begins in the larger central airways. at this stage, the chest radiograph frequently appears normal. the radiologic correlates of severe inflammation and edema of the bronchial walls include coarse reticular opacities in the form of rings and parallel lines (i.e., tram tracks) due to bronchial wall thickening in the central perihilar lung zones. when the small airways are involved, bronchiolitis develops. involvement of terminal bronchioles may lead to airway obstruction. this is more likely to occur in infants and young children because the cross-sectional area of the airways is small. diffuse overinflation and air trapping can be visualized. when the infection spreads to the alveoli, the disease is usually limited to the parenchyma around the terminal airways. the radiographic features in children and adults usually consist of a diffuse reticulonodular pattern, often with focal and patchy areas of consolidation (see fig. - ). multiple lobes are usually involved. ct may reveal the anatomic localization of the disease. the bronchiolitis and surrounding inflammation produces nodular opacities, which are located in the center of the lobules. branching centrilobular opacities represent impaction of small airways, and their appearance has been referred to as the treein-bud pattern ( fig. - ). other common ct findings of viral pneumonia include ground-glass attenuation with a lobular distribution and foci of segmental and subsegmental consolidation. influenza is one of the most frequently reported contagious diseases. symptoms include fever, nonproductive cough, weakness, and myalgias. most patients who develop severe pneumonia have underlying disease or superinfection with bacterial organisms. radiographic features may reflect the complicating bacterial pneumonia. however, a diffuse reticulonodular pattern may be seen in infants and children with the disease. adenovirus may occur in epidemic or pandemic proportions. when pneumonia develops, there may be destructive changes involving the peripheral airways, leading to chronic bronchitis, bronchiectasis, and bronchiolitis obliterans. symptoms tend to persist after resolution of pneumonia. radiographic features are very similar to pneumococcal pneumonia in pattern and distribution. rsv, rarely reported in adults, is the most prevalent respiratory viral pathogen in the first months of life. it usually produces focal and diffuse bronchiolitis. if radiographs are abnormal, they usually show increased lung volumes and air trapping, and linear interstitial opacities occasionally may be identified. varicella-herpes zoster (i.e., chickenpox) infection may be responsible for severe pneumonia in adults. the radiographic features are fairly characteristic. they consist of nodules ranging from to mm in diameter, with illdefined margins diffusely distributed throughout both lungs (fig. - ) . radiographic resolution usually occurs over many weeks. one of the interesting sequelae of chickenpox pneumonia is the development of diffuse, discrete pulmonary calcifications that can be identified on routine radiographs obtained after the infection (fig. - ) . histoplasmosis should be considered in the differential diagnosis of this radiologic appearance. cytomegalovirus infection is discussed in chapter . the epstein-barr virus is the presumed etiologic agent for infectious mononucleosis. although upper respiratory symptoms predominate, patients may develop a nonproductive cough. the chest radiograph is usually normal, but occasionally, pronounced hilar lymph node enlargement with an ill-defined, diffuse reticular pattern in the lungs may be seen. mycobacteria are aerobic, nonmotile, non-spore-forming rods that have in common the characteristics of staining bright red with carbol fuchsin and resistance to discoloration by strong acid solutions. the organisms are therefore referred to as acid-fast bacilli (afb). there are several mycobacterial species, but the most important include mycobacterium leprae, the cause of leprosy; m. tuberculosis and mycobacterium bovis, responsible for tuberculosis; and the nontuberculous mycobacteria that are important etiologic agents in the development of pulmonary disease. in the latter part of the th century, tuberculosis (box - ) was a leading cause of death in the united states. the advent of drug therapy and improved public health measures led to a steady decline in the incidence of tuberculosis after world war ii until . for the next years, a slow but steady increase in the incidence of tuberculosis was observed. this rise was primarily attributed to a large number of cases associated with acquired immunodeficiency syndrome (aids). immigration into the united states of individuals from third world countries also might have contributed to the increased prevalence of tuberculosis. since , the rate of tuberculosis has declined considerably. in , the rate of tuberculosis in the united states was the lowest since the beginning of national record keeping in . the tuberculosis rate is continuing to decline, but the rate of decline has recently slowed. respiratory or systemic symptoms patients older than years diarrhea common airborne spread through moist air exhaust or cooling towers diagnosis by serology with indirect fluorescent antibody affects upper lobes rapid spread to other lobes from to , there was also a decrease in the percentage of multidrug-resistant tuberculosis cases among persons with no prior history of tuberculosis, with a reduction from . % to . %. since , the rate has remained steady at approximately %. in the united states, tuberculosis case rates vary considerably among different racial and ethnic populations and are lowest among whites. for example, compared with whites, the case rates are nearly times higher for asians and times higher for blacks and hispanics. the rate of tuberculosis among foreign-born persons in the united states is nearly times higher than that of persons born in the united states. other susceptible populations include the aged and the immunocompromised, particularly patients with aids. infection with tuberculosis occurs as the result of inhalation of airborne droplets containing the tubercle bacilli. the initial infection, referred to as primary tuberculosis, is most common in the lower lobes. the bacteria are ingested by macrophages and initially spread to local lymph nodes at this stage, and they then may disseminate throughout the body. the infection is usually contained if the host is immunocompetent. however, walled-off tubercle bacilli representing a dormant focus of tuberculosis may activate under appropriate conditions. this may occur in the second type of tuberculosis, referred to as reactivation or postprimary tuberculosis. reactivation or post primary tuberculosis can occur any time after the primary infection, but the highest rate of reactivation occurs during the first and second years after the initial infection. reactivation tuberculosis usually involves the lung apex, but a dormant focus of tuberculosis may become active in other organs, such as the bones, kidney, or brain. clinically active disease may develop at the time of primary tuberculous infection (i.e., primary progressive tuberculosis) or when dissemination occurs (i.e., miliary tuberculosis). clinical reactivation disease results when there is an ineffective t-cell immune reaction. the typical pathologic feature of tuberculosis is the caseating granuloma. chlamydia pneumoniae (twar agent) nonproductive cough preceding pharyngitis localized consolidation in lower lobes patchy or homogeneous pattern patients with primary tuberculosis are usually asymptomatic but occasionally may have a symptomatic pneumonia. patients with acute or chronic reactivation tuberculosis usually present with a chronic cough, weight loss, and occasionally with hemoptysis and dyspnea. the symptoms are often insidious. ninety-five percent of patients with active tuberculosis have a positive tuberculin skin test result. the diagnosis must be made on the basis of culture of the organism, although the presence of afb on the smear from the sputum is strong presumptive evidence of tuberculosis. classification of tuberculosis into primary or reactivation phases is based on the radiographic appearance. in third world countries and in the united states during th and early th centuries, primary tuberculosis was a disease of children, and reactivation tuberculosis was typically a disease of young adults. however, a significant change in the pattern of adult tuberculosis has occurred in the past several decades. because of diminished exposure of children to tuberculosis, the disease often occurs in the primary form in adults. this has resulted in atypical radiographic manifestations of tuberculosis in adults, attributable to primary infection rather than reactivation of the disease. the radiographic features of primary tuberculosis are summarized in box - . primary tuberculous pneumonia can occur in any lobe of the lung but is more common at the lung bases (fig. - ) . in more than one half of cases, the disease occurs in the lower lobes. any chronic consolidation, particularly in the bases of the lungs, may suggest tuberculosis. cavitation, although rare in primary tuberculosis, is more frequently reported in adults than in children with the primary form of disease. mediastinal and hilar adenopathy is another feature of primary tuberculosis (fig. - ) . it may occur alone or in association with consolidation in the lung. it tends to be particularly predominant in children. ct may be helpful in identifying and localizing adenopathy. on ct scans, tuberculous adenopathy has a predilection for the right paratracheal, right tracheobronchial, and subcarinal regions. occasionally, atelectasis may result from extrinsic obstruction of a bronchus by enlarged lymph nodes. on ct scans obtained with intravenously administered contrast material, these nodes often demonstrate low-attenuation necrotic centers. pleural effusion due to tuberculous pleurisy, also a feature of primary infection, develops when subpleural foci of tuberculosis rupture into the pleural space. patients present to months after the initial exposure. organisms are rarely found in the fluid, and the diagnosis must be confirmed with a pleural biopsy. the ghon lesion (fig. - ) is a manifestation of primary tuberculosis, which usually occurs in childhood and is selflimited. the host defense mechanisms handle the initial infection, and the area of consolidation in the lung slowly regresses to a well-circumscribed nodule. this nodule then shrinks and may disappear completely or remain as a solitary, calcified granuloma. the adenopathy regresses and may also exhibit calcification (i.e., rhanke complex). reactivation tuberculosis usually occurs in the apical and posterior segments of the upper lobes and in the superior segment of the lower lobes. it is characterized by chronic, patchy areas of consolidation (fig. - ) . cavitation is a hallmark of reactivation tuberculosis (fig. - ) . cavities result when areas of caseation necrosis erode into the bronchial tree, expelling liquefied debris. ct is more sensitive than plain radiography in the detection of small cavities (fig. - ) . they may have thick or thin walls, which can be smooth or irregular. bronchogenic spread of tuberculosis occurs when a cavity erodes into an adjacent airway and organisms spread endobronchially to other parts of the lung. the typical radiographic features (fig. - ) consist of ill-defined nodules that usually are to mm in diameter. they are numerous and often bilateral. on ct, the pattern of bronchogenic spread can easily be recognized by a tree-in-bud pattern. this consists of centrilobular, branching, linear opacities with or without the presence of centrilobular nodules within to mm of the pleural surface or interlobular septa. this pattern is best appreciated on high-resolution ct (hrct). it is not specific for bronchogenic spread of tuberculosis and may occur in other inflammatory diseases involving the peripheral airways. the chronic lesion of reactivation tuberculosis usually consists of fibronodular opacities in the upper lobes, often with the presence of calcification (fig. - ) . it is usually associated with volume loss and retraction of the hila. another feature of chronic reactivation tuberculosis is bronchiectasis. tuberculosis should be considered in the differential diagnosis of upper lobe bronchiectasis. the activity of tuberculous disease cannot be determined by radiographs; it is confirmed only by positive cultures. however, tuberculosis is considered radiographically stable if there has been no change over months. unusual patterns of tuberculosis (box - ) may occur in the patient who has altered host resistance to the primary infection. miliary tuberculosis is a term used to describe diffuse hematogenous dissemination of tuberculosis that has progressed when the host defense system is overwhelmed by massive hematogenous dissemination of organisms. it may occur at any time after the primary infection. the radiographic appearance (fig. - ) is that of multiple, tiny nodules in the interstitium of the lung that are approximately to mm in diameter. ct may allow earlier detection than standard radiography (fig. - ) . miliary disease takes up to weeks to become apparent on plain radiographs. pneumothorax occasionally results from tuberculosis. tuberculosis may also cause ulceration of the bronchi, and advanced endobronchial tuberculosis may produce lobar atelectasis and strongly simulate a primary carcinoma of the lung. a localized nodular focus of tuberculosis, referred to as a tuberculoma (fig. - ) , occurs in any portion of the lung and may result from primary or reactivation tuberculosis. it is usually solitary, spherical, and smooth. it may contain a central calcification, but tuberculomas occasionally may be multiple and simulate metastatic disease. tuberculous empyema and bronchopleural fistula may result from a tuberculous pleural effusion. such effusions can become loculated and remain dormant for years. radiographic patterns of tuberculous disease in patients with acquired immune deficiency syndrome (aids) may vary. they are described in chapter . nodule communicating with the right upper lobe posterior segment bronchus (single arrow), with associated centrilobular nodular opacities in the superior segment of the right lower lobe (three arrows). b, ct of another patient shows a typical tree-in-bud pattern. centrilobular nodules and branching opacities can be identified close to the pleural surface (arrows). characteristics some nontuberculous mycobacteria (box - ) are pathogenic in humans. the most important of these organisms are mycobacterium avium-intracellulare, often referred to as the mac complex, and mycobacterium kansasii. these organisms often exhibit common features. they are usually found in the soil and water. bronchopulmonary disease is caused by inhalation of the organisms, but no human-tohuman transmission occurs. unlike tuberculosis, nontuberculous mycobacterial infections do not manifest separate patterns of primary or reactivation disease. certain geographic areas have a preponderance of these forms of nontuberculous mycobacterial disease. for example, m. kansasii is more prevalent in the western and southern united states, and mac is found more often in the southeastern united states. the three major clinical presentations depend to some degree on the immune status of the host (chapter describes mac disease in aids patients). in human immunodeficiency virus (hiv)-negative hosts, mac typically affects male patients who are heavy smokers with underlying copd. similar infections may occur in patients with silicosis or bronchiectasis. the radiographic features of m. kansasii and mac in this group of patients are indistinguishable from tuberculosis. however, mac lung disease may develop in older women who are considered immunologically competent and who do not have a background of thickening and multiple, calcified nodular and irregular opacities can be seen in the left upper lobe (arrows). volume loss is not a prominent feature in this case. although such an appearance suggests inactive disease, serial radiographs are necessary to determine stability. viable organisms may be present, and the development of clinically active disease may rarely occur. hematogenous dissemination diffuse, -to -mm nodules pneumothorax endobronchial tuberculosis lobar or segmental atelectasis tuberculoma single or multiple nodules larger than cm tuberculous empyema bronchopleural fistula copd. this disease is usually noncavitary. many women with this form of nontuberculous mycobacterial infection share similar clinical characteristics and bodily features, including scoliosis and pectus excavatum. it is uncertain whether these skeletal features predispose patients to infection due to poor tracheobronchial secretion drainage and ineffective mucociliary clearance or they are associated with markers for specific genotypes that affect body morphotype and susceptibility to infection. because nontuberculous mycobacteria are common contaminants, the identification of invasive disease caused by these infections should be made only when defined clinical, radiographic, and microbiologic criteria have been met as defined by the american thoracic society (ats) and infectious disease society of america (idsa) guidelines. radiologic criteria include the presence of nodular or cavitary opacities on the chest radiograph or an hrct scan that shows multifocal bronchiectasis with multiple small nodules. establishing a diagnosis of nontuberculous mycobacteria does not necessitate the need for treatment in all cases: rather, the decision to institute multidrug therapy should be based on an assessment of the relative risks and benefits of therapy on an individual patient basis. the classic form of atypical mycobacterial infection produces features almost identical to those of reactivation tuberculosis (fig. - ) . involvement occurs in the apical and posterior segments of the upper lobes and superior segment of the lower lobes. cavitation is common, and multiple cavities may be observed. the disease tends to be slowly progressive. mac lung disease occurring in older women who are usually nonsmokers without evidence of copd is noncavitary and is associated with bronchiectasis. the classic radiographic features are best appreciated on ct ( fig. - ) . the findings are those of cylindrical bronchiectasis associated with multiple, small, focal lung nodules that are approximately mm in diameter. any lobe may be involved, but disease in the lingula and middle lobe has the highest prevalence. occasionally, airspace disease may be delineated. evidence indicates that patients with these findings are truly infected and not colonized with mac and that the mac infection causes the bronchiectasis rather than colonizing preexisting disease. the wide variety of fungi that may produce lung disease can be divided into two groups. some are truly pathogenic and can produce pulmonary infection in normal hosts. they include histoplasma, coccidioides, blastomyces, and cryptococcus. a second group of fungi are secondary invaders or opportunistic organisms, which produce disease in immunosuppressed patients. this group includes aspergillus, candida, cryptococcus, and mucor. the latter group is discussed in chapter . histoplasma capsulatum (box - ) is a dimorphous fungus that gains entry to the lung by inhalation. distribution is worldwide, and in the united states, it occurs along river valleys, particularly the ohio, mississippi, and st. lawrence. the organism exists in the soil, particularly when it is contaminated by the excrement of birds (e.g., pigeons) or bats. many epidemics may occur when there is heavy exposure due to demolition or construction in areas containing these droppings, such as bat caves, chicken houses, or attics of old buildings. in endemic areas, up to % of the population may be infected, but most individuals are asymptomatic. inhalation of spores results in a localized infection of the lung, which then migrates to mediastinal and hilar lymph nodes and eventually migrates to the spleen and liver. the organisms usually are destroyed, and there is no residual of the initial infection, although a scar or calcification may occur. if individual foci of infection and necrosis persist, they may enlarge, resulting in a chronic cavitary lesion indistinguishable from that of tuberculosis. pathologically, well-defined granulomas may be found during the acute phase of disease in the lung, in the mediastinum, and in the various organs to which the organism disseminates. when healed, these granulomas are small and densely calcified. outbreaks of histoplasmosis are usually associated with constitutional symptoms and nonproductive cough. many cases never come to medical attention. the radiographic manifestations of histoplasmosis vary. the acute phase of the disease is characterized by single or multiple areas of consolidation, which are usually segmental or sublobar in distribution. these areas may be accompanied by ipsilateral hilar or mediastinal adenopathy, and occasionally, adenopathy alone may be the only finding. in the epidemic form of the disease, multiple, discrete nodules may be seen throughout both lungs; nodules may occur alone or be associated with hilar adenopathy (fig. - ) . they are usually to mm in diameter, discrete, and poorly marginated. with healing, the nodules may remain visible as multiple, discrete, calcified lesions less than cm in diameter with or without calcified hilar lymph nodes (fig. - ) . a third radiographic pattern consists of a solitary granuloma or histoplasmoma, which is usually well defined and can range in size from several millimeters to cm. it typically contains a central or target type of calcification. these lesions usually occur in the lower lobes, and they may have associated smaller, calcified satellite nodules. additional radiographic features may be identified in patients with histoplasma infection. they include calcifications in the spleen, which often are best detected on ct. mediastinal lymphadenopathy is common as a sole manifestation of histoplasmosis or accompanying pulmonary consolidation or nodules. nodes frequently calcify as healing occurs. calcified lymph nodes may lead to two complications: broncholiths and fibrosing mediastinitis. calcified lymph nodes may over time erode into a bronchus, producing broncholithiasis and its resulting symptom complex. patients may have unexplained chronic cough and hemoptysis. ct can best identify the intrabronchial calcification that may be associated with distal atelectasis of a segment or lobe (fig. - ) a rare chronic form of histoplasmosis can simulate tuberculosis. it usually consists of thin-or thick-walled cavities with patchy areas of consolidation, particularly involving the upper lobes with fibrosis and retraction. disseminated histoplasmosis, which may occur in normal individuals, is much more common in immunosuppressed patients. radiographically, the appearance is identical to that of miliary tuberculosis. coccidioides immitis infection (box - ) follows inhalation of infected spores in endemic areas such as desert areas of the southwestern united states and central and south america. clinical manifestations vary. most individuals are asymptomatic, or they may experience a mild flulike illness of the lower respiratory system. acute, severe disease may be associated with fever, cough, and pleuritic chest pain. with the initial inhalation of the spores, a local response or pneumonitis occurs. the immune system eventually destroys the organism, with resolution of the pneumonia. about % of individuals may have a chronic, often asymptomatic pulmonary lesion, such as a pulmonary nodule or cavity. similar to tuberculosis, reactivation of the initial focus can occur. dissemination of the organism to hilar and mediastinal nodes is common, and diffuse dissemination is rare but almost universally fatal. the initial pneumonic form of the disease is characterized by an area of consolidation anywhere in the lung but most commonly in the lower lobes. it is usually sublobar, segmental, or patchy. it may be bilateral. hilar and mediastinal lymph node involvement occurs in about % of cases, and rarely, it can be seen in the absence of the parenchymal consolidation. most of these lesions resolve spontaneously without therapy. the radiographic features of chronic coccidioidomycosis include solitary or multiple nodules. these tend to cavitate rapidly, and the cavities typically have very thin walls ( fig. - ) . the thin-walled cavity is the classic lesion of coccidioidomycosis, but it occurs in only % to % of cases. disseminated coccidioidomycosis is rare and is characterized radiographically by nodules ranging from mm to cm in diameter. a classic miliary pattern can also be observed. (box - ) is a dimorphic fungus that grows in a mycelial form in the soil. infection can occur by inoculation of the skin or by inhalation of organisms into the lungs. the organism is endemic in north america, occurring mostly in the same areas where histoplasmosis occurs but also in the southeastern united states. blastomycosis is an infection associated with hunters because the organisms are prevalent in wooded areas. the organism is usually inhaled from the soil, and if the initial port of entry is the lung, a focal pneumonic process will occur. the disease can be self-limited, or a disseminated form can occur. the radiographic findings are nonspecific but consist of areas of inhomogeneous consolidation in a segmental or nonsegmental distribution in any area of the lung. the next most common manifestation is that of solitary and multiple pulmonary nodules. the solitary nodules may simulate lung carcinoma. these nodules are to mm in diameter. a third pattern results from disseminated disease and consists of a diffuse nodular or micronodular pattern. cryptococcus neoformans (box - ) is an encapsulated, yeastlike fungus that exists in the soil and in the yeast form in humans. the soil may be contaminated by pigeon or chicken excreta. seventy percent of individuals who have clinical disease are immunocompromised (see chapter ). the central nervous system is the most frequently affected site. in the normal host, the most common finding is that of single or multiple pulmonary nodules that are approximately to cm in diameter and that usually occur in the lower lobes (fig. - ) . cavitation, lymph node enlargement, and pleural effusion are uncommon. adenopathy is rarely identified. characteristically, the single or multiple nodules tend to abut the pleura. characteristics candidiasis (box - ) may be caused by a group of various organisms in the candida genus, of which candida albicans is the most important species. c. albicans lives in human and animal sources and may be a normal inhabitant of the spores in soil contaminated with pigeon and chicken excreta of patients with clinical disease, % are immunocompromised central nervous system involvement single or multiple nodules larger than cm affects lower lobes oral pharynx. as a result, short of an open lung biopsy, the true invasiveness or pathogenicity of this organism when recovered from the sputum is difficult to determine. it is an unusual infection found in immunocompromised individuals. the most common sites of infection are the mucous membranes and skin. pulmonary candidiasis is unusual but may occur as a primary infection of the lungs, presumably resulting from aspiration of the organisms from the oral cavity. in most immunocompromised patients, pulmonary infection accompanies a diffuse, widespread fungemia. the radiographic findings are usually nonspecific. although most fungal diseases, particularly in immunocompromised hosts, are characterized by multiple nodules with cavitation, candida pneumonia is more likely to produce areas of consolidation that are multiple and patchy and involve both lungs. cavitation and hilar adenopathy are rare, and pleural effusion occurs in approximately % of cases. characteristics actinomyces (box - ) is a rod-shaped bacterium rather than a fungus, but it is often considered a fungus because of its clinical presentation and radiographic findings. the organism is found in the mouth, and pulmonary infection usually occurs in people with extensive dental caries and poor oral hygiene. involvement results from aspiration of these organisms. there are three forms of actinomycosis: cervicofacial, gastrointestinal, and thoracic. the hallmark of the pulmonary disease is a focal abscess with extension to the chest wall, with secondary complications such as osteomyelitis, bronchopleural fistula, and pericarditis. the organism is an anaerobe, and anaerobic cultures must be obtained to confirm the diagnosis. typical sulfur granules may be identified on pathologic specimens. the radiographic features initially consist of an area of consolidation in the lung. this area may become rounded and suggest an abscess. classic signs include extension of the disease process into the chest wall with bone destruction and osteomyelitis (fig. - ) . chest wall invasion is best appreciated on ct. pleural effusions are moderately common. invasion of the ribs or vertebral bodies characteristically causes bone destruction and fairly extensive reactive periostitis. notice the erosion of the cortex of the overlying rib (arrows). characteristics nocardia (box - ) is a gram-positive organism, and although it is classified as a bacterium, it shares many features with fungal disease. it is weakly acid fast and can be confused with mycobacteria or legionella. it is similar to actinomyces, but the disease usually occurs in immunocompromised patients rather than in normal hosts (see chapter ). focal consolidation is the most common finding, although the disease can appear as single or multiple nodules with cavitation. unlike aspergillosis, progression of disease usually is rather slow. chest wall involvement may occur but is rare. aspergillus (table - ) is a dimorphic fungus. the most common of the many species is aspergillus fumigatus. aspergillus grows widely in soil and water, in decaying vegetation, and in animal material. aspergillosis occurs in several different forms in the lung, including noninvasive (mycetoma) and semi-invasive aspergillosis, invasive aspergillosis, and allergic bronchopul-monary aspergillosis. the type of involvement depends on the immune status of the host. infection is initiated by the inhalation route, and aspergillus spores may exist in the mouth and airways of normal hosts. immunocompetent or mildly immunosuppressed patients may acquire mycetomas or semi-invasive aspergillosis, whereas those who are severely immunosuppressed develop invasive aspergillosis. allergic bronchopulmonary aspergillosis usually occurs in asthmatic patients. the most common radiographic form of aspergillosis is the mycetoma or fungus ball. the fungus ball consists of aspergillus hyphae, mucus, and cellular debris developing within a preexisting cyst, cavity, bulla, or area of bronchiectasis. it grows as a saprophytic organism and usually is noninvasive. a high prevalence of mycetoma has been found among patients with sarcoidosis or cystic fibrosis. symptoms usually include hemoptysis, which may be life threatening. the radiographic appearance of a fungus ball or mycetoma can be quite characteristic (fig. - ) . typically, there is a solid, round opacity within a cavity or thin-walled cyst. air may dissect into the solid mass, creating the appearance of an air crescent. in most cases, the fungus ball is mobile, and changes in position occur with changes in body posture. extensive pleural thickening at the apex of the thorax frequently accompanies the development of a mycetoma. in making the differential diagnosis, necrotizing squamous cell carcinoma and an intrapulmonary abscess should be considered. no treatment is necessary for asymptomatic individuals, but for those who develop severe hemoptysis, there gram-positive, acid-fast bacilli immunocompromised hosts single or multiple nodules with or without cavitation slow progression focal consolidation are several therapeutic options. one is an interventional radiologic technique that consists of embolization of bronchial arteries that supply the cavity. direct installation of amphotericin b in the form of a paste inserted through a percutaneous catheter into the cavity has been successful in some cases. semi-invasive aspergillosis occurs in mildly immunosuppressed patients, such as those with alcoholism, chronic debilitating illness, or advanced malignancy. the lesion usually begins as a focal consolidation in the apex of one or both lungs that progresses over a period of months to become cavitary. it may form a crescent of air (i.e., air crescent sign) similar to that seen in a mycetoma. a thick-walled cavity, which later becomes thin walled and contains a fungus ball, is then formed. the appearance may be identical to that of a mycetoma. it consists of a cavity with or without a fungus ball and air crescent, or it may be a localized area of consolidation. extensive pleural thickening can be identified. the features of invasive aspergillosis are described in chapter , which discusses pulmonary infections in the immunocompromised patient. characteristics allergic bronchopulmonary aspergillosis (see chapter ) occurs almost exclusively in asthmatic individuals. aspergillus spores contained within mucous plugs in the tracheobronchial tree incite an allergic reaction. the syndrome consists of blood eosinophilia with positive precipitins and marked elevation of ige antibodies. large masses of mucus and aspergillus hyphae can become trapped in the airways, producing mucoid impaction of the bronchi. the most characteristic pattern is that of mucoid impaction of the bronchus. central branching opacities, which sometimes are referred to as a finger-in-glove or v pattern, are identified. a more extensive description is provided in chapter . atelectasis distal to the areas of mucoid impaction usually does not occur because of collateral air drift. air trapping may be identified, and lobar consolidation may be present. as the mucous plugs are expectorated, areas of central bronchiectasis can be identified, particularly on ct scans. patients usually respond to steroids, but in the chronic form of the disease, scarring and upper lobe bronchiectasis are prominent features. mucormycosis, almost exclusively a disease in immunocompromised patients, is discussed in chapter . pneumocystis jiroveci (formerly called pneumocystis carinii) is discussed in chapter . in the united states, parasitic infection of the lung is rare. pneumonia is caused by a hypersensitivity reaction to the organisms, or it results from systemic invasion of the lungs and pleura. toxoplasma gondii pulmonary involvement usually develops as part of a more generalized disease. the congenital variety is the most common, and it results from transmission of the organism from mother to fetus. it is associated with a consolidative and hemorrhagic pneumonia in neonates. in adults, toxoplasmosis, like pneumocystosis, occurs in patients who are immunocompromised. the radiographic appearance is that of fairly diffuse reticulonodular opacities. echinococcus granulosus (box - ), the cause of most cases of human hydatid disease, occurs in two forms: pastoral and sylvatic, which differ in definitive and intermediate hosts and in geographic distribution. the pastoral variety is more common and occurs in sheep, cows, or pigs as the intermediate hosts, and in dogs as the definitive host. it is particularly common in sheep-raising areas. the sylvatic variety has as the definitive host the dog, wolf, or arctic fox. approximately % to % of echinococcus cysts occur in the liver, and % to % occur in the lungs. the hydatid cyst is composed of two layers, an exocyst and an endocyst. daughter cysts may be formed within the endocyst. cysts may rupture in the lung parenchyma, with resulting intense inflammation. rupture into the bronchus may result in severe hypotensive shock. echinococcal cysts are usually well-circumscribed, spherical or oval masses that may be single or multiple (fig. - ) . they are usually located in the lower lobes. if communication develops between the cysts and the bronchial tree, air may enter between the pericyst and exocyst, producing the appearance of a thin crescent of air around the periphery of the cyst, sometimes called the meniscus or crescent sign. bronchial communication occurs directly into the endocyst. occasionally, an air crescent sign and air-fluid level can be identified. the membrane of the cyst, which has ruptured into the bronchial tree, may float on the fluid within the cyst, giving rise to the classic water lily sign. ct can differentiate cystic from solid lesions and may identify the pathognomonic features in ruptured or complicated hydatid cysts, such as the presence of daughter cysts and endocyst membranes. calcification of a pulmonary hydatid cyst is rare. pulmonary amebiasis is rare and is usually a sequela of hepatic or gastrointestinal involvement. amebiasis is caused by the protozoan entamoeba histolytica. this organism causes dysentery and has a worldwide distribution. pleuropulmonary complications usually occur when the liver is involved. patients present with right upper quadrant and right-sided pleuritic chest pain. the common radiographic features are right-sided pleural effusion with basal consolidation. involvement of the lung may result from rupture of an amebic abscess in the liver. occasionally, areas of consolidation in the right lower lobe may progress to abscess formation with cavitation. schistosomiasis is a common disease in many areas of the world, including central and south america, the middle east, and the far east. the intermediate host of this parasite is the snail. humans contact the parasites in water. the parasites penetrate the skin, reach the circulation, and eventually grow in the mesenteric or pelvic venous plexus, where they mature into adult worms and lay eggs. pulmonary symptoms may occur during the larval migration phase in the lungs due to a hypersensitivity reaction. a progressive diffuse endarteritis and thrombosis may result from impaction of ova in the pulmonary circulation, with the eventual development of pulmonary arterial hypertension. pathologic changes in the lungs result from deposition of eggs or ova, which are released directly into the systemic venous blood or occasionally into the portal system, where eggs can reach the lungs through anastomotic channels as the liver becomes cirrhotic. the embolized ova become impacted in pulmonary arterioles and then extruded into the surrounding tissue. this causes an obliterative arteriolitis, which can result in increased pulmonary artery pressure. the ova may mature into adult worms in the lungs and can cause lung damage. pulmonary arterial hypertension is the most common finding in patients with pulmonary schistosomiasis (fig. - ) . the appearance consists of dilation of the central pulmonary arteries with rapid tapering. the passage of larva through the pulmonary capillaries can cause a transitory eosinophilic pneumonia, simulating loeffler's syndrome. this is characterized by the presence of peripheral areas of consolidation. the lungs may be infected by a number of worms, causing ascariasis, strongyloidiasis, trichinosis, ancylostomiasis (i.e., hookworm disease), and filariasis (i.e., tropical eosinophilia). most of these organisms produce hypersensitivity reactions in the lungs, similar to loeffler's syndrome (see chapter ). outbreaks of several newly recognized viral infections, including avian influenza, severe acute respiratory syndrome-associated coronavirus, and hantavirus, have been associated with high mortality rates. these infections have presented challenges to clinicians, radiologists, scientists, and public health officials. avian influenza is caused by the h n subtype of the influenza a virus. human transmission occurs through close contact with infected birds, usually from ingestion of infected poultry. the first documented case occurred in in hong kong. in , the virus resurfaced in vietnam. approximately people throughout southeast asia have been infected, with a nearly % mortality rate. affected patients present with a rapidly progressive pneumonia that may lead to respiratory failure and ards. chest radiographs usually show abnormalities at the time of presentation. the most common finding is multifocal consolidation (fig - ) , which is bilateral in % of cases. consolidation may infrequently be complicated by areas of cavitation. bilateral pleural effusions occur in about one third of cases. severe acute respiratory syndrome (sars) is caused by the sars-associated coronavirus. it results in a systemic infection that is manifested clinically as a progressive pneumonia. the first reported case in humans occurred in china in . in , sars spread to hong kong and subsequently to canada, singapore, and vietnam. before the infection could be contained by vigorous public health measures, more than persons were infected, with a nearly % fatality rate. no additional human infections have been reported since . after an initial incubation period of to days (mean, days), affected patients typically present with headache, malaise, fever, and nonproductive cough. chest radiographs show abnormalities at the time of clinical presentation in about % of cases. the most common radiographic finding is poorly defined airspace consolidation. although about one half of cases appear to have a focal distribution at the time of presentation, progression to multifocal involvement is common. areas of consolidation have a predilection for the lower lobes and lung periphery. ct shows abnormalities at the time of clinical presentation, even when chest radiographs do not. the most common ct finding is ground-glass opacification (fig - ) , which is often accompanied by small foci of consolidation and interlobular and intralobular thickening. severe sars may progress to diffuse alveolar damage. overall, % of patients with sars require mechanical ventilation, and % of patients do not survive the infection. survivors often have residual abnormalities seen on ct, reflecting interstitial fibrosis and small airways disease. hantaviruses are carried by rodent vectors. human infection occurs after inhalation of aerosolized rodent feces or urine. the sin nombre hantavirus (translated as "the nameless virus") was initially discovered in the southwestern united states in as a cause of pulmonary edema and respiratory failure accompanied by hematologic abnormalities. this clinical entity is referred to as the hantavirus pulmonary syndrome (hps). hps is caused by endothelial damage to the lung. the initial interstitial edema manifests radiographically as kerley lines, bronchial wall thickening, and subpleural edema. although some patients recover fully from the initial stage of infection, many progress to diffuse alveolar edema, which is manifested by symmetric perihilar and basilar airspace consolidation (fig - ). this phase of illness requires mechanical ventilation and is associated with a high mortality rate. as the disease progresses, it may be accompanied by myocardial depression, which worsens tissue hypoxia and contributes to the high mortality rate associated with this syndrome. the centers for disease control and prevention (cdc) lists several infectious agents as a category a threats, denoting the highest potential for public health impact. these agents include inhalational anthrax (bacillus anthracis), plague (y. pestis), smallpox (variola major), botulism (clostridium, botulinum), tularemia (francisella tularensis), and hemorrhagic fever (ebola and marburg filoviruses). among these infections, anthrax has the unique distinction that imaging studies may allow prompt diagnosis and institution of life-saving therapy before organ damage is irreversible. for this reason, the discussion focuses on anthrax. anthrax has been used as a biologic weapon since world war ii. the most recent episode occurred in , when highly refined anthrax spores were placed in envelopes and mailed through the united states postal system. this act of bioterrorism resulted in diagnosed cases of anthrax, which were evenly split between inhalational and cutaneous forms. almost one half of those with the inhalational form died. b. anthracis is a sporulating, gram-positive bacterium that may result in cutaneous, gastrointestinal, or pulmonary infection. the latter, which is also referred to as inhalational anthrax, is the deadliest form. the spores are to μm, an ideal size for deposition in the distal respiratory tract after inhalation. once inhaled, the spores are ingested by macrophages. surviving spores are transported to mediastinal lymph nodes, where they germinate for to days (mean, week). radiologic findings have not been identified before germination. after germination, the organisms synthesize a toxin, resulting in the prodromal phase of the disease. this is manifested by flulike symptoms of fever, chills, fatigue, and cough. the prodromal phase lasts about days and is rapidly followed by the second phase of the illness, which is characterized by stridor, respiratory failure, and shock. in many cases, death occurs despite antibiotic therapy. imaging findings for anthrax reflect hemorrhagic lymphadenitis and mediastinitis caused by the release of anthrax toxin within the mediastinum. in the prodromal phase of the illness, the chest radiograph typically demonstrates mediastinal widening and unilateral or bilateral hilar enlargement. these findings are frequently accompanied by pleural effusions. although limited peribronchovascular airspace opacities may be present, extensive consolidation is uncommon. imaging findings of mediastinal widening and pleural effusions are helpful for differentiating inhalational anthrax from a community-acquired respiratory infection. ct may provide convincing evidence of inhalational anthrax before confirmatory laboratory tests have returned (fig - ). unenhanced ct may show high-attenuation ( to hounsfield units) mediastinal and hilar lymph nodes, which may rapidly enlarge over a period of days. these findings reflect the presence of hemorrhage and edema within lymph nodes. because of this characteristic appearance, unenhanced ct is considered the imaging modality of choice for the diagnosis of inhalational anthrax. after contrast administration, rim enhancement and central low attenuation of lymph nodes may be seen. rapidly enlarging pleural effusions are commonly identified by ct, and they may contain dependently layering, highattenuation fluid, reflecting serosanguineous exudates. peribronchovascular thickening correlates with the presence of edema, hemorrhage, and necrosis of the airways and adjacent lymphatics. the constellation of these ct findings is almost pathognomonic for inhalational anthrax, but a variety of other causes of mediastinitis may produce similar findings in the appropriate clinical setting. inhalational anthrax is treated with an antibiotic regimen that includes ciprofloxacin or doxycycline combined with two other agents, usually rifampin and clindamycin. early recognition of anthrax and prompt administration of antibiotics before the onset of fulminant illness can dramatically improve patient survival. tree-in-bud pattern: frequency and significance on thin section ct aspiration and inhalation pneumonias pulmonary coccidioidomycosis reported tuberculosis in the united states. department of health and human services, cdc pulmonary 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aviumintracellulare complex: evaluation with ct mycoplasmal, viral, and rickettsial pneumonias viral pneumonia radiology of severe acute respiratory syndrome (sars): the emerging pathologic-radiologic correlates of an emerging disease radiology of bacterial weapons-old and the new? hantavirus pulmonary syndrome: radiologic findings in patients thoracic cryptococcosis: immunologic competence and radiologic appearance viral pneumonia in adults: radiologic and pathologic findings clinicoradiographic correlation with the extent of legionnaire disease ct features of thoracic mycobacterial disease pulmonary septic emboli: changes with ct anaerobic pleural and pulmonary infections pneumonia caused by mycoplasma pneumoniae infection ct features of pulmonary mycobacterium avium complex infection studies in chronic allergic bronchopulmonary aspergillosis. i. clinical and physiological findings thoracic manifestations of tropical parasitic infections: a pictorial review pneumatocele formation in adult pneumonia tuberculosis: frequency of unusual radiographic findings pulmonary infections granulomatous infections of the lung tuberculosis in the normal host: radiological findings spectrum of pulmonary non-tuberculous mycobacterial infection atypical mycobacterial infection in the lung: ct appearance pulmonary aspiration complexes in adults guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention pneumococcal pneumonia in hospitalized patients' clinical and radiological presentations pulmonary cryptococcosis adult respiratory distress syndrome infectious pneumonias-including aspiration states the radiologic manifestations of h n avian influenza hilar and mediastinal adenopathy caused by bacterial abscess of the lung viral pneumonitis thoracic histoplasmosis other mycobacterium species tuberculosis among elderly persons: an outbreak in a nursing home imaging of bacterial pulmonary infection in the immunocompetent patient severe acute respiratory syndrome: radiographic appearance and pattern of progression in patients pulmonary aspiration of gastric contents update: the radiographic features of pulmonary tuberculosis pulmonary bacterial and viral infections key: cord- -oots fe authors: laya, bernard f. title: infections date: - - journal: radiology illustrated: pediatric radiology doi: . / - - - - _ sha: doc_id: cord_uid: oots fe lower respiratory tract infection is a very common illness in children and is a significant cause of morbidity and mortality. clinical signs and symptoms are nonspecific especially in infants and younger children and some even present with nonrespiratory complaints. infectious agents causing pneumonia is not limited to viruses and bacteria, but it could also be due to mycoplasma, mycobacteria, fungi, protozoa, and parasites. coinfection with two or more microbial agents can also occur. the etiologic agent of lower respiratory infection in a child is often difficult to obtain, but the patient’s age can help narrow the possible cause. microbiological tests are important but could be difficult to obtain especially in younger children. various medical imaging modalities not only play an important role as an aid in diagnosis but can also help during and after therapy. imaging can also help evaluate complications to pneumonia and exclude other causes of respiratory distress including underlying developmental anomalies, foreign body, gastroesophageal reflux disease, and aspiration. in this chapter, the imaging modalities utilized in the detection of pulmonary infections will be discussed. the spectrum of typical imaging findings for various etiologic agents in both immunocompetent and immunocompromised children will be presented. lower respiratory tract infection is the most common cause of illness in children and is a signifi cant cause of morbidity and mortality. there are also associated complications, which should be recognized in order to make correct decisions regarding interventions or management. clinical signs and symptoms are nonspecifi c, especially in infants and younger children. some children with pneumonia even present with nonrespiratory symptoms including fever, malaise, decreased appetite, irritability, weakness, chest pain, and abdominal symptoms. physical examination is also less reliable in children than adults (donnelly ) . microbiological tests are important but could be diffi cult to obtain especially in younger children. various medical imaging modalities not only play an important role as an aid in diagnosis but can also help during and after therapy. diagnosis of pneumonia calls for a combination of clinical awareness, appropriate microbiological tests, and radiological studies. the cause of pneumonia in a child is often diffi cult to identify, but the patient's age can help narrow the possible etiologies. viral pneumonia is rare in the neonatal period because of conferred maternal antibody protection. group b streptococcus and gram-negative enteric bacteria are the most common pathogen in neonates (birth to days), obtained through vertical transmission from the mother during birth. from age weeks to months, streptococcus pneumoniae is the most common pathogen. viruses are the most frequent cause of community-acquired pneumonia in infants older than months and in preschool-aged children, with respiratory syncytial virus (rsv) being the most common. for school-aged children ( - years old), the incidence of bacterial infections from streptococcus increases, although viral disease remains the most common cause (condon ; ostapchuk et al. ) . bacterial pneumonia can occur at any time in preschool and school-aged children and adolescents. mycoplasma pneumoniae causes % of lower respiratory tract infections in school-aged children (condon ; donnelly ) . infectious agents causing pneumonia are not limited to viruses and bacteria, but it could also be due to mycobacteria , fungi, protozoa, and parasites. co-infection with two or more microbial agents can also occur. evaluation of suspected pulmonary infection is a very common indication for an imaging study in children. the role of imaging including chest radiographs, ultrasound, computed tomography (ct), and even magnetic resonance imaging (mri) is to detect the presence or exclusion of pneumonia, determine its location, characterize and describe the extent of pneumonia, exclude other causes of respiratory symptoms, and show complications. it is also an important tool for image-guided interventions. the cornerstone of imaging in children suspected of having pulmonary infection is the chest radiograph. the radiographic appearance refl ects the pathologic process occurring in the respiratory system (bramson et al. ) . frontal and lateral views are obtained when possible because hyperinfl ation and lymphadenopathy are more accurately evaluated on a lateral radiograph especially in younger children. lateral decubitus views may be useful in distinguishing free fl owing pleural fl uid versus loculated fl uid collections. chest radiographs have inherent limitations, but despite of this, there is moderate evidence to suggest that chest radiographs are suffi ciently sensitive and highly specifi c for the diagnosis of community-acquired pneumonia (westra and choy ). . . tuberculosis: progression of lymph node disease .................................................................. . the use of ultrasound as an imaging tool for pulmonary infections has been increasing especially for assessment of complications. its utility is even more important because there is no associated radiation, no sedation, no specifi c preparation, and the ultrasound machine can be transported to the patient's bedside. it can be used for planning thoracentesis, thoracotomy, and image-guided drainage procedures. lower-frequency ( . - mhz) sector transducers are initially used for overview through inter-and subcostal scanning, but higher-frequency ( - . mhz) linear transducers are helpful for more detail in the near fi eld. the development of helical and multidetector ct has revolutionized imaging evaluation of pulmonary infections. the use of intravenous contrast medium also helps optimize the assessment of pleura, mediastinum, and pulmonary parenchyma in cases of complicated pneumonia. high-resolution ct (hrct) shows greater accuracy in characterizing diseases into interstitial, airway, and airspace processes and gives a more accurate depiction of the extent of the disease. ct has an important role when a complication is suspected, to exclude an underlying abnormality in recurrent and persistent infections, for image-guided interventions, and for the evaluation of immunocompromised children (westra and choy ) . radiation-associated risks are important to consider, and thus, a clear indication for the procedure has to be present. low radiation dose technique with - kvp, age and thoracic thickness-adjusted low milliampere-seconds, along with radiation dose modulation should be utilized. evaluation of lung parenchyma with conventional mr imaging has limitations because of the inherent low proton density and weak mr signal as related to the low physical density of the lung. however, lung parenchymal, pleural, and lymph node infl ammatory abnormalities can be visualized and characterized by mri in children with pulmonary infections. peripheral airways disease or bronchiolitis are common terms ascribed to lower respiratory infection secondary to viruses. it commonly occurs in children less than years of age, typically presenting with cough, coryza, and wheezing. rsv is the most common cause, but other viral causes include rhinovirus, parainfl uenza virus, human metapneumovirus, adenovirus, infl uenza virus, coronavirus, and human bocavirus (eslamy and newman ) . following inhalation of infected aerosols, the virus migrates to small airways and alveoli resulting to bronchoconstriction and increased mucous secretion (aherne et al. ; swischuk and hayden ) . typical chest radiographic appearances are peribronchial thickening/opacities, hyperaeration, and subsegmental atelectasis ( fig. . ). the peribronchial infl ammation and edema manifests as increased peribronchial cuffi ng or thickening of the bronchial walls, which is usually asymmetric and radiates from the hila into the lung. narrowed distal airway lumen due to bronchiolar wall edema and mucus results in hyperinfl ation with areas of segmental and subsegmental atelectasis (condon ; donnelly ) . patchy areas of airspace consolidation have also been described in viral pneumonia. ct is rarely required in the investigation of viral lower respiratory infection, but the most common ct feature is peribronchial thickening and ground-glass attenuation without consolidation (tanaka et al. ) . varicella zoster virus infection is a highly contagious but a relatively benign, self-limited disease in childhood. varicella pneumonia is regarded as a serious manifestation in adults, but immunocompromised children are also at risk. clinically, cough, fever, dyspnea, chest pain, and vesicular rash are generally accompanied by mild constitutional symptoms (kim et al. ) . radiographs of the chest initially reveal nodular infi ltrates that may progress to large segmental areas of patchy consolidation, predominantly in the bases and perihilar regions. total clearing is virtually guaranteed, although punctate calcifi cations maybe evident within years after acute illness ( fig. . ). airspace disease associated with chicken pox in children occurs most often in the immunocompromised host (blickman ) . certain groups of viruses have been recently reported to cause severe respiratory infection leading to respiratory failure and even death. the severe acute respiratory syndrome (sars) caused by coronavirus a (sars-cov) created a scare in with over , cases reported from different countries. sars presents with a prodrome of fl u-like illness, followed by cough, dyspnea, and possibly acute respiratory distress. the initial radiographic manifestation is the presence of focal or diffuse interstitial opacities but rapidly progresses to bilateral areas of consolidation (thibodeau and viera ) (fig. . ). another pandemic virus is the infl uenza virus a h n (avian infl uenza virus), originating from asia and spreading over many parts of the world from to . more recently, infl uenza virus of swine origin, designated as infl uenza a h n , was fi rst reported in mexico in and has rapidly spread globally. symptoms range from asymptomatic infection to mild upper respiratory illness, viral syndrome, diarrhea, severe pneumonia, acute respiratory distress syndrome (ards), and progression to multiorgan failure. initial chest radiographs in children with a mild and self-limited clinical course are often normal, but they may demonstrate prominent peribronchial markings with hyperinfl ation and multifocal areas of consolidation (lee et al. ) (fig. . ) . the most common complication of viral pneumonia is a secondary bacterial infection. viral infection can compromise the respiratory mucosa and render the host pulmonary respiratory system susceptible to develop superimposed bacterial pneumonia (donnelly ) . postinfectious bronchiolitis obliterans (constrictive bronchiolitis or obliterative bronchiolitis) is a clinical syndrome of chronic airfl ow obstruction associated with infl ammatory changes in the small airways as response to epithelial injury associated with infections. it is particularly associated with adenovirus , rsv, varicella , and severe mycoplasma infection. the chest x-ray fi ndings are often nonspecifi c and can appear normal, but the most common abnormality is hyperaeration (yalcin et al. ). on hrct, there is a mosaic perfusion pattern ( fig. . ). perfusion is diminished in areas of parenchymal attenuation due to vasoconstriction secondary to hypoxia. inspiratory and expiratory phases of ventilation are important in hrct to better assess air trapping in this condition (hansell et al. ) . peribronchial thickening, atelectasis, bronchiectasis, and sometimes lung volume reduction can also be seen. swyer-james is a subtype of postinfectious bronchiolitis obliterans, which is typically unilateral. it can affect one lung segment, a lobe, or the entire lung. the characteristic chest radiographic and ct fi ndings are hyperlucency due to the pulmonary hypoperfusion, reduction of vascular and hilar markings, and volume reduction of the affected lung or lobe (daltro et al. ) (fig. . ). bacterial pneumonia occurs with the inhalation of the infectious agent into the airspaces. it is most commonly caused by s. pneumoniae , haemophilus infl uenza type b, and staphylococcus aureus . staphylococcus commonly occurs in early infancy, haemophilus most often between and months, and s. pneumoniae more commonly between and years of age. gram-negative aerobic bacteria such as pseudomonas aeruginosa and s. aureus are a major problem in patients with cystic fi brosis. patients present with cough, chest pain, and high fever. following inhalation of the infectious agent into the airspaces, acinar exudate and edema ensues, manifesting as localized airspace consolidation with air bronchogram on chest radiographs. the typical distribution is lobar or segmental, depending on the stage of progression at the time the x-ray was obtained ( fig. . a ) (condon ; donnelly ) . round pneumonia is a spherical pneumonia, usually caused by s. pneumoniae (rose and ward ) (fig. . b ). it is common in children less than years old, maybe due to poor development of collateral pathways of ventilation (pores of kohn and channels of lambert). when round pneumonia is seen in children over years old, other etiologies should be considered. the ct manifestations of bacterial infection are areas of consolidation with or without air bronchogram, typically with a segmental or lobar distribution and involving the lung periphery (tanaka et al. ) . parapneumonic effusions occur most commonly in bacterial pneumonia. it represents a spectrum of infl ammatory fl uid collections that ranges from transudative effusion to empyema. parapneumonic effusions complicate pneumonia in - % of cases in pediatric patients (kurt et al. ) , and empyema complicates an estimated . % of all childhood pneumonias (jaffe and balfour-lynn ) . pleural fl uid can usually be detected on a frontal chest radiograph, but layering of fl uid on the lateral decubitus view distinguishes a free fl owing fl uid from a loculated fl uid. ct scan gives a better characterization of parapneumonic effusions compared to radiographs. ct fi ndings include enhancement and thickening of the parietal and visceral pleura, thickening of the extrapleural subcostal tissues, and increased attenuation of the extrapleural subcostal fat (muller ) (fig. . ). these ct characteristics do not accurately predict empyema and should not be used to distinguish between empyema and transudative effusions. in ultrasound, pleural fl uid can be characterized as simple effusion, complicated effusion, or fi brothorax (pleural thickening or fi brosis) ( fig. . ) . a simple effusion appears as a clear anechoic or cloudy hypoechoic fl uid with or without swirling particles. a complicated effusion appears as a septated or multiloculated, hypoechoic fl uid with fi brinous septations, with no clear demarcation between the lung and pleural components, while a fi brothorax appears as a thickened, echogenic rind of pleural plaque (kim et al. ) . suppurative lung parenchyma complications represent a spectrum of abnormalities including cavitary necrosis, lung abscess, pneumatocele, bronchopleural fi stula, and pulmonary gangrene. necrotizing pneumonia or cavitary necrosis is a complication of severe lobar pneumonia, characterized by massive necrosis and liquefaction of lung tissues resulting to multiple cavities rather than a solitary one. it is most commonly caused by s. pneumoniae although aspergillus and legionella have also been implicated in the pediatric population (hodina et al. ) . evidence of cavitary necrosis complicating pneumonia is often seen on ct before or in the absence of fi ndings in chest radiography. ct fi ndings include lung consolidation with decreased parenchymal enhancement, loss of lung-pleura margin, and multiple thin-walled cavities lacking an enhancing border. the adjacent visceral pleura is particularly fragile and tends to rupture, causing bronchopleural fi stula (hoffer et al. ) (fig. . ). cavitary necrosis indicates an intense and prolonged illness, but it usually resolves without surgical intervention (donnelly and klosterman ) . lung abscesses are thick-walled cavities containing purulent material resulting from pulmonary infection. an airfl uid level with reactive rim is a typical imaging appearance, as compared to necrotizing pneumonia where cavities occasionally have air-fl uid level but without rim of enhancement (donnelly and klosterman ) (fig. . ). differentiating the two is important because abscess not responding to therapy may require drainage, whereas necrotizing pneumonia does not require invasive treatment, and intervention may even be harmful resulting in complications such as bronchopleural fi stula (hoffer et al. ) . pneumatoceles are thinwalled cysts without septations that develop within the lung parenchyma after an acute pneumonia (fig. . ) . it may represent a later or less severe stage of resolving or healing necrosis and is most often associated with s. aureus (daltro et al. ) . bronchiectasis is the most common long-term sequelae of lung parenchymal damage from pneumonia. it is best demonstrated on high-resolution chest ct scan, and the main diagnostic features are as follows: internal diameter of the bronchus is wider than its adjacent pulmonary artery, failure of the bronchus to taper peripherally, and visualization of bronchi in the outer - cm of the lung zones (eslamy and newman ) (fig. . ). pertussis is a highly contagious respiratory bacterial infection caused by bordetella pertussis . it infects mainly infants and young children causing symptoms that include mild fever, runny nose, and cough, which develops into a paroxysmal cough followed by whooping (whooping cough). pneumonia is a common complication, and untreated patients may be contagious for weeks or more following onset of the cough. the spread of pertussis can be prevented by immunization. histopathologic examination reveals an infection dominated by necrotizing bronchiolitis, intra-alveolar hemorrhage, fi brinous edema, and angiolymphatic leukocytosis (paddock et al. ) . conventional radiographs reveal streaky perihilar infi ltrates with most often unilateral hilar adenopathy, a pattern sometimes called the shaggy heart appearance (blickman ) (fig. . ) . m. pneumoniae is a common ubiquitous organism and treatable cause of community-acquired pneumonia, occurring primarily in children and young adults. it accounts for up to % of all pneumonia in the general population, but the highest incidence is seen in children between and years of age. of those infected, % get tracheobronchitis, % pneumonia, % pharyngitis, and % otitis media. clinically, symptoms are less severe but more common than in true bacterial pneumonia (blickman ) . the radiographic fi ndings are nonspecifi c, have a broad spectrum of appearances, and may present with a pattern intermediate between the classic viral and bacterial pneumonia patterns (hsieh et al. ). some authors reported that a reticulonodular pattern or nodular opacities are typical radiographic pattern (john et al. ) , while others stress the occurrence of confl uent and patchy consolidation (reittner et al. ) (fig. . ). hrct fi ndings are thickened bronchovascular bundles, ground-glass attenuation and consolidation, centrilobular nodules, and lobular distribution (tanaka et al. ; reittner et al. ) . chlamydia trachomatis is an obligate intracellular parasite. genital chlamydial infection is recognized as the world's most common sexually transmitted disease, and the high prevalence in women of childbearing age results in exposure of neonates during childbirth. chlamydia pneumonia is a neonatal infection acquired after passage of the fetus through the cervix and vagina. the infant typically presents at - weeks of age with respiratory symptoms and occasional pulmonary hemorrhage. c. trachomatis should be suspected in infants who are afebrile or nontoxic and have a dry cough. these patients often have a peripheral eosinophilic pleocytosis, sometimes with concomitant conjunctivitis (ostapchuk et al. ). most chest radiographs show bilateral hyperaeration and diffuse infi ltrates with a variety of radiographic patterns including interstitial, reticular nodular, atelectasis, coalescence, and bronchopneumonia (radkowski et al. ) (fig. . ). tuberculosis (tb) is caused by infection with the mycobacterium tuberculosis complex. once inhaled, the infected aerosolized droplet in the alveoli cascades a series of infl ammatory reaction, and the bacilli also spread to nearby mediastinal lymph nodes. the alveolar site of infection (ghon focus), the infected lymph nodes, and the associated lymphangitis form the "primary (ranke's) complex." in most immunocompetent children, the infection goes into latency and the bacilli become dormant. these children usually have a reactive tuberculin skin test (tst) and/or a positive interforon-gamma release assay (igra) test, but without clinical evidence of tb and generally no abnormalities on chest radiograph apart from the primary complex residual. primary tuberculosis disease occurs if the host is unable to contain the infection, and disease progression occurs in the lungs, the lymph nodes, and adjacent structures in the thorax or could disseminate in any part of the body. lymphadenopathy (present in %) with or without a visible ghon focus is the radiographic hallmark of tb infection and usually involves the hilar and paratracheal regions. the ghon focus may be too small to be radiographically visible but can also undergo caseation and calcify ( fig. . ). disease progression may occur at the site of ghon focus, within the regional lymph nodes, or following disease spread (fig. . ). parenchymal involvement in primary pulmonary tb most commonly appears as homogeneous consolidation, although it can appear patchy, linear, nodular, and mass-like. caseation necrosis, liquefaction, or calcifi cations can be seen within the consolidation and can progress into extensive lung damage (marais et al. ) (fig. . ). enlarged and edematous hilar, paratracheal, and subcarinal lymph nodes may cause compression of the adjacent bronchus and can lead to hyperinfl ation or atelectasis of the affected lung segment. contrast-enhanced ct shows a characteristic appearance consisting of central areas of low attenuation with peripheral rim enhancement and obliteration of perinodal fat (kim et al. ) (fig. . ) . pulmonary dissemination, usually seen in very young and immunocompromised patients, leads to the formation of pulmonary nodular interstitial granulomas, usually - mm in size, throughout the lungs. chest radiographs demonstrate the usual miliary nodular pattern but ct is more sensitive for the detection of miliary tb (kim et al. ) (fig. . ) . adult-type disease presentation is common after primary infection in children over years of age or via endogenous reactivation (postprimary tb) or reinfection. chest radiograph shows ill-defi ned, fi bronodular parenchymal disease and cavitation mainly involving the apical segments of the upper lobes (perez-velez and marais ) (fig. . ). aspergillus fumigatus is a ubiquitous saprophytic mold found in many environmental sites, and infection is usually via inhalation of spores, although other routes of entry also occur. infection can manifest as colonization of airway cavities and necrotic tissue, allergic disease, and invasive disease, which is usually acute and rapidly progressive severe disease (foster and alton ) . airway colonization occurs in patients with underlying airway disease such as asthma and bronchiectasis. intertwined fungal hyphae, called as mycetoma or aspergilloma, form in the pulmonary cavity or ectatic bronchi. important underlying causes are pulmonary tb with cavitation and cystic fi brosis with bronchiectasis. rounded soft tissue mass within a cavity forming an "air-crescent" sign is a typical appearance ( fig. . ). allergic bronchopulmonary aspergillosis is characterized by mucoid impaction of the proximal bronchi presenting as fi ngerlike shadows involving the upper lobes on the chest radiograph. ct demonstrates the mucoid impaction of the central airways and the bronchiectasis of the segmental or subsegmental airways (foster and alton ) . invasive disease is an aggressive, rapidly disseminating and destructive disease and occurs when host defenses are impaired. it is characterized by the occlusion of large-or medium-sized arteries by plugs of hyphae causing pulmonary hemorrhage, arterial thrombosis, and infarction. radiographic fi ndings are nonspecifi c, with multiple nodules or areas of consolidation (fig. . ) . the typical ct fi nding is the halo sign due to ground-glass attenuation representing hemorrhage surrounding the pulmonary nodule or mass (foster and alton ; eslamy and newman ) . histoplasmosis, caused by the fungus histoplasma capsulatum , is usually an asymptomatic and self-limited disease that rarely requires therapy in children other than the very young or immunocompromised. it is found in the soil of endemic areas including central united states, central america, and northern south america but has also been reported in some parts of asia (houston ) . after inhalation, the spores germinate within the alveoli inciting an intense tissue reaction characterized by granulomas, which may calcify. it spreads to the lymphatics and into the hilar or mediastinal lymph nodes, and systemic dissemination may occur in patients with impaired t-cell immunity (mcadams et al. ) . histoplasmosis falls in one of three categories: acute, chronic pulmonary, and disseminated disease. acute pulmonary histoplasmosis is a self-limited illness. chronic pulmonary histoplasmosis occurs in patients with chronic lung disease and presents similar to tuberculosis with predilection for apical and posterior segments of the lung. disseminated histoplasmosis in children is characteristically a fulminant illness, which may or may not have pulmonary involvement. radiologic manifestations parallel the clinical syndromes. acute disease usually manifests as focal parenchymal consolidation with or without ipsilateral hilar adenopathy (fig. . ) . with healing, a nodule representing a histoplasmoma may result. chronic histoplasmosis radiographically manifests as an upper lobe fi brocavitary disease indistinguishable from postprimary tuberculosis. chest radiographs of patients with disseminated disease may show miliary or diffuse reticulonodular pattern that could progress to diffuse airspace opacifi cation (mcadams et al. ) . echinococcosis, also known as hydatid disease or hydatidosis, is a parasitic infection in humans caused by dog tapeworm, echinococcus granulosus , in its larval stage. it is endemic in many sheep and cattle-raising countries throughout the world. humans are intermediate hosts and become infected through ingestion of contaminated water or vegetables. when eggs of adult tapeworm are ingested, embryos are freed and migrate through the host's gastrointestinal mucosa and enter the portal vein and lymphatic system to various parts of the body where the embryo develops into a cyst. the wall of the cysts contains three layers: the outermost, pericyst; the middle laminated membrane layer, ectocyst; and innermost germinal layer, endocyst (czermak et al. ) . the lungs are the most common sites of infection in children but majority remain asymptomatic until the cyst enlarges to cause symptoms due to mass effect or due to cyst rupture (santivanez and garcia ) . diagnosis is obtained by imaging evaluation, supported by serology. a high proportion of lung lesions are discovered incidentally on a routine x-ray, and the most prominent radiological fi nding is a dense, round, well-demarcated opacity that can resemble a neoplasm (fig. . a ) . when the growth of the cyst produces erosion in the bronchioles, air between the endocyst and pericyst can produce a "crescent or inverse crescent sign." if air continues to enter the cyst cavity, endocyst membrane can be seen fl oating in the most dependent part of the pericyst cavity producing the "waterlily sign" (fig. . b ) . ct recognizes the appearance of the cystic lesion including smaller cysts, assesses signs of cyst rupture, evaluates the surrounding structures, and helps exclude alternative differential diagnoses (santivanez and garcia ) . ascariasis and hookworms remain the most common intestinal nematodes in the world (sarinas and chitkara ) . in the western hemisphere, parasitic pneumonia secondary to toxoplasma gondii is associated with compromised hosts, particularly acquired immunodefi ciency syndrome (aids) patients. strongyloides stercoralis infestation is seen in patients receiving glucocorticoids or chemotherapy and in patients with aids or other causes of t-cell dysfunction (berk and verghese ) . ascaris infestation generally occurs through hand-to-mouth ingestion of food contaminated with parasite eggs, while hookworms are transmitted through larval penetration of the skin. symptomatic pulmonary disease may present with fever, cough, chest pain, hemoptysis, dyspnea, and wheezing. these pulmonary symptoms could be due to loffl er's syndrome, effects of larval tissue migration, airway reactivity or bronchospasm, superimposed bacterial infection, and chronic eosinophilic pneumonia (sarinas and chitkara ) . ascaris and hookworm infections present with peripheral eosinophilia during larval migration phase. chest radiographs could be normal or demonstrate nonspecifi c patchy pulmonary infi ltrates (fig. . ) . ct scan could depict abnormalities better and could show ground-glass pulmonary lesions with ill-defi ned margins as well as nodules (sakai et al. ). causes of immunodefi ciency can be divided into congenital (primary) and acquired (secondary). the range of respiratory complications encountered is broad and is infl uenced by both the type and degree of immunodefi ciency. chest radiographs are insensitive and may show only subtle change. hrct detects abnormalities not visible on the plain fi lm such as bronchial wall thickening, bronchial dilatation, and air trapping. various noninfectious pulmonary processes including alveolar hemorrhage, pulmonary edema, graft versus host disease, and drug reaction are also seen in the immunocompromised hosts, which can mimic pulmonary infection on imaging. the primary or congenital immunodefi ciency disorders are inherited group of disorders resulting from innate defects of the immune system. clinical manifestations are diverse and nonspecifi c, which include recurrent infections, infection with opportunistic organisms, failure to thrive, skin rashes, recurrent skin sepsis, and unusual wound healing (jeanes and owens ) . primary immunodefi ciency can be broadly divided into t-cell (cellular) immune defi ciency versus b cell (humoral defi ciency). humoral immunodefi ciencies are the most commonly encountered type characterized by defective antibody production with increased susceptibility to pyogenic infections but able to recover from viral infections (fig. . ). examples are x-linked agammaglobulinemia, iga defi ciency, and common variable immunodefi ciency. cellular immunodefi ciencies have increased susceptibility to disseminated viral and opportunistic infections. cellular immune disorders include digeorge syndrome and severe combined immunodefi ciency (collingsworth ) . acquired immunodefi ciencies in childhood can be caused by chemotherapy, radiation therapy, immunosuppressive therapy aimed at treating childhood malignancies, transplant rejection, rheumatologic disorders, or infl ammatory or infectious diseases. it can also be due to human immunodeficiency virus (hiv) infection, malnutrition, or any state of chronic debilitation. bone marrow transplant requires complete eradication of the immune system. early infectious complications are frequently caused by bacteria and fungi, most commonly gramnegative bacteria ( pseudomonas and klebsiella ) and aspergillus (fig. . ). widespread use of long-term indwelling catheters has led to an increased incidence of both staphylococcal and streptococcal pneumonia. chest radiographs may show classic focal or lobar consolidation although atypical appearance can also be seen. children are also at increased risk of viral infections, most importantly rsv, herpes simplex , adenovirus , and varicella . immunosuppressive therapy following solid organ transplantation predisposes a patient to recurrent pulmonary infections. in these patients, viral infections can be life-threatening, but pneumocystis and fungal infections ( aspergillus and candida ) can also be seen (collingsworth ) . children represent % of the reported cases of human immunodefi ciency virus (hiv) infection. most children are infected after vertical transmission from their mother, and majority develop acquired immunodefi ciency syndrome (aids) early in life. there is increased susceptibility to bacterial, viral, fungal, protozoal, and opportunistic infections. lobar or segmental consolidations are the most common patterns (marks et al. ) . mycobacterial infection can be seen in aids patients, and the radiographic appearance mimics that seen in immunocompetent children with primary tuberculosis. mycobacterium avium-intracellulare is also encountered later in the course of disease and imaging fi ndings cannot be distinguished with other forms of mycobacterial infections (collingsworth ) . pneumocystis jiroveci is the most common opportunistic pulmonary infection in children with aids, occurring in up to %, and is the leading pulmonary cause of death (jeanes and owens ) . radiographic appearances are variable and include hyperinfl ation with diffuse bilateral interstitial or nodular infi ltrates from the perihilar region to the periphery, which often progresses to widespread alveolar opacities with air bronchogram (fig. . ) . cavitary nodules and cysts can be seen, with pneumothorax and/or pneumomediastinum as common complications. hrct fi ndings include patchy or diffuse ground-glass opacity, consolidation, cyst or cavities, centrilobular opacities, nodules, peribronchial cuffi ng, and interlobular septal thickening (jeanes and owens ; collingsworth ) . pathological changes in virus 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pulmonary involvement in the tropics mycoplasma pneumonia: clinical and radiographic features management of empyema in children chest imaging in the immunocompromised child spectrum of clinical and radiographic fi ndings in pediatric mycoplasma pneumonia pulmonary tuberculosis in children: evaluation with ct high resolution ct fi ndings of varicella zoster pneumonia ultrasound in the diagnosis of pediatric chest diseases therapy of parapneumonic effusions in children: video-assisted thoracoscopic surgery versus conventional thoracostomy drainage swine-origin infl uenza a (h n ) viral infection in children: initial chest radiographic fi ndings the natural history of childhood intrathoracic tuberculosis: a critical review of prechemotherapy literature thoracic diseases in children with aids thoracic mycoses from endemic fungi: radiologic-pathologic correlation imaging of the pleura community acquired pneumonia in infants and children pathology and pathogenesis of fatal bordetella pertussis infection in infants tuberculosis in children chlamydia trachomatis in infants: radiography in cases mycoplasma pneumoniae pneumonia: radiographic and hrct features in patients spherical pneumonias in children simulating pulmonary and mediastinal masses pulmonary lesions associated with visceral larva migrans due to ascaris suum and toxocara canis : imaging of six cases pulmonary cystic echinococcosis ascariasis and hookworm viral versus bacterial infections in children: is roentgenographic differentiation possible? high resolution fi ndings in community acquired pneumonia atypical pathogens and challenges in community acquired pneumonia what imaging should we perform for the diagnosis and management of pulmonary infections? postinfectious bronchiolitis obliterans in children: clinical and radiological profi le and prognostic factors key: cord- -ftz a authors: richards, guy a.; schleicher, gunter; mer, mervyn title: viruses in the intensive care unit (icu) date: journal: tropical and parasitic infections in the intensive care unit doi: . / - - - _ sha: doc_id: cord_uid: ftz a whereas viruses are not usually considered to be important causes of icu admission this review has demonstrated this perception to be incorrect. viruses and their manifestations differ from continent to continent and hemisphere to hemisphere and it is essential that the intensivist be familiar with diagnosis and management of these ubiquitous organisms. infectious diseases in the developing world icu usually involve bacterial sepsis resulting from community-acquired pneumonia, pelvic inflammatory disease, ruptured abdominal viscus (traumatic or spontaneous), necrotising fasciitis, or more exotic infections such as malaria. despite their importance, viruses are rarely considered, except during outbreaks of hemorrhagic fever in which case they have short-lived notoriety. important viral infections in africa often differ from those found in the united states of america (usa). this chapter will focus on viral hemorrhagic fevers, influenza, varicella, viral hepatitis, cytomegalovirus, measles and the respiratory syncitial virus. the viral hemorrhagic fevers are generally characterized by a marked propensity for person-to-person spread and high mortality rates. this places them in the highest biohazard category (class ) and renders them liable to control by the state in countries that have the relevant bio-safety regulations. the viruses themselves are numerous ( , ) ( table ) and this chapter will confine discussion to those found in sub-saharan africa and some of those seen in south america and india. it is noteworthy that no cases of hanta virus have been reported in africa and in particular the hanta virus pulmonary syndrome ( ). the viruses known or considered to be associated with hemorrhagic fever fall into three groups with respect to the primary means of transmission and reservoir hosts (table ) . however, clinical manifestations are similar. they are febrile illnesses with an abrupt onset and usually with a short incubation period. headache, myalgia, lumbar pain, nausea, vomiting and diarrhea are frequent. hematological and serological findings are leukopenia (or leukocytosis), thrombocytopenia and elevated transaminases ( , , ) . coagulation profiles become progressively more abnormal and overt hemorrhagic features such as epistaxis; gingival bleeding and melena supervene from day onward. in those most affected, multiple organ system failure and death ensue. mortality is high, particularly with the filoviruses where marburg has a fatality rate of %, ebola zaire - %, with ebola ivory coast intermediate between these two ( ). the primary features of established illness are related to endothelial damage, hemorrhage and shock ( ). whereas direct cytopathogenesis appears to be a major mechanism of injury there is not extensive necrosis of endothelial cells ( ). endothelial dysfunction is more likely to be due to cytokine release as part of the systemic inflammatory response syndrome. hemorrhage may be related to disseminated intravascular coagulopathy (dic), but the presence of hepatic damage may confuse the picture. dic is a regular feature of marburg and crimean-congo hf but less frequent with arena-virus infections ( , ). shock occurs as a consequence of hypovolemia. only limited observations have been made in patients in whom shock persists after volume resuscitation and these have been contradictory with both an increased and a decreased systemic vascular resistance reported in association with a reduced cardiac index ( , ( ) ( ) ( ) . therapy is supportive and directed toward ensuring adequate oxygen delivery. hemorrhage is managed by replacement of appropriate clotting factors, platelets and blood as required, with monitoring of cardiac output mandatory given the uncertainty as to the etiology of hypotension ( , ). positive transfer of human antibodies has not been proven to be of benefit in filovirus infection but may be of value in cchf, although there has been no controlled trial ( ). it is of value in treatment of junin virus, with a reduction of mortality to - % from - % if initiated within the first days of illness ( ) and is also possibly of value in lassa virus infection ( ). promising results have been obtained with intravenous ribavirin in cchf in south africa and oral ribavirin in pakistan but the discontinuation of the intravenous preparation has prevented proper evaluation ( , ) . it is of particular value in lassa fever with a reduction in mortality from % to % if begun within days of onset of fever ( ). in addition, ribavarin has some benefit in argentine hf caused by junin virus and reduces mortality in hantan virus, which causes hemorrhagic fever renal syndrome in asia ( ). nursing and infection control are critical. it is possible that universal precautions may be sufficient to afford protection, however where a worry exists that airborne transmission is possible (this has been documented with the reston and zaire strains of ebola virus in monkeys ( )), high level barrier nursing may be preferable utilizing isolation, protective clothing plus hepa-filtered respirations. infection control extends to the transport of specimens and their examination in the laboratory, where procedures should be in place to manage these materials. influenza is increasingly being recognized as a cause of significant morbidity and mortality in the community, particularly among pediatric patients and the elderly ( , ). these viruses are subdivided into subtypes, which include host of origin, geographic location of first isolation, strain number and year of isolation ( ). the antigenic description is of the hemaglutinin (ha) and neuraminidase (na) and is given parenthetically. since major antigenic shifts have occurred in when the subtype replaced the subtype, in when the hong kong virus appeared, in when the virus reappeared and most recently in when the avian virus appeared ( , ). an epidemic was aborted in the latter case by eradication of the domestic bird population. pneumonia is the most common complication, which occurs in high-risk patients including those with comorbid illness such as cardiovascular or pulmonary disease, diabetes, renal failure, immunosuppression, the elderly, or residents of nursing homes. the pneumonia may be primary (of viral origin) or secondary (related to bacterial infection). primary viral pneumonia is the most severe, although the least common of the pneumonic complications and may occur in patients that are otherwise normal ( ). whereas secondary bacterial pneumonia has been reported to be the most frequent cause of death in previous pandemics ( ), this was not the case in the most recent outbreak in hong kong ( ). where secondary bacterial pneumonia occurs, the most common pathogens are s. pneumoniae ( %). s. aureus ( %) and h. influenzae. the incidence of s. aureus is significantly increased in influenza epidemic years ( ). other complications that may result in icu admission are rhabdomyolysis, encephalitis, transverse myelitis and less commonly reyes syndrome. management is supportive, though new antiviral agents may play a role, particularly if administered early. all currently available drugs should be started within days of onset of symptoms to be effective ( ). the practical effectiveness of drugs such as oseltamivir and rimantidine remains to be determined ( ). rsv is a frequently encountered, potentially severe infection in childhood. disease is less severe in adults but may be more severe in the elderly, and in those with comorbid disease or immunocompromise ( , ) . presentation is non-specific with fever, myalgia, arthralgias, wheeze and non-purulent or bloody sputum. x-ray changes are also non-specific and not helpful in the etiologic diagnosis of pneumonia. in one study in south africa, patients admitted to hospital with an acute lower respiratory tract infection were identified over a -month period ( ). of these, pneumonia was diagnosed in . %, bronchiolitis in . % and laryngotracheobronchitis in %. . % and % had moderate or severe disease respectively, the latter requiring admission to icu. rsv enzyme immunoassay was positive in . % of cases in all groups of diagnoses. viral culture performed in of the cases ( . %), grew rsv in . %, adenovirus in . %, parainfluenza in . % and influenza b in . %. diagnosis is made most frequently by rapid antigen detection, but is not a routinely performed investigation outside of research studies. enzyme immunoassays have sensitivities of - % and specificities of - % ( ). treatment of rsv is supportive although nebulized ribavirin has proven effective in infants ( ). this agent is not readily available in developing countries and it would be impractical to recommend routine enzyme testing for children or adults admitted to the icu. varicella pneumonia represents a severe complication of varicella and most frequently occurs in adults. estimates as to the incidence vary, with the highest being % of all adult cases and the overall incidence in the region of % ( - ). varicella pneumonia has been reported to carry an overall mortality of between and %. however, where mechanical ventilation is necessary, mortality is as high as % ( - ). risk factors include cigarette smoking, pregnancy, immunocompromise and male gender ( - ). whereas chickenpox is primarily a disease of childhood and less than % of reported cases occur in adults, more than % of all deaths take place in this group. recent evidence indicates that there is an upward shift in the age at which chicken pox is contracted and as a consequence it is possible that more critically ill patients with varicella may be seen ( ). varicella pneumonia causes an interstitial pneumonia with severe impairment of gas exchange. pathologically this manifests as a florid immune reaction characterized by an interstitial pneumonitis with mononuclear cell infiltrates, capillary endothelial cell destruction, intraalveolar exudates and hemorrhage, septal wall invasion by mononuclear cells and inflammatory changes in the bronchioles ( ). the pneumonitis appears to be due to the host response rather than to specific virally mediated tissue injury. whereas usual therapy involves support and acyclovir, the benefit of the latter is uncertain ( ). it is possible that acyclovir may hasten improvement in those that are less ill and do not require ventilation ( , ) but despite the recognition of limited efficacy it is still widely recommended as early primary therapy ( , ). a study performed in our icu indicates that corticosteroids may dramatically alter the course of the most severe disease and should be considered in addition to antiviral therapy along with appropriate supportive care in any previously well patient with life threatening varicella pneumonia ( ). little is known about the incidence and clinical cause of varicella pneumonia in hiv (human immunodeficiency virus) infected individuals ( , ) . patients with hiv or aids (acquired immunodeficiency syndrome) who are hospitalized with chickenpox appear to be at high risk for developing varicella pneumonia, which manifests in a similar clinical fashion to that in immunocompetent individuals. in a recent review conducted in a regional infectious diseases hospital affiliated to our institution, % of the patients who were hospitalized with chickenpox developed pneumonia ( ). this incidence is significantly greater than in any previously reported study in immunocompetent patients. immunocompromised patients with varicella pneumonia have previously been reported to do poorly, with mortality as high as %, despite prompt initiation of antiviral therapy and supportive care ( ). our experience suggests that response to adjunctive corticosteroid therapy in patients with hiv/aids is as favorable as in immunocompetent patients. interestingly, recurrent varicella pneumonia requiring acute treatment followed by secondary antiviral prophylaxis in an hiv-infected adult patient has been described, analogous to other aids complicating opportunistic infections ( ). the proportion of viral hepatitis infections that progress to acute liver failure caused by viruses is very low, occurring in less than % of patients with acute a or b hepatitis. however, viruses account for between - % of all cases of liver failure ( , ). most of these are related to hepatitis b (hbv) and a relatively smaller proportion to a (hav) or other newly identified viruses. fulminant hepatic failure is defined either as acute liver disease, occurring in the absence of pre-existing liver disease, which leads to encephalopathy within weeks of onset of symptoms, or as liver disease, which leads to encephalopathy within weeks of onset of jaundice ( ). clinical features are often non-specific, such as nausea and vomiting with progression to encephalopathy and coma. the prognosis is inversely proportional to the degree of encephalopathy. hepatitis a is an rna virus transmitted by the fecal-oral route. hepatitis b is a dna virus and accounts for % to % of virally caused fulminant hepatitis. transmission is via sexual contact, transplacentally, parenterally and in particular occupationally. hepatitis d is an incomplete rna virus that requires the presence of hepatitis b virus in order to infect an individual. it is an important cause of fulminant hepatitis and aggressive chronic hepatitis in hbv carriers ( ). hepatitis e virus is an rna virus transmitted by the fecal-oral route and possibly parenterally which for unknown reasons carries a high mortality from fulminant hepatitis in pregnant women and is also the commonest cause of fulminant hepatitis in india ( , ). hepatitis c virus is an rna virus of the flaviviridae family and is responsible for % of acute hepatitis, % of chronic hepatitis and % of end-stage cirrhosis in europe. % of patients infected with hepatitis c develop chronic infection consisting of either chronic hepatitis, fibrosis or cirrhosis. it is also not usual for it to cause a fulminant hepatic failure ( ) but this occurs only in areas with high hepatitis c serum prevalence ( ). the diagnosis of hav is made on the basis of the detection of high levels of igm antibodies in the serum. in fulminant hepatitic failure caused by hbv, the widespread hepatic necrosis that occurs as a consequence of immune mediated lysis of infected hepatocytes may result in igm antihepatitis b core (anti-hbc) being the only marker of hepatitis b, as hepatitis b surface antigen and hepatitis b dna may be absent from serum ( ). other viruses in the herpes group (cytomegalovirus, herpes simplex and ebstein barr virus), adenovirus and influenza virus may rarely cause fulminant hepatic failure. treatment involves identification of the cause and if possible, specific therapy. if facilities are available, patients with grade encephalopathy or greater should be transferred to a liver transplant center ( ). supportive therapy, involves hemodynamic management, ventilation, prevention and treatment of hemorrhage, dialysis, therapy of co-existent sepsis and electrolyte disturbance, and management of intracranial pressure ( ). orthoptic liver transplantation is not frequently available in developing countries, but in appropriate patients has been shown to improve survival significantly ( ). measles is a frequently encountered disease in the icu in developing countries. the presence of malnutrition and often the lack of an effective vaccination programme combine to convert this "harmless" childhood infection into a major killer. in one case series of patients admitted to an icu during a measles epidemic, were malnourished and none had been vaccinated. all required mechanical ventilation for pneumonia and ards, died and developed long-term sequelae, i.e. chronic lung disease, subacute sclerosing panencephalitis, hemiplegia or partial amputation of a limb ( ). young adults are not exempt from the ravages of this disease. in a study from greece, previously healthy young males were hospitalized with measles. had bacterial pneumonia on admission and developed pneumonia in hospital or post discharge ( ). in another study of adult patients admitted with measles diagnosed on clinical and serological grounds, required intensive care, six mechanical ventilation for approximately days, and two deaths occurred. prior vaccination history was not available ( ). it would be best to avoid measles entirely by means of vaccination, however once contracted a study conducted in south africa indicated that vitamin a supplements reduce morbidity and mortality significantly and concluded that these should be given regardless of the presence or absence of clinical evidence of vitamin a deficiency ( ). herpes encephalitis is the most common cause of fatal sporadic encephalitis in the united states, accounting for - % of the annual cases of viral encephalitis. no accurate figures are available as to the incidence of this disease in the developing world, however we see sporadic cases in our icu. this disease occurs in all age groups with the development of focal encephalitis with progressive oedema and necrosis. the syndrome is characterized by rapid onset of fever, seizures, focal neurological signs and impaired level of consciousness ( - ). in adults the etiology is herpes simplex type whereas in neonates type may also be involved and confers a worse outcome. brain biopsy is no longer a routine diagnostic test and polymerase chain reaction assays are considered the best non-invasive technique ( , ). this test is positive early in the disease and remains so during the first week. early aggressive antiviral therapy with acyclovir improves mortality and reduces subsequent cognitive impairment. acyclovir provides better outcome than vidaribine. whereas cmv is usually asymptomatic, severe morbidity may occur in the premature neonate and organ and bone marrow transplant recipients ( ). seronegative patients receiving a seropositive organ transplant will develop a primary infection in - % of cases ( , ). seropositive patients will develop cmv infection by superinfection or reinfection in - % of cases. primary infection is the most likely type and is also usually more severe. those who receive anti-thymocyte or antilymphocyte globulins and those who have bone marrow transplants also have more severe disease and a mortality of - % ( , ) . cmv infection occurs most frequently - weeks after transplantation. manifestations include, fever, hepatitis, leukopenia and thrombocytopenia. the most important condition resulting in admission to icu is interstitial pneumonitis. this is associated with variable changes in the chest radiograph, most commonly showing diffuse bilateral infiltrates, but focal consolidation or nodules may occur. in the developing world cmv is more frequently seen in association with hiv. despite the clear association with mortality in organ transplant recipients, in particular bone marrow transplants, the significance of cmv as a pathogen in patients with aids is unclear. autopsy studies demonstrate that although cmv pneumonitis is frequently present it is not commonly found as the sole pathogen ( , ). in addition bronchoalveolar lavage specimens are also positive for cmv in more than % of patients ( ). cmv has also been reported to be a potential cause of ventilator associated pneumonia in immunocompetent patients ( ) and it is suggested that cmv should be considered as a possibility in patients not responding to antimicrobials or if there is evidence of other hospital outbreaks of viral infection particularly in the pediatric wards ( ). diagnosis is made most frequently with an antigenemic assay incorporating antibodies directed at the pp matrix protein of the cmv virus ( ). this test has gained acceptance particularly in immunocompromised hosts and correlates with viremia ( , ). the polymerase chain reaction has an even higher sensitivity, but is not always widely available ( ). the mainstay of therapy for solid organ transplant is ganciclovir, which appears to reduce morbidity ( , , ) . in contrast, ganciclovir is not effective in bone marrow transplant recipients. it should not therefore be used as a single agent therapy in these patients ( , ) . it is possible that combinations with immunoglobulin or cytomegalovirus immunoglobulin may be of value ( , ). on november an unusual respiratory illness was reported in guangdong province, southern china, which was designated the severe acute respiratory syndrome (sars)( ). subsequent world -wide transmission was initiated by a doctor who traveled to hong kong, where he infected guests in the same hotel ( ). a global alert was issued by the who on / / , an unprecedented step, which nevertheless was proven to be appropriate when days later, as a consequence of this alert, similar cases were identified in singapore and canada. early international recognition of an impending crisis was precipitated in part by the detailed report by who clinician carlo urbani, who subsequently himself demised from sars ( ). local spread of this disease occurred in vietnam, canada, hong kong, singapore, china and taiwan. the organism. tissue culture isolation and electron microscopy resulted in rapid identification of the culprit virus as a novel coronavirus only distantly related to any that had previously infected humans ( , ). it is likely that it originated in animals, but it differs from all previously known coronaviruses in that most cause disease in only one host species whereas this virus appears also to have acquired the ability to infect humans. the high concentration of viral dna in the sputum suggested that droplet spread was the main mode of transmission. lack of antibody in the general community indicated that this virus had not circulated widely in humans. the rapid sequencing of the genome allowed early development of diagnostic tests. a number of pcr protocols have been developed ( ). these tests have high sensitivity, but a negative test cannot rule out infection. sars follows an unusual pattern in that during the initial phases of the illness, virus shedding is relatively low. because shedding peaks in respiratory specimens and stool only at around days after onset of clinical illness, tests of very high sensitivity, which do not yet exist, are necessary ( ). virus culture is extremely demanding and not useful for rapid diagnosis, however elisa, immunofluorescence and neutralization tests will soon be available commercially. detectable immune responses begin at day or but reliable antibody tests are available only after about day following onset of symptoms. seroconversion or a fourfold rise in titre indicates recent infection. diagnostic tests currently have severe limitations and extreme caution should be used before excluding the possibility of sars on the basis of a test alone. suspicious laboratory features include lymphopenia, thrombocytopenia and elevated lactate dehydrogenase levels ( ). from the perspective of clinicians, where local transmission has occurred, all cases of community-acquired pneumonia are suspect. otherwise a travel history to an affected country or contact with an infected patient is essential. the who case definition as of / / for a suspected or probable case of sars is a useful resource ( ). clinical features. in a recent study by peiris ( ), all patients became apyrexial within hours, but fever recurred in % ( patients) at a mean of . days (± . ). in only of these was nosocomial bacterial sepsis the cause. between days and , % of patients had another episode of fever. radiological worsening occurred in % of patients at a mean of . (± . days), % subsequently improved, % had remained unchanged at the time of writing and % had progressed further to a diffuse ground glass appearance at a mean of . (± . ) days. % developed desaturation of less than % in room air at . (± . ) days after onset of symptoms. % ( ) required icu at a mean of . (± . ) days of whom were intubated and required mechanical ventilation for ards. the development of ards had a bimodal pattern with a peak at days and another at days. on univariate analysis, the risk factors for development of ards were age, male sex, chronic hepatitis b carriage, raised creatinine and recurrence of fever. igg seroconversion had a % sensitivity at day even with corticosteroid therapy; however, nasopharyngeal viral rna detection was present in only % at presentation in the study by lee ( ) . % were admitted to icu, all for respiratory failure. mechanical ventilation was required in ( . %). died ( . %) all of whom had co-existing conditions. multivariate analysis defined age [odds ratio (or)/per decade of life . ( . - . ), p = . ; high peak ldh, o.r. per units . ( . - . ) p = . and a neutrophil count that exceeded the upper limit of normal at presentation, o.r. . ( . - . ) p= . ] as predictors of mortality. in those admitted to icu, dramatic increases in lung opacity, shortness of breath and hypoxia occurred at a median of . days (range to ). in a further study by booth ( ) , % were admitted to icu and of these died i.e. there was a . % -day mortality. diabetes, relative risk (rr) . ( % ci . - . ) p= . , and other comorbid conditions, rr . ( . - . ) p= . , were independently associated with outcome. treatment. viral amplification may be associated with cellular damage by cytolysis or immunopathological mechanisms ( ). once an immune response is mounted auto-immune tissue injury may occur. this has been the rationale for corticosteroid therapy in this condition ( ). interestingly sars behaves similarly to varicella, in that the disease is more severe in adults, pneumonic manifestations may occur some days after the onset of clinical symptoms and dramatic responses have been apparent after the use of corticosteroids (see varicella). whereas there has been concern regarding the use of corticosteroids there have also been many proponents, particularly from those at the coalface in hong kong. rivabirin was initially the antiviral of choice since it is an effective treatment of fulminant hepatitis in mice infected with the mouse hepatitis corona virus ( ). however, no anti-viral has been reported to be clinically effective in humans. this drug is extremely expensive in its intravenous form and health canada recently stated that it would no longer provide access to ribavirin because of side effects and lack of clear efficacy ( ). so et al ( ) have described a standard protocol for the management of sars which involves the administration of a combination of ribavirin and corticosteroids for those patients with: extensive or bilateral chest radiographic involvement, persistent chest radiographic involvement and high fever for days or worsening clinical, radiographic or laboratory findings, or oxygen saturation less than % in room air. late administration of corticosteroids appears to be less effective, correction of dose according to body weight results in more rapid improvement of symptoms in obese patients, and step-down within - days resulted in re-bound in some patients. steroids in this protocol were administered in high doses beginning with methylprednisone ( mg/kg mg x days) and weaning over days. there was no mortality and only required short periods of non-invasive ventilation. mortality. the who has revised its initial estimates of the case fatality rates on the basis of more complete data from china, hong kong, singapore and vietnam ( ). mortality varies according to age; being less than % aged years or younger, % aged - , % aged - and greater than % aged and older infection control. sars is highly contagious, specifically to health care workers and in particular where the index case is not immediately identified as having the disease. at the prince of wales hospital, a patient was admitted on the / / with "pneumonia" and was discharged well on the / / . on the / / however, health care workers became ill and a further potential cases were identified on that day. by march patients had been admitted to prince of wales hospital with sars, all traceable to this index patient ( ). in singapore similarly, initial transmission occurred from an index case to patients, of whom were primary contacts and of whom were health care workers ( ). in this latter case, singaporean media labeled this patient a super-spreader, a concept that, although as yet inadequately defined may possibly be correct ( , ). some patients do appear to spread the disease more readily and this may be related to the rate of shedding of viral particles. in toronto amongst cases ( %) were health care workers and the subsequent outbreak of at least patients occurred as a consequence of a cluster of unrecognized patients that had been admitted to north york hospital in toronto ( ). infection control measures should include negative pressure wards, the use of n masks, gloves at all times, disposable impermeable gowns and eye protection. hand washing after removal of gloves and avoidance of touching nose, eyes and mouth if at all possible are the most important practical measures ( ).hcws should be cohorted to decrease the number of people exposed and visiting should be strictly limited. alcohol, phenol and quaternary ammonium based disinfectants are highly active against coronavirus. certain features appear to enhance spread, in particular overcrowding of hospital wards, outdated ventilation systems and the use of nebulizers in the ward environment ( ). endotracheal intubation, open suctioning of respiratory secretions, the use of bi-pap and high frequency oscillatory ventilation in which air is forced around the face mask appear to be some of the most high-risk procedures numerous sources describing adequate infection control procedures are available, as well as those on the cdc website ( - ). the primary factor responsible for transmission seems to be inadequate training in or compliance with infection control procedures ( ). whereas viruses are not usually considered to be important causes of icu admission this review has demonstrated this perception to be incorrect. viruses and their manifestations differ from continent to continent and hemisphere to hemisphere and it is 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sars: lessions from singapore. published on-line ahead of print global outlook of severe acute respiratory syndrome (sars) advisors of expert sars group of hospital authority. effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (sars) health canada infection control guidance for respirators (masks) worn by health care workers -frequently asked questions key: cord- -pbahviaz authors: garg, shikha; jain, seema; dawood, fatimah s.; jhung, michael; pérez, alejandro; d’mello, tiffany; reingold, arthur; gershman, ken; meek, james; arnold, kathryn e.; farley, monica m.; ryan, patricia; lynfield, ruth; morin, craig; baumbach, joan; hancock, emily b.; zansky, shelley; bennett, nancy; thomas, ann; schaffner, william; finelli, lyn title: pneumonia among adults hospitalized with laboratory-confirmed seasonal influenza virus infection—united states, – date: - - journal: bmc infect dis doi: . /s - - -y sha: doc_id: cord_uid: pbahviaz background: influenza and pneumonia combined are the leading causes of death due to infectious diseases in the united states. we describe factors associated with pneumonia among adults hospitalized with influenza. methods: through the emerging infections program, we identified adults ≥ years, who were hospitalized with laboratory-confirmed influenza during october through april , and had a chest radiograph (cxr) performed. pneumonia was defined as the presence of a cxr infiltrate and either an icd- -cm code or discharge summary diagnosis of pneumonia. results: among , adults hospitalized with influenza, ( %) had pneumonia. in multivariable analysis, factors associated with pneumonia included: age ≥ years, adjusted odds ratio (aor) . ( % confidence interval . – . ), white race aor . ( . – . ), nursing home residence aor . ( . – . ), chronic lung disease aor . ( . – . ), immunosuppression aor . ( . – . ), and asthma aor . ( . – . ). patients with pneumonia were significantly more likely to require intensive care unit (icu) admission ( % vs. %), mechanical ventilation ( % vs. %), and to die ( % vs. %). conclusions: pneumonia was present in nearly one-third of adults hospitalized with influenza and was associated with icu admission and death. among patients hospitalized with influenza, older patients and those with certain underlying conditions are more likely to have pneumonia. pneumonia is common among adults hospitalized with influenza and should be evaluated and treated promptly. electronic supplementary material: the online version of this article (doi: . /s - - -y) contains supplementary material, which is available to authorized users. influenza illness is generally characterized by acute onset of fever, mylagias, and respiratory symptoms, and while disease usually resolves without complications in healthy indiviudals, influenza is associated with an annual increase in hospital admissions for pulmonary, cardiovascular and neuromuscular compliations [ ] [ ] [ ] . the etiology of influenza-associated pneumonia may include primary influenza pneumonia, secondary bacterial pneumonia, or concomitant viral and bacterial pneumonia [ , , ] . pulmonary complications of influenza, including pneumonia and exacerbations of chronic pulmonary disease, are common and result in significant morbidity and mortality. oliveira and colleagues found that among all patients admitted to a large metropolitan hospital with influenza during the - season, % had pneumonia [ ] . further, in a study conducted over influenza seasons ( ) ( ) ( ) ( ) ( ) , murata and colleagues found that among patients hospitalized with influenza a, % had some type of acute findings on chest radiograph and % had definitive pneumonic infiltrates [ ] . although there is evidence that adult patients with underlying cardiac or pulmonary disease are more likely to develop influenza-associated pneumonia than those without underlying medical conditions [ , ] , much of the data describing factors associated with influenzaassociated pneumonia among adults comes from case series conducted at single sites and during a limited number of seasons. using data from a large multi-center, geographically diverse, population-based surveillance system, we describe factors associated with pneumonia among adults hospitalized with influenza over three consecutive years in which seasonal influenza viruses circulated. the emerging infections program (eip) network conducts active population-based surveillance for laboratory-confirmed influenza-associated hospitalizations. the network began adult surveillance in and covers over counties in states (california, colorado, connecticut, georgia, maryland, minnesota, new mexico, new york, oregon, and tennessee), representing approximately % of the adult u.s. population [ ] . patients were included in eip influenza surveillance if they resided and were hospitalized in an eip catchment area and were hospitalized within days of a positive influenza diagnostic test result. patients were excluded if the first positive influenza specimen was obtained > days after hospital admission because these patients might have had healthcare-associated influenza infection. influenza testing was performed at the discretion of health care providers. medical charts of hospitalized patients with laboratory-confirmed influenza were retrospectively reviewed [ , ] . the study period comprised influenza seasons, - to - . patients were included in this analysis if they were ≥ years of age, were hospitalized with laboratory-confirmed influenza during the - through - influenza seasons, and had a chest radiograph (cxr) performed during hospitalization. the following data were collected on patients: demographics, results of laboratory tests for influenza, influenza vaccination status for the current season, underlying medical conditions, bacterial coinfections, cxr data, antiviral treatment, clinical outcomes, and discharge diagnoses. laboratory confirmation of influenza was based on viral culture, direct or indirect immunoflourescence antibody staining, reverse-transcription polymerase chain reaction, or a rapid antigen test. surveillance staff completed medical record abstractions using check boxes to indicate whether or not a new infiltrate or consolidation was recorded on the official cxr transcript. discharge diagnoses were captured in two ways: ) the first nine international classification of diseases (icd- -cm) codes for each case were abstracted from the medical record; ) check boxes were marked for certain diagnoses, including pneumonia, if they were recorded by clinicians on the discharge summary. pneumonia was defined as the presence of a new infiltrate on cxr and either an icd- -cm discharge diagnosis code for pneumonia ( - . ) or a diagnosis of pneumonia recorded on discharge summary. information on the presence of selected bacterial infections was available only for patients who had a positive culture. a bacterial infection was recorded if bacteria other than those that are commonly considered to be contaminants grew from a sterile body site or a non-sterile respiratory site culture obtained within calendar days of hospital admission. sterile body sites for bacterial infections included blood, pleural fluid, cerebrospinal fluid, bronchoalveolar lavage fluid, and deep tissue biopsy. non-sterile respiratory sites included sputum and endotracheal aspirates. use of influenza antiviral therapy was examined for all individuals. among those who were treated with antiviral agents, timing of treatment was assessed in relation to hospitalization date. early antiviral treatment was defined as initiation of antiviral treatment within days of hospital admission. we used bivariate analysis to compare adults hospitalized with influenza with and without pneumonia. we used χ and fisher exact tests for categorical variables and t-tests and wilcoxon-rank sum tests for continuous and ordinal variables. all variables significant in bivariate analysis, as well as biologically plausible variables, and potential confounders were included in a multivariable logistic regression model to identify factors independently associated with influenza-associated pneumonia. we used the breslow-day test for homogeneity to assess for effect modification of select variables. all tests were two-tailed and a p-value of . was considered significant. analyses were conducted using sas version . (sas institute inc., cary, nc). ethics statement eip adult influenza hospitalization surveillance activities during the - influenza seasons were determined by the centers for disease control and prevention (cdc) institutional review board (irb) not to involve research in accordance with the federal regulations for the protection of human subjects in research. starting with the - season, research questions were added to evaluate factors associated with severe outcomes during hospitalizations, and irb review was conducted at all surveillance sites and the cdc. the protocol was approved by the cdc irb and was either approved or received exempt status by all surveillance site irbs. because all surveillance data was analyzed anonymously, neither verbal nor written informed consent was obtained from participants. during the study period, of adults hospitalized with laboratory-confirmed influenza, ( . %) had an available cxr report and discharge diagnosis information and were therefore included in our study. of the adults, ( %) had pneumonia. the prevalence of pneumonia did not vary significantly over the influenza seasons included in the analysis. adults ≥ years of age represented the age group with the highest proportion of patients hospitalized with and without influenza-associated pneumonia (fig. ) . the median age of patients with pneumonia compared with patients without pneumonia was years versus years (p < . ) ( table ). the majority of patients hospitalized with and without influenza-associated pneumonia were white. white patients were older (median age years) than black patients ( years), hispanic patients ( years), and patients of other races including asian, pacific islander, american indian, alaskan native, and multi-race ( years) (p < . ). patients aged years and above had a higher proportion of underlying conditions ( %) compared to patients aged < years ( %) (p < . ). influenza was diagnosed by rapid test only in / ( %) patients with pneumonia and in / ( %) patients without pneumonia (p < . ). the median number of days from symptom onset to hospital admission was days for patients with and without pneumonia (table ) . patients with pneumonia were significantly more likely than patients without pneumonia to reside in a nursing home prior to hospital admission, to have received influenza vaccine, and to have the following underlying medical conditions: chronic lung disease, cardiovascular disease, and immunosuppression. patients with pneumonia were significantly less likely than patients without pneumonia to have asthma (table ) . a description of the most frequent discharge diagnoses (based on first listed icd- diagnosis code) among patients with and without pneumonia can be found in additional file : table s . except for influenza vaccination and cardiovascular disease, all factors included in a multivariable model remained independently associated with pneumonia including age ≥ years [adjusted odds ration (aor) . ], white race (aor . ), nursing home residence (aor . ) chronic lung disease (aor . ), immunosuppression (aor . ) and asthma (aor . ) ( table ) . sixty-one patients with pneumonia and patients without pneumonia had sterile site bacterial infections, % of which were cultured from the blood ( table ). the most common pathogens cultured from sterile sites in patients with pneumonia were staphylococcous aureus (s. aureus) and streptococcus pneumonia (s. pneumonia). patients with pneumonia had a longer median length of hospital stay than patients without pneumonia ( days versus days; p < . ). patients with pneumonia were also significantly more likely to have a hospital length of stay greater than one week (aor . ), require intensive care unit (icu) admission (aor . ), require mechanical ventilation (aor . ), and die (aor . ) ( table ) . among patients with pneumonia, factors independently associated with a poor outcome, defined as icu admission, need for mechanical ventilation or death, included nursing home residence (aor . ), chronic lung disease (aor . ), cardiovascular disease (aor . ), (table ). of note, older age was inversely associated with a poor outcome (aor . ) among patients hospitalized with pneumonia (table ) . patients with pneumonia [ / ( %)] were significantly more likely to receive influenza antiviral therapy than patients without pneumonia [ / ( %); p < . ]. through this large, population-based surveillance system, we found that pneumonia was present in almost one-third of u.s. adults hospitalized with laboratoryconfirmed influenza over three consecutive years in which seasonal influenza viruses circulated. patients with pneumonia were older and were more likely to have certain underlying medical conditions than patients without pneumonia. patients with pneumonia were also more likely to have a prolonged hospital stay, be admitted to an icu, require mechanical ventilation for respiratory failure, and die. while patients with pneumonia were more likely to receive antiviral therapy than those without pneumonia, treatment was more often delayed among patients with pneumonia. similar to findings from smaller inter-pandemic studies [ , ] pneumonia was common among adults hospitalized with influenza in this study. among those hospitalized with influenza, older adults and nursing home residents were at significantly increased risk for having influenza-associated pneumonia. respiratory viruses including influenza are a common etiology of pneumonia in older adults, and several factors may contribute to the development of severe lower respiratory tract disease in these individuals, including decreased respiratory muscle strength and lung compliance, and waning humoral and cell-mediated immunity [ ] [ ] [ ] . additional risk factors for lower respiratory tract disease among older nursing home residents include immobility and swallowing difficulties leading to aspiration [ ] . within closed settings such as nursing homes, large outbreaks of influenza and its subsequent complications, including severe pneumonia, may rapidly evolve and lead to significant morbidity and mortality [ , ] . influenza virus infection should thus be considered a potential cause of pneumonia in older individuals and nursing home residents during fall and winter months ( ) other streptococci c ( ) ( ) other pathogens d ( ) ( ) unknown pathogens ( ) ( ) [ ] and should be diagnosed and treated promptly. influenza vaccination is the most effective method to prevent influenza and its complications, and older adults, residents of nursing homes and other long-term-care facilities, and adults with underlying medical conditions should be considered high priority groups for receipt of annual influenza vaccination [ ] . similar to earlier studies conducted during periods of seasonal influenza virus circulation, patients with pneumonia in this study were more likely to have underlying medical conditions including chronic lung disease and heart disease [ , ] . an unexpected finding was that patients with asthma in our analysis were less likely to have a diagnosis of pneumonia than patients without pneumonia. our study results contrast with eip surveillance data in hospitalized children < years of age which has shown that children with influenza-associated pneumonia were more likely to have asthma than those without pneumonia [ ] . studies of the association between asthma and seasonal influenza-associated pneumonia among adults are lacking. a possible explanation for our finding is that respiratory distress caused by influenza-associated asthma exacerbation provided an alternate reason for hospitalization in adult patients in the absence of pneumonia. biases in hospital admission practices based on the presence of underlying conditions may have also contributed to admission of asthmatic patients with a less severe respiratory presentation compared to patients without underlying medical conditions. invasive bacterial infections, especially due to s. aureus and s. pneumoniae, were observed among patients with influenza-associated pneumonia in this study as well as other studies conducted during inter-pandemic [ ] and pandemic periods [ ] . among patients with pneumonia, s. aureus was the most common organism cultured from specimens collected from sterile sites. influenza virus and s. aureus co-infections are increasing [ ] [ ] [ ] and have been associated with particularly severe cases of community-acquired pneumonia during periods of seasonal influenza virus circulation [ ] . in patients hospitalized with influenza, sterile site cultures should be collected as early as possible for detection of bacterial infection and empiric antimicrobial coverage of the most likely bacterial organisms should be considered [ , ] . in our study, s. pneumoniae was the only organism to be cultured from a sterile site more frequently in patients with pneumonia that in patients without pneumonia. in addition to annual influenza vaccination, pneumococcal vaccine should be administered to adults aged - years with certain health conditions and to all persons aged ≥ years [ ] . patients with influenza-associated pneumonia had a significantly increased risk of icu admission, respiratory failure requiring mechanical ventilation, and death compared with patients without pneumonia. while case series conducted during the h n pandemic demonstrated elevated frequencies of icu admission ( - %) [ , ] , respiratory failure ( - %) [ , ] and death ( - %) [ ] [ ] [ ] [ ] among patients hospitalized with pandemic h n influenza-associated pneumonia, limited data is available on the association between seasonal influenzaassociated pneumonia and severe outcomes. in a small case series of patients hospitalized with influenza during the - season, ( %) of patients with pneumonia were admitted to the icu and ( %) patients died [ ] . in another observational study of patients hospitalized with influenza during - , ( %) of patients with acute pulmonary disease were admitted to the icu, ( %) required mechanical ventilation, and ( %) died [ ] . while pneumonia and acute respiratory distress syndrome (ards) have been shown to account for a majority of deaths associated with influenza virus infection during pandemics [ ] , data is limited on the association between seasonal influenza virus infection and death from pneumonia or ards. in our analysis, only % of patients hospitalized with laboratory-confirmed influenza received influenza antiviral treatment. when limiting the analysis to patients who presented to the hospital within days of symptom onset, only % of all patients received antiviral treatment; the majority received antiviral treatment within day of hospital admission. multiple studies have found early antiviral treatment to be associated with a reduction in serious influenza-associated outcomes including the development of lower respiratory tract infections [ ] [ ] [ ] . the advisory committee on immunization practices recommends empiric influenza antiviral treatment for all adults with suspected or confirmed influenza who are hospitalized, have severe, complicated, or progressive illness, or are at high risk for influenza-associated complications [ ] . several limitations to this study should be noted. influenza diagnostic testing was performed at the discretion of treating clinicians at the various eip hospital sites. while all hospitalized patients who tested positive for influenza were included in surveillance, data is unavailable for hospitalized patients who tested negative for influenza or who were not tested. thus, these data may not be representative of all individuals hospitalized with influenza who may not have been tested or have laboratory confirmation of influenza virus infection. it is possible that patients included in surveillance were more likely to be tested for influenza because they were more severely ill; thus a higher proportion of patients exhibiting pneumonia-like symptoms may have been tested for influenza than patients presenting with other symptoms. furthermore, in our analysis, patients with pneumonia were compared to patients without pneumonia but with a wide array of other diagnoses. clinican influenza testing practices based on patient diagnoses at presentation may have biased our findings. in one study conducted in an emergency department in australia, patients presenting with fever and respiratory diagnoses were more likely to be tested for influenza than patients presenting with cardiac or other diagnoses [ ] . this study assessed pneumonia specifically among adults hospitalized with laboratory-confirmed influenza, including those whose influenza virus infection preceded hospitalization by more than a few days, and findings are not generalizable to all hospitalized individuals with pneumonia of other etiologies or to non-hospitalized individuals. several of the findings in this study may have been biased by hospital admission practices. for example, the finding of an inverse association between asthma and pneumonia may have been due to more aggressive admission of asthmatic patients presenting with respiratory distress despite the absence of pneumonia, compared with patients without asthma. biases related to hospital admission practices were likely reduced by including patients from multiple hospital sites in geographically diverse settings. for certain underlying conditions such as chronic lung disease and cardiovascular disease, disease type and severity were not captured by the case report form. availability of detailed data on type and severity of underlying conditions may have helped to better identify factors more strongly associated with development of influenza-associated pneumonia. radiographic data were based on review of cxr reports by surveillance officers and not by actual review of radiographs by a designated study radiologist. as a result, some individuals may have been misclassified as having pneumonia based upon a report of infiltrates or opacities, when in fact they had a more chronic pulmonary condition or a transient episode of pulmonary edema or effusion. there was no requirement regarding timing of identification of radiologic abnormalities during the hospitalization, and the timing of chest radiographs during the hospitalization was not collected as part of eip surveillance; thus, some misclassification of communityacquired pneumonia versus nosocomial pneumonia may have occurred. using icd- -cm code data may also have led to misclassification if a diagnosis code was listed incorrectly or not listed at all. a joint case definition for pneumonia which used both radiographic data and discharge diagnosis data from icd- -cm codes or discharge summaries was utilized to minimize some of these biases. bacterial culture data was only available for patients with a positive culture result rather than for all specimens spent, thus limiting the interpretation of the culture data. pneumonia is common among adults hospitalized with seasonal influenza virus infection. among patients hospitalized with influenza, older adults and those with underlying medical conditions may be more likely to have pneumonia. further studies are needed to explore the association between influenza-associated pneumonia and asthma in adults. influenza-associated pneumonia can lead to severe outcomes including icu admission and death. adults hospitalized with suspected or confirmed influenza should receive early antiviral therapy, prompt evaluation for pneumonia, and appropriate management upon diagnosis of pneumonia. additional file : table s . the most frequent icd- diagnosis categories based on first icd- code listed among adults hospitalized with laboratory-confirmed influenza with and without pneumonia (n= ). abbreviations cxr: chest radiograph; aor: adjusted odds ratio; eip: emerging infections program; icd- -cm: international classification of diseases; cdc: centers for disease control and prevention; irb: institutional review board; icu: intensive care unit; s. aureus: staphylococcus aureus; s. pneumonia: streptococcus pneumonia. the authors declare that they have no competing interests. authors' contributions sg: contributed to conception and design of study, analysis of data and interpretation of results, and drafting of the manuscript; sj: contributed to conception and design of study, interpretation of data, and criticial review and revision of manuscript; fd: contributed to conception and design of study, analysis of data, and critical review of manuscript; mj: contributed to conception and design of study, interpretation of data, and criticial review of the manuscript; ap: contributed to analysis and cleaning of data, interpretation of results, and critical review of the manuscript; td: contributed to analysis and cleaning of data, interpretation of results, and critical review of the manuscript; ar: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; kg: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; jm: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; ke: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; mf: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; pr: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; rl: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; cm: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; jb: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; eh: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; sz: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; nb: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; at: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; ws: contributed to conception and design of study, acquisition of data, interpretation of results, and critical review of the manuscript; lf: contributed to conception and design of study, interpretation of data, and criticial review and revision of manuscript; all authors 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-recommendations of the advisory committee on immunization practices (acip) van hal sj. influenza a testing and detection in patients admitted through emergency departments in sydney during winter ; implications for rational testing we wish to thank the following individuals for their help with surveillance efforts: deborah submit your next manuscript to biomed central and take full advantage of: key: cord- -ptuelrqj authors: ferrer, miquel; difrancesco, leonardo filippo; liapikou, adamantia; rinaudo, mariano; carbonara, marco; li bassi, gianluigi; gabarrus, albert; torres, antoni title: polymicrobial intensive care unit-acquired pneumonia: prevalence, microbiology and outcome date: - - journal: crit care doi: . /s - - - sha: doc_id: cord_uid: ptuelrqj background: microbial aetiology of intensive care unit (icu)-acquired pneumonia (icuap) determines antibiotic treatment and outcomes. the impact of polymicrobial icuap is not extensively known. we therefore investigated the characteristics and outcomes of polymicrobial aetiology of icuap. method: patients with icuap confirmed microbiologically were prospectively compared according to identification of (monomicrobial) or more (polymicrobial) potentially-pathogenic microorganisms. microbes usually considered as non-pathogenic were not considered for the etiologic diagnosis. we assessed clinical characteristics, microbiology, inflammatory biomarkers and outcome variables. results: among consecutive patients with icuap, ( %) had microbiologic confirmation, and ( %) of them polymicrobial pneumonia. methicillin-sensitive staphylococcus aureus, haemophilus influenzae, and several enterobacteriaceae were more frequent in polymicrobial pneumonia. multi-drug and extensive-drug resistance was similarly frequent in both groups. compared with monomicrobial, patients with polymicrobial pneumonia had less frequently chronic heart disease ( , % vs. , %, p = . ), and more frequently pleural effusion ( , %, vs. , %, p = . ), without any other significant difference. appropriate empiric antimicrobial treatment was similarly frequent in the monomicrobial ( , %) and the polymicrobial group ( , %), as were the initial response to the empiric treatment, length of stay and mortality. systemic inflammatory response was similar comparing monomicrobial with polymicrobial icuap. conclusion: the aetiology of icuap confirmed microbiologically was polymicrobial in % cases. pleural effusion and absence of chronic heart disease are associated with polymicrobial pneumonia. when empiric treatment is frequently appropriate, polymicrobial aetiology does not influence the outcome of icuap. intensive care unit (icu)-acquired pneumonia (icuap) is the leading infection in critically-ill patients, accounting for prolonged mechanical ventilation and length of stay, and poor outcome [ ] [ ] [ ] [ ] . the use of inappropriate initial antibiotic therapy is a major determinant of mortality in patients with icuap [ ] , emphasizing the importance of a timely and accurate therapy for this infection [ ] . for this reason, it is often necessary to use a combination of broad-spectrum empiric antibiotics, particularly in patients who are at risk for difficult-to-treat bacteria [ , ] . recent investigations have shown that multi-drug-resistant (mdr) or high-risk pathogens have been isolated in around half of patients with an episode of ventilator-associated pneumonia (vap) or icuap confirmed microbiologically [ , ] . icuap, and particularly vap, can be caused by more than one microbial pathogen. multiple etiologic pathogens are potentially an additional challenge for achieving appropriate antimicrobial treatment in these patients. a previous study reported a % rate of polymicrobial etiology in episodes of vap with microbiologic confirmation [ ] . these authors concluded that the epidemiology and outcomes of patients with monomicrobial and polymicrobial vap did not differ significantly. however, in this study, a substantial proportion of episodes classified as polymicrobial vap had positive isolation of bacteria usually considered as non-pathogenic microorganisms. moreover, between % and % patients with an episode of icuap are not previously intubated [ , , ] , namely non-ventilator icuap (nv-icuap). to our knowledge, no previous studies have comprehensively assessed polymicrobial icuap strictly considering the identification of potentially pathogenic microorganisms (ppm). we have recently shown that positive microbiology is associated with worse outcomes in patients with clinical diagnosis of icuap [ ] . therefore, whether patients with polymicrobial etiology of icuap have different characteristics and outcomes to those with monomicrobial etiology is unknown. we therefore investigated the incidence, characteristics, risk factors, systemic inflammatory response and outcomes of polymicrobial, compared with monomicrobial, etiology of icuap. the study was conducted between october and september in six medical and surgical icus, comprising beds, at hospital clinic, barcelona, spain, an -bed university hospital. the investigators made daily rounds in each icu. patients older than years, admitted to these icus for h or more, with clinical diagnosis of icuap were consecutively enrolled in the study, and this being only the first episode, were analyzed. exclusion criteria were: ) severe immune suppression (neutropenia after chemotherapy or hematopoietic transplant, druginduced immune suppression in solid-organ transplant or cytotoxic therapy, and patients with human immunodeficiency virus) and ) absence of microbiologic confirmation. the institution's internal review board approved the study (comite etic d'investigacio clinica, registry number / ) and written informed consent was obtained from patients or their next of kin. definition of pneumonia, microbiologic processing, and antimicrobial treatment clinical diagnosis of icuap was based on clinical criteria: new or progressive radiological pulmonary infiltrate together with at least two of the following: temperature > °c or < °c, leukocytosis > , / mm or leukopenia < , /mm , and purulent respiratory secretions [ , , ] . non-ventilated icuap was defined when patients acquired pneumonia after more than h of icu admission and without previous mechanical ventilation [ ] . we considered vap in patients with previous invasive mechanical ventilation for h or more. early-onset pneumonia was defined as occurring within the first days of hospitalization [ ] . the microbiologic evaluation included the collection of at least one lower respiratory tract sample: sputum in non-ventilated patients, tracheobronchial aspirates (tbas) in intubated patients, and/or bronchoscopic [ ] or blind bronchoalveolar lavage (bal) [ ] , whenever possible, within the first h of inclusion [ ] . bronchoscopic bal and blind bal were performed as previously described [ ] . the same sampling method was performed on the third day if clinically indicated. blood cultures and cultures from pleural fluid, if puncture was indicated, were also taken. urinary antigens of legionella pneumophila and streptococcus pneumoniae were systematically collected. microbiologic confirmation of pneumonia was defined by the presence of at least one ppm in respiratory samples above predefined thresholds (bal > , sputum or tbas > colony-forming units/ml, respectively), in pleural fluid or in blood cultures if an alternative cause of bacteremia was ruled out [ , ] . drug resistance of pathogens was defined according to a recent report [ ] . mdr pathogens were defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories. extensive drug resistance (xdr) was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e., bacterial isolates remain susceptible to only one or two categories). pan drug resistance (pdr) was defined as non-susceptibility to all agents in all antimicrobial categories. we considered methicillin-resistant staphylococcus aureus (mrsa), and enterobacteriaceae producing extended-spectrum β-lactamase as mdr pathogens [ ] . monomicrobial and polymicrobial pneumonia were defined when one and more than one ppm, respectively, were identified as etiologic agents at onset of pneumonia. isolation of candida spp, streptococcus viridans, staphylococcus epidermidis, neisseria spp, enterococcus spp, and corynebacterium spp in lower respiratory tract samples were not considered etiologic agents. the initial empiric antimicrobial treatment was administered according to local adaptation of the american thoracic society/infectious disease society of america guidelines [ ] , based on the most frequently isolated ppm and their patterns of antimicrobial sensitivity in our institution, and subsequently revised according to the microbiologic results. the empirical antimicrobial treatment was considered appropriate when the isolated pathogens were susceptible in vitro to at least one of the antimicrobials administered at an adequate dose [ ] . we assessed the initial response to treatment after to h of antimicrobial treatment, as previously described [ , ] . non-response was considered when at least one of the following criteria were present: ) no improvement of the arterial o tension to inspired o fraction ratio or need for intubation because of pneumonia (defined as need for intubation after h from the beginning of antibiotics); ) persistence of fever (temperature ≥ °c) or hypothermia (< . °c) together with purulent respiratory secretions; ) increase in the pulmonary infiltrates on chest radiograph ≥ %; or ) occurrence of septic shock or multiple organ dysfunction syndrome, defined as three or more organ system failures not present on day . we evaluated the serum levels of interleukin (il)- , il- , tumor necrosis factor-alpha (tnf-alpha), c-reactive protein, procalcitonin and mid-regional pro-adrenomedullin within the first h after the diagnosis of pneumonia. all methods of these analyses have been recently described in detail [ , ] . all relevant data were collected at admission and at onset of pneumonia from the medical records and bedside flow charts, including laboratory, radiologic and microbiologic information. we calculated the acute physiology and chronic health evaluation (apache)-ii score [ ] and the simplified acute physiology score (saps)-ii [ ] on icu admission. the simplified clinical pulmonary infectious score (cpis) [ ] and the sepsis-related organ failure assessment (sofa) [ ] scores were also evaluated on icu admission and up to days after the onset of pneumonia. septic shock [ ] and acute respiratory distress syndrome (ards) [ ] were defined according to previously described criteria. patients were followed until death or up to days after the diagnosis of pneumonia. the outcomes of patients with monomicrobial pneumonia were compared to those with polymicrobial pneumonia. the primary outcome variable was mortality at days after the diagnosis of icuap. secondary outcomes included initial non-response to treatment, length of icu and hospital stay, ventilator-free days at day [ ] , and mortality at days. categorical and continuous data are presented as number (percentage) and as mean ± sd (or median (inter-quartile range)), respectively. categorical variables were compared with the chi square (χ ) test or the fisher exact test. quantitative continuous variables were compared using the t test or the mann-whitney test for normally and non-normally distributed variables, respectively. survival curves for patients with monomicrobial and polymicrobial pneumonia were obtained using the kaplan-meier method and compared using the log-rank test. the association between polymicrobial or monomicrobial etiology and patients' outcomes was adjusted for variables potentially related to mortality, such as age, apache-ii and saps scores at icu admission, sofa score, cpis and arterial partial pressure of oxygen/inspired oxygen fraction (pao /fio ) ratio at onset of pneumonia, vap or nv-icuap, and unilateral or bilateral chest x-ray infiltrates. we used cox proportional hazard regression analysis for -day and -day mortality. all reported p values are two-sided and not adjusted for multiple comparisons. a p value < . was considered significant. all statistical analyses were performed using ibm spss statistics version (armonk, ny, usa). we prospectively identified consecutive patients with icuap; ( %) were excluded because a positive microbiological diagnosis could not be made. therefore, we included patients: ( %) with monomicrobial, and ( %) with polymicrobial icuap (fig. ) . the characteristics of patients at icu admission and at onset of pneumonia are summarized in tables and . the rate of chronic heart disease was lower, and the rate of pleural effusion was higher, in patients with polymicrobial, compared to monomicrobial pneumonia. no other significant differences were found between the two groups in the remaining baseline characteristics, comorbidities, reasons for icu admission, disease severity, and laboratory variables at the onset of pneumonia. the proportions of lower respiratory tract samples processed for microbiology were similar in the two groups (table ) . however, blood and pleural fluid culture were performed more often in patients with polymicrobial pneumonia, in case of pleural fluid, owing to the higher incidence of pleural effusion in this group. there were patients ( %) in the polymicrobial pneumonia group with methicillin-sensitive staphylococcus aureus (mssa) isolated in pleural fluid. in the monomicrobial pneumonia group, patients ( %) had positive pleural fluid cultures: mssa and pseudomonas aeruginosa in patients, and mrsa in patients. there were patients ( %) in the polymicrobial pneumonia group with positive blood cultures: serratia table . all patients with polymicrobial pneumonia had two different pathogens identified, except two who had three different pathogens identified ( table ). the most frequently isolated pathogens were p. aeruginosa, enterobacteriaceae, and mssa. several bacteria, such as mssa, haemophilus influenzae, klebsiella spp., e. coli, enterobacter spp., citrobacter spp., and serratia spp., were more frequently isolated in patients with polymicrobial pneumonia. the remaining pathogens were isolated at similar rates in both groups. these findings were similar when we analyzed patients with vap and non-ventilator icuap separately. the proportion of patients with mdr and xdr pathogens isolated were similar in both groups (table ). there were no patients with pdr microorganisms. patients treated with antibiotics before the onset of icuap more frequently had mdr or xdr pathogens than those not treated previously with antibiotics ( ( %) vs. ( %), respectively, p = . ). a new microbiologic evaluation was done on the third day of evolution in patients ( %) and patients ( %) from the monomicrobial and polymicrobial groups, respectively. the microbiologic evolution is shown in table . the serum levels of all inflammatory biomarkers were similar in patients from the two groups (table ). the appropriateness of the empirical antimicrobial treatment, the initial non-response to treatment, the length of stay, the ventilator-free days, and mortality at and days were similar in both groups (table and fig. ) . mortality of patients adjusted for initial non-response to treatment did not differ between groups ( days: p = . ; days: p = . ). the most frequent cause of death was shock-multiple organ failure. even when adjusted for variables potentially related to mortality, the polymicrobial etiology of icuap was not associated with -day mortality (adjusted hazard ratio . , % confidence interval . - . , p = . ) or -day mortality (adjusted hazard ratio . , % confidence interval . - . , p = . ). polymicrobial etiology accounted for % cases of icuap with positive microbiology. except for less frequent chronic heart disease and more frequent pleural effusion in polymicrobial pneumonia, there were no other significant differences between patients with monomicrobial and polymicrobial pneumonia in their baseline characteristics, inflammatory response or outcomes. information about the polymicrobial etiology of icuap is limited. the only study that specifically addressed this issue in vap, published in [ ] , found a substantially higher proportion of polymicrobial etiology ( %) compared to the present one. unlike our study, those authors included some bacteria that are considered nonpathogenic for the lung in non-immunosuppressed patients, such as several streptococcus species, neisseria spp, enterococcus spp, and coagulase-negative staphylococci. indeed, a substantial proportion of microbial isolates reported in polymicrobial vap in that study ( %) represented these types of microbes [ ] . similarly, previous observational studies reported rates of polymicrobial etiology of vap that ranged between % and % when ppms and non-pathogenic microbes were analyszed [ ] [ ] [ ] [ ] . having included non-pathogenic microbes would have increased the rate of polymicrobial pneumonia to % in our population. conversely, we report in our study that % of patients with icuap had polymicrobial etiology when we restricted the analysis to ppms. a previous study that used the same criteria reported a similar rate ( %) for vap of polymicrobial etiology [ ] . a relevant issue in the polymicrobial etiology of icuap is the potential prognostic implications. for that reason, finding predictors of polymicrobial pneumonia reported values are median (interquartile range). a number of patients with samples processed for each inflammatory biomarker in each group. il interleukin, mr-proadm mid-regional pro-adrenomedullin, tnf tumor necrosis factor could hypothetically be of potential interest. however, in a clinical setting of highly appropriate initial antibiotic treatment, as reported in the present study for both groups, all the outcomes, including length of stay, ventilator-free days and mortality, were similar in the two groups. indeed, in our study the numbers of patients with mdr or xdr pathogens in our study did not differ with pneumonia of polymicrobial etiology. in addition, when patients were clustered into non-ventilated icuap and vap, there were also no statistically significant differences in these outcomes. in our study, the only variables associated with polymicrobial etiology were absence of chronic heart disease and prior hospital admission, and the presence of pleural effusion, which was twice as high in the polymicrobial group. we have previously reported that patients with clinical diagnosis of both community-acquired pneumonia and icuap and negative microbiology more frequently have chronic heart disease [ , ] . both studies suggested that some of these cases might also represent, at least in part, fluid overload due to congestive heart failure added to the underlying inflammatory process potentially mimicking pneumonia. similarly, underlying chronic heart disease might hypothetically have contributed to the development of pulmonary congestion in patients with presumably lower bacterial burden, such as those with pneumonia of monomicrobial etiology. we do not have a clear explanation for the association between a higher rate of pleural effusion and polymicrobial pneumonia. the isolation of mssa in pleural fluid culture from two patients was not sufficiently decisive to allocate them to the polymicrobial pneumonia group; in one patient, this pathogen was concomitantly identified in blood and tracheal aspirate cultures, while in the other, both h. influenzae and klebsiella spp were isolated in a tracheal aspirate culture. the association between pleural effusion and icuap of polymicrobial etiology needs to be confirmed in future prospective studies. neither prior antibiotic treatment nor late-onset pneumonia, as in the previous french study [ ] , were predictors of polymicrobial pneumonia in our study. however, prior antibiotic treatment was associated with the presence of mdr or xdr pathogens in our study. in addition we found no association between the severity of presentation and polymicrobial etiology. this finding complements a previous study in patients with icuap that concluded that severity of illness seems not to affect etiology [ ] . we also found no differences in the serum levels of any inflammatory biomarkers that we measured at the onset of pneumonia. in relation to the etiology of icuap, we have recently reported that inflammatory biomarkers were unable to differentiate between patients with positive and negative microbiology [ ] , or patients with or without mdr pathogens [ ] . all these studies confirm that inflammatory biomarkers are not useful in predicting the etiology of icuap. the main strengths of our study are the prospective design, the detailed description of microbiology in icuap, the inclusion of both vap and non-ventilator icuap, the exclusion of non-potentially pathogenic microorganisms from the analysis, the assessment of several inflammatory biomarkers, and the follow up of patients up to days. however, in our study we excluded immunosuppressed patients. consequently, we cannot extrapolate our results to this population. this study has some limitations. first, it was conducted in a single center, so the extrapolation of these findings to other settings must be done cautiously. second, we did not use molecular microbiological techniques that are potentially more sensitive. however, the experience of using these techniques in icuap, and in non-ventilator icuap and vap, is still scarce. third, the sample size of our study is not enough large to make a robust analysis of all related questions; when comparing several characteristics between the two groups of patients the current study was underpowered. it is important to outline that this is a non-interventional study and our purpose was only to describe clinical findings. fourth, there were no adjustments made for multiple comparisons. the etiology of icuap with microbiologic confirmation was polymicrobial in % of patients. pleural effusion and absence of chronic heart disease are associated with polymicrobial pneumonia. when empiric antibiotic treatment is frequently appropriate, polymicrobial etiology does not influence the outcome of icuap. polymicrobial etiology of icu-acquired pneumonia accounted for % cases with microbiologic confirmation polymicrobial etiology of icu-acquired pneumonia was associated with pleural effusion and absence of chronic heart disease polymicrobial etiology did not result in higher incidence of multi-drug-and extensive-drugresistant pathogens when empiric treatment is appropriate, polymicrobial etiology does not influence the outcome of icu-acquired pneumonia abbreviations apache: acute physiology and chronic health evaluation; ards: acute respiratory distress syndrome; bal: bronchoalveolar lavage; cpis: clinical pulmonary infectious score; icu: intensive care unit; icuap: icu-acquired pneumonia; il: interleukin; mdr: multi-drug-resistant; mrsa: methicillin-resistant staphylococcus aureus; mssa: methicillin-sensitive staphylococcus aureus; pao /fio : arterial partial pressure of oxygen/inspired oxygen fraction; pdr: pan-drug resistance; ppm: potentially pathogenic microorganism; saps: simplified acute physiology score; sofa: sepsis-related organ failure assessment; tbas: tracheobronchial aspirates; tnf: tumor necrosis factor; vap: ventilator-associated pneumonia; xdr: extensive-drug-resistant. infectious diseases society of america. guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia nosocomial pneumonia in the intensive care unit acquired during mechanical ventilation or not impact of nosocomial infections on clinical outcome and resource consumption in critically ill patients attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. icu-acquired pneumonia study group de-escalation therapy: is it valuable for the management of ventilator-associated pneumonia? early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia assessment of severity of icu-acquired pneumonia and association with etiology prevalence, risk factors, and mortality for ventilator-associated pneumonia in middle-aged, old, and very old critically ill patients* incidence and outcome of polymicrobial ventilator-associated pneumonia pneumonia associated with invasive and noninvasive ventilation: an analysis of the german nosocomial infection surveillance system database hospital and long-term outcomes of icu-treated severe community-and hospitalacquired, and ventilator-associated pneumonia patients icu-acquired pneumonia with or without etiologic diagnosis: a comparison of outcomes clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies definition and classification of community-acquired and nosocomial pneumonias the standardization of bronchoscopic techniques for ventilator-associated pneumonia the safety and diagnosis accuracy of minibronchoalveolar lavage in patients with suspected ventilator associated pneumonia noninvasive versus invasive microbial investigation in ventilator-associated pneumonia: evaluation of outcome hospital-acquired pneumonia: coverage and treatment adequacy of current guidelines diagnostic value of quantitative cultures of endotracheal aspirate in ventilator-associated pneumonia: a multicenter study resistance patterns and outcomes in intensive care unit (icu)-acquired pneumonia. validation of european centre for disease prevention and control (ecdc) and the centers for disease control and prevention (cdc) classification of multidrug resistant organisms causes and predictors of non-response to treatment of the icu-acquired pneumonia validation of predictors of adverse outcomes in hospital-acquired pneumonia in the icu* inflammatory biomarkers and prediction for intensive care unit admission in severe community-acquired pneumonia prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology apache ii: a severity of disease classification system a new simplified acute physiology score (saps ii) based on a european/north american multicenter study resolution of ventilator-associated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome the sofa (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. on behalf of the working group on sepsis-related problems of the european society of intensive care medicine surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock acute respiratory distress syndrome: the berlin definition statistical evaluation of ventilator-free days as an efficacy measure in clinical trials of treatments for acute respiratory distress syndrome nosocomial pneumonia in patients receiving continuous mechanical ventilation. prospective analysis of episodes with use of a protected specimen brush and quantitative culture techniques nosocomial bronchopneumonia in the critically ill: histologic and bacteriologic aspects incidence and etiology of pneumonia acquired during mechanical ventilation ventilator-associated pneumonia caused by potentially drug-resistant bacteria effect of ventilator-associated pneumonia on mortality and morbidity factors associated with unknown aetiology in patients with community-acquired pneumonia the authors declare that they have no competing interests.authors' contributions mf participated in the study design, recruitment of patients, data analysis and writing of the manuscript. lfd participated in the study design, recruitment of patients and writing of the manuscript. al participated in the study design, recruitment of patients and writing of the manuscript. mr participated in recruitment of patients, interpretation of data and critical review of the manuscript. mc participated in recruitment of patients, interpretation of data and critical review of the manuscript. glb participated in interpretation of data, critical review and writing of the manuscript. ag participated in the data analysis, management of database and, drafting of the manuscript. at participated in the study design, interpretation of date and critical review and writing of the manuscript. all the authors have read and approved the final version of the manuscript.• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord- - ebmd authors: ferreira-coimbra, joão; sarda, cristina; rello, jordi title: burden of community-acquired pneumonia and unmet clinical needs date: - - journal: adv ther doi: . /s - - - sha: doc_id: cord_uid: ebmd community-acquired pneumonia (cap) is the leading cause of death among infectious diseases and an important health problem, having considerable implications for healthcare systems worldwide. despite important advances in prevention through vaccines, new rapid diagnostic tests and antibiotics, cap management still has significant drawbacks. mortality remains very high in severely ill patients presenting with respiratory failure or shock but is also high in the elderly. even after a cap episode, higher risk of death remains during a long period, a risk mainly driven by inflammation and patient-related co-morbidities. cap microbiology has been altered by new molecular diagnostic tests that have turned viruses into the most identified pathogens, notwithstanding uncertainties about the specific role of each virus in cap pathogenesis. pneumococcal vaccines also impacted cap etiology and thus had changed streptococcus pneumoniae circulating serotypes. pathogens from specific regions should also be kept in mind when treating cap. new antibiotics for cap treatment were not tested in severely ill patients and focused on multidrug-resistant pathogens that are unrelated to cap, limiting their general use and indications for intensive care unit (icu) patients. similarly, cap management could be personalized through the use of adjunctive therapies that showed outcome improvements in particular patient groups. although pneumococcal vaccination was only convincingly shown to reduce invasive pneumococcal disease, with a less significant effect in pneumococcal cap, it remains the best therapeutic intervention to prevent bacterial cap. further research in cap is needed to reduce its population impact and improve individual outcomes. also high in the elderly. even after a cap episode, higher risk of death remains during a long period, a risk mainly driven by inflammation and patient-related co-morbidities. cap microbiology has been altered by new molecular diagnostic tests that have turned viruses into the most identified pathogens, notwithstanding uncertainties about the specific role of each virus in cap pathogenesis. pneumococcal vaccines also impacted cap etiology and thus had changed streptococcus pneumoniae circulating serotypes. pathogens from specific regions should also be kept in mind when treating cap. new antibiotics for cap treatment were not tested in severely ill patients and focused on multidrug-resistant pathogens that are unrelated to cap, limiting their general use and indications for intensive care unit (icu) patients. similarly, cap management could be personalized through the use of adjunctive therapies that showed outcome improvements in particular patient groups. although pneumococcal vaccination was only convincingly shown to reduce invasive pneumococcal disease, with a less significant effect in pneumococcal cap, it remains the best therapeutic intervention to prevent bacterial cap. further research in cap is needed to reduce its population impact and improve individual outcomes. keywords: cap; community-acquired pneumonia; epidemiology; infectious disease introduction community-acquired pneumonia (cap) is a frequent and deadly infection, having considerable implications for healthcare systems worldwide. cap is responsible globally for million deaths annually [ ] . poor outcomes are usually related to cap severity and patient characteristics and co-morbidities. some recent advances emphasise in the importance of continuous research in cap. cap classification has varied over the last years. recently, american guidelines [ ] abandoned healthcare-associated pneumonia (hcap) because of the lack of evidence showing differences in microbiology of cap and hcap. this definition change could introduce differences in epidemiological reporting. important advances in cap have also been reported since pneumococcal vaccines and diagnostic tests for viruses. recently, nature medicine published the first use of phages to treat a multidrug-resistant (mdr) microorganism [ ] and lancet infectious diseases reported the first use of pneumolysin in severe cap treatment added to standard of care in a phase ii trial [ ] . these advances emphasise the importance of continuously updating cap management and research and development. in this review, we aim to provide a perspective of cap burden that is critical to allocating resources to improve patient outcomes and also to support new research focused on unmet clinical needs. this article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. in europe, cap incidence varies widely ranging from . / , in iceland [ ] to . / , person-years in the uk [ ] . data from italy [ ] in adults (over years of age) between and reported cap incidence between . and . per , inhabitants and a hospitalization rate lower than % within days from diagnosis. in france, cap incidence is estimated as per , person-years [ ] with % of patients being admitted in the -day period after cap diagnosis. in the usa, in adults under years old, cap incidence varies between . / , personyears [ ] and / , person-years [ ] . moreover, as expected, elderly people have a higher incidence, representing . / , person-years in - -year-olds and reaching . / , person-years after years old. a study in latin america (including argentina, paraguay and uruguay) reported incidence varying between . and / , person-years in people aged -- years and - / , person-years in those over years [ ] . another study in latin america (argentina, brazil, chile, colombia, mexico and venezuela) reported cap incidence varying between . and . / , personyears in a population over years [ ] . south korea has an incidence rate of . / , person-years [ ] with high importance of pneumococcal pneumonia [ ] . cap incidence in japan in middle-aged adults ( -- years) is / , person-years, increasing markedly over age to and / , person-years in adults aged - years and -- years, respectively. a recent study of three asian countries [ ] reported that cap is responsible for . , . and . episodes per , discharges in the philippines, indonesia and malaysia, respectively. in china, cap incidence is estimated as . - . per , admissions including children [ ] . in australia, a study between and reported an incidence of . / , personyears [ ] in patients older than years. an australian study estimated cap incidence in all age groups (including children) as . / , , rising to . / , and . / , person-years in patients between and years and over years, respectively [ ] . a retrospective analysis in new zealand estimates cap incidence as / , in the general population and . / , in patients older than years [ ] . table summarizes global data on cap incidence in adults. to properly analyze this data it is important to keep in mind that the real clinical incidence of cap is difficult to determine because of differences in reporting and case selection from epidemiological studies. cap notification is optional even in developed countries, except when presenting as invasive pneumococcal disease (when cap is accompanied by the identification of pneumococcus in sterile fluids such as blood, cerebrospinal fluid, and pleural, joint or peritoneal fluid) and legionnaires disease in some countries. worldwide differences in access to healthcare services also preclude direct comparison of incidence [ ] . furthermore, scarce data are available from primary care or representing patients treated in ambulatory settings. moreover, cap incidence varies considerably according to geographic location, study methods, case definition and study population [ , ] . cap incidence varies and is also highly influenced by age and co-morbidities (such as chronic obstructive pulmonary disease, diabetes mellitus, renal failure, congestive heart failure, coronary artery disease and liver disease). a seasonal effect that doubles the rate of pneumonia in the winter months impacts, additionally, incidence studies [ ] . according to the world health organisation (who) data, lower respiratory tract infections are the primary infective cause of death globally accounting for . % of deaths [ ] . the global burden of disease study showed that deaths from low respiratory tract infections decreased both in the total number of deaths . % ( % ui, - . , - . ) and age-standardized rates . % ( % ui, - . , - . ), from to [ ] . in the usa, cap causes around , deaths per year, a mortality of %, . % and . % at month, months and months, respectively [ ] . cap alone is responsible for at least , deaths annually in europe [ ] . one-year cap mortality in canada is estimated as % [ ] . in the asia-pacific region cap mortality is estimated between . % and % [ ] . in low-income countries, mortality tends to be higher, as proved in a study addressing mortality in lowincome countries that showed higher mortality than in high-income countries, reporting a mortality rate of % in cambodia, % in senegal, % in uganda and % in the central african republic [ ] . mortality occurs largely in hospitalized patients ( - %) [ , , ] , but it varies widely according to treatment setting and severity disease, while mortality in primary care and ambulatory patients is inferior to % in most of the population, rising in patients over years [ , ] . one-ninth of patients hospitalized with cap will need intensive care unit (icu) admission because of severe respiratory failure, severe sepsis, or septic shock [ , ] and cap mortality in these patients remains very high, reaching near % [ ] . a progressively higher incidence of severe cap was reported in icu, but the mortality rate had decreased by % over a -year period [ ] . data reporting on severity could be driven by reimbursement and, therefore, not represent a real increase in severity cap. patients who had been treated in the hospital for cap have a clinically significant long-term poor survival when compared to matched controls. this increased post-discharge mortality is driven by pulmonary complications, new cap episodes and cardiovascular events, probably in the course of a persistent inflammatory response [ , ] . cap mortality reflects the enrollment of different patient populations in epidemiological studies as well as their methodology. hospital and icu admission criteria vary among different countries and hospitals, which hinders a comparison between them. different admission criteria across countries, as well as the availability of icu dedicated beds, technological and human resources could change reported mortality, as well as data regarding icu admission. other factors such as guideline adherence and quality of care could also reduce mortality [ ] . this data is infrequently reported in epidemiological studies. numerous patient risk factors and co-morbidities can hardly affect disease severity as well as the risk of death. patient risk factors age, co-morbidities and immune status, together with microbiological pathogens and the absence of response to treatment also influence mortality [ ] . despite most of cap episodes being caused by few microorganisms, several bacteria, viruses and fungi are recognized as causes of cap. however, even when prospective studies were performed, less than half of patients presenting with cap had a microbiologic diagnosis [ , [ ] [ ] [ ] . important variations are found according to patient severity and used diagnostic tools. the emergence of new diagnostic tests improved the recognition of pathogens compared with previous tests [ ] , not only for viruses but also for bacterial pathogens, allowing earlier directed therapy and antibiotic deescalation. a higher rate of microorganism isolation was reported when newer diagnostic approaches and molecular techniques were used [ ] [ ] [ ] . some of these approaches are not widely available in clinical practice and their use remains controversial because no studies prove their outcome benefits and tests are costly. moreover, antiviral agents are inactive against some viruses which precludes the utility of viral identification in clinical practice. streptococcus pneumoniae remains the most isolated bacterial pathogen in cap worldwide in all treatment settings (outpatient, general ward and icu) [ , , , [ ] [ ] [ ] [ ] [ ] . s. pneumoniae resistance patterns remain different across countries. in recent studies, mycoplasma pneumoniae, chlamydia pneumoniae and legionella pneumophila, which are well-established causes of cap, have been isolated more frequently than before [ , , , ] (table ) . however, except for l. pneumophila, the diagnosis is difficult in clinical practice but could improve with multiplex pcr tests. haemophilus influenzae account for . - % [ , ] of all cases of bacterial cap; however, this rose to around % in some studies [ ] . h. influenzae is a major public health problem because of its increasing antimicrobial resistance. given this resistance, specially to beta-lactams, h. influenzae was listed in the priority list of who antibiotic-resistant bacteria [ ] . unlike in other global areas, gram-negative pathogens are also frequent pathogens (mostly klebsiella pneumoniae and burkholderia pseudomallei) in asia. meloidosis is a life-threatening infectious disease (caused by b. pseudomallei) that is endemic in south and southeast asia, northern australia and china, peaking in the wet season. in some places, it is the third most common deadly disease after hiv and tuberculosis. pneumonia is the most frequent presentation, with a mortality rate reaching % [ , ] , related to shock and bacteremia. several cases are also reported in travellers returning from endemic areas [ , ] . even subject to some variations, generally methicillin-resistant s. aureus and mdr gramnegative bacilli together cause cap in approximately % of patients [ , ] , presenting even lower incidence in non-critically ill patients. while their empirical coverage is almost always unnecessary in cap, in some areas and in patients with specific risk factors it could be considered; thus, inappropriate therapy is related to increasing mortality. the precise role of viruses in cap is not yet well established e.g. pathogens, co-pathogens, triggers or all-in-one. respiratory viruses are isolated in up to one-third of patients with cap [ ] [ ] [ ] . however, it is not straightforward to rw review article, r retrospective study, p prospective study, nr not reported assume that the presence of virus isolates in nasopharyngeal swabs (as performed in most studies) is sufficient to explain cap pathogenesis. almost all studies (table ) using polymerase chain reaction (pcr) reported influenza, rhinovirus and respiratory syncytial virus (rsv) as the commonest isolated, but whether they are true pathogens remains debatable. metapneumovirus was first described as a pathogen in children; however, it also infects adults, but the incidence is lower than in children [ ] . adults can carry the virus asymptomatically. however, it was recognized as a single cap pathogen in % of patients in the usa [ ] and recently had been implicated in severe cap [ ] . similarly to other viruses, metapneumovirus appears to have a seasonal variation with a peak after influenza season. microbiology remains of utmost importance given that it has a significant prognostic impact. cap unmet clinical needs set priorities for research topics in cap therapy and prevention through vaccines, that are, in our opinion, important to be perform in the next few years, table . in the last decade, many efforts were made to develop new drugs, resulting in newly approved antibiotics listed in table . however, new antibiotics were often being developed to improve their activity against several mdr microorganisms, which are, as previously shown, uncommon in cap. most of these trials focused on patients with non-severe cap requiring hospitalization [ ] [ ] [ ] [ ] [ ] [ ] [ ] , excluding severely ill patients (or icu patients), so recommendations for these groups of patients are why is evidence of short duration antibiotic therapy in cap not applied in clinical management? which patients should be treated with antiviral therapy in cap? should antiviral therapy be used empirically during influenza seasonal epidemics or all year? could pk/pd interventions change the outcomes in severe cap? in non-severe cap might new oral antibiotics be directed to once-daily dosages? what is the role of tetracyclines in cap treatment? in severe cap what is the best drug on top of beta-lactam therapy: macrolide or quinolone? adjunctive therapies which patients will benefit from steroid therapy in cap? what are the best steroid, steroid dose and duration in cap? in patients with cap presenting with high inflammatory response, can steroid therapy improve hard outcomes? how should viral infection be excluded before steroid treatment? can steroids and macrolides have an addictive anti-inflammatory effect? is pcv superior to ppv in invasive pneumococcal disease and pneumococcal cap? which is the best scheme/schedule of anti-pneumococcal vaccination? is vaccine efficacy equivalent in immunocompetent and immunosuppressed patients? is adult pneumococcal vaccination cost-effective in settings with high childhood vaccination rates? will vaccines directed to s. pneumoniae virulence factors be more efficient than current ones? new randomized controlled trial (rct) to study performance of new drugs in patients with severe cap (psi [ , port class v) which is the epidemiology of lethal cap? what is the real burden of morbidity and mortality after cap? how should microbiologic surveillance be performed in a global way? derived from studies without their representation. it is an important limitation for the widespread use of new antibiotics, in spite of drug usage specificities in critically ill patients. studies are needed in more severely ill patients. rcts showing superiority instead of ''non-inferiority'' are needed to show a clear advantage of new drugs. in the period after introduction of new antibiotics, microbiological resistance surveillance remains essential because of new antibiotic pressure among pathogens, which could lead to resistance. long-term side effects should also be studied. several therapies have been tested to improve cap outcomes using different strategies, to target innate immunity and adaptive immunity, as well as other immunomodulatory or anti-inflammatory drugs. for the purpose of this review we focus on adjunctive therapies to steroids and macrolides that are clinically available and the subject of many studies. difficulties in showing an impact on hard outcomes, and difficulties in properly identifying the patients that will benefit more of them, impair the use of adjunctive therapies. furthermore, as these therapies focus mainly on the inflammatory response, long-term outcome studies should be performed to analyze how they modulate long-term mortality that is related to chronic inflammatory status. the use of steroid therapy in patients with bacterial cap remains uncertain, mainly because of the lack of knowledge about which phenotypes of disease and patient groups will have greater benefits from this therapy. inflammatory response contributes to cap mortality. steroid therapy reduces the inflammatory response and is therefore believed to improve outcomes in patients with cap . however, this assumption remains controversial because of conflicting results regarding mortality [ ] [ ] [ ] [ ] [ ] . although it is likely to enhance patient performance, the published positive results focused on soft outcomes (reduction of treatment failure, length of stay, progression to acute respiratory distress [ ] [ ] [ ] [ ] [ ] . steroid treatment depending on high inflammatory response should also be retested addressing hard endpoints [ ] because the previous published rct used radiological improvement as a primary outcome. the only study that established mortality as the primary outcome [ ] has not yet been published. precise identification of patients that will benefit from steroids is critical, given that these drugs have important side effects. steroids have the potential to reduce survival in viral respiratory infections. the ideal method to convincingly exclude viral infection before steroid therapy initiation should also be addressed. for that, new studies are needed in specific populations (i.e. studying separately severe and non-severe cap) to improve the body of evidence about steroid usage in cap. macrolide therapy is used frequently in respiratory diseases for its antimicrobial activity and anti-inflammatory effects. several in vitro and in vivo studies proved this ability through a reduction in pro-inflammatory interleukins and improved levels of anti-inflammatory ones, as well as the ability to reduce polymorphonuclear neutrophil (pmn) recruitment and decrease reactive oxygen species [ ] [ ] [ ] [ ] [ ] . the clinical meaning of these findings remains controversial because, for now, there is no randomized clinical trial confirming the superiority of therapies containing macrolides regarding mortality [ , ] . however, observational studies [ ] [ ] [ ] [ ] showed consistently improved outcomes in invasive pneumococcal disease in severely ill patients (i.e. invasively ventilated and under vasopressor treatment). some guidelines [ ] [ ] [ ] [ ] recommend use of macrolides in combination therapy with betalactams as first-line therapy in cap, either in icu and non-icu patients. those recommendations were mainly driven by observational studies that are subject to bias. evidence from recent rcts [ ] , failed again to show the advantages of this approach in non-critically ill patients that had never been clearly shown. the generalized use of macrolides has the potential to promote antibiotic resistance, so until an rct shows evidence of benefit macrolides should be judiciously used in non-critically ill patients, whereas macrolides are associated with qtc interval prolongation, gastrointestinal events and drug interactions. pneumococcal vaccination [ ] , where the vaccination rate is higher, contributes to pneumococcal vaccine-type disease reduction. data regarding herd protection is not consensual, but its disparity could be explained by the different time intervals between generalized vaccination and studies [ , ] . further, vaccine introduction also leads to serotype shifting; meanwhile, no effects in resistance patterns were noted [ ] . several efforts were made to develop a vaccine to prevent pneumococcal infection resulting in two available vaccines: pneumococcal polysaccharide -valent (ppv , contains capsular polysaccharides of % of serotypes causing disease in adults) and pneumococcal conjugate -valent (pcv , stimulates antibody production against - % of serotypes causing disease, varying according different geographical areas). for both, vaccine efficacy has been proven for invasive pneumococcal disease [ , ] . only pcv has been clearly associated with the prevention of non-invasive and invasive pneumococcal community-acquired pneumonia (capita trial [ ] ) regarding vaccine-targeted serotypes. in different countries, vaccine indications vary, some based on believing that pcv could boost immunity created by ppv (when previously administered) [ ] . it is controversial whether pcv is superior to ppv , because comparative trials are lacking. new outcomes should also be determined for invasive pneumococcal disease and pneumococcal cap, as well as all-cause mortality and pneumococcal cap-related mortality. the definition of immunosuppressed patients also varies according to different studies, which impairs the process of studying real immunosuppressive risk factors for pneumococcal infection. while in immunocompromised patients indications for vaccination are well established (table ), in other groups evidence is less clear, allowing different recommendations in different countries. pneumococcal vaccine calendar, administration of one or both vaccines [ ] , should be further elucidated in new studies. after introduction of vaccines, pneumococcal microbiology in cap moved to serotypes that are not included in vaccines [ ] . new vaccines immunizing widely for other serotypes will be valuable, as well as other vaccine approaches targeting s. pneumoniae virulence factors. costeffectiveness of vaccination in adults should be evaluated to analyze whether high child pneumococcal immunization could modify its costeffectiveness in adults and the elderly. the large body of evidence discussed has exposed the high incidence and mortality of cap, usually related to older age and co-morbidities. cap microbiology had been changed because new diagnostic tests have turned viruses into the most identified pathogens, while their role in pathogenesis is not fully explained. adjunctive therapies should remain part of cap tailored management. vaccines should remain the backbone of bacterial cap prevention. further studies are needed to improve outcomes in patients with cap. funding. no funding or sponsorship was received for this study or publication of this article. authorship. all named authors meet the international committee of medical journal editors (icmje) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. ferreira-coimbra and cristina sarda have no conflicts of interest. jordi rello was nabriva advisor. jordi rello is a member of the journal's editorial board. compliance with ethics guidelines. this article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. open access. this article is licensed under a creative commons attribution-noncommercial . international license, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by 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misharin, alexander v.; singer, benjamin d.; wunderink, richard g. title: alveolitis in severe sars-cov- pneumonia is driven by self-sustaining circuits between infected alveolar macrophages and t cells date: - - journal: biorxiv doi: . / . . . sha: doc_id: cord_uid: jyp gjh some patients infected with severe acute respiratory syndrome coronavirus- (sars-cov- ) develop severe pneumonia and the acute respiratory distress syndrome (ards) [ ]. distinct clinical features in these patients have led to speculation that the immune response to virus in the sars-cov- -infected alveolus differs from other types of pneumonia [ ]. we collected bronchoalveolar lavage fluid samples from patients with sars-cov- -induced respiratory failure and patients with known or suspected pneumonia from other pathogens and subjected them to flow cytometry and bulk transcriptomic profiling. we performed single cell rna-seq in bronchoalveolar lavage fluid samples collected from patients with severe covid- within hours of intubation. in the majority of patients with sars-cov- infection at the onset of mechanical ventilation, the alveolar space is persistently enriched in alveolar macrophages and t cells without neutrophilia. bulk and single cell transcriptomic profiling suggest sars-cov- infects alveolar macrophages that respond by recruiting t cells. these t cells release interferon-gamma to induce inflammatory cytokine release from alveolar macrophages and further promote t cell recruitment. our results suggest sars-cov- causes a slowly unfolding, spatially-limited alveolitis in which alveolar macrophages harboring sars-cov- transcripts and t cells form a positive feedback loop that drives progressive alveolar inflammation. this manuscript is accompanied by an online resource: https://www.nupulmonary.org/covid- / one sentence summary sars-cov- -infected alveolar macrophages form positive feedback loops with t cells in patients with severe covid- . secondary to other pathogens or non-pneumonia controls (intubated for reasons other than pneumonia) according to a standardized adjudication procedure (see methods). patients were designated as viral pneumonia if a multiplex pcr for respiratory viruses obtained by nasopharyngeal swab or bal was positive in the absence of an alternative diagnosis based on quantitative culture of bal fluid or multiplex pcr. a complete list of viral and bacterial pathogens identified as the cause of pneumonia is in table . for some patients without covid- the diagnosis of pneumonia was made based on clinical suspicion, radiographic findings and response to antimicrobial therapy in the absence of an identified pathogen. for all patients with covid- , samples were collected from regions of greatest chest radiograph abnormality by a critical care physician using a disposable bronchoscope. the majority of samples prior to the pandemic were collected by respiratory therapists using non-bronchoscopic bronchoalveolar lavage (nbbal) with the catheter directed to the most radiographically affected lung [ ] . compared with patients with known or suspected pneumonia requiring mechanical ventilation, patients with severe sars-cov- pneumonia were similar in age, race, and sex, but had a significantly higher body mass index and a lower proportion of patients were current smokers, compared with historic control populations diagnosed with other viral pneumonias, non-viral pneumonia, or non-pneumonia control patients (figure b-g) . patients with severe sars-cov- pneumonia required longer periods of ventilation and had longer lengths of stay in the icu compared with all pneumonia and non-pneumonia controls (figure h-i) . severity of illness estimated using the sequential organ failure assessment (sofa) score and the acute physiology score (aps) was similar in patients with sars-cov- pneumonia compared with other pneumonia and was comparable to that observed in a recent study of ards [ ] (supplemental figure s c and table ). nevertheless, mortality was significantly lower (q = . , chi-square tests of proportions) in patients with sars-cov- pneumonia, compared with the entire cohort ( % vs %), but was not significantly different as compared with any individual comparison group (figure j) . figure . demographics of the script cohort. we compared bal fluid obtained sequentially from patients with severe sars-cov- pneumonia requiring mechanical ventilation with patients with confirmed pneumonia secondary to other respiratory viruses (other viral pneumonia) and patients with non-viral pneumonia (other pneumonia) and mechanically ventilated patients without pneumonia undergoing bal (non-pneumonia controls). a. timing of hospital admission (square), bal collection (diamonds) and length of mechanical ventilation (bold red line) and hospital stay (thin grey line) in patients with severe covid- grouped by outcomes (crossed open red circles -death; green circles -discharged home; light blue circles -discharged to inpatient facility). day is defined as the day of the first intubation. an average of . (range - ) bal samples were collected per patient. b. distribution of patient ages. differences not significant by pairwise t-test with fdr correction. c. sex. proportions of females (red) and males (blue) were similar between groups (pairwise chi-square tests of proportions with continuity and fdr correction). d. self-reported race. proportions were similar between groups (pairwise chi-square tests of proportions with continuity and fdr correction). e. self-reported ethnicity. a significant increase in the proportion of individuals identifying as hispanic or latino was observed in the covid- cohort, relative to all controls (q < . , pairwise chi-square tests of proportions with continuity and fdr correction). f. self-reported smoking status. significantly fewer active smokers were observed in the covid- cohort, as compared with all control groups (q < . , pairwise chi-square tests of proportions with continuity and fdr correction). g. body mass index (bmi). bmi was elevated in the covid- cohort relative to patients with viral pneumonia, and other pneumonia, but not to non-pneumonia controls (q < . , t-test with fdr correction). h. icu length of stay. icu length of stay was longer in the covid- cohort, relative to all control cohorts (pairwise t-tests with fdr correction). i. duration of mechanical ventilation. the duration of mechanical ventilation was significantly increased in the covid- cohort relative only to non-pneumonia controls (pairwise t-tests with fdr correction). j. mortality in patients with covid- was similar to patients with other respiratory viruses, non-viral pneumonia and non-pneumonia controls. differences are not significant (q > . ) unless otherwise noted. figure s : overview of the study and biomarkers. a. sankey diagram illustrating relationship between number of participants with covid- , other viral pneumonia, non-viral pneumonia (other pneumonia) and non-pneumonia controls ) enrolled in the script study ( patients), ) analyzed via flow cytometry ( patients), ) bulk rna-seq on flow-sorted alveolar macrophages ( patients) and ) single-cell rna-seq ( patients). some samples were cryopreserved and sorted post-cryorecovery. since cryopreservation affects the number of granulocytes, these samples were not included in flow cytometric analysis, but were used for bulk rna-seq profiling of flow-sorted alveolar macrophages. skipped analyses are represented by alluvia flowing over the grouping bars. b. sankey diagram illustrating relationship between number of bal samples from participants with covid- , other viral pneumonia, non-viral pneumonia (other pneumonia) and non-pneumonia controls ) enrolled in the script study ( samples), ) analyzed via flow cytometry ( samples), ) bulk rna-seq on flow-sorted alveolar macrophages ( samples) and ) single-cell rna-seq ( samples). c. the sequential organ failure assessment (sofa) score, the acute physiology score (aps) and inflammation biomarkers: creatine phosphokinase (cpk), c-reactive protein (crp), ddimer, ferritin, lactate dehydrogenase (ldh), procalcitonin (q = . x - , pairwise wilcoxon rank-sum tests with fdr correction). green-shaded area indicates normal range. to define the immune cell profile over the course of severe sars-cov- -induced pneumonia, we analyzed samples from patients with confirmed covid- in our cohort. we compared those samples with samples from patients with severe pneumonia secondary to other causes. we used multicolor flow cytometry with a panel of markers sufficient to identify neutrophils, cd + and cd + t cell subsets, macrophages and monocytes in the bal fluid (figure s a ,b) [ , ] . we first focused analysis on patients who had a sample collected within hours of intubation, comparing samples from patients with confirmed covid- to samples from patients with severe pneumonia secondary to other causes. we found that, despite a diagnosis of severe ards requiring mechanical ventilation, only . % of patients with severe covid- exhibited neutrophilia in bal fluid within hours of intubation, defined as a neutrophil frequency over % (figure a-c) . instead, we found that in patients with severe sars-cov- pneumonia, the alveolar space was significantly enriched for both cd + and cd + t cells and monocytes (figure a,b) . this observation significantly differs from patients with pneumonia secondary to other respiratory viruses, bacteria or mechanically ventilated non-pneumonia controls [ ] . this pattern was not due to the differences in co-infections between different types of pneumonia (figure d) . collectively, these findings suggest that unusual factors related to sars-cov- pneumonia result in the recruitment of t cells and monocytes, rather than neutrophils, to the infected alveolus. pneumonia are characterized by neutrophilia while bal fluid from most patients with sars-cov- pneumonia is enriched for cd + and cd + t cells and monocytes. samples were clustered by euclidean distance using ward's method. b. proportions of cells detected within hours of intubation. proportion of cd + and cd + t cells is increased in the covid- cohort (q < . , pairwise wilcoxon rank-sum tests with fdr correction) and proportion of neutrophils is reduced in these patients, relative to non-viral pneumonia controls (q < . , pairwise wilcoxon ranksum tests with fdr correction). comparisons are not significant unless otherwise noted. c. averaged cell-type compositions in the first hours of intubation, binned by diagnosis. d. comparison of rates of co-infection. coinfection was defined by detection in a single sample of any bacterial or fungal pathogen listed in table by culture or multiplex pcr analysis. no significant differences were observed between the covid- cohort and pneumonia controls (q ≥ . , pairwise chi-square tests of proportions with continuity and fdr correction). transcriptomic analysis of flow-sorted alveolar macrophages identifies an interferon response signature as a unique feature of sars-cov- pneumonia. we performed rna-seq on flow-sorted alveolar macrophages from patients with severe sars-cov- pneumonia ( samples from patients) and compared them with patients with pneumonia secondary to other causes ( samples from patients with any other viral pneumonia, samples from patients with non-viral pneumonia), non-pneumonia controls ( samples from patients) and healthy volunteers ( samples from volunteers). k-means clustering of the , most variable genes across diagnoses using a likelihood-ratio test (lrt) identified clusters ( . interestingly, il , the protein product of which has been implicated in cytokine storm in severe covid- and serves as a predictor of morbidity and mortality in severe covid- [ ] , was not among differentially expressed genes and its overall expression was not different between the groups with the exception of healthy controls, where il transcripts were never detected (supplemental figure b) . we then asked whether we can detect sars-cov- transcripts in flow-sorted alveolar macrophages and whether the presence of viral transcripts correlates with specific changes in alveolar macrophage transcriptomes. to allow detection of viral rna, we aligned sequences to a hybrid genome including human, sars-cov- and influenza a/california/ / reference genomes. an additional negative strand transcript, which is transiently formed during viral replication, was added to the sars-cov- transcriptome to detect replicating virus [ ] . we queried macrophage transcriptomes from all patients for the presence of positive-and negative-strand transcripts encoding sars-cov- . we detected sars-cov- transcripts in macrophage transcriptomes from % of patients with pcr-confirmed sars-cov- infection. in % of these patients, we detected both positive-and negative-strand sars-cov- transcripts (figure b, supplemental figure c ). as would be expected during recovery, we also observed a significant negative correlation between abundance of sars-cov- transcripts in patients with confirmed covid- and days of ventilation (ρ = - . , spearman correlation; supplemental figure d ). in order to identify more specific macrophage gene modules, particularly those that distinguish pneumonia type and outcome, we performed weighted gene coexpression network analysis (wgcna) (figure c , supplemental data file ). as predicted, we identified some modules related to composition of the bulk samples, correlating strongly with flow cytometry results. module exhibited a strong association with the percentage of cd hi alveolar macrophages, and was characterized by genes expressed in mature tissueresident alveolar macrophages, including fabp and pparg (r = . ) [ ] . module exhibited a strong negative correlation with percentage of cd hi macrophages, and was identified by expression of genes found in immature monocyte-derived alveolar macrophages including spp (r = - . ). strikingly, module correlated with the detection of sars-cov- transcripts, levels of c-reactive protein, cd + t cell abundance, and covid- diagnosis (r = . , . , . , . , respectively). notably, all sars-cov- genes included in this analysis were assigned to this module, further underscoring disease relevance. in confirmation of the k-means clustering results, this module was highly enriched for type i and type ii interferon response genes (go: type i interferon signaling pathway; go: interferongamma-mediated signaling pathway). this association was further confirmed by umap projection of all bulk rna-seq samples, which separated largely by diagnosis with module as a major driver of clustering (figure d ). significant negative correlations of average module expression, type i interferon signaling (go: ), and type ii interferon signaling (go: ) were observed over the time-course of mechanical ventilation, suggesting reductions during the recovery phase (figure e -g). (figure b) . all macrophage clusters were represented by cells from - patients (supplemental figure s a) . as our analysis of transcriptomic data from alveolar macrophages suggested that sars-cov- pneumonia is uniquely associated with the activation of pathways induced by interferons, we looked for the expression of type i interferons in our single cell dataset. we did not detect type i interferon expression in any of the sequenced cells (data not shown). similarly, we did not detect type i interferon transcripts in other publicly available single cell rna-seq datasets obtained from bal fluid [ , ] . in contrast, expression of type ii interferon -ifng -was detected in t cells from all patients (figure c, supplemental figure b) . these results suggest the interferon response gene signature we observed in flow-sorted alveolar macrophages is induced by ifnγ released from activated t cells. we next looked for sars-cov- positive-and negative-strand transcripts within our data. as expected, both were detected in epithelial cells and migratory ccr + dendritic cells. interestingly, they were also detected in moam and tram subclusters (figure d, supplemental figure c ). coronaviruses generate large numbers of positive strand transcripts from a single negative strand transcript [ , ] . consistent with this known biology, we detected more transcripts for positive compared with negative strands in both our single cell and bulk rna-seq data supplementary figure d) . these data suggest that alveolar macrophages harbor virus and suggest they may support viral replication as has been reported for sars-cov and mers-cov [ ] [ ] [ ] . interestingly, tram harboring sars-cov- showed distinct clustering compared with uninfected tram (clustering was performed without sars-cov- transcripts). importantly, these tram also clustered differently when compared with tram from a patient with bacterial pneumonia (supplemental figure e , f, supplemental data file ). marker genes distinguishing infected tram from non-infected tram included several chemokines and cytokines important for t cell recruitment. these include ccl , which attracts dendritic cells and t cells via ccr and only weakly attracts neutrophils (figure b, e) , cxcl and cxcl , which attract t cells and plasmacytoid dendritic cells via cxcr , and ccl , which attracts monocytes, nk and t cells via ccr (figure b, f) . these cells also expressed genes important in the innate immune response to virus. these include il b (figure b, g) , tnfsf , a member of tnf ligand family, and the antimicrobial peptide defensin b (defb ) (figure b, supplemental data file ) . finally, these cells were marked by increased expression of interferon response genes (isg , ifit , ifit , ifit , mx and others). consistent with this observation, we found higher average levels of expression of a curated list of ifn-response genes in infected (tram ) compared with non-infected (tram ) alveolar macrophages (figure b,h; supplemental figure g) . these results indicate a positive feedback loop in which sars-cov- -infected alveolar macrophages release chemokines that recruit t cells, which release ifnγ to further activate the infected alveolar macrophages. high serum levels of il- and its transcriptional target c-reactive protein have been observed in patients with severe covid- . il- induces the transcription of clotting factors in the liver and tissue factor in the endothelium that promote thrombosis [ ] . these mechanisms are thought to contribute to the microvascular thrombosis in the lung and other tissues observed in autopsy studies conducted on patients with covid- , which in turn is thought to contribute to multiple organ dysfunction [ , ] . as increased transcripts encoding il- have not been observed in single cell rna-seq studies of the peripheral blood [ ] , some have suggested il- is generated by inflammatory cells in the alveolus [ ] . the overall expression of il was low, and was not restricted to a specific cell type in our single cell rna-seq dataset. despite this, the levels of c-reactive protein at the time of intubation were increased in patients with severe covid- , relative to the upper limit of the normal range of mg/l (p = . x - , one-sample wilcoxon rank-sum test; supplemental figure s c ). these results suggest that the resident and recruited immune cells in the infected alveoli do not directly contribute to systemic increase of il- (supplemental figure s h ). severe sars-cov- pneumonia unfolds slowly over time. our studies of bal fluid collected from patients with covid- within hours of intubation revealed an already established feedback loop between activated t cells and infected alveolar macrophages. this stable, slowly amplifying feedback loop is consistent with the long duration between symptom onset and the development of respiratory failure in patients with covid- ( - days) and the prolonged course of mechanical ventilation in many of these patients (figure a , h, i) [ ] . a prediction from this model is that these circuits will persist over time until the virus is cleared. hence, we examined serial bal fluid samples collected from patients with severe sars-cov- pneumonia over time (figure a, b) . we used clinical measures performed on the bal fluid (quantitative culture or multiplex pcr for respiratory pathogens) to identify bacterial superinfections, defined as detection of a new bacterial pathogen acquired during the hospitalization. in the absence of a detected bacterial superinfection, bal fluid remained non-neutrophilic in % of samples from patients admitted with sars-cov- pneumonia. bal neutrophilia developed in % of patients with covid- who developed bacterial superinfection. hierarchical clustering of the composition of bal samples from all time points demonstrated that in comparison to samples from other types of pneumonia samples from patients with covid- were enriched for t cells irrespective of the time of bal collection (figure a, b) or presence or absence of superinfection (figure c ). our data suggest that composition of immune cells in sars-cov- pneumonia is relatively stable and continues to unfold slowly over time, resulting in a loss of tissue-resident alveolar macrophages and continuous recruitment of monocyte-derived alveolar macrophages. to test this hypothesis, we performed cell type deconvolution to estimate the proportion of individual cell types in bulk rna-seq data from flowsorted alveolar macrophages using cell type-specific signatures from single cell rna-seq. this approach confirmed that only a small portion of the samples from patients with pneumonia contained tissue-resident alveolar macrophages. instead, the majority of alveolar macrophages were mature monocyte-derived alveolar macrophages (moam ) (figure d, supplemental figure i ). interestingly, samples from patients with covid- contained more immature moam alveolar macrophages than samples from patients with other types of pneumonia, supporting our hypothesis that sars-cov- pneumonia is characterized by the ongoing recruitment of monocyte-derived alveolar macrophages. (figure a ) was performed using signatures from integrated single-cell rna-seq (figure a) . asterisks indicate statistical significance, wilcoxon rank-sum tests with fdr correction: * p < . , ** p < . , *** p < . . e. schematic illustrating interpretation of the main findings. . normal alveolus contains ace -expressing alveolar type and type cells (at and at , correspondingly) and tissue-resident alveolar macrophages (tram). . sars-cov- infects at cells and tram. infected tram are activated and express il b and t cell chemokines. . cross-reactive or de novo generated t cells recognize sars-cov- antigens presented by tram and produce ifnγ, further activating tram to produce cytokines and chemokines. . activated t cells proliferate and continue to produce ifnγ, eventually leading to death of infected tram and recruitment of monocytes, which rapidly differentiate into monocyte-derived alveolar macrophages (moam). moam in turn produce chemokines that further promote t cell and monocyte recruitment, thus sustaining pneumonia. . recruited moam either become mature and repopulate alveoli or become infected with sars-cov- , continuing to present antigens to t cells and maintain the feedback loop. our data represent the earliest sampling of the alveolar space of patients with covid- pneumonia reported to date [ , ] . it is possible to use these data to speculate about early events that lead to pneumonia in patients with sars-cov- infection (figure e) . strong evidence suggests sars-cov- initially infects and replicates in epithelial cells in the nasopharynx, which express relatively high levels of ace in comparison with epithelial cells in airways or the distal lung [ , ] . there the virus replicates and escapes clearance by suppressing type i interferon responses [ ] [ ] [ ] and broadly disrupting protein translation [ ] . whether by progressive movement distally in the tracheobronchial tree or via aspiration of nasopharyngeal contents, some virus gains access to the distal alveolar space. in the alveolar space, we confirm that sars-cov- infects alveolar epithelial cells and alveolar macrophages [ ] . alveolar macrophages might be infected with sars-cov- by ) phagocytosis of infected epithelial cells, ) via direct infection, as was shown for sars-cov and mers-cov [ , ] or ) through other mechanisms, such as antibody mediated enhancement as was shown for sars-cov [ , ] . indeed, it is estimated that ~ % of adults have antibodies against one of four major seasonal coronaviruses [ ] , and antibodies cross-reacting with sars-cov- might facilitate viral entry into alveolar macrophages. while tissue-resident alveolar macrophages are poor antigen-presenting cells and do not migrate to lymph nodes to participate in conversion of naive t cells into effector t cells [ ] , a low level of antigen presentation by alveolar macrophages in the alveolar space might be sufficient to drive activation of pre-existing memory t cells that target endemic seasonal coronaviruses, but cross-react with sars-cov- . existence of such cross-reactive memory t cells has been reported for sars-cov [ ] and, recently, sars-cov- [ ] [ ] [ ] [ ] . this mechanism might explain the epidemiology of sars-cov- , which disproportionately affects elderly individuals, while children and young adults often have only mild symptoms, despite having viral load in upper airways compatible to adults [ , ] . children and young individuals have fewer encounters with seasonal coronaviruses during their lifetime than elderly individuals and therefore would have fewer crossreactive antibodies or memory t cells. we did not detect substantial expression of type i interferons in our datasets. this could be either related to the timing of sampling, undersampling cell types producing type i interferons, or inhibition of type i interferon production by sars-cov- proteins [ , ] . however, we readily detected ifnγ production by t cells. this supports a model where infection and activation of tissue-resident alveolar macrophages with sars-cov- , followed by antigen presentation to cross-reactive or sars-cov- -specific t cells, leads to a delayed interferon response. this in turn amplifies the inflammatory response by recruiting proinflammatory monocyte-derived macrophages, as has been suggested from animal models of sars-cov infection [ ] . interestingly, in agreement with our observation that the inflammatory environment in the lung during severe covid- is characterized by the paucity of neutrophils, we found that alveolar macrophages produced chemokines preferentially driving recruitment of t cells and monocytes, but not neutrophils. our results also explain the slow progression of sars-cov- pneumonia relative to other respiratory viruses, most notably influenza a. specifically, the time from the onset of symptoms to respiratory failure in patients with sars-cov- infection is - days, compared with - days or even less in patients with influenza a infection [ ] . consistent with a slower course, the duration of illness is longer in patients with severe sars-cov- infection. while both viruses might gain access to the distal lung by similar mechanisms, the sialic acid residues that serve as receptors for influenza a are abundantly expressed in alveolar type cells [ ] . in contrast, single cell rna-seq atlases of the human lung and sm-fish studies of the normal lung show that only a small number of alveolar epithelial cells express ace [ , ] . thus, while influenza a would infect large numbers of cells causing widespread injury, rapid viral replication and robust antiviral responses, infection by sars-cov- is likely to lead to more localized areas of infection. these more localized areas of infection and injury are consistent with radiographic patterns of early covid- , and the presence of discrete radiographic abnormalities in asymptomatic covid- patients [ ] . because tissue-resident alveolar macrophages have limited motility [ ] , the uptake and persistence of sars-cov- -infected alveolar macrophages would not be predicted to spread the virus to adjacent lung regions. however, recruited monocyte-derived alveolar macrophages, which we found can also harbor replicating sars-cov- , are typically more numerous, and could conceivably spread the virus to adjacent alveoli. in each new area of infection, positive feedback loops between alveolar macrophages harboring the virus and activated t cells could promote ongoing injury and systemic inflammation. this model would also explain the heterogeneity we observed in alveolar macrophages recovered from the same individual. different stages of sars-cov- infection might be spatially localized to subsegmental regions such that the bal procedure samples alveoli in various stages of infection. further studies using spatial techniques and a time-course analysis of patients with early disease will address these questions. human subjects: all human subjects research was approved by the northwestern university institutional review board. samples from patients with covid- , viral pneumonia, other pneumonia and nonpneumonia controls were collected from participants enrolled in successful clinical response in pneumonia therapy (script) study stu . alveolar macrophages from healthy volunteers were obtained under study stu . all subjects or their surrogates provided informed consent. patients ≥ years of age with suspicion of pneumonia based on clinical criteria (including but not limited to fever, radiographic infiltrate, and respiratory secretions) were screened for enrollment into the script study. inability to safely obtain bal or nbbal were considered exclusion criteria. in our center, patients with respiratory failure are intubated based on the judgement of bedside clinicians for worsening hypoxemia, hypercapnia, or work of breathing refractory to high-flow oxygen or non-invasive ventilation modes. extubation occurs based on the judgement of bedside clinicians following a trial of spontaneous breathing in patients demonstrating physiologic improvement in their cardiorespiratory status during their period of mechanical ventilation. management of patients with covid- was guided by protocols published and updated on the northwestern medicine website as new information became available over the pandemic. clinical laboratory testing including studies ordered on bronchoalveolar lavage fluid was at the discretion of the care team, however, quantitative cultures, multiplex pcr (biofire film array respiratory panel), and automated cell count and differential were recommended by local icu protocols. most patients also underwent urinary antigen testing for streptococcus pneumoniae and legionella pneumophilia on admission. clinicians were encouraged to manage all patients, including those with covid- , according to ardsnet guidelines including the use of a higher peep/lower fio strategy for those with severe hypoxemia. prone positioning ( hours per day) was performed in all patients with a pao /fio < who did not have contraindications. in those who had a response to prone positioning evident by improved oxygenation, prone positioning was repeated. esophageal balloon catheters (cooper surgical) were placed at the discretion of the care team to estimate transpulmonary pressure and optimize peep, particularly in patients with a higher than normal bmi. pneumonia category adjudication was performed by five critical care physicians (rgw, jmk, bds, cop, jmw) using a standardized reporting tool (supplemental data file ). clinical laboratory data were obtained from the northwestern medicine enterprise data warehouse using structured query language (sql). aps and sofa scores were generated from the electronic health record using previously validated programming. nbbal and bal procedures: consent was obtained from patients or legal decision makers for the bronchoscopic procedures. bronchoscopic bal was performed in intubated icu patients with flexible, single-use ambu ascope (ambu) devices. patients were given sedation and topical anesthetic at the physician proceduralist's discretion. vital signs were monitored continuously throughout the procedure. the bronchoscope was wedged in the segment of interest based on available chest imaging or intraprocedure observations, aliquots of cc of normal saline at a time, generally - cc total, were instilled and aspirated back. the fluid returned following the first aliquot was routinely discarded. samples were split (if sufficient return volume was available) and sent for clinical studies and an aliquot reserved for research. a similar procedure was applied to non-bronchoscopic bal (nbbal); however nbbal was performed with directional but not visual guidance, and as usual procedural care by a respiratory therapist rather than a pulmonologist [ ] . for the bronchoscopies performed in the covid- patients, additional precautions were taken to minimize the risk to healthcare workers including only having essential providers present in the room, clamping of the endotracheal tube, transient disconnection of the inspiratory limb from the ventilator, and preloading of the bronchoscope through the adapter; sedation and neuromuscular blockade to prevent cough, was administered for these procedures at the physician's discretion. in most cases the early bronchoscopy was performed immediately after intubation. flow cytometry and cell sorting: nbbal and bal samples were filtered through a um cell strainer, pelleted by centrifugation at rcf for min at c, followed by hypotonic lysis of red blood cells with ml of bd pharmlyse reagent for min. lysis was stopped by adding ml of macs buffer. cells were pelleted again and resuspended in ul of fc-block (human trustain fcx, biolegend), and ul aliquot was taken for counting using k cellometer (nexcelom) with ao/pi reagent. the volume of fc-block was adjusted so the concentration of cells was always less than x cells/ml and the fluorophore-conjugated antibody cocktail was added in : ratio ( table ) . after incubation at c for min cells were washed with ml of macs buffer, pelleted by centrifugation and resuspended in ul of macs buffer + ul of sytox green viability dye (thermofisher). cells were sorted on facs aria ii sorp instrument using um nozzle and psi pressure. cells were sorted into ul of macs buffer for bulk rna-seq or ul of % bsa in pbs for single cell rna-seq. sample processing was performed in bsl- facility using bsl- practices. bulk rna-seq of flow-sorted alveolar macrophages: immediately after sorting, cells were pelleted by centrifugation and lysed in ul of rlt plus lysis buffer (qiagen) supplemented with -mercaptoethanol. lysed cells were stored at - c until rna isolation using allprep dna/rna micro kit according to manufacturer's protocol (qiagen). rna quality and quantity were assessed using tapestation high sensitivity rna tapes (agilent) and rna-seq libraries were prepared from pg of total rna using smarter stranded total rna-seq kit v (takara bio). after qc using tapestation high sensitivity dna tapes (agilent) dual indexed libraries were pooled and sequenced on a nextseq instrument (illumina), cycles, single-end, to an average sequencing depth of . m reads. fastq files were generated using bcl fastq (illumina). to enable detection of viral rna, a custom hybrid genome was prepared by joining fasta, gff, and gtf files for grch . , sars-cov- (nc_ . ) -virus causing covid- , and influenza a/california/ / (gcf_ . ), which was the dominant strain of influenza throughout bal fluid collection at our hospital [ ] . an additional negative strand transcript spanning the entirety of the sars-cov- genome was then added to the gtf and gff files to enable detection of sars-cov- replication. normalized counts tables later revealed extremely high enrichment of sars-cov- transcripts in diagnosed covid- patients, and strong enrichment of iav genes in patients marked as other viral pneumonia. to facilitate reproducible analysis, samples were processed using the publicly available nf-core/rna-seq pipeline version . . implemented in nextflow . . using singularity . . - with the minimal command nextflow run nf-core/rnaseq -r . . -singleend -profile singularity -unstranded --three_prime_clip_r [ ] [ ] [ ] . briefly, lane-level reads were trimmed using trimgalore! . . and aligned to the hybrid genome described above using star . . d [ ] . gene-level assignment was then performed using featurecounts . . [ ] . bulk differential expression analysis (dea). all analysis was performed using custom scripts in r version . . using the deseq version . . framework [ ] . correspondence between lanes was first confirmed by principal component analysis before merging counts using the command collapsereplicates(). one outlier sample with low rin score and exhibiting extreme deviation on pca and poor alignment and assignment metrics was excluded from downstream analysis. for differential expression analysis (dea), both moam content from flow cytometry data and diagnosis were used as explanatory factors. a "local" model of gene dispersion was employed as this better fit dispersion trends without obvious overfitting; otherwise default settings were used. k-means clustering of bulk samples. for k-means clustering, a custom-built function was used (available at https://github.com/nupulmonary/utils/blob/master/r/k_means_figure.r). briefly, variable genes were identified using a likelihood-ratio test (lrt) with local estimates of gene dispersion in deseq with diagnosis as the "full" model, and a reduced model corresponding to intercept, alone. genes with q ≥ . were discarded. extant genes were then clustered using the hartigan-wong method with random sets and a maximum of iterations using the kmeans function in r stats . . . samples were then clustered using ward's method and plotted using pheatmap version . . . go term enrichment was then determined using fisher's exact test in topgo version . . , with org.hs.eg.db version . . as a reference. weighted gene coexpression network analysis (wgcna). wgcna was performed manually using wgcna version . with default settings unless otherwise noted [ ] . genes with counts > and detection in at least % of samples were included in analysis. to best capture patterns of co-regulation, a signed network was used. using the picksoftthreshold function, we empirically determined a soft threshold of to best fit the network structure. a minimum module size of was chosen to isolate relatively large gene modules. module eigengenes were then related back to patient and sample metadata using biweight midcorrelation. module go enrichment was then determined as above using fisher's exact test in topgo version . . , with org.hs.eg.db version . . as a reference. umap plotting was performed using uwot version . . using the first principal components of the same genes used in wgcna analysis after zscaling and centering, with a minimum distance of . [ ] . default parameters were otherwise used. single cell rna-seq of flow-sorted bal cells: cells were sorted into % bsa in dpbs, pelleted by centrifugation at rcf for min at c, resuspended in . % bsa in dpbs to ~ cells/ul concentration. concentration was confirmed using k cellometer (nexcelom) with ao/pi reagent and ~ , - , cells were loaded on x genomics chip a with chromium single cell ' gel beads and reagents ( x genomics). libraries were prepared according to manufacturer protocol ( x genomics, cg _revm). after quality check single cell rna-seq libraries were pooled and sequenced on novaseq instrument. data was processed using cell ranger . . pipeline ( x genomics). to enable detection of viral rna, reads were aligned to a custom hybrid genome containing grch . and sars-cov- (nc_ . ). an additional negative strand transcript spanning the entirety of the sars-cov- genome was then added to the gtf and gff files to enable detection of sars-cov- replication. data was processed using scanpy v . . [ ] , doublets were detected with scrublet v . . [ ] and removed, ribosomal genes were removed and multisample integration was performed with bbknn v . . [ ] . gene set enrichment analysis was performed with signatures retrieved from gsea-msigdb.org website [ ] using following terms: hallmark_interferon_gamma_response m , hallmark_interferon_alpha_response m . computations were automated with snakemake v . . [ ] . deconvolution of bulk rna-seq alveolar macrophage signatures was performed using autogenes v . . [ ] and signatures derived from integrated single cell rna-seq object. for details of the functions used and their parameters see the code https://github.com/nupulmonary/ _grant. statistical analysis: all statistical analysis was performed using r version . . . for all comparisons, normality was first assured using a shapiro-wilk test and manual examination of distributions. for parameters exhibiting a clear lack of normality, nonparametric tests were employed. in cases of multiple testing, p-values were corrected using false-discovery rate (fdr) correction. adjusted p-values < . were considered significant. visualization: all plotting was performed using ggplot version . . , with the exception of heatmaps, which were generated using pheatmap version . . . sankey/alluvial plots were generated using ggalluvial version . . [ ] . figure layouts were generated using patchwork version . and edited in adobe illustrator . bulk rnaseq: counts tables and metadata are included as supplemental data files and . single-cell rna-seq: counts tables and integrated objects are available through geo with accession number gse . raw data is in the process of being deposited to sra/dbgap. code: https://github.com/nupulmonary/ _grant. tables: table : demographics of the script cohort, grouped by diagnosis. table : pneumonia-causing pathogens detected in the script cohort. table : flow cytometry panels, reagents and instruments configuration. supplementary data file : data related to k-means clustering and differential expression analysis (dea) of bulk rna-seq samples: gene cluster assignments, cluster go cluster is part of quest, northwestern university's high performance computing facility, with the purpose to advance research in genomics and world peace rogan grant was supported by nih grant luisa morales-nebreda was supported by t hl and f hl gr scott budinger was supported by nih grants u ai , p ag , r hl and veterans affairs grant i cx misharin was supported by nih grants u ai , p ag , r hl , r hl and nucats covid- rapid response grant singer was supported by nih awards k hl , u ai , r hl , and p ag wudnerink was supported by nih grant u ai and a glaxosmithkline distinguished scholar in respiratory health grant from the chest foundation diagnosis: covid- (n = ) diagnosis: non-pneumonia control (n = ) diagnosis: other pneumonia (n = ) diagnosis: other viral pneumonia clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study covid- does not lead to a "typical" acute respiratory distress syndrome. american journal of respiratory and critical care medicine real estimates of mortality following covid- infection clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study effect of dexamethasone in hospitalized patients with covid- : preliminary report. infectious diseases (except hiv/aids). medrxiv multidimensional assessment of alveolar t cells in critically ill patients early neuromuscular blockade in the acute respiratory distress syndrome multidimensional assessment of the host response in mechanically ventilated patients with suspected pneumonia elevated levels of il- and crp predict the need for mechanical ventilation in covid- the architecture of sars-cov- transcriptome single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis single-cell landscape of bronchoalveolar immune cells in patients with covid- cross-talk between the airway epithelium and activated immune cells defines severity in covid- . infectious diseases (except hiv/aids). medrxiv continuous and discontinuous rna synthesis in coronaviruses active replication of middle east respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis antibody-dependent infection of human macrophages by severe acute respiratory syndrome coronavirus metformin targets mitochondrial electron transport to reduce air-pollution-induced thrombosis thrombosis and covid- pneumonia: the clot thickens! the european respiratory journal: official journal of the european society for clinical respiratory physiology immunology of covid- : current state of the science a single-cell atlas of the peripheral immune response in patients with severe covid- covid- severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis sars-cov- entry factors are highly expressed in nasal epithelial cells together with innate immune genes sars-cov- reverse genetics reveals a variable infection gradient in the respiratory tract imbalanced host response to sars-cov- drives development of covid- sars-cov- orf b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant comparative replication and immune activation profiles of sars-cov- and sars-cov in human lungs: an ex vivo study with implications for the pathogenesis of covid- structural basis for translational shutdown and immune evasion by the nsp protein of sars-cov- anti-severe acute respiratory syndrome coronavirus spike antibodies trigger infection of human immune cells via a ph-and cysteine protease-independent fcγr pathway prevalence of antibodies to four human coronaviruses is lower in nasal secretions than in serum division of labor between lung dendritic cells and macrophages in the defense against pulmonary infections t-cell response profiling to biological threat agents including the sars coronavirus presence of sars-cov- reactive t cells in covid- patients and healthy donors targets of t cell responses to sars-cov- coronavirus in humans with covid- disease and unexposed individuals sars-cov- -specific t cell immunity in cases of covid- and sars, and uninfected controls selective and cross-reactive sars-cov- t cell epitopes in unexposed humans epidemiology of covid- among children in china an analysis of sars-cov- viral load by patient age. infectious diseases (except hiv/aids). medrxiv impaired type i interferon activity and inflammatory responses in severe covid- patients dysregulated type i interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in sars-cov-infected mice prevalence of asymptomatic sars-cov- infection: a narrative review immune surveillance of the lung by migrating tissue monocytes fluview and flunet: tools for influenza activity and surveillance nextflow enables reproducible computational workflows the nf-core framework for community-curated bioinformatics pipelines singularity: scientific containers for mobility of compute star: ultrafast universal rna-seq aligner featurecounts: an efficient general purpose program for assigning sequence reads to genomic features moderated estimation of fold change and dispersion for rna-seq data with deseq wgcna: an r package for weighted correlation network analysis umap: uniform manifold approximation and projection for dimension reduction scanpy: large-scale single-cell gene expression data analysis scrublet: computational identification of cell doublets in single-cell transcriptomic data bbknn: fast batch alignment of single cell transcriptomes gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles snakemake--a scalable bioinformatics workflow engine automatic gene selection using multi-objective optimization for rnaseq deconvolution layered grammar for alluvial plots northwestern university flow cytometry core facility is supported by nci cancer center support grant p ca awarded to the robert h. lurie comprehensive cancer center. cell sorting was performed on bd facsaria sorp cell sorter purchased through the support of nih s od - .this research was supported in part through the computational resources and staff contributions provided by the genomics compute cluster which is jointly supported by the feinberg school of medicine, the center for genetic medicine, and feinberg's department of biochemistry and molecular genetics, the office of the provost, the office for research, and northwestern information technology. the genomics compute key: cord- -ug ler e authors: ramos-rincón, josé m.; pinargote-celorio, héctor; belinchón-romero, isabel; gonzález-alcaide, gregorio title: a snapshot of pneumonia research activity and collaboration patterns ( – ): a global bibliometric analysis date: - - journal: bmc med res methodol doi: . /s - - - sha: doc_id: cord_uid: ug ler e background: this article describes a bibliometric review of the scientific production, geographical distribution, collaboration, impact, and subject area focus of pneumonia research indexed on the web of science over a -year period. methods: we searched the web of science database using the medical subject heading (mesh) of “pneumonia” from january , to december , . the only document types we studied were original articles and reviews, analyzing descriptive indicators by five-year periods and the scientific production by country, adjusting for population, economic, and research-related parameters. results: a total of , references were retrieved. the number of publications increased steadily over time, from publications in to in (r( ) = . ). the most productive country was the usa ( . %), followed by the uk ( . %) and japan ( . %). research production from china increased by more than %. by geographical area, north america ( . %) and europe ( . %) were most dominant. scientific production in low- and middle-income countries more than tripled, although their overall contribution to the field remained limited (< %). overall, . % of papers were the result of an international collaboration, although this proportion was much higher in sub-saharan africa ( . %) and south asia ( . %). according to the specific mesh terms used, articles focused mainly on “pneumonia, bacterial” ( . %), followed by “pneumonia, pneumococcal” ( . %) and “pneumonia, ventilator-associated” ( . %). conclusions: pneumonia research increased steadily over the -year study period, with europe and north america leading scientific production. about a fifth of all papers reflected international collaborations, and these were most evident in papers from sub-saharan africa and south asia. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. acquired pneumonia (cap) remains the primary cause of death from infectious disease globally, and its high impact on morbidity and mortality is especially concentrated in children under five and the elderly [ , [ ] [ ] [ ] . the world health organization (who) predicted that deaths from lower respiratory tract infections would remain among the top four causes of deaths up to at least [ ] . antibiotic-resistant strains have also been on the rise, although resistance does not appear to be related to mortality. however, pneumonia is associated with high rates of hospitalization and length of hospital stay. moreover, it has considerable long-term effects on quality of life, and long-term prognosis is worse in patients with pneumococcal pneumonia [ ] . despite the public health importance of the disease, few studies have evaluated research in the area using bibliometric methods. indeed, only head et al. ( ) have analyzed publications on pneumonia, and their work was limited in geographical scope to the uk [ , ] . in this study, by analyzing scientific papers on pneumonia published in the main international scientific journals, we aimed to identify the scientific contribution of different countries to the worldwide research effort, the most cited landmark articles, the degree and nature of scientific collaboration, and the topics addressed. this bibliometric description can provide relevant information for researchers in the field, particularly new scientists, giving a snapshot of strong research areas in pneumonia and global health as well as possible gaps requiring additional investments [ ] [ ] [ ] . the paper also provides clues for addressing the weaknesses observed, such as the need to promote north-south collaborations and other research initiatives with countries that have relatively little scientific development on the topic [ , ] . the aim of the present study is to assess the scientific literature on pneumonia that is indexed in the web of science (wos). specifically, we will analyze: ( ) the evolution of scientific production; ( ) its distribution by countries and regions; ( ) the impact of the research papers; and ( ) the degree of international collaboration. finally, we will present details on the subject area focus of different publications according to the medical subject headings (mesh). for the performance of the study, we opted to identify documents about pneumonia by means of the mesh thesaurus in the medline database because this is a detailed instrument for controlled terminology. the thesaurus employs both a human team of specialist indexers to analyze each article and assign medical subject headings to it, plus automated processes to improve indexing; the result is a highly consistent system of classification for research topics [ ] [ ] [ ] . the pneumonia descriptor was introduced in as a disease of the respiratory tract and the lung, and it was defined as "infection of the lung often accompanied by inflammation" [ ] . synonyms of this descriptor (and therefore also included in search results) are "lung inflammation" and "pulmonary inflammation". additional file : table s shows the mesh tree structure for "pneumonia". the next step was to identify the documents assigned with the medline descriptor of "pneumonia" indexed in the wos. this body of research constitutes the population of documents for the present study. conceived by eugene garfield but now maintained by clarivate analytics, wos is the top scientific citation search and analytical information platform worldwide, serving both as a multidisciplinary research tool supporting a variety of scientific tasks and as a dataset for large, dataintensive studies [ ] . the use of the wos databases enables the analysis of all institutional affiliations reported in the documents and the calculation of citation indicators. the wos brings together the most visible literature at a global level. these qualities justify its choice as the database platform used in this study despite some limitations related to covering non-english biomedical journals [ ] . although initially no limitations were imposed on our search, to calculate the bibliometric indicators we considered only two types of documents, articles and reviews, as these are the primary references for researchers. the study period was limited to - , as delays associated with assigning mesh descriptors to documents mean that information on the most recent articles on pneumonia is not updated. the searches took place on the clarivate analytics wos platform, which includes medline database, on march , . for each of the retrieved documents, data on the following bibliographic characteristics were extracted: year of publication, journal of publication and wos subject category, document type, authorship, citations, institutional affiliation(s), and mesh descriptors. data were then standardized: institutional affiliations corresponding to england, northern ireland, scotland and wales were grouped together under "united kingdom," while affiliations in overseas france, british overseas territories, and island dependencies were also assigned to their ruling countries (for example, the documents signed by authors from french polynesia, guadeloupe, martinique, new caledonia, and reunion were assigned to france), although regional designations correspond to geographical rather than political criteria. scientific production from taiwan, which in wos is considered independently from the democratic republic of china (china) but whose status is disputed at an international level, was analyzed separately. countries responsible for publications were categorized according to their world bank classification by income level: low-income (< usd ), lower-middleincome (usd to usd ), upper-middle-income (usd to usd , ) , and high-income (≥ usd , ) countries. each of the countries identified was assigned to a macro geographical (continental) region according to the groups established by the world bank based on geopolitical and economic criteria and reflected in the world bank country and lending groups (see additional file : tables s and s ) [ ] . two kinds of indicators were obtained: descriptive indicators for the evolution of scientific production production by country, adjusted for demographic and economic parameters as well as for human resources dedicated to research activities we determined standardized indicators for each country's productivity with respect to: -population: number of publications per million inhabitants (population index). data were obtained from world development indicators in the world bank online databases [ ] . we calculated a mean value for each indicator based on available data from the study period. the analysis was limited to countries participating in the top articles in the field of pneumonia in order to facilitate comparison between countries' scientific production, demographic indicators, and economic development. results for the top articles are shown in the main text, while those for the top are provided in additional file . we calculated the following citation indicators by journal, country, and geographic region: -citation of the publications. absolute number of citations received. -citation rate (cr). number of citations divided by number of publications. -hirsch index (h-index). the h-index is a semiqualitative proxy measure to assess the impact of an author's or country's research output on the scientific community [ ] . an h-index of indicates that out of published papers have been cited at least times. in order to assess the differences in the distributions of the publications according to the prestige of the journals, we performed a specific analysis of a sub-sample of publications in journals occupying the top % in the impact factor ranking in their respective subject categories in the journal citation reports ( edition). we analyzed participation in these "prestigious journals" according to geographical location (regions and countries), collaboration level and number of citations. we calculated the percentage of documents produced in international collaboration and the evolution by quinquennium in order to estimate the scope of cooperative practices at a global level, considering the whole population of documents analyzed (research field) by country and geographic region. to specifically analyze collaboration between countries, collaboration networks were generated for each of the three quinquenniums using pajek software. to specifically analyze collaboration between countries, collaboration networks were generated for each of the three quinquenniums using pajek software. the collaboration network is a graphic representation (graph), wherein the nodes represent authors' countries (as determined from their institutional affiliations) and links between the nodes represent coauthorships between countries, that is, an international collaboration in published research. the more intense the collaboration, the thicker the links between the nodes. the spatial distribution of the nodes responds to the execution of the kamada-kawai algorithm in pajek, which places the most prominent nodes (those with a greater number of documents and collaboration links) in the center of the map, and the nodes with a smaller number of publications and degree of collaboration towards the periphery. based on an analysis of mesh terms, we identified the main research focus of the studies in the area, generating density maps using the vosviewer program with a spatial description of the main mesh terms for each type of pneumonia [ ] : (a) "pneumonia, aspiration" (b) "pneumonia, bacterial," (c) "pneumonia, ventilator-associated," (d) "pneumonia, viral," and (e) "pneumonia, pneumocystis"). the process of generating and interpreting the maps proceeded as follows: -determination of the co-occurrence of the descriptors assigned to the documents and generation of a matrix of absolute values. the joint assignment of two descriptors in a single document implies a thematic affinity, as both aspects are addressed simultaneously in the same paper. this affinity will be more intense as it is repeated a greater number of times in the collection of documents analyzed. -elimination of generic descriptors. in order to facilitate the analysis, we eliminated some excessively generic descriptors (like "humans" or "animals"), along with geographical descriptors and those related to age groups. these descriptors showed very high-density relationships, complicating the analysis and the interpretation of the results, so we analyzed their frequency more specifically. -visual representation of the network. to establish the main topics that exist for each type of pneumonia and to represent them visually, we used a clustering algorithm in the vosviewer program, which helps to detect the communities (clusters) within a network, made up of groups of homogeneous items that are strongly related to each other. the different groupings, in the form of "islands" in red tones, represent the main clusters of the thematic networks, while the chromatic gradation illustrates the areas with a lower density of relations between the mesh in yellow and green tones. the spatial distribution of the mesh and their proximity to each other responds to the intensity of co-occurrence between them. all data used to perform the study, including the information downloaded from the database as well as that derived from the treatment of the bibliographic entries, are available in the dataverse project, an open access public repository [ ] (https://dataverse.harvard.edu/, doi: https://doi.org/ . /dvn/ bune). due to the nature of the study and dataset, it was not necessary to obtain informed consent or approval from an institutional ethics committee. the search yielded a total of , documents published between and and assigned with the descriptor "pneumonia" in the medline database. of these, , ( . %) were indexed in the wos core collection databases; , ( . %) of them were classified as articles and ( . %) as reviews. thus, the population of study documents was a dataset of , articles and reviews, which we used to calculate the indicators presented below. letters (n = ; . %), editorials (n = , ; . %), news (n = ; . %), proceedings (n = ; . %) and other document types (n = , . %) were excluded from the analysis. the number of publications rose from in to in .the evolution of scientific production by year was fitted to a linear growth model, showing an r value of . . overall, the study period saw a two-fold increase in scientific production (additional file : figure s ). the country with the greatest number of documents was the usa ( . %), followed at some distance by the uk ( . %), japan ( . %), germany ( . %) and france ( . %). table shows the number of documents and the evolution of scientific production in the most productive countries by quinquennium (see additional file : table s for results on the top countries). although the usa ranks first in all periods, its relative contributions have declined, from . % of all documents in - to . % in - . on the other hand, china's emergence is highly notable, with a . % share of total scientific production in the first period (rank = ), compared to a . % share in the third (rank = ). south korea has also seen considerable growth, contributing just . % to total research production in - (rank = ) but . % in - (rank = ). likewise, taiwan and brazil have increased their production from . and . %, respectively, to . and . %. scientific production in different countries and geographic regions, and its evolution by quinquennium, is concentrated in north america and europe & central asia; together these regions are responsible for . table ) (see additional file : figure s for a visual representation of density equalizing mapping projections). table ranks the production of the top countries, adjusted for demographic and economic indicators (see additional file : table s for results on the top countries). when normalized by population, the most productive countries were switzerland, the netherlands, iceland, and denmark. adjusted for the gdp index, the most productive lmics were the gambia, malawi, uganda, and guinea bissau. if we calculate the ratio of pneumonia publications to gni per capita index, the usa, china, india, malawi y brazil were the most productive. adjusting by r&d expenditure index, the usa ranked first, followed by spain, the uk, china, and italy. in relation to the researchers in r&d index, the usa also leads the ranking, followed by india, uganda, and china. (see additional file figure s and figure s for a visual representation of density equalizing mapping projections of the number of documents and world development indicators, by gni per capita index, gdp index and population index plus r&d expenditure index). figure shows the collaboration networks between different countries by quinquennium. the most prominent countries in all time periods, occupying central positions in the networks with multiple cooperative links, are the usa, canada, the uk, germany, france, and the netherlands. the presence of south american and african countries is scarce in all periods. only south africa has a notable presence in the third quinquennium (fig. a) . a few other countries also "emerge" with a high degree of collaborative links in the second period, like spain, greece, italy, australia, china, and japan, although the latter two countries are not fully integrated in global networks, showing collaborative ties only with the usa (fig. b) . finally, other european countries, while present throughout all three periods, stand out to a greater degree in the third period. this is the case of sweden, switzerland, belgium, and austria. at the same time, china and japan seem more implicated in the network in this third period, while india and south korea also gain relevance (fig. c) . the documents we analyzed were published in scientific journals. twelve journals accounted for . % of the pneumonia literature table table s for results on the top journals with highest absolute and relative citations). the comparative analysis of the scientific production and crs of different journals is noteworthy in that some journals (such as the american journal of respiratory and critical care, critical care medicine, and intensive care medicine) present a very high cr in relation to their total scientific production (additional file : figure s for the top journals producing the most research on pneumonia, plus citation rates). with regard to the subject categories to which the journals are assigned, the most prominent are "infectious diseases" ( . % of the documents), "respiratory system" ( . %), "immunology" ( . %), "microbiology" ( . %), and "critical care medicine" ( . %) table . many of the most productive journals in pneumonia also fall into these subject categories. moreover, over the course of the three study periods, nearly all of the subject categories saw a moderate decrease in their relative contribution, as research articles became more dispersed and made headway into different disciplines producing less research on pneumonia table . the analysis of the documents published in the top % of prestigious journals shows a higher participation from the usa ( . %, compared to . % in the overall body of documents) and from some other european countries like the uk or spain. in contrast, the weight of asian countries, particularly japan and china, is much lower (table ) . overall, international collaboration in these journals (n = , . %) was sensibly higher than in the overall body of documents ( . %), and the greater degree of collaboration was much more pronounced for countries like brazil, japan, china, and even european countries like italy and germany ( table ). the high degree of collaboration was also confirmed between regions in the publications appearing in these journals (table ). with regard to the degree of citation, we observed notable increases in the citation rate of the usa and the european countries; these were even more significant for countries in the middle east & north africa, and for sub-saharan africa when they participated in these journals ( table ). with regard to types of pneumonia studied, the mesh terms to appear most frequently were "pneumonia, bacterial" ( . %), followed by "pneumonia, pneumococcal" ( . %), and "pneumonia, ventilator-associated" ( . %). table shows the number of documents assigned to each term describing the different types of pneumonia (additional file : table s for the top general mesh). table ranks the top countries in crude numbers of retrieved articles, stratified by types of pneumonia (additional file : table s for information on the most productive countries). for "pneumonia, aspiration", the main countries were the usa, japan, and germany; for "pneumonia, bacterial", the usa, france, and spain; for "pneumonia, pneumocystis", the usa, france, and the uk; for "pneumonia, ventilator-associated", the usa, france, and spain; and for "pneumonia, viral", the usa, china, and japan. table shows the relationship between mesh terms referring to age groups with those corresponding to different types of pneumonia. the closest associations for "aged, and over" and "aged" were with "pneumonia, aspiration" ( . and . %, respectively), while "pneumonia, viral" was the most frequent topic for studies in pre-adults ("infant", "child", "child, preschool" and "adolescent"). the one exception to this was "infant, newborn", where the highest proportion of articles was about "pneumonia, pneumocystis." in "adult" and "middle aged" people, studies most frequently focused on "pneumonia, bacterial" and "pneumonia, ventilator-associated." figure shows the subject area maps with the main mesh terms in the documents on (a) "pneumonia, aspiration"; (b) "pneumonia, bacterial"; (c) "pneumonia, ventilator-associated"; (d) "pneumonia, viral"; and (e) "pneumonia, pneumocystis." the principal mesh term related to "pneumonia, aspiration" is "deglutition disorder", but research is linked to a broad array of topics, including epidemiological aspects ("incidence", "risk factor", "retrospective studies"), treatment approaches in intensive care, and surgical techniques procedures facilitating breathing, swallowing, and feeding (fig. a) . the two main mesh terms that appear most frequently with "pneumonia, bacterial" are "community-acquired infections" and "anti-bacterial agents", reflecting the central focus that research has taken to identify risk factors and test different therapeutic approaches. mesh terms related to specific bacteria and infections, such as streptococcus, chlamydia, acinetobacter, and haemophilus influenzae, are also prominent (fig. b) . for its part, research on "pneumonia, ventilatorassociated" seems more disperse, although three areas of interest can clearly be differentiated: (a) epidemiological studies, clinical protocols, and treatment in intensive care units (the term "intensive care unit" is the most prominent in this area); (b) treatment outcomes ("treatment outcome" and "anti-bacterial agents"); and (c) cross infections ("cross infection") (fig. c) . research on "pneumonia, viral" also shows a disperse nature, with different areas of interest. epidemiological aspects are covered under terms such as "communityacquired infections" and "hospitalization", while at a researcher level, interests reside in the virus "influenza, human" and "orthomyxoviridae infections" (fig. d) . with regard to "pneumonia, pneumocystis", one prominent subject focus is on "aids-related opportunistic infections" and another is on "pneumocystis jirovecii" (fig. e ). our analysis shows that the number of publications on pneumonia increased notably over the study period, with annual research outputs doubling from to . different factors may have contributed to this. the first of these is the growing research relevance of pneumonia as a clinical entity, as this disease is one of the community-acquired infections with the highest incidence and is an important cause of hospital admissions. it is also associated with a high global burden of morbidity and mortality in both children and adults [ ] [ ] [ ] ] . the second potential factor relates to advances in basic immunological and microbiological research along with deepening knowledge on the pathogenesis of the disease with regard to aspects like microbiological resistance and preventive interventions (e.g. vaccines) [ ] . thirdly, increased funding has been directed toward research and particularly "proactive investments for emerging infectious threats" [ , ] , and finally, the increase in scientific production could be related to scientific development and international dissemination of scientific research in the wos databases. this is particularly the case of china and other emerging economies like brazil, where the rates of growth were highest relative to their respective regions [ ] [ ] [ ] . we observed a substantial increase in research worldwide, but particularly in some geographical regions and countries of south asia, east asia & the pacific, latin america & and the caribbean, and sub-saharan africa. to a great extent, this increase is simply a reflection of the limited contribution to global research that these countries made in the first period analyzed ( ) ( ) ( ) ( ) ( ) . the bulk of scientific production continues to come from countries with more economic and scientific development in europe and north america (together, these countries participated in % of all publications). despite the striking increase in scientific production across lmics, the relative contribution to pneumonia research remains very modest, and the fact that some countries rank highest in demographic and economic indicators may not be a positive feature, but rather a reflection of the scant development in their scientific systems. furthermore, the increase in international collaboration could have played a role in these indicators, multiplying the assignment of articles to different countries and possibly inflating some values, masking the real contribution of countries with less scientific development in research activities [ ] . the usa is undoubtedly the main reference for pneumonia researchers in quantitative terms, as it produces by far the largest volume of publications-four times that of the next most productive country in the last period. other european countries with important scientific systems (e.g. the uk, germany, france, and spain), along with other countries like japan, canada, china, india, and brazil, also stand out in relation to some of the indicators of scientific production and economic development (gni per capita index, and r&d expenditure index). the other significant aspect in the analysis of how scientific production evolved over the study period is the emergence of china, which in the last period of study ( ) ( ) ( ) ( ) ( ) trailed only the usa in research output. this growth has come about in large part from the investments and scientific policies to foster openness that have been implemented over the past several decades to promote internationalization [ , ] . the level of international scientific collaboration that we have observed in the field of pneumonia ( %) is below that seen in other areas of knowledge [ , , , [ ] [ ] [ ] [ ] . thus, even though the trend is toward increased international cooperation, rising from to % over the study period, implementing new strategies that favor collaboration is still necessary [ ] . initiatives promoting research could include those launched by international organizations, such as the world health organization (who) and the bill & melinda gates foundation, which have both invested considerable resources to investigate the etiology of childhood pneumonia in low-income countries [ ] [ ] [ ] . however, these initiatives [ ] are also collaborating in different projects related to hiv, tuberculosis, and malaria, and these organizations are largely responsible for the important degree of collaboration between european and sub-saharan african countries [ ] . research for operational health services is necessary to improve the distribution and accessibility of pneumonia treatments, including antibiotics in primary healthcare centers and oxygen in hospitals. likewise, new vaccines still need to be developed for strains of pneumococcus that current multivalent conjugate vaccines do not protect against [ ] . in addition to programs focused on financing and implementing collaborative north-south and south-south projects, other efforts could be directed toward reducing obstacles associated with publication processes fig. subject area maps with the main mesh terms associated with different types of pneumonia-(a) "pneumonia, aspiration" (b) "pneumonia, bacterial, " (c) "pneumonia, ventilator-associated, " (d) "pneumonia, viral, " and (e) "pneumonia, pneumocystis" groupings in the form of "islands" in red tones represent the main clusters of the thematic networks, while the chromatic gradation in yellow and green tones illustrates the areas with a lower density of relations between the mesh. the spatial distribution of the mesh and their proximity to each other responds to the intensity of co-occurrence between them that limit the dissemination of lmics through the main international scientific journals. the literature has described obstacles related to linguistic skills and methodological deficiencies, which highlights the need to improve these areas in particular [ , ] . other authors have pointed to the costs associated with publishing in open access journals, so it is worth assessing whether the programs to support open access publishing implemented at an institutional level and by publishers such as plos, biomed central, or the lancet journals, are sufficient [ ] [ ] [ ] . with regard to the impact of research, although europe and north america are balanced in terms of the absolute number of citations, north america holds an advantage in terms of the citation rate. research from sub-saharan africa also has a very high citation rate, which almost reaches that achieved in europe. the fact that these african countries present a high degree of collaboration with researchers in the usa and europe, who represent the "mainstream" international research interests, could help explain the high citation rates seen in this region. on the other hand, latin america & caribbean, south asia, and east asia & pacific are all regions with generally lower citation rates, although this difference is not so pronounced in the case of papers produced in collaboration, as reported elsewhere [ ] . by country, the hegemony of the usa and several european countries in terms of the number of citations received was evident, as was the lower ranking of some asian countries, such as japan and china, in relation to their scientific production. the positioning of china as a reference for scientific production and participation in international research networks does not correspond to its ranking with regard to citation indicators, despite their improved standing over the past several years [ ] . on these indicators, china still lags behind the usa as well as the leading european countries, canada, australia and even nearby countries such as japan. for now at least, the countries that have traditionally occupied the "mainstream" of scientific research still maintain their hegemony [ ] . as with the relative indicators of scientific production adjusted for economic and demographic parameters, some countries surpass the major scientific systems with regard to the citation rate, which links the degree of citation with the volume of scientific production [ ] . these countries may have participated in certain highly relevant contributions, or they may be small countries with highly developed scientific systems, such as vietnam, switzerland, south africa, new zealand, and saudi arabia. these countries also stand out for their high levels of international collaboration, which is a factor associated with more citations. the high mean citations received by publications produced in sub-saharan africa, and the participation of different emerging countries like vietnam and south africa in some of the highest cited papers we identified, underlines the capacity of these countries to contribute to high-impact and excellent-quality scientific studies. this result is consistent with previous studies that have also demonstrated these countries' capacity to participate in emerging research topics [ ] . these specialists therefore represent an excellent asset, strengthening the human capital from high-income countries and enabling the advancement of research [ , ] . in general, the most prestigious journals show a greater concentration of research from the usa and europe, with greater collaboration and impact when countries from other geographical regions also participate [ ] . bacterial pneumonia is the main branch for the multidisciplinary and multipathological mesh of "pneumonia", with the main areas of interest ("community-acquired infections", "anti-bacterial agents" and "treatment outcome") reflecting the focus of research on identifying risk factors and assessing different treatments and their outcomes. in publications pertaining to the mesh "pneumonia, ventilator-associated," the main axes of the subject content according to the mesh terms were the group of epidemiological studies and clinical and treatment protocols in intensive care. "pneumonia pneumocystis," is closely related to infection due to hiv and immunodepression. the main areas of research interest for "pneumonia, viral," were the epidemiological aspects related to the setting for the infection ("community-acquired infections" and "hospitalization") along with the viruses responsible ("influenza, human" and "orthomyxoviridae infections"). finally, for the mesh "pneumonia, aspiration" the main research focus is "deglutition disorder". the main limitation of this present study is its analysis of only the documents included in the wos databases and medline ( % of the documents). thus, a number of papers were excluded from the study, particularly those written in languages other than english, as well as the proceedings included in wos, as our searches were based on the journals included in medline. on the other hand, our approach also allowed us to precisely characterize collaboration in the area, as only recently has medline begun to include all the institutional affiliations of the authors. we were also able to analyze the citations of the publications, with a focus on the journals with the highest impact and dissemination at an international level [ ] . in conclusion, pneumonia research increased steadily over the -year study period, with europe and north america leading scientific production. about a fifth of all papers reflected international collaborations, and these were most evident in papers from sub-saharan africa and south asia. additional file : table s . descriptors included under the mesh "pneumonia" in pubmed. table s . top countries in crude numbers of retrieved articles in "pneumonia, aspiration", "pneumonia, bacterial", "pneumonia pneumocystis", "pneumonia, ventilator-associated", and "pneumonia, viral" mesh. figure s . evolution of scientific production on pneumonia ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . clinical and economic burden of communityacquired pneumonia among adults in europe burden of community-acquired pneumonia in north american adults global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for causes of death, - : a systematic analysis for the global burden of disease study impact of age and comorbidity on cause and outcome in communityacquired pneumonia the burden of community-acquired pneumonia in the elderly: the spanish evan- study burden of pneumococcal community-acquired pneumonia in adults across europe: a literature review all cause mortality estimates for - . who mapping pneumonia research: a systematic analysis of uk investments and published outputs - investments in respiratory infectious disease research - : a systematic analysis of uk funding scientometrics analysis of research activity and collaboration patterns in chagas cardiomyopathy evolution of cooperation patterns in psoriasis research: co-authorship network analysis of papers in medline bibliometric analysis of leishmaniasis research in medline ( - ) investment in pneumonia and pneumococcal research medical subject headings used to search the biomedical literature mesh now: automatic mesh indexing at pubmed scale via learning to rank years on -is the nlm medical text indexer still useful and relevant? mesh datebase: pneumonia web of science use in published research and review papers - : a selective, dynamic, cross-domain, content-based analysis world bank country and lending groups world bank open data. the world bank an index to quantify an individual's scientific research output software survey: vosviewer, a computer program for bibliometric mapping replication data for: mapping global pneumonia research: a systematic analysis of scientifical production global, regional, and national causes of child mortality: an updated systematic analysis for with time trends since a distinct lineage of cd t cells regulates tissue inflammation by producing interleukin characterization and complete genome sequence of a novel coronavirus, coronavirus hku , from patients with pneumonia comparison of pubmed, scopus, web of science, and google scholar: strengths and weaknesses coverage and quality: a comparison of web of science and scopus databases for reporting faculty nursing publication metrics inflationary bibliometric values: the role of scientific collaboration and the need for relative indicators in evaluative studies brics countries and scientific excellence: a bibliometric analysis of most frequently cited papers in-depth analysis on china's international cooperation in science dominance and leadership in research activities: collaboration between countries of differing human development is reflected through authorship order and designation as corresponding authors in scientific publications respiratory syncytial virus: a systematic scientometric analysis of the global publication output and the gender distribution of publishing authors human t-lymphotropic virus (htlv- ) and human t-lymphotropic virus (htlv- ): geographical research trends and collaboration networks density equalizing mapping of the global tuberculosis research architecture the pneumonia etiology research for child health project: a st century childhood pneumonia etiology study gates annual letter. our big bet for the future gatenotes background paper -priority diseases and reasons for inclusion. bp . -depression. who the bill &amp melinda gates foundation's grant-making programme for global health european and developing countries clinical trials partnership (edctp): the path towards a true partnership bibliometric assessment of european and sub-saharan african research output on poverty-related and neglected infectious diseases from publication bias -a reason for the decreased research output in developing countries geography of africa biomedical publications: an analysis of - pubmed papers bmc: apc waivers and discounts secondary instructions for authors nassi-calò l. articles by latin american authors in prestigious journals have fewer citations bibliometrics evaluation of research performance in pharmacology/pharmacy: china relative to ten representative countries scientometric research assessment in the developing world: a tribute to michael j. moravcsik from the perspective of the twentyfirst century experiences and perceptions of south--south and north--south scientific collaboration of mathematicians, physicists and chemists from five southern african universities the impact of african science: a bibliometric analysis differences in citation rates by country of origin for papers published in top-ranked medical journals: do they reflect inequalities in access to publication? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we gratefully acknowledge the assistance of meggan harris in translating our manuscript from spanish.authors' contributions jmrr: study conception, study, design, data analysis, manuscript writing and final manuscript approval; hpc: data collection, data analysis, manuscript writing and final manuscript approval; ibr: study conception, manuscript writing and final manuscript approval; gga: study conception, study design, data collection, data analysis, manuscript writing and final manuscript approval no funding was received for this work. all data used to perform the study, including the information downloaded from the database as well as that derived from the treatment of the bibliographic entries, are available in the dataverse project, an open access public repository [ ] (https://dataverse.harvard.edu/, doi: https://doi.org/ . /dvn/ bune). due to the nature of the study and dataset, it was not necessary to obtain informed consent or approval from an institutional ethics committee. the authors give consent to publish the manuscript. the authors declare that they have no competing interests. key: cord- -jqlz yt authors: katz, sophie e.; williams, derek j. title: pediatric community-acquired pneumonia in the united states changing epidemiology, diagnostic and therapeutic challenges, and areas for future research date: - - journal: infectious disease clinics of north america doi: . /j.idc. . . sha: doc_id: cord_uid: jqlz yt community-acquired pneumonia (cap) is one of the most common serious infections in childhood. this review focuses on pediatric cap in the united states and other industrialized nations, specifically highlighting the changing epidemiology of cap, diagnostic and therapeutic challenges, and areas for further research. pneumonia is an infection of the lower airways (distal bronchi and alveoli) caused by both viruses and bacteria. community-acquired pneumonia (cap) specifically refers to clinical signs and symptoms of pneumonia acquired outside a hospital setting. it is one of the most common serious infections in childhood, accounting for more than , deaths among children younger than years of age in . although the rate of mortality due to cap is much lower in the developed world compared with the developing world, cap continues to account for a significant proportion of health care visits and hospitalizations in high-income countries. this review focuses on pediatric cap in the united states and other industrialized nations, specifically highlighting the changing epidemiology of cap, diagnostic and therapeutic challenges, and areas for further research. in the united states, cap accounts for approximately million outpatient visits annually and is among the most common causes for hospitalization, with approximately , pediatric hospitalizations annually (annual incidence of . - . hospitalizations per , children). [ ] [ ] [ ] the highest rate of health care utilization occurs in children younger than years of age and decreases with increasing age in the pediatric population. children with pneumonia most often present with fever, tachypnea, and other signs of respiratory distress ( table ) . signs and symptoms may include tachypnea, cough, dyspnea, retractions, grunting, hypoxemia, abdominal pain, or lethargy, and physical examination findings of decreased breath sounds, crackles, rales, or wheezing on auscultation of lung fields. many of these findings overlap with other acute lower respiratory tract diseases (eg, asthma and viral bronchiolitis), and identifying children with pneumonia based only on clinical signs and symptoms is sometimes difficult. as a result, chest radiographs are commonly used to confirm the diagnosis. even when a chest radiograph reveals an infiltrate, however, it is sometimes difficult to differentiate between consolidation representing pneumonia and atelectasis commonly seen in children with asthma or bronchiolitis. as a result, variation in chest radiograph interpretation is common and may contribute to antibiotic overuse. , for this reason, the guideline developed by the pediatric infectious diseases society (pids) and infectious diseases society of america (idsa) discourages use of chest radiographs in children with suspected uncomplicated pneumonia in an outpatient setting. chest radiographs are recommended in children who are hospitalized with hypoxemia or respiratory distress and in those with suspected complications, such as parapneumonic effusions, necrotizing pneumonia, or pneumothorax ( fig. ) . chest ultrasound is most often used for evaluating local complications, such as parapneumonic effusion and empyema, but recent studies have demonstrated high sensitivity ( %- %) and specificity ( %- %) for detecting lung consolidation compared with chest radiography. [ ] [ ] [ ] [ ] [ ] additional benefits of chest ultrasound include a lack of ionizing radiation and availability in most emergency department settings. an important limitation of ultrasound is that evaluation and interpretation are highly operator dependent. thus, despite these promising early studies, large-scale, pragmatic studies are needed to better evaluate the effectiveness of this imaging technique versus standard chest radiography. pneumonia is a heterogeneous disease caused by a variety of pathogens, including viruses and bacteria. historically, cap was largely considered a bacterial process, most often due to streptococcus pneumoniae, haemophilus influenzae, streptococcus pyogenes, and staphylococcus aureus. [ ] [ ] [ ] [ ] [ ] the introduction of routine childhood vaccination against both streptococcus pneumoniae and h influenzae, however, has dramatically reduced disease caused by these pathogens. at the same time, highly sensitive molecular diagnostics for viral respiratory pathogens have heightened awareness of the impact of viruses as a cause of cap. a study by michelow and colleagues exemplifies pre-pneumococcal conjugate vaccine (pcv) era etiology studies. that study used traditional culture methods, pneumolysin-based polymerase chain reaction (pcr) assays, viral direct fluorescent antibody tests, and serologic tests for viruses, mycoplasma spp, and chlamydia spp to identify pathogens in hospitalized children with radiographically confirmed lower respiratory infections at a single institution. a majority of patients ( %) were noted to have infection with typical respiratory bacteria (most commonly, streptococcus pneumoniae, detected in % of children with documented bacterial disease), with viruses identified in % of children. a -valent pcv (pcv ) targeting the most common clinically important pneumococcal serotypes was introduced into the united states childhood immunization schedule in . rates of invasive pneumococcal disease caused by pcv serotypes in children less than years of age plummeted from an average of . cases to . cases per , population within years after the introduction of pcv . by , hospitalization rates for cap and pneumonia-associated complications among young children decreased by % and %, respectively. , despite these declines, disease caused by nonvaccine serotypes soon emerged, and rates of complicated pneumonia increased, prompting introduction of an expanded, -valent pct (pcv ) into the us childhood immunization program in . since that time, hospitalization rates decreased from . per , admissions in the pre-pcv era to . per , admissions in the post-pcv era, and rates of complicated pneumococcal pneumonia decreased significantly. pneumonia etiology in the post-pneumococcal conjugate vaccine era the multicenter centers for disease control and prevention (cdc) etiology of pneumonia in the community (epic) study was a prospective, population-based surveillance study of greater than pediatric cap hospitalizations in the united states conducted from to . this study used serology and nasopharyngeal pcr to identify different viruses, culture-based methods and whole-blood pcr (pneumococcal lyt-a) to identify typical bacteria, and nasopharyngeal pcr to identify atypical bacterial pathogens. viruses were identified in greater than % of children, whereas bacteria were identified in only % of children (fig. ) . the most common viral pathogens included respiratory syncytial virus (rsv), human rhinovirus, human metapneumovirus, and adenovirus, all detected in greater than % of children. rsv, adenovirus, and human metapneumovirus were more commonly identified in children younger than years of age compared with older children. bacteria were identified in approximately % of children in the cdc epic study, although streptococcus pneumoniae was only identified in % of children, further underscoring the impact that pcv has had on the epidemiology of pediatric cap. mycoplasma pneumoniae was the most frequently identified bacterial pathogen, detected in % of children, including % of school-aged children, but only % of children younger than years of age. other bacteria were identified in % or less of children. importantly, % of children in the cdc epic study had no pathogen identified, highlighting the continued need for enhanced diagnostics and novel pathogen discovery techniques. other pathogens that are less commonly seen among us children include mycobacterium tuberculosis, fungi, burkholderia cepacia, aspergillus fumigatus, and pseudomonas aeruginosa and usually occur in patients with underlying risk factors, such as immunocompromising conditions; chronic conditions, such as cystic fibrosis and spinal muscular atrophy; or history of international travel ( table ) . these pathogens should also be suspected in patients who experience treatment failure for more common etiologic agents. the pids/idsa cap guideline recommends obtaining blood cultures in children hospitalized with cap. , , in this setting, however, blood cultures identify a pathogen in only % to % of children with cap. [ ] [ ] [ ] [ ] blood cultures are more often positive in children with parapneumonic effusion, ranging from % to %. , , in the outpatient setting, blood cultures are not routinely recommended, because positivity rates are low and results are unlikely to change management. regardless, despite group b streptococci neonatal pneumonia and sepsis. neonatal pneumonia and sepsis. gram-negative enterics neonatal pneumonia and sepsis. potential pathogens in aspiration pneumonia. cause of afebrile pneumonia in young infants < mo of age. anaerobes (oral flora) potential pathogens in aspiration pneumonia. legionnaires' disease. rare in children but associated with community outbreaks. exposure to contaminated artificial freshwater systems. coxiella burnetti q fever. exposure to wild and domesticated herbivores or unpasteurized dairy (eg, cattle, sheep, and goats). also potential bioterrorism agent. psittacosis. bird (eg, pet birds and pigeons) exposure. tularemia. rabbit exposure. yersinia pestis pneummonic plague. rodent flea exposure. anthrax. woolsorter's disease. wild and domesticated herbivore (eg, cattle, sheep, goats) exposure. also potential bioterrorism agent. leptospirosis. exposure to urine of wild and domestic animals carrying the bacterium. rare in us children. usually associated with high-risk exposures. brucellosis. exposure to wild and domesticated animals or unpasteurized dairy (eg, cattle, sheep, pigs, goats, deer, and dogs). histoplasmosis. exposure to bird or bat droppings (eg, poultry/ bird roosts and caves). endemic to eastern and central united states. blastomycosis. environmental exposure to fungal spores (wooded areas). endemic to southeastern and midwestern united states. cryptococcosis. exposure to soil contaminated with bird droppings. significant pathogen nearly exclusively among immunocompromised. their low yield, blood cultures currently provide the best opportunity to identify typical bacterial pathogens in most children with cap. diagnostic yield of blood cultures can be optimized by restricting their use to those patients with increased pretest probability of having a positive culture, such as those who are severely ill or have parapneumonic effusion. [ ] [ ] [ ] isolation of pathologic organisms occurs significantly less frequently in patients exposed to antibiotics before specimen collection. , studies have also demonstrated increased yield of blood cultures with each additional milliliter of blood drawn. [ ] [ ] [ ] obtaining adequate weight-based blood volumes is also associated with lower rates of blood culture contamination, for reasons yet unknown. , contamination rates can also be minimized by adhering to proper sterile collection methods. , , cultures of the lower respiratory tract pleural fluid cultures are positive in up to % of cases and should be performed whenever pleural fluid is obtained. , , , [ ] [ ] [ ] the invasive methods associated with sampling the pleural space, however, make it impractical to obtain pleural fluid specimens except when dictated for clinical care. bronchoalveolar lavage is rarely indicated in cap, except in instances of lack of response to therapy, very severe pneumonia, or immunocompromised hosts in whom opportunistic pathogens are suspected. sputum cultures are of low diagnostic yield in children, due to the inability of most young children with pneumonia to produce an adequate sputum sample. pretreatment with antibiotics further hinders diagnostic yield. induced sputum has been explored as an opportunity to collect sputum samples in young children, although utility is limited by frequent detection of upper respiratory tract bacteria and similar rates of recovery of pathogens in pneumonia cases compared with children without pneumonia. , molecular diagnostics pneumococcal urinary antigen testing is often used in the evaluation of pneumonia in adults. in children, however, detection of streptococcus pneumoniae urinary antigen is associated with false-positive results due to high rates of nasopharyngeal colonization. , more recently, a serotype-specific urinary antigen detection method has been developed and validated in adults with pneumonia ; whether or not this test could prove useful in children remains to be determined. although not widely used in clinical settings, whole-blood pneumococcal pcr (lyt-a) has been used in epidemiologic studies, including epic and pneumonia etiology research for child health (perch). potential benefits include improved sensitivity, rapid turnaround time, and less influence of antibiotic pretreatment compared with culturebased methods. , in the epic study, . % of children tested were pcr-positive for streptococcus pneumoniae, whereas blood cultures were positive for pneumococcus in only % of children (p<. ). in the perch study, children with pneumonia ( . %) were pneumococcal pcr-positive, whereas only children (denominator not provided) had a positive blood culture for streptococcus pneumoniae. moreover, although prior studies demonstrated % specificity of lyt-a pneumococcal pcr from the blood, the perch study also identified pneumococcal dna in the blood of control children ( . %). thus, although pneumococcal pcr may increase rate of detection over blood culture, suboptimal test specificity hampers interpretation. pcr also increases yield for pleural fluid specimens. in a study evaluating archived pleural fluid specimens from pediatric patients with cap, a pathogen was detected in % of samples using pcr compared with only % of samples when using conventional culture methods (p<. ). the most frequent pathogen detected using pediatric community-acquired pneumonia both methods was streptococcus pneumoniae, % using pcr and % using conventional culture. the next most frequent pathogens identified were streptococcus pyogenes ( % using pcr and % using conventional culture) and s aureus ( % using pcr and % using conventional culture). this study also highlighted the potential for bias with respect to pathogen identification introduced when relying on culture alone for epidemiologic studies, because penicillin-resistant pneumococcal isolates and s aureus were more likely to be positive in culture, whereas other serotypes of streptococcus pneumoniae and bacterial pathogens commonly susceptible to penicillins were more commonly identified by pcr. up to two-thirds of children younger than years are colonized in the upper respiratory tract with common bacterial pathogens known to cause pneumonia, and pcr from the upper respiratory tract is not a reliable method for ascertaining bacterial etiologies of pneumonia. a possible exception is m pneumoniae, which has not previously been considered a frequent colonizer of the upper respiratory tract. consistent with this theory, the cdc epic study demonstrated that although m pneumoniae was detected in % of children with pneumonia, fewer than % of controls had evidence of m pneumoniae. in contrast, a cross-sectional, observational study in the netherlands of asymptomatic children and children with symptoms of upper and lower respiratory tract infection detected m pneumoniae dna not only in % of symptomatic children but also in % of asymptomatic children. given the conflicting results of these studies and the increasing commercial availability of m pneumoniae pcr tests, caution is warranted when interpreting test results in the clinical setting. in contrast to bacteria, pcr testing for viruses from upper respiratory samples has largely replaced culture and serology-based methods to investigate pneumonia etiology, owing to superior sensitivity, rapid turnaround time, and ability to identify viruses that are difficult to grow in culture. a major concern, however, is whether lower respiratory tract disease can be attributed to a viral pathogen detected in the upper airway. the scope of the problem is well illustrated in a study conducted by self and colleagues that compared pcr detections of viruses from the upper respiratory tract among children with cap and healthy, asymptomatic children enrolled in the cdc epic study. overall, approximately % of asymptomatic children had or more viruses detected compared with approximately % of children with cap. detection of most viruses was higher among children with cap compared with asymptomatic controls, including influenza ( % vs %), rsv ( % vs %), and human metapneumovirus ( % vs %), with attributable fractions greater than % for all. conversely, rhinovirus was detected at a similar frequency in both children with cap and asymptomatic children ( % vs %; attributable fraction %; % ci, % to %). attributable fractions for other viruses studied ranged from % to %. thus, although some viruses detected in the upper airway likely reflect lower airway disease (eg, rsv, influenza, and human metapneumovirus), detection of other viruses must be interpreted with caution. as proposed for adults, investigating viral loads may further help to differentiate disease versus asymptomatic colonization. because sensitive methods of diagnosing viral infections have become more widely available, the recognition of viral and bacterial coinfection has also increased. it is well known that upper tract disease with respiratory viruses often precedes the development of bacterial pneumonia. [ ] [ ] [ ] although it is not always clear if a virus detected in the upper airway represents prior or concurrent infection in a subject with bacterial pneumonia, studies suggest that viral-bacterial codetections are associated with a more severe clinical course compared with single viral or bacterial detections. [ ] [ ] [ ] the association between influenza and coinfection with pneumococcal or staphylococcal pneumonia is perhaps the best described of these viral and bacterial coinfections. , elevated leukocyte count was traditionally considered to be associated with serious bacterial infection, but the specificity of leukocyte count in making the diagnosis of bacterial pneumonia in children is poor, and the degree of elevation does not reliably distinguish between viral and bacterial pneumonia. , - as such, routine measurement of leukocyte count is likely not beneficial. more recent biomarkers used in the detection of pneumonia include c-reactive protein (crp) and procalcitonin (pct). these biomarkers may perform better than leukocyte count for identifying bacterial infections, , , although identifying relevant clinical cutpoints remains a challenge. to evaluate the impact of crp in the etiologic diagnosis of pneumonia, a meta-analysis of studies with more than children with viral or bacterial causes of cap demonstrated that crp levels greater than or equal to mg/l to mg/l were associated with only a % positive predictive value for identifying children with bacterial pneumonia. pct is a peptide precursor of calcitonin and is produced by c cells in the thyroid gland and by neuroendocrine cells in the lung and intestine. levels are usually undetectable in healthy individuals but increase in response to systemic inflammation. cytokines typically associated with bacterial infection enhance pct release, whereas interferons, which are more often associated with viral infections, inhibit pct release. , thus, much interest has been directed at pct as a potential biomarker for bacterial disease. among hospitalized children enrolled in the cdc epic study, a pct cutoff value of . ng/ml demonstrated a sensitivity of % and specificity of % for cap caused by typical bacterial pathogens. the study also found that higher pct levels were associated with more severe disease. multiple studies have shown utility in using pct levels to guide antibiotic initiation and duration. [ ] [ ] [ ] [ ] [ ] [ ] biomarker studies using transcriptomics show promise for enhancing diagnostic capabilities by using host responses to identify possible pathogens and study disease severity. [ ] [ ] [ ] [ ] transcriptomics uses gene expression profiling to measure the activity or expression of thousands of genes at once, thereby creating a global picture of cellular activity. profiles of peripheral blood leukocytes in patients with lower respiratory tract infection can accurately distinguish influenza viral infection from bacterial infection and predict disease severity. host transcriptional profiling has also been shown useful in distinguishing symptomatic rhinovirus infection from incidental detection in children. these promising studies will likely add much to the understanding of pneumonia etiology and outcomes, although much work remains prior to translating these new technologies to the bedside. several prognostic models are available for adults with pneumonia, , and their application has been shown to contribute to improved outcomes. unfortunately, no analogous models have been validated in children, a recognized key knowledge gap. recently, williams and colleagues derived prognostic models to identify risk for severe outcomes among children with cap; each model demonstrated good predictive accuracy (concordance index . - . ) . in that study, extremes of age, vital signs, chest indrawing, and radiographic infiltrate pattern ranked among the most important predictors of disease outcomes. although these models require further validation, their use could reduce variability and improve care for children with pneumonia. although viruses are a major cause of childhood pneumonia, a majority of children with pneumonia receive antibiotics. pneumonia is associated with more antibiotic use in us pediatric hospitals than any other condition. when antibiotics are indicated, amoxicillin or ampicillin is recommended as first-line therapy in most children (table ) . prior to release of the national guideline, however, broader-spectrum third-generation cephalosporins and macrolides were commonly used. to date, the impact of the national guideline on prescribing has been mixed. approximately years after guideline publication, penicillin use increased approximately . % and cephalosporin use decreased approximately . % across tertiary care children's hospitals in the united states, although substantial variability was noted across institutions. similar variability persists in the outpatient setting. antimicrobial stewardship programs, local clinical practice guidelines, and quality improvement methods all play important roles in raising awareness of these recommendations and reducing unnecessary and inappropriate antibiotic use. , , current practices for treatment of uncomplicated cap generally use -day to -day antibiotic courses, although large pediatric randomized controlled studies are currently evaluating the safety and efficacy of shorter courses of antibiotics, a united kingdom community-acquired pneumonia study (cap-it) and the us phase iv double-blind, placebo-controlled, randomized trial short course outpatient therapy of community acquired pneumonia (scout-cap). , consideration of alternative etiologies, such as s aureus, is warranted in children with severe or rapidly progressive disease, extensive local complications, or poor treatment response. s aureus is an uncommon cause of cap, detected in only % of children hospitalized with pneumonia. thus, to preserve the effectiveness of antistaphylococcal antibiotics, care must be taken when considering when to use these agents empirically, and efforts to de-escalate therapy whenever possible should be emphasized. although m pneumoniae is a frequent cause of cap in children, it is impossible to reliably distinguish this pathogen from other common causes of pneumonia. questions regarding the utility of currently available pcr tests for m pneumoniae, as outlined previously, further complicate treatment considerations. moreover, azithromycin use is associated with the development of multidrug resistance. , perhaps the most important consideration governing when to use macrolide therapy, however, is that currently available studies have failed to consistently demonstrate their benefit in children with pneumonia. despite advances in recent years, cap continues to cause significant morbidity and mortality and poses diagnostic and therapeutic challenges. vaccination against haemophilus influenzae type b and streptococcus pneumoniae has greatly reduced invasive disease rates caused by these pathogens, and the introduction of molecular diagnostics has highlighted the important role that respiratory viruses play in disease pathogenesis while also introducing new challenges. this updated understanding brings into question whether all children with cap would benefit from antibiotic therapy, and if so, which therapies might be most effective. limitations of current diagnostics, however, impede advances toward addressing these important questions. biomarkers and host responses to infection are current areas of intense study that may facilitate a deeper understanding of pneumonia etiology and disease outcomes. as this important work progresses, future epidemiologic studies using state-of-the-art diagnostics will continue to serve an important role in informing understanding of the changing epidemiology of cap. british thoracic society guidelines for the management of community acquired pneumonia in children: update world health organization ambulatory visit rates and antibiotic prescribing for children with pneumonia community-acquired pneumonia requiring hospitalization among u.s. children national hospitalization trends for pediatric pneumonia and associated complications healthcare cost and utilization project (hcup) the management of communityacquired pneumonia in infants and children older than months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america disagreement in the interpretation of chest radiographs among specialists and clinical outcomes of patients hospitalized with suspected pneumonia prospective evaluation of point-of-care ultrasonography for the diagnosis of pneumonia in children and young adults ultrasound diagnosis of pneumonia in children lung ultrasound for the diagnosis of pneumonia in children: a meta-analysis lung ultrasound as first-line examination for the diagnosis of community-acquired pneumonia in children performance of chest ultrasound in pediatric pneumonia etiology of community-acquired pneumonia in hospitalized children epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children etiology and treatment of communityacquired pneumonia in ambulatory children etiology of community-acquired pneumonia in children based on antibody responses to bacterial and viral antigens etiology of childhood pneumonia: serologic results of a prospective, population-based study incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (pcv ) serotypes in the united states during the era of widespread pcv vaccination decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the usa: a time-series analysis population snapshot of emergent streptococcus pneumoniae serotype a in the united states pneumococcal pneumonia requiring hospitalization in us children in the -valent pneumococcal conjugate vaccine era the contribution of blood cultures to the clinical management of adult patients admitted to the hospital with communityacquired pneumonia: a prospective observational study utility of blood cultures in pediatric patients found to have pneumonia in the emergency department prevalence of bacteremia in hospitalized pediatric patients with community-acquired pneumonia blood cultures in the emergency department evaluation of childhood pneumonia blood culture in evaluation of pediatric community-acquired pneumonia: a systematic review and meta-analysis molecular analysis improves pathogen identification and epidemiologic study of pediatric parapneumonic empyema diagnosis of bloodstream infections in children reducing blood culture contamination in the emergency department: an interrupted time series quality improvement study reducing the blood culture contamination rate in a pediatric emergency department and subsequent cost savings the effect of antibiotic exposure and specimen volume on the detection of bacterial pathogens in children with pneumonia influence of antibiotics on the detection of bacteria by culture-based and culture-independent diagnostic tests in patients hospitalized with community-acquired pneumonia effect of number of blood cultures and volume of blood on detection of bacteremia in children effects of volume and site of blood draw on blood culture results bacteremia among children admitted to a rural hospital in kenya how reliable is a negative blood culture result? volume of blood submitted for culture in routine practice in a children's hospital an epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations parapneumonic empyema in children: decortication hastens recovery in patients with severe pleural infections predictive factors of morbidity in childhood parapneumonic effusion-associated pneumonia: a retrospective study role of bronchoalveolar lavage in the diagnosis of pulmonary infiltrates in immunocompromised patients limited utility of polymerase chain reaction in induced sputum specimens for determining the causes of childhood pneumonia in resource-poor settings: findings from the pneumonia etiology research for child health (perch) study the diagnostic utility of induced sputum microscopy and culture in childhood pneumonia evaluation of a rapid immunochromatographic test for detection of streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia evaluation of binax now, an assay for the detection of pneumococcal antigen in urine samples, performed among pediatric patients validation of an immunodiagnostic assay for detection of streptococcus pneumoniae serotype-specific polysaccharides in human urine comparison of the effect of antibiotic treatment on the possibility of diagnosing invasive pneumococcal disease by culture or molecular methods: a prospective, observational study of children and adolescents with proven pneumococcal infection determining the microbiological cause of a chest infection detection of pneumococcal dna in blood by polymerase chain reaction for diagnosing pneumococcal pneumonia in young children from low-and middle-income countries pneumococcal dna is not detectable in the blood of healthy carrier children by real-time pcr targeting the lyta gene the descriptive epidemiology of streptococcus pneumoniae and haemophilus influenzae nasopharyngeal carriage in children and adults in kilifi district carriage of mycoplasma pneumoniae in the upper respiratory tract of symptomatic and asymptomatic children: an observational study respiratory viral detection in children and adults: comparing asymptomatic controls and patients with communityacquired pneumonia frequent detection of respiratory viruses without symptoms: toward defining clinically relevant cutoff values seasonal invasive pneumococcal disease in children: role of preceding respiratory viral infection respiratory viruses predisposing to bacterial infections: role of neuraminidase outbreak of pneumonia in a long-term care facility: antecedent human parainfluenza virus infection may predispose to bacterial pneumonia critically ill children during the - influenza pandemic in the united states coinfection with staphylococcus aureus increases risk of severe coagulopathy in critically ill children with influenza a (h n ) virus infection viral-bacterial coinfection affects the presentation and alters the prognosis of severe community-acquired pneumonia insights into the interaction between influenza virus and pneumococcus complications and associated bacterial coinfections among children hospitalized with seasonal or pandemic influenza erythrocyte sedimentation rate, white blood cell count and serum c-reactive protein in assessing etiologic diagnosis of acute lower respiratory infections in children clinical features and inflammatory markers in pediatric pneumonia: a prospective study the utility of biomarkers in differentiating bacterial from non-bacterial lower respiratory tract infection in hospitalized children: difference of the diagnostic performance between acute pneumonia and bronchitis diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review association of c-reactive protein with bacterial and respiratory syncytial virus-associated pneumonia among children aged < years in the perch study the utility of serum c-reactive protein in differentiating bacterial from nonbacterial pneumonia in children: a meta-analysis of children procalcitonin as a biomarker in respiratory tract infection in vitro and in vivo calcitonin i gene expression in parenchymal cells: a novel product of human adipose tissue procalcitonin accurately identifies hospitalized children with low risk of bacterial community-acquired pneumonia effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infection in children and adolescents (propaed): a randomized controlled trial procalcitonin measurements for guiding antibiotic treatment in pediatric pneumonia whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection superiority of transcriptional profiling over procalcitonin for distinguishing bacterial from viral lower respiratory tract infections in hospitalized adults association of rna biosignatures with bacterial infections in febrile infants aged days or younger rhinovirus detection in symptomatic and asymptomatic children: value of host transcriptome analysis gene expression patterns in blood leukocytes discriminate patients with acute infections a prediction rule to identify low-risk patients with community-acquired pneumonia smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia predicting severe pneumonia outcomes in children identifying targets for antimicrobial stewardship in children's hospitals impact of a national guideline on antibiotic selection for hospitalized pneumonia variability in antibiotic prescribing for community-acquired pneumonia effectiveness of antimicrobial guidelines for community-acquired pneumonia in children quality improvement methods increase appropriate antibiotic prescribing for childhood pneumonia cap-it: efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with community-acquired pneumonia (cap): a randomised controlled trial placebo-controlled, randomized trial to evaluate short course vs. standard course outpatient therapy of community acquired pneumonia in children (scout-cap) active bacterial core surveillance team. outpatient antibiotic prescribing and nonsusceptible streptococcus pneumoniae in the united states mycoplasma pneumoniae infections-does treatment help? treatment of mycoplasma pneumonia: a systematic review the authors thank kathryn edwards, md, and ritu banerjee, md, phd, vanderbilt university medical center, for their critical review and input during article preparation.pediatric community-acquired pneumonia key: cord- - ekgabx authors: luby, james p. title: southwestern internal medicine conference: pneumonias in adults due to mycoplasma, chlamydiae, and viruses date: - - journal: am j med sci doi: . / - - sha: doc_id: cord_uid: ekgabx pneumonias in adults due to mycoplasma, chlamydiae, and viruses are a common clinical problem. these microorganisms contribute to the etiologies in – % of all cases of pneumonia and are the sole pathogens in – % of hospitalized cases. important trends and developments in the field include ( ) the emergence of a chlamydia psittaci strain (twar) that is passaged from human to human, causes a mycoplasma-like illness, and that is relatively resistant to erythromycin, ( ) the recognition of respiratory syncytial virus as a pathogen in nursing home outbreaks and in immunosuppressed adults, the continuing high lethality of fully developed influenza pneumonia, ( ) the efficacy of acyclovir and adenine arabinoside in limiting the complications of varicella-zoster virus infections, and ( ) the increasing frequency of pneumonia caused by cytomegalovirus and the severity of this disorder in highly immunosuppressed patients. developments in the rapid diagnosis and therapy of respiratory syncytial virus infections with an aerosolized antiviral drug in children may pave the way for comparable advances in difficult pneumonias in adult patients. southwestern internal medicine conference: pneumonias in adults due to mycoplasma, chlamydiae, and viruses by james p. luby, md abstract: pneumonias in adults due to mycoplasma, chlamydiae, and viruses are a common clinical problem. these microorganisms contribute to the etiologies in - % of all cases of pneumonia and are the sole pathogens in - % of hospitalized cases. important trends and developments in the field include ( ) the emergence of a chlamydia psittaci strain (twar) that is passaged from human to human, causes a mycoplasma-like illness, and that is relatively resistant to erythromycin, ( ) the recognition of respiratory syncytial virus as a pathogen in nursing home outbreaks and in immunosuppressed adults, ( ) the continuing high lethality of fully developed influenza pneumonia, ( ) the efficacy of acyclovir and adenine arabinoside in limiting the complications of varicella-zoster virus infections, and ( ) the increasing frequency of pneumonia caused by cytomegalovirus and the severity of this disorder in highly immunosuppressed patients. developments in the rapid diagnosis and therapy of respiratory syncytial virus infections with an aerosolized antiviral drug in children may pave the way for comparable advances in difficult pneumonias in adult patients. key population-based studies on the incidence ofpneumonia have been performed infrequently. in one study, during an -year interval from december , , through november , , foy and her col- leagues determined the incidence of pneumonia in a prepaid medical health insurance plan comprising more than , members in seattle, washington. they found that total pneumonia rates varied yearly and ranged between . and . cases/ , population/year. only % of the cases seen by the physicians caring for this group were hospitalized; % of the total number of cases were managed as outpatients. in adults, % of all cases of pneumonia were associated with cultural and/or serologic evidence of mycoplasma and/or viral infection. total rates for all cases of pneumonia increased during influenza a epidemic years. the highest rates were generally found in the winter quarter, followed by rates occurring during the spring quarter ( figure ). the major viral and mycoplasma agents contributing to the etiology of pneumonia in this study were influenza a virus, and mycoplasma pneumoniae, followed by a smaller number of cases due to adenoviruses, influenza b virus, respiratory syncytial virus (rsv), and parainfluenza viruses. most of the parainfluenza virus infections were caused by types and , but no attempt was made to ascertain the exact contribution of specific agents involved because of antigenic overlap in the complement fixation test. it was recognized that the majority of pneumonias associated with influenza a were related to bacterial suprainfection. rates for all pneumonia were highest in young children, followed by a peak in pneumonia due to m. pneumoniae in the - -year age group. pneumonia due to influenza a virus increased in incidence above the age of years. of interest is their finding that sometimes pneumonia was associated with laboratory evidence of infection with more than one respiratory nonbacterial agent. the severity of disease did not appear different between patients with a single infection and those with multiple infections, as measured by duration of illness and hospitalization rates. in individual reports, however, it has been suggested that in certain individuals, multiple infections can sometimes lead to a more severe course than would have been predicted by infection with a single agent. overall rates for pneumonia as determined in this study were similar to those observed in the national health survey. in houston, texas, during the years - , adult hospitalizations for pneumonia increased sharply during influenza a epidemics but did not change much during influenza b epidemics, a finding that was also seen in the seattle study (figure ) . although hospitalizations for pneumonia did not increase in houston during the - influenza b epidemic, an increased number of patients hospitalized with complications due to influenza b virus infection was seen in dallas, texas, at this time. the etiology of community-acquired pneumonia in adult outpatients in sweden has been determined. using rises in antibody titer between acute and convalescent sera to determine etiology, these investigators found evidence of mycoplasma pneumoniae infection in %; streptococcus pneumoniae in %; hemophilus in{luenzae in % ( % type band % nontypeable); influenza a virus in %; chlamydia psittaci in %; and influenza b virus, parainfluenza virus, respiratory syncytial virus, and adenovirus in % each. multiple infections occurred in several patients and there was no serologic evidence of infection with a particular microorganism in %. the etiologic agents of community-acquired pneumonia in adult patients hospitalized for their disease can be examined (table ) . six recent studies were selected for analysis because they had a worldwide authorship and because an attempt had been made to estimate the contribution made by both bacterial and nonbacterial agents. - bacterial etiologies contributed most significantly to the problem of community-acquired pneumonia in adult hospitalized patients. the most frequent microorganisms were streptococcus pneumoniae followed by staphylococcus aureus, haemophilus in{luenzae, legionella pneumophila, and other gram-negative bacteria. the role of anaerobic bacteria in the etiology of pneumonia was not studied systematically in five of the series. a nottingham, england, study accentuated the role of l. pneumophila in the etiology of pneumonia and showed the propensity of this microorganism to be associated with specific geographic sites. the major nonbacterial agents implicated in these studies included m. pneumoniae, influenza a and b viruses, adenoviruses, rsv, parainfluenza viruses, varicella, and c. psittaci. all of these latter agents could be seen as single pathogens but influenza a and b viruses, adenoviruses, rsv, parainfluenza viruses, and varicella virus also were associated with bacterial pneumonia. nonbacterial agents contributed from to % to the etiologies of all cases. an indication of the approximate incidence of nonbacterial pneumonia without bacterial suprainfection can be ascertained in five of the series and ranged from to % of the cases. the association of influenza a and b viruses, rubeola virus, and varicella virus with bacterial suprainfection has been well established. recently, bacterial suprainfection has been shown to occur in adults who have evidence of infection with adenoviruses and rsv. the frequency of bacterial suprainfection in association with m. pneumoniae infections is difficult to ascertain. it has been considered the concept of primary atypical pneumonia was set forth in an article by hobart a. reimann in . the major bacteria-causing pneumonia were known at that time with the exception of l. pneumophila. the clinical entity of psittacosis had been elucidated. influenza a virus had been grown in ferrets by laidlaw, andrews, and smith. reimann described eight cases of what he called atypical pneumonia, which he thought was due to a filterable virus. the description of cases allows a view of untreated primary atypical pneumonia. it now seems probable that m. pneumoniae was the etiologic agent in most of his cases. the illness often began in-the american journal of the medical sciences sidiously with fever, headache, and pharyngitis. with descent of the disease into the respiratory tract, the larynx became involved and hoarseness was present. finally, laryngotracheobronchitis and pneumonia occurred. a troublesome cough developed in the patient that could not be alleviated and was only slightly productive. in some patients, a pulse-temperature dissociation occurred. during the course of the disease, which often lasted several weeks, patients became dyspneic and cyanotic. two of the patients became delirious and had central nervous system dysfunction during the course of the infection. on physical examination, the patient was flushed and had evidence of pharyngitis. the physical examination of the chest usually revealed scattered rales without striking evidence of consolidation; in one patient a large pleural effusion was present. the white blood count was only modestly elevated. chest radiographs revealed mottled or diffuse areas of infiltration. attempts to isolate pathogenic bacteria and influenza a virus were unsuccessful in establishing an etiology for this syndrome. reimann considered diagnoses such as typhoid, psittacosis, and epidemic influenza, but the history in none of these cases was consistent and influenza virus could not be recovered. to summarize reimann's words, "the infection occurred in adults and began as a mild infection of the respiratory tract; this was followed by severe diffuse atypical pneumonia and in two cases by the symptoms of encephalitis. dyspnea, cyanosis, hoarseness, cough without sputum, drowsiness, and profuse sweating were the chief characteristics. the disease lasted several weeks." in , finland found elevated cold agglutinin titers in cases of atypical pneumonia. eaton later isolated the agent in embryonated eggs, and chanock and colleagues were able to grow it on defined media and demonstrate it to be a mycoplasma. the entity of primary atypical pneumonia became well known and later was defined as pneumonia that did not clear with penicillin or sulfonamides, or nonbacterial pneumonia, or pneumonia with no sputum or a mucoid sputum without a predominant organism on gram's stain. we recognize today that the clinical entity of primary atypical pneumonia has multiple etiologies, particularly m. pneumoniae, but also c. psittaci, the twar strain ofc.psittaci, chlamydia trachomatis, q-fever, and viruses such as adenoviruses, rsv, influenza viruses, and para- influenza viruses. l. pneumophila infections often are considered in the differential diagnosis. ls early bacterial pneumonia also should be considered when the patient is first seen. in retrospect, persons with this diagnosis are often excluded from series of cases to focus specifically on the nonbacterial nature of the problem. in pertinent geographic areas, acute histoplasmosis and coccidioidomycosis may present like primary atypical pneumonia. major attempts to identify the etiologic agent on clinical grounds have been made, but the exact diagnosis usually depends on laboratory determination of the offending agent. in one study of patients of all ages, with viral pneumonia, with mycoplasma pneumonia, and with bacteremic i:meumococcal pneumonia were compared. the best discriminating variables were the c-reactive protein determination, the presence or absence of predisposing disease or previous antibiotic treatment, the erythrocyte sedimentation rate, the presence of lymphocytosis, and the band neutrophile count. signs of an upper respiratory tract infection and the presence or absence of auscultatory abnormalities also aided significantly in the discrimination. determinations favoring bacteremic pneumococcal pneumonia included predisposing disease, a short duration of illness before hospitalization, alcoholism, the absence of signs of an upper respiratory tract infection, high c-reactive protein determinations and erythrocyte sedimentation rates, no prior antibiotic treatment, total leukocyte counts exceeding , , relative lymphocyte counts less than %, relative band neutrophile counts greater than %, abnormal auscultatory findings, and the presence of lobar consolidation on chest radiograph. differentiation between viral and mycoplasma pneumonia could not be made easily. however, symptoms of mycoplasma pneumonia before hospitalization lasted a longer time and these patients were more likely to have received antibiotic treatment in the interval before hospitalization. patients with mycoplasma pneumonia were more likely to have lobar consolidation on chest radiograph than those with viral pneumonia, but in this study no distinction could be made between mycoplasma pneumonia and bacteremic pneumococcal pneumonia on the basis of roentgenographic findings alone. in another study comparing community-acquired pneumonias, mycoplasma pneumonia tended to occur at an earlier age than legionnaire's disease, pneumococcal pneumonia, or psittacosis.l homogeneous shadowing on chest radiograph was more common in legionnaire's disease and pneumococcal pneumonia than mycoplasma pneumonia. pleural effusions were uncommon in all groups but occurred most commonly in bacteremic pneumococcal pneumonia as did multilobe disease on presentation. hilar lymphadenopathy occurred only in mycoplasma pneumonia. roentgenographic resolution was fastest in mycoplasma pneumonia, intermediate in psittacosis and nonbacteremic pneumococcal pneumonia, and slowest in legionnaire's disease and bacteremic pneumococcal pneumonia. deterioration on chest radiograph after hospital admission characterized legionnaire's disease and bacteremic pneumococcal pneumonia. because the differential diagnosis of primary atypical pneumonia at a clinical level includes pneumonia due to m. pneumoniae, chlamydial species, q fever, adenoviruses, rsv, influenza viruses, parainfluenza viruses, as well as l. pneumophila infections and early bacterial pneumonia, therapy should include an antibiotic to which the majority of these the american journal of the medical sciences luby microorganisms are susceptible. chlamydial species are more susceptible to tetracycline than erythromycin. tetracycline is effective against rickettsiae but not for l. pneumophila infections. up to % of pneumococcal isolates are resistant to tetracycline. a reasonable antibiotic choice is erythromycin at an equivalent dose of mglkg of erythromycin base per day for - days. if legionnaire's disease is diagnosed, a higher dose of erythromycin may be necessary. if a chlamydial or rickettsial etiology is recognized, tetracycline at a dose of gmiday should be given. occasionally patients with proven m. pneumoniae have been treated with erythromycin, failed to respond to therapy, but subsequently responded to a course of tetracycline therapy.ls conversely, some patients with m. pneumoniae infections have responded to erythromycin after a suboptimal response to tetracycline therapy. viruses may cause primary atypical pneumonia; however, antibiotic treatment in these instances is useless, does not prevent suprainfection, and may actually change the nature of the bacterial species suprainfecting the patient. antibiotic therapy seems reasonable in this syndrome, however, because it is usually impossible to differentiate clinically between mycoplasma pneumonia and an entity such as adenovirus pneumonia in the adult. advances in rapid laboratory diagnosis may be able in the future to influence treatment options but these techniques are still under development, are expensive, and are not widely available. mycoplasmas, the smallest free-living microorganisms, are cell-wall deficient, but have no relationship to cell-wall deficient bacteria with which they were once confused. m. pneumoniae attaches to the mucosal epithelium of the respiratory tract through a specific protein that enables the microorganism to adhere to neuraminic acid residues on respiratory epithelial cells. if mycoplasmas cannot attach, there is no damage to the host. upon adherence, mycoplasmas are able to generate hydrogen peroxide and superoxide anion, resulting in injury to epithelial cells. because infection occurs commonly in children younger than years of age, although disease is rare at this time of life, mycoplasmas may induce disease primarily by immunopathologic mechanisms. l . lb in experimental animals not primed by prior mycoplasma exposure, inflammatory changes occur only after a long interval. with reinfection, inflammatory changes occur more briskly. the extrapulmonic manifestations of my coplasma infection have never been explained completely, but there are reports demonstrating m. pneumoniae in sites such as cerebrospinal fluid and blood. l alternatively, immunopathologic reactions may be the primary mechanism involved. path-ologically, the disease in man is characterized by tracheobronchial, bronchiolar and septal lymphoplasmocytic infiltrates, luminal exudates rich in polymorphonuclear leukocytes, bronchiolar and alveolar cell metaplasia, and occasionally diffuse alveolar injury. o the bronchiole appears to be the major site of attack. the microorganisms colonize the nasopharynx and transmission of infection occurs only by close contact. especially conducive to the transmission of m. pneumoniae are situations in which persons are housed in closed quarters, such as military platoon barracks or family unit dwellings. in families, there is a high attack rate and cases continue to occur over a - -month interva . . the cumulative attack rate of mycoplasma infections in families may approach % (figure ). mycoplasma carriage is not affected by antibiotic therapy, thereby allowing the family epidemic to continue. mycoplasma disease occurs throughout the year but is particularly frequent during fall and winter. increased numbers of cases occur with a - -year periodicity. although pneumonia may occur soon after infection, the disease is usually manifested as an upper respiratory tract infection progressively descending into the lung. pharyngitis progresses into laryngitis followed by tracheobronchitis, and, finally, pneumonia. hoarseness and dysphonia may be present. middle ear involvement may occur with bullous myringitis, which usually heals without scarring. occasionally, otitis may lead to tympanic membrane perforation. sinus involvement is frequent but usually asymptomatic. the cough is often intractable and usually only slightly productive of a mucoid sputum that contains mainly polymorphonuclear leukocytes but no predominant bacterial microorganism on gram's stain. when pneumonia develops, the patient has an elevated temperature and, occasionally, a 'temperature-pulse dissociation. headache, irritation, a flushed facies, myalgias, and arthralgias are common. - on physical examination, the patient is febrile, appears flushed, and usually has physical evidence of pharyngitis. hemorrhagic bullous myringitis may be present in up to % of cases. physical findings on chest examination usually are limited to scattered rales, wheezes, and rhonchi and are often localized to the lung bases. evidence of consolidation is not striking, although m. pneumoniae infections can cause lobar pneumonia. the white count is usually elevated with a shift to the left, but rarely exceeds , white blood cells/mm and the neutrophile band count is usually less than %. chest radiograph reveals peribronchial infiltrates with accentuation of interstitial markings in adjacent lung segments, patchy alveolar infiltrates usually localized to the lower lobes, especially on the left, and occasionally hilar lymphadenopathy. more than one lobe may be involved and a confluent lobar infiltrate may be present in some patients ( figure ). less commonly, there is a diffuse interstitial infiltrate and rarely an x-ray picture indistinguishable from the adult respiratory distress syndrome. . without therapy, the disease course usually lasts approximately weeks, but may extend up to weeks. extrapulmonic manifestations of mycoplasma infection often are a clue to the diagnosis and include bullous myringitis; neurologic disturbances suggesting encephalitis or aseptic meningitis and, rarely, transverse myelitis; arthritis; myopericarditis; hepatic dysfunction; splenomegaly; and skin eruptions.~u a stevens-johnson syndrome may occur. japanese workers have described typical cases of pityriasis rosea that followed mycoplasma infection. the cerebrospinal fluid (csf) may be abnormal with an increased number of cells and an elevated protein concentration. hemolytic anemia may be present resulting from antibody directed against the i antigen on the red-cell membrane. almost all patients recover completely after mycoplasma infection but cigarette smokers may have prolonged abnormalities in diffusion capacity. individual case reports have described pulmonary fibrosis, bronchiolitis obliterans, and bronchiectasis following m. pneumonia. ~ glomerulonephritis with continuing renal dysfunction also has been reported. • the diagnosis is established by culture of the microorganism or the demonstration of a fourfold rise in antibody by complement fixation or other serologic test. a single high complement fixation test antibody titer (~ : ) may be used as presumptive evidence of infection. cold agglutinin antibody titers at low level are norispecific but very high values (~ : ) also can be used to support the diagnosis. treatment consists of the administration of either erythromycin or tetracycline as outlined in the therapy of primary atypical pneumonia. the patient usually responds, but it should be remembered that there are reports of inadequate resolution of the disease and the necessity to switch to the alternate drug to achieve more rapid clinical improvement. antibiotic therapy does not eliminate the carrier state. immunity is relatively short-lasting and documented episodes of repeated mycoplasma infection have been reported. a vaccine against m. pneumoniae, given present priorities, appears only a hopeful future development. mycoplasma pneumonia. an -year-old man was well until days before admission into the hospital, at which time he developed fever, a sore throat, and a nonproductive cough. his oral temperature reached ° c. a "pounding" headache developed. the cough persisted and became productive of a mucoid sputum. oral penicillin was prescribed but did not alleviate his symptoms. physical examination on admission into the hospital revealed a young man who was confused about time and uncertain about recent events. the oral temperature was . ° c and the pulse rate was . the pharynx was described as normal. chest examination revealed harsh breath sounds with bilateral inspiratory rales, especially on the right, anteriorly and inferiorly. there was no egophony or decreased fremitus. rhonchi were present more on the right than left. hepatosplenomegaly was present. laboratory examination revealed , white blood cells with % polymorphonuclear cells, % lymphocytes, one monocyte, and one eosinophile. the serum aspartate aminotransferase was (normal < ). arterial blood gases on room air showed a ph of . , pc of , and p of . a lumbar puncture was performed that showed white blood cells, % of which were mononuclear cells. the csf glucose was mg/dl and the simultaneous plasma glucose mg/dl. the patient was treated initially with intravenous penicillin for presumed pneumococcal pneumonia and partially treated bacterial meningitis. his condition deteriorated but finally he was placed on erythromycin therapy at the advice of a consultant. mycoplasma complement fixation test titers rose from less than : to : . comment. encephalitis, hepatosplenomegaly, and mild hepatic dysfunction were the extrapulmonic manifestations of mycoplasma disease. typical of mycoplasma pneumonia were the long duration of illness before admission into the hospital, prior antibiotic administration, presence of a sore throat, physical examination of the chest, and characteristics of the sputum. psittacosis was first described by ritter in switzerland in as a disease of the lungs in patients in contact with sick psittacine birds. later, in - , a pandemic of psittacosis occurred involving psittacine birds exported from south america. the clinical manifestations were described fully and the epidemiology was established, leading to control measures that have kept psittacosis or the better, more inclusive term, ornithosis, at a low level of occurrence. occasionally migrant birds can carry c. psittaci, and persons dealing with them may develop ornithosis. more importantly now, ornithosis is an occupational hazard to the farmer who manages poultry such as ducks and turkeys. ,lb, , clinically, patients with ornithosis have headache, fever, pulse-temperature dissociation, pneumonia, hepatic function abnormalities, and hepatosplenomegaly. intra-alveolar inflammatory changes predominate in ornithosis with interstitial changes being secondary and less prominent. the chest radiograph reflects this and lobar consolidation may be seen. when lung involvement is minor, the disease can be diagnostically confusing, and present as a fever of undetermined origin. granuloma formation can be found in both the liver and the bone marrow and may be a diagnostic clue. ornithosis can be diagnosed by serologic tests with a chlamydial common group antigen by either complement fixation or the enzyme-linked immunoabsorbent assay (eia). treatment is with tetracycline for - days. chlamydia trachomatis can cause an afebrile pneumonia-like syndrome in young infants beginning at the age of - months, and is characterized by an afebrile state, failure to gain weight, and a staccato-like cough. on examination, there are rales, expiratory wheezing, and evidence of hyperaeration of the lungs. chest radiograph usually reveals diffuse interstitial pneumonia and hyperaerated lung fields. laboratory determinations show a modest eosinophilia and hyperglobulinemia. upon this identification, the infants can be treated with oral erythromycin syrup for weeks with benefit. recently, c. trachomatis has been isolated from the lower respiratory tract of immunosuppressed patients with pneumonia, although four of the six patients reported and the only ones tested did not show a serologic response to that microorganism. cases of community-acquired pneumonia in normal adults also have been reported with serologic evidence of infection with c. trachomatis. fifty-two patients were studied and seven were found to have definite or suggestive serologic evidence of infection. the seven ranged in age from to . the chest radiographs of these patients have been analyzed and the infiltrates were found to be patchy and characteristically streaky with areas of plate atelectasis. there was no particular localization to a single lobe and three patients had radiographic evidence ofmultilobar involvement. further studies need to be done to corroborate these reports and determine the frequency with which lung involvement occurs. in finland, an epidemic of mild pneumonia has been related to a newly described strain of c. psittaci, capable of being passaged from human to human. this epidemic occurred in adolescents and young adults and had a point prevalence of pneumonia of - cases/ , students at the time of x-ray survey. the contribution of this particular strain of c. psittaci, designated the twar strain from tw- and ar- , the first two isolates, has been examined best during a . -year study at the university of washington. infected students usually presented with a mild pneumonia that simulated mycoplasma infection and was often associated with pharyngitis and laryngitis. in this study, the twar strain of c. psittaci caused % of the pneumonias in the student population. the twar strain of c. psittaci was isolated from the students, and serial sera showed conversion to the common chlamydial group antigen by complement fixation tests. microimmunofluorescence tests revealed specific reactions to the twar strain of c. psittaci. the microorganisms isolated from the students formed typical inclusion bodies in tissue culture, were not stained by iodine, and were considered typical of c. psittaci. the clustering of cases had an epidemiology that suggested human-to-human transmission. bird-to-human transmission could not be demonstrated in any of the cases. treatment with tetracycline shortened the course, but, occasionally, patients did not respond to gm of erythromycin given for - days. this new strain of c. psittaci was isolated from the patients and serologic reactions to specific antigens were demonstrated. the evidence linking c. trachomatis to lung disease has either been by isolation alone or just by serologic testing. further studies similar to the one in seattle need to be performed to link c. trachomatis to lung disease. it is clear, however, that a new strain of c. psittaci exists and can cause disease commonly. the disease due to this microorganism can be diagnosed by complement fixation or eia tests using chlamydial group antigen. specialized laboratories can isolate the organism and also perform microimmunofluorescence tests. a major new development in the evaluation of patients with primary typical pneumonia is the emergence of this c. psittaci strain that is capable of being passaged from human to human, and that may not have the desired response to erythromycin treatment. adenoviruses are ubiquitous nonenveloped dna viruses that colonize the human nasopharynx and are transmitted to other persons by close contact. types and are recognized for their capacity to produce epidemics in military recruit populations. because the transmission of this group of viruses is dependent upon close human contact, disease is often produced in the home or the military recruit barracks. pathogenetically, lung infection usually follows pharyngitis and a movement of the disease process down the respiratory tract. although most cases of pneumonia are not severe, cases coming to autopsy show that the tracheobronchial mucosa is denuded of the normal epithelial structures down to the basal layer. squamous metaplasia occurs along with interstitial space thickening due to the presence of chronic inflammatory cells. alveolar edema and mononuclear cell infiltrates are present. as with m. pneumoniae infections, infiltrates are often peribronchial or peribronchiolar in distribution. nuclear inclusion bodies or nuclei with a smudged appearance may be found in epithelial cells. clinically, the disease often begins with pharyngitis associated with fever and anterior cervical lymphadenopathy with or without conjunctivitis, then involves the tracheobronchial tree, and, finally, the parenchyma of the lung. pneumonia is most common in infants, young children, and military recruits. in military recruit populations, mycoplasma and adenovirus pneumonia have been found to be indistinguishable clinically except for an increased luby frequency of exudative pharyngitis with adenovirus infection. physical examination reveals pharyngitis and rhinitis and scattered rales and rhonchi. evidence of consolidation is infrequent but occasionally lobar consolidation can occur, as can a pleural effusion ( figure ). virus rarely has been isolated from pleural fluid. fatal cases of adenovirus pneumonia can occur in infants, immunosuppressed patients, and rarely in normal persons. - in these cases, the pneumonia is progressive with the development of diffuse bilateral alveolar infiltrates and hypoxemia requiring ventilator assistance for its correction. as the infiltrates progress, leukopenia ensues with marked lymphocytopenia. rhabdomyolysis occurs along with evidence of disseminated intravascular coagulation and renal failure. terminally, the patient becomes obtunded. bacterial suprainfection can be associated with adenovirus pneumonia. suprainfecting species of. bacteria include s. pneumoniae, group a strepto-· cocci, h. influenzae, s. aureus, and group y neisseria meningitidis. in military recruits, an increased frequency of group y meningococcal suprainfection has been observed because these microorganisms commonly colonize the nasopharynx in this population. administration of antibiotics during the course of the adenovirus pneumonia does not prevent bacterial suprainfection. although most persons recover uneventfully from adenovirus pneumonia, occasional patients have residual abnormalities such as restrictive lung disease, bronchiectasis, or bronchiolitis obliterans. , extrapulmonic mani- festations of adenovirus infection include pharyngitis, conjunctivitis, pericarditis, arthritis, skin rashes, and hepatic dysfunction. reye's syndrome has been described during the course of adenovirus pneumonia. the occurrence of one or more of these manifestations during the course of pneumonia can lead the physician to order appropriate diagnostic tests to make a specific etiologic diagnosis. virus can be isolated from the nasopharynx, sputum, or endotracheal secretions. antigen can be detected by immunofluorescence tests, eia, or dna hybridization within epithelial cells derived from the respiratory tract. these latter tests are specific but at the present time less sensitive than viral culture. there is no specific therapy for the infection. oral live attenuated vaccines are available against types and adenoviruses, and these are used now in the military to prevent epidemic disease. fatal adenovirus pneumonia. a -year-old man with an unremarkable past history except for hypertension was controlled on medication. two weeks before admission he developed a nonproductive, hacking cough and began to have dyspnea, which increased to the time of admission. on physical examination he appeared in moderate respiratory distress. oral temperature was . ° c, pulse rate was /min, blood pressure was , and respiratory rate was /min. the oropharynx was described as normal. scattered rhonchi and rales were heard diffusely through the lungs. a summation gallop was heard at the cardiac apex. laboratory examination revealed a white blood count of , with % polymorphonuclear cells, % band forms, % lymphocytes, and % monocytes. arterial blood gases on room air showed a ph of . , pco. of , and po. of . ekg showed left ventricular hypertrophy. chest radiograph revealed an enlarged cardiac silhouette with patchy alveolar infiltrates ofthe entire right lung and left lower lobe. the patient was started on erythromycin mg every hours intravenously. he continued to spike temperatures to · c. cefamandole and tobramycin were added to his antibiotic therapy. two days after admission, the creatine phosphokinase value rose to , and the next day was , . his creatinine rose to . mg/dl. his heart was enlarged on radiograph and the pulmonary infiltrates continued to increase. his mental status gradually deteriorated and he was transferred to the intensive care unit. the white blood count was , with % lymphocytes. he developed evidence of disseminated intravascular coagulation and died on the eighth hospital day of respiratory insufficiency. postmortem examination revealed changes of viral pneumonia, with some epithelial cells showing intranuclear inclusions and the appearance of "smudged" nuclei, an enlarged heart due to idiopathic myocardial disease, only minimal pathologic evidence of hypertension, and findings of disseminated intravascular coagulation. electron microscopy oflung sections revealed adenovirus. the adenovirus complement fixation test titer rose from less than : to : . comment. the patient had a -week febrile period before admission, and pulmonary infiltrates progressed on antibiotic therapy. he developed leukopenia, lymphocytopenia, rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. his illness occurred in the setting of idiopathic myocardial disease, and it is possible that mild, chronic, left ventricular failure might have predisposed him to severe adenoviral pneumonia similar to the manner in which cardiac failure augments influenza pneumonia. pneumonia due to respiratory syncytial virus. respiratory syncytial virus is the predominant respiratory tract viral pathogen of infancy and young childhood. infection in adults usually results in no symptoms or a mild upper respiratory tract illness such as the common cold. it is now recognized that immunosuppressed patients and elderly persons can develop pneumonia because of rsv and that it can be severe and complicated by bacterial suprainfection. - furthermore, since immunosuppressed and elderly persons may aggregate in hospitals and nursing homes, these institutions are often sites of acquisition of infection. an epidemic of pneumonia and febrile respiratory illness took place in los angeles in february-march, . forty of residents were affected, having pneumonia. eight persons died for a case-fatality rate of %. other such outbreaks have been recorded. nosocomial acquisition ofrsv is very difficult to prevent. hospital personnel become colonized and may have no or mild respiratory tract symptoms. transfer of virus can occur by patient to personnel to patient transmission or directly from the personnel themselves. hands and fomites become contaminated by respiratory secretions and virus is spread to patients by direct contact with these sources. the pathology of pneumonia due to rsv is similar to that of other viral pneumonias; however, epithelial cells with intracytoplasmic inclusion bodies can be seen. the x-ray appearance of the pneumonia can be that of a diffuse interstitial process or have interstitial and patchy alveolar infiltrates in the lower lobes, or have an appearance indistinguishable from the adult respiratory distress syndrome. pneumonia due to rsv in immunosuppressed and elderly persons is a newly described phenomenon, but one that may be of increasing importance. it is also important because rsv infections can be diagnosed early by antigen detection techniques (immunofluorescence or eia) and because effective therapy has been developed recently. antigen detection tests for rsv now equal or exceed the efficacy of viral cultures for diagnosis of infection. respiratory syncytial virus infections in infancy now have been treated successfully with aerosolized ribavirin. • this therapy is indicated for infants and children with lower respiratory tract involvement with rsv who are exceptionally ill or who may have congenital heart disease or bronchopulmonary dysplasia. with aerosol delivery by oxygen tent, hood, or mask, concentrations of ribavirin are quite high in the upper and lower respiratory tract and exceed the minimum inhibitory concentration necessary to inhibit the growth of the virus in tissue culture. to achieve this concentration by oral administration of the drug, unacceptable toxicity would be en-countered. this toxicity would include bone marrow depression and particularly anemia related both to maturation arrest and, to a lesser extent, hemolysis. this latter event occurs because ribavirin triphosphate can accumulate in erythrocytes, having a halflife greater than days, and interferes with the formation of guanosine triphosphate. aerosolized ribavirin therapy is expensive, but is presently approved by the food and drug administration for the therapy of complicated rsv infections in infants and young children. it represents the first example of an effective drug for treating a significant lower respiratory tract viral infection. it is conceivable that this technology could be applied to influenza infections. influenza and rubeola will be covered in detail but it is now recognized that other rna viruses can cause lower respiratory tract involvement in adults. these viruses include the parainfluenza viruses, respiratory enteroviruses such as coxsackie b viruses and coxsackie virus a , rhinoviruses, and coronaviruses. the magnitude of the problem, however, appears to be limited. documented instances of severe lower respiratory tract infection due to parainfluenza ii and iii viruses have occurred, however. there is presently no accepted therapy for these latter infections, although aerosolized ribavirin has been used successfully to control persisting parainfluenza virus infections of the lower respiratory tract in immunodeficient children. influenza a virus is the cause of pandemics and epidemics that occur every or every other year. all influenza a viruses possess a common group complement fixation test antigen, the nucleoprotein antigen. influenza a viruses differ in the antigenic character of the hemagglutinin and neuraminidase. the h n strain of influenza a circulated in the world from - through , when asian influenza strains (h n ) became predominant. these strains circulated until - , when hong kong influenza (h n ) appeared; strains of this virus continue to be transmitted. h n strains again began to circulate during and they continue to do so. influenza b strains have the same common complement fixation test antigen, and this differs from that of influenza a virus. the hemagglutinin and neuraminidase of influenza b virus are less prone to change; pandemic disease due to this virus does not occur and the interepidemic interval is longer than that of influenza a, namely, every - years. serious morbidity due to influenza a virus occurs because of host factors such as age, underlying disease, and immunosuppression; because immunity wanes with time; and because influenza a viruses are constantly changing their antigenic character. in pandemic years, when both the hemagglutinin and neuraminidase change concomitantly, the american journal of the medical sciences luby there is a tendency for more serious disease to occur than if just one of the surface proteins changes. this is well illustrated by the - and pandemics. influenza a viruses may, on certain occasions, be more virulent. in the - epidemic the pneumonia rate in persons from the ages of to years was approximately % of those who had influenza. this and other facts have been cited to indicate the virulence and striking pneumotropism of the virus that led to million deaths occurring throughout the world during the pandemic. influenza b viruses are more likely to cause disease in younger persons and only occasionally do epidemics occur in which there is excess mortality. pathogenetically, influenza virus attaches to cells of the respiratory epithelium and enters by a process termed "receptor-mediated endocytosis." the virion is uncoated in the endosome by fusion with the membrane of this structure, a process requiring an acidic ph. the particle then undergoes a cytoplasmic and a nuclear stage of replication. virion rna is capped and polymethylated in the nucleus so that the rna message now can be recognized by the cell and translated at the ribosome. in the process of replication, the virus rapidly destroys respiratory tract epithelial structures in order to compromise natural defense mechanisms of the lung, such as mucous production and ciliary activity. in cases of severe pneumonia the epithelium of the trachea and bronchi are destroyed down to the basal layer and then metaplasia occurs, leaving the respiratory tract coated with a layer of squamous cells. there is involvement of bronchiolar structures and an intense peribronchiolar inflammatory process. in uncomplicated influenza, small airways are commonly affected, producing diffuse dysfunction in these structures, mild hypoxemia, and a compensated respiratory alkalosis. . in severe influenza pneumonia, there is alveolar cell destruction and disruption of the alveolar-capillary membrane resulting in hemorrhage into the alveoli along with edema, a mononuclear cell infiltrate, and the presence ofhyaline membranes. thickening of the interstitium occurs with a chronic inflammatory cell infiltrate. the process can be fulminant, occurring coincident with the onset of illness, or it can be more protracted, leading to the occurrence of progressive infiltrates over - days. when an adult respiratory distress syndrome-like picture is produced, influenza pneumonia has a high case-fatality rate, which may approximate %. . not all influenza a pneumonia is this severe, however, and there are cases in which only an interstitial or bronchopneumonic process is apparent and the disease simulates m. pneumonia, except that in influenza the leukocyte count tends to be normal or decreased. . influenza pneumonia can coexist with bacterial suprainfection or bacterial suprainfection can occur alone. the offending bacterial pathogens may vary between pandemics; in - , h. in{luenzae evidently was a major pathogen. in the - pandemic, the group a streptococcus was considered a major pathogen; more recently, s. pneumoniae has been the most common offending agent followed by s. aureus andh. in{luenzae. occasionally, other gram-negative bacteria may be involved. influenza b virus can cause a similar spectrum of pulmonary disease, but the number of patients involved is fewer. the hospitalization rate for lower respiratory tract disease nearly always increases during influenza a epidemics. this rate tends not to increase during influenza b epidemics, although total hospitalizations may be increased during this period; like influenza a virus, influenza b virus can cause a variety of disease processes outside the lung. these include myopericarditis, rhabdomyolysis, disseminated intravascular coagulation, nervous system disturbances such as encephalitis, reye's syndrome, the landry-guillan-barre : syndrome, the stevens-johnson syndrome, and others. • . clinically, the patient with influenza virus pneumonia has the sudden onset off ever, prostration, and myalgias followed shortly by dyspnea. blood-tinged sputum may be produced. the dyspnea progresses until hospitalization and ventilatory support are required. the illness can also assume a more protracted course leading to progressive interstitial and alveolar infiltrates over a week ( figure ). some pa-tients simply have viral pneumonia with pulmonary dysfunction but do not need ventilator assistance. complicating bacterial suprainfection may coexist with viral pneumonia or more commonly presents after an afebrile interval, during which the patient appears to be recovering from the primary infection. morbidity and mortality are greatest in elderly persons, in those with chronic disease states such as chronic obstructive pulmonary disease, chronic congestive heart failure or diabetes mellitus, and in immunosuppressed patients. morbidity due to influenza a and b viruses is not limited to these groups, however. women in the third trimester of pregnancy also may have an increased rate of developing influenza pneumonia and death due to this disease process. in renal transplant recipients who contract influenza a, illnesses are often prolonged, with the development of viral pneumonia, bacterial suprainfection, and myopericarditis. there may be loss of the renal allograft due · to the combination of these disease processes. influenza a and b virus infections are diagnosed by serial titer rises in a suitable serologic test such as the complement fixation or the hemagglutination inhibition test. a single complement fixation test titer ::: : has been shown to correlate highly with recent influenza b infections. virus can be grown from the nasopharynx or endotracheal secretions by inoculation of the specimen into rhesus monkey kidney or madin-darby canine kidney tissue culture. embryonated eggs sometimes need to be used for figure . influenza pneumonia. the radiograph on the lett shows combined influenza pneumonia with lett lower lobe consolidation indicating bacterial supra infection. the radiograph on the right shows diffuse alveolar infiltrates in the course of serologically documented influenza a infection. bacterial cultures from endotracheal secretions consistently showed no growth. optimal recovery of virus. virus may be able to be identified within hours by using immunofluorescence. direct detection of antigen by immunofluorescence or eia can be applied to appropriate secretions, but these tests are not yet as sensitive as viral culture. amantadine and rimantadine are two compounds that have both prophylactic and therapeutic efficacy against influenza a but not influenza b virus. they act by preventing uncoating of influenza a virus, perhaps by preventing the development of an acidic ph so that the envelope of the virion cannot fuse with the endosomal membrane. at the dosage given, mg twice a day, amantadine has more central nervous system side effects and the dose has to be adjusted with renal failure. the dose of rimantadine does not have to be adjusted with renal dysfunction because the compound is metabolized in the body. a study sponsored by the national institutes of health is underway evaluating whether rimantadine can be used effectively in the therapy of hospitalized patients with influenza a, and would include patients with influenza a virus pneumonia. ribavirin has in vitro efficacy against both influenza a and b viruses. it has multiple sites of action including interference with the formation of guanosine triphosphate and deoxyguanosine triphosphate and prevents placement of the polymethylated cap structure on the influenza a viral rna message. with the aerosolization of ribavirin, high concentrations of the drug can be produced within the respiratory tract but serum levels are low. , o attempts most likely will be made in the future to treat influenza a virus pneumonia with aerosolized ribavirin or a combination ofribavirin and rimantadine. influenza b virus pneumonia may be able to be treated with aerosolized ribavirin. vaccines exist for both influenza a and b viruses, and standard medical care necessitates yearly immunization of elderly patients or those with underlying medical conditions. a recent emphasis of the public health service is to have medical personnel also immunized yearly, since they are. exposed to persons with influenza, may develop that illness themselves, and may then transmit the infection to sick patients within the hospital. nosocomial influenza pneumonia. a -year-old alcoholic man was admitted to the hospital on january with alcoholic liver disease, macrocytic anemia, and symptoms of bladder neck obstruction. he was a heavy smoker and had evidence of chronic obstructive pulmonary disease. 'lwelve days after admission into the hospital, he developed fever to . ° c while awaiting a urologic procedure. he "felt terrible" with myalgias and developed a cough, mild diarrhea, and dyspnea. chest examination revealed diffuse rales and rhonchi. chest radiograph showed new interstitial infiltrates, more prominent on the right. the sputum was mucoid. the diagnosis of pneumonia was made and the diag-the american journal of the medical sciences luby nosis of congestive heart failure with pulmonary edema considered. however, his heart examination revealed no gallop sounds and his neck veins were not distended. he was placed on ampicillin, became afebrile after days, and his dyspnea improved with low flow oxygen by face mask. influenza a complement fixation test titer on a single convalescent serum specimen was :: : . comment. influenza virus pneumonia occurred during hospitalization. the pneumonia cleared with symptomatic therapy. the public health service now recommends widespread immunization of medical personnel in an attempt to prevent nosocomial acquisition of influenza. although predictions were made that rubeola would be eradicated in this country during the early s, this has not been achieved. in dallas, texas, during more than cases of rubeola occurred. this marked a resurgence of cases after a relatively disease-free interval after , when a large epidemic occurred in dallas, causing more than , cases, including three deaths. as a consequence ofthis and other epidemics, in texas adopted a law requiring the compulsory immunization of children against measles, mumps, rubella, poliomyelitis, diphtheria, and tetanus. present rubeola vaccines are at least % effective, but universal immunization of the preschool child is not practiced, particularly in lower socioeconomic class population groups. furthermore, rubeola virus has been found to violate the concept of herd immunity, a major principle on which eradication was based, because outbreaks occur in high schools and colleges in which a large percentage of the population has been immunized. an inactivated vaccine was available from through . children who received the inactivated vaccine may have developed atypical measles on exposure to rubeola virus. following this, an attenuated, live strain of measles virus was used as vaccine but the high sidereaction frequency necessitated the concomitant administration of 'v-globulin. it is now recognized that the concurrent use of 'v-globulin sometimes rendered immunization ineffective. many children were immunized before the age of months; for effective immunization to occur, vaccine must be given after the age of months. as a consequence of the lack of universal preschool immunization and difficulties related to the vaccine, there now exist two population groups who may be nonimmune with respect to rubeola, ie, preschool children, and adolescents and young adults. a few years ago rubeola epidemics were common in military recruits. following the occurrence of these outbreaks, recruits now routinely undergo serologic testing, and if antibody to rubeola virus is not detected by either hemagglutination inhibition or indirect immunofluorescence tests, live attenuated vaccine is given. this practice essentially has stopped the occurrence of these outbreaks in the military. persons who received the inactivated vaccine can develop atypical measles. the first cases of this new syndrome were misdiagnosed as rocky mountain spotted fever. they were confused with this disease because the rash began on the extremities and spread inward to involve the trunk. the rash could be maculopapular, vesicular, or petechial. in atypical measles, pulmonary involvement consists of nodular infiltrates, lobar consolidation, and the occurrence of pleural effusions. hilar lymphadenopathy may also present in these patients. s • s they have an anamnestic response in antibody production with the infection. mild eosinophilia may also be present and the virus cannot be recovered from the nasopharynx. in young adults with typical measles, approximately % develop clinical evidence of pneumonia. radiographic evidence of pneumonia, however, may be seen in up to % of the patients. the pneumonia is usually characterized by diffuse bilateral interstitial or fine reticulonodular infiltrates, particularly affecting the lower lobes. bacterial suprainfection occurs in as many as % of cases of recognized viral pneumonia. the types of bacteria causing infection may be determined by the circumstances in which disease occurs, such as military recruit populations. recognized pathogens include h. influenzae, s. pneumoniae, group a streptococci, group y meningococci, and s. aureus. bacterial suprainfection generally occurs between the fifth and tenth days after the rash and is heralded by clinical worsening, new or different lung infiltrates, or changes in sputum characteristics or the white blood count. antibiotic treatment of viral pneumonia does not prevent bacterial suprainfection. in immunodeficient children, measles pneumonia occurred without a rash and pathologically was called giant-cell pneumonia. it is now recognized that these children lacked cell-mediated immunity and had depressed and delayed antibody production. s intact cell-mediated immunity is essential for rash production. in fatal rubeola pneumonia, the entire tracheobronchial tree may be denuded of cells down to the basal layer; squamous metaplasia of the cells occurs; there is widening of the interstitial space with edema and inflammatory cells; and alveoli are filled with edema, hyaline membranes, and mononuclear cells. in addition, giant cells containing multiple nuclei are found within the tracheobronchial epithelium. extrapulmonic manifestations of measles occur and include otitis media, sinusitis, encephalitis, and the common presence of hepatic dysfunction in young adults, mostly consisting of mild elevations of the serum aspartate aminotransferase and lactic dehydrogenase. there presently is no specific therapy. some public health authorities now think that reimmunization with measles, mumps, and rubella vaccines should be given before or when the child enters high school. medical personnel not sure of their rubeola immunity should have that status assessed by determination of specific antibody. varicella-zoster virus can produce pneumonia during the course of varicella or disseminated herpes zoster and can be a severe disease that can lead to mortality. varicella in childhood is not usually associated with viral pneumonia, but bacterial suprainfection can occur, necessitating appropriate antibiotic treatment. in immunosuppressed children, however, pure viral pneumonia can occur in association with varicella. in adults, there is a tendency for the virus to affect the lung relatively commonly during varicella. fifteen to twenty percent of all adults with varicella may have x-ray evidence of pneumonia but only about % require hospitalization. most frequently in adults, varicella pneumonia is not complicated by bacterial suprainfection; however, this can occur, particularly when patients require intubation. the virus reaches the lung both by passage down the respiratory tract and by hematogenous seeding because the rash is occurring at the same time as the pneumonia. initially, the pneumonic process appears as nodular infiltrates, - mm in diameter associated with an interstitial inflammatory infiltrate. a the lesions are more dense toward the hilum and are the counterpart in the lung of the pox occurring on the skin (figure ) . peribronchial inflammatory infiltrates, hilar adenopathy, and pleural effusions may occur. the reticulonodular interstitial infiltrate can progress to widespread alveolar damage and diffuse pulmonary parenchymal infiltrates. pathologically, the pneumonia resembles influenza pneumonia except that areas of coagulative necrosis can be seen. although these necrotic areas generally clear during the course of clinical disease, they can become calcified, and the radiograph shows a picture of miliary calcifications. it has been shown that this area of coagulative necrosis can become surrounded by an inflammatory infiltrate and resemble a granuloma. a fibrous tissue envelopes the necrotic granulomatous process and the lesion eventually calcifies. another process occurring in varicella pneumonia is destruction of the epithelium of the trachea and bronchi. in cases in which the illness is protracted, the development of a thick, fibrinopurulent crust may occur over the lower pharynx, larynx, and upper trachea. this thick crust can cause respiratory embarrassment and can pose a problem for intubation. disseminated herpes zoster can cause the same processes in the lung. most normal adults recover from varicella pneumonia without difficulty, but there can be substantial respiratory morbidity and mor- figure . varicella pneumonia. the chest radiograph on the lett is from the case report described in the protocol. the close-up film on the right in another pallent shows peribronchial infiltrates and multiple - -mm rounded opacities in the right lung field. tality in immunosuppressed patients or in women during the third trimester ofpregnancy. clinically, the patient with varicella-zoster virus pneumonia presents with a rash followed by cough and dyspnea. the sputum is initially white and modest in amount, but can become hemorrhagic. the process can be complicated by the development of chest pain and pleural effusions, which are often blood tinged and related to the presence of pox on the pleural surface. extrapulmonic manifestations of varicella occur and consist of the characteristic skin rash, otitis media with bacterial suprainfection, myopericarditis, hepatic dysfunction, and encephalitis. reye's syndrome can complicate the course ofvaricella. there can be an associated glomerulonephritis and varicella virus can occasionally induce frank arthritis. in caring for patients with varicella-zoster virus pneumonia, it is important to realize that the external appearance of the patient or his apparent well-being may disguise underlying hypoxemia. if efforts are not made to diagnose and correct the hypoxemia, the patient may become confused, perform inappropriate activity, and become more hypoxemic. ventilator support may become necessary. deaths in varicella pneumonia occur because of respiratory insufficiency, the development of tension pneumothoraces, bacterial suprainfection, or progressive pulmonary fibrosis. two antiviral compounds, adenine arabinoside (ara-a) and acyclovir (acv), have been proven to be efficient in the treatment of significant, complicated varicella-zoster virus infections. adenine arabinoside inhibits viral dna polymerase and is given at a dosage of mglkg over a -hour period for at least days. the dosage could be increased to mglkg the american journal of the medical sciences but the majority of experience with varicella-zoster virus infections is with mglkg/day. the drug is sparingly soluble so that ml of vehicle are required for each milligram of drug administered to the patient. at a dose of mglkg, bone marrow suppression does not usually occur. if the dose is not decreased in the setting of hepatic and renal dysfunction, central nervous system disturbances, which consist of insomnia, hallucinations and tremulousness, may occur. these central nervous system manifestations usually fade with stopping the drug and rarely lead to death, but can persist for a protracted period after the drug has been discontinued. acyclovir also has been used to treat varicella-zoster virus infections. it inhibits viral dna polymerase and also acts as a chain terminator. its dosage is mg/m every hours for at least days. the only significant problem with the administration with acyclovir in this setting is the production of an obstructive nephropathy, due to salting out of the drug in the collecting tubules ofthe kidney. this is usually easily managed by administration of a fluid bolus, a diuretic, or mannitol. a comparison of the two drugs in complicated varicella-zoster virus infection has been made. . one group found that acyclovir was more efficacious; the other study determined that ara-a was equally as effective. because the administration of ara-a requires an increased volume of fluid and can be associated with central nervous system side effects, some authorities now consider acyclovir the drug of choice in the treatment of complicated infections due to varicella-zoster virus. oral acyclovir is absorbed poorly by the gastrointestinal tract and its efficacy in uncomplicated herpes zoster is apparent only when mg are given times a day for at least a -day period. there has been no experience with oral acv in treating varicella pneumonia. future modes of therapy may include combining ara-a with acv or administering one or other of the drugs with an interferon preparation. alpha-interferon also has been shown to be effective as therapy in complicated varicella-zoster virus infections but its use has been superceded by acv and ara-a. case report varicella pneumonia. a -year-old man was exposed to his two children with chicken pox. two days before admission he developed a rash, then dyspnea. on physical examination, a typical varicella rash was present. he was in severe respiratory distress. rales were present diffusely over both lung fields. the chest radiograph revealed bilateral extensive alveolar infiltrates. arterial blood gases showed a ph of . , pc of , and a p of . he was intubated and begun on positive end-expiratory pressure (peep) with a fi of %. he was started on intravenous acyclovir mg/m every hours. he improved and was able to be extubated after days. comment. severe varicella pneumonia responded to intravenous acyclovir while his oxygenation was maintained on peep with a high fi . herpes simplex virus can cause a necrotizing bronchopneumonia in neonatal infections and can also cause pneumonia in severely immunosuppressed adult patients. the largest series of patients with herpes simplex virus pneumonia was reported from seattle in bone-marrow transplant recipients 'and consisted of patients with either a focal pneumonia ( patients) or a diffuse interstitial pneumonia (eight patients). the focal pneumonia was found associated with herpetic esophagitis and tracheitis and probably resulted from contiguous spread of herpes virus to the lung parenchyma. diffuse interstitial pneumonia most probably resulted from hematogenous dissemination of virus to lung. pathologically, the process can be one of a necrotizing bronchopneumonia or of a widening of the interstitial space in the lung associated with diffuse alveolar injury. in these highly immunosuppressed patients, both bacterial and fungal suprainfection occurred and it was difficult to sort out which process was responsible for what proportion of lung damage. acyclovir has been shown to be an effective treatment of complicated herpes simplex virus infections in immunosuppressed patients. its dose in the usual patient is mg/m every hours for at least days, but if the process has been ascertained to be a rapidly progressive herpetic pneumonia, the dose could be increased to mglkg every hours until a therapeutic response had been obtained. with the development of potent antiviral chemotherapy, there is a need to consider and diagnose herpetic pneumonia. specific diagnosis can only be accomplished readily by lung biopsy. although involvement of the lung in infectious mononucleosis due to epstein-barr virus must be considered a rare occurrence, recent studies and case reports demonstrate that it probably can happen. . careful attention should be given to possible coexisting mycoplasma and other viral infections, particularly since the former can be treated. radiographic abnormalities may consist of hilar adenopathy, strand-like parenchymal infiltrates, diffuse bilateral pneumonia, and a picture consistent with primary atypical pneumonia. although epstein-barr virus is susceptible to acyclovir, there are no reports treating lung involvement with this drug. cytomegalovirus (cmv) rarely causes pneumonia in normal adults as part of the cmv mononucleosis syndrome. however, it is more common for cmv to induce pneumonia in normal hosts than epstein-barr virus. of patients with communityacquired pneumonia, had virologic, pathologic, or serologic evidence of cmv infection. ten of these patients were not immunosuppressed. in five of the ten, cmv was the only pathogen. the remaining five patients had one or more coexisting infections; c. trachomatis in two, m. pneumoniae in one, epstein-barr virus in one, and bacteria in three, both aerobic and anaerobic. cytomegalovirus more commonly causes pneumonia in immunosuppressed patients. it occurs particularly in renal, heart, liver, and bone-marrow transplant recipients. it is now becoming an increasing problem in patients with aids. in the transplant recipient experiencing a primary cmv infection, the virus most probably reaches the lung parenchyma through the hematogenous route, and the first finding is that of a reticulonodular infiltrate and the presence of - mm opacities ( figure ). pathologically, these focal areas usually consist of necrotic tissue, hemorrhage and alveolar damage with edema, a mononuclear infiltrate, and typical cytomegalic cells. the process can extend leading to diffuse interstitial and alveolar infiltrates. an attempt has been made to separate the foregoing process from that of an insidiously developing interstitial pneumonia that occurs more commonly in reactivated infections and has a better prognosis. in bone marrow transplant recipients, diffuse interstitial pneumonitis due to cmv is much more common in patients receiving allogeneic transplants, and the case-fatality rate approximates %. in some renal transplant recipients, the pneumonic process can be focal and does not have to be exceptionally severe. small pleural effusions can occur occasionally. in other renal transplant recipients, however, cmv pneumonia can progress rapidly and lead to death as part of a widely disseminated infectious process. in cardiac transplant recipients a variety of pulmonary opportunistic suprainfections has been well documented to occur in the course of cmv pneumonia. typical microorganisms causing suprainfections include p. carinii and nocardia species. in patients with aids, there may be co-existing infection with pneumocystis. cure of the pneumocystis can be effected by drugs, leaving cmv as the major pulmonary pathogen. in patients with aids, rapid development of cmv pneumonia can occur and lead to the death of the patient. extrapulmonic manifestations of cmv in the renal transplant recipient include fever, malaise, hepatic dysfunction, splenomegaly, leukopenia, and an increase in serum creatinine. with extensive cmv dissemination in heavily immunosuppressed patients, including those with aids, extrapulmonic manifestations include gastrointestinal ulceration with bleeding and perforation, hepatic dysfunction, adrenal cortical involvement, and central nervous sytem dysfunction. cytomegalovirus can be thought of as an immunosuppressive viral agent, and infection with this microorganism may lead to further immunosuppression with consequent bacterial, fungal, and parasitic suprainfection. clinically, patients with cmv pneumonia complain of dyspnea with a nonproductive cough. there can be an associated pleurisy. the process can be transient or can extend to respiratory insufficiency necessitating ventilatory support. therapy of fully developed cmv pneumonia has been shown not to be effective and this includes the use of the adenine arabinoside, acyclovir, ganciclovir (dhpg), and combinations of interferon with all the above. ganciclovir has been successful in achieving an antiviral effect in the lung, yet has not improved outcome in the american journal of the medical sciences bone marrow transplant recipients with cmv pneumonia. in an occasional renal transplant recipient who has the potential of a good immune response to the virus, the cmv illness that can include localized pneumonia might be benefited by the judicious use of ganciclovir. attempts at preventing cmv pneumonia have included donor selection, avoidance of white blood cell transfusions, and prophylactic administration of alpha-interferon or 'y-globulin preparations given before and through the first days after transplantation. alpha-interferon does prevent cmv viremia in the renal transplant recipient; 'y-globulin protects partially against cmv pneumonia if white blood cell transfusions have not been given. studies are in progress trying to make this latter effect more consistent, and consist of determining whether total antibody content is the necessary component or whether the effect necessitates the presence oflarge quantities of neutralizing antibody. on a priority basis, live, attenuated cmv vaccine development has been curtailed for the immediate future. a -year-old homosexual man presented to the hospital with fever, cough, and an erythematous rash. he had been followed in clinic with aids-related complex with lymphadenopathy, thrush, lymphopenia, anergy, diarrhea, and a positive antibody test to human immunodeficiency virus. at the time of his acute terminal illness he had a temperature of . ° c and had a diffuse, erythematous pruritic rash over the trunk and upper legs. the admission chest radiograph was interpreted as normal. on the second hospital day, the patient became delirious, had a worsening cough, and developed severe dyspnea. arterial blood gases on room air revealed a ph of . , pco. of , and a po. of . chest radiograph now revealed bilateral diffuse reticulonodular infiltrates. he was started on sulfatrimethoprim but had a respiratory arrest and died. postmortem examination revealed cmv pneumonia without evidence ofpneumocystis. lung viral cultures rapidly grew cmv, with the cytopathic effect being present the second day. comment. explosive illness in a patient with arc revealed only cmv at autopsy and on viral culture of the lung. viral and mycoplasmal pneumonia in a prepaid medical care group during an eight-year period primary atypical pneumonia in a family due to concomitant mycoplasma pneumoniae and adenovirus type infection viral pneumonia as a cause and result of hospitalization severe illness with influenza b strannegard , trollfors b: etiology of community-acquired pneumonia in out-patients etiologies and characteristic features of pneumonias in a municipal hospital etiology of community-acquired pneumonia in patients requiring hospitalization adult community-acquired pneumonia in central london virological investigations in adults with acute pneumonia hospital study of adult community-acquired pneumonia acute community-acquired pneumonias an acute infection of the respiratory tract with atypical pneumonia. a disease entity probably caused by a filtrable virus causes of atypical pneumonia: results of a -year prospective study differential diagnosis of viral, mycoplasmal and bacteraemic pneumococcal pneumonias on admission to hospital comparative radiographic features of community acquired legionnaires' disease, pneumococcal pneumonia, mycoplasma pneumonia, and psittacosis mycoplasma pneumonia: failure of erythromycin therapy lung infections caused by viruses, mycoplasma pneumoniae, and rickettsiae pneumonias due to rickettsiae, chlamydiae, viruses and mycoplasma neurologic disease associated with mycoplasma pneumoniae pneumonitis. demonstration of viable mycoplasma pneumoniae in cerebrospinal fluid and blood by radioisotopic and immunofluorescent tissue culture techniques open lung biopsy in myco- plasma pneumoniae pneumonia mycoplasma pneumoniae infection in families pulmonary involvement in mycoplasma pneumoniae infection in families the clinical spectrum and diagnosis of mycoplasma pneumoniae infection clinical features of mycoplasmal pneumonia in adults mycoplasmal pneumonias in the community hospital. the "unusual" manifestations become common lobar pneumonia caused by mycoplasma pneumoniae radiographic appearances of mycoplasma pneumonia mycoplasmal pneumonia and adult respiratory distress syndrome: a complication to be recognized acute respiratory failure due to atypical pneumonia the protean manifestations of mycoplasma pneumoniae infection in adults weekly clinicopathological exercises: case - pityriasis rosea gibert and mycoplasma pneumoniae infection abnormalities in lung function following clinical recovery from mycoplasma pneumoniae pneumonia van der straeten m: mycoplasma pneumonia with fulminant evolution into diffuse interstitial fibrosis bronchiolitis obliterans due to mycoplasma pneumoniae mycoplasma pneumonia complicated by bronchiectasis mycoplasmal pneumonia associated with mesangiocapillary glomerulonephritis type ii (dense deposit disease) mycoplasma pneumoniae pneumonia associated with iga nephropathy new york city medium for enhanced recovery of mycoplasma pneumoniae from clinical specimens principles and practice of infectious diseases psittacosis. a diagnostic challenge isolation of chlamydia trachomatis from the lower respiratory tract of adults chlamydia trachomatis infection in adults with community-acquired pneumonia chlamydia trachomatis pneumonia in adults: radiographic appearance an epidemic of mild pneumonia due to an unusual strain of chlamydia psittaci a new chlamydia psittaci strain, twar, isolated in acute respiratory tract infections clinical features of adenoviral pneumonia in air force recruits lobar pneumonia associated with adenovirus type fatal pneumonia associated with adenovirus type in three military trainess fatal adenovirus pneumonia in a young adult associated with adv- vaccine administered days earlier fatal disseminated adenovirus infection in a renal transplant recipient adenovirus infections in patients undergoing bone-marrow transplantation fatal disseminated adenovirus pneumonia in an agammaglobulinemic patient bacterial pneumonia complicating adenoviral pneumonia bronchopneumonia with serious sequelae in children with evidence of adenovirus type infection diffuse pneumoniti~ due to adenovirus type in a civilian association of adenovirus type with reye's-syndrome-like illness and pneumonia rapid diagnosis of respiratory adeno-vi~us infections in young adult men fatal haemorrhagic pneumonia in an adult due to respiratory syncytial virus and staphylococcus aureus respiratory syncytial virus pneumonitis in adults case report: presumed respiratory syncytial virus pneumonia in three immunocompromised adults an outbreak of respiratory syncytial virus pneumonia in a nursing home for the elderly ribavirin treatment of respiratory syncytial viral infection in infants with underlying cardiopulmonary disease ribavirin aerosol treatment of bronchiolitis due to respiratory syncytial virus infection in infants coronavirus infections of man associated with diseases other than the common cold influenza: the newe acquayantance orthormyxo-and paramyxoviruses and their replication, in fields bn sanfordjp: pulmonary function in uncomplicated influenza pulmonary mechanics after uncomplicated influenza a infection studies on influenza in the pandemic of - . ii. pulmonary complications of influenza severe influenza virus pneumonia in the pandemic of - mycoplasma and influenza pneumonia in a series of adults the leukocyte response during viral respiratory illness in man acute myocarditis in influenza a infections. two cases of non-bacterial myocarditis, with isolation of virus from the lungs fatal influenza a pneumonia in pregnancy epidemic renal transplant rejection associated with influenza a victoria rapid diagnosis of primary influenza pneumonia pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function ribavirin small-particle aerosol treatment of influenza ribavirin small-particle aerosol treatment of infections caused by influenza virus trains anictoriaj / (h n ) and bltexas/ / measles pneumonia. bacterial suprainfection as a complicating factor measles pneumonia in young adults. an analysis of cases isolation of measles virus at autopsy in cases of giant-cell pneumonia without rash report of seven cases and a review of literature persistent pulmonary granulomas after recovery from varicella pneumonia varicella pneumonia complicating pregnancy treatment of varicellazoster virus infection in severely immunocompromised patients comparative trial of acyclovir and vidarabine in disseminated varicella-zoster infections in immunocompromised patients coreyl: herpes simplex virus pneumonia. clinical, virologic, and pathologic features in patients diffuse pneumonia and acute respiratory failure due to infectious mononucleosis clinical, virologic, and serologic evidence of epstein-barr virus infection in association with childhood pneumonia pneumonia associated with rising cytomegalovirus antibody titres in a healthy adult does cytomegalovirus playa role in communityacquired pneumonia? cytomegalovirus pneumonia in bone marrow transplant recipients: miliary and diffuse patterns nonbacterial nonfungal pneumonia following marrow transplantation in identical twins disease due to cytomegalovirus and its long-term consequences in renal transplant recipients. correlation of allograft survival with disease due to cytomegalovirus and rubella antibody level clinical characteristics of the lethal cytomegalovirus infection following renal transplantation diagnosis of cytomegalovirus pneumonia in compromised hosts activity of -[ -hydroxy- -(hydroxymethyl)-ethoxymethyl]guanine in the treatment of cytomegalovirus pneumonia key: cord- -utbuj iz authors: dear, jonathan d. title: bacterial pneumonia in dogs and cats date: - - journal: vet clin north am small anim pract doi: . /j.cvsm. . . sha: doc_id: cord_uid: utbuj iz bacterial pneumonia is a common clinical diagnosis in dogs but seems to occur less commonly in cats. underlying causes include viral infection, aspiration injury, and foreign body inhalation. identification of the organisms involved in disease, appropriate use of antibiotics and adjunct therapy, and control of risk factors for pneumonia improve management. bacterial pneumonia remains one of the most common clinical diagnoses in dogs with either acute or chronic respiratory disease. new research suggests a complex relationship between viral respiratory diseases and development of bacterial pneumonia in dogs. over the past decade, much has been discovered about the convoluted interplay between host and environmental factors that leads to this complex of diseases. in cats, bacterial pneumonia is less commonly identified than inflammatory feline bronchial disease. aspiration pneumonia results from the inadvertent inhalation of gastric acid and/or ingesta and remains a common cause of bacterial pneumonia, accounting for roughly % of clinical diagnoses in a study of human patients admitted to the intensive care unit. although inhalation of gastroesophageal material is a common theme, different factors lead to the development of this phenomenon. risk factors that have been identified for the development of aspiration pneumonia include esophageal disease, refractory vomiting, seizures, prolonged anesthesia, and laryngeal dysfunction ( table ) . in a healthy animal, physiologic and anatomic features reduce the chance of aspiration. during a normal swallow, fluid and food are propelled caudally in the oropharynx and through the upper esophageal sphincter by contraction of the oral cavity and tongue. at the same time, the epiglottis retracts to cover the laryngeal aditus and protect the trachea from particulate inhalation. adduction of the arytenoid cartilages then contributes to further occlusion of the upper airways. any process impeding these primary defenses or inhibiting the normal swallowing reflexes increases the likelihood of aspiration. aspiration injury results from inhalation of either sterile, acidic gastric contents (resulting from vomiting or gastric regurgitation) or of septic material from gastric or oral secretions. irritation induced by acid inhalation promotes a local environment in which bacterial colonization can develop and lead to bacterial pneumonia. the severity of disease varies depending on the quantity and nature of the material aspirated as well as the length of time between the event and its diagnosis. conscious patients with intact airway reflexes tend to cough and prevent massive aspiration injury. animals under anesthesia or with reduced airway reflexes because of neurologic disorders are less likely to cough in response to the aspiration event and are, therefore, more likely to develop diffuse pulmonary infiltrates and acute lung injury. in many instances aspiration injuries occur under general anesthesia and the presence of a cuffed endotracheal tube does not prevent inadvertent aspiration. infectious, or community-acquired, pneumonias in dogs commonly begin with viral colonization and infection of the upper respiratory tract (canine respiratory coronavirus, herpesvirus, pneumovirus, and parainfluenza virus, among others). often, such diseases are acute and self-limiting, but in a subset of dogs inflammation associated with these organisms immobilizes the host's immune defenses and predisposes infection with other (often bacterial) respiratory pathogens. many bacteria have been implicated in canine infectious respiratory disease (cird), although special focus has been directed toward streptococcus (specifically streptococcus equi subsp zooepidemicus and s canis), mycoplasma cynos, and bordetella bronchiseptica. cird is especially prevalent in dogs naive to the pathogens and exposed in overcrowded, stressful environments such as animal shelters, boarding kennels, and treatment facilities. the pathophysiology associated with this disease and infectious lower respiratory tract disease in cats is discussed later in this article (boxes and ). inhaled foreign bodies carry mixed bacterial and fungal organisms into the lung and are associated with focal pneumonias that are often initially responsive to antimicrobial medications but relapse shortly after discontinuation of therapy. , foreign bodies reported in the veterinary literature include grass awns, plant materials, or plastic materials. organisms associated with grass awn inhalation include pasteurella, streptococcus, nocardia, actinomyces, and anaerobic bacteria. , most often, foreign material remains at the carina or enters caudodorsal principal bronchi (accessory, right and left caudal lobar bronchi). features associated with pulmonary foreign bodies include: young, sporting breeds environmental exposure to grass awns focal, recurrent radiographic alveolar pattern history of other cutaneous or visceral foreign bodies spontaneous pneumothorax or pyothorax box cird complex: changing the nature of kennel cough cird complex (formerly known as kennel cough) is a syndrome in which multiple pathogens, both viral and bacterial, coinfect either naive, immunocompromised dogs or previously vaccinated dogs. this complex is multifactorial and it is likely that both host and environmental factors play a role in the development of illness. organisms associated with this disease are ubiquitous, especially in overcrowded housing facilities such as animal shelters and training facilities. it is likely that stress induced by the new environment and exposure to novel pathogens both play a role in development of disease. in most cases, respiratory signs are present for days to weeks and most animals show mild to moderate clinical signs. viral infections typically cause either a bronchopneumonia or bronchointerstitial pneumonia because of their propensity to infect and damage type i pneumocytes. as the condition progresses, desquamation of the respiratory epithelium and aggregation of inflammatory cells further reduce the lungs' natural defenses, increasing the potential for secondary bacterial colonization and infection. previous studies have implicated viral organisms such as canine adenovirus or canine parainfluenza as major participants in cird, although recent studies have proposed novel respiratory pathogens such as canine respiratory coronavirus, , , , canine influenza virus, and canine herpesvirus as additional important pathogens associated with cird. b bronchiseptica, streptococcus canis, s equi subsp zooepidemicus, and m cynos , have been implicated as secondary bacterial infections associated with cird. s equi subsp zooepidemicus infections, in particular, have been associated with a rapidly progressive and often fatal hemorrhagic pneumonia. , some strains identified in outbreaks of this pathogen have been identified as resistant to tetracycline antibiotics, which are often the drug of choice prescribed for other bacterial pathogens associated with this complex. normal thoracic radiographs do not rule out the possibility of an airway foreign body and even computed tomography (ct) can fail to identify an affected bronchus. chronic pulmonary foreign bodies are associated with marked inflammation that can lead to massive airway remodeling and bronchiectasis that, when seen on radiographs, should raise the degree of suspicion for foreign body. ventilator-associated pneumonia (vap) is a common cause of hospital-acquired pneumonia in people, although there are few veterinary reports in the literature. colonization of the oropharynx by pathogenic and multidrug-resistant bacteria occurs and the endotracheal tube acts as a conduit to transmit pathogens into the airways, which leads to tracheobronchitis and potentially pneumonia. in addition, any animal with a compromised respiratory tract or serious systemic disease is particularly prone to development of infectious airway disease while hospitalized. the use of mechanical ventilation in human patients raises the risk of nosocomial infection by -fold to -fold. no published studies assess the risk in ventilated veterinary patients, although a study investigating differences in bacterial sensitivity between ventilated and nonventilated patients suggested that patients requiring mechanical ventilation were more likely to be infected with bacteria resistant to the antimicrobials most commonly used in veterinary practice. this finding parallels the increase in incidence of multidrug-resistant vap in human medicine. both the innate and adaptive immune systems protect against the development of infectious airway disease, and a breakdown in either increases the likelihood of opportunistic infection ( table ). congenital immunodeficiencies have been recognized that make an animal particularly sensitive to infectious disease. young animals are especially prone to the development of bacterial pneumonia because of their naive immune systems, and when coupled with alterations to the innate immune system, such as primary ciliary dyskinesia (pcd) or complement deficiency, the risk of life-threatening infection increases greatly (see veterinary clinics of north america ; ( ): - for a comprehensive review of respiratory defenses in health and disease). any cause of systemic immunocompromise increases the risk for bacterial pneumonia, and any additional alterations to the body's natural defense mechanisms increase the risk. medications such as chemotherapy, immunosuppressive therapy, or antitussive therapy significantly increase the likelihood of bacterial pneumonia. organisms that have been reported as lower respiratory pathogens of cats include pasteurella spp, escherichia coli, staphylococcus spp, streptococcus spp, pseudomonas spp, b bronchiseptica, and mycoplasma spp, and specific attention has been paid to mycoplasma spp because of a possible association with the induction and exacerbation of asthma in adult and pediatric human patients. however, the association between lower respiratory infection and chronic inflammatory lower airway disease in cats is unclear and is a topic of ongoing interest. mycoplasma species are considered normal flora in the upper respiratory tract and their role is controversial in lower respiratory tract infection. because they are rarely identified cytologically, and specific culture or polymerase chain reaction is needed to document the presence of these organisms, the role of mycoplasma in cats (as well as in dogs) remains difficult to define. underlying respiratory viruses or systemic viruses such as feline leukemia virus and feline immunodeficiency virus have the potential to enhance the severity of respiratory illness. clinical signs of bacterial pneumonia vary depending on its cause, severity, and chronicity of disease. they can be acute or peracute in onset or can display an insidious onset, resulting in chronic illness. early in disease, mild signs such as an intermittent, soft cough might be the only evidence of disease. as infection spreads, clinical signs worsen and often include a refractory, productive cough, exercise intolerance, anorexia, and severe lethargy. owners can note a change in the respiratory pattern, with increased panting or rapid breathing and, in cases of severe infection, cyanosis and orthopnea can be observed. in general, these systemic signs are more obviously displayed in dogs than in cats. cats with pneumonia can display similar clinical signs, although the cough can be misinterpreted as a wretch or vomit by owners. clinical signs and radiographic findings can also be considered consistent with inflammatory airway disease. as disease worsens, cats can become tachypneic with short, shallow breaths and nasal flaring. owners rarely notice exercise intolerance associated with bacterial pneumonia. as with the history and clinical signs of bacterial pneumonia, physical examination findings vary with the state and severity of disease. dogs or cats with mild disease can have no abnormalities detected on physical examination. an early clue to the diagnosis might be a change in the respiratory pattern, with an increase in rate and effort. the clinician needs to pay close attention to thoracic auscultation because adventitious lung sounds (crackles and wheezes) can be subtle, focal, or intermittent. in many cases, only harsh or increased lung sounds are detected rather than crackles. the examination should also include a thorough auscultation of the trachea and upper airway for evidence of upper airway signs (eg, nasal congestion or discharge) that can result from lower airway infection, either as an extension of epithelial infection or from nasopharyngeal regurgitation of lower airway secretions. animals with bacterial pneumonia generally present with mixed inspiratory and expiratory signs, similar to those seen with other diseases of the pulmonary parenchyma. fever is detected in % to % of cases, so it is not a reliable indicator of disease. , [ ] [ ] [ ] diagnosis bacterial pneumonia implies sepsis of the lower airway and lungs, so the diagnosis is confirmed by showing septic suppurative inflammation on airway cytology obtained through bronchoalveolar lavage (bal) or tracheal wash, along with a positive microbiology culture. in some cases, this is completed easily and yields results consistent with clinical suspicion. however, financial limitations or patient concerns can inhibit the ability to collect samples needed to document specifically a bacterial infection, and in those cases a clinical diagnosis of bacterial pneumonia might be presumed based on available information. a clinical diagnosis of bacterial pneumonia should be reached after obtaining compelling evidence to suggest a bacterial cause for the animal's clinical signs (after excluding other causes), with appropriate resolution of signs following suitable antimicrobial therapy. acute bacterial pneumonia is a common diagnosis in the small animal clinic and can often be easily identified; however, early and chronic pneumonias are more challenging to recognize because clinical signs can be subtle. the complete blood count is a useful diagnostic test in animals with respiratory signs. bacterial pneumonias are typically associated with an inflammatory leukogram, characterized primarily by a neutrophilia, with or without a left shift and variable evidence of toxic changes, , although the absence of inflammatory change does not exclude the possibility of pneumonia. , furthermore, the leukogram and differential can provide clues to suggest that bacterial pneumonia is less likely. for example, eosinophilia in an animal with respiratory signs would suggest eosinophilic bronchopneumopathy or parasitic lung diseases as an underlying cause rather than a bacterial cause. the erythrogram and platelet evaluation are generally not helpful in determining a bacterial cause of respiratory disease. a biochemistry panel, urinalysis, and fecal flotation do not always contribute to the diagnosis of bacterial pneumonia but can provide clues to the presence of metabolic or endocrine diseases that could make the development of bacterial pneumonia more likely. thoracic radiographs are crucial diagnostic tests in the evaluation of lower airway and pulmonary parenchymal disease. radiographic evidence of bacterial pneumonia can appear as a focal, multifocal, or diffuse alveolar pattern, although early in the disease process infiltrates might be primarily interstitial (figs. and ) . ventral lung lobes are most commonly affected in aspiration pneumonia, and a caudodorsal pattern is expected with inhaled foreign bodies or hematogenous bacterial spread. a lobar sign can be seen in cases of aspiration pneumonia in which the right middle lung lobe is most often affected ( table ) . three-view thoracic radiographs (left lateral, right lateral, and either dorsoventral or ventrodorsal views) should be obtained when screening for pneumonia because differential aeration associated with positional atelectasis can either mask or highlight pulmonary changes. for example, a radiograph taken in left lateral recumbency is preferred when aspiration is suspected because it increases aeration of the right middle lung lobe, the most commonly affected lobe. diffuse radiographic involvement is expected to suggest more severe disease, although radiographic changes lag behind clinical disease. consequently, bacterial pneumonia cannot be ruled out in patients with acute onset of clinical signs and unremarkable radiographs. advanced imaging is rarely necessary in the diagnosis of uncomplicated bacterial pneumonia, although it can be helpful in more complicated cases. thoracic ultrasound can be used to characterize peripheral areas of consolidation and to obtain fine-needle aspirates for cytology. cytology is often helpful in distinguishing inflammation from neoplastic infiltration. in addition, sonographic evaluation is particularly fig. . dorsoventral (a) and right lateral (b) thoracic radiographs from a dog with an alveolar pattern in the cranioventral lung lobes, suggesting aspiration. in this case, the left cranial lobes were most affected which are most easily examined on the right lateral view. in many cases the right middle lung lobe is most affected, necessitating a left lateral orthogonal view. useful in the detection of superficial foxtail foreign bodies when they remain in the periphery of the lobe (fig. ) . ct provides greater detail and resolution of lesions within the pulmonary parenchyma and gives the clinician better spatial information regarding the severity and extent of pulmonary involvement (fig. ) . in some cases, ct can be useful to identify migration tracts associated with inhaled foreign bodies. however, in most cases, general anesthesia is required for ct acquisition and prolonged recumbency can dear lead to atelectasis, which is difficult to differentiate radiographically from infiltrates. repeating the ct in a different position after providing several maximal inspirations can alleviate atelectasis. nuclear scintigraphy can be useful for the evaluation of ciliary dyskinesia, although secondary causes of mucociliary stasis (ie, infection with mycoplasma or bordetella, as well as exposure to smoke) must be excluded before assuming the diagnosis of pcd. because of the time necessary for image acquisition, magnetic resonance imaging is not commonly used for the diagnosis of most respiratory diseases. examination of the trachea and bronchial tree should be performed systematically. the endoscopist should note the color and character of the mucosa and any airway sections, making sure to evaluate all branches of the lower airways for evidence of foreign bodies, bronchiectasis, or collapse (diffuse or focal changes). airway mucosa in a normal animal should be pale pink with visible mucosal and pulmonary vessels. airway bifurcations should appear as narrow, crisp mucosal margins. animals with pneumonia can have hyperemia of the epithelium, prominent mucosal vessels, and evidence of airway inflammation, appearing as rounded, thickened airway bifurcations and airway nodules. airway secretions are usually opaque, viscous, and discolored (brown, yellow-green, or red tinged). when available, bal is preferred for collection of a lower airway sample rather than tracheal wash because the trachea and carina are not sterile, even in healthy dogs. in addition, the sensitivity for detecting cytologic features of sepsis is greater with bal than tracheal wash. however, when only a tracheal wash specimen can be obtained, because of the lack of equipment for bal or because of patient instability, collection of a lower airway sample is desirable to identify infecting bacteria and to determine appropriate antibiotic therapy through susceptibility testing. fig. . ct image of a dog with severe, diffuse pneumonia resulting from a chronic foxtail foreign body (see fig. ). the foreign body was not visible on thoracic radiographs, but is clearly evident in the left principal bronchus on this image. bal cell counts in animals with bacterial pneumonia are markedly higher than in patients with chronic bronchitis or other respiratory disease. septic, suppurative inflammation is a reliable indicator of bacterial pneumonia in dogs and is likely to indicate bacterial pneumonia in cats. in those cases that lack evidence of airway sepsis (intracellular bacteria), bal cytology generally reveals suppurative or mixed inflammation. in animals with suspected or confirmed foreign bodies, a bal sample should always be obtained from the affected airway and submitted individually for cytologic analysis. airway bacteria are more likely to be found in the cytologic sample from the site of the foreign body than from an alternate site. furthermore, cytology of bal samples obtained from multiple lobes can reveal different findings, even in cases of sterile inflammatory diseases like feline bronchial disease, thus reliance on a single-segment bal cytology could lessen the chance of yielding diagnostic results. diagnosis of bacterial pneumonia relies on identification of septic inflammation in conjunction with a positive bacterial culture. aerobic and mycoplasma culture and sensitivity are typically requested, and, in cases with markedly purulent secretions or a history of known aspiration or foreign bodies, anaerobic cultures should also be requested. samples should be refrigerated in sterile containers until submitted. if multiple alveolar segments are sampled during bal, these are usually are pooled for culture submission. cultures should always be performed when possible in order to guide appropriate antimicrobial therapy. with the liberal use of antibiotics, increasing populations of resistant microbes are being identified, particularly in patients with hospitalacquired pneumonia. , however, airway samples cannot be collected in all animals and, in those instances, judicious use of antibiotics must be followed. common bacteria cultured from lung washes of cats or dogs with bacterial pneumonia include enteric organisms (escherichia coli, klebsiella spp), pasteurella spp, coagulase-positive staphylococcus spp, beta-hemolytic streptococcus spp, mycoplasma spp, and b bronchiseptica ( table ) . , , pulmonary function testing arterial blood gas analysis is a useful test to measure the lung's ability to oxygenate. for patients with significant respiratory compromise, arterial blood samples ideally should be collected and analyzed to determine the severity of pulmonary disease. furthermore, trends in arterial oxygen partial pressures can be used to track progression or resolution of disease. in many cases, blood gas analysis is not available or patient factors preclude the acquisition of samples. pulse oximetry is a quick, noninvasive evaluation of oxygen delivery to body tissues that measures percentage of hemoglobin saturation with oxygen. it provides only a crude assessment of oxygenation and is subject to variability; however, trends in hemoglobin saturation can provide additional clinical support to progression or resolution of disease. treatment treatment of bacterial pneumonia varies considerably with the severity of disease, and appropriate antibiotic therapy is essential. the international society for companion animal disease is currently constructing guidelines for antibiotic therapy for respiratory infections. pending those guidelines, antibiotic recommendations from previous literature should be considered ( table ) . for stable animals with mild disease, outpatient therapy consisting of administration of a single, oral antibiotic is often all that is necessary. antimicrobial choices should ideally be based on culture and sensitivity results from airway lavage samples, although sometimes empiric therapy is more practical. regardless, in cases of severe pneumonia, initial empiric therapy should be instituted while awaiting culture results. antibiotics are typically administered for to weeks, and at least to weeks beyond the resolution of clinical and/or radiographs signs of disease. animals with more advanced disease require more intensive care, including hospitalization with intravenous fluids to maintain hydration. adequate hydration is essential to facilitate clearance of respiratory exudates. nebulization to create particles that enter the lower airways (< mm) can also enhance clearance of secretions. nebulizer types include ultrasonic devices, compressed air nebulizers, and mesh nebulizers. nebulization with sterile saline can be achieved by directing the hosing from the pneumonia in dogs and cats nebulizer into a cage or animal carrier covered in plastic. depending on how viscous secretions are, therapy can be provided for to minutes to times daily. in many cases, nebulization coupled with coupage helps the animal expectorate airway secretions. coupage is performed by cupping the hands and gently and rhythmically pounding on the lateral thoracic walls in dorsal to ventral and caudal to cranial directions. coupage should not be performed in animals with regurgitation because any increase in intrathoracic pressure could exacerbate regurgitation and subsequent reaspiration. supplemental oxygen is necessary for animals with moderate to marked hypoxemia (documented by a pao less than mm hg or oxygen saturation via pulse oximetry less than % on room air) in conjunction with increased respiratory effort. oxygen supplementation at % to % is provided until respiratory difficulty lessens and the animal can be weaned to room air. animals with refractory pneumonia that fail to improve on supplemental oxygen can succumb to ventilatory fatigue and need to be referred to an intensive care facility for mechanical ventilation. administration of an oral mucolytic agent such as n-acetylcysteine can be useful for animals with moderate to severe bronchiectasis that are prone to recurrent pneumonia. decreasing the viscosity of airway secretions might improve expectoration of fluid and debris that accumulates in dependent airways, although no published information is available on use of mucolytics in animals. n-acetylcysteine is typically not used via nebulization because of the risk of bronchoconstriction and epithelial toxicity. under no circumstances are cough suppressants (such as butorphanol or hydrocodone) appropriate for use in the management of bacterial pneumonia, particularly when it is complicated by bronchiectasis. by decreasing the cough reflex, these drugs perpetuate retention of mucus, debris, and other material in the airways and therefore hinder clearance of infection. also, furosemide should not be used because drying of secretions traps material in the lower airway and perpetuates infection. in cases in which aspiration pneumonia is suspected, strategies should be used to reduce the chance of reaspirating through appropriate treatment of the underlying condition. with disorders of esophageal motility, upright feedings of either slurry or meatballs can enhance esophageal transit. furthermore, diets low in fat can increase gastric emptying. in patients with refractory vomiting, antiemetic and prokinetic agents can be used to reduce the episodes of vomiting. drugs like maropitant (cerenia; mg/kg subcutaneously once daily) or ondansetron (zofran; . - mg/kg intravenously or subcutaneously once to twice daily) act peripherally and centrally to decrease the urge to vomit and are safe to use in both cats and dogs. the role of antacids in management of aspiration pneumonia remains controversial. by neutralizing the ph of gastric secretions, animals with refractory vomiting or regurgitation are less likely to succumb to chemical injury related to aspiration. however, in cases treated with acid suppression, the aspirant is likely to contain a greater concentration of bacteria that can colonize the lower airways and lead to bacterial pneumonia. no controlled studies have assessed the severity of aspiration pneumonia or the relative risk of using antacid therapy in dogs or cats. because radiographic findings lag behind clinical disease, recheck radiographs are not helpful early into the disease process, although they are useful to document resolution of disease and should be obtained within a week of discontinuation of antimicrobial therapy. in cases of refractory pneumonia, recheck radiographs midway through therapy can be used to assess resolution or progression of disease and help to guide further therapy. in animals suspected of having contagious or multidrug-resistant pathogens, appropriate contact precautions should be used. isolation gowns, examination dear gloves, and good hand washing technique along with appropriate quarantine facilities are essential to preventing transmission of disease to other patients or members of the health care team. prognosis for animals with bacterial pneumonia varies depending on the severity of disease, the animal's immunocompetence, and the virulence of the infectious agent. in general, between % and % of patients diagnosed with pneumonia are discharged from the hospital. , no long-term studies assess the overall prognosis of patients with multidrug-resistant bacteria or recurrent pneumonia. the outcome associated with these cases presumably will be worse. an -year-old female spayed chihuahua mix presented for a wet cough. cough had been present for months and there had been minimal response to antibiotics combined with a cough suppressant and no response to heart failure medication (furosemide, enalapril, and pimobendan). temperature ( . c [ f]), pulse ( beats per minute [bpm]), and respiratory rate ( breaths per minute) were normal. no murmur was auscultated and lung sounds were normal. chronic cough in a small-breed dog is often associated with airway collapse or chronic bronchitis; however, infectious and neoplastic disease must remain on the differential list. congestive heart failure is unlikely given the lack of a heart murmur and the lack of response to diuretic therapy. a white blood cell count was normal ( cells/ml) with neutrophils. thoracic radiographs revealed scattered bronchial markings in the caudal thorax (fig. ) . fluoroscopic examination did not reveal evidence of tracheal or airway collapse. laryngoscopy indicated lack of abduction of the arytenoid cartilages consistent with bilateral laryngeal paralysis. secretions were evident throughout the upper and lower airways. diffuse airway hyperemia and irregularities of the mucosa were apparent. bal cytology was remarkable for septic suppurative inflammation, and bacterial cultures were positive for pasteurella, mycoplasma spp, and anaerobic bacteria, consistent with an aspiration cause. a -year-old male castrated domestic medium hair cat was presented for evaluation of acute respiratory distress. lethargy and anorexia had been noted days before the onset of respiratory signs. temperature ( . c [ . f]) and pulse ( bpm) were normal. tachypnea was noted (respiratory rate, breaths per minute) with increased respiratory effort on inspiration and expiration. diffuse expiratory wheezes were auscultated. acute onset of respiratory difficulty in a cat is most commonly related to inflammatory airway disease. the physical examination is consistent with this diagnosis, although it is uncommon for affected cats to show lethargy and anorexia. infectious and neoplastic diseases were also on the differential diagnosis list, along with aspiration and foreign body pneumonia. thoracic radiographs revealed a focal opacity in the left caudal lung lobe and a diffuse bronchial pattern (fig. ) . complete blood count revealed a normal white blood cell count ( /ml) with a left shift ( /ml neutrophils, /ml bands). bronchoscopy with lavage was performed. a moderate amount of airway hyperemia and edema was noted along with purulent material obstructing several airways. bal cytology showed increased cellularity ( , normal cells/ml) with neutrophilic inflammation ( %, normal %- %). neutrophils contained dark blue granular debris, suspicious for sepsis. aerobic and anaerobic cultures were negative but a pure culture of mycoplasma was isolated on special medium. a diagnosis of mycoplasma bronchopneumonia was made. community-acquired aspiration pneumonia in intensive care units. epidemiological and prognosis data potential risks, prognostic indicators, and diagnostic and treatment modalities affecting survival in dogs with presumptive aspiration pneumonia: cases mycoplasmas and novel viral pathogens in canine infectious respiratory disease community-acquired infectious pneumonia in puppies: cases capnocytophaga cynodegmi in a rottweiler dog with severe bronchitis and foreign-body pneumonia the role of bronchoscopy in foreign body removal in dogs and cats: cases radiographic, computed tomographic, and ultrasonographic findings with migrating intrathoracic grass awns in dogs and cats airway microbial culture and susceptibility patterns in dogs and cats with respiratory disease of varying severity ventilator-associated tracheobronchitis and pneumonia: thinking outside the box bordetella bronchiseptica infection in cats. abcd guidelines on prevention and management clinical, clinicopathologic, and radiographic findings in dogs with aspiration pneumonia: cases cytological analysis of bronchoalveolar lavage fluid in the diagnosis of spontaneous respiratory tract disease in dogs: a retrospective study microbiologic and cytologic assessment of bronchoalveolar lavage fluid from dogs with lower respiratory tract infection: cases quantitative bacterial cultures and cytological examination of bronchoalveolar lavage specimens in dogs bacterial isolates from the lower trachea of clinically healthy dogs interpretation of multisegment bronchoalveolar lavage in cats genetic diversity of streptococcus equi subsp. zooepidemicus and doxycycline resistance in kennelled dogs molecular epidemiology of feline bordetellosis in two animal shelters in california, usa etiology and clinical outcome in dogs with aspiration pneumonia: cases a serological survey of canine respiratory coronavirus and canine influenza virus in korean dogs clinical factors associated with death before discharge and overall survival time in dogs with generalized megaesophagus age-related thoracic radiographic changes in golden and labrador retriever muscular dystrophy primary ciliary dyskinesia in newfoundland dogs immunoglobulin deficiency in cavalier king charles spaniels with pneumocystis pneumonia x-linked severe combined immunodeficiency in the dog comparison of clinical signs, diagnostic findings, organisms isolated, and clinical outcome in dogs with bacterial pneumonia: cases ( - ) a clonal outbreak of acute fatal hemorrhagic pneumonia in intensively housed (shelter) dogs caused by streptococcus equi subsp. zooepidemicus textbook of respiratory disease in dogs and cats. st louis (mi): saunders the association of streptococcus equi subsp zooepidemicus with canine infectious respiratory disease the seroprevalence of canine respiratory coronavirus and canine influenza virus in dogs in new zealand tropism and pathological findings associated with canine respiratory coronavirus (crcov) nosocomial outbreak of serious canine infectious tracheobronchitis (kennel cough) caused by canine herpesvirus infection recent advances in canine infectious disease. international veterinary information service mycoplasmas associated with canine infectious respiratory disease streptococcus zooepidemicus: an emerging canine pathogen lower respiratory tract infections in cats: cases ( - ) mycoplasma pneumoniae in children with acute and refractory asthma key: cord- -zuqx ksy authors: tang, pingping; wang, jiangshan; song, yingna title: characteristics and pregnancy outcomes of patients with severe pneumonia complicating pregnancy: a retrospective study of cases and a literature review date: - - journal: bmc pregnancy childbirth doi: . /s - - - sha: doc_id: cord_uid: zuqx ksy background: pneumonia during pregnancy has been proven to be associated with increased maternal and fetal morbidity and mortality. the management of severe pneumonia in gravid patients is even more challenging. thus, we summarized the characteristics and pregnancy outcomes of these patients and explored the probable risk factors and predictive factors for pneumonia during pregnancy and the appropriate timing of delivery in severe pneumonia patients. methods: a retrospective cohort study was conducted with patients who were diagnosed with severe pneumonia complicating pregnancy at peking union medical college hospital between january and june . the clinical features, treatment strategies, and pregnancy outcomes were collected from medical records and telephone calls. results: all patients were in their late second or third trimester. the patients had a higher prevalence of anemia ( %) and preeclampsia ( %) than ordinary pregnant women. delayed diagnoses were not uncommon. two mothers died in our series, resulting in a mortality rate of %. two intrauterine deaths were observed. elective delivery was not performed in any of the four patients in their second trimester. six of the seven patients who presented after weeks of gestation and had live fetuses underwent emergency deliveries. preterm births ( / ) and cesarean sections ( / ) were the two leading adverse outcomes in newborns. conclusions: anemia, advanced gestational age, and preeclampsia might be associated with the severity of pneumonia. chest radiographs should be taken as soon as pneumonia is highly suspected to facilitate an early diagnosis. high incidences of adverse fetal outcomes were observed; thus, termination of the pregnancy is recommended for patients in their third trimester when respiratory function deteriorates progressively. however, it might be reasonable to continue pregnancy for those in their first or second trimester. pneumonia is the most common cause of fatal nonobstetric infections in pregnant patients [ ] . in the united states, pneumonia complicates approximately per pregnancies [ ] . in taiwan, pneumonia complicates . per pregnancies [ ] . in mainland china, this rate may be even higher. a true estimate of the incidence of severe pneumonia during pregnancy is difficult to obtain because the few published studies in this area are mostly case reports. considering the potential teratogenicity of radiography and drugs, both patients and their physicians tend to postpone radiation examinations and medical treatment when pneumonia is suspected. as a result, delayed diagnoses and referral are common in patients with pneumonia complicating pregnancy [ ] . several physiological and immunological changes that are experienced during pregnancy, such as altered t lymphocyte immunity, increased oxygen consumption, decreased functional residual capacity, decreased chest compliance, and increased risk of aspiration, may predispose pregnant women to a more severe course of pneumonia, which may result in greater maternal and fetal morbidity and mortality [ , ] . a meta-analysis revealed that influenza infection in pregnant individuals resulted in a higher risk of hospital admission than influenza infection in nonpregnant individuals [ ] . early recognition and prompt treatment of severe pneumonia are essential to improve maternal and perinatal outcomes [ ] . because of the complexity of such cases and the ethical considerations, no randomized controlled trials have been performed in this area, and few high-quality studies with large samples for the diagnosis and treatment of severe pneumonia during pregnancy have been published. herein, we report a series of twelve gravid patients with severe pneumonia who were treated at a single institution. both the clinical features and the maternal-fetal outcomes were reviewed. the retrospective study was conducted at peking union medical college hospital (pumch), which is a tertiary comprehensive hospital and referral center offering medical care for high-risk pregnancies in beijing, china. we searched the medical records of pumch to identify patients who were diagnosed with pneumonia complicating pregnancy between january and june . we found such patients. the patients' clinical data including symptoms at presentation, laboratory tests, and treatment strategies were reviewed carefully to screen for severe pneumonia. severe pneumonia was defined according to the american thoracic society guidelines for the management of adults with community-acquired pneumonia as the presence of either one of two major criteria or two of three minor criteria. the major criteria include the need for mechanical ventilation and septic shock. the minor criteria include systolic blood pressure ≤ mmhg, multilobar infiltrates, and pao /fio ratio < [ ] . according to this diagnostic standard, we excluded patients who had mild symptoms or who recovered soon after preliminary treatment. ultimately, gravid patients who were diagnosed with severe pneumonia were included. their detailed data including demographic data, gestational age at diagnosis, symptoms, physical examinations, laboratory tests, chest radiograph findings, treatment strategies, and obstetric and neonatal outcomes were collected from the medical records. major medical complications were simultaneously documented. after the data were collected, they were organized into summary forms to indicate the points in common in patients with severe pneumonia. a total of pregnant women were diagnosed with severe pneumonia at pumch during our study period ( table ) . the maternal age ranged between and years, with a mean age of years. only patient attended regular antenatal care visits at our hospital. the other women were all transferred from other hospitals. eight women were in their third trimester ( - weeks), and the other patients were in their late second trimester ( - weeks) at presentation. the mean gestational age was weeks. anemia was found in six patients ( %) at presentation. the hemoglobin levels of anemic patients ranged from g/l to g/l. patient was previously diagnosed with membranous nephropathy but was cured years prior to becoming pregnant. patient had a history of tuberculosis. patient had a history of severe preeclampsia during her last pregnancy. patient had chronic hypertension. the remaining eight patients had unremarkable past medical histories. all patients had high fevers (> °c) and dyspnea. eight patients ( / , %) reported a productive cough. other symptoms, such as chest pain, malaise, and headache, were also reported. physical examination revealed decreased or bronchial breath sounds in ( %) patients and rales in ( %) patients. dull percussion was found in patient . leukocytosis (> . × /l) was observed in patients ( %) at presentation, and leukopenia (< . × /l) was observed in patient . arterial blood gas analysis showed severe hypoxemia in all patients, with pao /fio ratio ranging from to . the two patients with the lowest pao /fio ratio both died. routine screening tests for the causative pneumonia pathogen, such as sputum culture, blood culture, nasal and throat swabs, and serologic testing, were carried out in patients (except for patient ). tuberculosis was diagnosed in two patients, and viral pneumonia was diagnosed in three patients; the pathogenic virus was confirmed to be h n , h n , and respiratory syncytial virus. patient died within h after admission; thus, none of these tests were carried out. a chest radiograph revealed pulmonary infiltration or consolidation of the bilateral lungs with or without pleural effusion in all patients. for most patients, the disease progression was quick. the time interval between the onset of fever and the confirmation of the diagnosis was typically less than days. for patients and , the interval was longer, at and days, respectively. interestingly, the final diagnoses of these two patients were both tuberculosis. all patients were admitted to the intensive care unit (icu) because of severe hypoxemia ( table ). the length of stay in the icu ranged from day to days. mechanical ventilation was performed in all patients, and the duration of mechanical ventilation ranged from day to days. two patients also received extracorporeal membrane oxygenation (ecmo) therapy for and days. all patients were administered broad-spectrum antibiotics, such as beta-lactams, macrolides, or fluoroquinolones. antiviral medications, namely, oseltamivir, ganciclovir or acyclovir, were administered to patients ( %). standard anti-tuberculosis therapy was initiated in patient and patient as soon as tuberculosis was diagnosed. intravenous courses of pulsed methylprednisolone were administered to patients ( %). four patients also received intravenous immunoglobulin therapy. two of these patients (patient and patient ) died of progressive respiratory failure and heart failure ( table ) . the remaining ten patients recovered well. the major complications observed among these patients included septic shock ( / , %), adult respiratory distress syndrome ( / , %), liver failure ( / , %), acute renal failure ( / , %), severe preeclampsia ( / , %), and stress ulcers ( / , %). patient was diagnosed with the syndrome of inappropriate secretion of antidiuretic hormone (siadh), and patient was diagnosed with thrombotic thrombocytopenic purpura (ttp). ( ) cough -- ( of the patients who presented during their second trimester, patients (patients , , and ) chose to terminate their pregnancies after they had recovered from pneumonia for social reasons. patient experienced intrauterine fetal death and spontaneous miscarriage days after the diagnosis of h n pneumonia. after the miscarriage, the progression of multiple organ dysfunction syndrome (mods) ceased, and she recovered well. of the patients who presented during their third trimester, patient had spontaneous preterm labor on the first day of admission, and she delivered a baby with severe asphyxia (apgar score of at min) who died after several hours. patient had preterm delivery days after recovery. patient experienced intrauterine death at presentation. the other patients, whose gestational ages ranged from weeks to weeks, underwent emergency cesarean section as soon as the diagnosis of severe pneumonia was made. after delivery, the ventilator settings were downregulated for patients, but for patient , who had h n pneumonia, no improvement was observed. although ecmo was used, her cardiorespiratory condition worsened, and she died days later. her newborn infant had mild asphyxia (apgar score of at min) but recovered well after primary resuscitation. the risk of pneumonia during pregnancy appears to be lowest during the first trimester [ ] . advanced gestational age has been proven to be an independent maternal risk factor for pneumonia [ ] . other risk factors for pneumonia in pregnancy include anemia, asthma, smoking, and the use of antepartum corticosteroids and tocolytic agents [ ] [ ] [ ] . in this case series, all the patients presented during their second or third trimester with a mean gestational age of weeks. six patients ( / , %) had anemia at presentation. among these patients, five ( / , %) had hemoglobin levels below g/l. these findings highlighted the possibility of anemia and advanced gestational age as risk factors for severe pneumonia. twenty-five percent of our patients ( / ) had severe preeclampsia, which is much higher than reported prevalence of severe preeclampsia of . % in china [ ] . romanyuk et al. and chen et al. also reported that women with pneumonia had a higher prevalence of preeclampsia/eclampsia than women without pneumonia [ , ] . this increased incidence of preeclampsia/eclampsia might be the result of the pathophysiological changes associated with pneumonia. severe pneumonia is characterized by hypoxemia, which subsequently causes placental hypoxia. the hypoxic placenta releases antiangiogenic and proinflammatory factors that converge upon the maternal endothelium, inducing endothelial dysfunction, hypertension, and organ damage [ ] . the three patients complicated with preeclampsia had significantly lower pao /fio ratios than those without preeclampsia (mean value: vs , p = . ), and two of these patients died. preeclampsia may cause pulmonary edema. of all obstetric causes of respiratory failure before delivery, severe preeclampsia is the leading cause [ ] . a possible explanation for this outcome is that the pulmonary edema caused by severe preeclampsia aggravates the oxygen desaturation caused by pneumonia, predisposing the patient to require a mechanical ventilator. preeclampsia complicated with pneumonia may be an unfavorable predictive factor for a poor maternal outcome. table maternal and fetal/neonatal outcomes case proportion (%) death ( ) septic shock - ( ) fetal/neonatal outcomes ( ) preterm birth na na na na ards adult respiratory distress syndrome, pe preeclampsia, iud intrauterine death, cs cesarean section initial misdiagnosis in pregnant patients is not uncommon. when reviewing the clinical data of these patients, we observed that the initial clinical symptoms were similar to those in nonpregnant women, such as fever, cough, malaise, and dyspnea. it is not easy to distinguish between symptoms related to physiological changes and more sinister symptoms of pneumonia during pregnancy. patient in this case series attended regular antenatal care visits at our hospital; this patient's pneumonia began with the symptoms of a common cold. three days later, when she developed dyspnea, labor started. her respiratory symptoms were intermixed with the discomfort of labor pain. this made the early recognition of pneumonia more difficult. it must be emphasized that close observation is very important; chest radiography should never be withheld from a pregnant woman in whom pneumonia is suspected since the radiation exposure through even multiple diagnostic x-ray procedures or chest ct rarely reaches the dose associated with fetal harm [ ] . there are limited publications regarding the timing of delivery. previous reviews and articles have noted that early delivery is beneficial and potentially life-saving for both mother and fetus [ , ] . however, earlier on in gestation, the size of the uterus should not affect mechanical ventilation significantly, and the fetus may be nonviable at this younger gestational age. additionally, the risk of a surgical procedure for a patient in such a critical condition is extremely high. in our case series, pregnancies were continued in patients during to weeks of gestation; the mothers all recovered from pneumonia, but one of them had a spontaneous miscarriage days after the onset of illness. the other pregnancies were uneventful, and live fetuses were discharged from the hospital. chang et al. and liao et al. also reported cases of atypical pneumonia requiring mechanical ventilation during the second trimester without complications to either the mother or the newborn [ , ] . however, during the third trimester, since elective delivery causes a % reduction in oxygen requirements within h [ ] , and since there is a high rate of adverse pregnancy outcomes in maternal pneumonia [ , ] , most case series in the literature suggest an expeditious delivery after weeks of gestation [ , ] . in our case series, % of our patients ( / ) who presented after weeks of gestation with live fetuses underwent delivery soon after the diagnosis of severe pneumonia was made. their fetal and maternal outcomes were mostly good, except for one neonatal death (patient ) and one maternal death (patient ). according to the reported cases in the literature and the experiences of our hospital, it seems reasonable to terminate pregnancies for patients in their third trimester and to continue pregnancies for those in their first or second trimester. our study included only patients, and it was a retrospective study. these limitations should be taken into account when interpreting the results of the study. in conclusion, severe pneumonia complicating pregnancy was associated with high maternal morbidity and mortality. high incidences of adverse fetal outcomes, such as intrauterine death, preterm birth and cesarean section, were also observed. anemia, advanced gestational age, and preeclampsia were associated with the severity of pneumonia. patients with dyspnea, fever and chest pain should be evaluated carefully; chest radiographs should be taken when the diagnosis of pneumonia is highly suspected. termination of pregnancy is recommended when respiratory function deteriorates progressively despite treatment for patients in their third trimester; it might be reasonable to continue pregnancies for those in their first or second trimester. respiratory disease in pregnancy. best practice & research clinical obstetrics & gynaecology an appraisal of treatment guidelines for antepartum community-acquired pneumonia pneumonia and pregnancy outcomes: a nationwide population-based study infection and acute respiratory distress syndrome during pregnancy: a case series of preventable maternal deaths from southern india pregnancy as a risk factor for severe outcomes from influenza virus infection: a systematic review and meta-analysis of observational studies pneumonia in pregnancy guidelines for the management of adults with communityacquired pneumonia. diagnosis, assessment of severity, antimicrobial therapy, and prevention maternal infectious morbidity following multiple courses of betamethasone cigarette smoking and invasive pneumococcal disease. active bacterial core surveillance team pneumonia as a complication of pregnancy. the journal of maternal-fetal medicine is ethnicity a risk factor for developing preeclampsia? an analysis of the prevalence of preeclampsia in china pneumonia during pregnancy: radiological characteristics, predisposing factors and pregnancy outcomes hypertension in pregnancy: taking cues from pathophysiology for clinical practice maternal and neonatal outcomes of respiratory failure during pregnancy committee opinion no. : guidelines for diagnostic imaging during pregnancy and lactation adult respiratory distress syndrome in pregnancy: report of three cases and review of the literature does delivery improve maternal condition in the respiratory-compromised gravida? successful management of atypical pneumonia in acute respiratory distress syndrome patient during pregnancy severe pneumonia caused by adenovirus in pregnant woman: case report and review of the literature acute and chronic respiratory diseases in pregnancy: associations with placental abruption the authors would like to thank aje (http://www.aje.cn/) for the english language review. availability of data and materials all data generated or analyzed during this study are included in this published article. authors' contributions pt and jw reviewed the medical records. pt and ys conducted the literature review. pt, jw and ys contributed equally to the writing and revision of the manuscript. all authors read and approved the final manuscript. the study protocol was approved by the institutional review board of peking union medical college hospital (protocol number: s-k ), and written informed consent was obtained from all patients or their families for data collection. written informed consent for publication was obtained from all patients or their families at the same time of obtaining consent for data collection. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -xmsfkaoc authors: brown, james; lipman, marc title: community-acquired pneumonia in hiv-infected individuals date: - - journal: curr infect dis rep doi: . /s - - -x sha: doc_id: cord_uid: xmsfkaoc community-acquired pneumonia continues to be an important complication of hiv infection. rates of pneumonia decrease with the use of antiretroviral therapy but continue to be higher than in hiv uninfected individuals. risk factors for pneumonia include low blood cd + count, unsuppressed plasma hiv load, smoking, injection drug use and renal impairment. immunization against streptococcus pneumoniae and smoking cessation can reduce this risk. it is unclear whether newly reported viral respiratory pathogens (such as the middle east respiratory syndrome coronavirus, will be more of a problem in hiv-infected individuals than the general population. community-acquired pneumonia (cap) remains an important cause of morbidity and mortality in hiv-positive individuals [ ] . although the incidence has decreased with the use of antiretroviral therapy (art), rates continue to be elevated compared to hiv-uninfected individuals in both developing and developed societies [ ] . the clinical presentation, range of typical pathogens and outcomes of cap are similar to those without hiv infection, but important differential diagnoses and implications for future health merit particular attention in hiv-infected individuals [ ] . this review considers the evidence concerning cap in hiv-infected individuals, with particular emphasis on studies reported in the last year. we consider the role of bacterial and viral causes of pneumonia and other conditions that can mimic pneumonia. the management of hospital-acquired pneumonia and infections caused by opportunistic pathogens such as pneumocystis jirovecii, cmv, fungal and mycobacterial organisms are covered elsewhere and are not discussed here, beyond stressing that they can all present as an acute pneumonic illness, and hence will often need to be considered as part of the differential diagnosis. prior to the development of effective art, respiratory tract infection was the most common complication of hiv infection [ ] . the advent of art has been associated with a substantial decline in the rates of opportunistic infections and as the frequency of pulmonary infections such as p. jirovecii pneumonia have fallen, bacterial pneumonias have become increasingly prominent in the care of hiv-infected people [ •, •] . although there has been debate as to the increased rate of pneumonia in hiv-infected persons following art, recent data from several large observational cohorts have significantly increased our current knowledge on this subject. the patient cohorts in the multicentre aids cohort study (macs) and the womens interagency hiv study (wihs) have been followed since and , respectively, and allow analysis of rates of pneumonia in the art era. in the macs cohort the adjusted odds ratio for bacterial pneumonia compared with hiv-uninfected individuals has declined from . in the pre-art period to . following the introduction of art [ ••] . the wihs cohort of hiv-infected women have also shown an elevated incidence of pneumonia despite art use with an adjusted odds ratio of . compared with hiv-uninfected controls. similarly, in the veterans aging cohort study (which involved a virtual cohort of , hiv-infected individuals using data from the us national va health information system from the date of hiv diagnosis until ) a rate of per , person-years was found in hiv-infected individuals compared with . per , person-years in hivnegative controls [ ••] . a lower incidence has been seen in the eurosida study of more than , patients in countries studied between and , in which an incidence of pneumonia of . / person-years was found [ ••] . this may reflect the better immune status of participants in the latter era, who had a mean blood cd + count of cells/μl, as very low levels of severe bacterial infections were demonstrated in the eurosida study in those with cd counts above cells/μl (a level generally regarded as near normal). studies in populations other than in europe and the us have confirmed the importance of bacterial pneumonia in hiv-infected individuals, with recent work in taiwan showing this to be the most common respiratory complication of hiv infection in those with cd counts above cells/μl [ ] . however, the general improvement in incidence rates has not been found in all populations, as surveillance data from soweto, south africa, indicate persisting high rates of invasive pneumococcal disease, with no decrease since the introduction of art [ ] . this may be due to the high levels of immunocompromise in this population despite the availability of art, although an increase in invasive pneumococcal disease was found amongst women in that study, suggesting that general uptake of the childhood pneumococcal conjugate vaccination (pcv; which now forms part of the childhood immunization schedule in south africa) may be particularly effective at reducing rates of invasive pneumococcal disease amongst hiv-infected adults in this community. specific risk factors for cap can be identified in the cohorts studied. most have studies have shown that pneumonia is more common in hiv-infected people at any level of immunosuppression, and rates of pneumonia increase with increasing immunosuppression [ ••] . cigarette smoking is consistently reported to increase the risk of pneumonia, with a hazard ratio of . in former smokers compared to current smokers in a cohort study from france [ •] . injecting drug use increases the risk of pneumonia, and although this may be due to confounding diseases, poor adherence to art or socioeconomic factors, some recent evidence suggests that direct effects of opiates or their withdrawal may play a role [ ] . ethnic differences in pneumonia rates, which may be reflective of socioeconomic factors, have been found in some cohorts: rates of pneumonia in african-americans in california are significantly higher than in other ethnic groups [ ] , aboriginal ethnicity is a risk factor for invasive pneumococcal disease in canada [ ••] , and asian ethnicity was associated with reduced risk in the evaluation of subcutaneous interleukin- (esprit) trial [ ] . being a care-giver to young children (who have high rates of pneumococcal carriage) may predispose to invasive pneumococcal disease, and a recent study from south africa confirms significant child-to-mother transmission of pneumococcal strains [ •] . the eurosida study showed that a reduced estimated glomerular filtration rate (egfr) is a significant risk factor for severe bacterial infections including pneumonia, with an incidence rate ratio of . for those with egfr < ml/min/ . m compared to those with egfr > ml/min/ . m [ ••] . it is not clear if this is a direct effect on immune function caused by renal impairment, or the result of other comorbid conditions or lifestyle factors. art is an important protective factor against pneumonia. several cohorts have demonstrated that suppressed hiv loads are associated with a lower incidence of pneumonia, most recently the icona study in italy, which showed an overall incidence of . per , person-years with increased risk in people with low nadir cd + count, low current cd count or high viral load [ •] . this trial followed , individuals for a median of . months between and ; % had an aids diagnosis prior to art initiation and % had a nadir cd count below cells/μl. a low nadir cd count was associated with a hazard ratio for an episode of bacterial pneumonia of . (per cells/μl higher). low current blood cd was associated with a hazard ratio of . (per cells/μl higher) and an unsuppressed plasma viral load was associated with a hazard ratio of . . the strategies for management of antiretroviral therapy (smart) trial demonstrated reductions in the incidence of pneumonia in those on continuous compared to those on intermittent art, as well as a lower incidence in those with an undetectable plasma hiv load [ •] . in this trial (which recruited patients with a cd count of > cells/μl between and ) intermittent rather than continuous art was associated with a . -fold increase in pneumonia incidence. this finding is of particular importance as the randomized trial methodology of intermittent versus continuous art allows confidence that the observed differences in pneumonia incidence are the result of art rather than unmeasured confounding factors. the esprit trial (which evaluated the effect of subcutaneous il- in hiv-infected patients on or starting art with a cd count > cells/μl) also found that a higher hiv plasma viral load was associated with increased risk of pneumonia with a (hazard ratio for a log higher viral load of . ) [ ] . a reduction in pneumonia incidence has also been reported in hiv-infected children in the us, this has been attributed to the use of art and pneumococcal vaccination. an observational cohort study of hiv-infected children observed between and showed lower cd counts in those with pneumonia than in those without pneumonia ( cells/ μl, or %. in a multivariate analysis a hiv viral load of > , copies/ml was associated with a hazard ratio for pneumonia of . [ ] . work in hiv-uninfected populations suggests that the use of statins (hmg coenzyme a reductase inhibitors) may reduce pneumonia-related mortality, possibly by attenuating the associated inflammatory response [ ] . however, a recent study in the netherlands using population-based data found there to be neither a reduction in the frequency of pneumonia nor a worse outcome, when it did occur, in hiv-infected individuals taking regular statin therapy [ ] . it should be remembered that the higher incidence of pneumonia in hiv-infected individuals means that presentation with cap should prompt consideration of hiv testing in patients not known to be hiv-infected. it is estimated that around % of the hiv-infected population in the uk and % of the hiv-infected population in the us are unaware of their serostatus [ , ] . surveys from sub-saharan africa undertaken by usaid have shown that in many countries the majority of hiv-infected individuals do not know their serostatus [ ] . bacterial pneumonia should be regarded as an indicator condition that must prompt discussion of hiv testing. british hiv association guidelines recommend that all patients admitted with bacterial pneumonia should be offered an hiv test, and analysis of primary care data confirms that bacterial pneumonia is one of the strongest indicator conditions for hiv infection [ ••] . invasive pneumococcal disease is particularly strongly associated with hiv infection, with recent uk population-based data showing that . % of patients with invasive pneumococcal disease have undiagnosed hiv infection [ ••] . recent studies have contributed to our understanding of the pathogenesis of pneumonia in hiv-infected individuals. although depletion of the cd + t cell is the hallmark of hiv infection, it is recognized that impairment of innate immune responses plays an important role in the increased susceptibility to pneumonia [ ] . reduced cd + t-cell responses to respiratory antigens have been demonstrated in bronchoalveolar cd + cells when compared with those in hiv-uninfected controls, and a disruption in the t-cell response to pneumococcus appears to precede cd + t-cell depletion [ , •] . hiv causes chronic activation of dendritic cells of the innate immune system, triggering immune dysregulation and apoptosis of cd + and cd + t cells [ , ] . impairment of cd + t-cell responses may also be important, as cd levels have been found to be predictive of pneumonia in the hiv epidemiologic research study (hers) of hiv-infected women in the us after adjustment for age, cd + cell count, viral load and antiretroviral use [ •] . impairment of immune responses within the lung of hivinfected individuals results in changes to the oral and airway microbiota with increased numbers and diversity of microorganisms, including potentially pathogenic species found in hiv-infected patients with pneumonia compared to hivnegative controls [ ] . hiv-infected individuals appear to be particularly susceptible to pneumococcal disease [ ] . rates of carriage of streptococcus pneumoniae were found to be higher in hiv-infected individuals in a prospective cohort of hiv-infected and hiv-uninfected mothers in zambia, although it should be noted that the cd counts in these subjects were not known [ ] . smoking appears to increase rates of pneumococcal carriage [ ] as does a lower nadir cd count and an aids diagnoses [ ] . there may be an interaction between respiratory viral pathogens and rates of invasive pneumococcal disease, as influenza infection has been reported to be associated with increased blood pneumococcal load [ ] . viral pathogens are responsible for a large proportion of respiratory tract infections in hiv-infected individuals, although there are limited data available on the role of viral pathogens. a prospective study in montreal found that among hiv-positive patients with fever and symptoms consistent with respiratory tract infection, viruses accounted for % of these illnesses [ ••] . in this study, % of patients were on art and had a median cd + t cell count of cells/μl, and a median viral load of < copies/ml. influenza was the most important viral cause of respiratory tract infections with of identified viral infections due to influenza, with equal numbers of influenza a and b. other viruses isolated were human metapneumovirus types a and b, respiratory syncytial virus, parainfluenza types and and coronavirus. these pathogens also cause respiratory tract infections in hivuninfected individuals, and it is not known if the incidence or severity of these infections is different in hiv-infected individuals, although respiratory syncytial virus has been reported to be a cause of severe cap in hiv-positive individuals [ , ] . although it is often suggested that hiv-infected individuals may be more susceptible to viral respiratory tract infections, or suffer more severe disease associated with viral pathogens, the evidence to support this is mixed. studies prior to the availability of art suggested that hiv-infected individuals have more severe disease due to influenza infection [ ] . cohen et al. have reported an excess mortality amongst hiv-infected persons during influenza epidemic periods in south africa and the us, with reductions in this excess mortality since the widespread use of art in the us [ ] . however, it is not clear if this excess mortality arises directly from influenza infectionfor example, an observational study in barcelona found no difference in the severity of influenza in patients with and without hiv infection admitted with influenza h n [ ] . the excess deaths in influenza epidemic periods found by cohen et al. may instead be the result of other conditions which are more prevalent at these times, including pneumococcal pneumonia. in general, data from the h n pandemic of do not support the suggestion that hiv-infected individuals experience more severe disease [ , ] . emerging respiratory pathogens such as the middle east respiratory syndrome coronavirus (mers cov) may pose a threat to everybody. no data are yet available on the relative susceptibility of hivinfected individuals to this condition [ ] . it is possible that antiretroviral medication may modify the presentation of influenza infection as protease inhibitors have been shown to block influenza viral replication, although the clinical impact of this observation remains unclear [ ] . hiv-infected individuals with pneumonia present with typical clinical features of an acute illness characterized by fever, pleuritic chest pain, breathlessness and hypoxaemia [ ] . the use of established severity scores has been found to be valid in hiv infection, with the pneumonia severity index (psi) being the best-studied scoring system to assess severity and predict the likelihood of mortality, as confirmed by a recent study from california [ ] . although the management of cap in hiv-infected persons is specifically excluded from pneumonia guidelines from the us and europe [ ] [ ] [ ] . treatment should follow similar principles to those in patients without hiv infection. patients with high curb- or psi scores have a significant risk of death and should be managed in critical care areas where possible. typical bacterial pathogens are similar to those in hiv-negative populations, with s. pneumoniae consistently found to be the most common pathogen. other significant pathogens include haemophilus influenza, klebsiella pneumoniae, staphylococcus aureus, moraxella catarrhalis and pseudomonas aeruginosa [ ] . "atypical" organisms such as legionella pneumophila, mycoplasma spp. and chlamydia pneumoniae represent less than % of cases, although the incidence of these infections in hiv-infected people has not been systematically evaluated. it should be remembered that opportunistic pathogens such as p. jirovecii and cryptococcus neoformans can present with acute pneumonic illnesses and these should be considered in the differential diagnosis of pneumonia in immunocompromised individuals. the incidence of mycobacterium tuberculosis infection is greatly increased in hiv-infected individuals and can present with clinical and radiological features identical to those of bacterial pneumonias (fig. ) . the choice of empirical antibiotic treatment will differ between populations depending on local antibacterial drug resistance. in , rates of penicillin resistance in s. pneumoniae in europe ranged from < % to % [ ] . some data suggest that antibiotic resistance in respiratory pathogens may be higher in hiv-infected individuals, a finding that may be related to the use of cotrimoxazole for pneumocystis pneumonia prophylaxis, or to differences in serotypes infecting hiv-positive individuals [ , ] . mortality rates in cap differ among published series, but most fall in the range - % of cases [ ] . although this has been the subject of some controversy, mortality and length of hospital stay in hiv-infected persons with pneumonia do not seem to differ from those in patients without hiv infection [ ] . it should be noted that most data arise from the us and europe, and may not be applicable to resource-limited settings. recent studies have added to the evidence that blood cd counts do not predict mortality and should not be used to guide therapy or decisions regarding admission to intensive care units [ ••] . changes in the demographic composition of hiv-infected populations may lead to changes in outcome as hiv-positive populations age. for example, information derived from hospital claims databases in the us suggest a higher case fatality rate for pneumonia and influenza in hiv-infected elderly individuals compared to those without hiv infection [ ••] . pneumonia is an important cause of morbidity and mortality in hiv-infected persons and several interventions can reduce this risk. in particular smoking cessation and immunization against pneumococcus and influenza offer the opportunity to modify a patient's risk of pneumonia. hiv-infected populations continue to have high rates of exposure to cigarette smoke [ ] [ ] [ ] . rates of pneumonia are higher in smokers than nonsmokers, and smoking cessation can reduce this [ ••] . a recent systematic review of the literature by de et al. found that current smokers have an increased risk of bacterial pneumonia compared to nonsmokers (hazard ratio . , % confidence interval . - . ) and that this risk is reduced by smoking cessation. in a prospective study in france, a hazard ratio of . was found in former smokers compared to current smokers (p= . ) [ •] . the use of medication as an adjunct to smoking cessation has been extensively investigated in hiv-uninfected smokers, but there are few data from hiv-infected people. a small study of the safety and tolerability of varenicline tartrate in hiv-positive individuals found a high frequency of adverse events, most commonly nausea, but excellent quit rates with a % abstinence rate at weeks. there were no adverse changes in hiv viral loads detected [ ] . given the high incidence of invasive pneumococcal disease in hiv-infected persons, and the efficacy of pneumococcal vaccination in other at-risk groups, there has been considerable interest in immunization against pneumococcus. two forms of pneumococcal vaccination, the -valent pneumococcal polysaccharide vaccine (ppv- ) and pcv have been developed. ppv- has been studied in one randomized trial and observational studies, which are the subject of a recent systematic review [ ••] . this concluded that the current evidence base lends only moderate support for the efficacy of the ppv immunization. the only randomized trial was carried out in africa in a population without widespread access to art and with a high mortality rate, and found an increased rate of pneumonia in the immunized group. however, these results may not be applicable to a population with access to art and lower background rates of pneumococcal pneumonia, and most observational studies have shown that ppv- immunization is associated with a reduced rate of pneumococcal disease, although in many studies confounding factors that could have influenced this observation were not completely accounted for. ppv- suffers from relatively poor immunogenicity, particularly in those with low cd counts, and one study of hiv-infected individuals found that antibody responses declined to pre-immunization levels after months [ ] . in an observational cohort study in canada, % of pneumococcal serotypes isolated were from ppv- , despite the fact that % of this population had received this immunization, and vaccine failure was associated with low cd counts [ ••] . pcv has theoretical advantages in that it induces t celldependent immune responses and has been demonstrated to be immunogenic in hiv-infected adults in several studies [ ] . these have recently been reviewed by nunes and madhi who concluded that pcv is effective at reducing rates of invasive pneumococcal disease, and produces more effective and durable antibody responses in individuals on art than in those who are art-naive [ ] . it should be noted that immune responses to pneumococcal vaccination are significantly better in those with a higher cd count [ ] . apart from the possible direct benefits of pneumococcal immunization, vaccination of young children with pcv- (which offers protection against seven common serotypes) has been associated with indirect benefits in hiv-infected individuals. in the us, widespread use of the pcv- as part of the childhood immunization schedule has been associated with a % reduction in invasive pneumococcal disease caused by vaccine serotypes in hiv-infected adults. these changes in pneumococcal epidemiology following routine childhood immunization have also been observed in other populations, with an % reduction in invasive pneumococcal disease caused by vaccine serotypes in spain [ ] . however, this study also noted an increase in severity and need for mechanical ventilation for pneumococcal pneumonia. work in south africa has also demonstrated reduced levels of pneumococcal carriage following the introduction of childhood pcv, including reductions amongst unvaccinated adults. there appeared to be reductions in nonvaccine pneumococcal serotypes which were not restricted to hiv-infected individuals [ ] . analysis of data from england and wales since the introduction of childhood pcv- immunization suggests that there has been a % reduction in invasive pneumococcal disease caused by the serotypes targeted by the vaccine [ ••] . this study found that % of invasive pneumococcal disease in hiv-infected patients was caused by the serotypes that would be covered by the new -valent pcv (pcv- ). at present, guidelines from the british hivassociation ( ) recommend pneumococcal polysaccharide vaccination in hivinfected individuals with a cd count above cells/μl whilst stating that this should be considered in individuals with lower cd counts and noting that efficacy may be poorer in those with low cd counts who are not on art [ ] . the infectious disease society of america recommends the combination of pcv- and pneumococcal polysaccharide (ppv- ) immunizations with one dose of pcv- followed by ppv- after weeks, although they suggest that this may be delayed until blood cd counts are above cells/μl, when on art [ ] . a health-economic analysis by rozenbaum et al. concluded that the addition of pcv- for hiv-infected adults in england would not be cost effective [ • ]. smith et al. have explored the current recommendations in the us and conclude that a single dose of pcv may be more cost-effective than the current dual immunization strategy, whilst cho et al. have report that the current recommendations would still be cost-saving [ , ] . it should be noted that these studies of cost-effectiveness are very sensitive to the assumptions made regarding vaccine effectiveness. however, these estimates of the cost-effectiveness of pneumococcal immunization are limited by the poor uptake of the pneumococcal immunization amongst hiv-positive adults which appears to be below that of other immunizations [ ] . clinical guidelines in the us and uk advise immunization of hiv-infected individuals with the influenza vaccine. a metaanalysis by beck et al. of published studies suggests that influenza vaccination is effective at reducing the incidence of influenza and is well tolerated [ ] . it should be noted that respiratory comorbidities such as copd are common in hivinfected individuals and immunization of these individuals against influenza may be particularly important. recent work suggests that the immunogenicity of influenza immunization in hiv-infected persons may be improved by high-dose (four times the standard trivalent dose) vaccination [ ] . whilst the increased dose was well tolerated, it was not clear whether the enhanced antibody response translates into better clinical, cost-effective protection. cap is a major cause of morbidity and mortality amongst hiv-infected individuals. although a wealth of evidence attests to the increased rates of pneumonia in immunocompromised individuals prior to the use of art, there have been clear reductions over recent years. hiv-infected populations have high rates of smoking and comorbid respiratory pathologies but current data suggest that hiv infection remains an independent risk factor for cap. at present it is not known whether hiv-infected individuals will have an increased susceptibility to new respiratory pathogens such as mers-cov. the management and outcome of pneumonia in hivinfected individuals does not appear to differ from those in hiv-uninfected persons. several interventions can be made that have been shown to reduce this risk; these include: the use of art and achievement of an undetectable plasma hiv load, smoking cessation, and the uptake of the pneumococcal and influenza immunizations, which international guidelines recommend for hiv-infected individuals. despite an increasing knowledge base there continues to be uncertainty regarding the degree of increased risk of pneumonia in hiv-infected individuals and the best option to reduce this. smoking cessation is of importance, and evidence is required as to the best immunization strategy for this population. conflict of interest marc lipman and james brown have no conflicts. human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by the author. american thoracic 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audit of pneumococcal and hepatitis vaccination in an outpatient hiv clinic university of nottingham influenza and the immunocompromised (uniic) study group. influenza vaccination for immunocompromised patients: systematic review and meta-analysis by etiology improved immunogenicity with high-dose seasonal influenza vaccine in hiv-infected persons: a single-center, parallel, randomized trial key: cord- -u dola authors: morimoto, konosuke; suzuki, motoi; ishifuji, tomoko; yaegashi, makito; asoh, norichika; hamashige, naohisa; abe, masahiko; aoshima, masahiro; ariyoshi, koya title: the burden and etiology of community-onset pneumonia in the aging japanese population: a multicenter prospective study date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: u dola background: the increasing burden of pneumonia in adults is an emerging health issue in the era of global population aging. this study was conducted to elucidate the burden of community-onset pneumonia (cop) and its etiologic fractions in japan, the world’s most aged society. methods: a multicenter prospective surveillance for cop was conducted from september to january in japan. all pneumonia patients aged ≥ years, including those with community-acquired pneumonia (cap) and health care-associated pneumonia (hcap), were enrolled at four community hospitals on four major islands. the cop burden was estimated based on the surveillance data and national statistics. results: a total of , cop episodes out of , hospital visits were enrolled during the surveillance. the estimated overall incidence rates of adult cop, hospitalization, and in-hospital death were . ( % confidence interval, . to . ), . ( . to . ), and . ( . to . ) per , person-years (py), respectively. the incidence rates sharply increased with age; the incidence in people aged ≥ years was -fold higher than that in people aged - years. the estimated annual number of adult cop cases in the entire japanese population was , , , and . % were aged ≥ years. aspiration-associated pneumonia ( , ) was the leading etiologic category, followed by streptococcus pneumoniae-associated pneumonia ( , ), haemophilus influenzae-associated pneumonia ( , ), and respiratory virus-associated pneumonia ( , ), including influenza-associated pneumonia ( , ). conclusions: a substantial portion of the cop burden occurs among elderly members of the japanese adult population. in addition to the introduction of effective vaccines for s. pneumoniae and influenza, multidimensional approaches are needed to reduce the pneumonia burden in an aging society. guardians. the requirement for obtaining written consent from all participants was waived by all irbs because of the study's observational nature without any deviation from the current medical practice. hospital doctors verbally described the study objectives and methods to eligible patients and their guardians during their consultations. we also provided the necessary information to patients and their guardians using a standardized questionnaire sheet and a poster presentation at the outpatient department. anonymized data were used for the analysis. according to the national statistics, the total population in japan was million in [ ] . of this population, . % were ! years of age, and . % were ! years of age [ ] . although no national recommendation for the -valent polysaccharide pneumococcal vaccine (ppv ) existed at the time of study, the cost of ppv was partially or fully subsidized by the local government. the estimated coverage rate of ppv for adults aged ! years was approximately % in [ ] . the study was conducted at four community-based hospitals in four prefectures (hokkaido, chiba, kochi, and nagasaki) in japan from september through january . one hospital is located on each of the four main islands (ebetsu city hospital in hokkaido, kameda medical center in honshu, chikamori hospital in shikoku, and juzenkai hospital in kyusyu). because of japan's universal health insurance system, % of the medical costs for people aged < years and - % of the medical costs for people aged ! years are covered, regardless of whether the individual is treated in the private or public sector [ ] . therefore, we assume that the characteristics of the pneumonia patients visiting these hospitals do not significantly differ from those visiting neighboring hospitals. all the outpatients were screened by hospital physicians, and eligible patients were identified using a standardized case definition. patients who fulfilled all the following criteria were enrolled in the study: ) age ! years, ) with symptoms compatible with pneumonia (e.g., fever, cough, sputum, pleuritic chest pain, and dyspnea), and ) with new pulmonary infiltrates on chest x-ray (cxr) or computed tomography (ct) scan films that were consistent with pneumonia. to ensure that all eligible cases were enrolled, the study investigators screened the hospital database for international classification of diseases, th revision (icd- ) codes and reviewed hospital medical records. all the enrolled cases were classified into cap and hcap groups according to the definitions in the ats/idsa guideline [ , ] . if a patient developed the disease hours after admission, he or she was classified as having hap and was excluded. repeated episodes of pneumonia in the same patient within a -week period were regarded as a single episode. demographic and clinical information were collected from patients and medical charts using a standardized data collection form. sputum and blood samples were collected from the participants on admission; sputum was induced with the inhalation of hypertonic saline solution if the patients were unable to cough up sputum. cxrs were taken from all patients within hours of admission, and ct scans were ordered by clinicians based on their judgment. clinical specimens were immediately transported to the laboratory at each hospital. gram staining was performed on each sputum specimen, and the specimen quality was evaluated by trained laboratory technicians according to miller and jones' classification [ ] . all sputum samples were examined using semi-quantitative or quantitative culture methods. sputum samples were further tested at the institute of tropical medicine, nagasaki university, using in-house multiplex polymerase chain reaction (pcr) assays to identify bacterial and viral pathogens. three typical bacterial pathogens (s. pneumoniae, h. influenzae, and m. catarrhalis), three atypical bacterial pathogens (mycoplasma pneumoniae, chlamydophila pneumoniae, and legionella pneumophila), and thirteen viral pathogens ( [ , ] . we also performed urinary antigen tests for s. pneumoniae and l. pneumophila using commercial kits (binax now streptococcus pneumoniae, binax now legionella; alere inc., waltham, ma, usa). all pneumococcal isolates were serotyped using the capsular quelling method. the etiological category of pneumonia was defined according to the microbiological findings of sputum, blood, and urine samples. the causative pathogens were determined by hospital clinicians and study investigators. because no culture, pcr or rapid urine test is perfect, we estimated the prevalences of s. pneumoniae and h. influenzae using two different methods: ) positivity was defined if either a sputum culture or a urinary antigen test showed a positive result (standard estimation), and ) positivity was defined if a sputum culture, sputum pcr, or urinary antigen test showed a positive result (maximum estimation). to estimate the etiology-specific incidence of pneumonia, aspiration-associated pneumonia was defined independent of microbiological profiles. cases were classified as aspirationassociated pneumonia when the patients had any of the following known risk factors: episodes of aspiration, the presence of dysphagia, consciousness disturbances, neuromuscular diseases, cerebrovascular diseases, tube feeding, and bedridden status [ ] . the prevalence of aspiration-associated pneumonia was calculated separately from those of pathogenspecific category. the age-group specific incidence rates of pneumonia, hospitalization and death in the four prefectures were estimated using the surveillance data and the national statistics. we used the pneumonia-outpatient ratio (por)-based estimation model that was used in our previous study [ ] . in this model, the number of age group-specific pneumonia cases was estimated using the age group-specific number of outpatients and the age group-specific por. pors were calculated for hospitals and clinics separately. the model used to estimate the number of pneumonia outpatient visits was as follows: c ijk : the annual number of outpatients reported to the patient survey in age group i, prefecture j, and facility type k (k = , hospitals; k = , clinics) α ijk : the ratio of confirmed pneumonia patients to the number of total outpatients in age group i, prefecture j, and facility type k p ij : the population in age group i and prefecture j c ijk was obtained from the patient survey conducted by the mhlw in [ ] . the survey was conducted at hospitals and clinics on one designated date set for each hospital on one of three days in october. p ij was obtained from the national demographic survey in [ ] . the proportion of pneumonia cases among outpatients in hospitals (α ij ) was calculated from the surveillance data. to estimate the proportion of pneumonia cases among outpatients in clinics (α ij ), we obtained the clinic databases from two clinics in nagasaki city. pneumonia diagnosis was confirmed using the case definition identical to that used for the hospital-based surveillance. α was estimated for each age group using curve fitting. age-standardized rates were calculated using the who world standard population [ ] . the number of pneumonia cases in the entire japanese population was estimated assuming that the incidence rates (i ij ) were constant across all prefectures. during the study period, a total of , patients visited the study hospitals; , of these patients were enrolled in the study. after excluding cases that did not meet the criteria, , patients were eligible for our analysis (see supplementary material, s fig) . ct scans were administered to , patients ( . %), including ( . %) who did not demonstrate any infiltrates on their cxrs. the demographic and clinical characteristics of the enrolled cases are shown in table . fifty-nine percent of all patients were male, and the median age was years (range: to ). seventy-five percent of the patients were elderly people aged ! years, and % were aged ! years. the case fatality rate was %. seventy-two percent of our cases were hospitalized, and these cases were more likely to be male, older, smokers, and classified as having hcap; more likely to have underlying conditions, aspiration-associated conditions, and severe conditions; more likely to visit the hospital early; and more likely to have a fatal outcome compared with outpatients. among , sputum samples tested using conventional cultures, causative bacterial pathogens were isolated from ( %) samples; ( %) were monoclonal and ( %) were polyclonal (table ). h. influenzae was the most common bacterial pathogen isolated ( %), followed by s. pneumoniae ( %). h. influenzae was more frequently isolated from outpatient cases, while staphylococcus aureus, klebsiella pneumoniae, and escherichia coli were more frequently isolated from hospitalized cases. among the sputum samples tested using multiplex pcr, ( %) were positive for any bacterial pathogens; % were positive for s. pneumoniae, and % were positive for h. influenzae. h. influenzae and m. pneumoniae were more frequently detected in samples from outpatient cases than those from hospitalized cases. s. pneumoniae was isolated by blood culture from . % (n = / , ) of cases, and s. pneumoniae urinary antigen was detected in % (n = / ). taken together, . % of samples were positive for s. pneumoniae either by culture, pcr, or urinary antigen tests. among s. pneumoniae isolates, were serotyped; serotype was the most dominant (n = , %), followed by serotypes a (n = , %) and f (n = , %). ppv covered % of all serotypes, and % were covered by -valent pneumococcal conjugate vaccine (pcv ) (see supplementary material, s fig) . multiplex pcr was used to test , sputum samples for rvs, and % of the samples were positive for at least one rv (table ) . hrv was the leading virus identified, followed by infa and rsv. the positivity rates for rvs were similar between the outpatient cases and the hospitalized cases. among sputum samples tested for viral and bacterial pcrs, ( %) were both positive. among all , patients, ( . %) were with aspiration-associated conditions (ie, aspiration-associated pneumonia): ( . %) had episodes of aspiration, ( . %) dysphagia, ( . %) consciousness disturbances, ( . %) neuromuscular diseases, ( . %) cerebrovascular diseases, ( . %) tube feeding, and ( . %) bedridden status. among sputum samples available from aspiration-associated pneumonia, staphylococcus aureus was the most common bacterial pathogen isolated by culture ( %), followed by s. pneumoniae ( %) and klebsiella pneumoniae ( %) (see supplementary material, s table) . s. pneumoniae and h. influenzae were less frequently detected in samples from aspiration-associated pneumonia than those from non-aspiration-associated pneumonia by culture and pcr. the burden of cop the overall annual incidence rate of adult pneumonia in the four prefectures was . per , py ( % ci, . to . per , py) in japan, and the asr was . ( . to . ; table ). the incidence rate was highest in kochi ( . per , py) and lowest in chiba ( ) ( ) ( ) . m. pneumoniae ( ) ( ) ( ) < . ( . per , py), while the asr did not differ significantly by prefecture, ranging from to . per , py (see supplementary material, s table) . the rate was higher in males than in females ( . vs . per , py in all age groups; . vs . per , py in people aged ! years). it was lowest in those aged - years ( . per , py), increased sharply with age, and became highest in the population aged ! years ( . per , py; %ci, . to . ; fig ) . this age-associated increase in the rate was more apparent in males than in females (the point estimates of the rate ratios comparing males and females in people aged - years, - years, - years, and years were . , , . , and . , respectively). this increasing trend was also observed for pneumonia-related hospitalizations and in-hospital death. for the etiology-specific incidence estimates, the etiology-associated incidence rate was calculated according to age group (table ) . although aspiration-associated pneumonia had the highest incidence, there were substantial numbers of infection-associated pneumonia cases among older people; s. pneumoniae-, h. influenzae-, and rv-associated pneumonia followed. the exception was atypical pneumonia; the incidence of atypical bacteria-associated pneumonia was highest among younger people (aged - years). in our study population, only out of , cases had positive blood cultures, indicating that the incidence of bacteremic pneumococcal pneumonia was per , py ( % ci, . to . per , py). assuming that these proportions of pneumonia etiologies were constant across all prefectures, the estimated annual number of cop in the entire japanese adult population was , , ; of these, , , cases ( %) occurred in people aged ! years (fig ) . seventy percent were hospitalized cases, and % of all pneumonia cases were cap. among cop cases, , died in hospitals. , cases were aspiration-associated, and % of patients with this condition were aged ! years. , cases were s. pneumoniae-associated, , were h. influenzae-associated, and , were rv-associated pneumonia. to our knowledge, this study is the first to estimate the burden of pneumonia in the entire japanese adult population. in , the overall incidence of community-onset pneumonia, including cap and hcap, among people aged ! years was . per , py; the incidence sharply increased with age and reached up to . per , py among people aged > years. the estimated annual number of adult cop patients in japan was , , , % of which were elderly people aged ! years. aspiration was the leading etiologic category of pneumonia, though a substantial number of cases were still associated with infections, such as s. pneumoniae. our findings clearly indicate that pneumonia is an age-related disease that causes an enormous burden in this aging population. the incidence of pneumonia in japanese elderly people was higher than the incidences observed in large-scale population-based studies in both the united states and european countries. in japan, the incidence of cop among people aged ! years was . per , py; in contrast, cop incidences were . per , py in the united states [ ] , per , py in spain [ ] , and per , py in the united kingdom [ ] . the high pneumonia incidence in japan may be partially explained by its high proportion of extremely elderly people aged ! years ( % of the elderly population in [ ] ). however, the trend did not fundamentally change after the incidence was standardized using the who world standard population: the asrs of cop among the elderly in japan, the united states, spain, and the united kingdom were . , . , . , and . per , py, respectively. the in-hospital mortality rate for cop in japan ( . %) was lower than that reported for other countries ( . % in the united states [ ] , % in spain [ ] , and > % in the united kingdom [ ] ). these findings suggest that patients with mild pneumonia cases that may be overlooked in other countries are visiting clinics and being diagnosed in japan. in fact, % of our pneumonia cases were examined with ct scans to diagnose pneumonia. the good access to healthcare facilities resulting from universal health coverage and the wide use of sensitive diagnostic tools may explain this high incidence. however, it does not indicate that the hospitalized cases in japan are milder than those in other countries; the proportion of severe cases (curb score ! ) in the current study was %, compared with % in the united kingdom [ ] and % in spain [ ] . the pneumonia incidence and in-hospital morality were higher among males than among females, especially among the older age group, confirming previous works [ , , ] . considering the higher incidence of childhood pneumonia among males, they may be genetically vulnerable to pneumonia; however, there is no evidence to support this hypothesis. according to our estimates, aspiration was the leading cause of pneumonia, and the burden of pneumonia associated with aspiration was higher than that associated with any single pathogen, including s. pneumoniae. the burden was particularly high among the elderly population; . % of aspiration-associated pneumonia cases occurred in patients aged ! years. the inhospital mortality for aspiration-associated pneumonia ( . %) was higher than that for other pneumonia categories ( %). aspiration-associated pneumonia has been overlooked in current pneumonia control programs. although previous studies have shown that this condition is common among hospitalized pneumonia patients [ , ] , its burden has never been evaluated at the population level in the past. aspiration-associated pneumonia is a multi-factorial condition observed in older people. impaired swallowing and an abnormal cough reflex increase the risk of oropharyngeal aspiration; the aspiration of colonized pathogens and gastric acid causes lower respiratory tract infection and/or lung injury [ ] . compromised immunity, comorbidity and changes in lung function in this age group underlie this condition and are associated with the high mortality. nursing home residents are at high risk for aspiration, but hcap and aspiration-associated pneumonia are not identical conditions. in fact, in our study, . % of cap and . % of hcap cases were associated with aspiration. effective clinical management and preventive measures targeting aspiration-associated pneumonia remain underdeveloped. ats guidelines recommend using β-lactam/β-lactamase inhibitors for this condition [ , ] , but the management of recurrent and refractory cases is challenging. for prevention, oral hygiene care and dysphagia rehabilitation have been suggested for reducing the risk of aspiration pneumonia, but with limited supporting evidence [ ] . the burden of aspiration-associated pneumonia may further increase as the number of elderly people who require long-term care increases. effective clinical and public health intervention measures are urgently needed. in the current study, s. pneumoniae was the leading single etiological pathogen and was associated with - % of pneumonia, confirming previous reports [ ] . recent studies in japan have shown that the positivity of s. pneumoniae among cap cases was % [ ] to % [ ] . according to a recent meta-analysis, the proportion of pneumococcal pneumonia among cap cases was - % [ ] . the proportion of pneumococcal pneumonia among all pneumonia cases is declining in high-income countries, reflecting the wide use of antibiotics and pneumococcal vaccines [ ] . in our study, the positivity of s. pneumoniae by sputum culture was only %. considering the low sensitivity of sputum culture, we included urinary antigen test-positive cases for the standard estimation and further included pcr-positive cases for the maximum estimation. the true value must lie between these values (i.e., to %). the proportion of bacteremia among pneumococcal pneumonia cases was % in our study. a meta-analysis showed that approximately % of pneumococcal pneumonia is bacteremic [ ] ; our figure was lower than this estimate. however, our results showed that the incidence of bacteremic pneumococcal pneumonia among japanese adults was per , py, a figure that was comparable with those reported for other countries, such as the united states [ ] and australia [ ] . the findings suggest that pneumococcal pneumonia, either bacteremic or non-bacteremic, remains the leading target for pneumonia control programs in japan. ppv reduces the risk of invasive pneumococcal diseases (ipds) among adults; however, its effectiveness against pneumococcal pneumonia is still controversial, particularly for the elderly [ ] . the recently approved pcv is expected to prevent almost half of the pneumococcal pneumonia cases in the elderly [ , ] ; however, the vaccine covers only serotypes of pneumococcus, and its long-term effects remain unknown. in japan, before the introduction of pcv for children in , % of ipd isolates were ppv serotypes, and % were pcv serotypes [ ] . in the current study, % of the isolates were ppv serotypes, and % were pcv serotypes. the vaccination policy for pneumococcus has been dramatically changing in japan. pcv for children was replaced by pcv in late , and ppv was also included in the ministry of health, labour and welfare recommended vaccines for elderly people in late . the proportion of vaccine-covered serotypes is known to decline after widespread use of pcv [ ] ; thus, these figures will decrease in coming years. the true efficacy of pcv for adult pneumonia among the japanese population must be evaluated along with cost-effectiveness analyses before it is introduced into the national immunization program. a substantial proportion of pneumonia was associated with rvs ( % of all pneumonia cases). recent studies suggest that rvs play crucial roles in the development of pneumonia, including severe cases [ , , [ ] [ ] [ ] ; however, their biological mechanisms remain largely unknown. rvs such as influenza, rsv, and human metapneumovirus (hmpv) cause outbreaks among the elderly in nursing homes [ , ] , and these rvs are potential targets for vaccination. currently, only seasonal influenza vaccines are available for adults, but their effects on pneumonia prevention have not yet been established [ ] . further investigations are needed to clarify the public health impact of rv-associated pneumonia in aging societies. our findings have important implications for effective pneumonia control programs in the aging society. the burden of pneumonia is higher in older people, and the pneumonia etiology largely varies by age group: the incidences of aspiration-, s. pneumoniae-, h. influenzae-, rv-, and pdr pathogen-associated pneumonia increase with age, while the incidence of atypical bacteria-associated pneumonia decreases. it must be noted that the proportion of pneumonia caused by unknown pathogens is higher among elderly people. this category most likely represents multifactorial conditions. therefore, in coming decades, the pneumonia burden will likely increase, and its etiology will become more diverse. in this situation, the current etiologyspecific approach (i.e., vaccinations for pneumococcus and influenza, guidelines for appropriate antibiotics use) must have only a limited impact. a multidimensional approach integrating vaccination programs, clinical management guidelines, training for health care workers, and education for people must be needed; further studies are warranted. this study is the first to estimate the national burden of cop in japan. although pneumonia is a common disease, its true burden remains unclear, even in high-income countries. a number of studies have reported the incidence of adult pneumonia, but their estimates substantially varied from setting to setting [ , , - , , , ] . several factors explain this variation. first, the definition of pneumonia differs among studies. some studies have reported incidences of cap that include outpatients and hospitalized patients [ , , ] , while other studies have reported hospitalized cases only [ , ] . it was not clear whether these studies included hcap cases. additionally, the diagnosis of pneumonia is not standardized in clinical settings; thus, the burden estimates based on existing database are unreliable. second, study designs vary. pneumonia is a common disease, and it is not included in national surveillance. cohort studies may not represent the entire population of a country, while hospital-based studies do not capture all the cases in the community. different designs may produce different estimates in an identical population. third, the health care-seeking pattern affects the incidence estimates. mild cases must be overlooked in countries in which access to health care is limited. in the current study, we enrolled pneumonia cases prospectively, and all were confirmed by study clinicians using the standardized case definition. considering the high reliability of national statistics in japan, our estimates can be reasonably assumed to reflect the true pneumonia burden among japanese adults. our study has limitations. for the incidence estimation, we assumed that the pneumonia-outpatient ratios in the study hospitals were constant across all hospitals in the four prefectures. additionally, to calculate the national burden, we assumed that the incidence of cop in the four prefectures was constant across all prefectures. our hospitals were community-based general hospitals that provided primary, secondary, and tertiary care for residents; thus, the patients visiting these hospitals reflected the general population. in fact, the asrs in the four prefectures were almost identical in our study. furthermore, according to the national patient survey, the proportion of reported acute respiratory infections among all outpatients in the four prefectures was identical to the national average (see supplementary material). we believe that these assumptions are reasonable. in contrast, we did not consider seasonal differences in the pneumonia etiology. our etiology-specific burden estimates must be confirmed using multi-year surveillance data. in this study, aspiration-associated pneumonia was defined based on the presence of known risk factors; thus, we could not distinguish between "aspiration pneumonia" caused by aspiration of colonized oropharyngeal pathogen or "aspiration pneumonitis" caused by aspiration of gastric contents [ ] . however, there is no reliable marker to identify aspiration [ ] . further studies are needed to better define this pneumonia category. a substantial portion of the cop burden in the japanese adult population occurs in the elderly. aspiration was the leading etiology of pneumonia, followed by s. pneumoniae. in addition to the introduction of vaccines for s. pneumoniae and influenza, multidimensional approaches are urgently needed to reduce the pneumonia burden in this aging society. supporting information s database. database of community-onset pneumonia cases. table. microbiological profiles of patients with community-onset pneumonia with and without aspiration-associated conditions. 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laboratory staff at the participating hospitals. we would like to thank rina shiramizu and kyoko uchibori for performing pcr and yumi yamasaki for administrative work. we also wish to thank hidefumi yamamoto and masatoshi ide for sharing their data. adult pneumonia study group-japan (apsg-j) are: masahiko abe , takao wakabayashi , masahiro aoshima , naoto hosokawa , norihiro kaneko , naoko katsurada , kei nakashima , yoshihito otsuka , eiichiro sando , kaori shibui , daisuke suzuki , kenzo tanaka , kentaro tochitani , makito yaegashi , masayuki chikamori , naohisa hamashige , masayuki ishida , hiroshi nakaoka , norichika aso , hiroyuki ito , kei matsuki , yoshiko tsuchihashi , koya ariyoshi , bhim g dhoubhadel , akitsugu furumoto , sugihiro hamaguchi , , tomoko ishifuji , shungo katoh , , satoshi kakiuchi , emi kitashoji , takaharu shimazaki , motoi suzuki , masahiro takaki , konosuke morimoto à , kiwao watanabe , lay-myint yoshida key: cord- -gl uuqej authors: del borrello, giovanni; stocchero, matteo; giordano, giuseppe; pirillo, paola; zanconato, stefania; da dalt, liviana; carraro, silvia; esposito, susanna; baraldi, eugenio title: new insights into pediatric community‐acquired pneumonia gained from untargeted metabolomics: a preliminary study date: - - journal: pediatr pulmonol doi: . /ppul. sha: doc_id: cord_uid: gl uuqej background: available diagnostics often fail to distinguish viral from bacterial causes of pediatric community‐acquired pneumonia (pcap). metabolomics, which aims at characterizing diseases based on their metabolic signatures, has been applied to expand pathophysiological understanding of many diseases. in this exploratory study, we used the untargeted metabolomic analysis to shed new light on the etiology of pcap. methods: liquid chromatography coupled with mass spectrometry was used to quantify the metabolite content of urine samples collected from children hospitalized for cap of pneumococcal or viral etiology, ascertained using a conservative algorithm combining microbiological and biochemical data. results: fifty‐nine children with cap were enrolled over months. pneumococcal and viral cases were distinguished by means of a multivariate model based on metabolites, of which were identified and considered as putative biomarkers. among these, six metabolites belonged to the adrenal steroid synthesis and degradation pathway. conclusions: this preliminary study suggests that viral and pneumococcal pneumonia differently affect the systemic metabolome, with a stronger disruption of the adrenal steroid pathway in pneumococcal pneumonia. this finding may lead to the discovery of novel diagnostic biomarkers and bring us closer to personalized therapy for pcap. community-acquired pneumonia (cap) is the single most common cause of death among children worldwide, and a leading cause of hospitalization. , although the body of knowledge of the epidemiology, etiology, microbiology, and pathophysiology of cap has expanded over the last few decades, basic patient management questions remain largely unanswered. in fact, when confronted with a feverish child with respiratory symptoms, the single most important management question is whether or not to start antibiotics, which translates into how confident is the treating physician that the child in question does not have a bacterial lower respiratory tract infection. , although epidemiological research has repeatedly pointed out that the large majority of lower respiratory infection in pediatric patients are caused by viruses, physicians often lack the tools to reliably discriminate between bacterial and viral etiology [ ] [ ] [ ] and a large percentage of children presenting with respiratory symptoms and fever are ultimately administered antibiotics. the absence of certainty regarding cap etiology thus prompts an overtreatment with the consequence of increasing the emergence of bacterial resistance. metabolomics is the newest branch of the systems biology approach to biomedical research. [ ] [ ] [ ] it aims to provide an unabridged description, both qualitative and quantitative, of all the metabolites (ie, molecules with a molecular weight of less than da) found in human biofluids and tissues at a given time. in other words, it aims to define particular metabolic signatures, or fingerprints, characterizing a disease state. powerful analytical tools are used to amass large amounts of data, which are analyzed and applied to previously-unsolvable, complex questions of biology. in particular, metabolomics can provide a more comprehensive overview of a diseaseʼs pathophysiology, identify new biomarkers for use in diagnostics, and point to potential therapeutic targets to consider in the search for new drugs. in the present exploratory investigation, a hypothesis-free approach based on untargeted metabolomics was applied to pediatric cap (pcap) in an effort to improve the diagnosis and clinical management of this common childhood infection. more specifically, our study aimed to elucidate whether a specific metabolic signature differentiates pneumococcal from viral pcap. the study was approved by each centerʼs institutional ethics committee. written informed consent, signed by both parents, was required for a child to be included in the study; for children aged years or older, the childʼs written informed assent was also required. cases eligible for this study were hospitalized children less than years of age with a diagnosis of moderate to severe pneumonia. this diagnosis of cap was based on clinical presentation (presence of fever, symptoms suggestive of an acute respiratory illness defined as new cough or sputum production, chest pain, dyspnea, tachypnea), abnormal lung examination and chest x-ray results. , chest x-rays were evaluated by a blinded radiologist to the study participants. the decision to admit a child to the hospital for cap was made by the attending physician in the emergency department. to increase the specificity of our findings and reduce the role of confounding variables, three exclusion criteria were strictly applied, concerning: infants (ie, children under year of age), to avoid any diagnostic overlap between pneumonia and bronchiolitis; children with a previous diagnosis of chronic disease (hiv, asthma, immunodeficiency, chd), to reduce the pathophysiological heterogeneity between cap cases; and children given any oral or injected antibiotic therapy in the hours preceding enrollment, to avoid cases of partially treated pneumonia, as the related pathophysiological profile differs from that of a lung infection devoid of any treatment. the pharmacological treatment of the recruited subjects was monitored during hospitalization to evaluate potential confounding effects on our findings. a three-step algorithm combining microbiological information obtained from the pcr assays and pct levels was used to ascertain pneumonia etiology for subsequent metabolomic analysis. three variables were considered sequentially: presence or absence of respiratory viruses revealed by the multiplex pcr assay; presence or absence of s. pneumoniae on the pcr assay; and pct cutoffs of . and . ng/ml. using this algorithm, a viral etiology was assumed in the presence of respiratory viruses, the absence of s. pneumoniae, and pct < . ng/ml; a pneumococcal etiology was assumed in the absence of respiratory viruses, the presence of s. pneumoniae, and pct ≥ . ng/ml. cases not falling into either category were labeled as "undetermined" and not included in the subsequent analysis. this strategy was applied to obtain "pure" groups for metabolomic investigation, by limiting the number of false-positive cases (ie, s. cases with inconsistent results between pct measurement and pcr analysis) and were excluded from any further subclass analysis. table contains the clinical and demographic characteristics of the patients searching the available online metabolite databases generated a putative identification for of these variables ( table ) . pneumoniae pleural infection, probably as a consequence of the aggressive metabolic activity and amino acid biosynthesis induced by s. pneumoniae replication. cyclic guanosine monophosphate (cgmp), the next significant molecule emerging from our analysis, mediates many of the proinflammatory and anti-inflammatory functions of nitric oxide (no). tolllike receptor ligands induce the expression of cgmp by increasing the activity of no synthetase; in fact, endotoxin infusions in healthy volunteers have been shown to raise both exhaled no and cgmp plasma concentrations. bacteria may also increase the synthesis of cgmp by producing no directly. our study corroborates these previous reports and provides evidence for the plausibility of using this metabolite as a diagnostic marker of bacterial infection. another two molecules of interest to this discussion are -methylglutaryl-carnitine (an acyl-carnitine), and ′-n-acetyl-neuraminyl-n-acetyllactosamine (a sialyl oligosaccharide). carnitine metabolism is tied to mitochondrial homeostasis and has long been studied in the context of severe infections. septic patients show many abnormalities in lipid metabolism, including a depletion of the cellular levels of l-carnitine, a reduction in its plasma levels, and an increase in its urinary excretion. three recent metabolomic studies also found an increase in the urinary concentration of acyl-carnitines in patients with bacterial pneumonia. , , indeed, the pneumococcal cytotoxin pneumolysin causes mitochondrial damage, which may account for the observed disarray in lipid metabolism. , sialyl oligosaccharides are broken down and digested by lysosomes, and a relative increase in sialyl oligosaccharides in the course of bacterial infections may represent a transient lysosomal dysfunction. indeed, the role of lysosomes in human health and disease is just starting to be unveiled, but evidence is already accumulating of lysosomes serving as regulators of macrophage function, and as key effectors of s. pneumoniae intracellular killing. a recent meta-analysis of transcriptomic studies also showed that messenger rna pathway associated with lysosomal function were among the most profoundly disrupted in the course of human sepsis. in short, our study points to organelle dysfunction as a crucial discriminator between bacterial and viral infection. viral pneumonia is associated with an increase in urine concentrations of glycyl-l-hydroxy-proline (gly-pro), an end product of collagen metabolism and the substrate of the enzyme prolidase, which promotes the surface expression of the interferon-i receptor and is a target of viral antagonism. , the higher urinary levels of gly-pro found in our study may, therefore, reflect an impaired prolidase activity, which could be expected in the course of viral infection. although state-of-the-art, high-throughput analytical methods and chemometric data processing methods were used in our study, it has some weaknesses. the most important concern the fact that we did not collect samples in therapy-naive patients, and this constitutes a veritable source of bias. this issue could have been avoided by collecting urine samples from all therapy-naive children presenting to the emergency department with respiratory symptoms and a fever, and then analyzing only those obtained from children actually enrolled in the study. this will be worth bearing in mind for future metabolomic studies conducted in acute care settings. another weakness of our study concerns the small number of patients in our two groups, which may limit the validity of our findings. on the other hand, our adoption of stringent enrollment criteria and a conservative diagnostic algorithm ensured that the two groups were etiologically pure, thus enhancing the specificity of our findings. a further potential limitation of this exploratory study lies in the lack of any external validation set against which to test our models, which could only be validated internally by means of a cross-validation and stability selection to ensure the reliability of the findings emerging from the data collected. though ours is only a preliminary study, the present findings seem to be a promising starting point for the conduction of larger, validated studies. in global, regional, and national causes of child mortality in - , with projections to inform post- priorities: an updated systematic analysis community-acquired pneumonia requiring hospitalization among u.s. children a systematic review on the diagnosis of pediatric bacterial pneumonia: when gold is bronze antibiotic therapy for pediatric community-acquired pneumonia: do we know when, what and for how long to treat? does this child have pneumonia?: the rational clinical examination systematic review specimen collection for the diagnosis of pediatric pneumonia laboratory methods for determining pneumonia etiology in children antibiotic prescribing in ambulatory pediatrics in the united states 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platelet inhibition and increases vascular endothelial permeability via nitric oxide regulated pathways plasma carnitine levels and urinary carnitine excretion during sepsis lipid mediators of inflammation as novel plasma biomarkers to identify patients with bacteremia virulence factors in pneumococcal respiratory pathogenesis pneumolysin causes neuronal cell death through mitochondrial damage activator of g-protein signaling -induced lysosomal biogenesis limits macrophage intracellular bacterial infection streptococcus pneumoniae invades endothelial host cells via multiple pathways and is killed in a lysosome dependent manner lysosome and cytoskeleton pathways are robustly enriched in the blood of septic patients: a meta-analysis of transcriptomic data flavivirus antagonism of type i interferon signaling reveals prolidase as a regulator of ifnar surface expression supporting information additional supporting information may be found online in the supporting information section. how to cite this article new insights into pediatric communityacquired pneumonia gained from untargeted metabolomics: a preliminary study the authors declare that there are no conflict of interests. http://orcid.org/ - - - key: cord- -hnbgaxft authors: krishnamurthy, a.; palombo, e. title: current therapeutics and prophylactic approaches to treat pneumonia date: - - journal: the microbiology of respiratory system infections doi: . /b - - - - . - sha: doc_id: cord_uid: hnbgaxft bacterial pneumonia caused by streptococcus pneumoniae, haemophilus influenzae, staphylococcus aureus, mycoplasma pneumoniae, and klebsiella pneumoniae represents a frequent cause of mortality worldwide. the increased incidence of pneumococcal diseases in both developed and developing countries is alarmingly high, affecting infants and aged adult populations. the growing rate of antibiotic resistance and biofilm formation on medical device surfaces poses a greater challenge for treating respiratory infections. over recent years, a better understanding of bacterial growth, metabolism, and virulence has offered several potential targets for developing therapeutics against bacterial pneumonia. this chapter will discuss the current and developing trends in treating bacterial pneumonia. the mucosal epithelium of the nasopharynx is a well-recognized primary site of bacterial colonisation including the opaque and transparent phenotypes of the pneumococcus. the pneumococcus can traverse down to the lung upon aspiration and start adhering to the alveolar type ii cells to initiate bacterial infection. the progress to pneumonia can occur more rapidly if there is a preexisting respiratory viral infection or increased bacterial adherence facilitated by viruses or cytokines. the different stages of pneumococcal pneumonia are well known. the first stage is characterized by a bulge or engorgement due to the bacterial presence and serous exudate in the alveoli which provides nutrients to the bacteria and facilitates further infection in the lung. the next stage is the intense inflammatory reaction involving leakage of erythrocytes into the alveoli (red hepatisation), followed by the migration of leukocytes into the consolidated area (gray hepatisation), and surface phagocytosis by the leukocytes. due to the intact immune system of the host, normally the type-specific antibodies and the polymorphonuclear leukocytes phagocytise the pneumococci and the lung returns to its normal state. however, in patients with a compromised immune system having certain complement deficiencies or hypogammaglobulinemia (absence of type-specific antibodies), bacteremia can occur and the pneumococcus with its virulence factors (mostly cell wall components such as peptidoglycan, techoic acid, and proteins such as pneumolysin) induce inflammation causing subsequent tissue damage. since the early s, the lrti caused by s. pneumoniae in certain developing countries, such as ghana and south africa, have been reported at > - % of all cases in children less than years of age, and per population of adults per year, and has remained at equivalent rates even a decade later. [ ] [ ] [ ] the incidence of pneumonia in children less than years of age was higher in regions such as south-east asia, africa and western pacific countries in comparison with those in the developed countries like the americas and europe. more recently, the incidence of childhood pneumonia has been estimated to be > million globally, of which ∼ % progressed to severe disease with % vaccination mortality in children < years of age. the risk factors for childhood pneumonia, especially in the developing countries, include nutrition deficiencies, lack of breastfeeding, indoor air pollution due to passive smoking, hiv infection, and substandard housing and living conditions. the etiological agents causing pneumonia include both bacteria and respiratory viruses. certain vaccine studies have indicated the predominant bacterial agent causing pneumonia to be s. pneumoniae resulting in almost - % severe cases and - % mortality, followed by h. influenzae accounting for % of severe cases and % of deaths. influenza virus remains the dominant viral etiological agent responsible for % of the severe cases and % of deaths. , s. pneumoniae is also well-recognized to cause community-acquired pneumonia (cap) in children with lower fatality rates of . %. in addition to these etiological agents, bacteria such as staphylococcus aureus, klebsiella pneumoniae, and respiratory viruses such as rsv, rhinovirus, human metapneumovirus, human bocavirus and parainfluenza viruses are the other commonly identified agents that contribute to the burden of childhood pneumonia. , community-acquired pneumonia (cap) is an increasing health problem and the third most common reason for hospitalization for adults, especially the elderly aged > years. the prevalence of cap has been reported as - cases per population with an increase from % in - year olds to % in - year olds, and % in > year olds. , several predisposing factors such as impaired immunity and lung function, dysfunctional nasal mucociliary clearance, lung and heart diseases, smoking have been identified as independent predictors for cap in adults and the elderly. certain studies have reported s. pneumoniae, legionella species, h. influenzae, moraxella catarrhalis, and s. aureus as the predominant pathogens in cap. although the role of respiratory viruses has been well-recognized in cap in children and infants, it is not well understood in adults and the elderly. it is still unclear whether a virus by itself can cause pneumonia or whether the virus can act in conjunction with other respiratory pathogens. one study has reported that respiratory viruses such as influenza virus, rsv, adenovirus, and rhinovirus were commonly isolated as part of a co-infection, especially with s. pneumoniae. thus, viral agents in adults with cap most often seem to be part of a mixed infection, usually with s. pneumoniae as the co-pathogen. the world health organisation (who) recommends routine childhood immunization programs that include vaccines that offer protection from various respiratory disease such as pneumonia, influenza (flu), measles, and pertrussis. the haemophilus influenzae type b (hib) vaccine and the pneumococcal conjugate vaccines are increasingly available in both developed as well as developing countries, especially the -and -valent pneumococcal conjugate vaccines which have shown effectiveness in reducing the incidence and severity of pneumonia and other lower respiratory infections in children. currently, there are three vaccines in the childhood routine immunization schedule; measles, hib, and the pneumococcal conjugate vaccine that is well-recognized to reduce childhood mortality from and related to pneumonia. vaccination remains the primary preventative strategy for pneumonia, including cap in the elderly. the hib vaccine has a proven efficiency of > % against invasive meningitis and bacteremia and noninvasive pneumonia caused by h. influenzae type b. , this impressive efficiency has resulted in the introduction and addition of the hib vaccine worldwide into national immunization programs, and has resulted in a significant reduction in the vaccination gap between developed and developing countries. a recent review from several randomized controlled trials (from s to ) from different developing countries indicated a significant reduction of severe pneumonia by %, pneumonia-associated mortality by %, and reduction of radiological confirmed cases of pneumonia by %. based on the preventative approach of pneumonia and pneumonia-related mortality with effective vaccination, a certain modeling-based study has estimated that if implemented at present annual rates of increase in developing countries, the vaccine could save up to % of pneumonia deaths by at a cost saving of us$ . billion. high coverage of the hib vaccine immunization in children less than years of age could reduce childhood pneumonia resulting in decreased incidence of severe pneumonia. the -valent polysaccharide vaccine (ppv ) and the -valent protein-conjugated polysaccharide vaccine (pcv ) are the two vaccines that offer protection against pneumococcal disease, and have replaced the -valent conjugate vaccine (pcv ). as the polysaccharide vaccine (ppv) is t-cell independent, it does not boost immunological memory and the immunity offered may not last for a long time. for this reason, this vaccine is not offered to infants aged < years of age, but is provided to children aged > years and to elderly people who are at risk (> years of age) for developing pneumonia. in contrast, the conjugate vaccines stimulate a t-cell dependent response and are more effective in infants and children < years of age. the different pneumococcal vaccines, serotypes covered, and the conjugate protein used are mentioned in table . pcv and pcv are offered for children aged from weeks to years of age, whereas pcv is given to children aged between weeks and years, and to adults aged > years of age. since the introduction of the pcv vaccine in , its efficacy against invasive meningitis, pneumonia, and otitis media is well documented. [ ] [ ] [ ] the subsequent vaccines, pcv and pcv , have also demonstrated comparable immunogenicity to pcv in several clinical trials. [ ] [ ] [ ] although ppv covers serotypes of s. pneumoniae, and is recommended for adults aged > years of age, its effectiveness in reducing invasive pneumococcal disease remains uncertain. , as pcv has equal or greater immunogenicity than ppv , and has greater immunological memory, the use of pcv is now recommended for adults in addition to ppv , particularly the elderly and high risk individuals. in addition to this, newer pcv's have been shown to reduce the number of healthy carriers of the pathogen in the community because of "herd immunity" where unvaccinated people are protected from the pathogen. since the introduction of pcv's as a part of "herd immunity", the incidence of invasive pneumococcal diseases was shown to decline by almost % among vaccinated children < years of age, and by % in adults aged - years, and by % in the elderly aged > years of age, who were not previously vaccinated. the classification of antibiotics is based on the cellular component that they affect, as well as on whether they can induce cell death (bactericidal) or inhibit cell growth (bacteriostatic). antibiotic-mediated cell death is a complex process involving physical interaction between a drug molecule and its bacterial-specific target, and/or modulation of the affected bacterium at the biochemical, molecular, and ultrastructural levels. fig. . summarizes the different drug targets and mechanism of actions of various antimicrobials such as; inhibition of cell wall synthesis, inhibition of protein synthesis, injury to cytoplasmic membrane, and inhibition of nucleic acid synthesis and replication. dna synthesis and cell division are well-recognized processes that involve modulation of chromosomal supercoiling through topoisomerase-catalyzed strand breakage and rejoining reactions. antimicrobials such as quinolone target enzymes like dna gyrase (topoisomerase ii) and topoisomerase iv (topoiv) that are required for bacterial dna synthesis and replication, and prevent dna strand rejoining. peptidoglycan, a covalently cross-linked polymer matrix composed of peptide-linked β-( - )-n-acetyl hexosamine, is the main component of bacterial cell walls that contributes towards the structural integrity of the bacterial cell. the peptidoglycan layer is maintained through the activity of transglycosylase and transpeptidase enzymes, which add disaccharide pentapeptides to extend the glycan strands of existing peptidoglycan molecules and cross-link adjacent peptide strands of immature peptidoglycan units, respectively. βlactams and glycopeptides are among the classes of antibiotics that interfere with cell wall biosynthesis resulting in changes to bacterial cell shape and size and induction of cellular stress responses that leads to bacterial cell lysis. the process of protein synthesis via mrna translation involves the ribosome that is composed of two major components, the s and s subunits. drugs that inhibit protein synthesis are divided into two subclasses: the s inhibitors and s inhibitors. the s ribosome inhibitors include the macrolide, lincosamide, streptogramin, amphenicol, and oxazolidinone classes of antibiotics. the s inhibitors include the tetracycline and aminocyclitol families of antibiotics. the mortality caused due to pneumonia can be avoided through cost-effective and life-saving treatment from antibiotics for bacterial pneumonia, thereby significantly increasing the patient's chances of survival. the pneumonia management strategy with the use of appropriate antibiotics and supportive care including oxygen systems remains an effective cornerstone in the treatment and management of children suffering from pneumonia. the who integrated management of childhood illness program has consistently reported a reduction of childhood mortality rates by approximately %, while certain community based management strategies have reported a decrease in % mortality due to the usage of oral antibiotics such as amoxicillin. [ ] [ ] [ ] the four types of antibiotics recommended for children < years of age for the treatment of pneumonia are; cotrimoxazole, amoxicillin, cephalosporins, and macrolides, with oral amoxicillin ( mg/kg/dose) used for days (nonsevere pneumonia) and days for children with severe pneumonia. during severe pneumonia, the first line of treatment is often parenteral ampicillin (penicillin) and gentamicin, followed by ceftriaxone if the first line of treatment is not effective. various randomized controlled studies from the cochrane database of systemic reviews have shown a multitude of available treatments for pneumonia in children with ( ) cefpodoxime proving to be more effective than amoxicillin, ( ) amoxicillin more effective than chloramphenicol, ( ) amoxicillin being an effective alternative to cotrimoxazole for cap patients, ( ) coamoxyclavulanic acid and cefpodoxime as alternative second-line drugs of choice, and ( ) penicillin/ampicillin plus gentamicin more effective than chloramphenicol for children hospitalized with severe cap. a -year pediatric study of the susceptibility of s. pneumoniae isolates, including serotype a, using antibiotics such as second-and third-generation cephalosporins showed significant efficacy against - % of the isolates, with clindamycin susceptibility of - %, levofloxacin %, and ceftriaxone > %. the american thoracic society and the european respiratory society recommend that hospitalized patients with cap are preferably treated with a respiratory fluoroquinolone or combination therapy with a β-lactam and a macrolide. the success rates of incorporating the fluoroquninolone or combination with a macrolide based on the clinical, bacteriological, or radiological examinations ranged from - %. vancomycin or clindamycin (based on local susceptibility data) should also be provided in addition to β-lactam therapy if clinical, laboratory, or radiological characteristics are consistent with infection caused by s. aureus. although nonsevere and severe cap have been managed by many antimicrobials as a result of various studies from developing countries that compared different types of antibiotics, there is need for more studies and larger clinical trials for better management of pneumonia in developed countries. another major health concern is the continual rise in antibiotic resistance with approximately % of the isolates being resistant to macrolides including erythromycin, azithromycin, and clarithromycin. the introduction and inclusion of the hib vaccine over the past years has resulted in almost complete elimination of h. influenzae in children, therefore it is not considered as a pathogen in cap. nontypeable h. influenzae is also not considered as a pathogen in pediatric pneumonia unless detected in lung disease or copd. when detected as a true pathogen in cap, oral amoxicillin is considered effective against β-lactamase negative strains, and for β-lactamase producing strains, amoxicillinclavulanate, cefuroxime, cefdinir, cefixime, cefpodoxime are all considered effective therapies, while children allergic to oral β-lactam agents are only given fluoroquinolones. although an infrequent cause of cap, group a streptococcus may cause severe necrotizing pneumonia. penicillin g at the dosage of , - , u/kg/day in - divided doses is used to treat patients suffering from cap due to group a streptococcus. as macrolide resistance is greater in streptococcal infections, along with lower tolerability by tissues, erythromycin and other macrolides are not administered. s. aureus capable of causing pneumonia are usually methicillin-sensitive and are treated with either a β-lactamase stable penicillin (oxacillin or nafcillin) or a first-generation cephalosporin, like cefazolin. community-associated methicillin-resistant s. aureus (mrsa) represents > - % of the clinical isolates in some region of the united states, but are shown to be susceptible to vancomycin, clindamycin, and linezolid. however, children intolerant to vancomycin and clindamycin could be treated with linezolid. however, severe adverse effects, including suppression of platelets and neutrophils, nerve injury, mean that this drug should be used with caution. in situations where mycoplasma pneumoniae and chlamydophila pneumoniae are of significant consideration upon diagnostic evaluation, empiric combination therapy with a macrolide and a β-lactam antibiotic is considered. children with moderate to severe cap consistent with influenza virus infection during widespread local circulation of influenza viruses should be administered with influenza antiviral therapy. the susceptible strains of influenza a virus are commonly treated with adamantanes and neuraminidase inhibitors. as the occurrence of genetic variations is highly substantial among influenza strains, resistance to either class of antiviral agents may develop quickly. however, the dosages of antiviral agents currently recommended for seasonal influenza are developed for fully susceptible strains and evaluated in clinical trials mandating the requirement of treatment within days of the onset of symptoms. early antiviral treatment has been shown to provide maximal benefit, and treatment should not be delayed until confirmation of positive influenza test results. negative results of influenza diagnostic tests, especially the rapid antigen tests, do not conclusively exclude influenza disease. therefore, treatment after h of symptomatic infection may still provide some clinical benefit to those with more severe disease. the efficacy of ribavirin for the treatment of rsv cap in infants is debatable, as certain in vitro studies have shown activity of ribavirin against rsv, but its usage for rsv infection is not routinely recommended in the management of lower respiratory tract disease because of the high cost, aerosol administration, and possible toxic effects among healthcare providers. palivizumab (synagis), a humanised murine monoclonal antibody is another effective prophylaxis for rsv infection that is administered intramuscularly. although parainfluenza virus, adenovirus, metapneumovirus, rhinovirus, coronavirus, and bocavirus are associated with pediatric cap, there are no prospective, controlled studies for antiviral therapy against these viruses. since the introduction of penicillin in s, it has been the first choice for treating pneumococcal pneumonia. during the early s, infants and children were successfully treated with amoxicillin ( - mg/kg/day divided into equal doses) because of the susceptible nature of the strains at that time. resistance to the commonly used antibiotics poses a major problem and concern for health practitioners while choosing an empirical therapy against bacterial pneumonia, and there are large geographical variations indicating different resistance patterns. in the s with the widespread pneumococcal resistance to penicillin, the dosage was increased to ∼ mg/kg/day given twice daily for treating children with acute otitis media. a recent review has highlighted advances in the understanding of the various mechanisms by which bacteria acquire resistance to antibiotics, how they prevent access to different drug targets, and modulate or inactivate antibiotics. the introduction of pneumococcal conjugate vaccine and the changes in antimicrobial usage have both significantly altered the resistance patterns of s. pneumoniae. the decreased degree of penicillin resistance further prompted a decrease in amoxicillin dosage compared to that administered in the prevaccine era. over the last decade, a certain multicentre clinical trial study has reported a significant decrease in the susceptibility rates of the commonly used antibiotics such as amoxicillin/clavulante, penicillin, and ceftriaxone from . % to . %, . % to . %, and . % to . %, respectively. the susceptibility rates of macrolides such as erythromycin and clindamycin were also reported to be decreased from . % to . % and from . % to . %, respectively. recently, increasing resistance against macrolides has been reported in several european countries, including the united kingdom. a -year surveillance study involving clinical isolates reported around % and % increase in the rates of ampicillin and trimethoprim/sulfamethoxazole resistance against h. influenzae, respectively, while antibiotics such as ceftaroline, ceftriaxone, amoxicillin/clavulante, and levofloxacin showed - % susceptibility. this study also showed increasing resistance of penicillin ( . %) towards m. catarrhalis, because of the prevalence of β-lactamase that is known to reduce the susceptibility to penicillins. the resistance to macrolides against m. pneumoniae in children and adults with cap has been increasingly emerging in countries like japan, france, denmark, united states, and china, with rates as high as % in japan, % in china, and - % in the europe and the united states. , community-acquired mrsa, although primarily associated with skin and soft tissue infections, are now being recognized to cause invasive infections including cap, with almost % mortality rates reported in the united states and europe. , there are certain ways by which resistance to antimicrobials can be minimized, such as: limiting the exposure to any antibiotic, whenever possible; limiting the spectrum of usage of antimicrobials to that specifically required to treat the identified pathogen; using the proper dosage of antimicrobial to achieve a minimal effective concentration at the site of infection; treatment for the shortest effective duration that will minimize the exposure of both pathogens and normal microbiota to antimicrobials and further minimize the selection for resistance. the increasing incidence of antimicrobial resistance remains one of greatest challenges against emerging bacterial infections and has resulted in some bacteria being essentially untreatable with the current available treatment options. as a result, newer antimicrobials with novel modes of action against multidrug resistant strains are being developed. a recent review has highlighted how combinations of drugs can offer synergistic and antagonistic drug interactions, and how these drug interactions can provide opportunities for discovery of newer drugs. in recent years, the availability of new antimicrobials for human consumption has been lower than in the recent past, with no new classes of antimicrobials developed since the introduction of nalidixic acid ( ) and linezolid ( ) . the availability of antimicrobials in recent years has mostly been the result of modification of existing molecules. one of the reasons for this is that the development of any new antimicrobial agent is very expensive and time consuming, with research and development of infective drugs taking around - years, and costing around us$ million, with further additional costs for bringing the new drug into the market. there is a strong need for newer unexploited targets and strategies for the next generation of antimicrobial drugs against drug resistant and emerging pathogens. some of the new antimicrobial agents that are in the clinical development stage are listed in table . . some of the new antibiotics that have shown promising results in the treatment of pneumonia and cap are as follows: ceftaroline: a fifth generation cephalosporin known to bind to penicillin-binding proteins and preventing synthesis of bacterial cell walls. it is a novel broad-spectrum antibiotic effective against mrsa, penicillin and cephalosporin resistant s. pneumoniae, vancomycin-intermediate s. aureus (visa), and vancomycin-resistant s. aureus (vrsa). it is also active against many gram-negative pathogens but inactive against extended-spectrum β-lactamase (esbl) producing bacteria. it has been approved for the treatment of cap. different randomized, double-blind, multicentre trials have demonstrated the efficacy (> % clinical cure) and safety of ceftaroline (intravenous, mg twice daily) for the treatment of cap. ceftobiprole: another newer cephalosporin that has a broad-spectrum activity against mrsa, penicillin-resistant s. pneumoniae, p. aeruginosa and enterococci. a randomized trial consisting of hospitalized adults with severe cap who were administered ceftobiprole (intravenous, mg over min every h) showed no significant differences between the treatment groups but found adverse events including nausea and vomiting in % of the patients. telavancin: a semi-synthetic lipoglycopeptide derivative of vancomycin known to disrupt peptidoglycan synthesis and alter cell membrane function. it has been in use for treating complicated skin infections caused by s. aureus, and hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia caused by susceptible isolates of s. aureus. telithromycin: the first ketolide to enter clinical use for the treatment of cap, chronic bronchitis and acute sinusitis. telithromycin is a protein synthesis inhibitor blocking the progression of the growing polypeptide chain by binding to the s subunit of the bacterial ribosome. it exhibits times higher affinity to the subunit s subunit than erythromycin. in addition, telithromycin strongly binds simultaneously to two domains of s subunit of the s ribosomal subunit; older macrolides bind to only to one domain and weakly to the second domain. an in vitro study showed activity of telithromycin against s. pneumoniae and, compared with clarithromycin and azithromycin, was found to maintain its activity against macrolide-resistant strains of s. pneumoniae and s. pyogenes. it is formulated as mg tablet for oral administration with good absorption and bioavailability. however, the fda withdrew its approval in the treatment of cap in due to its safety concerns involving hepatotoxicity, myasthenia gravis exacerbation, and visual disturbances. cethromycin: a -keto, , carbamate derivative of erythromycin a with an o- linked aromatic ring. it binds strongly to the s ribosomal subunit and inhibits bacterial protein synthesis. cethromycin displays in vitro activity against streptococci, including strains of s. pneumoniae that are resistant to penicillins and macrolides. its activity was greater than telithromycin against macrolide-resistant streptococci and is more potent than macrolides and fluoroquinolones against penicillin-resistant streptococci. it also displays comparable in vitro activity to azithromycin against respiratory gram-negative organisms including β-lactamase-producing h. influenzae and m. catarrhalis. it was shown to be more potent than erythromycin and clarithromycin but less potent than fluoroquinolones against β-lactamase-producing h. influenzae. , it showed similar potency against β-lactamase-producing m. catarrhalis. solithromycin: a new macrolide, and the first fluoroketolide in clinical development, with proven activity against macrolide-resistant bacteria. solithromycin is being developed in both intravenous and oral formulations for the treatment of cap, which should allow both oral therapy and i.v.-to-oral stepdown therapy in appropriate patients. a recent multicentre, double-blind, randomized phase ii study consisting of patients with moderate to severe cap administered with oral solithromycin ( -mg loading dose and mg maintenance dose/ days) showed efficacy comparable to that of levofloxacin in the treatment of cap, with a favorable safety and tolerability profile. nemonoxacin: a novel nonfluorinated quinolone with proven in vitro and in vivo activity against cap pathogens including multidrug resistant s. pneumoniae. a randomized multicentre trial consisting of cap patients treated with an oral administration of nemonoxacin ( and mg/ days) showed a remarkable - % clinical and bacteriological success rate, which was comparable tolevofloxacin therapy. a recent comprehensive review has well documented all the data available on the pharmacodynamics, the pharmacokinetics, and the clinical treatment studies of this antimicrobial agent. zabofloxacin: is being developed as a new fluoroquinolone antibiotic that is a potent and selective inhibitor of the essential bacterial type ii topoisomerases and topoisomerase iv and is indicated for community-acquired respiratory infections due to gram-positive bacteria. two dosing regimens of zabofloxacin (zabofloxacin hydrochloride mg capsule andzabofloxacin aspartate mg tablet) were well-tolerated with no adverse effects. jnj-q and kpi- : two novel fluoroquinolones that are being developed for the treatment of bacterial pathogens responsible for respiratory infections including cap, and other skin infections. both agents have demonstrated increased potency when compared with the marketed fluoroquinolones, thus encouraging further clinical development. , bc- : a recent semisynthetic pleuromutilin antibiotic with excellent antibacterial activity against skin pathogens such as s. aureus, β-haemolytic streptococci, viridans streptococci, and enterococcus faecium as well as against respiratory pathogens. its activity against respiratory pathogens has also been confirmed in various murine models of infection using s. pneumoniae, h. influenzae, s. aureus, and mrsa (nosocomial and community-associated), with better drug penetration, strongly supporting its potential use in the treatment of bacterial respiratory tract infections. although there are a wide variety of clinically efficacious antibiotics in use today, the development of bacterial resistance has rendered them less effective, with most being bacteriostatic, and acting by either protein or cell wall synthesis inhibition. further research is needed in the design of novel antibacterial agents with new targets. one approach could be to design antibiotics that can be used against novel drug targets such as the bacterial enzymes β-ketoacyl-acyl-carrier-protein synthase i/ii which are required for fatty acid biosynthesis. platensimycin is one such drug undergoing preclinical trials and is known to block these enzymes that are involved in the biosynthesis of essential fatty acids by gram-positive bacteria. it has potent antibacterial activity against gram-positive bacteria including multidrug resistant staphylococci and enterococci. another approach worth investigating could be to combine β-lactam antibiotics with naturally occurring β-lactamase enzymes in the gastrointestinal microbiota. these enzymes are shown to hydrolyse various antibiotics including penicillin, ampicillin, and piperacillin. p a protein ( kda) is one such example of having both structural and functional similarities to the β-lactamase enzyme. the emergence of resistant microbes can be significantly reduced by taking advantage of combining this naturally occurring hydrolysis of the antibacterial drug with currently available β-lactam drugs. a phase ii trial for the treatment of serious respiratory infections which incorporated treatment with p a (β-lactamase product) and ampicillin showed only a % change in gut microbiota compared to % change in patients treated with ampicillin alone. apart from antimicrobials, strategies involving immunomodulation of inflammatory responses (targeting pattern recognition receptor signaling, corticosteroids, complement inhibitors etc.), improving pulmonary barrier function (using adrenomedullin, angiopoietin etc.) during pneumonia and its associated complications could add a new dimension in providing better therapeutics for patients. despite great advances in management and preventative approaches, pneumonia still remains a major burden of mortality and morbidity in young children and the elderly, especially in the developing and under-developed countries. prevention by means of vaccination is critical for reducing pneumonia mortality in children < years of age, and an effective antibiotic therapy is important for the elderly. the widespread emergence of antimicrobial resistance is a well-recognized cause of the ineffectiveness of the large number of the currently used antimicrobials. although numerous efforts have been made to combat this, newer targets need to be identified for the generation of the next level of effective antimicrobials. in addition, a complete understanding of the various aspects of drug resistance in microbes is essential to assist us in designing better targets and help us discover new antibacterial drugs. in the near future, the next challenge will be to identify newer agents for the treatment of multidrug resistant pathogens which are emerging at a rapid rate. the constant and unpredictable nature of pneumococcal pathogens can outpace technological and drug development strategies. therefore, it is critical for researchers, pharmaceutical companies, and governments and other funding bodies to continue making progress in developing new strategies and antimicrobials towards respiratory infections, including pneumonia. the continuing challenge of lower respiratory 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community-acquired pneumonia antimicrobial activity of the novel pleuromutilin antibiotic bc- against organisms responsible for community-acquired respiratory tract infections (cartis) platensimycin, a new antibiotic and "superbug challenger" from nature p a recombinant beta-lactamase prevents emergence of antimicrobial resistance in gut microflora of healthy subjects during intravenous administration of ampicillin therapeutic strategies in pneumonia: going beyond antibiotics key: cord- -xxvol t authors: amos, louella b. title: cough date: - - journal: nelson pediatric symptom-based diagnosis doi: . /b - - - - . - sha: doc_id: cord_uid: xxvol t nan cough is an important defense mechanism of the lungs and is a common symptom, particularly during winter months. in most patients, it is self-limited. however, cough can be ominous, indicating serious underlying disease, because of accompanying problems (hemoptysis) or because of serious consequences of the cough itself (e.g., syncope and hemorrhage). the cough reflex serves to prevent the entry of harmful substances into the tracheobronchial tree and to expel excess secretions and retained material from the tracheobronchial tree. cough begins with stimulation of cough receptors, located in the upper and lower airways, and in many other sites such as the ear canal, tympanic membrane, sinuses, nose, pericardium, pleura, and diaphragm. receptors send messages via vagal, phrenic, glossopharyngeal, or trigeminal nerves to the "cough center," which is in the medulla. because cough is not only an involuntary reflex activity but also one that can be initiated or suppressed voluntarily, "higher centers" must also be involved in the afferent limb of the responsible pathway. the neural impulses go from the medulla to the appropriate efferent pathways to the larynx, tracheobronchial tree, and expiratory muscles. the act of coughing ( fig. . ) begins with an inspiration, followed by expiration against a closed glottis (compressive phase), resulting in the buildup of impressive intrathoracic pressures ( - cm h o). these pressures may be transmitted to vascular, cerebrospinal, and intraocular spaces. finally, the glottis opens, allowing for explosive expiratory airflow ( m/sec) and expulsion of mucus, particularly from the larger, central airways. the inability to seal the upper airway (tracheostomy) impairs, but does not abolish, the effectiveness of cough. weak ventilatory muscles (muscular dystrophy) impair both the inspiratory and the compressive phase. the patient history often provides the most important body of information about a child's cough. a diagnosis can often be discerned with relative certainty from the family history, the environmental and exposure history, and the acute nature and characterization of the cough. the patient's age (table . ) helps to focus the diagnostic possibilities. congenital anatomic abnormalities may be symptomatic from birth, whereas toddlers, who may have incomplete neurologic control over swallowing and often put small objects in their mouths, are at risk for foreign body aspiration; adolescents may experiment with smoking or inhaled drugs. socioeconomic factors must be considered; a family that cannot afford central heating may use a smoky wood-burning stove; spending time at a daycare center may expose an infant to respiratory viruses; and several adult smokers in a small home expose children to a high concentration of respiratory irritants. the various cough characteristics can help determine the cause of cough. the causes of acute, recurrent, and chronic coughs may be quite different from each other ( fig. . ; see also table . ). a cough can be paroxysmal, brassy, productive, weak, volitional, and "throatclearing," and it may occur at different times of the day (tables . and . ). the previous response or lack of response to some therapies for recurrent and chronic cough can provide important information (see table . ). furthermore, some coughs may be caused or worsened by medications (table . ). a history of accompanying signs or symptoms, whether localized to the respiratory tract (wheeze, stridor) or elsewhere (failure to thrive, frequent malodorous stools) can give important clues (table . ; see also tables . and . ). it is essential to remember that the daily language of the physician is full of jargon that may be adopted by parents but with a different meaning from that understood by physicians. if a parent says that a child "wheezes" or "croups" or is "short of breath," it is important to find out what the parent means by that term. because many disorders of childhood have genetic or nongenetic familial components, the family history can provide helpful information: • are there older siblings with cystic fibrosis (cf) or asthma? • is there a coughing sibling whose kindergarten class has been closed because of pertussis? • is there an adolescent or adult with chronic cough (bronchitis) who may have pertussis or tuberculosis? • was the child premature, and, if so, did he or she spend a month on the ventilator, and does he or she now have chronic lung disease (bronchopulmonary dysplasia)? • did the toddler choke on a carrot or other food months ago? • did the child have rsv, bronchiolitis, or rhinovirus infection as an infant? • did the child receive a bone marrow transplant a year ago? • is the child immunized? • did the infant have a tracheoesophageal fistula repaired in the neonatal period? chest, abdomen, and spine. the shape of the chest gives information. is the anteroposterior (ap) diameter increased, which indicates hyperinflation of the lungs from obstruction of small airways (asthma, bronchiolitis, cf)? is this diameter small, as can be seen with some restrictive lung diseases with small lung volumes (muscular dystrophy, spinal muscular atrophy)? the normal infant has a "round" chest configuration, with the ap diameter of the chest about % of the transverse (lateral) diameter. with growth, the chest becomes more flattened in the ap dimension, and the ap-to-transverse ratio is between % and %. although obstetric calipers can be used to give an objective assessment of the ap diameter of the chest, most clinicians rely on their initial inspection often reveals the seriousness of an illness: • is the child struggling to breathe (dyspnea)? • does the child have an anxious look? • can the child be calmed or engaged in play? • is the child's skin blue (representing cyanosis) or ashen? • does the child appear wasted, with poor growth that may indicate a chronic illness? the respiratory rate is often elevated with parenchymal lung disease or extrathoracic obstruction. respiratory rates vary with the age of the child (fig. . ) and with pulmonary infection, airway obstruction, activity, wakefulness and sleep, fever, metabolic acidosis, and anxiety. odors may also give helpful clues. does the examining room or the clothing smell of stale cigarette smoke? is there a foul odor from a diaper with a fatty stool, which may suggest pancreatic insufficiency and cf? is the child's breath malodorous, as can be noticed in sinusitis, nasal foreign body, lung abscess, or bronchiectasis? fingers. cyanotic nail beds suggest hypoxemia, poor peripheral circulation, or both. the examiner looks for the presence of digital clubbing (fig. . ) , which makes asthma or acute pneumonia extremely unlikely. the absence of digital clubbing but a history of severe chronic cough in an older child makes cf unlikely. † anatomic abnormality includes tracheobronchomalacia, tracheoesophageal fistula, vascular ring, abnormal position or take-off of large bronchi. common; less common; much less common. cf, cystic fibrosis; ger, gastroesophageal reflux. less easy to notice than intercostal retractions is their bulging out with expiration in a child with expiratory obstruction (asthma). contraction of the abdominal muscles with expiration is easier to notice and is another indication that a child is working harder than normal to push air out through obstructed airways. inspection of the spine may reveal kyphosis or scoliosis. there is a risk of restrictive lung disease if the curvature is severe. palpating the trachea, particularly in infants, may reveal a shift to one side, which suggests loss of volume of the lung on that side or extrapulmonary gas (pneumothorax) on the other side. placing one hand on each side of the chest while the patient breathes may enable the examiner to detect asymmetry of chest wall movement, either in timing or in degree of expansion. the former indicates a partial bronchial obstruction, and the latter suggests a smaller lung volume, voluntary guarding, or diminished muscle function on one side. palpating the abdomen gently during expiration may allow the examiner to feel the contraction of the abdominal muscles in cases of expiratory obstruction. hyperinflation may push the liver down making it palpable below the costal margin. palpation for tactile fremitus, the transmitted vibrations of the spoken word ("ninety-nine" is the word often used to accentuate these subjective assessment of whether the diameter is increased: does the patient look "barrel-chested"? intercostal, subcostal, suprasternal, and supraclavicular retractions (inspiratory sinking in of the soft tissues) indicate increased effort of breathing and reflect both the contraction of the accessory muscles of respiration and the resulting difference between intrapleural and extrathoracic pressure. retractions occur most commonly with obstructed airways (upper or lower), but they may occur with any condition leading to the use of the accessory muscles. any retractions other than the mild normal depressions seen between an infant's lower ribs indicate a greater than normal work of breathing. because lung sounds tend to be higher-pitched than heart sounds, the diaphragm of the stethoscope is better suited to pulmonary auscultation than is the bell, whose target is primarily the lower-pitched heart sounds (table . ). the adult-sized stethoscope generally is superior to the smaller pediatric or neonatal diaphragms, even for listening to small chests, because its acoustics are better (figs. . and . ). adventitious sounds come in a few varieties, namely, stridor, crackles, rhonchi, and wheezes. other sounds should be described in clear, everyday language. • stridor is a continuous musical sound usually heard on inspiration and is caused by narrowing in the extrathoracic airway, as with croup or laryngomalacia. • crackles are discontinuous, representing the popping open of air-fluid menisci as the airways dilate with inspiration. fluid in larger airways causes crackles early in inspiration (congestive heart failure). crackles that tend to be a bit lower in pitch ("coarse" crackles) than the early, higher-pitched ("fine") crackles are associated with fluid in small airways (pneumonia). although crackles usually signal the presence of excess airway fluid (pneumonia, pulmonary edema), they may also be produced by the popping open of noninfected fibrotic or atelectatic airways. fine crackles are not audible at the mouth, whereas coarse crackles may be. crackles is the preferred term, rather than the previously popular "rales." • rhonchi, or "large airway sounds," are continuous gurgling or bubbling sounds typically heard during both inhalation and exhalation. these sounds are caused by movement of fluid and secretions in larger airways (asthma, viral uri). rhonchi, unlike other sounds, may clear with coughing. , or the phalangeal depth ratio, is normally less than but increases to more than with finger clubbing. the dpd/ipd ratio can be measured with calipers or, more accurately, with finger casts. the hyponychial angle is measured from lateral projections of the finger contour on a magnifying screen and is normally less than degrees but greater than degrees with finger clubbing. schamroth sign is useful for bedside assessment. the dorsal surfaces of the terminal phalanges of similar fingers are placed together. with clubbing, the normal diamond-shaped aperture or "window" at the bases of the nail beds disappears, and a prominent distal angle forms between the end of the nails. in normal subjects, this angle is minimal or nonexistent. ( • wheezes are continuous musical sounds (lasting longer than msec), caused by vibration of narrowed airway walls, as with asthma, and perhaps vibration of material within airway lumens. these sounds are much more commonly heard during expiration than inspiration. the chest radiograph is often the most useful diagnostic test in the evaluation of the child with cough. table . highlights some of the radiographic features of the most common causes of cough in pediatric patients. radiographic findings are often similar for a number of disorders, and thus these studies may not indicate a definitive diagnosis. chest radiographs are normal in children with psychogenic (habit) cough and in children with sinusitis or gastroesophageal reflux (ger) as the primary cause of cough. a normal chest radiograph indicates the unlikelihood of pneumonia caused by respiratory syncytial virus (rsv), influenza, parainfluenza, adenovirus, chlamydia species, or bacteria. although children with cough resulting from cystic fibrosis (cf), mycoplasma species, tuberculosis, aspiration, a bronchial foreign body, or an anatomic abnormality usually have abnormal chest radiographs, a normal radiograph does not exclude these diagnoses. hyperinflation of the lungs is commonly seen on chest radiographs of infants with rsv bronchiolitis or chlamydia pneumonia, and a lobar or round (coin lesion) infiltrate is the radiographic hallmark of bacterial pneumonia. the diagnosis of sinusitis cannot be sustained with normal sinuses on radiograph or computed tomography (ct) scan. the white blood cell (wbc) count may help exclude or include certain entities for a differential diagnosis. for example, a wbc count of infections are the most common cause of acute cough in all age groups and are responsible for some chronic coughs. the age of the patient has a large impact on the frequency of the type of infection. viral upper respiratory infections (common cold); croup (laryngotracheobronchitis); viral bronchiolitis, particularly with rsv or human metapneumovirus; and viral pneumonia are the most frequently encountered respiratory tract infections and hence the most common causes of cough in infancy. viral illness may predispose to bacterial superinfection (croup and staphylococcus aureus tracheitis or influenza and h. influenzae or s. aureus pneumonia). viral upper respiratory infections (uri). viral uri symptoms and signs usually include stuffy nose with nasal discharge, sore throat, and sneezing. there may be fever, constitutional signs (irritability, myalgias, and headache), or both. cough is common and may persist for - days. the mechanism by which uris cause cough in children is undetermined. in adults, it is generally thought that "postnasal drip"-that is, nasal or sinus secretions draining into the posterior nasopharynx-causes cough and, in fact, may be one of the most frequent causes of cough. indeed, sinus ct in older patients with uris often reveals unexpected involvement of the sinus mucosa. other authorities believe that cough in a child with a uri indicates involvement (inflammation or bronchospasm) of the lower respiratory tract. over-the-counter cough and cold medications are commonly used. evidence of efficacy of these medications for children with uri is lacking. because of the known risk for unintentional overdose from these medications, their use is not recommended in children under age years. , with % lymphocytes strongly suggests pertussis, but not every child with pertussis presents such a clear hematologic picture. the presence of a high number or large proportions of immature forms of wbcs suggests an acute process, such as a bacterial infection. immunoglobulins provide supportive evidence for a few diagnoses, such as chlamydial infection, which rarely occurs without elevated serum concentrations of immunoglobulins g and m. specific bacteriologic or virologic diagnoses can be made in a number of disorders causing cough, including rsv, influenza, parainfluenza, adenovirus, and chlamydia pneumonia. in most cases, the viruses can be rapidly identified with amplification of the viral genome through polymerase chain reaction (pcr). in bacterial pneumonia, the offending organism can be cultured from the blood in a small proportion ( %) of patients. a positive culture provides definitive diagnosis, but a negative culture specimen is not helpful. throat cultures are seldom helpful (except in cf) in identifying lower respiratory tract bacterial organisms. sputum cultures and gram stains may help guide initial empirical therapy in older children with pneumonia or purulent bronchitis, but their ability to identify specific causative organisms with certainty (with the exception of cf) has not been shown clearly. infants and young children usually do not expectorate but rather swallow their sputum. specimens obtained via bronchoscopy may be contaminated by mouth flora, but heavy growth of a single organism in the presence of polymorphonuclear neutrophils certainly supports the organism's role in disease. if pleural fluid or fluid obtained directly from the lung via needle aspiration is cultured, the same rules apply: positive cultures are definitive, but negative cultures are not. a number of specific tests can help to establish diagnoses in a child with cough (see table . ). these include a positive response to bronchodilators in a child with asthma; visualizing the red, swollen epiglottis in epiglottitis (to be done only under very controlled conditions); the bronchoscopic visualization of the peanut, plastic toy, or other offender in foreign body aspiration; a positive purified protein diaphragm, with an enlarged retrosternal air space in as many as % of patients, peribronchial thickening in approximately %, and consolidation and/or atelectasis in - %. the diagnosis is confirmed with demonstration of rsv by pcr of nasopharyngeal secretions. in most cases, no treatment is needed because the disease does not interfere with the infant's eating or breathing. apnea is a common complication of rsv bronchiolitis in neonates and may necessitate close monitoring. in severe cases, often those in which there is underlying chronic heart, lung, or immunodeficiency disease, rsv can be life-threatening. in severe cases, hospital care with supplemental oxygen and intravenous fluids is indicated. suctioning of secretions is an essential part of the treatment. many other treatment modalities have been tried for hospitalized infants with bronchiolitis. aerosolized bronchodilators and systemic glucocorticoids do not seem to alter clinical outcome and are not recommended in most patients. nebulized saline may reduce the length of hospitalization. use of high-flow nasal cannula may reduce the need for more invasive forms of respiratory support in infants with impending respiratory failure. viral pneumonia. viral pneumonia can be similar to bronchiolitis in its manifestation, with cough and tachypnea, after a few days of apparent uri. there can be variable degrees of fever and of overall illness. infants and children with viral pneumonia may appear relatively well or, particularly with adenovirus or influenza, may have a rapidly progressive course. frequent symptoms include poor feeding, cough, cyanosis, fever (some patients may be afebrile), apnea, and rhinorrhea. frequent signs include tachypnea, retractions, crackles, and cough. cyanosis is less common. the most common agents causing viral pneumonia in infancy and childhood are rsv, influenza, and parainfluenza. adenovirus is less common, but it is important because it can be severe and leave residua, including bronchiectasis and bronchiolitis obliterans. adenovirus pneumonia is often accompanied by conjunctivitis and pharyngitis, in addition to leukocytosis and an elevated erythrocyte sedimentation rate (esr); the esr and leukocyte count are usually not elevated in other types of viral pneumonia. additional viral agents include enteroviruses, human metapneumovirus and rhinovirus. radiographs most often reveal diffuse, bilateral peribronchial infiltrates, with a predilection for the perihilar regions, but occasionally lobar infiltrates are present. pleural effusions are not common. on occasion, if an infant is extremely ill, bronchoscopy with bronchoalveolar lavage may be indicated to isolate the virus responsible for the pneumonia. treatment is largely supportive, with oxygen and intravenous fluids. mechanical ventilation may be necessary in a small minority of infants. in young infants, the afebrile pneumonia syndrome may be caused by chlamydia, ureaplasma, or mycoplasma species; cytomegalovirus; or pneumocystis jiroveci. in this syndrome, cough and tachypnea are common. severe pneumonia may develop in neonates as a result of herpes simplex. pertussis (whooping cough). pertussis is a relatively common cause of lower respiratory tract infection in infants, children, adolescents, and adults, especially in those who are underimmunized or not immunized. the causative organism, bordetella pertussis, has a tropism for tracheal and bronchial ciliated epithelial cells; thus the disease is primarily bronchitis, but spread of the organism to alveoli, or secondary invasion by other bacteria, can cause pneumonia. the disease can occur at any age, from early infancy onward, although its manifestations in young infants and in those who have been partially immunized may be atypical. most commonly, pertussis has three stages: • catarrhal, in which symptoms are indistinguishable from a viral uri common viral pathogens include rhinovirus, rsv, coronaviruses, and parainfluenza viruses. the differential diagnosis includes allergic rhinitis, which often demonstrates clear nasal secretions with eosinophils and pale nasal mucosa, and sinusitis, which presents with mucopurulent nasal secretions containing neutrophils and erythematous mucosa. croup (laryngotracheobronchitis). infectious croup (see chapter ) is most common in the first years of life. its most dramatic components are the barking ("croupy") cough and inspiratory stridor, which appear a few days after the onset of a cold. in most cases, the patient has a low-grade fever, and the disease resolves within a day or two. in severe cases, the child can be extremely ill and is at risk for complete laryngeal obstruction. there may be marked intercostal and suprasternal retractions and cyanosis. stridor at rest signifies significant obstruction. diminishing stridor in a child who is becoming more comfortable is a good sign, but diminishing stridor in and of itself is not necessarily good: if the child becomes fatigued because of the tremendous work of breathing through an obstructed airway and can no longer breathe effectively, smaller-than-needed tidal volumes make less noise. it is important to distinguish croup from epiglottitis in the child with harsh, barking cough and inspiratory stridor because the natural histories of the two diseases are quite different (see table . ). epiglottitis occurs more commonly in unimmunized toddlers than in infants (see chapter ). treatment of mild croup is usually not needed. for decades, pediatricians have recommended putting a child with croup in a steamy bathroom or driving to the office or emergency department with the car windows rolled down. it is likely that these remedies are effective because of the heat exchange properties of the upper airway; air that is cooler or more humid than the airway mucosa will serve to cool the mucosa, thus causing local vasoconstriction and probably decreasing local edema. in a child who has stridor at rest, evaluation is indicated. symptomatic, often dramatic relief through decreased laryngeal edema can usually be achieved with aerosolized racemic epinephrine ( . % solution, . to . ml/dose). it is essential to remember that the effects of the epinephrine are transient, lasting only a few hours, although the course of the illness is often longer. the result is that when the racemic epinephrine's effect has worn off, the child's cough and stridor will probably be as bad or even worse than before the aerosol was administered. this is not a "rebound" effect: the symptoms are not worse because of the treatment but, rather, because of the natural progression of the viral illness. repeating the aerosol will probably again have a beneficial effect. a child who responds favorably to such an aerosol needs to be observed for several hours because further treatment may be needed. a single dose of dexamethasone ( . mg/kg orally, intramuscularly, or intravenously) reduces the severity and hastens recovery. aerosolized steroids (budesonide) may also be effective in patients with mild to moderately severe croup. bronchiolitis. bronchiolitis is a common and potentially serious lower respiratory tract disorder in infants (see chapter ). it is caused usually by rsv but on occasion by parainfluenza, influenza, human metapneumovirus, adenovirus, enterovirus, and human rhinovirus. it mostly occurs in the winter months, often in epidemics. rsv bronchiolitis is seen uncommonly in children older than years. typically, "cold-like" symptoms of rhinorrhea precede the harsh cough, increased respiratory rate, and retractions. respiratory distress and cyanosis can be severe. the child's temperature is seldom elevated above °c. the chest is hyperinflated, widespread crackles are audible on inspiration, and wheezing marks expiration. the chest radiograph invariably reveals hyperinflation, as depicted by a depressed .e (see nelson textbook of pediatrics, p. .) (see nelson textbook of pediatrics, p. .) colds and cough in infants (see previous discussion) apply to this older age group. the differential diagnosis of rhinorrhea is noted in table . . sinusitis. the sinuses may become the site for viral and subsequent secondary bacterial infection spreading from the nasopharynx (fig. . ) . the signs and symptoms are usually localized, including nasal congestion, a feeling of "fullness" or pain in the face (fig. . ) , headache, sinus tenderness, day or night cough, and fever. maxillary toothache, purulent nasal discharge for more than days, and a positive transillumination (opacification) are important clues. sinus radiographs or (more accurate) ct scan may facilitate the diagnosis of sinusitis by demonstrating opacification of the sinus with mucosal thickening. sinusitis is thought to be a cause of cough in adults and can probably be listed, with lower certainty, as a cause of cough in children. sinusitis is frequently seen in other conditions known to cause cough, especially cf, asthma, ciliary dyskinesia, and granulomatosis with polyangiitis with or without eosinophilia. it may be difficult to ascertain whether the cough is a direct result of the sinus infection or the underlying problem (purulent bronchitis in the child with cf or ciliary dyskinesia, exacerbation of asthma). in the first two situations, it may not matter because treatment is the same. in the case of the child with asthma, it is important to treat the asthma with bronchodilating and antiinflammatory agents, as well as to treat the infected sinuses with antibiotics. • paroxysmal, dominated by repeated forceful, paroxysmal coughing spells; spells may be punctuated by an inspiratory "whoop," posttussive emesis, or both • convalescent, in which the intensity and frequency of coughing spells gradually diminish each stage typically lasts - weeks, except the paroxysmal stage, which lasts many weeks. (pertussis is known as the " day cough" in china.) most children are entirely well between coughing spells, when physical findings are remarkably benign. infants younger than months of age are at highest risk for complications. the majority of infants with pertussis need to be hospitalized. diagnosis can be difficult because the definitive result-namely, culturing the organism from nasopharyngeal secretions-requires special culture medium (bordet-gengou, which must be prepared fresh for each collection). culture specimens are much less likely to be positive during the paroxysmal stage than during the catarrhal stage, when the diagnosis is not being considered. pcr assay of an adequate nasopharyngeal (np) specimen is the most commonly used test because of improved sensitivity and faster turnaround time compared to culture. an elevated wbc count, as high as , - , , with lymphocytes predominating is suggestive of pertussis in infants and children but often absent in adolescents. chest radiographic findings are nonspecific. infants with severe disease may require hospitalization. treatment is largely supportive, with oxygen, fluids, and small frequent feedings for patients who do not tolerate their normal feedings. treatment with azithromycin decreases infectivity and may ameliorate the course of the disease if given during the catarrhal stage. complications include those related to severe coughing (table . ) and those specific to pertussis, such as seizures and encephalopathy. the risk of acquiring pertussis is markedly reduced by immunizations (three primary immunizations and regular booster immunizations). neither pertussis infection nor immunization produces lifelong immunity. chlamydial infection. chlamydia trachomatis can cause pneumonia in young infants, particularly those aged - weeks. cough, nasal congestion, low-grade or no fever, and tachypnea are common. conjunctivitis is an important clue to chlamydial disease but is present in only % of infants with chlamydial pneumonia at the time of presentation. affected infants may have a paroxysmal cough similar to that of pertussis, but post-tussive emesis is less common. crackles are commonly heard on auscultation, but wheezing is much less common than the overinflated appearance of the lungs on radiographs would suggest. the organism may be recovered from the nasopharynx by culture or antigen testing. the complete blood cell count may reveal eosinophilia. chlamydial infection responds to oral erythromycin therapy. ureaplasmal infection. ureaplasma urealyticum pneumonia is difficult to diagnose but causes cough in some infants. there are no particularly outstanding features to distinguish this relatively uncommon infection from viral pneumonias. bacterial pneumonia. bacterial pneumonia is relatively less common in infants than is viral pneumonia but can cause severe illness, with cough, respiratory distress, and fever. chest radiographs are abnormal, and the wbc count is elevated. treatment is with antibiotics effective against pneumococci, group a streptococci, and, if illness is severe, s. aureus. viral uris. in early childhood, as children attend daycare and nursery schools, they are constantly exposed to respiratory viruses to which they have little or no immunity (e.g., rsv, rhinoviruses, adenoviruses, parainfluenza, and enteroviruses). young children may have as many as - or even more uris in a year. the remarks concerning the treatment of sinusitis involves the use of oral antibiotics active against the common pathogens (i.e., streptococcus pneumoniae, nontypable h. influenzae, moraxella catarrhalis, and, in rare cases, anaerobic bacteria or streptococcus pyogenes). treatment regimens include the use of amoxicillin, amoxicillin-clavulanate, cefuroxime, cefpodoxime, or cefdinir. amoxicillin is considered the initial agent of choice. oral (pseudoephedrine, phenylephrine) or topical (phenylephrine, oxymetazoline) decongestants may be of benefit by increasing the patency of the sinus ostia, which permits drainage of the infected and obstructed sinuses. oral antihistamines may benefit patients with an allergic history. treatment with antimicrobial agents should continue for at least days after the patient has responded. this may require - days of therapy. many patients with presumed sinusitis recover without antibiotic therapy. complications of acute sinusitis include orbital cellulitis, abscesses (orbital, cerebral), cranial (frontal) osteomyelitis (pott puffy tumor), empyema (subdural, epidural), and thrombosis (sagittal or cavernous sinus). pneumonia. the features discussed for viral pneumonia in infants are relevant for viral pneumonia in older children. the differentiation of viral or atypical pneumonia from classical bacterial pneumonia is noted in table . . adenovirus and influenza pneumonia may present similar to bacterial pneumonia in severity and acuteness. bacterial pneumonia is more common in toddlers and older children than in infants. the most common pathogen is s. pneumoniae. (table . ). cough may not be as prominent a presenting symptom or sign as tachypnea and grunting. raised respiratory rates (> in infants - months old, > in children - years old) plus retractions and grunting with or without hypoxia (oxygen saturation < %) have a high specificity and sensitivity for pneumonia. chest pain, abdominal pain, headache, or any combination of these symptoms may occur. upper lobe pneumonia may produce meningeal signs, and lower lobe involvement may cause abdominal pain and an ileus. examination of the chest shows tachypnea but may be otherwise surprisingly normal. in older children, there may be localized dullness to percussion, with crackles or amphoric (bronchial) breath sounds over a consolidated lobe. the chest radiograph may be normal in the first hours of the illness, inasmuch as the radiographic findings often lag behind the clinical manifestations. nonetheless, both anteriorposterior and lateral views are the main diagnostic tools; lobar consolidation is usual, with or without pleural effusion. in infants, the pattern may be more diffuse and extensive. *atypical pneumonia syndrome (see table . ); atypical in terms of extrapulmonary manifestations, low-grade fever, patchy diffuse infiltrates, poor response to penicillin-type antibiotics, and negative sputum gram stain. sars, severe acute respiratory syndrome. some clinical and radiographic features may be suggestive of the bacterial cause of pneumonia. children (especially infants) with staphylococcal pneumonia are more likely to have a rapid overwhelming course. staphylococcal pneumonia may be accompanied by more extensive radiographic abnormalities, including multilobar consolidation, pneumatocele formation, and extensive pleural (empyema) fluid. the presence of a pleural effusion is not helpful in indicating the specific bacterial diagnosis because other bacterial pneumonias may be accompanied by pleural effusion. pleural effusions may represent a reactive parapneumonic effusion or an empyema. pleural fluid may be characterized as transudate, exudate, or empyema (table . ). if the effusion is of sufficient size, as demonstrated by a lateral decubitus radiograph or ultrasonography, a thoracentesis may be indicated to differentiate the nature of the effusion and to identify possible pathogens. for young children who require sedation for thoracentesis and who have an effusion needing drainage, a primary chest tube placement is preferred over thoracentesis to decrease the risks from multiple procedures with sedation. differentiating among the causes of bacterial pneumonia can be done with certainty only with positive cultures from blood, pleural fluid, fluid obtained by direct lung tap, or, in rare cases, sputum. current or previous antibiotic treatment diminishes the yield of such cultures. bronchoscopy with or without lavage may yield helpful specimens from the progressively ill child or the child who has not responded promptly to empirical antibiotics. treatment of uncomplicated presumed bacterial pneumonia is with antibiotics. ampicillin is the drug of choice for the previously healthy child who requires hospitalization with lobar pneumonia who is fully immunized. if the child is not fully immunized, either cefotaxime or ceftriaxone is indicated. for the critically ill child, vancomycin and cefotaxime/ceftriaxone may be considered for possible drug-resistant s. pneumoniae and methicillin-resistant s aureus (mrsa). many children with pneumonia do well with oral antibiotics and respond within hours to the first dose. repeated or follow-up chest radiographs may remain abnormal for - weeks after appropriate treatment and are not indicated for a single episode of uncomplicated pneumonia (i.e., to an adult with active tuberculosis. nonetheless, tuberculosis is an infrequent cause of cough in children, even in those with active disease. the diagnosis is made primarily by skin testing (purified protein derivative [ppd]) or a positive quantiferon test; a history of contact with a person who has tuberculosis; and recovery of the organism from sputum, bronchoalveolar lavage, pleural fluid or biopsy, or morning gastric aspirates (table . ). the yield from these procedures is relatively low, even from children with active pulmonary tuberculosis. no effusion, no abscess, and good response to treatment). mycoplasma pneumoniae is a common cause of pneumonia among school-aged children. the disease often occurs in community outbreaks in the fall. the illness typically begins with extrapulmonary symptoms (i.e., sore throat, myalgias, headache, fever), which then progress to include cough, which can be paroxysmal at times. patients do not often appear acutely ill, but cough may persist for weeks. there may be no specific abnormalities on the chest examination, although a few crackles may be heard, and about one third of younger patients wheeze. the radiographic findings in mycoplasmal pneumonia can mimic almost any intrathoracic disease; scattered infiltrates with nonspecific "dirty" lung fields, predominantly perihilar or lower lobes, are common, and lobar infiltrates and pleural effusion are occasionally seen. laboratory data (complete blood cell count, esr, sputum culture) may not be helpful. a rise in antimycoplasma immunoglobulin g over - weeks may be demonstrated but is seldom helpful in guiding therapy. a positive immunoglobulin m response may be useful, although it can persist in serum for several months and, consequently, may not indicate current infection. pcr is helpful. the cold agglutinin test yields positive results in about % of patients with mycoplasmal pneumonia, but they are also positive in other conditions, including adenovirus infection. the more severe the illness is, the greater is the frequency of positive cold agglutinins. the diagnosis is often made from the history of an older child who has a lingering coughing illness in the setting of a community outbreak, unresponsive to most (nonerythromycin) antibiotic regimens. treatment with azithromycin, clarithromycin, or erythromycin in children < years old or tetracycline or doxycycline in children ≥ years old usually shortens the course of illness. extrapulmonary complications of mycoplasmal infection include aseptic meningitis, transverse myelitis, peripheral neuropathy, erythema multiforme, myocarditis, pericarditis, hemolytic anemia, and bullous otitis media (myringitis). in patients with sickle cell anemia, severe respiratory failure and acute chest syndrome may develop. infection with chlamydia pneumoniae mimics respiratory disease resulting from m. pneumoniae, inasmuch as it occurs in epidemics, is seen in older children, and produces an atypical pneumonia syndrome and pharyngitis. tuberculosis. tuberculosis is uncommon in developed countries; % of the disease burden worldwide is in developing countries. tuberculosis must be considered in the child with chest disease that is not easily explained by other diagnoses, especially if the child lives in or has migrated from an endemic area of the world or has been exposed cutaneous induration ≥ mm • close exposure to known or suspected active tb • chest radiograph consistent with tb (old or active) • clinical evidence of tb • children receiving immunosuppresive therapy or with immunosuppressive conditions cutaneous induration ≥ mm children at increased risk • age < yr of age • medical high risks (chronic renal failure, malnutrition, diabetes mellitus, lymphoma) children with likelihood of increased exposure • children born in high-prevalence regions of the world • children who travel to high-prevalence regions of the world • children frequently exposed to adults who are hiv infected, homeless, users of illicit drugs, residents of nursing homes, incarcerated, or institutionalized cutaneous induration ≥ mm • all children ≥ yr of age without any identifiable risk the patterns of disease in normal hosts include primary pulmonary tuberculosis, with subsequent inactivation usually noted in young children and reactivation pulmonary disease among adolescents. primary pulmonary disease is often noted as a lower or middle lobe infiltrate during the period of t lymphocyte reaction to the initial infection. before resolution, the mycobacterium tuberculosis infection may disseminate to the better oxygenated upper lobes and extrathoracic sites, such as bone, or the central nervous system. if the immune response contains the initial infection, the radiographic findings may be indistinguishable from those of any other pneumonic process. with altered immune function, however, there may be progressive local disease, dissemination to miliary pulmonary disease, or early reactivation (months to years) at distal sites, which produces tuberculous meningitis or osteomyelitis. reactivation of upper lobe pulmonary disease may produce cavities that are similar to the disease among adults. cavitary and endobronchial lymph node involvement are highly infectious, in contrast to the much less contagious nature of the hypersensitivity reaction noted in primary pulmonary disease. inhaling food, mouth or gastric secretions, or foreign bodies into the tracheobronchial tree causes acute, recurrent, or chronic cough. interference with normal swallowing disrupts the coordination of swallowing and breathing that prevents aspiration. structural causes of disordered swallowing include esophageal atresia (in neonates), strictures, webs, or congenital stenoses. mediastinal lesions (tumors, lymph nodes), including vascular rings, may compromise the esophageal lumen and esophageal peristalsis, increasing the likelihood of aspiration. functional disorders include central nervous system dysfunction or immaturity, dysautonomia, achalasia, and diffuse esophageal spasm. prior neck surgery, including tracheostomy, may alter normal swallowing. tracheoesophageal fistula and laryngeal clefts are congenital malformations with direct physical connections between the tracheobronchial tree and the upper gastrointestinal tract; thus oral contents enter the lungs directly. making the diagnosis of aspiration as the cause of cough may be difficult. barium contrast studies during swallowing may help characterize these disorders if barium enters the trachea. because most patients aspirate sporadically, a normal barium swallow does not rule out aspiration. radionuclide studies can be helpful if ingested radiolabeled milk or formula is demonstrated over the lung fields at severalhour intervals after the meal. bronchoscopy and bronchoalveolar lavage that recover large numbers of lipid-laden macrophages suggest that aspiration has taken place; however, the finding is neither sensitive nor specific for aspiration. treatment depends largely on the cause of aspiration. because many patients who aspirate do so because of lack of neurologic control of swallowing and breathing, it is often difficult to prevent. even gastrostomy feedings cannot prevent aspiration of oral secretions. in extreme cases, tracheostomy with ligation of the proximal trachea has been employed. this not only prevents aspiration but also prevents phonation, and it must be considered only in unusual situations. aspiration pneumonia is often treated with intravenous ampicillinsulbactam or clindamycin to cover mouth flora of predominant anaerobes. additional coverage against gram-negative organisms may be indicated if the aspiration is nosocomial. any child with cough of abrupt onset should be suspected of having inhaled a foreign body into the airway. toddlers, who by nature put all types of things into their mouths and who have incompletely matured swallowing and airway protective mechanisms, are at high risk. infants with toddlers or young children in the household who may "feed" the baby are also at risk. in older children, it is usually possible to obtain an accurate history of the aspiration event. these events are described as choking, gagging, and coughing while something (e.g., peanuts, popcorn, small toys, sunflower seeds) is in the mouth. the child may come to the physician with cough and wheeze immediately after the event, with a clear history and a straightforward diagnosis. in many children with a tracheobronchial foreign body, however, the initial episode is not recognized; these children may not come to medical attention for days, weeks, or even months. the initial episode may be followed by a relatively symptom-free period lasting days or even weeks, until infection develops behind an obstructed segmental or lobar bronchus. at this point, cough, perhaps with hemoptysis, with or without wheeze, recurs. on physical examination early after an aspiration episode, there is cough, wheeze, or both, often with asymmetry of auscultatory findings. there may be locally diminished breath sounds. later, localized wheeze or crackles may be detected. the triad of wheezing, coughing, and decreased breath sounds is present in fewer than % of patients. the presence of laryngotracheal foreign bodies often manifests with stridor, retractions, aphonia, cough, and normal radiographs. chest radiographs may be normal in % of patients with intrathoracic foreign bodies but should be obtained in both inspiration and expiration because in some cases the only abnormality is unilateral or unilobar air trapping, which is occasionally more clearly identified with an expiratory radiograph. in this view, an overdistended lung that had appeared normal on the inspiratory view does not empty, but the normal, unobstructed lung empties normally. this phenomenon causes a shift of the mediastinum toward the emptying lung, away from the side with the obstructing foreign body (fig. . ) . in other patients, localized infiltrate or atelectasis may be present behind the obstructing object. in a few patients, it may be possible to identify the foreign body itself; nonetheless, most inhaled food particles are not radiopaque and cannot be seen on radiographs. aspiration is usually unilateral ( %); - % of the objects are in the right lung (the lobe depends on body position-supine versus standing-but is often the right middle lobe). the definitive diagnostic and therapeutic maneuver is bronchoscopy; either the flexible or rigid open-tube bronchoscope enables direct visualization of the object; the rigid instrument also enables its removal. ger is a common cause of cough in all age groups (see chapter ). the typical patient is an infant in the first months of life who spits up small amounts of milk frequently after feedings. this "regurgitant reflux" most commonly resolves by year of age. however, many toddlers and children continue to have reflux, although it may be "silent" or nonregurgitant (without spitting up). in most people with ger, it is merely a nuisance or not noticed. in some there are sequelae, and this condition is designated gastroesophageal reflux disease (gerd). one manifestation is cough; the mechanisms for the cough are not fully understood. aspiration of refluxed material is one mechanism for cough but is probably not very common in neurologically intact children. a major mechanism for gerd with cough is mediated by vagal esophagobronchial reflexes (bronchoconstriction), stimulated by acid in the esophagus. whether acid in the esophagus is sufficient stimulus to cause bronchoconstriction by itself or whether it merely heightens bronchial reactivity to other stimuli is not yet clear. many children with reactive airways disease have cough or wheeze that is difficult to control until their concurrent ger is also treated. many episodes of cough caused by gerd occur in children with asthma that is difficult to control. (cftr), which acts as a chloride channel and affects other aspects of membrane transport of ions and water. not all the consequences of the defective gene and protein have been determined. in general, however, the defective gene product results in the long-observed clinical manifestations of the disease, including thick, viscid mucus in the tracheobronchial tree, leading to purulent bronchiolitis and bronchitis with subsequent bronchiectasis, pulmonary fibrosis, and respiratory failure; pancreatic duct obstruction, leading to pancreatic insufficiency with steatorrhea and failure to thrive; and abnormally high sweat chloride and sodium concentrations. the airway disease in cf is characterized by infection, inflammation, and endobronchial obstruction. the infection begins with s. aureus, h. influenzae, escherichia coli, klebsiella species, or combinations of these organisms but eventually is dominated by nonmucoid or mucoid pseudomonas aeruginosa. other organisms, such as burkholderia cepacia, stenotrophomonas maltophilia, alcaligenes xylosoxidans, aspergillus fumigatus, or nontuberculous mycobacteria may also appear; their significance remains undetermined. in some patients, b. cepacia has been associated with rapid deterioration and death, and in others, aspergillus species has caused allergic bronchopulmonary aspergillosis (abpa). the airway inflammation in all patients with cf appears to be the result of toxic substances, including elastase, released by neutrophils as they respond fig. . .) a b the diagnosis of gerd must also be considered in the child with chronic or recurrent cough with no other obvious explanation. the child who coughs after meals or at night, when the supine position may provoke ger, should be evaluated for ger. if ger is confirmed, the next step is a therapeutic trial of antireflux therapy. treatment in a child whose cough is related to ger may be accomplished by treating the reflux (see chapter ) or by a combination of antireflux and antiasthma treatment (see chapter ). on occasion, the cough may be abolished by stopping all antiasthma medications. in such cases, the cough was a manifestation of reactive airways with esophageal acidification as the trigger for bronchospasm; the esophageal acidification was caused by the bronchodilator effects on the lower esophageal sphincter. cough is frequently the sole or most prominent manifestation of asthma; wheezing may be entirely absent. in fact, asthma is almost certainly the most common cause of recurrent and chronic cough in childhood (see chapter ). some of the features that characterize the cough of a child with asthma are listed in table . . treatment for asthma manifesting as cough is the same as the treatment for asthma. cystic fibrosis (cf) is a common cause of recurrent or chronic cough in infancy and childhood. cf occurs in in - live births among white persons, is far less common among african americans ( in , ), and is rare among native americans and asians. early diagnosis improves the prognosis for untreated cf; if untreated, many patients die in infancy or early childhood. with current state-of-the-art care, median length of survival is upper s. cf is a genetic disorder, inherited as an autosomal recessive trait. the cf gene is on the long arm of chromosome ; more than mutations have been identified at the cf locus. of these mutations, one (Δf , indicating a deletion, Δ, of a single phenylalanine, f, at position of the protein product) is the most common, responsible for - % of all cf chromosomes. the mutation affects the gene's protein product, termed cystic fibrosis transmembrane regulator any age (even infants) coexistence of allergy increases likelihood, but absence of allergy does not decrease likelihood wheeze need not be present ↑cough with upper respiratory infections ↑cough with (and especially after) exercise ↑cough with hard laughing or crying ↑cough with exposure to cold ↑cough with exposure to cigarette smoke usually a history of dramatic response to inhaled β-agonists cf may manifest at birth with meconium ileus ( - % of patients), or later, with steatorrhea and failure to thrive despite a voracious appetite, in an apparent effort to make up for the calories that are lost in the stool (see chapter ). the most common presenting symptom is cough, which may appear within the first weeks of life or may be delayed for decades. the cough can be dry, productive, or paroxysmal. cough may respond to antibiotics or perhaps steroids, but it is less likely to improve with bronchodilators (see tables . and . ). although cf is a genetic disease, there is often no family history. furthermore, in atypical cases, patients may not have pancreatic insufficiency (~ % of patients) and thus may not demonstrate steatorrhea and failure to thrive. in addition, malabsorption may not be evident in the neonatal period. there is no such thing as a child who looks "too good" to have cf; common abnormalities found on physical examination are noted in table . . one of the most important physical findings is digital clubbing. in most patients with cf, clubbing develops within the first few years of life. although the list of conditions associated with digital clubbing (table . ) is long, they are less common than cf, or the incidence of digital clubbing with these conditions is low. there is some relationship between the degree of pulmonary disease severity and the degree of digital clubbing. a child who has had years of severe respiratory symptoms without digital clubbing is not likely to have cf. the diagnosis is confirmed by a positive sweat test or confirming the presence of two cf mutations on chromosome . the sweat test, if not performed correctly in a laboratory with extensive experience with the technique (as, for example, in an accredited cf center), yields many false-positive and false-negative results. the proper technique is to use quantitative analysis of the concentration of chloride in the sweat produced after pilocarpine iontophoretic stimulation. chloride concentrations higher than mmol/l are considered positive, and those lower than mmol/l are negative (normal). healthy adults have slightly higher sweat chloride concentrations than do children, but the same guidelines hold for positive tests in adults. the non-cf conditions yielding elevated sweat chloride concentrations are listed in table . . false-negative results of sweat tests can be seen in cf children presenting with edema or hypoproteinemia and in samples from children with an inadequate sweat rate. sweat testing can be performed at any age. newborns within the first few weeks of life may not produce a large enough volume of sweat to analyze ( mg minimum), but in those who do (the majority), the results are accurate. indications for sweat testing are noted in table . . in patients for whom sweat testing is difficult (e.g., because of distance from an experienced laboratory, small infants who have not produced enough sweat, patients with extreme dermatitis, or patients with intermediate-range sweat chloride concentrations), dna mutation testing can be useful. demonstration of two known cf mutations confirms the diagnosis. finding one or no known mutation makes the diagnosis less likely but is not exclusive, inasmuch as there are patients all states are using a neonatal screen for cf. the cf screen assays include measuring serum immunoreactive trypsinogen (irt) levels, which are elevated in most infants with cf for the first several weeks of life, and dna analysis for cftr mutations. the main drawback of the irt assay is that it has relatively poor specificity; as many as % of the positive results on the initial screen are false-positive results. if an infant's irt screen is positive, the test should be repeated, or dna analysis for the most common cftr mutations should be performed. at - weeks of age, which is when the irt is repeated, the false-positive rate has fallen dramatically but is still quite high ( %). definitive testing with the sweat chloride test needs to be carried out on infants with positive screening results. laboratory data that may support the diagnosis of cf include low levels of fecal elastase. this suggests pancreatic insufficiency, which occurs most commonly in cf but can be seen in other diseases. the test is not perfect for confirming cf as some cf patients have sufficient pancreatic function. pulmonary function test findings with an obstructive pattern, incompletely responsive to bronchodilators, are consistent with cf but, of course, can be seen in other conditions. conversely, some patients with cf also have asthma and may show a marked response to a bronchodilator. complications of cf that should suggest the diagnosis are noted in table . . the treatment of patients with cf requires a comprehensive approach, best performed in, or in conjunction with, an approved cf center. several studies have shown survival to be significantly better in center-based care than in non-center-based care. table . lists the main anatomic abnormalities that cause cough. vascular rings and slings. vascular rings and slings are often associated with inspiratory stridor because the abnormal vessels compress central airways, most commonly the trachea (see chapter ). the patient may also have difficulty swallowing if the esophagus is compressed. the diagnosis may be suspected from plain radiographs of the chest, especially those showing tracheal deviation and a right-sided aortic arch. further support for the diagnosis can be found at bronchoscopy (which shows extrinsic compression of the trachea or a main stem bronchus), barium esophagram (which shows esophageal compression), or both. the definitive diagnosis is made with computed tomographic angiography or magnetic resonance angiography. treatment is surgical. pulmonary sequestration. pulmonary sequestration is relatively unusual, occurring in in , children. it occurs most commonly in the left lower lobe and can manifest in several ways (fig. . ; see also table . ). the chest radiograph usually shows a density in the left lower lobe; this density often appears to contain cysts (fig. . ) . the feature distinguishing a sequestered lobe from a complicated pneumonia is that the blood supply arises from the aorta and not the pulmonary circulation. doppler ultrasonography and ct angiography provide the definitive diagnosis. the treatment is surgical removal. congenital pulmonary airway malformation (cpam). congenital pulmonary airway malformations (formerly known as congenital cystadenomatoid malformations or ccams) are rare. they manifest in infancy with respiratory distress in nearly % of cases; the other half may manifest as cough with recurrent infection later in childhood or even adulthood. the chest radiograph reveals multiple cysts, separated by dense areas. chest ct scans can help make the diagnosis with near certainty. surgical removal is the treatment of choice if the lesion is symptomatic. congenital lobar emphysema. congenital lobar emphysema occurs in one of , live births. it can manifest dramatically with with not-yet-characterized mutations. furthermore, commercial laboratories do not identify all of the mutations. recovery of mucoid pseudomonas aeruginosa from respiratory tract secretions is strongly suggestive of cf. similarly pansinusitis is nearly universal among cf patients but is quite uncommon in other children. respiratory distress in the neonatal period or later (fig. . ) , with cough or wheeze, or as an incidental finding on a chest radiograph. radiography shows localized overinflation, often dramatic, with compression of adjacent lung tissue and occasionally atelectasis of the contralateral lung because of mediastinal shift away from the involved side. the appearance on chest ct scan is typical, with widely spaced blood vessels (as opposed to congenital cysts, for example, which have no blood vessels within the overinflated area). bronchoscopy can document patent bronchi and should probably be performed in older children in whom congenital lobar emphysema can be confused with acquired overinflation of a lobe as the result of bronchial obstruction, as with a foreign body. if the disease is symptomatic, treatment is surgical. tracheoesophageal fistula. tracheoesophageal fistula is common, with an incidence of about one in live births. of these fistulas, the large majority ( %) are associated with esophageal atresia; only % are the isolated, h-type fistula (a patent esophagus with fistulous tract connecting the esophagus and trachea). a neonate with esophageal atresia experiences respiratory distress, excessive drooling, and choking and gagging with feeding. the h-type fistula causes more subtle signs and may be undiagnosed for months or even years. the child may have only intermittent feeding trouble, especially with liquids. there may be recurrent lower respiratory tract infections. the diagnosis is not challenging in the infant with esophageal atresia; a nasogastric tube cannot be passed, and swallowed barium outlines the trachea. in the older child with h-type fistula, a barium esophagogram may or may not reveal the fistula. bronchoscopy and esophagoscopy should permit direct visualization of the fistula; however, the opening may be hidden in mucosal folds. treatment is surgical. many children born with tracheoesophageal fistula have recurrent cough and lower respiratory tract infection for many years, even after successful surgical correction. the cough is characteristically the harsh cough of tracheomalacia, which is present at the site of the fistula. the infections result from several causes, including ger, with or without aspiration, and altered mucociliary transport. treatment involves regular chest physiotherapy and early and aggressive use of antibiotics whenever there is evidence of increased pulmonary symptoms. hemangiomas. hemangiomas may be present within the airway and can cause cough, rarely with hemoptysis. stridor (if the hemangioma is high in the airway) and respiratory distress (if the hemangioma is large) may also occur. in rare cases, with very large airway hemangiomas, there may even be dysphagia from extrinsic compression. children with cutaneous hemangiomas in the mandibular or neck region ("beard" distribution) are at risk for an airway hemangioma. the diagnosis is made with bronchoscopy. these lesions may resolve spontaneously over the first year or so. however, if they cause symptoms, it may not be advisable or possible to wait for them to resolve. many airway hemangiomas regress with steroid treatment; however, due to the side effect profile, propranolol is considered the treatment of choice. asthma is a contraindication for propranolol treatment due to its beta-blocking effect and potential to worsen asthma. laser ablation may be indicated in some refractory cases that do not respond to first-line treatment. in the case of a large subglottic hemangioma, a tracheostomy is performed and maintained until the mass regresses. enlarged lymph nodes. enlarged mediastinal lymph nodes, such as those resulting from tuberculosis, leukemia, other hematologic malignancies, or other infections, are occasionally a cause of cough in children ( plain radiographs of the chest. the x-ray study or bronchoscopy may show extrinsic compression of the trachea. treatment is directed at the underlying cause. bronchial stenosis. occasionally bronchial stenosis, either congenital or acquired, may cause cough. the diagnosis is made with bronchoscopy, after suspicion has been raised by the child having recurrent infiltrates in the same lobe, especially with localized wheeze. treatment may be difficult. in some cases, endoscopic balloon dilatation or airway stent placement is successful; in others, surgical resection of stenotic areas may be necessary. bronchogenic cysts. bronchogenic cysts are uncommon, but they can cause cough, wheeze, stridor, or any combination of these. they may also cause recurrent or persistent pneumonia if they block a bronchus sufficiently to interfere with normal drainage of the segment or lobe. radiography may show localized overinflation if the cyst causes a ball-valve-type obstruction. the cyst itself may or may not be seen on plain radiographs. bronchoscopy reveals extrinsic compression of the airway. ct studies often definitively show the lesion. surgical removal is indicated. on occasion, a school-aged child may develop a cough that lasts for weeks, often after a fairly typical cold. this cough occurs only during wakefulness, never during sleep. in many cases, the cough is harsh and foghorn-like. it often disrupts the classroom, and the child is asked to leave. the child is otherwise well and may seem rather unbothered by the spectacle created. there is no response to medications. it seems that this type of cough, previously termed "psychogenic," or "psychogenic cough tic," but now called habit cough, has given the child valuable attention. this attention then serves as the sustaining force, and the cough persists beyond the original airway inflammation. in the small minority of cases, there may be deep-seated emotional problems of which the cough is the physical expression. during the history or physical examination, the child appears completely well and may cough when attention is drawn to the child or when the word "cough" is uttered. the physical examination findings are otherwise completely normal, as are laboratory values. because this may occur in any child, evidence of mild reactive airways disease (history or pulmonary function testing) does not rule out the diagnosis. once a physician has seen a child with this problem, it is usually possible to make the diagnosis with certainty on entering the examining room or, indeed, from the hallway outside the room. treatment can prove more difficult. the child and family should be reassured that the child is well. suggestion therapy empowers and encourages the patient to suppress the cough for short increments of time. the goal is for them to gradually lengthen the cough-free intervals. speech therapy may be helpful ( infiltrates, and there is invariably iron deficiency anemia. the diagnosis is based on lung biopsy findings. tumors. tumors causing cough are rare in childhood. cough occurs because of bronchial blockage, either extrinsic or endobronchial (see table . ). the diagnosis is usually made from bronchoscopy, chest ct, or both. treatment depends on the cell type, but it usually involves at least some surgical removal. chemotherapy or radiation may be used in some cases. tracheomalacia and bronchomalacia. isolated tracheomalacia or bronchomalacia is uncommon but can cause cough in some children. the cough of tracheomalacia is typically harsh and brassy. treatment is difficult but, fortunately, is seldom needed. spasmodic croup. some children, usually preschoolers, may episodically awaken at night with stridor and a harsh, barking cough indistinguishable from that of viral croup. this entity is termed spasmodic croup and is of unclear origin. viral and allergic causes have been postulated. ger may be the cause in some patients. treatment with cool mist or racemic epinephrine is effective in most patients. if ger is the underlying cause, antireflux treatment is beneficial. obliterative bronchiolitis. obliterative bronchiolitis is very rare except in lung transplant recipients. in other instances, it may arise after adenovirus, measles, or influenza pneumonia; after exposure to certain toxins; or in other rare circumstances. children may exhibit cough, respiratory distress, and exercise intolerance. the diagnosis is suggested by the pulmonary function test or radiographic evidence of small airways obstruction; however, these findings are not always present. not all chest radiographs show overinflated lungs, and not all pulmonary function tests show decreased small airways function. the definitive diagnosis is histologic via open or transbronchial biopsy. no specific treatment is available. most children with obliterative bronchiolitis recover, but many progress to chronic disability or death. the child who coughs out blood or bloody mucus presents special diagnostic and therapeutic challenges. although hemoptysis is relatively uncommon in children, particularly among those without cf, many conditions can cause it (table . ). it is important (and not always easy) to distinguish cases in which blood has originated in the tracheobronchial tree (true hemoptysis), the nose (epistaxis), and the gastrointestinal tract (hematemesis). table . gives some guidelines to help localize sites of origin of blood that has been reported or suspected as hemoptysis. none of these guidelines is foolproof, partly because blood that has originated in one of these sites might well end up in another before being expelled from the body; for instance, blood from the nose can be swallowed and vomited or aspirated and expectorated. infection is among the most common causes of hemoptysis. lung abscess and tuberculosis need to be considered. bronchiectasis can readily cause erosion into bronchial vessels, often made tortuous by years of local inflammation, and produce hemoptysis. other infectious causes are less common and include necrotizing pneumonias and fungal and parasitic lung invasion. foreign bodies in the airway can cause hemoptysis by direct irritation, by erosion of airway mucosa, or by secondary infection. pulmonary embolus is uncommon in children and adolescents, but it needs to be considered in the differential diagnosis of an adolescent with hemoptysis of unclear origin. clues to the diagnosis of pulmonary embolus include a positive family history, severe dyspnea, chest pain, hypoxia, a normal chest radiograph, an accentuated second bronchiectasis. bronchiectasis is defined as an abnormal dilation of the subsegmental bronchi and is usually associated with chronic cough and purulent sputum production. it occasionally occurs after severe pneumonias (bacterial or viral); it eventually develops in nearly all patients with cf. diagnosis may, on occasion, be made with plainchest radiographs, but high-resolution ct scanning is the diagnostic procedure of choice. treatment of bronchiectasis consists of airway clearance with chest physiotherapy with postural drainage or highfrequency chest wall oscillation, occasionally bronchodilators and mucolytic agents, and antibiotic therapy during exacerbations. surgical resection may be indicated in cases that are progressive and localized when medical therapy has failed. the prognosis of bronchiectasis depends on the underlying cause. cf-associated bronchiectasis is a major cause of cf-related morbidity and mortality; whereas, non-cf bronchiectasis may remain stable or even regress with therapy. ciliary dyskinesia. conditions in which the cilia do not function properly (immotile cilia or ciliary dyskinesia) lead to cough, usually because infection (and bronchiectasis) occurs in the absence of normal mucociliary transport. treatment is similar to that for cf, with regular chest physiotherapy and frequent and aggressive use of antibiotics at the first sign of airways infection, most commonly increased cough. interstitial lung disease. interstitial lung diseases are now classified based on those that occur during the neonatal period and those that are not as prevalent in infancy. interstitial lung diseases that manifest with cough include aspiration (chronic and recurrent) pneumonitis, hypersensitivity pneumonitis, bronchiolitis obliterans, and cryptogenic organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia or boop). lung biopsy may be required for a diagnosis. pulmonary hemosiderosis. pulmonary hemosiderosis is a rare, and often fatal, condition of bleeding into the lung that can manifest with cough. if sputum is produced, it is often frothy and blood-tinged. there may be frank hemoptysis. however, the cough may be nonproductive, or the sputum may be swallowed. some cases are associated with milk hypersensitivity (heiner syndrome), and affected children may have upper airway obstruction. some cases are associated with collagen vascular disorders. radiographs usually show diffuse fluffy postnasal drip (?) bronchiectasis ciliary dyskinesia interstitial lung disease heart failure/pulmonary edema pulmonary hemosiderosis drug-induced (see table bronchoscopy can sometimes localize a bleeding site, identify a cause (e.g., a foreign body or endobronchial tumor), or recover an offending bacterial, fungal, or parasitic pathogen. in many instances, bronchoscopy does not help except by excluding some possibilities, because either no blood or blood throughout the tracheobronchial tree is found. bronchial artery angiography may help to identify the involved vessel or vessels. treatment of hemoptysis depends on the underlying cause. it can be a terrifying symptom to children and their parents, and a calm, reassuring approach is essential. because hemoptysis is seldom fatal in children, reassurance is usually warranted. furthermore, hemoptysis most often resolves, and treatment of the bleeding itself is not often needed. what is required is treatment of the underlying cause of the hemoptysis, such as therapy for infection, removal of a foreign body, or control of collagen vascular disease. when death occurs from hemoptysis, it is more likely to be from suffocation than from exsanguination. in cases of massive bleeding, the rigid open-tube bronchoscope may help suction large amounts of blood while ventilating and keeping unaffected portions of lung clear of blood. interventional radiologists treat as well as localize a bleeding site by injecting the offending vessel with occlusive substances (embolization). in extremely rare instances, emergency lobectomy may be indicated. heart sound, an abnormal compression ultrasonographic study of the leg veins, a positive homans sign, a positive helical ct scan, and a high-probability lung ventilation-perfusion scan. the diagnosis of several causes of hemoptysis is straightforward. for example, hemoptysis that occurs immediately after a surgical or invasive diagnostic procedure in the chest should suggest an iatrogenic problem. the chest radiograph can help suggest lung abscess, pulmonary sequestration, bronchogenic cyst, or tumor. chest ct can help with cases of arteriovenous malformations, and additional laboratory values can support the diagnosis of collagen vascular disease. cough that may produce significant complications (see table . ). for most diseases, suppressing the cough offers no advantage. disadvantages include narcotic addiction and loss of the protective cough reflex with subsequent mucous retention and possible superinfection. demulcent preparations (sugar-containing, bland soothing agents or honey) temporarily suppress the cough response from pharyngeal sources, and decongestant-antihistamine combinations may reduce postnasal drip. cough itself seldom necessitates specific treatment. nonetheless, cough is not always completely benign (see table . ). most complications are uncommon, and most accompany only very severe cough, but some are serious enough to justify treatment of the cough itself. cough suppressants include codeine and hydrocodone (two narcotics) and dextromethorphan (a nonnarcotic d-isomer of the codeine analog of levorphanol). such agents should be used only for severe cough is important because it is a symptom and sign of underlying disease that frequently merits treatment. in the acute setting, severe disease, including massive hemoptysis or profound dyspnea or hypoxemia, warrants immediate attention, rapid diagnosis, and rapid management. certain chronic conditions, including those that suggest cf and those in which symptoms have persisted and interfere with a child's daily activities and quality of life, warrant further evaluation and treatment. finally, a child whose cough fails to respond to what should have been reasonable treatment should be referred to a pulmonary specialist (table . ). evaluation of chronic or recurrent cough guidelines for evaluating chronic cough in pediatrics recommendations for the assessment and management of cough in children upper respiratory infection bacterial tracheitis: report of eight new cases and review the common cold adverse events from cough and cold medication in children does this patient have sinusitis? diagnosing acute sinusitis by history and physical examination pertussis (whooping cough) report of the committee on infectious diseases bts guidelines for the management of pleural infection in children chlamydial respiratory infections the management of communityacquired pneumonia in infants and children older than months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america infant pneumonitis associated with cytomegalovirus, chlamydia, pneumocystis, and ureaplasma: follow-up value of radiological follow-up of childhood pneumonia british thoracic society guidelines for the management of community acquired pneumonia in children: update tuberculosis (myconbacterium tuberculosis) etiology and treatment of pneumonia pulmonary manifestations of acquired immunodeficiency syndrome standardized diagnosis of pneumonia in developing countries hypoxaemia in young kenyan children with acute lower respiratory infection tuberculosis in children clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis the evaluation of the child with recurrent chest infections nebulised hypertonic saline solution for acute bronchiolitis in infants bronchoscopic removal of aspirated foreign bodies in children tracheobronchial foreign bodies subglottic foreign bodies in pediatric patients tracheobronchial foreign bodies cystic fibrosis the cystic fibrosis genotype-phenotype consortium. correlation between genotype and phenotype in patients with cystic fibrosis cystic fibrosis therapeutics. the road ahead wheezing in infants with cystic fibrosis: clinical course, pulmonary function, and survival analysis cystic fibrosis physiotherapy in cystic fibrosis efficacy and safety of short-term administration of aerosolised recombinant human dnase i in adults with stable stage cystic fibrosis the diagnosis of cystic fibrosis: a consensus statement emerging therapies for cystic fibrosis pseudomonas cepacia: pulmonary infection in patients with cystic fibrosis effect of long-term treatment with inhaled budesonide on adult height in children with asthma a clinical index to define risk of asthma in young children with recurrent wheezing airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age statement: asthma control and exacerbations. standardizing endpoints for clinical asthma trials and clinical practice low-dose inhaled corticosteroids and the prevention of death from asthma venous thromboembolic complications in children clinical assessment and management of massive hemoptysis massive haemoptysis: medical management will usually arrest the bleeding pathogenesis and management of hemoptysis in children key: cord- -kiccsa authors: chen, wei-chieh; chuang, hsiao-mei; huang, jin-long; hung, siu-wan; tsai, chia-i; fu, pin-kuei title: adjuvant therapy with traditional chinese medicine in a heart failure patient complicated by hospital-acquired pneumonia: a case report date: - - journal: complement ther med doi: . /j.ctim. . . sha: doc_id: cord_uid: kiccsa objective: we report a case of congestive heart failure complicated by hospital-acquired pneumonia that was successfully treated with traditional chinese medicine (tcm) and antibiotics. clinical features and outcome: a -year-old man with a history of heart failure developed pneumonia during hospitalization. after the standard antibiotic therapy for days, he continued to experience persistent fever and progressive cough with purulent sputum. broad spectrum antibiotics did not relieve the fever or the purulent sputum; therefore, the patient requested tcm for integrated therapy, and was subsequently treated with a regiment of “clearing heat and damp excreting” decoction according to tcm theory. after three days of tcm combination therapy, the pneumonia patches significantly improved on chest x-ray. his sputum was obviously decreased in amount and the fever was complete remission in the (th) day of tcm adjuvant therapy. conclusion: integrated therapy with a “clearing heat and damp excreting” decoction may have improved hospital-acquired pneumonia in a patient comorbid with congestive heart failure. the anti-pyretic, anti-inflammatory, antitussive and diuretic effects of tcm may be responsible for the observed improvement. further experimental studies are warranted to confirm the efficacy and mechanism of tcm action in the treatment of pneumonia. pneumonia is one of the most common infectious diseases causing significant morbidity and mortality in adults even in the modern medical care system. according to the world health organization statistics, pneumonia was the th leading cause of death, causing . million deaths worldwide in . as the rd leading cause of death in , the social-economic burden of pneumonia in taiwan is significant. pneumonia is classified as community acquired (cap) or hospital acquired (hap) according to the acquisitionsite. the prognosis of hap patients is unfavorable, especially for those with comorbidities such as chronic obstructive pulmonary disease, immunocompromised status, and congestive heart failure (chf). the standard treatment for hap includes antimicrobial therapy and supportive care. antibiotics can attenuate the infectious process. however, with the widespread overuse and misuse of antibiotics, multiple-drug-resistant pathogens give rise to pneumonia that is difficult to treat. the morality rate for hap ( . %) is greater than that of cap and is especially high in those patients with multiple comorbidities. , xu et al conducted a prospective, multi-center, double-blind, parallel, randomized controlled trial to evaluate integrated therapy consisting of traditional chinese medicine (tcm) and antibiotics in elderly patients with pneumonia. their findings indicate that tcm combination therapy is safe and effective in ameliorating expectoration and promoting the absorption of pneumonia lesions. here, we report a hap patient comorbid with chf who was treated with tcm adjuvant therapy. the patient exhibited rapid, significant improvement in symptoms and image findings. on december , , a -year-old man presented with fever offand-on up to . °c, chills, and cough with purulent sputum. he had been discharged from a rehabilitation ward - days before this admission. his medical history included acute myocardial infarction complicated by cardiogenic shock over the previous year, and his present left ventricular ejection fraction (lvef) was reduced to %. serial laboratory examinations showed no leukocytosis but neutrophil dominance ( . %) and an elevated c-reactive protein (c-rp) level of . mg/dl. sputum and blood culture analysis were performed on december , yielding negative findings. thoracic radiography revealed a bilateral perihilar alveolar pattern,a dilated azygos vein, and diffuse pulmonary consolidations with air bronchograms in bilateral lower lung fields (fig. ) . accordingly, hap accompanied by pulmonary edema was diagnosed. empiric intravenous antibiotic treatment with piperacillin/tazobactam . g every h was promptly initiated on december , .nevertheless, the patient continued to experience fever and progressive cough with purulent sputum during antibiotic treatment. he asked for tcm combination therapy, which was started on december , (the rd hospital day). the diagnosis according to the tmc theory was "exterior evil inward invasion" and "accumulation of phlegm and heat in the lung" in a yang-deficiency constitution. the "clearing heat and damp excreting" decoction was prescribed three times a day as shown in table . after a -day course of treatment, the pneumonia lesions significantly improved on chest x-ray (fig. ) . the sputum clearly decreased in volume, and the fever had completely abated by day of tcm adjuvant therapy (fig. ) . the patient's report of cough decreased. he also felt much better and more energetic. we report a hap patient comorbid with chf who experienced rapid and significant improvement in symptoms and image findings following treatment with tcm adjuvant therapy. because the bacterial cultures from sputum and blood were all negative, we believe that the antipyretic, anti-inflammatory, and antitussive effects of the tcm regiment acted against the persistent inflammation in this patient. the integration of tcm and western medicine has been shown effective for treating patients with pneumonia in a previous clinical trial and an animal study of the anti-inflammatory effects of tcm. , ma-xing-gan-shi-tang (mxgst) is an old tcm formula consisting of four ingredients: herbaephedrae (ma huang), semen armeniacae (xing ren), gypsum fibrosum (shi gao), and radix glycyrrhizae (gan cao). this formula has been used to treat patient with common-cold-related fever and bronchial asthma for several centuries. in a rat model of bronchial asthma, mzgst was shown to exertanti-tussive and anti-pyretic effects through promoting airway smooth muscle relaxation and inhibiting neutrophil recruitment in the airway. in an animal study, treatment of lipopolysaccharide-induced lung injury with mxgst resulted in decreased inflammation and a hyperpermeability reaction in lungs through regulation of the toll-like receptor , src, and nf-κb pathways. in this case, we chose herbaephedrae (ma huang), gypsum fibrosum (shi gao) and radix glycyrrhizae (gan cao) as the major components of our mixture because of their antipyretic and anti-asthmatic effects. we added yu xing cao (houttuyniacordata), huang qin (radix scutellariae), mu dan pi (cortex mountan), sang bai pi (cortex mori), and gua lou shi (fructus trichosanthis) to increase the antipyretic and antiinflammatory effects. we added ting li zi (semenlepidii) and fu ling (poria cocos) to improve the edema status of this patient and huang qin (scutellariae radix) and mu dan pi (moutan cortex) to ameliorate lung inflammation, based on the results of previous investigations. the main component of moutan cortex is paeonol, which is reported to have anti-inflammatory effect and anti-pyretic effects against lipopolysaccharide-induced acute lung injury. , yu xing cao (houttuyniacordata) was chosen as a key herb for the treatment of severe acute respiratory syndrome and exhibits anti-inflammatory effects according to multiple studies. , , lianqiao (fructus forsythiae) was confirmed by studies to have antibacterial, antivirus, antioxidant, and anti-inflammatory effects. fu ling (poriacocos) has anti-inflammatory and diuretic effects, which are reported to improve cardiac function in chf rats via the avp-v r-aqp axis. , fuzi (radix aconiti lateralis preparata) is proven to have cardiotonic action and reverse the dysfunction in chf processing. , although the pharmacological mechanisms underlying the actions of gua lou shi (fructustrichosanthis), sang bai pi (cortex mori), and tinɡ li zi (semen lepidii) remain unclear, their functions in dealing with phlegm retention are abundantly documented in the "compendium of materia medica" (bencaogangmu), an ancient tcm herbal text book. the role of tcm in this case was not to act as antibiotics to kill pathogens. in fact, the patient had been treated with antibiotics and all the culture reports showed negative results. therefore, tcm was prescribed to help patient with "clearing heat and damp excreting" and have some diuretic effects to improve pulmonary congestion. we suggest that tcm was helpful for the edema and sputum in this case for two reasons: first, after the administration of standard antibiotic therapy, the fever and the progressive cough with purulent sputum persisted. tcm was an extra intervention administered during the fever period. second, because the bacterial cultures of sputum and blood were all negative before and after antibiotic treatment, the intermittent fever due to inflammatory reaction was highly suspicious after exclusion of other comment causes of fever, such as tumor fever and endocrine disorders. the "clearing heat and damp excreting" decoction we use was proven to have anti-inflammatory effects in a previous clinical trial and animal study. we suggest that the decreased time to fever abatement was caused by the improvement of lung inflammation after tcm adjuvant therapy. adjuvant therapy with a "clearing heat and damp excreting" decoction may improve hap in a patient comorbid with chf. these effects may be exerted through the anti-pyretic, anti-inflammatory, antitussive and diuretic effects of tcm. further investigations are warranted to confirm the efficacy and mechanism of tcm treatments for pneumonia. the institutional review board (irb) of the taichung veterans general hospital approved this case report with a reference number ce a on december , . the organized irb operates according to the good clinical practice and applicable laws and regulations. management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the the top causes of death taiwan's leading causes of death in epidemiology and outcomes of health-care-associated pneumonia: results from a large us database of culture-positive pneumonia use of severity scoring and stratification factors in clinical trials of hospital-acquired and ventilator-associated pneumonia optimising antibiotic usage to treat bacterial 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lipopolysaccharide-induced acute lung injury in mice via nf-kappa b signaling moutan cortex radicis improves lipopolysaccharide-induced acute lung injury in rats through anti-inflammation evaluation of lps-induced acute lung injury attenuation in rats by aminothiazole-paeonol derivatives anti-inflammatory effect of houttuynia cordata injection immunomodulatory and anti-sars activities of houttuynia cordata houttuynia cordata, a novel and selective cox- inhibitor with anti-inflammatory activity improvement of intestinal absorption of forsythoside a in weeping forsythia extract by various absorption enhancers based on tight junctions bioactivity-guided isolation of anti-inflammatory triterpenoids from the sclerotia of poria cocos using lps-stimulated raw . cells sclederma of poria cocos exerts its diuretic effect via suppression of renal aquaporin- expression in rats with chronic heart failure a review on phytochemistry and pharmacological activities of the processed lateral root of aconitum carmichaelii debeaux effects of active components of fuzi and gancao compatibility on bax, bcl- , and caspase- in chronic heart failure rats the authors declare that they have no conflict of interest. key: cord- - njrml x authors: facciolongo, nicola; menzella, francesco; castagnetti, claudia; cavazza, alberto; piro, roberto; carbonelli, cristiano; zucchi, luigi title: eosinophilic infiltrate in a patient with severe legionella pneumonia as a levofloxacin-related complication: a case report date: - - journal: j med case reports doi: . / - - - sha: doc_id: cord_uid: njrml x introduction: legionella pneumonia can appear with different levels of severity and it can often present with complications such as acute respiratory distress syndrome. case presentation: we report the case of a -year-old caucasian man with legionella pneumonia with successive development of severe acute respiratory distress syndrome. during his stay in intensive care the clinical and radiological situation of the previously observed acute respiratory distress syndrome unexpectedly worsened due to acute pulmonary eosinophilic infiltrate of iatrogenic origin. conclusion: levofloxacin treatment caused the occurrence of acute eosinophilic infiltrate. diagnosis was possible following bronchoscopic examination using bronchoaspirate and transbronchial biopsy. since the pneumonia epidemic that struck the delegates of the american legion convention in philadelphia in , legionella spp. has become a relatively frequent cause of community acquired pneumonia [ ] . legionella may appear in different forms, from subclinical presentations to legionnaires' disease, which has a mortality rate as high as to % in cases of hospital infections and in cases of complications such as acute respiratory distress syndrome (ards). the fatality rate is to % even in patients who are immunocompetent [ ] . other complications are rare, although a significant number of drugs used in the treatment of legionella pneumonia can be associated with the appearance of pulmonary eosinophilic infiltrates, especially non-steroidal anti-inflammatory drugs (nsaids) and antibiotics [ ] . the diagnosis is mainly based on the temporal correlation between the administration of drugs and the appearance of the clinical condition, but it is often not easy to determine the etiologic agent with certainty. this report concerns the case of a man with legionella pneumonia that evolved into ards and then became complicated with eosinophilic infiltration as an effect of treatment with levofloxacin. usually this drug is safe, though in some cases can cause eosinophilic pneumonia [ ] . a -year-old caucasian man presented to our hospital for hyperpyrexia (over °c) for about a week, with general weakness and strong headaches; he had been treated by his general practitioner with amoxicillin and clavulanate administrated orally with no improvement. his case history revealed that he was a smoker ( packs/year). no other pathologies or trips abroad had been registered in the last months. on admission, he had hyperpyrexia ( . °c), headache, dry cough, diarrhea, general weakness and sinus tachycardia ( beats/minute); his oxygen saturation was % (no oxygen supplement). the results of a physical examination of his chest were reduced vesicular respiration and crackling in the median axillary line to the left and in front; a chest x-ray showed extensive inconsistent parenchymal consolidation at the fissure of the left upper lobe ( figure a ). the results of initial laboratory examinations revealed his white blood cell count was cells/mm , total bilirubin level was ( . mg/dl), he had reduced albuminemia ( . g/dl), increased alkaline phosphatase ( u/l), γ-glutamyl transferase ( u/l) and creatine phosphokinase ( u/l). his serology test results were negative for hepatitis b virus, hepatitis c virus and hiv. his initial blood culture test results were negative for aerobic and anaerobic germs and mycetes. our patient began treatment with intravenous piperacillin and tazobactam ( . g/day) and clarithromycin orally ( g/day). on the third day the results of his urinary antigen test were found to be positive for legionella serogroup , so clarithromycin was suspended and substituted with intravenous levofloxacin ( mg/day). we maintained the piperacillin and tazobactam treatment to help prevent secondary infection from other gram-positive and gram-negative bacteria. on the sixth day, his clinical condition worsened. after consultation with an infectious disease specialist, we added rifampicin ( mg/day) to support the levofloxacin action against legionella pneumonia. on the ninth day he showed respiratory distress ( breaths/minute). an arterial blood gas analysis in room air gave the following results: partial o pressure (po ) of mmhg, partial co pressure (pco ) of mmhg, ph . and oxygen saturation (sao ) of %. a computed tomography (ct) scan of his chest revealed multiple areas of parenchymal consolidation in the entire upper left pulmonary lobe, mixed with ground-glass areas and abundant pleural effusion. in the right lung, in the dorsal and basal regions, there were ground-glass areas mixed with consolidation areas (figure b) . on the th day pao /fraction of inspired o (fio ) ratio was and he was moved to our intensive care there was an absence of pleural effusion and no cardiomegaly. b) a chest ct scan taken on the ninth day: consolidation areas can be seen on the whole superior left lobe, mixed with ground-glass areas and air bronchogram. there was an absence of pleural effusion. c, d) a ct scan taken on the st day: on the left there is parenchymal consolidation with air bronchogram and pneumothorax, and several areas of parenchymal consolidation on the right superior lobe. there was an absence of pleural effusion. unit. here he was placed on a ventilator on continuous positive airway pressure modality, with noticeable improvement of the respiratory parameters (pao /fio ratio of ). on the th day, levofloxacin was suspended in order to allow wash-out and taking of further blood cultures. on the th day levofloxacin was resumed; after advice from an infectious diseases specialist intravenous levofloxacin mg per day together with intravenous fluconazole mg per day were given on the st day, after an initial improvement, he showed respiratory distress. a ct scan showed increased parenchymal consolidation with left pneumothorax ( figure c, d) . on the nd day, because of the unexpected occurrence of muscular exhaustion, orotracheal intubation was performed and he was placed on a mechanical ventilator in synchronized intermittent mandatory ventilation mode associated with appropriate kinetic therapy on a reclining bed. a fibrobronchoscopy study, carried out with bronchoalveolar lavage (bal) for bacteriological reasons and in order to define the cytological profile, revealed the presence of numerous macrophages ( %), lymphocytes ( %; cd /cd ratio . ), neutrophilic granulocytes ( %) and some eosinophilic granulocytes ( %). protozoa, fungus and neoplastic cells were absent. on the rd day, methylprednisolone ( mg/day intravenously) was added to the therapy. on the th day, he underwent another bronchoscopy, with bal and transbronchial biopsy in the basal segments of the lower right lobe, which revealed a histological condition compatible with acute eosinophilic pneumonia (figures and ) . the bal confirmed the presence of eosinophils %, macrophages %, lymphocytes %, neutrophilic granulocytes % and a cd /cd ratio of . incidental findings showed masses of finely pigmented macrophages (due to our patient's smoking habit). serum levels of total ige were within normal limits, and the specific ige antibody results for allergens (food, pollen, fungal) were also negative. fecal and serological test results were negative for parasites. on the th day, his steroid therapy was increased (methylprednisolone g/day) while levofloxacin was suspended. his response to steroid therapy was rapid, with a general improvement starting from the fifth day of treatment (the nd day overall), associated with accompanying improvement of respiratory exchange and subsequent return to spontaneous breathing on the st day (pao /fio ratio of ). on the st day, a chest x-ray showed that the pneumonia bilateral consolidation had completely resolved ( figure ). ards is a common medical emergency and is usually a complication of a previous illness, which is the etiological cause [ ] . in our patient, the unusual fact was the overlapping of acute eosinophilic infiltrate in legionellosis. eosinophilic pneumonias include a wide range of pulmonary pathologies, characterized by alveolar and peripheral blood eosinophilia. peripheral eosinophilia may be absent, in particular in the early stages of acute idiopathic eosinophilia pneumonia or in patients taking systemic corticosteroids. it may occur with extremely variable forms of seriousness, from asymptomatic pulmonary infiltrates to acute respiratory distress syndrome associated with respiratory insufficiency. the possible causes, such as drugs or parasitic infections, have been widely studied, but are, in most cases, idiopathic [ ] . in our opinion, in accordance with the findings of other [ ] , early low-dose steroid therapy leads to a better outcome of pneumonia with severe respiratory distress; however it could determine a delayed onset of eosinophilic pneumonia. in our patient, we are inclined to consider it as having an iatrogenic etiopathogenesis. other causes were excluded by laboratory tests for differential diagnosis options (serum total and specific ige, fecal and serologic examinations for parasite infections). eosinophilic pneumonia has been linked to more than drugs, although only of these (for the most part nsaids and antibiotics) can be considered as common causes of this pathology [ ] . all the drugs administered in the weeks prior to the appearance of eosinophilic infiltrate should be suspected as a possible cause of the pathology. iatrogenic eosinophilic infiltrates usually develop progressively, with dyspnea, cough and fever in subjects who have taken certain drugs for weeks or months. the diagnosis of drug-induced eosinophilic pneumonia is mainly based on a detailed history of drug exposure, evidence of eosinophil accumulation in the lung and exclusion of other causes. numerous methods have been studied in order to demonstrate sensitivity to one or more drugs. one of the most commonly applied methods is the lymphocyte stimulation test (lst), which measures the proliferation of t lymphocytes in response to a drug in vitro, in order to diagnose a previous reaction in vivo. this concept was confirmed by the finding of drug-specific t lymphocyte clones that can interact with cellular receptors without being metabolized and without bonding to protein carriers [ ] . we did not consider it necessary to carry out the lst with our patient because this method is not specific and sensitive, and it has the major drawback of being difficult to interpret [ ] . with regard to the challenge test in vivo, this was not performed because of the serious clinical condition of our patient, who in any case did not give his consent. however, voluntary challenge may cause life-threatening adverse reactions and it should be limited to rare situations [ ] . among the possible causes we considered, the first was levofloxacin. there are some reports in the literature regarding the possibility of development of eosinophilic pneumonia during the course of levofloxacin therapy [ ] ; moreover, it was the drug administered to our patient for the greatest number of days ( in total). other points can be taken into account: ( ) the drug was suspended for four days in order to allow for washout and subsequent blood culture; afterwards, the same drug was resumed. at the same time, the clinical radiological findings became worse, with an unintentional challenge effect. ( ) the bal on the nd day, as some other authors have reported, still showed compatibility with ards legionella, [ ] while the following bal showed eosinophilia ( %) compatible with an acute eosinophilic pneumonia [ ] , which histological exams confirmed ( figure ) . with regard to the other drugs administered, there are reports of isolated cases of eosinophilia associated with parenchymal infiltrates as a consequence of rifampicin therapy [ ] . there is only one reported case where clarithromycin may have led to eosinophilic pneumonia [ ] , but our patient was only treated with this drug for two days. moreover, it is possible that eosinophilic pneumonia could be an adverse reaction to smoking in predisposed subjects: this sometimes happens to patients who have recently started smoking or who have modified their 'way' of smoking (for example, increasing or changing type of smoking). our patient, however, did not report any changes, either in quantity or in quality, in his smoking habits, so this would seem to exclude any relation to smoking [ ] . however, it is plausible that smoking could have acted as a cofactor (together with the drugs) in triggering the clinical condition, because it is a known fact that acute eosinophilic infiltrates are often frequent in smokers [ ] . in conclusion, levofloxacin may be the most probable cause of the occurrence of acute eosinophilic infiltrate in this patient. it is important to emphasize that we decided to change the diagnostic and therapeutic approach only when the presence of eosinophilic infiltrate was proven by transbronchial biopsy. published studies dealing with risks of invasive endoscopic procedures in a patient who was critically ill on mechanical ventilation showed a higher incidence of complications such as hemorrhage and pneumothorax. correlating the endoscopic risk to the percentage of correctly carried out diagnoses, which varies from % to %, with consequent change in therapeutic strategy, it may be stated that the risk/benefit ratio of the endoscopic procedure in terms of therapeutic response is surely in its favor and it is, therefore, recommended [ ] . written informed consent was obtained from the patient for publication of this case report and any accompanying images. a copy of the written consent is available for review by the editor-in-chief of this journal. legionella spp. and legionnaires' disease severe sepsis and acute respiratory distress syndrome from community-acquired legionella pneumonia: case report ask k: drug-induced infiltratives lung disease levofloxacin-induced eosinophilic pneumonia complicated by bronchial asthma acute respiratory distress syndrome and pneumonia: a comprehensive review of clinical data pulmonary eosinophilia hydrocortisone infusion for severe community-acquired pneumonia. a preliminary randomized study the lymphocyte transformation test in the diagnosis of drug hypersensitivity drug allergy diagnosis in humans: possibilities and pitfalls bronchoalveolar lavage findings in severe community-acquired pneumonia due to legionella pneumophila serogroup eosinophilia caused by rifampicin clarithromycin-induced eosinophilic pneumonia alterations of smoking habits are associated with acute eosinophilic pneumonia cigarette smoke-induced acute eosinophilic pneumonia accompanied with neutrofilia in the blood combined bronchoalveolar lavage and transbronchial lung biopsy: safety and yield in ventilated patients submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution authors' contributions nf coordinated diagnostic and therapeutic stages and was one of the principal contributors in writing the manuscript. mf contributed to the clinical approach, analyzed and interpreted the data and was a major contributor in writing the manuscript. cc was a contributor in writing the manuscript. ac performed the histological examination of the lung and was a contributor in writing the manuscript. cc was a contributor in writing the manuscript. rp was a contributor in writing the manuscript. lz was a contributor in writing the manuscript and he gave final approval of the version to be published. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord- -tg yqzrt authors: kirkby, charles; mackenzie, marc title: is low dose radiation therapy a potential treatment for covid- pneumonia? date: - - journal: radiother oncol doi: . /j.radonc. . . sha: doc_id: cord_uid: tg yqzrt nan fatal cases of covid- are characterised by acute respiratory distress syndrome (ards), sepsis, pneumonia and respiratory failure. ( ) the high transmission rate of the virus and the corresponding rapid escalation in the number of infections has resulted in unprecedented strains on healthcare systems worldwide, particularly as healthcare workers struggle to treat covid- pneumonia. we would like to draw the radiotherapy community's attention to the potential for low doses (< cgy) of low let radiation to treat viral pneumonia as a possible therapy for covid- patients. it was not uncommon in the early twentieth century to treat pneumonia with x-rays. a review showed low doses from kilovoltage x-rays reduced pneumonia mortality from roughly percent to percent on average.( ) doses reported were generally in the -few hundred roentgen range, which given the attenuation through chest wall would likely have resulted in mean lung doses in the tens to < cgy range. some reports noted rapid symptom relief on the order of hours ( , ) animal models suggested ldrt could reduce the acute phase of pneumonia by half. ( ) in light of the current mortality rates associated with covid- pneumonia, it is therefore reasonable to re-examine this old treatment. pneumonia arises as an inflammatory immune response to infection when the alveoli become inflamed and secrete fluid compromising their gas exchange function. in a viral infection, viruses trigger immune cells to synthesize pro-inflammatory cytokines and chemokines, ( ) inciting the immune response. historical evidence points to the induction of an antiinflammatory phenotype induced by low doses of radiation as a potential explanation for the observed effects.( ) while doses  cgy tends to exert pro-inflammatory effects, triggering common toxicities observed in radiation therapy, more recent work shows low doses (< cgy) incite anti-inflammatory properties ( , ) such as decreasing levels of pro-inflammatory cytokines like il- ( ), or inhibiting leukocyte recruitment ( ) . therefore, it stands to reason that an ldrt treatment of to cgy to the lungs of a patient with covid- pneumonia could reduce the inflammation and relieve the life-threatening symptoms. a single fraction to cgy treatment could easily be delivered on a conventional megavoltage radiation therapy unit. routinely, much higher, single fraction doses are delivered in a palliative context with fast-tracked patients going through the full workflow process of education, scanning, planning and treatment delivery in a matter of hours. proof of principle simulations suggest that a pop treatment with a megavoltage beam could easily ensure % of the whole lung volume received between % and % of a cgy prescribed dose. and because of the low doses, common radiotherapy toxicities would be avoided. while a large scale up of such ldrt treatments would not be without obstacles (e.g. existing strain on radiotherapy resources, separating covid- patients and cancer patients, etc.), we believe clinical trials to further investigate the efficacy of whole lung ldrt would present a very low risk to covid- pneumonia patients, and have the potential to reduce mortality and alleviate covid- related strains on healthcare systems. clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study how radiotherapy was historically used to treat pneumonia: could it be useful today? radiation therapy of lobular pneumonia roentgen therapy of interstitial pneumonia the effect of roentgen therapy on experimental virus pneumonia; on pneumonia produced in white mice by swine influenza virus inflammatory mechanisms in the lung radiobiological mechanisms in inflammatory diseases of lowdose radiation therapy low-dose radiation therapy for benign pathologies radiation treatment of acute inflammation in mice time course of anti-inflammatory effect of low-dose radiotherapy: correlation with tgf-beta( ) expression key: cord- -k vdqlgs authors: eisenberg, ronald l. title: pneumonia date: - - journal: what radiology residents need to know: chest radiology doi: . / - - - - _ sha: doc_id: cord_uid: k vdqlgs this chapter describes the imaging patterns of pneumonia (lobar, lobular, interstitial, round) and its complications (abscess, empyema, pneumatocele); bacterial, fungal, and viral infections; and the many manifestations of pulmonary tuberculosis. electronic supplementary material : the online version of this chapter ( . / - - - - _ ) contains supplementary material, which is available to authorized users. • any pneumonia developing in a patient at least hours after being hospitalized • second most common nosocomial infection (after urinary tract infections) • unlike community-acquired pneumonia, hap is usually caused by a bacterial infection, rather than a virus • high morbidity and mortality rates and the primary cause of death in intensive care units • any pneumonia developing in a patient at least - hours after endotracheal tube intubation • typically affecting critically ill patients in an intensive care unit, vap develops in up to % of ventilated individuals and is associated with a mortality rate of up to % lobar pneumonia • homogeneous consolidation of all or a substantial percentage of a single lobe • sharply marginated by one or more fissures ( [ ] • silhouette sign when the consolidation is adjacent to the heart, aorta, or hemidiaphragm ( fig. • foreign material entering into the tracheobronchial tree secondary to gastroesophageal reflux, altered mental status (drug overdose, anesthesia), or neurologic disorder (stroke, traumatic brain injury) • often develops in intubated patients, despite the presence of an inflatable cuff • usually occurs in the most dependent portions of the lung ○ supine -superior and posterior basal segments of the lower lobes or posterior segment of the upper lobes ( fig. . ) ○ upright -lower lobes (typically on the right, because the right main bronchus runs more vertically and is wider) • rapid appearance of air-space consolidation, especially in bedridden patients. • noninfectious aspiration -usually clearance in less than week ○ mendelson syndrome -large-volume aspiration of gastric acid, which produces a chemical pneumonitis and acute lung injury (even ards) and a diffuse radiographic pattern simulating pulmonary edema ( • radiographic clearance of pneumonia usually lags well behind clinical improvement • follow-up chest radiographs are recommended in approximately - weeks to ensure complete resolution of the consolidation and to assess persistent abnormality of the lung parenchyma (scarring, bronchiectasis) • failure of a pneumonia to resolve by weeks suggests an inaccurate diagnosis or an endobronchial obstruction as a cause of postobstructive pneumonia ( fig. . ) • especially in patients with smoking history or over age , ct should be considered to exclude an underlying bronchial lesion (see fig. e . ) • irregular infectious cavity containing necrotic debris or fluid. • often an air-fluid level, which usually has the same extent on both frontal and lateral views thicker, often irregular wall disparity in length of air-fluid levels air-fluid levels of relatively equal lengths split pleura sign on ct empyema necessitans (fig. . ) • chronic empyema draining via a sinus tract into the subcutaneous tissues of the chest wall, most commonly related to tuberculosis or fungal infection (actinomycosis, aspergillosis, blastomycosis, mucormycosis) • loculated pleural fluid collection or mass with associated rib destruction and often bubbles of loculated gas in soft tissues • gram-negative bacterial pneumonia that is most common in debilitated middle-aged and older men with alcoholism (about two-thirds of cases); high mortality rate • tends to form a voluminous exudate that produces a homogeneous parenchymal consolidation containing an air bronchogram • lobar enlargement (especially the right upper) with the characteristic bulging fissure sign (fig. . ) ○ bulging fissure sign also in haemophilus influenzae pneumonia (predominantly in compromised hosts, such as chronic pulmonary disease, immune deficiency, alcoholism, diabetes) (see fig. e . ) • most frequently result from infectious particles reaching the lung from an infected heart valve (especially the tricuspid), intravenous catheter, or injected debris • persons at risk include drug abusers, immunocompromised patients, individuals with septal defects, and those with indwelling venous catheters, pacemakers, or prosthetic heart valves • initially, multiple ill-defined round or wedge-shaped opacities with a swirling pattern that are usually peripheral and tend to involve the lower lobes (starry night sign -mimicking the brush strokes in van gogh's painting of that name) • cavitary pulmonary nodules tend to develop rapidly ( - days) • transient, rapidly changing, migrating, nonsegmental areas of parenchymal consolidation, which are associated with blood eosinophilia and minimal (or no) pulmonary symptoms • bilateral patchy consolidations with ill-defined margins that are predominantly located in the periphery of the lung • may produce single or multiple air-space nodules with surrounding ground-glass opacities (fig. . ) • unlike chronic eosinophilic pneumonia (see below), the transient air-space abnormalities resolve in some areas and reappear in others over days • loeffler's syndrome (also known as simple pulmonary eosinophilia) is applied to idiopathic cases; a similar imaging pattern can occur in response to parasitic infection or be drug-induced chronic eosinophilic pneumonia (fig. . ; see fig. e . ) • classic appearance of multifocal areas of consolidation in both lungs, especially the upper lobes, reflecting inflammatory eosinophils filling alveoli and infiltrating the interstitium • characteristic peripheral predominance ("reverse pulmonary edema pattern") • rapid response to steroid therapy (clinical improvement within hours, radiographic clearing within a few days) fig. . loeffler's syndrome. peripheral air-space nodule with surrounding ground-glass opacity in the right lower lobe (arrow). follow-up study showed that the nodule had disappeared [ ] fungal pneumonia aspergillosis • common fungus found in soil, on plants, and in decaying matter, as well as in household dust and building materials, which does not harm persons with normal immune systems and no allergic hypersensitivity • invasive aspergillosis (most aggressive form) is essentially limited to debilitated patients, diabetics, and neutropenic individuals with severely compromised immune systems (organ or bone marrow transplants, high-dose steroids or chemotherapy, lymphoma, leukemia) • central mass within a cavity in invasive aspergillosis is almost always necrotic lung (fig. . ; see figs. e . -e . ) • ct halo sign -early finding of a zone of ground-glass opacity (usually related to hemorrhage) surrounding a nodule or mass is strongly suggestive of invasive aspergillosis in an immunocompromised patient (fig. . ; see fig. e . ) • aspergilloma -solid homogeneous, rounded, mobile mycetoma that develops in a pre-existing cyst or cavity (primarily upper lobe) in a patient with underlying lung disease and is separated from its wall by a crescentic air space (air crescent sign) (see fig. e . ) • histoplasmosis -central united states; nodules often calcify ( fig. . ) • coccidioidomycosis -southwestern united states (also northern mexico and central and south america) • actinomycosis, nocardia -pleural effusion and extension to the chest wall are common (may develop empyema) (see fig. e . ) • candidiasis, aspergillosis, sporotrichosis, and mucormycosisessentially limited to debilitated patients and those with underlying diseases (diabetes mellitus, lymphoma, leukemia) (see fig. e . ) • caused by a yeast-like fungus and almost exclusively seen in immunosuppressed patients (especially aids, lymphoproliferative diseases, or renal transplants) • initially, bilateral diffuse interstitial opacities spreading outward from the hila • if untreated, this soon progresses to a homogeneous diffuse alveolar consolidation that may simulate pulmonary edema • thin-walled, air-filled lung cysts (especially apical and subpleural) occur in about % of patients and may cause a pneumothorax • thick-walled cavities usually indicate superinfection • hilar adenopathy and significant pleural effusions are rare (their presence should raise the possibility of an alternate diagnosis) • although a clinical diagnosis, may appear on chest radiographs as bilateral hilar enlargement due to lymphadenopathy (see fig. e . ) • important to look for medial displacement of gas within the stomach and splenic flexure caused by splenomegaly varicella (chickenpox) pneumonia (fig. . ; see fig. e . ) • diffuse distribution of small ( - mm), poorly defined nodules, which may coalesce to produce extensive bilateral fluffy infiltrates that tend to develop near the hilum and lung bases • healed varicella pneumonia classically appears as tiny military calcifications scattered widely throughout both lungs (develops several years after the pulmonary infection) • no calcification of hilar lymph nodes (unlike histoplasmosis or tuberculosis, the two other major causes of diffuse pulmonary calcifications) • cytomegalovirus, which typically occurs in immunosuppressed individuals (especially after transplantation) (fig. . ) • respiratory syncytial virus in infants and young children (see fig. e . ) • although traditionally considered a disease of children and young adults, with the dramatic decrease in the prevalence of tuberculosis (especially in children and young adults), primary pulmonary disease can develop at any age • primary tuberculosis may affect any lobe, so that the diagnosis cannot be excluded because the infection is not in the upper lobe fig. . tree-in-bud pattern (cytomegalovirus). centrilobular groundglass opacities in addition to nodules and "tree-in-bud" opacities in a patient with chronic myelogenous leukemia who underwent bone marrow transplantation [ ] • "latent" tb refers to someone who has a positive tst with no history of tuberculous infection or imaging evidence of active or old disease (most often detected when undergoing routine screening for employment or school) • "inactive" tb refers to someone with imaging evidence of prior tuberculosis but no sign of active disease imaging • one or more foci of lobar or segmental air-space consolidation that is usually homogeneous, dense, and well defined (fig. . ) • if multiple, randomly distributed throughout the lungs • cavitation is infrequent. • characteristic apical pleural thickening and fibronodular appearance in one or both upper lungs (fig. . ; see fig. e . ) • ct -enlarged lymph nodes typically have a low-density center (due to caseous necrosis) with rim enhancement (reflecting granulomatous tissue); may demonstrate subtle cavitation that is not visible on chest radiographs (see fig. e and is almost diagnostic of postprimary tuberculosis • because an apical lesion may be obscured by overlying clavicle or ribs, an apical lordotic view is often of value • cavitation is common (about %) and characteristic of postprimary disease (figs. . and . ; see fig. e . ) • the presence of cavitation indicates that the disease is highly contagious, and this finding alone warrants putting the patient in respiratory isolation • air-fluid levels in cavities are uncommon and usually a manifestation of superinfection (see fig. e . ) • tuberculous cavities may result in endobronchial spread and the classic "tree-in-bud" pattern of centrilobular bronchial dilatation and filling by mucus, pus, or fluid, associated with a linear a b note the thickening of bronchial walls (white arrow) [ ] branching pattern that resembles a budding tree and is generally more pronounced in the lung periphery (see figs. e . -e . ) • other complications of cavitation include rupture into the pleural space (leading to empyema or bronchopleural fistula) and the development of a pseudoaneurysm of the pulmonary artery (rasmussen aneurysm) • pleural effusion and lymph node enlargement are rare in postprimary tuberculous disease (though common and sometimes the only finding in primary disease) • as the disease heals, fibrotic changes develop in the surrounding lung, which cause volume loss in the affected segment with displacement of the fissures and hilar structures (see fig. e . ) • ct -because the diagnosis of typical postprimary tuberculosis is generally evident on chest radiographs, ct is primarily used to assess the extent and nature of the disease (more sensitive for demonstrating cavitation and such complications as vascular erosion, rupture into the pleural space, and miliary and endobronchial spread) • hematogenous dissemination that usually occurs in patients with altered host resistance to the primary infection • almost invariably leads to a dramatic febrile response with night sweats and chills • there may be minimal symptoms in severely debilitated patients, especially elderly persons and those receiving steroids imaging • diffuse pattern of innumerable tiny ( - mm), discrete, relatively well-defined pulmonary nodules distributed uniformly throughout both lungs (fig. . ; see figs. e . and e . ) • ct -may detect the presence of diffuse lung involvement when corresponding chest radiographs are normal or show only minimal or limited disease clinical imaging: an atlas of differential diagnosis lower lobe-predominant diseases of the lung mosaic attenuation multiple cystlike lung lesions in the adult pulmonary tuberculosis: role of radiology in diagnosis and management eosinophilic lung diseases: a clinical, radiologic, and pathologic overview upper lobe-predominant diseases of the lung tree-in-bud pattern key: cord- -rbblg pu authors: poole, stephen; clark, tristan w. title: rapid syndromic molecular testing in pneumonia: the current landscape and future potential date: - - journal: j infect doi: . /j.jinf. . . sha: doc_id: cord_uid: rbblg pu community acquired pneumonia (cap), hospital-acquired pneumonia (hap) and ventilator associated pneumonia (vap) are all associated with significant mortality and cause huge expense to health care services around the world. early, appropriate antimicrobial therapy is crucial for effective treatment. syndromic diagnostic testing using novel, rapid multiplexed molecular platforms represents a new opportunity for rapidly targeted antimicrobial therapy to improve patient outcomes and facilitate antibiotic stewardship. in this article we review the currently available testing platforms and discuss the potential benefits and pitfalls of rapid testing in pneumonia. lower respiratory tract infections were accountable for an estimated . million deaths in , making them the third most common cause of death worldwide . community acquired pneumonia (cap) caused nearly , deaths in england and wales in and costs europe around € million annually . it is estimated that per , adults are hospitalised with pneumonia each year . hospital acquired pneumonia (hap) is defined as occurring > h after admission to a healthcare facility. it is caused by a different spectrum of more antibiotic resistant bacterial pathogens than those occurring in the community. ventilator associated pneumonia (vap) is defined as occurring > h after intubation for invasive artificial ventilation. the two entities combined (hap and vap) are the most common nosocomial infection in the developed world with hap complicating around % of hospital admissions . the incidence of vap in intubated patients is around % and is associated with mortality of around % . a retrospective matched cohort study by kollef et al. found patients who developed vap were intubated for longer, spent longer on icu, and were in hospital for a greater period of time. they estimated the additional cost of vap from to be $ , per patient. large amounts of empirical 'broad spectrum' antibiotics are used to treat pneumonia which inadvertently promote antimicrobial resistance (amr): a problem identified by the who as one of the leading threats to global health today. the o'neill report, commissioned by the uk government in , has highlighted the need for developed nations to take a lead in tackling amr. as part of this there is a specific recommendation that all antibiotic prescriptions should be supported by diagnostic tests where available by . the uk government recently published a five-year action plan for tackling amr, which emphasised the need for improved diagnostics to support antibiotic prescribing. this included a target to be able to report the percentage of antimicrobial prescriptions which are supported by a diagnostic test or decision making tool by . timely administration of appropriate antibiotics is a central tenant of care for patients with pneumonia , and yet the goldstandard for microbiological diagnosis remains traditional, slow, culture based methods. these take greater than h to identify an organism and often greater than h to provide phenotypic antibiotic sensitivity data. culture is insensitive, only detecting a pathogen in - % of patients with clinically diagnosed pneumonia , - and an even smaller proportion after the administration of antibiotics. in recent years several rapid syndromic molecular tests for pneumonia have been developed. these offer the potential to revolutionise treatment by providing information to clinicians in 'real-time' on the pathogens present and their likely antibiotic sensitivity by also detecting genotypic markers of resistance. multiple studies have demonstrated the superior diagnostic accuracy of pcr based platforms for detecting bacterial pathogens in the sputum compared with standard culture [ ] [ ] [ ] [ ] . this review will discuss the commercially available syndromic molecular panels for pneumonia, their potential clinical impact and the challenges to implementing them as a 'front line' diagnostic test. the greatest potential clinical benefit of a rapid syndromic test for pneumonia is being able to better utilise antibiotics. the superior diagnostic yield of multiplex pcr means that a pathogen is detected rapidly in a much greater proportion of patients, so therapy can be quickly tailored to the responsible organism. in some situations, this will allow narrowing of antimicrobial therapy: for example, identification of streptococcus pneumoniae facilitating a change of antibiotics to penicillin, in geographical areas with a low prevalence of penicillin resistant s. pneumoniae . in other cases, it may facilitate a change or escalation of antimicrobial therapy: for example, the identification of methicillin resistant staphylococcus aureus (mrsa) which would not be covered by empirical regimens in many areas. the absence of detection is also helpful: the sensitivity when compared to culture of molecular assays is very high so can reassure clinicians that organisms are not present and so support decisions to stop unnecessary antibiotics or to deescalate antibiotics that were used empirically to cover organisms subsequently not detected. the impact of this improved use of antibiotics are twofold: firstly, earlier appropriate antibiotics should improve clinical outcomes including mortality and length of stay. secondly, it prevents unnecessary broad-spectrum antibiotic use, which facilitates antibiotic stewardship and reduces antibiotic related adverse events. the aetiology of cap and hap/vap are highly variable between different regions and times, and this is reflected in studies of causative microbial agents as identified by culture. patients with underlying lung diseases, for example chronic obstructive pulmonary disease, can be colonised with microbial flora which are more typical pathogens of hap. as a result, they may develop community acquired infections caused by these agents. s. pneumoniae, haemophilius influenzae, s. aureus, moraxella catarrhalis and 'atypical' organisms including mycoplasma pneumoniae and legionella pneumophila are all cultured from the sputum of patients with cap. many of these organisms have predictable resistance patterns when interpreted with local epidemiological data. gadsby et al. developed and internally validated their own syndromic molecular assay for pneumonia. they used this to test sputum samples of adults admitted to hospital with cap . their assay detected a pathogen in % of patients (as opposed to % of patients using only routine culture). as a result, they proposed that % of antibiotic prescriptions in cap could have been deescalated based on results from multiplex pcr testing. the majority of these potential interventions involved stopping clarithromycin when atypical organisms were not detected or 'narrowing' antibiotics when a likely sensitive pathogen had been detected. in hap and vap, frequently cultured bacterial pathogens include s. aureus, pseudomonas aeruginosa, klebsiella species, escherichia coli, acinetobacter species and enterobacter species . empirical regimens are therefore broad spectrum and large numbers of antibiotics are consumed. the absence of certain organisms (for example p. aeruginosa ) could facilitate a narrowing of the antimicrobial spectrum with a knock-on effect of reducing antibiotic related adverse effects and improving stewardship. furthermore, common gram negative isolates are increasingly resistant in pneumonia surveillance studies . rapid molecular detection of these resistance genes should facilitate earlier initiation of effective antibiotics and this should lead to better outcomes. in adults, respiratory viruses are found in approximately one third of community acquired pneumonia cases , . one study found that % of patients admitted to intensive care with pneumonia were positive for a respiratory virus, with a broad range of viruses detected . detection of certain viruses such as influenza and adenovirus which are known to cause pneumonia, coupled with the absence of detection of bacteria and low levels of serum biomarkers such as procalcitonin (which is elevated in patients with bacterial infection), could support decisions to stop or use an abbreviated course of antibiotics. the respoc trial was a pragmatic randomised controlled trial that tested patients with community acquired acute respiratory illness using the biofire respiratory panel (which tests comprehensively for respiratory viruses and atypical bacteria) at the point-of-care. it found that patients who were tested with the filmarray were significantly more likely to receive a single dose or shorter course of antibiotics than those who were not. it also found a significant reduction in length of hospital stay in the intervention group along with improved use of neuraminidase inhibitors (nai) in patients with influenza. currently there are no licenced antiviral agents for respiratory viruses other than influenza. the benefit from nai treatment is greatest when they are started within h of symptom onset but there is evidence in adults to suggest ongoing benefit when started beyond this time and a recent study suggests that treatment earlier in admission to hospital improves outcome irrespective of overall duration of illness . as such, timely identification and treatment is critical. antiviral treatments for other respiratory viruses, including respiratory syncytial virus (rsv) are in development. since the s infection control methods including patient source isolation and deep cleaning with targeted decolonisation have been highly successful at reducing the spread of mrsa. enhanced infection control practices are recommended for a number of pathogens that may be present in patients with pneumonia. early identification of these should reduce the spread of these organisms, especially in hospitalised patients. some examples of these which are found on commercially available molecular tests are extended spectrum beta lactamases (esbls), carbapenemase producing enterobacteriaceae (cpes), mrsa, influenza and rsv. in the uk there is a mandatory requirement to report certain infectious diseases to public health england, so they can be investigated. l. pneumophilia is associated with outbreaks from devices that aerosolize water. there were cases in the uk in , earlier sensitive detection of these would allow outbreak investigation to occur sooner and potentially stop further cases occurring. at the current time there are fda approved, ce marked syndromic molecular panels for pneumonia which are commercially available: the filmarray (biofire diagnostics llc, salt lake city, utah, us) pneumonia panel and the unyvero (curetis gmbh, holzgerlingen, germany) hospitalised pneumonia (hpn) panel. fast track diagnostics respiratory panel (fast track diagnostics sarl, luxembourg) is another available platform with a large number of targets, but insufficient bacterial targets for it to be considered a true pneumonia panel so this will only be considered in brief. the commercially available platforms are summarised in table . the authors are aware of further panels in development from mobidiag, bruker, accelerate and axo science but published data is only available for the latter. there are also several research groups who have developed their own syndromic molecular pneumonia tests, most notably gadsby et al . there are a multitude of other 'respiratory pathogen' multiplex panels which have targets only for respiratory viruses, atypical bacterial targets or a very small range of typical bacteria. these are beyond the scope of this review article. we have only included assays with targets for a wide range of typical pathogens for pneumonia. this is an fda approved and ce marked platform that uses nested real-time pcr to detect clinically important respiratory targets ( semi-quantitative bacterial targets, qualitative atypical bacterial targets, [ ] [ ] [ ] furthermore, the pneumonia panel detects pathogens in a much higher proportion of samples than culture. buchan et al reported that the filmarray detected a bacterial target in % more specimens than routine culture, equating to over % increase in total bacterial detections. the relative abundance of organism for the bacterial targets is estimated based on real-time pcr relative to a material of known quantity and is grouped for reporting into bins. these represent approximately , , and > genomic copies of bacterial nucleic acid per millilitre of specimen respectively. concordance with reference molecular testing is very high but as expected the overall concordance between bin and reference sputum culture (cfu/ml) concentration was lower at around % and was highly variable between organisms. as such the manufacturer advises clinical correlation in interpretation of semi-quantitative results. to date there have been no published prospective interventional studies evaluating the clinical impacts of using the pneumonia panel in patients with pneumonia. observational data based on lower respiratory tract assays which preceded the final, fda approved pneumonia panel suggested change of antibiotics could be supported in > % of cases , . the hpn panel is ce marked and runs on the unyvero platform which includes the unyvero lysator, the unyvero cockpit and the unyvero analyzer. amplicons generated by parallel multiplex pcr reactions are qualitatively detected by hybridisation on arrays in a single use cartridge. it has a wide range of bacterial and resistance gene targets including the assay is validated for use on sputum (including expectorated sputum, bal and et aspirate). like the filmarray, the unyvero is a platform designed as a 'sample-to-answer' solution taking min of low skill hands-on time with a total turnaround time of - h. an equivalent test, the lower respiratory tract panel (lrt) has fda approval in the us but is only validated for use on tracheal aspirates. manufacturer reported diagnostic sensitivity for bacterial detection (when compared to reference culture and molecular detection in cases of discrepancy) is between and % with the majority of targets in the diagnostic performance data presented by the manufacturer, resistance marker detection aligned poorly with organism antibiogram: for example, matching in only / meca detections or / quinolone resistance markers in e. coli . this issue was noted by gadbsy et al for the p assay where the sensitivity for antibiotic resistance detection was %. two predecessors to the hpn cartridge have been developed and ce marked: the earlier p , and the later p . the former of these was evaluated most extensively by personne et al. who found the test to be sensitive for bacterial detection but with a run failure rate of . % and extensive discrepancies with regards to sensitivity testing . furthermore, the test was unable to differentiate s. pneumoniae from the s. mitis group. papan et al. reported that the p had a low sensitivity for gram positive organisms (when evaluated on paediatric samples) . the resistance panel on the p was broad but lacked several key emerging carbapenemase gene targets. the p panel rebalanced this by removing less clinically relevant resistance genes. it added targets for s. pneumoniae and m. pneumoniae . again, the sensitivity for bacterial detection remained high when assessed by ozongwu et al. albeit with a high overall run failure rate of % . the targets on the panel for the hpn are the same as the p , but the manufacturer claims it has a higher sensitivity and specificity. to date there are no published randomised controlled trials evaluating the clinical impact of the unyvero hpn system in patients with pneumonia. jamal et al performed a non-randomised interventional study using the p assay where antibiotics were adjusted based on the results and pathogens detected were compared to culture. the turnaround time for result was very quick ( ∼ h) compared to culture ( - h) and a large proportion of patients had antibiotics changed based on the p results, however the small number of patients studied and the lack of a comparator group make definitive conclusions impossible. gadsby et al. retrospectively tested bal samples with the p and reviewed patient notes. they reported that . % of patients who had positive standard of care microbiology could potentially have had a change in antibiotics earlier based on p results . conversely, they reported a false negative p result in ∼ % of those with a positive culture which could have caused harm if acted upon. the respiratory pathogens panel differs from the first two tests discussed in that it is exclusively a laboratory centred assay. the ce marked respiratory pathogens kit can be used on several standard laboratory cyclers. as such there is no reported standard turnaround time although it is greater than h. positive signals are detected from eight multiplex real-time pcr reactions. it is not an automated process so will have a considerably longer hands-on time requiring skilled extraction and setup. the there is very little published data comparing different syndromic molecular pneumonia tests. enne et al. and the inhale group presented data at eccmid where they compared the unyvero and the filmarray on surplus intensive care respiratory tract samples . the filmarray had slightly greater sensitivity for common pathogens, fewer major discordances (defined as routine culture finding or more undetected organisms) and fewer machine failures. the unyvero had slightly higher specificity and overall concordance with reference culture. whilst the data presented for syndromic molecular test for pneumonia clearly demonstrates high accuracy and the detection of many more pathogens than culture, no data has yet been published showing that this translates into improved antibiotic use or clinical benefit. other molecular diagnostics studies for blood stream infection have shown improved diagnostic performance, but negligible impact on clinical outcomes when results were not provided to clinicians along with infection specialist advice. it seems likely that such a wealth of information generated will require careful interpretation by an infection specialist in consultation with the clinicians directly caring for the patient, for these benefits to be maximised. rapid syndromic molecular platforms have the potential to significantly improve the use of antibiotics and clinical outcomes in patient with pneumonia, but high quality randomised controlled trials are urgently required to evaluate their clinical impact. we are aware of trials that are currently underway or in set up that may address this evidence gap: the saripoc study is a single centre randomised controlled trial (rct) recruiting critically unwell patients with pneumonia in southampton, uk. the inhale study is a uk multicentre, rct recruiting critically unwell patients with hap and vap. pibcap is a uk multicentre rct recruiting patients with cap. the norcap trial, in norway is a single centre rct in set up, also aiming to recruit patients with cap. a further single centre rct in edinburgh is using molecular testing for broader community acquired lrti microbial diagnosis. the first of these two studies are testing patients at the point-of-care, whereas the others use rapid laboratory-based testing. antibiotic de-escalation based on results is a key component of antibiotic stewardship and is widely accepted as good practice. trials looking at the efficacy and safety of antimicrobial de-isolation based on culture results are sparse. the vast majority of published studies are observational and comparison between studies for so many variables (hap, cap, vap, icu/ non-icu, severe sepsis etc.) are fraught with difficulties. furthermore, due to the geographic variability in causative organisms and prescribing practices, they are often poorly transferrable between regions. to our knowledge no interventional studies have looked at the safety or efficacy of antimicrobial de-escalation based on multiplexed pcr for pathogens of pneumonia. studies to date have made their de-escalation intervention after at least h when the patient has stabilised, and culture results are available. both the idsa and the national institute for clinical excellence (nice) cite an urgent need for well-run rcts on the impact of de-escalating antimicrobial therapy , . the idsa and the american thoracic society advise antibiotic de-escalation in hap/vap according to culture results on the basis of expert opinion, citing a high level of confidence that it 'reduces costs, burdens, and side effects, and that it is very likely that deescalation also reduces antimicrobial resistance' . there a small number of interventional studies looking at antibiotic de-escalation based upon microbiological culture results in hap/vap which have suggested this practice is safe , . high quality data for outcomes, including length of intensive care stay and antibiotic savings, are lacking and conflicting. a meta-analysis by khan et al of observational studies reviewing antibiotic de-escalation in pneumonia in icu (hap and vap only) found no difference in mortality between those who were de-escalated according to culture result and those that weren't. in the context of cap, both the idsa and nice/bts guidelines recommend organism directed therapy when a pathogen has been identified by culture. high quality data is lacking but observational data and limited interventional data suggests this is safe [ ] [ ] [ ] . a systematic review by paul et al included studies with cap, hap, vap and blood stream infection. the reviewers found no association between de-escalation and survival with pneumonia (or . , % ci . - . ). concern has been raised that the high sensitivity of molecular tests will lead to excessive detection of colonising flora which may paradoxically increase unnecessary antibiotic use. this is particularly pertinent in expectorated sputa where small numbers of potentially pathogenic bacteria can be present in the absence of disease. a potential solution to this is the development of semi-quantitative molecular methods such as with the biofire r filmarray r pneumonia panel. this provides a representation of the amount of bacterial dna present which is highly concordant with reference molecular techniques. as highlighted by studies using the unyvero , , molecular detection of resistance genes may correlate poorly with phenotypic sensitivity in its current form. detection of genes from 'off panel' organisms, for example mec a genes in colonising coagulase negative staphylococci, may be incorrectly attributed to those organisms which are on the panel. as such, clinicians will need to be cautious in interpreting these results. as well as having relatively quicker run times, syndromic multiplex molecular tests could potentially be deployed at the pointof-care. the resppoc trial by brendish et al., demonstrated with a respiratory viral panel that this was logistically feasible and associated with a number of clinical benefits compared to routine clinical care . a post hoc analysis of patients who tested positive for respiratory viruses in the trial highlighted an association between rapid turn-around time (defined as < . h), shorter hospital admission and shorter durations of antibiotic therapy. it is our belief that point-of-care testing represents the ideal strategy for new, rapid diagnostic test platforms allowing clinicians to maximise the benefit from such accurate tests early in the decision-making process. clearly, rigorous quality assurance is essential for any diagnostic test irrespective of the site of testing. it should also be noted that the tests described in this article are not currently clia waivereda requirement for use at the point-of-care in the us. rapid syndromic molecular tests for pneumonia have improved diagnostic accuracy compared to the current gold standard of culture and can provide results in real time. in the era of widespread amr their use has the potential to dramatically improve the rational use of antibiotics and to improve clinical outcomes in patient with pneumonia. high quality data from well conducted randomised controlled trials are now urgently needed to assess the impact of these platforms on antibiotic use and patient outcome. poole, s. -declarations of interest: none. clark, t.w. has received speaker fees, reimbursement for travel and honoraria from biofire llc and biomerieux and has also received equipment and consumables from these companies for the purposes of independent research. no commercial entities had any input into this manuscript. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. global, regional, and national life expectancy, all-cause mortality, and causespecific mortality for causes of death, - : a systematic analysis for the global burden of disease study - ): 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analysis of the unyvero p pneumonia assay a review of novel technologies and techniques associated with identification of bloodstream infection etiologies and rapid antimicrobial genotypic and quantitative phenotypic determination diagnosis and management of community-and hospital-acquired pneumonia in adults. nice clinical guideline . nice, national clinical guidelines centre management of adults with hospital-acquired and ventilatorassociated pneumonia: clinical practice guidelines by the infectious diseases society of america and the american thoracic society early use of imipenem/cilastatin and vancomycin followed by de-escalation versus conventional antimicrobials without de-escalation for patients with hospitalacquired pneumonia in a medical icu: a randomized clinical trial de-escalation versus continuation of empirical antimicrobial treatment in severe sepsis: a multicenter non-blinded randomized noninferiority trial antibiotic de-escalation in patients with pneumonia in the intensive care unit: a systematic review and meta-analysis infectious diseases society of america/american thoracic society consensus guidelines on the management of communityacquired pneumonia in adults prospective, randomised study to compare empirical treatment versus targeted treatment on the basis of the urine antigen results in hospitalised patients with community-acquired pneumonia comparison between pathogen directed antibiotic treatment and empirical broad spectrum antibiotic treatment in patients with community acquired pneumonia: a prospective randomised study antibiotic de-escalation for bloodstream infections and pneumonia: systematic review and meta-analysis impact of turnaround time on outcome with point-of-care testing for respiratory viruses: a post hoc analysis from a randomised controlled trial the authors would like to thank paula sands, research engagement librarian at the southampton general hospital healthcare library for her help and expertise in constructing search terms for literature review. key: cord- -w a wa authors: habib, nahida; hasan, md. mahmodul; reza, md. mahfuz; rahman, mohammad motiur title: ensemble of chexnet and vgg- feature extractor with random forest classifier for pediatric pneumonia detection date: - - journal: sn comput sci doi: . /s - - -y sha: doc_id: cord_uid: w a wa pneumonia, an acute respiratory infection, causes serious breathing hindrance by damaging lung/s. recovery of pneumonia patients depends on the early diagnosis of the disease and proper treatment. this paper proposes an ensemble method-based pneumonia diagnosis from chest x-ray images. the deep convolutional neural networks (cnns)—chexnet and vgg- are trained and used to extract features from given x-ray images. these features are then ensembled for classification. to overcome data irregularity problem, random under sampler (rus), random over sampler (ros) and synthetic minority oversampling technique (smote) are applied on the ensembled feature vector. the ensembled feature vector is then classified using several machine learning (ml) classification techniques (random forest, adaptive boosting, k-nearest neighbors). among these methods, random forest got better performance metrics than others on the available standard dataset. comparison with existing methods shows that the proposed method attains improved classification accuracy, auc values and outperforms all other models providing . % accurate prediction. the model also exhibits potential generalization capacity when tested on different dataset. outcomes of this study can be great to use for pneumonia diagnosis from chest x-ray images. pneumonia is an infection in one or both lungs in which lungs' alveoli may fill up with fluid or pus causing cough, fever or making it difficult to breathe. it is the major cause of morbidity and mortality for infants under years old and people over years old in many countries. every year in the us alone, more than , people are hospitalized and around , die [ ] . pneumonia causes death of more than , children where the death toll was more than the sum of malaria, aids and measles [ , ] . according to a study, conducted by a uk based ngo in india [ ] , around million people could have been saved if appropriate actions were taken. thus, early and accurate diagnosis and treatment of pneumonia is of utmost important. different diagnosing methods of pneumonia are blood test, chest radiograph, lung ultrasound, ct scan, pulse oximetry and bronchoscopy [ ] . the advances in artificial intelligence (ai) specially machine learning (ml) and deep learning (dl) algorithms have made robust improvement in automatic diagnosis of diseases. the computer aided diagnosis (cad) tool makes disease detection and prediction task easier, cheaper and more accessible. the cad may be referred to a diagnosis made by a radiologist considering the results obtained through computer analysis [ ] . cad methods using deep convolutional neural network (cnn) and ml are now using in successful diagnosis of lung diseases-lung cancer, pneumonia, covid- , tuberculosis, breast cancer, colon cancer, prostate cancer, coronary artery disease, congenital heart defects, brain diseases, skin lesions etc. chest x-ray is one of the most commonly used painless and non-invasive radiological tests to screen and diagnose many lung diseases also other methods such as ct and mri can be used [ ] . as chest x-ray is fast, easy and inexpensive than ct and mri, they are mostly used in emergency diagnosis and treatment of lungs, hearts and chest wall diseases. chexnet is a -layer convolutional neural network model proposed by some researchers of stanford university to diagnose pneumonia. the model is trained on chestx-ray dataset and diagnose all the pathologies of the dataset with best results [ ] . vgg- is a -layer trained convolutional neural network invented by visual geometry group of oxford university. this cnn architecture contains convolutional layers and fully connected layers. this paper proposed an ensemble technique of two cnn models-fine-tuned chexnet and vgg- models for the diagnosis of pediatric pneumonia from chest x-ray images. the kermany dataset [ ] of chest x-ray images are used here for this purpose. cnn features from the two models are collected and ensembled. the number of pneumonia and normal images are not same in the dataset. so, to level the dataset random under sampler (rus), random over sampling (ros), and smote over sampling techniques are applied on the ensembled features. for the detection and classification of pneumonia from normal images different ml algorithms-random forest (rf), adaptive boosting (adaboost), k-nearest neighbors (knn) are applied on the features afterword's. among the models rf achieves the best classification accuracy of almost %. the rest of the paper is organized as follows. related works are mentioned in "related works" section. the proposed method of this paper is described in "proposed methodology" section. "results and discussion" section describes and discusses the results. finally, last but not least conclusion and future work of this research can be found in "conclusion" section. this section highlights the studies or works done by other researchers related to this research. modern technology has made diagnosis and treatment easier and more convenient than before. the availability of large datasets and unbeatable success of deep learning has made diagnosis task more accurate. authors of ref. [ ] , mentioned that, due to pneumonia at least children die every day and it is the leading cause of children death. rudan et al. [ ] , shared that on an annual basis more than million people get infected with pneumonia especially children under years old. lobar pneumonia, pulmonary tuberculosis and lung cancer, these three types of diseases are discriminated from chest x-ray by authors of ref. [ ] on their paper. ghimire et al. [ ] indicated that influenza was the cause in % of all childhood pneumonia and % of all children with influenza developed pneumonia in bangladesh. the rate of pneumonia affected children is seen more to poor family with unhygienic livelihood than economically stable families. for successful diagnosis of pneumonia various deep learning cnn models have already been developed and still developing to get more accurate results. chest x-ray is easy to use medical imaging and diagnostic technique performed by expert radiologists to diagnose pneumonia, tuberculosis, interstitial lung disease, and early lung cancer [ ] . stephen et al. [ ] . proposed a deep learning method on their research for pneumonia classification. pneumocad is a computer aided diagnosis system developed by ref. [ ] that uses handcrafted features to diagnose pediatric pneumonia from chest x-ray images. vamsha deepa et al. [ ] , proposed a feature extraction method that classify normal lungs and pneumonia infected lungs from x-ray images. the method extracts haralick texture features of x-rays and detect pneumonia with an accuracy of %. to detect clouds of pneumonia in chest x-rays, [ ] used otsu thresholding method that separates the healthy part of the lung from the pneumonia infected lungs. based on segmentation, feature extraction and artificial neural networks [ ] defined a method for the classification of lung diseases such as tuberculosis, pneumonia and lung cancer from chest radiographs. glcm features, haralick features and congruency parameter are used by some authors for pneumonia detection. in rapid childhood pneumonia diagnosis, wavelet augmented analysis is used by ref. [ ] for the cough sound while ref. [ ] proposed a deep convolutional neural network with transfer learning for detecting pneumonia on chest x-rays. for pediatric pneumonia diagnosis a transfer learning method with deep residual network is proposed by ref. [ ] . the national institutes of health (nih) cxr dataset released by ref. [ ] is comprised of , frontal cxrs, individually labeled to include up to different diseases. for creating these labels from the associated radiological reports, the authors used natural language processing to text-mine disease classifications whose expected accuracy is more than %. the chexnet deep cnn model uses this nih cxr dataset and is said to exceed the average radiologist performance on the pneumonia detection task [ ] . both vgg- and chexnet image classification models accept input images of size × . in this paper, here an ensemble of two deep cnn models (chexnet and vgg- ) is proposed with transfer learning and fine tuning. the features collected from the ensembled models are then balanced and fed to the ml model for successful and accurate classification of pneumonia and non-pneumonia (normal) images. the proposed model is also tested on a different to dataset [ ] for generalization. each and every steps of the proposed methodology-from data collection to the classification of the x-ray images is discussed here. the proposed methodology includes image preprocessing using an image enhancement technique and resizing of images, augmentation of training images, finetuning cnn models, model's training, extraction of cnn's feature vector, ensemble of extracted feature vectors, dataset imbalance handling and pneumonia classification using different machine learning algorithms. figure shows the overall procedure of the proposed methodology. table describes the datasets used to train and evaluate the proposed method. this study uses two kaggle datasets-one is the dataset of ref. [ ] collected from guangzhou women and children's medical center to train, test and validate the cnn model's performance and the other datasets is of ref. [ ] to validate the proposed method performances. the dataset [ ] contains chest x-ray images collected by x-ray scanning of pediatric patients between and years old. this dataset also comes with the ground truth of each x-ray image and the data is distributed into train, validation and test folder [ ] . there are images of pneumonia patients and rest are the chest x-ray images of healthy people. the other dataset [ ] named 'covid- chest x-ray database' from kaggle challenge which is the 'winner of the covid- dataset award' is used to evaluate the generalization performance of this proposed method. the dataset contains chest x-ray images of covid- , normal healthy people and viral pneumonia patients. there are covid- positive images, normal images and viral pneumonia images. but as this research only focuses on the diagnosis of pneumonia, only the normal and pneumonia images are selected and tested on the proposed final model. this section narrates the image preprocessing operations performed on the x-ray images. the preprocessing operation consists of two different tasks-image enhancement and data augmentation. different image enhancement techniques such as-gabor filtering, local binary pattern, histogram equalization, adaptive histogram equalization etc. are applied on the x-ray images. among them, adaptive histogram equalization (ahe) does well in cnn based feature extraction. the ahe technique enhances the contrast of the images. to retrain a transfer learned cnn model, the x-ray images need to be rescaled as required for the transfer learned model. for training the transfer learned, fine-tuned chexnet and vgg model, the images are resized to × size images. besides that, the images are rescaled into - range to match input types of models. training deep cnn models requires an extensive amount of labeled data. a model trained with limited data may produce models that perform well on train set however fails to generalize. the obnoxious condition of overfitting to training example leads to poor performance on the test dataset. increasing dataset size is an excellent solution to reduce this overfitting or memorization problem. data augmentation or artificial increase of data from available data is one of the best practices to reduce overfitting in the research community. this study utilizes geometric translations of images to increase dataset size. shearing, zooming, flipping and shifting (width shift and height shift) are the operations applied for data augmentation. convolution), relu activation and batch normalization. figure shows the architectural design of the fine-tuned chexnet model. the vgg- model consists of five blocks, and each contains few convolution layers followed by a maxpooling layer. for convolution operation, vgg- uses the kernel of size × with , , , and channels on its five convolution blocks, respectively. figure represents the architecture of the fine-tuned vgg- model. both of the models are fine-tuned for the detection and classification of pneumonia images. during fine-tuning, following modification are performed on the models for retraining the models using dataset [ ] . for fine-tuning chexnet, at first the neural network part of the pre-trained chexnet model is eliminated. the redesigned new classifier part of the model uses , and neurons on its hidden dense layers. the output layer of the model has one neuron to classify images into two classes (normal and pneumonia). each dense layer (except output layer) of the classifier part is followed by a dropout. dropout reduces the capability of the model while training and guides the model during training against overfitting. the dense layer usages relu activation function while output layer usages sigmoid activation function for binary classification. fine-tuning vgg- includes retraining only the last convolution block of the vgg- , while freezing the first four blocks of the model. instead of using a flattening layer after feature extractor, this research has applied global average pooling to reduce the number of learning parameters. both of the model usages adam optimizer with binary cross-entropy as the loss function. learning rate of the models is maintained based on the validation accuracy of the model. the training procedure uses learning rate decay by a dataset with a severe skew in the distribution of data among classes is a tricky situation known as dataset imbalance. the inconsistent distribution of data may produce a biased model and perform poorly on generalization. as the dataset [ ] used here contains more pneumonia images than normal images though the difference is not severe, it may cause the model get slightly biased towards pneumonia image detection. thus, as a dataset balancing technique random under sampling (rus), random over-sampling (ros) and synthetic minority oversampling technique (smote) are applied on the ensembled feature vector to balance the dataset. the rus randomly deletes images from the majority class while ros technique increases the dataset size by reproducing the minority class data randomly and smote randomly creates new minority class points by interpolating between the existing minority points and their neighbors [ ] . all of the techniques create the same number of images for each class. among the techniques ros performs little better than the rus and smote. the classification techniques used for pneumonia detection from the feature vector are discussed in this section. this study experimented with different ml classification methods from tree-based and non-tree-based techniques. random forest uses bagging ensemble technique for classification. the rf classifier contains decision trees (dt) as a building block. each decision tree is trained with a randomly selected samples of the dataset and these facilitates to train uncorrelated dt. then, the output of all dts is combined to make the final decision. figure illustrates the random forest classifier. adaptive boosting or adaboost is an ensemble method that aims to creates a strong classifier from a number of weak classifiers. in adaboost, at first a base model is trained then other models are added which tries to correct the errors of the previous one. this research uses logistic regression (lr), dts and support vector machines (svm) as the base model of adaboost. adaboost with lr works better here. k-nearest neighbors is a simple supervised algorithm that can be used for both classification and regression problems. based on a distance functions knn classifies new cases while storing all available cases. using number of neighbors gives the best result in this research. among these different methods, random forest (rf) classifier achieved better performance than others. as, rf is an ensemble of high variance and low bias dts where the output of each of the dt acts as a vote for the output class. besides, ensemble of these dts also creates a final model containing low bias and moderate variance. thus, rf ensured here better performances than others. this section justifies each of the steps of the proposed methodology by discussing the experimental results of each method and showing related comparison with other pneumonia detection models. both of the two x-ray image dataset [ ] and [ ] are collected and preprocessed using the techniques mentioned in "data preprocessing" section. as training a cnn model with huge amount of data helps to make the model more accurate, generalize and robust, augmentation is applied only on the training datasets to artificially increase the size of training images, to get more different images and to resolve the overfitting problems. moreover, the proposed method is also tested on a different dataset [ ] to ensure strong generalization ability of the model. figures , displays the preprocessed images of dataset [ ] and [ ] . the images are also labeled as and respectively for normal and pneumonia images. the cnn models chexnet and vgg- used in this research were trained using the preprocessed chest x-ray images of size × . both of the model is then tested and validated on the test and validation images of dataset [ ] . chexnet achieves . % test accuracy and % validation accuracy while vgg- obtained . % and % test and validation accuracy on test and validation images. the ensemble of two models will help to increase the overall performances of the model. figure a , b shows the validation performances of the chexnet and vgg- models on the validation dataset. the features of all the train and test images are now collected separately and combined them altogether to make a feature vector of the dataset. to make the pneumonia detection model more realistic and increase accuracy the model's feature vectors are then ensembled. the coding part of this task is done completely in python keras framework with tensorflow backend using google colab gpu on a mac operating system. the ensembled feature vector has pneumonia images and normal images. thus, to ensure unbiased results from the classifier rus, ros and smote data balancing techniques are applied on the feature vector. after applying rus, there will be pneumonia images and normal images and both of ros and smote makes total images for each normal and pneumonia class. ml models such as random forest, adaboost, knn are then applied with five-fold cross validation on the balanced dataset. among the techniques ros with rf performs better than other. table below shows the mean accuracy of five-fold cross validation for different ml models using different data balancing techniques. the table shows that the best mean accuracy obtains using rf with ros. in table , comparative accuracy of rf, adaboost and knn is shown for each five-fold with ros. in every fold, rf achieves the best classification accuracy than adaboost and knn. so, rf is selected as final classifier and ros as the data imbalance handler. and the best mean accuracy obtained by the proposed model is . % or % approx. with % precision, % recall and % f-score on average. to validate the model performances again the previous validation images are tested on the final proposed model which achieves % validation accuracy. figure displays the validation report of our final model with confusion matrix. to test the model's generalization performances a different dataset [ ] is used. all of the normal and pneumonia images of new test dataset [ ] are tested using the final model for generalization. the model achieves . % generalization accuracy on this new test dataset. figure presents the model's performance on the test dataset. the proposed model performance on this new dataset proves the model's strong and appropriate generalization capability. among the images the model successfully classifies images while only images are misclassified. the above discussion proved that the proposed model acts so well in diagnosing pediatric pneumonia from chest x-rays. this section demonstrates the comparison of our model's performances with existing models and methods. the most frequently used models for medical image classifications are vgg , resnet, densenet , inceptionv , xception which achieves approximately - % accuracy on pneumonia classification. the proposed model performs much better than these models. the models proposed on paper [ , , ] and paper [ ] shows that their models perform better than the other existing models for pneumonia detection. comparison of these models with proposed model is given in table . the comparison table clearly proves that the proposed model is the best performing pediatric pneumonia classification model. the model achieves an average auc (area under the roc curve) value of . %. the two-dimensional area under the roc curve is defined by auc. figure shows the roc curve (receiver operating characteristic curve) with % auc area. roc curve is a graphical representation showing the performance of a model. an automated cad tool is presented in this paper, for the detection of childhood pneumonia from chest x-ray images. in this research a fusion of two fine-tuned cnn model is proposed which is then ensembled with ml random forest classifier. the proposed final model classifies pneumonia . % accurately and comparing to other models provide better prediction. so, our proposed model can be referred to as one of the best pneumonia classification models. in future, the authors will try to optimize the model to classify two or more diseases with an effective result. prateek et al. [ ] . liang et al. [ ] . stephen et al. [ ] . saraiva et al. [ ] . proposed model . epidemiology and etiology of childhood pneumonia childhood pneumonia as a global health priority and the strategic interest of the bill & melinda gates foundation lakh indian children to die due to pneumonia by ; here's how it can be averted feature extraction and classification of x-ray lung images using haralick texture features role of gist and phog features in computer-aided diagnosis of tuberculosis without segmentation a transfer learning method with deep residual network for pediatric pneumonia diagnosis radiologist-level pneumonia detection on chest x-rays with deep learning. . arxiv identifying medical diagnoses and treatable diseases by image-based deep learning global estimate of the incidence of clinical pneumonia among children under five years of age pair-wise discrimination of some lung diseases using chest radiography pneumonia in south-east asia region: public health perspective computer-aided detection in chest radiography based on artificial intelligence: a survey an efficient deep learning approach to pneumonia classification in healthcare. hindawi j healthcare eng computer-aided diagnosis in chest radiography for detection of childhood pneumonia detection of pneumonia clouds in chest x-ray using image processing approach automatic detection of major lung diseases using chest radiographs and classification by feed-forward artificial neural network wavelet augmented cough analysis for rapid childhood pneumonia diagnosis deep convolutional neural network with transfer learning for detecting pneumonia on chest x-rays chest x-ray : hospital-scale chest x-ray database and benchmarks on weakly-supervised classification and localization of common thorax diseases covid- chest x-ray database visualizing and explaining deep learning predictions for pneumonia detection in pediatric chest radiographs handling data irredularities in classification: foundations, trends, and future challenges. pattern recogn classification of images of childhood pneumonia using convolutional neural networks, in: th international conference on bioimaging publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors are grateful to the participants who contributed to this research. no financial support is provided from any organization during the research project. conflict of interest the authors declare that there is no conflict of interests regarding the publication of this work. key: cord- -tm s wvj authors: lim, wei shen title: pneumonia—overview date: - - journal: reference module in biomedical sciences doi: . /b - - - - . - sha: doc_id: cord_uid: tm s wvj pneumonia is very common and continues to exact a high burden on health. the global burden of disease study found lower respiratory infections (lris) were the leading infectious cause of death and the fifth leading cause of death overall. pneumococcal pneumonia caused % of lri deaths in all ages ( . million deaths). novel pathogens, particularly viruses, continue to emerge as causes of pneumonia. the rise of drug-resistance among common respiratory pathogens is a further challenge. pneumonia is commonly classified according to patient location at the time of infection, leading to the categories of community-acquired, hospital-acquired and ventilator-acquired pneumonia. pneumonia may be defined as an infection of the lung characteristically involving the alveolar space. the presence of microorganisms in the alveolar space without an accompanying inflammatory response represents colonization and does not constitute pneumonia. a range of other types of infection may also affect the lung and can be classified according to their principle site of infection ( fig. ). the term lower respiratory tract infection (lrti) is often considered to include both acute bronchitis and pneumonia. however, it is sometimes used to designate non-pneumonic infections of the lower respiratory tract alone. in patients with chronic lung disease (e.g., chronic obstructive pulmonary disease (copd)), an infection of the bronchi often results in an exacerbation of the underlying lung illness. in these circumstances, the illness is usually designated as an exacerbation of disease (e.g., exacerbation of copd) rather than "acute bronchitis." in general, the more distal the infection within the respiratory tract, the greater the likelihood of bacterial infection and the greater the severity of illness. exceptions to this include acute epiglottitis, diphtheria and pertussis which may present as severe bacterial infections of the upper respiratory tract without causing pneumonia. pneumonia is further classified in various different manners. these are mainly clinical classifications that broadly describe differences in the likely range of pathogens involved (table ). the commonest grouping is according to patient location at the time of acquisition of infection. infections arising within a hospital setting may involve more drug-resistant pathogens compared to infections arising in the community. within the grouping of hospital-acquired pneumonia (hap), further distinction is usually made according to whether the patient was on an intensive care unit, or intubated (ventilator-acquired pneumonia (vap)) at the time of infection (torres et al., ; kalil et al., ) . a specific category of healthcare-associated pneumonia (hcap) was previously advocated as describing pneumonia developing outside a hospital setting that shared features of pathogenesis, causative pathogens and antibiotic resistance patterns with nosocomial (hospital-acquired) pneumonia. this category was never fully adopted internationally and the latest evidence does not support the continued use of this classification. host factors play an important role in the manifestation and management of pneumonia. pneumonia arising in immunocompromised hosts usually warrants distinct treatment. in general, the greater the degree of immune compromise, the wider the range of potential pathogens. the classic symptoms of infection, which are partly related to the host immune response, may also be absent, altering the clinical presentation. a third common classification is according to the causative pathogen(s). until recently, a microbiological diagnosis used to take days to confirm. however, with the advance of rapid, point-of-care diagnostics, microbiological confirmation within minutes/hours of clinical presentation is becoming more realistic. hence, this classification will hopefully become more clinically relevant in guiding patient management at the time of presentation. anatomically, pneumonias may be classified as bronchopneumonia or lobar pneumonia. bronchopneumonia occurs when infection leads to multiple discrete foci of consolidation within the lung, whereas lobar pneumonia is described when the area of consolidation is confined to the affected lobe which is diffusely involved. it was once thought that the pattern of consolidation (whether described radiologically or pathologically) was indicative of the causative pathogen (e.g., lobar pneumonia caused by streptococcus pneumoniae). however, it is now recognized that such discrimination is unreliable because of the large overlap in patterns caused by infecting pathogens. aspiration pneumonia refers to a specific situation when a patient who is manifestly at risk of aspiration develops pneumonia and anaerobic pathogens from the digestive tract are implicated, usually alongside multiple other microorganisms. an accompanying pleural reaction or lung abscess may develop. micro-aspiration events are common and the aspiration of microorganisms into the lower airways likely accounts for how pneumonia develops in the majority of cases (see "pathogenesis" section). hence, the presence of micro-aspiration alone in a patient with pneumonia does not invariably denote aspiration table classification of pneumonia. description/comments pneumonia. stroke-associated pneumonia has been advocated as the desired terminology for lrti occurring within days of acute stroke (smith et al., ) . the lung is not a sterile environment. the normal lung microbiome includes bacterial species that may be implicated in the development of pneumonia, such as streptococcus spp. and mycoplasma spp. (beck et al., ) . these, and other microorganisms, are normally held in check by pulmonary host defenses. disruption of these host defenses allow externally transposed pathogenic microorganisms to grow and displace the normal flora, or allow overgrowth of selected resident flora, leading to infection. there is growing interest in the role of antecedent viral respiratory tract infections as triggers for the disruption of the normal lung microbiome, providing an avenue for bacterial pathogens to take hold. the acute inflammation generated by the host immune response to infection results in an influx of inflammatory cells into the alveolar space, giving rise to the radiological pattern of consolidation (fig. ) . in most cases, the predominant inflammatory cell involved reflects the inciting pathogen; neutrophils in bacterial infections, lymphocytes in viral infections and granulomatous inflammation in mycobacterial and fungal infections. the systemic cytokine response gives rise to many of the characteristic features of infection, such as fever, myalgia and a rise in c-reactive protein levels. the introduction of microorganisms to the lung is most commonly via micro-aspiration. haematogenous spread from other sites in the body, and direct spread from a contiguous source are less common. a range of host factors that predispose to pneumonia have been identified (wunderink and waterer, ; almirall et al., ) (table ) . these factors mostly increase the susceptibility to pneumonia through reducing host defenses. some commonly used non-immunosuppressive drugs have been associated with pneumonia, but the mechanisms of action for all of these have not been fully described. immunocompromised patients are not only at higher risk of developing pneumonia but the range of possible pathogens is also wider. as the number of therapeutic interventions that modify the immune system (such as monoclonal antibodies and tyrosine kinase inhibitors) expands, patients with widely differing levels of immune integrity are being described. in addition, multiple immune insults may exist together. for instance, the severe immune defects caused by hematological malignancies are often compounded by their treatments which may include cytotoxic drugs and/or total bone marrow ablation followed by hematopoietic stem cell transplantation. immunologically, defects can be broadly grouped into (a) cell-mediated defects, (b) antibody deficiencies and (c) neutrophil dysfunction, most commonly neutropenia. understanding the type of immune defect facing a patient can aid as a guide to the likely range of pathogens involved, prior to confirmatory microbiological diagnosis. a definitive diagnosis of pneumonia comprises four aspects: (i) symptoms and signs of a respiratory tract infection, (ii) radiological changes, (iii) identification of a putative pathogen and (iv) a treatment response, or clinical course, consistent with pneumonia. it is not always easy to make this diagnosis. in settings where investigations are not readily available, such as in primary care, a clinical (or working) diagnosis of pneumonia may be made without recourse to radiological or microbiological tests. the accuracy of a clinical diagnosis of pneumonia made in primary care is reasonable; - % of patients clinically diagnosed with cap have radiologically confirmed cap. however, of patients with acute cough in whom a radiological diagnosis of cap is made, only about % are clinically diagnosed as cap (van vugt et al., ) . even in secondary care, up to % of cases of pneumonia diagnosed in the emergency department are eventually discharged from hospital with an alternative diagnosis (sikka et al., ) . the differential diagnosis of pneumonia includes other cardiac and pulmonary conditions that present acutely with features of cough and/or dyspnoea together with radiological abnormalities. (table ) in patients who are mechanically ventilated, diagnosing pneumonia amidst the wide range of differential diagnoses is challenging. patients with pneumonia usually present with a combination of (i) respiratory symptoms, specifically cough ($ %), dyspnoea ($ %), sputum production ($ %) and chest pain ($ %), and (ii) systemic symptoms including fever, rigors, myalgia and confusion. confusion is commoner in older patients and those who are severely ill. immunocompromised patients, and to a lesser extent, older patients, may not mount as rigorous an immune response and therefore may present with more subtle symptoms. about % of patients with cap present to hospital with extra-pulmonary features alone; these include falls, generalized weakness and acute abdominal pain. a high index of suspicion is required in these circumstances. until recently, identification of consolidation on a chest radiograph (cxr) has been regarded as the "gold standard" radiological investigation in the diagnosis of pneumonia. it is recognized that in patients with chronic lung abnormalities (e.g., pulmonary fibrosis, bronchiectasis, lung cancer) or in certain settings (e.g., intensive care unit), the sensitivity and specificity of a cxr for the identification of pneumonic changes can be limited. however, computed tomography (ct) scanning ( fig. ) has raised further questions regarding the reliability of the cxr for the diagnosis of pneumonia more generally. when evaluated against ct imaging, the cxr results in both over-diagnosis and under-diagnosis of pneumonia with up to a third of patients diagnosed with pneumonia on cxr having no infiltrate on ct scanning (claessens et al., ) . ultrasonography is also being evaluated for the diagnosis of pneumonia with promising initial findings when compared against cxr (orso et al., ) . it remains necessary to determine if these imaging modalities will enable discrimination of patients suspected of having pneumonia into groups that warrant different management strategies. table risk factors for pneumonia. age > years chronic co-morbid conditions copd, cancer, diabetes, chronic liver disease, renal impairment immunosuppressive disorders hiv, solid organ transplantation, immunosuppressive agents factors that increase the risk of aspiration placement of endotracheal tube, stroke, neurological disorder lifestyle factors smoking, high alcohol intake, malnutrition drugs proton-pump inhibitors, anti-psychotic medication, inhaled corticosteroids (in patients with copd) table differential diagnosis of pneumonia. identification of a causative pathogen not only aids in the diagnosis and classification of pneumonia, it also guides antimicrobial therapy and infection control measures. a wide array of microbiological tests is available (table ) . however, even with the use of modern molecular-based microbiological investigations (e.g., pcr, antigen detection tests) in patients with cap, a pathogen is identified in only - % of cases (jain et al., ) . in routine care where microbiology testing is still based mainly around cultural techniques (e.g., from blood and respiratory tract samples), a pathogen may be identified in only - % of cases. conversely, in patients with suspected vap, extensive colonization of airways creates difficulties in the interpretation of positive microbiology results. the use of highly sensitive pcr techniques can compound the difficulty. similar challenges confront the management of immunocompromised patients. in these instances, careful attention to the coherence of microbiology test results with the clinico-radiological pattern is necessary to distinguish colonization from infection. sometimes, a diagnosis of pneumonia can only be confirmed or refuted following review of the subsequent clinical course of illness, including the clinical response to empirically initiated antimicrobial agents. microbiological investigations are rarely performed in primary care settings due in part to a lack of access to laboratory facilities, low yield and delays in obtaining results in time to influence clinical management. advances in science and technology have come together to enable the development of rapid point-of-care (poc) tests that can provide microbiology test results within - min. the benefits of definitive identification of the causative pathogen (or in some cases, definitive exclusion of a specific pathogen, such as influenza) at the time of clinical presentation need to be weighed against the resource demands of these newer technologies and their costs. because lrtis can be caused by a range of pathogens, singlepathogen specific technologies are less helpful. multi-array pcr platforms may overcome some of these hurdles, but come with increased costs. the cost-effectiveness of poc-driven management strategies compared to more empirical approaches remains to be proven in many circumstances. an alternative approach to the management of patients with lrtis is to rapidly discriminate those may have a bacterial infection and who would therefore require antibiotic therapy, versus those with a viral infection or a non-infectious condition. several hostresponse biomarkers have been investigated in this regard (table ) . c-reactive protein (crp) and procalcitonin (pct) are the two most extensively studied biomarkers in respiratory tract infections. levels of these biomarkers increase more extensively in bacterial compared to viral infections. procalcitonin has a more responsive kinetic profile than crp, which means that levels of procalcitonin increase and decrease more swiftly in line with bacterial load. apart from informing the decision whether or not to initiate antibiotics, the other role of crp-and procalcitonin-guided treatment strategies in patients with pneumonia may be to guide the duration of antibiotic therapy through serial assessments of biomarker levels. a meta-analysis of individual participant data from rcts found that pct-directed treatment in the management of acute respiratory tract infections (of varying types and severity, including cap and hap) was associated with a reduction in antibiotic exposure ( . vs. . days) composed of a decrease in both (a) the proportions initiating antibiotics and (b) the duration of antibiotics ( . vs. . days), as well as a reduction in -day mortality ( . % vs. . %) (schuetz et al., ) . proadrenomedullin, neopterin, strem- and pentraxin- are other biomarkers that have been found in a small number of early studies to be potentially of value in lrtis (saleh et al., ) . measuring pentraxin- and strem- in bronchoalveolar lavage fluid table biomarkers studied in respiratory tract infections. c-reactive protein acute phase protein synthesized by hepatocytes procalcitonin prohormone of calcitonin which is induced by the activation and adherence of monocytes to the endothelial layer of blood vessels proadrenomedullin precursor for adrenomedullin which is involved in immuno-modulation strem- soluble triggering receptor expressed on myeloid cells - (strem- ) levels rise following an increase of trem- expression on neutrophils, granulocytes, monocytes and alveolar macrophages. trem- expression is increased by microbial products pentraxin- acute inflammatory marker and a component of innate immunity neopterin produced in monocytes and macrophages. a marker of cell-mediated immunity. levels rise in viral infections copeptin stable byproduct of vasopressin biosynthesis lipocalin- protein involved in innate immunity. it limits bacterial growth by sequestering iron-containing siderophores syndecan- receptor in intracellular signaling. present in alveolar macrophages midregional proatrial natriuretic peptide (mr-proanp) a byproduct of atrial natriuretic peptide (anp) biosynthesis. anp regulates macrophage activity in innate and acquired immunity samples has been found to be more discriminatory for bacterial versus viral infections than their levels in blood. other biomarkers (e.g., copeptin, lipocalin- , syndecan- ) display poorer performance characteristics. it may be that diagnostic performance can be further improved by combining different biomarkers (e.g., pct and mr-proanp) or matching certain biomarkers to selected target patient populations (e.g., hap vs. cap). most of the investigated biomarkers aim to differentiate between bacterial or viral infections according to the host's immunological response. the role of these biomarkers in patients with impairments of the immune system is therefore more limited, depending on the nature of the immune defect. data on the epidemiology of pneumonia are drawn from two broad sources-(a) datasets that rely on the coding of pneumonia following clinical episodes, and (b) cohort studies of patients with radiology-confirmed pneumonia. the accuracy of clinical coding of pneumonia reflects the difficulties with making a firm diagnosis. in the uk, up to % of coded cases of hospitalized-pneumonia may have no radiographic evidence of infection (daniel et al., ) . changes in the way pneumonia is coded can also affect the interpretation of data. in the us, there has been a shift in recent years from assigning a primary diagnosis code of "pneumonia" in patients hospitalized with severe cap, towards a primary diagnosis code of "sepsis" with "pneumonia" as the secondary diagnosis (lindenauer et al., ; ruhnke et al., ) . prospective studies of radiology-confirmed pneumonia provide more robust data but are often less comprehensive in scope. the global burden of disease study estimated that in , the incidence of lrti in children aged < years old was . episodes per child-year, and in all ages it was . episodes per person-year (collaborators, ) . most episodes of lrti/cap are treated in community settings. in the uk, cap affects approximately % of the uk adult population each year, accounting for over , hospital admissions. the average length of stay is days and estimated direct healthcare costs are £ million. in the us, the annual incidence of cap requiring hospitalization has been estimated at around per , adults (hayes et al., ) . this compares with lower estimates from other parts of the world (table ). incidence rises steeply in adults aged > year (table ) . changes in the prevalence of risk factors for pneumonia can be expected to influence the incidence of pneumonia. in the uk, a % increase in the incidence of cap requiring hospitalization was observed from to (trotter et al., ) . such trends of increasing incidence are thought to be explained by an aging population and a higher proportion of persons living with co-morbid illnesses, the latter encompassing an increase in persons with complex multi-morbidity. some have implicated alterations in the epidemiology of causative pathogens (quan et al., ) . changing patient expectations may also influence how healthcare is accessed and hospital admission policies. in contrast, in the us between and , a decrease in the annual age-adjusted rate of pneumonia-associated hospitalisations was noted despite an increase in the proportion of co-existing immunocompromising conditions from . % in to . % in (hayes et al., ) . in sub-saharan africa, the incidence of cap is dominated by the effect of hiv infection. the prevalence of hiv within cohorts of patients with cap is - %. in a community surveillance study in kenya, the annual incidence of pneumococcal acute respiratory infection was per , persons in hiv negative individuals compared to per , persons in hiv positive individuals (aston, ) . effective vaccination against respiratory pathogens has the potential to prevent infection and decrease the incidence of pneumonia. national immunization programmes involving pneumococcal vaccines have contributed towards a reduction in overall pneumococcal infections and attendant mortality. however, in some countries, replacement disease, involving pneumococcal serotypes not covered by existing vaccines, has since begun to offset the reductions in vaccine serotype disease. further vaccine development incorporating other serotypes, or effective against all pneumococcal serotypes/serogroups, will hopefully curtail this rise in replacement disease. estimates of the incidence of hospitalisations for cap (takahashi et al., ; ewig et al., ; trotter et al., ; hayes et al., ) . annual incidence (per , adults) globally, lrtis are the leading infectious cause of death and the fifth-leading cause of death overall. in , lrtis caused Á million deaths in all ages, with children < years of age bearing a disproportionate burden ( , deaths). between and , the number of deaths due to lrti decreased by . % in children younger than years, and by . % in all ages; most of these decreases occurred in countries with a low to middle socio-demographic index (sdi). in high-sdi countries, the lrti mortality rate in all ages increased by . % over the same period (from . per , to . per , ) (collaborators, ) . in the us, pneumonia remains the leading infectious cause of death, and the eighth commonest cause of death overall. since , mortality from pneumonia and influenza in the us has stayed below deaths per , population. most deaths occur in hospitalized patients. in the period - , in-hospital deaths occurred in . % of pneumonia-associated hospitalisations (hayes et al., ) . in europe, mortality rates for hospitalized patients are mostly around - % though a wide range is reported likely reflecting differences in healthcare systems, data sources and possibly microbiological patterns. in patients admitted to icu with cap, mortality rates are in the region of - %. in africa, an even wider range of mortality rates have been reported, from < % to nearly %. in most high-income countries, advancing age is associated with increasing mortality rates. however, in sub-saharan africa, this trend is not always evident; % of lrti-related deaths in adults occur in persons under years, including % in adults aged - years. rates of admission to icu vary globally according to availability of resources and admission policies. a higher proportion of hospitalized patients are admitted to icus in north american (> %) compared to europe ( - %). hospital acquired pneumonia is the second commonest nosocomial infection after urinary tract infections. estimated incidence rates are - cases per hospital admissions (torres et al., ) . these rates are influenced by the hospital ward setting and patient groups affected. the majority of hap ( %) occurs on non-icu wards, however, the incidence of hap is greater among patients in icu compared to patients on general wards. higher rates are also observed in at-risk patient groups such as the elderly, those who have had surgery and immunocompromised hosts. the incidence of vap is - episodes per ventilator-days according to data from the us. during the first days of mechanical ventilation (mv), the estimated risk of vap is % per day, decreasing to % per day from days to of mv, and to % per day from day of mv onwards. patients with brain injury and trauma are at particularly high risk of vap ( %) (kalil et al., ) . hospital acquired pneumonia is the leading cause of death from nosocomial infections in critically ill patients. the crude mortality from hap is high (up to %). however, patients who develop hap are often already severely ill and the factors that predispose to hap may also increase the risk of mortality. accordingly, mortality is higher for patients with vap than for patients with hap on general wards. in some studies of vap, - % of vap-related deaths are deemed to be a direct result of infection. the vapattributable mortality has been estimated at % with surgical patients carrying the highest associated risks (melsen et al., ) . infection with pseudomonas aeruginosa or acinetobacter spp. is associated with higher mortality as well. an extensive range of pathogens can cause pneumonia. the respiratory pathogens commonly implicated in patients with cap remain important aetiological agents in all other types of pneumonia, including hap and pneumonia in the immunocompromised host (table ). factors that modify (usually extend) the range of pathogens that might be implicated include alterations in immune status, exposure to specific environments/pathogens and prior exposure to antibiotics. s. pneumoniae is the predominant bacterial pathogen in pneumonia, especially cap. geographical differences are important in two broad regards: (a) the spectrum and frequency of likely pathogens, (b) the patterns of drug-resistance likely to be encountered. in countries where tuberculosis (tb) is endemic, acute tb pneumonia is a well-recognized cause of cap in both immunocompetent and immunocompromised persons. in thailand particularly, and to a less extent in some surrounding countries such as northern australia, burkholderia pseudomallei (a gram-negative bacillus that is present as free-living saprophytes in soil and surface waters in endemic areas) is a common cause of fulminant cap with high mortality. time from hospital admission to the development of hap influences the likely pathogens encountered. alterations in a patient's normal flora increase with duration of stay in hospital, potentially modified by illness, medical procedures and drug (antibiotic) exposure. as a general guide, the risk of infection from drug-resistant pathogens increases with duration of hospital stay. the main additional pathogens to consider are gram-negative enteric bacilli and methicillin-resistant s. aureus (mrsa) ( table ) . the additional pathogens to consider in immunocompromised patients with pneumonia depends on the degree of immune dysfunction at the time of infection. in patients with hiv, the risk of infection with s. pneumoniae (and subsequent bacteraemia) is increased over -fold even with normal cd counts (> cells/ml). similarly, the risk of infection by mycobacterium tuberculosis is increased in early hiv infection. with cd counts < cells/ml, the risk from "opportunisitc" infections increases vastly (table ) (segal et al., ) . infections with fungal pathogens are of particular concern in patients with severely impaired immune defenses. of note, some pathogens which commonly cause systemic infections in immunocompromised hosts rarely involve the lung (e.g., candida spp.). other pulmonary infections represent reactivation of disease as immune function declines rather than the acquisition of new disease (e.g., non-tuberculous mycobacteria, toxoplasma gondii). certain pathogens are associated with specific environmental exposures, or in the case of zoonosis, exposure to animal reservoirs (table ) . some pathogens display seasonal patterns of higher incidence. for instance, infections with influenza, respiratory table common microbial pathogens in pneumonia. mycobacterium tuberculosis non-tuberculous mycobacteria syncytial virus and s. pneumoniae are commoner in winter, whilst legionella infections are commoner in summer when the weather is hotter and more humid. over the years, the list of pathogens causing pneumonia has continued to increase through a combination of factors; advances in microbiological diagnostics, better recognition of clinical syndromes and the expansion of human populations into new territories. in particular, a number of viral pathogens have been recognized in the last two decades as implicated in the development of pneumonia. these include coronavirus, human metapneumovirus and enterovirus-d . infection by more than one pathogen can occur in up to a third of patients with pneumonia. these are mostly viral-bacterial pathogen combinations and may reflect recognized associations between certain infections. for instance, influenza-related pneumonia is associated strongly with the bacterial pathogens s. aureus and s. pneumoniae. particular attention is necessary with immunocompromised patients when multiple pathogens may co-exist to cause disease. in , the world health organization (who) published a global priority list of antibiotic-resistant bacteria to guide research, discovery and development of new antibiotics. the list includes a number of important respiratory pathogens, such as penicillin non-susceptible s. pneumoniae, ampicillin-resistant h. influenzae, methicillin and vancomycin-resistant s. aureus, carbapenemresistant a. baumannii, carbapenem-resistant p. aeruginosa, and carbapenem-and third-generation-cephalosporin resistant enterobacteriaceae (such as k. pneumoniae). whilst many of these pathogens are mainly implicated in nosocomial infections, some are important in cap as well. rates of drug-resistant s. pneumoniae (drsp) vary globally. northern european countries have tended to have lower numbers of drsp (< % of pneumococcal isolates) while some other countries (southern europe, japan and the united states) report figures of drsp approximating - % of isolates. the introduction of childhood pcv vaccination programmes in many countries has generally led to a reduction in rates of drsp. the epidemiology of drsp continues to change under vaccine pressure. in europe, during the era of pcv vaccination, the most frequent serotypes to display resistance to penicillin (from samples taken in to ) were serotypes , a and a. multi-drug resistance (defined as resistance to or more classes of antimicrobial agents) was commonest in serotype a, a non-vaccine serotype (yahiaoui et al., ) . an assessment of illness severity is fundamental to the management of patients with pneumonia. severity assessment guides decisions around (a) place of treatment (whether in the community, in hospital, or in intensive care), (b) depth of investigations, (c) speed of treatment and (d) type of treatment, including the choice of antimicrobial agents and route of administration. various severity assessment tools have been developed for the management of patients presenting with cap. the two most widely validated and adopted tools are the pneumonia severity index (psi) and the curb score. both of these were developed to predict shortterm, -day mortality in patients presenting to hospital with cap. prognostic tools to predict icu admission are not as widely used partly due to differences in icu admission policies influencing the predictive accuracy of tools developed in one healthcare system and applied to a different healthcare system. severity assessment tools for hap are less well validated. this reflects the much broader diversity of factors influencing prognosis in patients with hap, including type of hospital ward, reason for hospital admission, time from hospital admission, medical interventions, exposure to nosocomial pathogens and preceding antibiotic exposure. similarly, there are no pneumonia-specific tools for assessing severity in immunocompromised patients. in these patients, the degree of immune compromise is often the dominating factor in severity assessment. patients who are severely immunocompromised may lack many of the symptoms or signs associated with severe illness. a high degree of vigilance is therefore important. early treatment with appropriate antimicrobial agents is the goal. in patients who are severely ill, earlier treatment (measured in hours) is associated with improved clinical outcomes, such as mortality. in patients presenting with signs indicative of severe sepsis, antibiotic administration within an hour is advocated. the impetus for early antimicrobial treatment limits the window in which to complete investigations to confirm the diagnosis of pneumonia and associated microbiology, prior to antimicrobial administration. in many instances, empirical broad-spectrum treatment must be started whilst awaiting results. in the case of influenza infection, time from onset of illness to antiviral treatment is the critical factor. viral load peaks rapidly within the first days of illness. in line with this, evidence of clinical benefit from neuraminidase inhibitors is greatest when treatment is started within h of symptom onset. concepts such as "start smart, then focus" acknowledge the inevitable uncertainty that often exists at the time of commencement of antimicrobials, and emphasis the equally important role of reviewing the diagnosis and treatment plan in the light of emerging results and response to empirical treatment. this pertains not only to antibiotics, but also to antiviral and antifungal agents. the optimal duration of antimicrobial therapy in the treatment of pneumonia has not been adequately studied. traditionally, a -day course of antibiotics has been standard. increasing awareness of the importance of good antimicrobial stewardship has led to efforts to refine the required duration of antimicrobial therapy. shorter -day courses of treatment are gaining acceptance, as are biomarker-driven antibiotic prescribing strategies (see section on "biomarkers"). some infections, such as legionella pneumonia, are still treated with longer courses of antibiotics ( - days) based on clinical experience rather than evidence derived from clinical trials. in the treatment of pneumonia, adjuvant therapy refers broadly to interventions that are aimed at modulating the immune response to infection. the use of systemic corticosteroids has been extensively tested in patients with severe sepsis, a large proportion of whom have pneumonia. a meta-analysis of trials involving > , patients found, with low certainty, a small mortality benefit in favor of low-dose corticosteroids (rochwerg et al., ) . fewer trials have been conducted in patients with cap and the existing debate around the value of corticosteroids for this specific indication reflects the weaker evidence base; evidence from trials involving > patients indicate a mortality benefit in patients with severe pneumonia, but not in those with non-severe pneumonia (stern et al., ) . macrolide antibiotics have immunomodulatory properties apart from their antibiotic effects. large observational cohort studies of patients with both all-cause pneumonia (i.e., involving a range of respiratory pathogens) and pneumococcal pneumonia suggest the combination of macrolide with beta-lactam antibiotics is associated with improved prognosis. in contrast, data from available randomized controlled trials are conflicting. hmg-coa reductase inhibitors (statins) have a range of immunomodulatory effects and in murine models of sepsis, pre-dosing with statins has been associated with improved outcomes. studies in adults with pneumonia support the notion that patients already taking a statin at the time of infection have a better prognosis, but the value of statins started as adjuvant therapy in patients presenting with pneumonia has not been established. immunization programmes against common respiratory pathogens are cost-effective public health interventions for the prevention of cap in many countries. in relation to s. pneumoniae, two types of pneumococcal vaccines are commercially available. the current multivalent pneumococcal polysaccharide vaccine (ppv) was first introduced in and covers of over pneumococcal serotypes/serogroups ( , , , , , b, f, , n, v, a, aa!, f, , b, f, c, a, f, , f, f, f.) . the -valent ppv offers good protection against invasive pneumococcal disease but relatively weak protection against pneumococcal pneumonia (falkenhorst et al., ) . in older persons who are most at risk of pneumonia, immunosenescence adversely influences the protective effect of these vaccines. pneumococcal conjugate vaccines (pcvs) promote a more robust immune response and are able to reduce nasopharyngeal carriage of vaccine-type s. pneumoniae strains, but cover a smaller range of pneumococcal serotypes. as children are the main carriers of s. pneumoniae, vaccination of children with pcvs has been associated not only with a reduction in the incidence of childhood pneumococcal infections, but also in the incidence of adult pneumococcal pneumonia (herd protection) (tsaban and ben-shimol, ) . countries vary in the target groups for pneumococcal vaccination and the vaccines offered. trivalent influenza vaccines against of the main circulating influenza strains ( influenza a strains and influenza b strain) have been available for many years. due to antigenic shifts within influenza viruses, the components of these vaccines are reviewed (and renewed) each year to maximize vaccine-pathogen "match." vaccines against all four of the common seasonal influenza viruses (quadrivalent vaccines covering influenza a strains and influenza b strains) are now available. in addition, and perhaps more importantly, is the development of newer conjugated vaccines and high-dose vaccines that promote stronger immune responses in older at-risk persons compared to previous "standard" influenza vaccines, hence offering greater protection. influenza vaccines that are not strain-specific (so-called "universal" vaccines) and therefore less subject to mismatch are also being developed as are vaccines against respiratory syncytial virus. the h. influenzae type b (hib) vaccine is available for the prevention of childhood pneumonia. however, in adults, non-typeable h. influenzae (nthi) is much more important and there are some data to suggest that childhood carriage of nthi may be increasing. an effective vaccine for nthi is not currently available. smoking cessation and a reduction in alcohol use are important modifiable lifestyle factors for the prevention of pneumonia. current tobacco smokers are over two times more likely (pooled odds ratio . , from meta-analysis) to develop cap compared to adults who have never smoked, while people who consume alcohol (or in higher amounts) have a % increased risk of cap compared to those who consume no (or less) alcohol (simou et al., ) . for every - g higher alcohol intake per day, there is an % increase in the risk of cap. a large number of specific interventions have been advocated in the prevention of vap. these may be grouped as functional (e.g., semi-recumbent position), mechanical (e.g., silver-coated endotracheal tube) and pharmacological (e.g., selective decontamination of the digestive tract) interventions. the institute of health improvement (ihi) developed the concept of "bundles" of care in the icu to improve clinical outcomes. implementation of a vap prevention bundle may enable the ideal goal of "zero vap" to be achieved (Álvarez-lerma et al., a,b) . recovery from pneumonia usually takes several weeks. at - weeks following discharge from hospital for an episode of cap, one or more symptoms continue to be reported by % of patients, including cough, dyspnoea and fatigue in roughly equal proportions. functional impairment is reported by - % of patients at weeks (pick et al., ) . cardiac complications (including heart failure, acute coronary syndrome and arrhythmias) have been observed in % of patients within days following occurrence of cap, with higher rates among patients who are hospitalized compared to those treated in the community (corrales-medina et al., ) . the risk of cardiac complications remains high for at least the first - years following hospitalization (corrales-medina et al., ) . higher rates of long-term mortality ( % at year, % at years) have been observed in patients following hospitalization for cap compared to patients hospitalized for other reasons. the predominant causes of long-term mortality are vascular and respiratory in nature. although studies have attempted to adjust for co-existing medical illnesses, it remains uncertain whether the association of pneumonia with long-term mortality is causal or whether pneumonic events are simply markers of poorer overall health (wagenvoort et al., ) . many of the current treatment strategies for pneumonia have remained broadly unchanged over the last decade. efforts at reducing the burden of disease through vaccination have been rewarded with some success but continued innovation is required to maintain gains made so far. the rise of antimicrobial resistance threatens our ability to treat infections that occur, urging a more judicious approach than the empirical antimicrobial strategies that characterize much of current clinical practice. the future expectation is a shift towards targeted treatments supported by rapid diagnostics, thus enabling the use of non-antibiotic pathogen-specific therapies (such as anti-toxins) and promising the eradiation of inappropriate antimicrobial use. immune-modulating agents may offer further benefits in relation to short-term recovery, and improved post-pneumonia care could translate into better longer-term outcomes. risk factors for community-acquired pneumonia in adults: a systematic review of observational studies prevention of ventilator-associated pneumonia: the multimodal approach of the spanish icu "pneumonia zero" program the multimodal approach for ventilator-associated pneumonia prevention"-requirements for nationwide implementation pneumonia in the developing world: characteristic features and approach to management multicenter comparison of lung and oral microbiomes of hiv-infected and hiv-uninfected individuals early chest ct-scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in countries: a systematic analysis for the global burden of disease study cardiac complications in patients with community-acquired pneumonia: a systematic review and meta-analysis of observational studies association between hospitalization for pneumonia and subsequent risk of cardiovascular disease adults miscoded and misdiagnosed as having pneumonia: results from the british thoracic society pneumonia audit new perspectives on community-acquired pneumonia in patients. results from a nationwide mandatory performance measurement programme in healthcare quality effectiveness of the -valent pneumococcal polysaccharide vaccine (ppv ) against pneumococcal disease in the elderly: systematic review and meta-analysis burden of pneumonia-associated hospitalizations: united states management of adults with hospital-acquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the association of diagnostic coding with trends in hospitalizations and mortality of patients with pneumonia attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies lung ultrasound in diagnosing pneumonia in the emergency department: a systematic review and meta-analysis patient reported outcome measures in the recovery of adults hospitalised with community-acquired pneumonia: a systematic review peto te, and infections in oxfordshire research database (iord) ( ) increasing burden of community-acquired pneumonia leading to hospitalisation corticosteroids in sepsis: an updated systematic review and meta-analysis mortality reduction among pneumonia patients still substantial despite the impact of coding changes host-response biomarkers for the diagnosis of bacterial respiratory tract infections procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections hiv- and bacterial pneumonia in the era of antiretroviral therapy diagnosis of pneumonia in the ed has poor accuracy despite diagnostic uncertainty alcohol and the risk of pneumonia: a systematic review and meta-analysis diagnosis of stroke-associated pneumonia: recommendations from the pneumonia in stroke consensus group corticosteroids for pneumonia the incidence and aetiology of hospitalised community-acquired pneumonia among vietnamese adults: a prospective surveillance in central vietnam international ers/esicm/escmid/alat guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (hap)/ventilator-associated pneumonia (vap) of the increasing hospital admission for pneumonia indirect (herd) protection, following pneumococcal conjugated vaccines introduction: a systematic review of the literature diagnosing pneumonia in patients with acute cough: clinical judgment compared to chest radiography long-term mortality after ipd and bacteremic versus non-bacteremic pneumococcal pneumonia advances in the causes and management of community acquired pneumonia in adults distribution of serotypes and patterns of antimicrobial resistance among commensal streptococcus pneumoniae in nine european countries key: cord- -ttae b authors: haddad, imad y.; cornfield, david n. title: pneumonia and empyema date: - - journal: the respiratory tract in pediatric critical illness and injury doi: . / - - - - _ sha: doc_id: cord_uid: ttae b nan pneumonia is defi ned as infection and infl ammation of the lower respiratory tract in association with parenchymal radiographic opacity. this defi nition excludes bronchiolitis, tracheitis, neonatal pneumonia, and noninfectious causes of pneumonia and pneumonitis, and these are not discussed in this chapter. in the pediatric intensive care unit (picu), several pneumonia types may be encountered. first, a previously healthy child may be admitted to the picu because of severe community-acquired pneumonia (cap). the pneumonia is usually caused by organisms that are prevalent in the out-of-hospital environment. second, patients with genetic or acquired immune defi ciency commonly develop severe pneumonia with opportunistic infections that usually do not infect healthy children. these immunocompromised patients commonly have been given chemo-radiotherapy for cancer or are receiving immune-suppressive agents to prevent rejection episodes following solid organ and hematopoietic stem cell transplantation. third, both previously healthy and immunocompromised patients may acquire nosocomial pneumonia during their hospital stay. mechanically ventilated patients are at especially high risk to develop nosocomial ventilator-associated pneumonia (vap). finally, aspiration pneumonia caused by chronic inoculation of the lower respiratory tract with large amounts of less virulent bacteria in a susceptible host prone to aspiration is also observed in the picu. this classifi cation of pneumonia types in the picu is important because it has major implications on the causative microbial agent and, thus, the choice of initial empiric treatment that may be life saving. this chapter reviews respiratory host defenses that maintain sterility of the lower respiratory tract. in addition, the pathogenesis, classifi cation, and treatment options for pneumonia and empyema in the picu patient are briefl y discussed. potent expiratory maneuver is of fundamental importance in preventing material from being aspirated into the lungs. the conducting airways also contain several antimicrobial substances, including immunoglobulins (igg and secretory iga), and complement that bind and enhance the elimination of microbial agents. in addition, airway epithelial and alveolar type (at) ii cells secrete several antimicrobial peptides. one of the best characterized families of antimicrobial peptides are the defensins, which are cysteine-rich peptides possessing broad antimicrobial activity [ ] . an important recent discovery is the expanding role of respiratory airway epithelium in innate immune defenses by mechanisms that mimic those noted in phagocytic cells. respiratory epithelial cells, including atii cells, express tlr and are capable of expressing a variety of cytokines that amplify infl ammation. the importance of innate immunity in epithelial cells was confi rmed in mice with specifi c inhibition of nuclear factor (nf) κb activation that was restricted to distal airway epithelial cells. mice lacking the ability to activate nfκb in epithelial cells exhibited impaired infl ammatory response to inhaled lps [ ] . these data provide evidence that distal airway epithelial cells and the signals they transduce play a key physiologic role in lung infl ammation in vivo. alveolar type ii cells also secrete surfactant proteins (sp)-a and d. both sp-a and sp-d are collagen-like lectins (collectins) that agglutinate and/or opsonize pathogens and enhance their phagocytosis by innate immune cells such as alveolar macrophages and neutrophils [ ] . surfactant proteins a and d may have additional immunoregulatory functions [ ] and also may exhibit direct bactericidal effects by inducing damage to the bacterial cell membrane [ ] . the functions of sp-a and sp-d in host defense are listed in table . . in the distal airspaces, alveolar macrophages are the fi rst phagocytic cell type encountered by pathogens entering the lung. macrophages have the capacity to induce the generation of large amounts of cytokines, chemokines, matrix metalloproteinases (mmp), nitric oxide, and potent oxidants that participate in antimicrobial defenses. in contrast, interstitial macrophages are located in the lung connective tissue and serve as both phagocytic cells and antigen-processing cells. tumor necrosis factor (tnf)-α, a macrophage-derived multifunctional cytokine, is expressed early in both patients with and animal models of pneumonia [ ] . microbes also induce macrophages to generate potent chemokines that attract circulating neutrophils and monocytes into the lungs. cytokines/ chemokines amplify infl ammatory responses and orchestrate the polarization and transition of innate to adaptive immunity that function to eliminate invading microorganisms [ ] . figure . summarizes the cellular and secretory peptides that are components of host defense against microbes in the lower respiratory tract. disorders associated with impaired mechanical, innate, and adaptive host responses that may lead to the development of pneumonia in a susceptible host are listed in table . . the upper respiratory tract is normally colonized with nonpathogenic bacterial fl ora, but physical and immunologic host defenses generally ensure that bacteria that gain access to the lower respiratory tract are cleared. pneumonia occurs because of an impairment of host defenses (as discussed earlier), invasion by a virulent organism, or invasion by an overwhelming inoculum of less virulent organisms. there are fi ve main modes of pathogen entry into the lower respiratory tract. inhalation of infectious particles is probably the most important pathogenic mechanism in the development of cap, with particular importance in pneumonia of those caused by legionella species and mycobacterium tuberculosis. contact with contaminated fomites also may be important in the acquisition of viral agents, especially respiratory syncytial virus. the viral agents that cause pneumonia proliferate and spread by contiguity to involve lower and more distal portions of the respiratory tract. inhalation is also a common cause of pneumonia caused by contaminated ventilator tubes. endosome tlr tlr / trl tlr tlr tlr tlr tlr cd figure . . toll-like receptors (tlr) and their ligands. lps, lipopolysaccharide; hsps, heat shock proteins. in addition to inhalation, pneumonia arises following the aspiration of microorganisms from the oral cavity or nasopharynx. invasive disease most commonly occurs upon acquisition of a new serotype of the organism with which the patient has not had previous experience. most episodes of vap are thought to develop from the aspiration of oropharyngeal secretions containing potentially pathogenic organisms. aspiration of gastric secretions may also contribute, although likely to a lesser degree. tracheal intubation interrupts the body's anatomic and physiologic defenses against aspiration, making mechanical ventilation a major risk factor for vap. the term aspiration pneumonia should be reserved for pneumonia or pneumonitis resulting from the aspiration of large amounts of gastric or oropharyngeal contents that may contain a large inoculum of relatively nonvirulent bacteria. the pathogens that commonly produce cap or vap, such as streptococcus pneumoniae, gram-negative bacilli, and staphylococcus aureus, are relatively virulent bacteria so that only a small inoculum is required and the aspiration is usually subtle. in immunocompromised individuals, an additional mode of pneumonia acquisition is bacteremia and sepsis. hematogenous deposition of bacteria is responsible for some cases of pneumonia caused by staph. aureus, pseudomonas aeruginosa, and escherichia coli. reactivation of pathogens can take place in the setting of defi cits of cell-mediated immunity. pathogens such as pneumocystis carinii/jiroveci, m. tuberculosis, and cytomegalovirus (cmv) may remain latent for many years after exposure, with fl ares of active disease in the face of immune compromise. reactivation tuberculosis occasionally occurs in immunocompetent hosts. direct inoculation rarely occurs as a result of surgery or bronchoscopy but may play a role in the development of pneumonia in patients supported with mechanical ventilation. the direct extension of infection to the lung from contiguous areas such as the pleural or subdiaphragmatic spaces is rare. community-acquired pneumonia community-acquired pneumonia refers to pneumonia in a previously healthy person who acquired the infection outside a hospital. it is one of the most common serious infections in children, with an incidence of to cases per , children in the industrialized world [ ] . a subset of these patients will require picu admission. admission to the intensive care unit should be considered for patients with persistent hypoxemia despite oxygen therapy, recurrent apnea, signs of respiratory fatigue with or without mental status changes, or evidence of compensated or decompensated shock. infants less than months of age and children with comorbid conditions such as bronchopulmonary dysplasia, cystic fi brosis, neuromuscular disorders, congenital heart disease, and immunodefi ciency disorders have limited respiratory reserves and, therefore, are at increased risk for respiratory failure during a pneumonia episode. for the adult population, the american and british thoracic societies have developed guidelines for hospital and icu admissions for patients with severe cap [ ] . according to the american thoracic society guidelines, admission to the icu is needed for patients with severe cap, defi ned as the presence of either one of two major criteria, or the presence of two of three minor criteria. the major criteria include need for mechanical ventilation and septic shock; the minor criteria include systolic blood pressure ≤ mm hg, multilobar disease, and a pao /fio ratio < . in addition, a pneumonia severity index (psi) score identifi es adults at increased risk of medical complications and death [ ] . however, similar guidelines or scores to grade the severity of pneumonia in children have not been developed. children admitted to the picu because of cap are more commonly infected with bacterial than viral pathogens. streptococcus pneumoniae is the most commonly identifi ed bacterial cause of cap in infants and children older than month. pneumonias caused by group a streptococcus and staph. aureus are less frequent. haemophilus infl uenzae pneumonia has become uncommon following the widespread use of haemophilus infl uenza type b immunization. viruses are identifi ed most often in children < years of age. respiratory syncytial virus is the most common viral etiology during infancy, with adenovirus, infl uenza virus, parainfl uenza virus, and the recently described human metapneumonovirus ( ) also not infrequently detected. mycoplasma pneumoniae and chlamydia pneumoniae are more common in older children and adolescents [ ] . in may an outbreak of an acute febrile illness associated with respiratory failure, shock, and high mortality was identifi ed by investigators from the centers for disease control and prevention (cdc) as being caused by a hantavirus. in the united states, % of the cases occurred west of the mississippi after environmental exposure to infected deer mouse saliva, urine, or feces. in addition, a novel coronavirus was identifi ed as the causative agent of severe acute respiratory syndrome (sars), a new respiratory illness that affects adults and children, although the severity of the disease is less in children than in adults [ ] . another cause of severe pneumonia that should be considered is tuberculosis. a history of contact with a person with pulmonary tuberculosis is usually elicited. finally, uncommon causes of cap in otherwise healthy children are fungal infections including coccidiodes immitis, histoplasma capsulatum, and blastomyces dermatitidis. these organisms should be included in the differential diagnosis as a cause of pneumonia only if there is a history of residence or travel to an area of endemic infection. occasionally, infection with strep. pneumoniae [ ] and mycoplasma pneumoniae [ ] can cause necrotic pneumonia secondary to an invasive organism or exaggerated host immune response. compared to patients with pneumonia and parapneumonic effusions, children who developed necrotizing pneumonia exhibited a more protracted hospital course associated with higher rates of complications, including bronchopleural fi stulas and need for thoracotomy for fi stula repair or lobectomy. none of the necrotizing pneumonia patients were immune defi cient [ ] . the diagnosis of cap is usually made based on the presence of respiratory symptoms (cough, retractions) in a febrile and tachypneic child. the presence of infi ltrates on chest radiographs confi rms the diagnosis of pneumonia. infi ltrates are generally either interstitial or alveolar. although alveolar infi ltrates are more commonly observed during bacterial pneumonia [ ] , in most studies, the pattern of infi ltrates has not been shown to correctly differentiate viral from bacterial pneumonia [ ] . chest radiographs will also detect the presence of pleural effusions, pneumatoceles which are observed during staphylococcal pneumonia, or presence of air-fl uid levels indicative of abscess formation. after initial stabilization, diagnostic testing should be performed rapidly, avoiding delays in the administration of initial empiric therapy. in addition to a chest radiograph, an admitted patient should have a complete blood count and differential and routine blood chemistry testing (including glucose, serum sodium, liver and renal function tests, and electrolytes). all admitted patients should have oxygen saturation assessed by pulse oximetry and supplemental oxygen administered as needed. arterial blood gas should be measured in any patient with severe illness to assess both the level oxygenation and the degree of carbon dioxide retention. for critically ill patients with pneumonia, an aggressive approach to determine the causative microbial agent is warranted. microbiologic confi rmation is ultimately obtained for approximately %- % of children with cap [ ]. if a pleural effusion is present, aspiration of pleural fl uid for gram stain and culture prior to starting antibiotics is valuable. blood culture may reveal organisms in up to % of patients with bacterial pneumonia [ ] . sputum collection is usually not practical for infants and children, and bacterial organisms recovered from the nasopharynx do not accurately predict the etiology of pneumonia. however, recovery of viruses and other atypical pathogens from the nasopharynx is more predictive. bacterial organisms recovered from tracheal secretions obtained through an endotracheal tube may or may not refl ect the causative agent(s) responsible for lower respiratory tract infection. specimens are considered appropriate for examination if they contain ≤ epithelial cells and ≥ polymorphonuclear leukocytes under low power [ ] . the primary purpose of tracheal aspirate samples is to visualize a bacterial morphology of an organism that was not anticipated so that appropriate drugs can be added to the initial antibiotic regimen (e.g., staph. aureus or an enteric gram-negative antibiotic). bronchoalveolar lavage (bal) has been shown to be a rapid, relatively safe, and relatively noninvasive diagnostic procedure to obtain lower respiratory tract samples for microbial identifi cation and analysis. other techniques that can be used to identify pathogens include antigen detection of bacteria and viruses using immunofl uorescence, polymerase chain reaction, and serology such as cold agglutination test for m. pneumonia. the specifi city of the cold agglutination test for m. pneumonia is almost absolute, although the sensitivity is only about %. detection of mycoplasma igm by enzyme-linked immunoabsorbant assay (elisa) is a sensitive technique and should be considered for children [ ] . immunocompromised patients are those whose immune mechanisms are defi cient because of congenital immune defi ciency syndromes, acquired immunologic disorders, or exposure to cytotoxic chemotherapy and steroids. in addition, recipients of solid organ and hematopoietic stem cell transplantation (hsct) are frequently given life-long treatment with immunosuppressive agents designed to prevent graft rejection or graft-versus-host disease. patients who develop severe neutropenia (i.e., an absolute neutrophil count ≤ cells/ml) or lymphopenia for prolonged periods of time are at greatest risk to develop a variety of infectious complications, including life-threatening pneumonia. the lung is the predominant site of opportunistic infection in the immunocompromised patient [ ] . immunosuppressed patients are predisposed to develop infections by ubiquitous microorganisms that do not normally cause disease in healthy people. they are also more susceptible to the usual causes of pneumonia, which can affect anyone. the sequence in which different organisms appear in the immunosuppressed and post-transplant recipients is fairly characteristic. nosocomial bacterial infections remain the most common cause of pneumonia during the early posttransplant, neutropenic phase. staphylococcus aureus and gramnegative pathogens predominate. in addition, fungal infections with candida and aspergillus species are not uncommonly seen during a severe neutropenic phase. the second period, from to months after solid organ transplant, is the time when opportunistic infections more commonly associated with transplantation, including nocardia, p. carinii/jiroveci, and cmv are observed [ ] . during the third period, after months, patients are categorized into different risk groups depending on the level of function of their allograft and the degree of immunosuppression they have received. those who are on minimal immunosuppression therapy are subject mainly to the same pathogens as the rest of the community. those with allograft dysfunction and ongoing heavy immunosuppressive therapy remain subject to all of the opportunistic infections seen during the second period. lung transplant recipients who develop bronchiolitis obliterans and hsct recipients who develop graft-versus-host disease remain especially at risk for infections [ ] . pulmonary infi ltrates in the immunocompromised host may be caused by a variety of organisms, and may have noninfectious causes. because progression to respiratory failure may be rapid, an aggressive approach to diagnosis and treatment is necessary to limit morbidity and mortality. initial broad-spectrum therapy is important, with alterations of the empiric regimen once the clinical situation has stabilized and more diagnostic information has been obtained. in the immunocompromised host, bal procedure should be performed promptly to rule out infectious etiologies. lists suggested bal fl uids analysis studies and cultures. bronchoalveolar lavage is very helpful in the diagnosis of p. carinii/jiroveci, cmv, tuberculosis, and some fungal infections. however, the ability of bal fl uids analysis and culture to detect invasive aspergillosis, one of the most lethal infectious complication after transplantation, is limited [ ] . the diagnostic yield for aspergillus species infection has been enhanced by the recently developed elisa that detects galactomannan, a fungal cell wall component released during invasive disease [ ] . histopathologic analysis and culture of open lung biopsy specimens may provide accurate determination for the cause of pulmonary infi ltrates in pediatric patients [ ] . however, open lung biopsy is associated with a signifi cant surgical risk in critically ill patients. open lung biopsy is most effective and least risky when performed early in the course of patients who develop nodular infi ltrates that require rapid differentiation between fungal infections and more benign lesions [ ] . chemoprophylaxis against opportunistic infections is an important component of management of the post-transplant immunosuppressed patients. before the widespread introduction of chemoprophylaxis, p. carinii pneumonia (pcp) was observed to be a common opportunistic infection among transplant recipients. with the administration of low-dose trimethoprim-sulfamethoxazole or an alternative prophylactic agent such as pentamidine, pcp can be effectively prevented [ ] . prophylaxis is also recommended for cmv in high-risk cmv seronegative recipients. such prophylaxis includes intravenous ganciclovir for days, followed by oral ganciclovir capsules for three months [ ] . aspiration pneumonia refers to the pulmonary consequences resulting from the abnormal entry of fl uid, formula, or endogenous secretions into the lower airways. there is usually compromise in host defenses that protect the lower airways, including glottic closure, cough refl ex, and other clearing mechanisms. histories of seizure, anesthesia, or other episode of reduced level of consciousness, neurologic disease, dysphagia, or gastroesophageal refl ux are all risk factors for aspiration. the risk of aspiration is especially high after removal of an endotracheal tube because of the residual effects of sedative drugs, the presence of a nasogastric tube, and swallowing dysfunction related to alterations of upper-airway sensitivity, glottic injury, and laryngeal muscular dysfunction [ ] . aspiration pneumonia may be classifi ed into three clinical syndromes: chemical pneumonitis, bacterial infection, and airway obstruction. in animal models, development of chemical pneumonitis requires a to ml/kg inoculum of fl uid with a ph of . to initiate an infl ammatory reaction that may lead to pulmonary fi brosis [ ] . bacteria, present in the aspirated oropharyngeal and gastric secretions, may also lead to pneumonia. aspiration pneumonia may involve particulate matter or foreign body, which, in addition to causing airway obstruction or refl ux airway closure, may synergistically contribute to acid-induced lung injury [ ] . true aspiration pneumonia, by convention, usually refers to an infection caused by less virulent bacteria, primarily anaerobes, which are common constituents of the normal fl ora in a susceptible host prone to aspiration. pneumonia is commonly caused by oropharyngeal fl ora, including anaerobic gram-negative bacilli (bacteroides fragilis, fusobacterium nucleatum, peptostreptococcus, and prevotella) and anaerobic gram-positive bacilli (clostridium, eubacterium, actinomyces, lactobacillus, and propionibacterium). aspiration usually occurs when the patient is supine during or immediately after feeding. in the supine position the right upper lobe is the most dependent part of the lung and is most frequently affected. commonly, impaired airway protective responses are observed. the presence of tracheoesophageal malformations should be investigated if recurrent aspiration is noted in an otherwise healthy infant. the clinical presentation and course of chemical pneumonitis after inhalation of gastric contents ranges from mild and selflimited to severe and life threatening, depending on the nature of the aspirate and the underlying condition of the host. in the absence of witnessed inhalation of vomit, diagnosis is diffi cult and requires a high index of suspicion in a patient who has risk factors for aspiration. in the absence of an obvious predisposition, the abrupt onset of a self-limited illness characterized by dyspnea, cyanosis, and low-grade fever associated with diffuse rales, hypoxemia, and alveolar infi ltrates in dependent lobes should suggest aspiration [ ] . if bal is performed, assessment of lipid-laden macrophage index using oil-red-o stain is helpful in confi rming the diagnosis [ ] . the presence of foul-smelling putrid discharge in sputum or pleural fl uid is regarded as diagnostic of anaerobic infection. patients often have prolonged fever and productive cough, frequently showing blood in the sputum, which indicates necrosis (tissue death) in the lung. if aspiration is persistent, fi brosis and bronchiectasis may result. a number of interventions (e.g., positioning, dietary changes, drugs, oral hygiene, tube feeding) have been proposed to prevent aspiration patients with an observed aspiration should have immediate tracheal suction or bronchoscopy to clear fl uids and particulate matter that may cause obstruction. the use of corticosteroids in the treatment of chemical pneumonitis is controversial [ ] , and antibiotics should not be used early in the course unless a superimposed bacterial infection is suspected. the national nosocomial infection surveillance (nnis) program sponsored by the cdc defi nes vap as pneumonia in patients who have been on mechanical ventilation for > hr and have developed new and persistent radiographic evidence of focal infi ltrates. in addition, patients had to have two of the following: temperature > ′c, leukocytosis (white blood cell > , /mm ), and purulent sputum (> white blood cells/high-powered fi eld on tracheal aspirate gram stain). after blood stream infections, vap is the second most common cause of nosocomial infections in picus. the mean vap rate in children ranges from to / , ventilator days, accounting for %- % of hospital-acquired infections [ , ] . infections acquired in the picu are associated with a signifi cantly increased risk of death [ ] . nosocomial pneumonia and vap are typically categorized as either early onset (occurring in the fi rst - days of mechanical ventilation) or late onset. this distinction is important microbiologically. early-onset nosocomial pneumonia and vap are commonly caused by antibiotic-sensitive, community-acquired organisms (e.g., strep. pneumoniae, and staph. aureus). late-onset nosocomial pneumonia and vap are commonly caused by anti-biotic-resistant nosocomial organisms (e.g., p. aeruginosa, methicillin-resistant staph. aureus, acinetobacter species, and enterobacter species). during the winter respiratory viral season, all patients in a medical care environment are at risk for disease due to respiratory syncytial virus, parainfl uenza, and infl uenza viruses. legionnaire's disease is a multisystem illness with pneumonia caused by legionella species usually present in contaminated water. legionnaire's disease is less common in children than adults. compared with postmortem lung biopsies and culture results, the use of clinical criteria to diagnose vap (lung infi ltrates, leukocytosis, purulent secretions, fever) had a sensitivity of % and a specifi city of % [ ] . clearly, a number of noninfectious causes of fever and pulmonary infi ltrates can also occur in these patients, making the above clinical criteria nonspecifi c for the diagnosis of vap. lung infi ltrates may be caused by pulmonary hemorrhage, chemical aspiration, or atelectasis. fever may be caused by a drug reaction, extrapulmonary infection, or blood transfusion. autopsy results in a series of patients with acute lung injury demonstrated that clinical criteria alone led to an incorrect diagnosis of vap in % of clinically suspected cases [ ] . these limitations have encouraged the use of invasive approaches to sample and culture material from the lower respiratory tract for accurate diagnosis of vap. ventilator-associated pneumonia is most accurately diagnosed by quantitative culture and microscopic examination of lower respiratory tract secretions, which are best obtained by bronchoscopy and bal [ ] . cultures of tracheal aspirates are not very useful in establishing the cause of vap [ ] . although such cultures are highly sensitive, their specifi city is low even when they are cultured quantitatively [ ] . combining clinical and bacteriologic evaluation is probably the best way to achieve the objectives of correctly diagnosing vap and appropriately using antimicrobial agents. the main aims of this diagnostic approach are to rapidly identify patients with true lung bacterial infection, to select appropriate initial antimicrobial therapy, to adjust therapy based on antibiotic sensitivities, and to withhold antibiotics from patients without vap. guidelines for the prevention of vap in children are lacking, but data extrapolated from adult studies support routine elevation of head of bed °, appropriate use of sedatives and muscle relaxants, and adequate oral and circuit hygiene [ ] . empyema is the presence of purulent material containing polymorphonuclear leukocytes and fi brin in the pleural cavity. empyema is usually a complication of inadequately treated bacterial cap, although it may occur after trauma, thoracic surgery, or intrathoracic esophageal perforation. although parapneumonic pleural effusions are noted in up to &- % of children with pneumonia, empyema is rare, present in %- % of cases [ ] . the formation of an empyema can be divided into three stages: exudative, fi brinopurulent, and organizing. during the exudative stage, pus accumu-lates. this is followed by fi brin deposition and loculation of pleural fl uid known as the fi brinopurulent stage. the organizing stage is characterized by fi broblast proliferation; at this time there is the potential for lung entrapment by scarring [ ] . typically, the pleural fl uid in empyema is exudative, caused by protein leakage from the capillaries because of increased permeability and increased hydrostatic pressure during the infl ammatory process. although the distinction between transudates and exudates is sometimes diffi cult to make, several features favor an exudative process. if at least one of the following three criteria is present, the fl uid is virtually always an exudate: ( ) pleural fl uid protein > . g/dl or protein/serum protein ratio greater than . ; ( ) pleural fl uid lactate dehydrogenase (ldh)/serum ldh ratio greater than . ; and/or ( ) pleural fl uid ldh greater than two thirds the serum ldh [ , ] . the most common organisms that cause empyema in children are strep. pneumoniae, staph. aureus, and group a streptococci. haemophilus infl uenzae is rarely encountered since the advent of the h. infl uenzae b vaccine. mycoplasma pneumoniae and viruses can rarely result in exudative pleural effusions. in a series of pediatric patients with empyema, % were secondary to anaerobic infection [ ] . these data highlight the importance of anaerobic bacteria in selected cases of empyema in children and adolescents. in addition, tuberculosis should always be considered in the differential diagnosis, and a purifi ed protein derivative test should be performed. the differential diagnosis of patients with pleural effusions is shown in table . . the presence of fever associated with clinical signs of bacterial pneumonia is a clue to an underlying pneumonia as the cause of the effusion. a lateral decubitus radiograph, ultrasonography, or computed tomography may differentiate whether the fl uid is loculated. a sample of the fl uid should be obtained by thoracentesis in order to determine if the effusion is a transudate versus exudate. pleural cultures are positive in approximately one half of pediatric patients with empyema. blood culture and urine latex agglutination may help to identify a bacterial pathogen. a pneumatocele or pneumothorax seen on chest fi lm suggests staph. aureus as the cause of the empyema. until a specifi c organism is identifi ed, empiric antibiotic therapy should be instituted. this might include a third-generation cephalosporin and antistaphylococcal β-lactamase-resistant penicillin. antibiotics can be adjusted once an organism is identifi ed. antibiotic therapy should be intravenous until the patient becomes afebrile and then should be continued orally for an additional - weeks. there is major debate as to the proper adjuvant treatment of children with empyema. prospective, randomized and controlled studies of children with empyema are lacking. with the exception of starting appropriate or empiric antibiotics, there is no consensus on when and in whom to place a chest tube, instill fi brinolytic agents, or take to the operating room [ ] . in , light suggested that chest tubes should be inserted if the pleural fl uid is gross pus, if the gram stain of the pleural fl uid is positive, if the pleural fl uid glucose level is below mg/dl, or if the pleural fl uid ph level is less than . [ ] . if drainage with a chest tube is unsatisfactory, either urokinase or tissue plasminogen activator (tpa) should be injected intrapleurally [ , ] . if drainage is still unsatisfactory, a decortication should be considered [ ] . a stage-related approach to the management of empyema is perhaps most effi cacious and cost-effective [ ] . in the exudative stage, conservative treatment using tube drainage may suffi ce. fibrinolytic treatment may be useful during the fi brinopurulent stage. in contrast, aggressive treatment using surgical decortication may be necessary during the organizing stage. with the advent of video-assisted thoracoscopy (vats), these traditional approaches to management of empyema in children are being challenged. video-assisted techniques offer distinct advantages in the accurate staging of the disease process, effectiveness of management of organizing pleural disease, and post-operative patient comfort [ ] . in a retrospective study, the performance of early vats (< hr after admission) in children with empyema was associated with signifi cantly decreased length of hospital stay compared with performance of late vats (> hr after admission) [ ] . children treated for empyema generally recover and have no residual sequelae. radiographs at the time of discharge usually show pleural thickening that later resolves. follow-up pulmonary function tests and physical examination are also usually normal or consistent with mild restrictive disease [ ] . most epidemiologic investigations have clearly demonstrated that the indiscriminate administration of antibiotic agents to patients in the picu has contributed to the emergence of multiresistant pathogens with potentially increased morbidity and mortality. the prevalence of penicillin-resistant strains of strep. pneumoniae, methicillin-resistant staph. aureus, vancomycin-resistant enterococcus, and gram-negative bacteria producing extended-spectrum β-lactamase is increasing. despite these concerns, it is clear that patient survival may improve if pneumonia is correctly and rapidly treated. in adults, inappropriate initial antibiotic therapy is strongly associated with fatality [ ] . therefore, it may be concluded that empiric antibiotics for the treatment of severe pneumonia are indicated. the choice of antibiotics is based on several factors, including the age of the patient, the type of pneumonia, and the local resistant patterns of predominant bacterial pathogens. suggested choices for initial empiric antibiotic coverage for pneumonia in the picu are listed in table . . aspiration pneumonia occurring in the community can be treated with ampicillin-sulbactam. empiric treatment for pneumonia in immunocompromised hosts requires broad-spectrum gram-positive and gram-negative coverage. immunocompromised patients are especially susceptible to a variety of life-threatening opportunistic viral and fungal pneumonias that require prompt diagnosis and aggressive treatment. for example, trimethoprim-sulfamethoxazole or pentamidine should be given for p. carinii/jiroveci, amphotericin b or caspofungin for candida and aspergillus species, acyclovir for herpes, amantadine for infl uenza, ganciclovir or foscarnet for cmv, and ribavirin for severe respiratory syncytial virus. empiric regimens may need to be modifi ed once results of cultures and antibiotic susceptibility testing are available. the infl ammatory response to infection is necessary for host defense but can contribute to the systemic toxicity and lung injury that may result from pneumonia. in some settings, adjunctive treatment of lower respiratory infections with antiinfl ammatory agents can reduce morbidity. corticosteroids have a well-documented role in the management of p. carinii/jiroveci pneumonia. in a multicenter trial, infusion of hydrocortisone signifi cantly decreased length of hospital stay and prevented mortality in adult patients with cap [ ] . corticosteroids also may be effective under some circumstances in the treatment of infl ammatory sequelae of respiratory tract infection, such as tuberculous pleurisy and bronchiolitis obliterans organizing pneumonia (boop). strategies targeting specifi c cytokines have not been effective to date but remain active areas of investigation. enhanced understanding of the interactions of pathogen components with tlrs may be helpful one day in controlling and containing infectious diseases. immunization has reduced the incidence of several serious childhood diseases. immunization against infl uenza and increasingly resistant pneumococci can play a critical role in the prevention of pneumonia, particularly in immunocompromised patients. pleiotropic function of toll-like receptors myeloid differentiation factor is essential for pulmonary host defense against pseudomonas aeruginosa but not staphylococcus aureus toll-like receptors: linking innate and adaptive immunity epithelial antibiotics induced at sites of infl ammation respiratory epithelial cells regulate lung infl ammation in response to inhaled endotoxin host defense functions of pulmonary surfactant human surfactant protein a suppresses t cell-dependent infl ammation and attenuates the manifestations of idiopathic pneumonia syndrome in mice interactions of pulmonary collectins with bordetella bronchiseptica and bordetella pertussis lipopolysaccharide elucidate the structural basis of their antimicrobial activities role of tnf-alpha in pulmonary host defense in murine invasive aspergillosis host innate defenses in the lung: the role of cytokines community-acquired pneumonia in children guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy a prediction rule to identify lowrisk patients with community-acquired pneumonia human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children clinical presentations and outcome of severe acute respiratory syndrome in children clinical manifestations and molecular epidemiology of necrotizing pneumonia and empyema caused by streptococcus pneumoniae in children in taiwan necrotizing pneumonitis caused by mycoplasma pneumoniae in pediatric patients: report of fi ve cases and review of literature necrotizing pneumonia in children comparison of radiological fi ndings and microbial aetiology of childhood pneumonia etiology of childhood pneumonia: serologic results of a prospective, population-based study acute pneumonia microscopic and bacteriologic analysis of expectorated sputum sensitivity and specifi city of fi ve different mycoplasma detection assays infection in organ-transplant recipients pulmonary complications of solid organ and hematopoietic stem cell transplantation diagnostic aspects of invasive aspergillus infections in allogeneic bmt recipients evaluation of serum sandwich enzymelinked immunosorbent assay for circulating galactomannan during caspofungin therapy: results from the caspofungin invasive aspergillosis study open lung biopsy in pediatric bone marrow transplant patients pulmonary nodular lesions in bone marrow transplant recipients: impact of histologic diagnosis on patient management and prognosis should prophylaxis for pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? oral ganciclovir in pediatric transplant recipients: a pharmacokinetic study swallowing dysfunction in patients receiving prolonged mechanical ventilation pathogenesis of gastric particulate lung injury: a comparison and interaction with acidic pneumonitis aspiration pneumonia the lipid-laden alveolar macrophage as a marker of aspiration in parenchymal lung disease effects of corticosteroids in the treatment of patients with gastric aspiration guidelines for preventing health-care-associated pneumonia, : recommendations of cdc and the healthcare infection control practices advisory committee nosocomial infections in pediatric intensive care units in the united states. national nosocomial infections surveillance system prevalence of nosocomial infections in pediatric intensive care unit patients at us children's hospitals fourth decennial international conference on nosocomial and healthcare-associated infections clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies diagnosis of nosocomial bacterial pneumonia in acute, diffuse lung injury management of bacterial pneumonia in ventilated patients. protected bronchoalveolar lavage as a diagnostic tool diagnosis and differential diagnosis of ventilatorassociated pneumonia diagnostic effi ciency of endotracheal aspirates with quantitative bacterial cultures in intubated patients with suspected pneumonia. comparison with the protected specimen brush the prevention of ventilator-associated pneumonia pleural empyema pathophysiology of pleural space infections pleural effusions: the diagnostic separation of transudates and exudates diagnostic value of tests that discriminate between exudative and transudative pleural effusions microbiology of empyema in children and adolescents thoracic empyema in children: early surgical intervention hastens recovery pleural diseases medical management of parapneumonic pleural disease tissue plasminogen activator as an adjuvant therapy for pleural empyema in pediatric patients management of postpneumonic empyemas in children rational treatment of empyema in children favorable outcome of parapneumonic empyema in children managed by primary video-assisted thoracoscopic debridement the changing face of pleural empyemas in children: epidemiology and management empyema in children: clinical course and long-term follow-up clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study key: cord- -f khcjdy authors: lópez, alfonso; martinson, shannon a. title: respiratory system, mediastinum, and pleurae date: - - journal: pathologic basis of veterinary disease doi: . /b - - - - . - sha: doc_id: cord_uid: f khcjdy nan diseases of the respiratory system (respiratory apparatus) are some of the leading causes of morbidity and mortality in animals and a major source of economic losses. thus veterinarians are routinely called to diagnose, treat, and implement health management practices to reduce the impact of these diseases. in companion animals, diseases of the respiratory tract are also common and, although of little economic significance, are important to the health of the animals and thus to clinicians and pet owners. in the past few years, animal shelters have been recognized as a major risk factor for respiratory diseases in dogs and cats, a comparable situation to what is reported in human beings with nosocomial infections. to facilitate the understanding of the structure and function, it is convenient to arbitrarily divide the respiratory system into conducting, transitional, and gas exchange systems ( fig. - ). the conducting system includes nostrils, nasal cavity, paranasal sinuses, nasopharynx, larynx, trachea, and extrapulmonary and intrapulmonary bronchi, all of which are largely lined by pseudostratified, ciliated columnar cells, plus a variable proportion of secretory goblet (mucous) and serous cells (figs. - and - and e- fig. - ). the transitional system of the respiratory tract is composed of bronchioles, which are microscopic structures that serve as a transition zone between the conducting system (ciliated) and the gas exchange (alveolar) system (see fig. - ). the disappearance of cilia in the transitional system is not abrupt; the ciliated cells in the proximal bronchiolar region become scarce and progressively attenuated, until the point where distal bronchioles no longer have ciliated cells. normal bronchioles also lack goblet cells but instead have other types of secretory cells, notably club cells (formerly clara cells) and neuroendocrine cells. club cells, also referred to as secretory bronchiolar cells, contain numerous biosynthetic organelles that play an active role in detoxification of xenobiotics (foreign substances), similar to the role of hepatocytes ( fig. - ) . club cells are also critical stem cells in the repair and remodeling of not only the bronchioles but also of most of the respiratory tract. in addition, club cells contribute to the innate immunity of the lung by secreting protective proteins (collectins) and pulmonary surfactant (see b) . in carnivores and monkeys, and to a much lesser extent in horses and human beings, the terminal portions of bronchioles are lined not only by cuboidal epithelium but also by segments of alveolar capillaries. these unique bronchioloalveolar structures are known as respiratory bronchioles ; also see fig. - ). the gas exchange system of the respiratory tract in all mammals is formed by alveolar ducts and millions of alveoli ( fig. - ; also see fig. - ). the surface of the alveoli is lined by two distinct types of epithelial cells known as type i (membranous) pneumonocytes and type ii (granular) pneumonocytes ( fig. - ) . all three-the conducting, transitional, and exchange systems of the respiratory system-are vulnerable to injury because of constant exposure to a myriad of microbes, particles and fibers, and toxic gases and vapors present in the air. vulnerability of the respiratory system to aerogenous (airborne) injury is primarily because of ( ) the extensive area of the alveoli, which are the interface between the blood in alveolar capillaries and inspired air; ( ) the large volume of air passing continuously into the lungs; and ( ) the high concentration of noxious elements that can be present in the air (table - ). for human beings, it has been estimated that the surface of the pulmonary alveoli is approximately m , roughly the area animal and cultured for microbes, yeasts, and fungi, many species of bacteria are recovered, such as mannheimia (pasteurella) haemolytica in cattle; pasteurella multocida in cats, cattle, and pigs; and bordetella bronchiseptica in dogs and pigs. the organisms that constitute the normal flora of the respiratory tract are restricted to the most proximal (rostral) region of the conducting system (nasal cavity, pharynx, and larynx). the thoracic portions of the trachea, bronchi, and lungs are considered to be essentially sterile. the types of bacteria present in the nasal flora vary considerably among animal species and in different geographic regions of the world. some present in the nasal flora are pathogens that can cause important respiratory infections under some circumstances. for instance, mannheimia (pasteurella) haemolytica is part of the bovine nasal flora, yet this bacterium causes a devastating disease in cattle-pneumonic mannheimiosis (shipping fever). experimental studies have established that microorganisms from the nasal flora are continuously carried into the lungs via tracheal air. despite this constant bacterial bombardment from the nasal flora and from contaminated air, normal lungs remain sterile because of their remarkably effective defense mechanisms. the conducting portion of the respiratory system is lined by pseudostratified columnar ciliated epithelium (most of the nasal cavity, paranasal sinuses, part of the larynx, and all of the trachea and bronchi), olfactory epithelium (part of the nasal cavity, particularly ethmoidal conchae), and squamous epithelium (nasal vestibulum and parts of the larynx). the pattern of injury, inflammation, and host response (wound healing) are characteristic for each of these three types of epithelium independent of its anatomic location. pseudostratified ciliated epithelium, which lines most of the nasal cavity and nasopharynx, part of the larynx, and all of the trachea and bronchi, is exquisitely sensitive to injury. when these cells are irreversibly injured, whether caused by viral infection, trauma, or inhalation of toxic gases, the ciliated cells swell, typically lose their attachment to underlying basement membrane, and rapidly exfoliate ( fig. - ) . a transient and mild exudate of fluid, plasma proteins, and neutrophils covers the ulcer. in the absence of of a tennis court. the alveolar surface of the equine lung is estimated to be approximately m . it has also been estimated that the volume of air reaching the human lung every day is approximately l. lungs are also susceptible to blood-borne (hematogenous) microbes, toxins, and emboli. this fact is not surprising because the entire cardiac output of the right ventricle goes into the lungs, and approximately % of the total blood volume is within the pulmonary vasculature. the pulmonary capillary bed is the largest in the body, with a surface area of m in the adult human; this area is equivalent to a length of km of capillaries, with ml of blood occupying up to km of capillary bed. the respiratory system has its own normal flora (microbiota), as does any other body system in contact with the external environment. if a sterile swab is passed deep into the nasal cavity of any healthy (rhinoviruses), infectious bovine rhinotracheitis (bovine herpesvirus ), feline rhinotracheitis (felid herpesvirus ), and viruses of the canine infectious respiratory disease (cird) group such as canine adenovirus (cav- ) and canine parainfluenza virus (cpiv) . if damage to the mucociliary blanket becomes chronic, goblet cell hyperplasia takes place, leading to excessive mucus production (hypersecretion) and reduced mucociliary clearance, and when there is loss of basement membrane, repair is by fibrosis and granulation tissue (scarring). in the most severe cases, prolonged injury causes squamous metaplasia, which together with scarring causes airway obstruction and an impediment to mucociliary clearance. in laboratory rodents, hyperplastic and metaplastic changes, such as those seen in nasal polyps and squamous metaplasia, are considered a prelude to neoplasia. the second type of epithelium lining the conducting system is the sensory olfactory epithelium, present in parts of the nasal mucosa, notably in the ethmoidal conchae. the patterns of degeneration, exfoliation, and inflammation in the olfactory epithelium are similar to those of the ciliated epithelium, except that olfactory complications or secondary bacterial infections, a specific type of progenitor cells known as basal cells or nonciliated secretory cells (preciliated cells) , which are normally present in the mucosa, migrate to cover the denuded basement membrane and undergoes mitosis, eventually differentiating into new ciliated epithelial cells (see fig. - ). cellular migration, proliferation, and attachment are regulated by locally released interleukins (il- β, il- , il- , and il- ), growth factors, integrins and extracellular matrix (ecm) proteins such as collagen, and fibronectin. the capacity of ciliated epithelium to repair itself is remarkably effective. for example, epithelial healing in an uncomplicated ulcer of the tracheal mucosa can be completed in only days. this sequence of cell degeneration, exfoliation, ulceration, mitosis, and repair is typically present in many viral infections in which viruses replicate in nasal, tracheal, and bronchial epithelium, causing extensive mucosal ulceration. examples of transient infections of this type include human colds epithelium. neurons in the olfactory mucosa have the unique ability to regenerate, a fact that is being explored as a potential source of new neurons in the treatment of spinal cord injury. squamous epithelium, located in the vestibular region of the nose (mucocutaneous junction), is the third type of epithelium present in the nasal passages. compared with ciliated and olfactory epithelia, nasal squamous epithelium is quite resistant to all forms of injury. the pharyngeal mucosa, composed of squamous epithelium, has similar patterns of necrosis and inflammation as the oral mucosa (see chapter ). the patterns of necrosis, inflammation, and repair in intrapulmonary bronchi are similar to those previously described for the nasal and tracheal epithelium. in brief, injury to ciliated bronchial epithelium may result in degeneration, detachment, and exfoliation of necrotic cells. under normal circumstances, cellular exfoliation is promptly followed by inflammation, mitosis, cell proliferation, cell differentiation, and finally by repair ( fig. - and see . depending on the type of exudate, bronchitis can be fibrinous, catarrhal, purulent, fibrinonecrotic (diphtheritic), and sometimes granulomatous. when epithelial injury becomes chronic, production of mucus is increased via goblet cell hyperplasia (chronic catarrhal inflammation). this form of chronic bronchitis is well illustrated in habitual smokers who continually need to cough out excessive mucus secretions (sputum). unfortunately, in some cases, excessive mucus cannot be effectively cleared from airways, which of the bronchial wall or cylindrical when destruction involves a large segment of a bronchus. grossly, bronchiectasis is manifested by prominent lumps in the lungs (bosselated appearance or having rounded eminences) resulting from distention of bronchi with exudate, which results in a concurrent obstructive atelectasis of surrounding parenchyma ( fig. - ). the cut surfaces of dilated bronchi are filled with purulent exudates; for this reason, bronchiectasis is often mistaken for pulmonary abscesses. careful inspection, usually requiring microscopic examination, confirms that exudate is contained and surrounded by remnants of a bronchial wall lined by squamous epithelium and not by a pyogenic membrane (connective tissue) as it is in the case of a pulmonary abscess. the squamous metaplasia further interferes with the normal function of the mucociliary escalator. the epithelial lining of the bronchiolar region (transitional zone) is exquisitely susceptible to injury, particularly to that caused by some respiratory viruses (bovine parainfluenza virus , bovine respiratory syncytial virus, adenovirus, or canine distemper virus), oxidant gases (nitrogen dioxide [no ], sulfur dioxide [so ], or ozone [o ]), and toxic substances ( -methylindole or paraquat). the precise explanation as to why bronchiolar epithelium is so prone to injury is still not clear, but it is presumably due in part to ( ) its high vulnerability to oxidants and free radicals; ( ) the presence of leads to chronic obstructive bronchitis and emphysema (see . chronic bronchial irritation causes squamous metaplasia of highly functional but vulnerable ciliated epithelium to nonfunctional, but more resistant, squamous epithelium. squamous metaplasia has a calamitous effect on pulmonary clearance because it causes a structural loss and functional breakdown of portions of the mucociliary escalator. hyperplasia of bronchial glands occurs frequently in chronic bronchitis, which translates to an increase of the reid index (bronchial-gland to bronchial-wall ratio) (e- fig. - ). this index is less than % in the healthy human lung and in the lungs of most domestic species, except for cats, which generally have an index higher than %. the term airway remodeling encompasses all the structural changes that accompany chronic bronchitis such as hypertrophy and hyperplasia of smooth muscle, submucosal glands, and goblet cells; fibrosis; and increased bronchial vascularity. bronchiectasis is one of the most devastating sequelae to chronic remodeling of the bronchi. it consists of a pathologic and permanent dilation of a bronchus with rupture of the bronchial wall as a result of obstruction or chronic inflammation. destruction of walls occurs in part when proteolytic enzymes and oxygen radicals released from phagocytic cells during chronic inflammation degrade and weaken the smooth muscle and cartilage (chondromalacia) that help to maintain normal bronchial diameter ( fig. - ). bronchiectasis may be saccular when destruction affects only a small localized portion . this same type of lesion is seen in viral or mechanical injury to the mucosa of the conducting system. two days after exposure, the basement membrane is lined by rapidly dividing preciliated cells, some of which exhibit mitotic activity (inset). ten days after injury, the nasal epithelium is completely repaired. h&e stain. b, schematic representation of the events of injury and repair in the respiratory mucosa of the conducting system. blue cell, ciliated mucosal epithelial cell; pink cell, goblet cell; red cell, neutrophil. (a from lópez a, prior m, yong s, et al: am j vet res : - , into well-organized, microscopic polyps inside the bronchiolar lumen. the external surface of the exudate eventually becomes covered by ciliated cells. this lesion is referred to as bronchiolitis obliterans, and the polyps may become so large as to cause airflow impairment ( fig. - and see fig. - ). in mild but persistent bronchiolar injury, goblet cells normally absent from bronchioles proliferate from basal cells, resulting in goblet cell metaplasia and causing a profound alteration in the physicochemical properties of bronchiolar secretions ( fig. - ). the normally serous bronchiolar fluid released by club (clara) cells becomes a tenacious material when mucus produced by goblet cells is added. as a result of increased viscoelasticity of the mucus, bronchiolar secretions cannot be removed effectively by ciliary action, leading to plugging and obstruction of distal airways. under such conditions, often grouped as chronic obstructive pulmonary disease, coughing is required to clear mucus from obstructed bronchioles. pulmonary emphysema and atelectasis are further sequelae to bronchiolar metaplasia and mucous hypersecretion blocking or partially blocking the lumens of these bronchioles. these two inflation abnormalities are characteristically present in chronic obstructive pulmonary disease (copd), which is called "recurrent airway obstruction (rao or "heaves") in horses (see recurrent airway obstruction, under disorders of horses). peribronchiolar club (clara) cells rich in mixed function oxidases, which locally generate toxic metabolites (see fig. - ); and ( ) the tendency for pulmonary alveolar macrophages and leukocytes to accumulate in this region of the lungs. depending on the types of injury and inflammatory response, bronchiolitis is classified as necrotizing, suppurative, catarrhal (mucous metaplasia), or granulomatous. once injury to bronchiolar ciliated cells becomes irreversible, the cells degenerate and exfoliate into the bronchiolar lumen, leaving a denuded basement membrane. repair in the bronchiolar region is similar to, but less effective than, that in the tracheal or nasal mucosa. under normal circumstances, recruited phagocytic cells remove exudate and cell debris from the lumina of affected bronchioles, thus preparing the basement membrane to be repopulated with new, undifferentiated cells originating from a rapidly dividing pool of club (clara) cells. after several days, these proliferating cells fully differentiate into normal bronchiolar cells. in severe acute injury, such as that caused by aspiration pneumonia or by highly pathogenic microorganisms, exudate attaches and cannot be removed from the basement membrane of bronchioles. the exudate becomes infiltrated by fibroblasts, which form small nodular masses of fibrovascular tissue that develop postviral bronchiolitis is associated with increased expression of tlrs and unusual susceptibility to inhaled endotoxin. hyperreactive animals typically have an increased number of mast cells, eosinophils, and t lymphocytes in the airway mucosa. clinically, airway hyperresponsiveness is characterized by an exaggerated bronchoconstriction after natural exposure to mild stimuli, such as cold air, or after animals are experimentally exposed to aerosols of histamine or methacholine. because of their extremely delicate structure, alveoli are quite vulnerable to injury once the local defense mechanisms have been overwhelmed. the alveolar wall is a thin membrane formed by a core of interstitium supporting an extensive network of alveolar capillaries. fibroblasts (septal cells), myofibroblasts, collagen, elastic fibers, and few interstitial macrophages and mast cells constitute the alveolar interstitium. the wall of the alveolar capillaries facing the airspace is remarkably thin and has three layers composed of vascular endothelium, basal lamina, and alveolar epithelium. these three layers of the alveolar capillaries constitute what is customarily referred to as the blood-air barrier (see fig. - ). the epithelial side of the alveolus is primarily lined by rather thin type i proliferation of lymphocytes (balt hyperplasia) is also a common microscopic lesion seen in chronic bronchiolitis. airway hyperresponsiveness, or hyperreactive airway disease, is another sequela of bronchiolar injury arising from gene-environment interactions. it develops in human beings and animals (experimentally) after a transient and often innocuous viral infection of the lower respiratory tract or from exposure to certain allergens. experimental work has shown that airway hyperreactivity in club (clara) cell edema. alveolar repair is possible as long as the basement membrane remains intact and lesions are not complicated by further injury or infection. within days, cuboidal type ii (granular) pneumonocytes, which are the precursor cells and more resistant to injury, undergo mitosis and provide a large pool of new undifferentiated cells . these new cells repave the denuded alveolar basement membrane and finally differentiate into type i pneumonocytes. when alveolar injury is diffuse, proliferation pneumonocytes, which are arranged as a very delicate continuous membrane extending along the alveolar surface (see fig. - ). type i pneumonocytes are particularly susceptible to noxious agents that reach the alveolar region either aerogenously or hematogenously. injury to type i pneumonocytes rapidly causes swelling and vacuolation of these cells . when cellular damage has become irreversible, type i cells detach, resulting in denudation of the basement membrane, increased alveolar permeability, and alveolar figure - hyperplasia of type ii pneumonocytes. a, acute alveolar injury, crude oil aspiration, cow. note proliferation of cuboidal epithelial cells (type ii pneumonocytes) (arrows) along the luminal surface of the alveolar wall. during alveolar repair, type ii pneumonocytes are the precursor cell for necrotic and lost type i pneumonocytes. h&e stain. b, chronic alveolar injury, interstitial pneumonia, horse. note entire alveolar membrane lined with cuboidal type ii pneumonocytes (arrowheads). the alveolar interstitium is expanded with inflammatory cells, and the alveolar lumens contain cell debris mixed with leukocytes. h&e stain. ( ( ). necrosis of these cells leads to transient alveolar edema (area that is pink) ( ), which is followed by hyperplasia of type ii pneumonocytes ( ), stem cells that differentiate ( ) into type i pneumonocytes as part of alveolar repair and healing ( ). (courtesy dr. a. lópez, atlantic veterinary college.) more information on postmortem examination of the lung can be found at www.expertconsult.com. information on this topic is available at www.expertconsult.com. information on this topic is available at www.expertconsult.com. microbes, toxins, and pneumotoxicants can gain access into the respiratory system by the following routes (table - ; also see table - ): aerogenous, hematogenous, direct extension, and by local production of free radicals and toxic metabolites. pathogens, such as bacteria, mycoplasmas, and viruses, along with toxic gases and foreign particles, including food, can gain access to the respiratory system via inspired air. this is the most common route in the transmission of most respiratory infections in domestic animals. some viruses, bacteria, parasites, and toxins can enter the respiratory system via the circulating blood. this portal of entry is commonly seen in septicemias, bacteremias, and with protozoa and viruses that target endothelial cells. also, circulating leukocytes may release infectious organisms such as retroviruses and listeria monocytogenes while traveling through the lungs. of type ii pneumonocytes becomes so spectacular that the microscopic appearance of the alveolus resembles that of a gland or fetal lung; this lesion has been termed epithelialization or fetalization. although it is part of the normal alveolar repair, hyperplasia of type ii pneumonocytes can interfere in gas exchange and cause hypoxemia. in uncomplicated cases, type ii pneumonocytes eventually differentiate into type i pneumonocytes, thus completing the last stage of alveolar repair (see fig. - ). in some forms of chronic interstitial lung injury, the surface of the alveolar basement membrane could become populated with migrating bronchiolar cells, a process known as alveolar bronchiolization or lambertosis. in severe cases, lambertosis, a metaplastic change, can be mistaken microscopically with alveolar adenomas. type i pneumonocytes are one of the three structural components of the blood-air barrier, so when these epithelial cells are damaged, there is an increase in alveolar capillary permeability and transient leakage of plasma fluid, proteins, and fibrin into the alveolar lumen (see fig. - ) . under normal circumstances, these fluids are rapidly cleared from the alveolus by alveolar and lymphatic absorption, and necrotic pneumonocytes (type i) and fibrin strands are phagocytosed and removed by pulmonary alveolar macrophages. when there is persistent and severe injury, fibroblasts and myofibroblasts may proliferate in the alveolar walls (alveolar interstitium), causing alveolar septal fibrosis, whereas in other forms of severe injury, fibroblasts and myofibroblasts actively migrate from the interstitium into the alveolar spaces, causing intraalveolar fibrosis. these two types of alveolar fibrosis are most commonly seen in toxic and allergic pulmonary diseases and have a devastating effect on lung function. endothelial cells are also major players in the normal and abnormal physiology of the alveolus (see . these cells trap and share circulating antigens with intravascular and interstitial macrophages. the junction between alveolar endothelial cells is not as tight as that of the type i pneumonocytes, allowing some movement of fluid and small-size molecular weight proteins into the alveolar interstitium. endothelial cells maintain an intimate cell contact with erythrocytes and leukocytes passing through the lung, since the lumen of alveolar capillaries is slightly smaller ( . µm) than the diameter of red and white blood cells. erythrocytes are easily deformable, so their transit time through the alveolar capillaries is shorter than that of leukocytes, which are less deformable cells. this longer transit time of leukocytes and their close cellular contact with alveolar endothelial cells have major impacts in lung inflammation and acute respiratory distress syndrome (ards). on a minute-to-minute basis, the pulmonary defense mechanisms deal effectively with noxious stimuli and mild tissue injury without the need for an inflammatory response. however, if normal defense mechanisms are ineffective or insufficient (overwhelmed), the inflammatory process is rapidly turned on as a second line of defense. postmortem examination of the respiratory tract should always be conducted in a thorough and systematic manner and include the conducting system (trachea, bronchi, and bronchioles), the lungs, and the thoracic cavity and pleura. detailed record keeping and photographic documentation are essential elements of a thorough examination. normal lungs typically have a homogeneous pink color and are slightly deflated from loss of negative intrathoracic pressure. the e-sections that follow describe a systematic approach to this process. .e chapter respiratory system, mediastinum, and pleurae the respiratory tract should always be examined in a systematic manner. to determine whether negative pressure is present in the thoracic cavity, the diaphragm is punctured through the abdominal cavity before the thoracic cavity has been opened. when the diaphragm is punctured in a fresh carcass, the loss of negative pressure in the thorax causes the diaphragmatic cupola to drop back caudally toward the abdominal cavity, and at the same time, there is an audible sound caused by the inrush of air into the thorax. lack of this movement may be an indication of advanced pneumothorax, pleural effusion, or the presence of uncollapsed lungs caused by pulmonary edema, pneumonia, fibrosis, or emphysema. in carcasses that have been dead for a long time, pulmonary air and gas produced by saprophytic bacteria leak into the pleural cavity, reducing the negative thoracic pressure and collapsing the lung. the rib cage must be removed by cutting along the costosternal joints and along the neck of the ribs (close to the costovertebral joints) in such a way that pleural adhesions and abnormal thoracic contents can be observed and grossly quantified (e.g., ml of clear, yellow fluid). the tongue, pharynx, esophagus, larynx, trachea, and thoracic viscera (lungs, heart, and thymus) should be removed as a unit (often called the pluck) and placed on the necropsy table. the pharynx and esophagus are opened starting at the pharynx by a single cut with scissors along the dorsal midline and are inspected for ulcers, foreign bodies, and neoplasms. the larynx and trachea must be examined by opening both along the dorsal midline from cranial to caudal ends and then extending the incision into the large bronchi of the caudal lung lobes. normal tracheobronchial mucosa has a smooth and glistening pearl-colored surface with empty lumina in airways. the presence of foamy fluid in airways indicates pulmonary edema. feed particles may suggest aspiration; however, careful examination of the mucosa is required because aspiration of ingesta from stomach or rumen into the lungs commonly takes place agonally or can be displaced into these areas when the carcass is moved. the lungs should be examined before incision. normal lungs typically have a homogeneous pink color (see fig. - ). external changes include the presence of rib imprints on the pleural surface when lungs fail to collapse. in addition, the lungs should be inspected for changes in color and texture and distribution of lesions. color changes can be various shades of red, indicating hypostatic congestion, hyperemia (acute pneumonia), and hemorrhage; dark blue collapsed lobules or areas are indicative of atelectasis; pale pink to white lungs indicate notable anemia, fibrosis, or emphysema; and uniformly or patchy yellow-brown lungs indicate chronic passive congestion and pulmonary fibrosis likely secondary to chronic heart failure. lungs from exsanguinated animals are generally paler than the normal pink color because of reduced blood in the pulmonary tissue. lungs with postmortem autolysis show green discoloration, a change that is also seen in other organs (e- fig. - ). a covering of yellowish material on the pleural surface indicates accumulation of fibrin. because it is impossible to describe the texture of normal lungs, experience in palpation is required to appreciate the actual texture of a normal lung. texture is determined by gently palpating the surface and parenchyma of the lungs. normal texture can change to firm, hard, elastic (rubbery), or crepitus (with a crackling sound or feeling). for a detailed description of lung texture, see the section on classification of pneumonias in domestic animals. palpation of the lungs, which should be gentle, also permits detection of nonvisible nodules or abscesses in the parenchyma. knowing the distribution of a lesion in the lungs also facilitates diagnosis because particular etiologic agents cause lesions with specific distribution. distribution of lesions is generally described as focal, multifocal, locally extensive, or diffuse. according to their topography, pulmo-nary lesions can also be classified as cranioventral, dorsocaudal, and so on. necropsy reports must also contain an estimate of the extent of the pulmonary lesions, preferably expressed as a percentage of the volume of the lungs affected. for instance, a report may read "cranioventral consolidation involving % of the lungs." if the lungs have focal lesions, a rough estimate of the number should also be included in the report. for instance, "numerous (approximately ), small ( to cm in diameter), hard nodules were randomly distributed in all lung lobes." two methods are used to examine the nasal structures. the first is making a midsagittal cut through the head and removing the nasal septum; the second is making several transverse sections of the nose at the level of the second premolar teeth. this latter method is preferred when examining pigs suspected of having atrophic rhinitis or animals suspected of having nasal neoplasms. microscopic examination of pulmonary tissue is routinely done in diagnostic laboratories. samples of normal and abnormal lungs, along with other appropriate tissue, should always be submitted in % buffered-neutral formalin for histopathologic evaluation. a minimum of four lung samples (left cranial, left caudal, right cranial, and right caudal) should be taken for histopathologic examination in animals with a history of respiratory signs. to improve fixation, a paper towel can be placed over the samples of lung floating in fixative. when detailed evaluation of the alveolar walls is required, lungs can be fixed by a gentle intratracheal injection of fixative; however, this technique displaces transudates and exudates and can artificially cause distention of the perivascular and peribronchial spaces. lung biopsy specimens are taken only sporadically because complications often outweigh the diagnostic value. however, the use of new techniques, such as endoscopic-directed biopsies, has notably reduced some of these complications. biopsies of the lungs are recommended in cases of chronic persistent pulmonary disease unresponsive to treatment or intrathoracic masses of undetermined origin. endoscopic-directed biopsies of the nasal and bronchial mucosa are routinely used in clinical practice and generally have a much better diagnostic value. two valuable diagnostic tools in human medicine, bronchoalveolar lavage (bal) and transtracheal wash (ttw), have in recent years become more widely used in veterinary clinical diagnosis of respiratory ailments, particularly in horses, dogs, and cats. the basis of bal and ttw is sampling the lung or trachea of a living animal by infusing sterile fluid into the trachea or deep lung (respectively) and retrieving it to determine the cellular and biochemical composition of this fluid. in other words, the composition of the fluid reflects what is present in the bronchioloalveolar spaces and trachea. these procedures are performed by inserting a tube directly through the larynx into the trachea or bronchus, or transtracheally by inserting a tube through a needle percutaneously into the cervical trachea. microscopic examination of properly collected, stored, and processed samples may reveal many erythrocytes and siderophages in pulmonary hemorrhage or left-sided heart failure; inclusion bodies or syncytial cells in viral pneumonias; increased number of leukocytes in pulmonary inflammation; abundant mucus in asthma or equine recurrent airway obstruction (rao); the presence of pulmonary pathogens, such as parasites, fungi, and bacteria; or tumor cells in cases of pulmonary neoplasia. in the healthy animal, % to % of the bal cells are pulmonary alveolar macrophages (see fig. - , a) . clearance, or a combination of both is the underlying pathogenetic mechanism in many pulmonary diseases ( fig. - ) . the anatomic configuration of the nasal cavity and bronchi plays a unique role in preventing or reducing the penetration of noxious material into the lungs, especially into the alveoli, which is the most vulnerable portion of the respiratory system. the narrow nasal meatuses and the coiled arrangement of the nasal conchae generate enormous turbulence of airflow, and as a result, physical forces are created that forcefully impact particles larger than µm onto the surface of the nasal mucosa ( fig. - ). although particles smaller than µm could escape trapping in the nasal cavity, these mediumsized particles meet a second barrier at the tracheal and bronchial in some instances, pathogenic organisms can also reach the pleura and lungs through penetrating injuries, such as gunshot wounds, migrating awns, or bites, or by direct extension from a ruptured esophagus or perforated diaphragm. the lungs, particularly the bronchioles and alveoli, are vulnerable to endogenous injury caused by the local generation of free radicals during inflammation or by toxic metabolites generated by club (clara) cells (see fig. - , b). inflammatory processes in the respiratory system, particularly those caused by infectious organisms, can spread to contiguous or distant tissues. for instance, rhinitis may spread into the sinuses causing rhinosinusitis. similarly, laryngeal inflammation may spread into the lungs when exudate in the larynx is aspirated. lung disease can have profound systemic effects when cytokines, produced locally during necrosis or inflammation, are released into circulation. as a result of the enormous vascular bed present in the lung, sepsis and septic shock often develop when proinflammatory molecules overwhelm the antiinflammatory response during the so-called "cytokine storm." it is axiomatic that a particle, microbe, or toxic gas must first gain entry to a vulnerable region of the respiratory system before it can induce an adaptive immune response or have a pathologic effect. the characteristics of size, shape, dispersal, and deposition of particles present in inspired air are studied in aerobiology. it is important to recognize the difference between deposition, clearance, and retention of inhaled particles. deposition is the process by which particles of various sizes and shapes are trapped within specific regions of the respiratory tract. clearance is the process by which deposited particles are destroyed, neutralized, or removed from the mucosal surfaces. the difference between what is deposited and what is cleared from the respiratory tract is referred to as retention. the main mechanisms involved in clearance are sneezing, coughing, mucociliary transport, and phagocytosis (table - ). abnormal retention of particles resulting from increased deposition, decreased same rate in all levels of a conducting system, a "bottleneck" effect would be created in major airways as the minor but more numerous airways enter the bronchi. for this reason, the mucociliary transport in proximal (rostral) airways is physiologically faster than that of the distal (caudal) ones. ciliary activity and mucus transport increase notably in response to stimuli such as in respiratory infections. the mucociliary blanket of the nasal cavity, trachea, and bronchi also plays an important role in preventing injury from toxic gases. if a soluble gas contacts the mucociliary blanket, it mixes with the mucus, thus reducing the concentration of gas reaching deep into the alveoli. in other words, mucus acts as a "scavenger system," whereby gases are solubilized and subsequently cleared from the respiratory tract via mucociliary transport. if ciliary transport is reduced (loss of cilia) or mucus production is excessive, coughing becomes an important mechanism for clearing the airways. in addition to the mechanical barrier and physical transport provided by the mucociliary escalator, other cells closely associated with ciliated epithelium contribute to the defense mechanism of the conducting and transitional systems. among the most notable are the microfold (m) cells, which are modified epithelial cells covering the bronchial-associated lymphoid tissue (balt), both of which are strategically situated at the corner of the bifurcation of bronchi and bronchioles, where inhaled particles often collide with the mucosa because of inertial forces. from here, inhaled particles and soluble antigens are phagocytosed and transported by macrophages, dendritic cells, and other professional antigen-presenting cells (apcs) into the balt, thus providing a unique opportunity for b and t lymphocytes to enter into close contact with inhaled pathogenic substances. pulmonary lymphocytes are not quiescent in the balt but are in continual traffic to other organs and contribute to both cellular (cytotoxic, helper, and suppressor t lymphocytes) and humoral immune responses. immunoglobulin a (iga), produced by mucosal plasma cells, and, to a lesser extent, immunoglobulin g (igg) and m (igm) play important roles in the local immunity of the conducting and transitional systems, especially with regard to preventing attachment of pathogens to the cilia. chronic airway diseases, especially those caused by infectious agents such as mycoplasmas or retroviruses, are often accompanied by severe hyperplasia of the balt. the mucociliary clearance terminates at the pharynx, where mucus, propelled caudally from the nasal cavity and cranially from the tracheobronchial tree, is eventually swallowed and thus eliminated from the conducting system of the respiratory tract. some respiratory pathogens, such as rhodococcus equi, can infect the intestines after having been removed and swallowed from the respiratory tract into the alimentary system. alveoli lack ciliated and mucus-producing cells; thus the defense mechanism against inhaled particles in the alveolar region cannot be provided by mucociliary clearance. instead, the main defense mechanisms of alveoli (exchange system) are phagocytosis provided by the pulmonary alveolar macrophages and antimicrobial molecules of the alveolar lining fluid ( fig. - ). pulmonary alveolar macrophages are highly phagocytic cells, which are not to be confused with pulmonary intravascular macrophages, and are derived largely from blood monocytes and, to a much lesser extent, from a slowly dividing population of interstitial macrophages. after a temporary adaptive stage within alveolar interstitium, blood monocytes reduce their glycolytic metabolism and increase their oxidative metabolism to function in an aerobic rather than an anaerobic environment. pulmonary alveolar macrophages contribute to the bifurcations. abrupt changes in the direction of air (inertia), which occurs at the branching of major airways, cause particles in the -to -µm size range to collide with the surface of bronchial mucosa (see fig. - ). because the velocity of inspired air at the level of the small bronchi and bronchioles has become rather slow, inertial and centrifugal forces no longer play a significant role in the trapping of inhaled particles. here, in the transitional (bronchiolar) and exchange (alveolar) regions, particles µm or smaller may come into contact with the mucosa by means of sedimentation because of gravitation or by diffusion as a result of brownian movement. infective aerosols containing bacteria and viruses are within the size range ( . to µm) that can gain access to the bronchiolar and alveolar regions. in addition to size, other factors, such as shape, length, electrical charge, and humidity, play an important role in mucosal deposition, retention, and pathogenicity of inhaled particles. for example, particles longer than µm may also reach the lower respiratory tract provided their mean aerodynamic diameter is less than µm. asbestos is a good example of a large but slender fiber that can bypass the filtrating mechanisms by traveling parallel to the airstream. once in the terminal bronchioles and alveoli, asbestos fibers cause asbestosis, a serious pulmonary disease in human beings. in summary, the anatomic features of the nasal cavity and airways provide an effective barrier, preventing the penetration of most large particles into the lungs. once larger particles are trapped in the mucosa of conducting airways and small particles are deposited on the surface of the nasal, tracheal, or bronchoalveolar mucosa, it is crucial that these exogenous materials be promptly removed to prevent or minimize injury to the respiratory system. for these purposes, the respiratory system is equipped with several defense mechanisms, all of which are provided by specialized cells operating in a remarkably well-coordinated manner. conducting system (nose, trachea, and bronchi) mucociliary clearance is the physical unidirectional movement and removal of deposited particles and gases dissolved in the mucus from the respiratory tract. mucociliary clearance, also referred to as the waste disposal system, is provided by the mucociliary blanket (mucociliary escalator) and is the main defense mechanism of the conducting system (nasal cavity, trachea, and bronchi) (see figs. - and - ). mucus acts primarily as a barrier and a vehicle, and it is a complex mixture of water, glycoproteins, immunoglobulins, lipids, and electrolytes. these substances are produced by goblet (mucous) cells, serous cells, submucosal glands, and fluid from transepithelial ion and water transport. once serous fluid and mucus are secreted onto the surface of the respiratory mucosa, a thin, double-layer film of mucus is formed on top of the cells. the outer layer of this film is in a viscous gel phase, whereas the inner layer, which is in a fluid or sol phase, is directly in contact with cilia (see fig. - and see e- fig. - ). the respiratory system of a healthy human produces approximately ml of mucus per day. each ciliated cell in the conducting system has approximately to motile and chemosensory cilia ( µm long), beating metachronously (forming a wave) at a ciliary beat frequency of approximately strokes per minute, and in a horse, for example, mucus moves longitudinally at a rate of up to mm per minute. rapid and powerful movement of cilia creates a series of waves that, in a continuous and synchronized manner, propel the mucus, exfoliated cells, and entrapped particles out of the respiratory tract to the pharynx. the mucus is finally swallowed or, when present in large amounts, is coughed up out of the conducting system. if mucus flow were to move at the activated alveolar macrophages. similarly, inhaled particles, such as dust, pollen, spores, carbon, or erythrocytes from intraalveolar hemorrhage, are all phagocytosed and eventually removed from alveoli by pulmonary alveolar macrophages. most alveolar macrophages leave the alveoli by migrating toward the bronchiolar (transitional) region until the mucociliary blanket is reached. once there, pulmonary macrophages are removed in the same way as any other particle: along the mucociliary flow to the pharynx and swallowed. in the cat, as many as million macrophages per hour move out from the alveoli into the conducting system and pharynx. destruction and removal of inhaled microbes and particles by alveolar macrophages is a well-orchestrated mechanism that engages many cells, receptors (i.e., toll-like receptors [tlrs]), and pulmonary secretions in the lung. the cell-to-cell interactions are complex and involve pulmonary alveolar macrophages, pneumonocytes, endothelial cells, lymphocytes, plasma cells, natural killer (nk) cells, and dendritic cells. antibodies are also important in the protection (acquired immune response) of the respiratory tract against inhaled pathogens. iga is the most abundant antibody in the nasal and tracheal secretions and prevents the attachment and absorption of antigens (immune exclusion). igg and, to a lesser extent, ige and igm promote the uptake and destruction of inhaled pathogens by phagocytic cells (immune elimination). igg is the most abundant antibody in the alveolar surface and acts primarily as an opsonizing antibody for alveolar macrophages and neutrophils. in addition to antibodies, there are several secretory molecules locally released into the alveoli that constitute the alveolar lining material and contribute to the pulmonary defense mechanisms. the most important of these antimicrobial products are transferrin, anionic peptides, and pulmonary surfactant (table - ). to facilitate phagocytosis and discriminate between "self" and "foreign" antigens, pulmonary alveolar macrophages are furnished with a wide variety of specific receptors on their cell surfaces. among the most important ones are fc receptors for antibodies; complement receptors (for c b, c a, and c a); tumor necrosis factor (tnf) receptor; and cd receptors, which facilitate phagocytosis and destruction of opsonized particles. toll-like receptors (tlrs) recognize microbial components, and apoptosis stimulating fragment (fas) receptors are involved in apoptosis and in the phagocytosis of apoptotic cells in the lung. "scavenger receptors," which are responsible for the recognition and uptake of foreign particulates, such as dust and fibers, are also present on pulmonary alveolar macrophages. lungs are also susceptible to hematogenously borne microbes, toxins, or emboli. the hepatic (kupffer cells) and splenic macrophages are the primary phagocytic cells responsible for removing circulating bacteria and other particles from the blood of dogs, some rodents, and human beings. in contrast, the cell responsible for the removal of circulating particles, bacteria, and endotoxin from the blood of ruminants, cats, pigs, and horses is mainly the pulmonary intravascular macrophage, a distinct population of phagocytes normally residing within the pulmonary capillaries (see fig. - ). in pigs, % of the pulmonary capillary surface is lined by pulmonary intravascular macrophages. in ruminants, % of intravenously injected tracer particles or bacteria are rapidly phagocytosed by these intravascular macrophages. studies have shown that an abnormally reduced number of kupffer cells in diseased liver results in a compensatory increase in pulmonary intravascular macrophages, even in animal species in which these phagocytic cells are normally absent from the lung. in some abnormal conditions, such as sepsis, pulmonary innate and adaptive immune response by rapidly attaching and phagocytosing bacteria and any other particles reaching the alveolar lumens. the number of free macrophages in the alveolar space is closely related to the number of inhaled particles reaching the lungs. this ability to increase, within hours, the number of available phagocytic cells is vital in protecting the distal lungs against foreign material, particularly when the inhaled particle load is high. unlike that of tissue macrophages, the life span of alveolar macrophages in the alveoli is notably short, only a few days, and thus they are continuously being replaced by newly migrated blood monocytes. alveolar phagocytosis plays a prominent role in the innate defense mechanism against inhaled bacteria without the need of an inflammatory reaction. bacteria reaching the alveoli are rapidly phagocytosed, and bactericidal enzymes present in lysosomes are discharged into the phagosome containing the bacteria (see b) . except for some facultative pathogens that are resistant to intracellular killing (e.g., mycobacterium tuberculosis, listeria monocytogenes, brucella abortus, rhodococcus equi, and some salmonella spp.), most bacteria reaching the lungs are rapidly destroyed by (ros) not only induce extensive pulmonary injury but also impair the defense and repair mechanisms in the lung. oxygen and free radical scavengers, such as catalase, superoxide dismutase, ubiquinone, and vitamins e and c, are largely responsible for protecting pulmonary cells against peroxidation. these scavengers are present in alveolar and bronchiolar epithelial cells and in the extracellular spaces of the pulmonary interstitium. in summary, the defense mechanisms are so effective in trapping, destroying, and removing bacteria that, under normal conditions, animals can be exposed to aerosols containing massive numbers of bacteria without any ill effects. if defense mechanisms are impaired, inhaled bacteria colonize and multiply in bronchi, bronchioles, and alveoli, and they produce infection, which can result in fatal pneumonia. similarly, when blood-borne pathogens, inhaled toxicants, or free radicals overwhelm the protective defense mechanisms, cells of the respiratory system are likely to be injured, often causing serious respiratory diseases. for many years, factors such as viral infections, toxic gases, stress, and pulmonary edema have been implicated in predisposing human beings and animals to secondary bacterial pneumonia. there are many pathways by which the defense mechanisms can be impaired; only those relevant to veterinary species are discussed. viral agents are notorious in predisposing human beings and animals to secondary bacterial pneumonias by what is known as viral-bacterial synergism. a good example of the synergistic effect of combined virus-bacterial infections is documented from epidemics of human beings with influenza virus in which the mortality rate has been significantly increased from secondary bacterial pneumonia. the most common viruses incriminated in predisposing animals to secondary bacterial pneumonia include influenza virus in pigs and horses; bovine herpesvirus (bohv- ), bovine parainfluenza virus (bpiv- ), and bovine respiratory syncytial virus (brsv) in cattle; canine distemper virus (cdv) in dogs; and felid herpesvirus (fehv- ) and feline calicivirus (fcv) in cats. the mechanism of the synergistic effect of viral-bacterial infections was previously believed to be the destruction of the mucociliary blanket and a concurrent reduction of mucociliary clearance, but in experimental studies, viral infections did not significantly reduce the physical removal of particles or bacteria out of the lungs. now, it is known that to days after a viral infection, the phagocytic function of pulmonary alveolar macrophages and, to a lesser extent, the mucociliary clearance are notably impaired (see fig. - ). other mechanisms by which viruses impair defense mechanisms are multiple and remain poorly understood (box - ). immunization against viral infections in many cases prevents or reduces the synergistic effect of viruses and thus the incidence of secondary bacterial pneumonia. certain gases also impair respiratory defense mechanisms, rendering animals more susceptible to secondary bacterial infections. for instance, hydrogen sulfide and ammonia, frequently encountered on farms, especially in buildings with poor ventilation, can impair pulmonary defense mechanisms and increase susceptibility to bacterial pneumonia. the effects of environmental pollutants on the defense mechanisms of human beings and animals living in crowded and polluted cities remain to be determined. excessive release of cytokines by pulmonary intravascular macrophages may result in acute lung injury. existing in an oxygen-rich environment and being the site of numerous metabolic reactions, the lungs also require an efficient defense mechanism against oxidant-induced cellular damage (oxidative stress). this form of damage is caused by inhaled oxidant gases (e.g., nitrogen dioxide, ozone, sulfur dioxide, or tobacco smoke), by xenobiotic toxic metabolites produced locally, by toxins reaching the lungs via the bloodstream (e.g., -methylindole and paraquat), or by free radicals (reactive oxygen species) released by phagocytic cells during inflammation. free radicals and reactive oxygen species anomalies localized congenital anomalies of the nasal cavity are rare in domestic animals and are often merely part of a more extensive craniofacial deformity (e.g., cyclops) or a component of generalized malformation (e.g., chondrodysplasia). congenital anomalies involving the nasal cavity and sinuses, such as choanal atresia (lack of communication between the nasal cavity and pharynx), some types of chondrodysplasia, and osteopetrosis, are incompatible with life. examples of nonfatal congenital anomalies include cystic nasal conchae, deviation of the nasal septum, cleft upper lip (harelip and cheiloschisis), hypoplastic turbinates, and cleft palate (palatoschisis) (see fig. - ). bronchoaspiration and aspiration pneumonia are common sequelae to cleft palate. nasal and paranasal sinus cysts are slowly growing and expansive lesions that mimic neoplasia and cause severe cranial deformation in horses. as in other organs or systems, it is extremely difficult to determine the actual cause (genetic vs. congenital) of anomalies based on pathologic evaluation. metabolic disturbances affecting the nasal cavity and sinuses are rare in domestic animals. immunodeficiency disorders, whether acquired or congenital, are often associated with increased susceptibility to viral, bacterial, and protozoal pneumonias. for example, human beings with acquired immunodeficiency syndrome (aids) are notably susceptible to pneumonia caused by proliferation of pneumocystis (carinii) jirovecii. a similar ubiquitous organism, which under normal circumstances is not pathogenic, is also found in the pneumonic lungs of immunosuppressed pigs, foals, dogs, and rodents. pigs infected with the porcine reproductive and respiratory syndrome (prrs) virus frequently develop pneumocystis carinii infection ( fig. - ) . arabian foals born with combined immunodeficiency disease easily succumb to infectious diseases, particularly adenoviral pneumonia. combined infections with two respiratory viruses, such as canine distemper virus (cdv) and canine adenovirus (cav- ), are sporadically reported in immunosuppressed puppies. also, large doses of chemotherapeutic agents, such as steroids and alkylating agents, cause immunosuppression in dogs, cats, and other animals, increasing susceptibility to secondary viral and bacterial infections. stress, uremia, endotoxemia, dehydration, starvation, hypoxia, acidosis, pulmonary edema, anesthesia, and ciliary dyskinesia are only some of the many conditions that have been implicated in impairing respiratory defense mechanisms and consequently predisposing animals to develop secondary bacterial pneumonia. the mechanisms by which each of these factors suppresses pulmonary defenses are diverse and sometimes not well understood. for example, hypoxia and pulmonary edema decrease phagocytic function of pulmonary alveolar macrophages and alter the production of surfactant (abnormal head tilt and abnormal gait), which in severe cases may lead to emaciation. based on the nature of exudate, rhinitis can be classified as serous, fibrinous, catarrhal, purulent, or granulomatous. these types of inflammatory reactions can progress from one to another in the course of the disease (i.e., serous to catarrhal to purulent), or in some instances exudates can be mixed, such as those seen in mucopurulent, fibrinohemorrhagic, or pyogranulomatous rhinitis. microscopic examination of impression smears or nasal biopsy, and bacterial or fungal cultures are generally required in establishing the cause of inflammation. common sequelae of rhinitis are hemorrhage, ulcers, and, in some cases, nasopharyngeal polyps (hyperplasia) arising from inflamed mucosa. rhinitis also can be classified according to the age of the lesions as acute, subacute, or chronic; to the severity of the insult as mild, moderate, or severe; and to the etiologic agent as viral, allergic, bacterial, mycotic, parasitic, traumatic, or toxic. serous rhinitis. serous rhinitis is the mildest form of inflammation and is characterized by hyperemia and increased production of a clear fluid locally manufactured by serous glands present in the nasal submucosa. serous rhinitis is of clinical interest only. it is caused by mild irritants or cold air, and it occurs during the early stages of viral infections, such as the common cold in human beings, upper respiratory tract infections in animals, or in mild allergic reactions. catarrhal rhinitis. catarrhal rhinitis is a slightly more severe process and has, in addition to serous secretions, a substantial increase in mucus production by hypersecretion of goblet cells and mucous glands. a mucous exudate is a thick, translucent, or slightly turbid viscous fluid, sometimes containing a few exfoliated cells, leukocytes, and cellular debris. in chronic cases, catarrhal rhinitis is characterized microscopically by notable hyperplasia of goblet cells. as the inflammation becomes more severe, the mucus is infiltrated with neutrophils, giving the exudate a cloudy appearance. this exudate is referred to as mucopurulent. purulent (suppurative) rhinitis. purulent (suppurative) rhinitis is characterized by a neutrophilic exudate, which occurs when the nasal mucosa suffers a more severe injury that generally is accompanied by mucosal necrosis and secondary bacterial infection. cytokines, leukotrienes, complement activation, and bacterial products cause exudation of leukocytes, especially neutrophils, which mix with nasal secretions, including mucus. grossly, the exudate in suppurative rhinitis is thick and opaque, but it can vary from white to green to brown, depending on the types of bacteria and type of leukocytes (neutrophils or eosinophils) present in the exudate . in severe cases, the nasal passages are completely blocked by the exudate. microscopically, neutrophils can be seen in the submucosa and mucosa and form plaques of exudate on the mucosal surface. neutrophils are commonly found marginated in vessels, in the lamina propria, and in between epithelial cells in their migration to the surface of the mucosa. fibrinous rhinitis. fibrinous rhinitis is a reaction that occurs when nasal injury causes a severe increase in vascular permeability, resulting in abundant exudation of plasma fibrinogen, which coagulates into fibrin. grossly, fibrin appears as a yellow, tan, or gray rubbery mat on nasal mucosa. fibrin accumulates on the surface and forms a distinct film of exudate sometimes referred to as pseudomembrane ( fig. - ). if this fibrinous exudate can be removed, leaving an intact underlying mucosa, it is termed a croupous or pseudodiphtheritic rhinitis. conversely, if the pseudomembrane is difficult to remove and leaves an ulcerated mucosa, it is referred to as diphtheritic or fibrinonecrotic rhinitis. the term diphtheritic was derived from human diphtheria, which causes a severe and destructive inflammatory process of the nasal, tonsillar, pharyngeal, and laryngeal mucosa. nasal amyloidosis. amyloidosis, the deposition of amyloid protein (fibrils with a β-pleated configuration) in various tissues, has been sporadically reported as a localized lesion in the nasal cavity of horses and human beings (see nasal amyloidosis, in disorders of horses). congestion and hyperemia. the nasal mucosa is well vascularized and is capable of rather dramatic variation in blood flow, whether passively as a result of interference with venous return (congestion) or actively because of vasodilation (hyperemia). congestion of the mucosal vessels is a nonspecific lesion commonly found at necropsy and presumably associated with the circulatory failure preceding death (e.g., heart failure, bloat in ruminants in which the increased intraabdominal pressure causes increased intrathoracic pressure impeding the venous return from the head and neck). hyperemia of the nasal mucosa is seen in early stages of inflammation, whether caused by irritation (e.g., ammonia and regurgitated feed), viral infections, secondary bacterial infections, toxemia, allergy, or trauma. hemorrhage. epistaxis is the clinical term used to denote blood flow from the nose (nosebleed) regardless of whether the blood originates from the nasal mucosa or from deep in the lungs, such as in horses with "exercise-induced pulmonary hemorrhage." unlike blood in the digestive tract, where the approximate anatomic location of the bleeding can be estimated by the color the blood imparts to fecal material, blood in the respiratory tract is always red. this fact is due to the rapid transport of blood out of the respiratory tract by the mucociliary blanket and during breathing. hemorrhages into the nasal cavity can be the result of local trauma, can originate from erosions of submucosal vessels by inflammation (e.g., guttural pouch mycosis), or can be caused by neoplasms. hemoptysis refers to the presence of blood in sputum or saliva (coughing or spitting blood) and is most commonly the result of pneumonia, lung abscesses, ulcerative bronchitis, pulmonary thromboembolisms or hemorrhage, and pulmonary neoplasia. inflammation of the nasal mucosa is called rhinitis, and inflammation of the sinuses is called sinusitis. these conditions usually occur together, although mild sinusitis can be undetected. clinically, rhinosinusitis is characterized by nasal discharge. rhinitis. the occurrence of infectious rhinitis presupposes an upset in the balance of the normal microbial flora of the nasal cavity. innocuous bacteria present normally protect the host through a process called competitive exclusion, whereby potential pathogens are kept at a harmless level. disruption of this protective mechanism can be caused by respiratory viruses, pathogenic bacteria, fungi, irritant gases, environmental changes, immunosuppression, local trauma, stress, or prolonged antibacterial therapy. inflammatory processes in the nasal cavity are not life-threatening and usually resolve completely. however, some adverse sequelae in cases of infectious rhinitis include bronchoaspiration of exudate leading to bronchopneumonia. chronic rhinitis often leads to destruction of the nasal conchae (turbinates), deviation of the septum, and, eventually, craniofacial deformation. also, nasal inflammation may extend into the sinuses causing sinusitis; into facial bones causing osteomyelitis; through the cribriform plate causing meningitis; into the eustachian tubes causing otitis media or guttural pouch empyema (eustachitis) in horses; and even into the inner ear causing otitis interna and vestibular syndrome the nasal septum has been removed to expose nasal conchae. the nasal mucosa is hyperemic and covered by yellow-white purulent exudate (arrows). inset, histological section showing submucosal congestion and edema and also large aggregates of neutrophils on the superficial mucosa (asterisk). h&e stain. (courtesy dr. a. lópez, atlantic veterinary college.) microscopically, the lesions include a perivascular edema with fibrin, a few neutrophils infiltrating the mucosa, and superficial plaques of exudate consisting of fibrin strands mixed with leukocytes and cellular debris covering a necrotic and ulcerated epithelium. fungal infections, such as aspergillosis, can cause a severe fibrinonecrotizing rhinitis. granulomatous rhinitis. granulomatous rhinitis is a reaction in the nasal mucosa and submucosa that is characterized by infiltration of numerous activated macrophages mixed with a few lymphocytes and plasma cells (figs. - and - ). in some cases, chronic inflammation leads to the formation of polypoid nodules that in severe cases are large enough to cause obstruction of the nasal passages ( fig. - ). granulomatous rhinitis is generally associated with chronic allergic inflammation or infection with specific organisms, such as fungi (see fig. - ), tuberculosis, systemic mycosis (see section on granulomatous pneumonia), and rhinosporidiosis ; also see fig. - ). in some cases, the cause of granulomatous rhinitis cannot be determined. sinusitis. sinusitis occurs sporadically in domestic animals and is frequently combined with rhinitis (rhinosinusitis), or it occurs as extend into the adjacent bone (osteomyelitis) or through the ethmoidal conchae into the meninges and brain (meningitis and encephalitis). nasal amyloidosis. amyloidosis, the deposition of amyloid protein (fibrils with a β-pleated configuration) in various tissues, has been sporadically reported as a localized lesion in the nasal cavity of horses. unlike amyloidoses in other organs of domestic animals where amyloid is generally of the reactive type (amyloid aa), equine nasal amyloidosis appears to be of the immunocytic type (amyloid al). affected horses with large amyloid masses have difficulty breathing because of nasal obstruction and may exhibit epistaxis and reduced athletic performance; on clinical examination, large, firm nodules resembling neoplasms (amyloidoma) can be observed in the alar folds, rostral nasal septum, and floor of nasal cavity. microscopic lesions are similar to those seen in other organs and consist of a deposition of hyaline amyloid material in nasal mucosa that is confirmed by a histochemical stain, such as congo red. progressive ethmoidal hematoma. progressive ethmoidal hematoma (peh) is important in older horses and is characterized clinically by chronic, progressive, often unilateral nasal bleeding. grossly or endoscopically, an ethmoidal hematoma appears as a single, soft, tumor-like, pedunculated, expansive, dark red mass arising from the mucosa of the ethmoidal conchae ( fig. - ) . microscopic examination reveals a capsule lined by epithelium and hemorrhagic stromal tissue infiltrated with abundant macrophages, most of which are siderophages. viral infections. viruses, such as equine viral rhinopneumonitis virus, influenza virus, adenovirus, and equine picornavirus, cause mild and generally transient respiratory infections in horses. the route of infection for these respiratory viruses is typically aerogenous. all of these infections are indistinguishable clinically; signs consist mainly of malaise, fever, coughing, conjunctivitis, and nasal a sequela to penetrating or septic wounds of the nasal, frontal, maxillary, or palatine bones; improper dehorning in young cattle, which exposes the frontal sinus; or maxillary tooth infection in horses and dogs (maxillary sinus). based on the type of exudate, sinusitis is classified as serous, catarrhal, fibrinous (rare), purulent, or granulomatous. paranasal sinuses have poor drainage; therefore exudate tends to accumulate, causing mucocele (accumulation of mucus) or empyema (accumulation of pus) ( fig. - ). chronic sinusitis may promised horses, particularly in arabian foals with inherited combined immunodeficiency disease. bacterial infections. strangles, glanders, and melioidosis of horses are all systemic bacterial diseases that cause purulent rhinitis and suppuration in various organs. these diseases are grouped as upper respiratory diseases because nasal discharge is often the most notable clinical sign. strangles. strangles is an infectious and highly contagious disease of equidae that is caused by streptococcus equi ssp. equi (streptococcus equi) . it is characterized by suppurative rhinitis and lymphadenitis (mandibular and retropharyngeal lymph nodes) with occasional hematogenous dissemination to internal organs. unlike streptococcus equi ssp. zooepidemicus (streptococcus zooepidemicus) and streptococcus dysgalactiae ssp. equisimilis (streptococcus equisimilis), streptococcus equi is not part of the normal nasal flora. infection occurs when susceptible horses come into contact with feed, exudate, or air droplets containing the bacterium. after penetrating through the nasopharyngeal mucosa, streptococcus equi drains to the regional lymph nodes-mandibular and retropharyngeal lymph nodes-via lymphatic vessels. the gross lesions in horses with strangles (mucopurulent rhinitis) correlate with clinical findings and consist of copious amounts of mucopurulent exudate in the nasal passages with notable hyperemia of the nasal mucosa. affected lymph nodes are enlarged and may contain abscesses filled with thick purulent exudate (purulent lymphadenitis). the term bastard strangles is used in cases in which hematogenous dissemination of streptococcus equi results in metastatic abscesses in such organs as the lungs, liver, spleen, kidneys, or brain or in the joints. this form of strangles is often fatal. common sequelae to strangles include bronchopneumonia caused by aspiration of nasopharyngeal exudate; laryngeal hemiplegia ("roaring"), resulting from compression of the recurrent laryngeal nerves by enlarged retropharyngeal lymph nodes; facial paralysis and horner syndrome caused by compression of sympathetic nerves that run dorsal to the medial retropharyngeal lymph node; and purpura hemorrhagica as a result of vasculitis caused by deposition of streptococcus equi antigen-antibody complexes in arterioles, venules, and capillaries of the skin and mucosal membranes. in severe cases, nasal infection extends directly into the paranasal sinuses or to the guttural pouches via the eustachian tubes, causing inflammation and accumulation of pus (guttural pouch empyema). rupture of abscesses in the mandibular and retropharyngeal lymph nodes leads to suppurative inflammation of adjacent subcutaneous tissue (cellulitis), and in severe cases the exudate escapes through cutaneous fistulas. strangles can affect horses of all ages, but it is most commonly seen in foals and young horses. it is clinically characterized by cough, nasal discharge, conjunctivitis, and painful swelling of regional lymph nodes. some horses become carriers and a source of infection to other horses. glanders. glanders is an infectious world organization for animal health (oie)-notifiable disease of equidae caused by burkholderia mallei (pseudomonas mallei) that can be transmitted to carnivores by consumption of infected horsemeat. human beings are also susceptible, and untreated infection is often fatal. this gramnegative bacterium has been listed as a potential agent for biologic warfare and bioterrorism. in the past, burkholderia mallei was found throughout the world, but today, glanders has been eradicated from most countries, except for some areas in north africa, asia, and eastern europe. there also have been sporadic outbreaks reported in brazil. the pathogenesis of glanders is not fully understood. results from experimental infections suggest that infection occurs discharge varying from serous to purulent. viral respiratory infections are common medical problems in adult horses. equine viral rhinopneumonitis. equine viral rhinopneumonitis (evr) is caused by two ubiquitous equine herpesviruses (ehv- and ehv- ) and may be manifested as a mild respiratory disease in weanling foals and young racehorses, as a neurologic disease (myeloencephalopathy), or as abortion in mares. the portal of entry for the respiratory form is typically aerogenous, and the disease is generally transient; thus the primary viral-induced lesions in the nasal mucosa and lungs are rarely seen at necropsy unless complicated by secondary bacterial rhinitis, pharyngitis, or bronchopneumonia. studies with polymerase chain reaction (pcr) techniques have demonstrated that, like other herpesviruses, ehv- and ehv- persist in the trigeminal ganglia for long periods of time (latency). reactivation because of stress or immunosuppression and subsequent shedding of the virus are the typical source of infection for susceptible animals on the farm. equine influenza. equine influenza is a common, highly contagious, and self-limiting upper respiratory infection of horses caused by aerogenous exposure to type a strains of influenza virus (h n [a/equi- ] and h n [a/equi- ]). equine influenza has high morbidity (outbreaks) but low mortality, and it is clinically characterized by fever, conjunctivitis, and serous nasal discharge. it occurs mainly in -to -year-old horses at the racetrack. as with human influenza, equine influenza is usually a mild disease, but occasionally it can cause severe bronchointerstitial pneumonia with pulmonary edema. in some horses, impaired defense mechanisms caused by the viral infection are complicated by a secondary bacterial bronchopneumonia caused by opportunistic organisms (streptococcus zooepidemicus, staphylococcus aureus, or bacteroides sp.) found in the normal flora of the upper respiratory tract. uncomplicated cases of equine influenza are rarely seen in the postmortem room. equine influenza virus (h n ) recently did an equine to canine "host-jump" causing extensive outbreaks of respiratory disease in dogs (see pneumonias of dogs). other equine respiratory viruses. equine picornavirus, adenovirus, and parainfluenza virus produce mild and transient upper respiratory infections (nasopharynx and trachea) in horses, unless complicated by secondary pathogens. in addition to reduced athletic performance, infected horses may have a temporary suppression of cell-mediated immunity leading to opportunistic infections such as pneumocystis carinii pneumonia. fatal adenoviral infections with severe pneumonia or enteritis occur commonly in immunocom- disorders of ruminants (cattle, sheep, and goats) infectious bovine rhinotracheitis. infectious bovine rhinotracheitis (ibr), or "rednose," occurs worldwide and is a disease of great importance to the cattle industry because of the synergism of the ibr virus with mannheimia haemolytica in producing pneumonia. the causative agent, bovine herpesvirus (bohv- ), has probably existed as a mild venereal disease in cattle in europe since at least the mid- s, but the respiratory form was not reported until intensive management feedlot systems were first introduced in north america around the s. typically, the disease is manifested as a transient, acute, febrile illness, which results in inspiratory dyspnea caused by obstruction of the airways by exudate only in very severe cases. other forms of bohv- infection include ulcerative rumenitis; enteritis; multifocal hepatitis in neonatal calves; nonsuppurative meningoencephalitis; infertility; and in experimental infections, mastitis, mammillitis, and ovarian necrosis. except for the encephalitic form, the type of disease caused by bohv- depends more on the site of entry than the viral strain. like other herpesviruses, bohv- also can remain latent in nerve ganglia, with recrudescence after stress or immunosuppression. this virus also causes bovine abortion, systemic infections of calves, and genital infections such as infectious pustular vulvovaginitis (ipv) and infectious balanoposthitis (ibp). the respiratory form of ibr is characterized by severe hyperemia and multifocal necrosis of nasal, pharyngeal, laryngeal, tracheal, and sometimes bronchial mucosa ( fig. - and see fig. - ). as in other respiratory viral infections, ibr lesions are microscopically characterized by necrosis and exfoliation of ciliated cells followed by repair. secondary bacterial infections of these areas of necrosis result in the formation of a thick layer of fibrinonecrotic material (diphtheritic) in the nasal, tracheal, and bronchial mucosa (see fig. - ). intranuclear inclusion bodies, commonly seen in herpesvirus infections, are rarely seen in field cases because inclusion bodies occur only during the early stages of the disease. the most important sequela to ibr is bronchopneumonia, which is caused either by direct aspiration of exudate from airways or as a result of an impairment in pulmonary defense mechanisms, thus predisposing the animal to secondary bacterial infection, most frequently mannheimia haemolytica (see pneumonic mannheimiosis discussion). postmortem diagnosis of ibr is confirmed by isolation of the virus or its identification by immunohistochemistry or pcr in affected tissues. other causes of rhinitis. nasal granulomas occur in cattle presumably as a result of repeated exposure to an unidentified inhaled antigen. nasal granulomas (atopic rhinitis) are reported mainly in cattle in australia, south africa, and the united kingdom, where affected cattle develop multiple, small, pink or red, polypoid nodules, starting in the nasal vestibule that in time extend into the caudal aspect of the nasal septum (see fig. - ). these nodules are composed of fibrovascular tissue mixed with lymphocytes (granulation tissue) superficially lined by hyperplastic epithelium with abundant mast cells and eosinophils in the lamina propria (nasal eosinophilia). the microscopic features suggest that hypersensitivity type i (immediate), type iii (immune complex), and type iv (delayed) may be involved in nasal granulomas of cattle. bovine (idiopathic) nasal granuloma must be differentiated from nasal mycetomas, nasal rhinosporidiosis, and nasal schistosomiasis, which also cause the formation of nodules in the nasal mucosa of cattle. an eosinophilic material consistent with the splendore-hoeppli phenomenon is occasionally observed in bovine mycotic granulomas. this phenomenon seen in some mycotic or bacterial infections is microscopically via the ingestion of contaminated feed and water and, very rarely, via inhalation of infectious droplets. the portals of entry are presumed to be the oropharynx or intestine, in which bacteria penetrate the mucosa and spread via lymph vessels to regional lymph nodes, then to the bloodstream, and thus hematogenously to the internal organs, particularly the lungs. lesions in the nasal cavity start as pyogranulomatous nodules in the submucosa; these lesions subsequently ulcerate, releasing copious amounts of burkholderia mallei-containing exudate into the nasal cavity (see fig. - , a) . finally, ulcerative lesions in conchal mucosa heal and are replaced by typical stellate (star-shaped), fibrous scars. in some cases, the lungs also contain numerous gray, hard, small ( to mm), miliary nodules (resembling millet seeds) randomly distributed in one or more pulmonary lobes because of the hematogenous route. microscopically, these nodules are typical chronic granulomas composed of a necrotic center, with or without calcification, surrounded by a layer of macrophages enclosed by a thick band of connective tissue infiltrated with macrophages, fewer giant cells, lymphocytes, and plasma cells. cutaneous lesions, often referred to as equine farcy, are the result of severe suppurative lymphangitis characterized by nodular thickening of extended segments of lymph vessels in the subcutaneous tissue of the legs and ventral abdomen (see fig. - , c). eventually, affected lymph vessels rupture and release large amounts of purulent exudate through sinuses to the surface of the skin. melioidosis (pseudoglanders). melioidosis (pseudoglanders) is an important, life-threatening disease of human beings, horses, cattle, sheep, goats, pigs, dogs, cats, and rodents caused by burkholderia pseudomallei (pseudomonas pseudomallei). this disease in horses is clinically and pathologically similar to glanders, hence the name pseudoglanders. in human beings, this infection can cause severe sepsis and septic shock and has also been considered to have potential for biologic welfare. melioidosis is currently present in southeast asia and, to a much lesser extent, in northern australia and some european countries where the causative organism is frequently found in rodents, feces, soil, and water. ingestion of contaminated feed and water appears to be the main route of infection; direct transmission between infected animals and insect bites has also been postulated as a possible mechanism of infection. after gaining entrance to the animal, burkholderia pseudomallei is disseminated by the bloodstream and causes suppuration and abscesses in most internal organs, such as nasal mucosa, joints, brain and spinal cord, lungs, liver, kidneys, spleen, and lymph nodes. the exudate is creamy or caseous and yellow to green. the pulmonary lesions in melioidosis are those of an embolic bacterial infection with the formation of pulmonary abscesses, which can become confluent. focal adhesive pleuritis develops where abscesses rupture through the pleura and heal. rhinosporidiosis. the protistan parasite, rhinosporidium seeberi, causes nasal infection in human beings, horses, mules, cattle, dogs, and cats. gross lesions vary from barely visible granulomas to large expansive polypoid nodules that may be mistaken as tumors. these granulomatous nodules are detected by direct observation when present in the nasal mucosa close to the nares or by rhinoscopy when located in the deep nasal cavity. the offending organism, rhinosporidium seeberi, is readily visible in histologic preparations and in impression smears, appearing as a large ( µm), oval sporangium containing thousands of endospores (see fig. - ). rhinosporidium seeberi was once considered a mycotic agent, but recent phylogenetic investigations suggest that it is an aquatic protistan parasite of the class mesomycetozoea. giant, basophilic, intranuclear inclusion bodies in the nasal epithelium, particularly in the nasal glands ( fig. - ). immunosuppressed piglets can develop a systemic cytomegalovirus infection characterized by necrosis of the liver, lungs, adrenal glands, and brain with intralesional inclusion bodies. inclusion body rhinitis is clinically a characterized by a deeply eosinophilic homogeneous material surrounded by bacteria or mycelia. it is thought to result from a localized antigen-antibody response in tissue. oestrus ovis. oestrus ovis (diptera: oestridae; nasal bot) is a brownish fly about the size of a honeybee that deposits its first-stage larvae in the nostrils of sheep in most areas of the world. microscopic larvae mature into large bots (maggots), which spend most of their larval stages in nasal passages and sinuses, causing irritation, inflammation, and obstruction of airways. mature larvae drop to the ground and pupate into flies. this type of parasitism in which living tissues are invaded by larvae of flies is known as myiasis ( fig. - ). although oestrus ovis is a nasal myiasis primarily of sheep, it sporadically affects goats, dogs, and sometimes human beings (shepherds). the presence of the larvae in nasal passages and sinuses causes chronic irritation and erosive mucopurulent rhinitis and sinusitis; bots of oestrus ovis can be found easily if the head is cut to expose the nasal passages and paranasal sinuses. rarely, larvae of oestrus ovis penetrate the cranial vault through the ethmoidal plate, causing direct or secondary bacterial meningitis. other causes of rhinitis. infectious rhinitis is only sporadically reported in goats, and most of these cases are caused by pasteurella multocida or mannheimia haemolytica. the lesions range from a mild serous to catarrhal or mucopurulent inflammation. foreign body rhinitis caused by plant material is sporadically seen cattle, sheep, and goats ( fig. - ). inclusion body rhinitis. inclusion body rhinitis is a disease of young pigs with high morbidity and low mortality caused by a porcine cytomegalovirus (suid herpesvirus- ) and characterized by a mild rhinitis. this virus commonly infects the nasal epithelium of piglets younger than weeks and causes a transient viremia. because this disease is seldom fatal, lesions are seen only incidentally or in euthanized animals. in uncomplicated cases, the gross lesion is hyperemia of the nasal mucosa, but with secondary bacterial infections, mucopurulent exudate can be abundant. microscopic lesions are typical and consist of a necrotizing, nonsuppurative rhinitis with toxigenic strains of pasteurella multocida. the only lesion associated with infection with bordetella bronchiseptica alone is a mild to moderate turbinate atrophy (nonprogressive atrophic rhinitis), but this bacterium actively promotes the colonization of the nasal cavity by pasteurella multocida. the toxigenic strains of pasteurella multocida produce potent cytotoxins that inhibit osteoblastic activity and promote osteoclastic reabsorption in nasal bones, particularly in the ventral nasal conchae, where abnormal bone remodeling results in progressive atrophy of conchae. the degree of conchal atrophy in pigs with atrophic rhinitis varies considerably, and in most pigs, the severity of the lesions does not correspond to the severity of the clinical signs. the best diagnostic method of evaluating this disease at necropsy is to make a transverse section of the snout between the first and second premolar teeth. in normal pigs, conchae are symmetric and fill most of the cavity, leaving only narrow airspaces (meatuses) between coiled conchae. the normal nasal septum is straight and divides the cavity into two mirror-image cavities. in contrast, the septum in pigs with atrophic rhinitis is generally deviated and the conchae appear smaller and asymmetric ( fig. - ). conchal atrophy causes dorsal and ventral meatuses to appear rather enlarged, and in the most advanced cases, the entire nasal conchae may be missing, leaving a large, empty space. it may seem logical to assume that after loss of conchae in an obligate nasal breather, such as the pig, the filtration defense mechanism of the nasal cavity would be impaired, thus enhancing the chances of aerogenous infections in the lung. however, the relationship between atrophic rhinitis, pneumonia, and growth rates in pigs is still controversial. osteoclastic hyperplasia and osteopenia of the conchae are the key microscopic lesions in atrophic rhinitis. depending on the stage of the disease, mucopurulent exudate may be found on the surface of the conchae. hyperplastic or metaplastic changes can occur in the nasal epithelium and glands, and infiltrates of lymphoplasmacytic cells can be present in the lamina propria. in summary, atrophic rhinitis is an important disease in pigs worldwide; morphologic characterized by a mild and transient rhinitis, causing sneezing, nasal discharge, and excessive lacrimation. atrophic rhinitis. a common worldwide disease of pigs, atrophic rhinitis (progressive atrophic rhinitis) is characterized by inflammation and atrophy of nasal conchae (turbinates). in severe cases, atrophy of the conchae may cause a striking facial deformity in growing pigs because of deviation of the nasal septum and nasal bones. the etiopathogenesis of atrophic rhinitis is complex and has been a matter of controversy for many years. pathogens historically associated with atrophic rhinitis include bordetella bronchiseptica, pasteurella multocida, haemophilus parasuis, and viral infections such as porcine cytomegalovirus (inclusion body rhinitis). in addition, predisposing factors have included genetic makeup, environment, and nutritional deficiencies. the cause of atrophic rhinitis is currently believed to be a combined infection by specific strains of bordetella bronchiseptica producing dermonecrotic toxin and linguatula serrata. linguatula serrata is a rare but highly specialized pentastomid parasite that shares some morphologic features with arthropods and annelids and causes infection when dogs consume uncooked ruminant meat containing infective larvae. it occurs primarily in carnivores, although sheep and goats may become aberrant hosts. human beings can also acquire the infection by ingesting raw ovine or caprine meat. the adult parasite is found throughout the nasal passages and sometimes can reach the sinuses and middle ear by moving through the exudate in the eustachian tubes. in common with other nasal parasites, linguatula serrata acts as an irritant, causing sneezing, catarrhal inflammation, and epistaxis. the eggs of this parasite leave the host in the exudate, which is coughed up or swallowed and eliminated in the feces. the nasal cavity and paranasal sinuses of dogs can occasionally be infested with other parasites, including mites (pneumonyssus caninum) and rhinosporidium seeberi (see figs. - and - ). allergic rhinitis. allergic rhinitis (hay fever; nasolacrimal urticaria), which is so common in human beings sensitized and reexposed to inhaled pollens or allergens, has been reported only sporadically in dogs and cats. hay fever in human beings and animals is a type i hypersensitivity reaction in which an ige-mediated degranulation of mast cells results in an acute rhinitis and conjunctivitis. microscopically, the nasal mucosa is edematous and infiltrated with numerous eosinophils, neutrophils, and some macrophages. clinically, allergic rhinitis is characterized by profuse serous nasal discharge and lacrimation. other causes of rhinitis. a nonspecific (idiopathic) chronic lymphoplasmacytic rhinitis is occasionally seen in dogs. immotile cilia syndrome (ciliary dyskinesia), a congenital disease, reduces mucociliary clearance and is an important factor in recurrent canine rhinosinusitis, bronchitis, bronchiectasis, and pneumonia. feline viral rhinotracheitis. feline viral rhinotracheitis (fvr) is a common, worldwide respiratory disease of cats caused by felid herpesvirus (fehv- ). the disease causes an impairment of pulmonary defense mechanisms predisposing cats to secondary bacterial pneumonia or to a coinfection with feline calicivirus. the virus also can remain latent in ganglia. the vast majority of cats that recover from fvr become carriers and shed fehv- , either spontaneously or following stress. susceptible animals, particularly kittens with low maternal immunity, become infected after exposure to a diseased or carrier cat. replication of fehv- in the nasal, conjunctival, pharyngeal, and, to a lesser extent, tracheal epithelium causes degeneration and exfoliation of cells. lesions caused by fehv- are fully reversible, but secondary infections with bacteria, such as pasteurella multocida, bordetella bronchiseptica, streptococcus spp., and mycoplasma felis, can cause a chronic, severe suppurative rhinitis and also conjunctivitis. intranuclear inclusion bodies are rarely seen in cats with fvr because inclusions are only present during the early stages of infection and have already disappeared by the time the cat is presented for diagnosis. respiratory sequelae to fvr can include chronic bacterial rhinitis and sinusitis with persistent purulent discharge; lysis of nasal bones, which can lead to conchal atrophy; permanent damage to the olfactory epithelium; and secondary bacterial pneumonia. in addition to rhinitis and interstitial pneumonia, fvr also causes ulcerative keratitis, hepatic necrosis, emaciation, abortion, and diagnosis is simple, but additional understanding of the pathogenesis will be necessary before effective preventive measures can be established. atrophic rhinitis is clinically characterized by sneezing, coughing, and nasal discharge. obstruction of the nasolacrimal duct is common and results in accumulation of dust and dried lacrimal secretions on the skin inferior to the medial canthus of the eye. viral infections. dogs have no specific viral infections affecting exclusively the nasal cavity or sinuses. acute rhinitis and sinusitis occurs as part of the canine infectious respiratory disease (cird) group caused by several distinct viruses, such as canine distemper virus, cav- and - , canine parainfluenza virus, reovirus, and canine herpesvirus. the viral lesions in the respiratory tract are generally transient, but the effect of the virus on other tissues and cells can be fatal, as in distemper encephalitis in dogs. bacterial infections. as in other species, secondary bacterial rhinitis, sinusitis, and pneumonia are possible sequelae of respiratory viral infections; bordetella bronchiseptica, escherichia coli, and pasteurella multocida are the most common isolates in dogs with bacterial rhinitis. mycotic infections. aspergillus spp. and penicillium spp. cause mycotic rhinitis and sinusitis in dogs (canine nasal aspergillosis) ( fig. - ). nasal biopsies reveal extensive necrosis of the nasal epithelium and thick plaques of fibrinopurulent exudate mixed with many fungal hyphae. cryptococcus neoformans and blastomyces dermatitides infections of the nasal cavity occur sporadically in dogs ( fig. - ). lesions are characterized by mucosal granulomas containing periodic acid-schiff (pas)-positive fungal organisms, and the infection is clinically characterized by mucopurulent nasal discharge. fvr; these two viral infections account for % of all cases of feline respiratory diseases. a febrile systemic hemorrhagic syndrome with high mortality (up to %) has been reported in cats infected with virulent strains of fcv. feline chlamydiosis. feline chlamydiosis is a persistent respiratory infection of cats caused by chlamydophila felis. infection results in a conjunctivitis (similar to the conjunctivitis seen in human trachoma caused by chlamydia trachomatis) and serous or mucopurulent rhinitis. in the past, chlamydophila felis was incriminated as the agent responsible for "feline pneumonitis," but its role in causing bronchointerstitial pneumonia in cats has been seriously challenged in recent years (see pneumonias of cats). mycotic infections. the most common mycotic infection in the feline nasal cavity is caused by cryptococcus neoformans and cryptococcus gatti, but not all animals exposed to these fungi necessarily develop cryptococcosis unless they are immunosuppressed. stillbirths. clinical signs of fvr infection are characterized by lethargy, oculonasal discharge, severe rhinitis, and conjunctivitis. feline calicivirus. feline rhinitis can be caused by different strains of feline calicivirus (fcv). it is an important infection of the respiratory tract of cats, and depending on the virulence of the strain, lesions vary from a mild oculonasal discharge to severe rhinitis, mucopurulent conjunctivitis, and ulcerative gingivitis and stomatitis. the lesions, in addition to rhinitis and conjunctivitis, include acute, diffuse interstitial pneumonia with necrotizing bronchiolitis (see pneumonias of cats) and in some cases prominent ulcers of the tongue and hard palate. primary viral lesions are generally transient, but secondary bacterial infections (bordetella bronchiseptica, pasteurella multocida, or escherichia coli) are a common complication. some kittens develop lameness after infection or vaccination with calicivirus because of an acute and self-limiting arthritis ("limping kitten syndrome"). carrier state and virus shedding from oronasal secretions and feces are natural sequelae after recovery from the acute phase of the disease. clinical and pathologic features of fcv disease are strikingly similar but not identical to those of hemorrhage, increased lacrimation as a result of obstruction of nasolacrimal ducts, and sneezing. in some instances, it is not possible to clinically or grossly differentiate neoplasms from hyperplastic nodules or granulomatous rhinitis. some neoplasms may infiltrate adjacent bone structures and produce notable facial deformities, loss of teeth, exophthalmus, and nervous signs. large neoplasms also project into the meatuses, narrow the lumen, and interfere with airflow, causing stertorous breathing (see . biopsies, as well as brush and imprint cytology, have proven effective in the antemortem diagnosis of nasal neoplasms, particularly in those of epithelial lineage. a unique group of nasal carcinomas (enzootic nasal tumors, enzootic intranasal tumors, and enzootic nasal carcinoma) of sheep and goats arise from the surface epithelium and glands of the ethmoidal conchae. these types of carcinomas are caused by betaretroviruses in sheep (entv- ) and goats (entv- ). the enzootic nasal tumor has been successfully transmitted to susceptible animals by the lesions vary from discrete nasal granulomas to large confluent masses of mucopurulent exudate filling the entire nasal cavity and paranasal sinuses. microscopic examination of the exudate reveals the typical thick-walled pas-positive organisms (see fig. - ). mycoplasma felis can also cause mucopurulent conjunctivitis and a mild upper respiratory infection, with clinical signs and lesions overlapping those seen with chlamydiosis, fvr, and fcr infections. respiratory infections and bronchopneumonia in cats may also be associated with the immunosuppressive effects of feline retroviruses such as feline leukemia virus (felv) and feline immunodeficiency virus (fiv). nasal aspergillosis and allergic rhinosinusitis are sporadically reported in cats (see disorders of the conducting system: species-specific diseases of the nasal cavity and paranasal sinuses: disorders of dogs: mycotic infections). neoplasms of the nasal cavity and paranasal sinuses may arise from any of the tissues forming these structures, including bone (osteoma or osteosarcoma), cartilage (chondroma or chondrosarcoma), connective tissue (fibroma or fibrosarcoma, myxoma or myxosarcoma), and blood vessels (hemangioma or hemangiosarcoma), and from all the different types of cells of glands and lining epithelium (adenoma, carcinoma, or adenocarcinoma). nasal tumors originating from stromal tissues, such as bone, cartilage, and connective tissue, are morphologically indistinguishable from those seen in other sites. in general, nasal neoplasms are rare in domestic animals, except for enzootic ethmoidal tumor (retroviral) in sheep and goats, which can occur in several animals in a herd (see the next section). in companion animals, nasal neoplasms are most common in dogs, particularly in medium to large breed dogs such as the collie, airedale terrier, basset hound, and german shepherd. the cat and the horse are less frequently affected. the main sites in order of frequency are the nasal passages and sinuses for dogs, the tip of the nose and nasal passages for cats, and the maxillary sinus and nasal passages for horses. the majority of neoplasms in the nasal cavity are malignant. benign nasal neoplasms (papilloma and adenoma) are rare and generally are either solitary or multiple, well-delineated nodules. in contrast, nasal carcinomas and nasal sarcomas are generally larger but vary in size and are often pale and multilobulated masses composed of fleshy to friable tissue (figs. - and - ). malignant neoplasms are locally invasive and tend to infiltrate sinuses, meninges, frontal brain, olfactory nerves, and vessels resulting in epistaxis. carcinomas vary from anaplastic (poorly differentiated) to well differentiated, in which cell and tissue morphology retains some glandular (adenocarcinoma) or squamous cell patterns. because nasal tumors in dogs and cats are usually large and invasive at the time of diagnosis, prognosis is usually poor and survival times are short. sarcomas originating in the nasal cavity and paranasal sinuses are less common than carcinomas. mesenchymal tumors can arise from bone (osteoma or osteosarcoma), cartilage (chondroma or chondrosarcoma), blood vessels (hemangioma or hemangiosarcoma), and connective tissue (fibroma or fibrosarcoma). overall, benign epithelial and mesenchymal tumors are less common than their malignant counterparts. secondary tumors in the nasal cavity are rare, with lymphoma being the most common secondary tumor in the nasal cavity of domestic animals ( fig. - ). nasal neoplasms become secondarily infected by bacteria, and clinical signs often overlap with those of infectious rhinitis and include catarrhal or mucopurulent nasal discharge, periodic anomalies congenital anomalies of the pharynx, guttural pouches, larynx, and trachea are rare in all species. depending on their location and severity, they may be inconsistent with postnatal life, pose little or no problem, interfere with quality of life, or manifest themselves in later life. if clinical signs of respiratory distress, such as stridor, coughing, dyspnea, or gagging, do occur, they are usually exacerbated by excitement, heat, stress, or exercise. brachycephalic airway syndrome. see disorders of the conducting system: species-specific diseases of the pharynx, guttural inoculation of cell-free tumor filtrates. enzootic nasal tumors are typically invasive but do not metastasize ( fig. - ). in some regions of the world, ethmoid tumors have been reported in horses and pigs, particularly in those farms where the endemic nasal tumors of ruminants are known to occur. nonneoplastic exophytic masses that resemble neoplasms are commonly found in horses, cats, and, to a lesser extent, other species. in horses, polyps tend to form in the ethmoidal region, whereas in cats, polyps are most frequently found in the nasopharynx and eustachian tubes. the pathogenesis of these benign growths is uncertain, although in many cases they follow chronic rhinitis or sinusitis. most recently, lymphatic obstruction secondary to inflammation has been postulated as the main culprit. grossly, polyps appear as firm, pedunculated nodules of various sizes protruding from the nasal mucosa into the nasal passages or nasopharynx ( fig. - ); the surface may be smooth, ulcerated, secondarily infected, and hemorrhagic. microscopically, polyps are characterized by a core of wellvascularized stromal tissue that contains inflammatory cells and are covered by pseudostratified or squamous epithelium (see fig. - ). nasal and paranasal sinus cysts are common idiopathic lesions in horses and are medically important because they clinically mimic table - for potential, suspected, or known genetic disorders. tracheal collapse and tracheal stenosis. tracheal collapse with reduction in tracheal patency occurs in toy, miniature, and brachycephalic breeds of dogs, in which the condition is also called tracheobronchial collapse or central airway collapse. the defect also occurs in horses, cattle, and goats. by radiographic, endoscopic, or gross examination, there is dorsoventral flattening of the trachea with concomitant widening of the dorsal tracheal membrane, which may then prolapse ventrally into the lumen ( fig. - ). most commonly, the defect extends the entire length of the trachea and only rarely affects the cervical portion alone. affected segments with a reduced lumen contain froth and even are covered by a diphtheritic membrane. in horses, the so-called scabbard trachea is characterized allergic reactions. grossly, the mucosa of the epiglottis and vocal cords is thickened and swollen, often protrudes dorsally onto the epiglottic orifice, and has a gelatinous appearance ( fig. - ). laryngeal and tracheal hemorrhage. hemorrhages in these sites occur as mucosal petechiae and are most commonly seen in coagulopathies; inflammation; septicemia and sepsis, particularly in pigs with classical swine fever (hog cholera); african swine fever or salmonellosis; and horses with equine infectious anemia. severe dyspnea and asphyxia before death can cause congestion, ecchymosis, and petechiae in the laryngeal and tracheal mucosa; this lesion must be differentiated from postmortem imbibition of hemoglobin in autolyzed carcasses (see chapter ). by lateral flattening so that the tracheal lumen is reduced to a narrow vertical slit. segmental tracheal collapse causing stenosis has been associated with congenital and acquired abnormalities. in severe cases, abnormal cartilaginous glycoproteins and loss of elasticity of tracheal rings causes the trachea to collapse. in some other cases, it is an acquired tracheal lesion that follows trauma, compression caused by extraluminal masses, peritracheal inflammation, and flawed tracheotomy or transtracheal aspirate techniques. other tracheal anomalies include tracheoesophageal fistula, which is most commonly found in human beings and sporadically in dogs and cattle. congenital fistulas can occur at any site of the cervical or thoracic segments of the trachea. acquired tracheoesophageal fistula can be a complication of improper intubation, tracheotomy, or esophageal foreign body. laryngeal hemiplegia. laryngeal hemiplegia (paralysis), sometimes called roaring in horses, is a common but obscure disease characterized by atrophy of the dorsal and lateral cricoarytenoid muscles (abductor and adductor of the arytenoid cartilage), particularly on the left side. muscular atrophy is most commonly caused by a primary denervation (recurrent laryngeal neuropathy) of unknown cause (idiopathic axonopathy) and, to a much lesser extent, secondary nerve damage (see the section on denervation atrophy in chapters and ). idiopathic laryngeal hemiplegia is an incurable axonal disease (axonopathy) of the cranial laryngeal nerve that affects mostly larger horses. secondary laryngeal hemiplegia is rare and occurs after nerve damage caused by other pathologic processes such as compression or inflammation of the left recurrent laryngeal nerve. the medial retropharyngeal lymph nodes are located immediately ventral to the floor of the guttural pouches. as a result of this close anatomic relationship, swelling or inflammation of the guttural pouches or retropharyngeal lymph nodes often results in secondary damage to the laryngeal nerve. common causes of secondary nerve damage (wallerian degeneration) include guttural pouch mycosis, retropharyngeal abscesses, inflammation because of iatrogenic injection into the nerves, neck injury, and metastatic neoplasms involving the retropharyngeal lymph nodes (e.g., lymphosarcoma). grossly, the affected laryngeal muscle in a horse with laryngeal hemiplegia is pale and smaller than normal (muscle atrophy) . microscopically, muscle fibers have lesions of denervation atrophy (see chapters and ). atrophy of laryngeal muscles also occurs in dogs as an inherited condition (siberian husky and bouvier des flanders), as a degenerative neuropathy in older dogs, secondary to laryngeal trauma in all species (e.g., choke chain damage), or secondary to hepatic encephalopathy in horses. the abnormal inspiratory sounds (roaring) during exercise in horses with laryngeal hemiplegia are caused by paralysis of the left dorsal and lateral cricoarytenoid muscles, which cause incomplete dilation of the larynx, obstruction of airflow, and vibration of vocal cords. laryngeal edema. laryngeal edema is a common feature of acute inflammation, but it is particularly important because swelling of the epiglottis and vocal cords can obstruct the laryngeal orifice, resulting in asphyxiation. laryngeal edema occurs in pigs with edema disease; in horses with purpura hemorrhagica; in cattle with acute interstitial pneumonia; in cats with systemic anaphylaxis; and in all species as a result of trauma, improper endotracheal tubing, inhalation of irritant gases (e.g., smoke), local inflammation, and animal species is classified as fibrinous, catarrhal, purulent, or granulomatous (figs. - and - ). chronic polypoid tracheitis occurs in dogs and cats, probably secondary to chronic infection. the most common causes of tracheitis are viral infections, such as those causing infectious bovine rhinotracheitis (see fig. - ), equine viral rhinopneumonitis, canine distemper, and feline rhinotracheitis. viral lesions are generally mild and transient but often become complicated with secondary bacterial infections. at the early stages, the mucosa is notably hyperemic and can show white foci of necrosis. in the most severe cases, the affected mucosa detaches from the underlying basement membrane, causing extensive tracheal ulceration. chemical tracheitis is also commonly seen after aspiration (see fig. - ). also, inhalation of fumes during barn fires can cause extensive injury and necrosis of the tracheal mucosa. in forensic cases, the presence of carbon pigment in the mucosal surface of trachea, bronchi, and bronchioles indicates that the burned animal was alive during the fire. parasitic infections of the larynx and trachea can cause obstruction with dramatic consequences, but burdens sufficient to cause such effects are not commonly seen in veterinary practice. besnoitiosis (besnoitia spp.) . besnoitiosis (besnoitia spp.) is caused by several species of this apicomplexan coccidian parasite, whose life cycle is still unknown. this parasite can cause pedunculated lesions on the skin, sclera, mucosa of the nasal cavity, and larynx of horses and donkeys, cattle, goats, and wild animals. besnoitiosis has been reported from africa, central and south america, north america, and europe. grossly, pale, round, exophytic nodules up to cm in diameter can be observed protruding from mucosal surfaces. microscopically, these nodules consist of finger-like projections covered by hyperplastic and sometimes ulcerated epithelium containing numerous thick-walled parasitic cysts with little inflammatory response. cattle. see disorders of cattle. inflammation of the pharynx, larynx, and trachea are important because of their potential to obstruct airflow and to lead to aspiration pneumonia. the pharynx is commonly affected by infectious diseases of the upper respiratory and upper digestive tracts, and the trachea can be involved by extension from both the lungs and larynx. pharyngeal obstruction and perforation. intraluminal foreign bodies in the pharynx, such as medicament boluses, apples, or potatoes, can move down and obstruct the larynx and trachea. also, pharyngeal obstruction can be caused by masses in the surrounding tissue, such as neoplasms of the thyroid gland, thymus, and parathyroid glands. a number of nonspecific insults can cause lesions and clinical signs. trauma may take the form of penetrating wounds in any species: perforation of the caudodorsal wall of the pharynx from the improper use of drenching or balling guns in sheep, cattle, and pigs; choking injury because of the use of collars in dogs and cats; and the shearing forces of bite wounds. the results of the trauma may be minimal (local edema and inflammation) or as serious as complete luminal obstruction by exudate. foreign bodies may be lodged anywhere in the pharyngeal region; the location and size determine the occurrence of dysphagia, regurgitation, dyspnea, or asphyxiation. pigs have a unique structure known as the pharyngeal diverticulum ( cm long in adult pigs), which is located in the pharyngeal wall rostral and dorsal to the esophageal entrance. it is important because barley awns may lodge in the diverticulum, causing an inflammatory swelling that affects swallowing. the diverticular wall may be perforated by awns or drenching syringes, which results in an exudate that can extend down the tissue planes between muscles of the neck and even into the mediastinum. the pharynx of the dog may also be damaged by trauma from chicken bones, sticks, and needles, resulting in the formation of a pharyngeal abscess. equine inflammation of the trachea (tracheitis). the types of injury and host inflammatory responses in the trachea are essentially the same as those described for the nasal mucosa. although tracheal mucosa is prone to aerogenous injury and necrosis, it has a remarkable capacity for repair. according to the exudate, tracheitis in all palate, are important causes of respiratory problems and reduced athletic performance in horses. an undersized epiglottis is prone to being entrapped below the arytenoepiglottic fold, causing an equine syndrome known as epiglottic entrapment. this syndrome also occurs in horses with lateral deviation and deformity of epiglottis, epiglottic cysts, or necrosis of the tip of the epiglottis. hypoplastic epiglottis also occurs in pigs. dorsal displacement of the soft palate, particularly during exercise, narrows the lumen of the nasopharynx and creates abnormal air turbulence in the conducting system of horses. epiglottic entrapment is clinically characterized by airway obstruction, exercise intolerance, respiratory noise, and cough. subepiglottic and pharyngeal cysts. anomalous lesions, such as subepiglottic and pharyngeal cysts, are occasionally seen in horses, particularly in standardbred and thoroughbred racehorses. these cysts vary in size ( to cm) and occur most commonly in the subepiglottic area and to a lesser extent in the dorsal pharynx, larynx, and soft palate. cysts are lined by squamous or pseudostratified epithelium and contain thick mucus. large cysts cause airway obstruction, reduced exercise tolerance, or dysphagia and predispose to bronchoaspiration of food. equine pharyngeal lymphoid hyperplasia. equine pharyngeal lymphoid hyperplasia, or pharyngitis with lymphoid follicular hyperplasia, is a common cause of partial upper airway obstruction in horses, particularly in -and -year-old racehorses. lymphoid hyperplasia is also seen in healthy horses as part of a response to mild chronic pharyngitis, which in many instances tends to regress with age in older animals. the cause is undetermined, but chronic bacterial infection combined with environmental factors may cause excessive antigenic stimulation and lymphoid hyperplasia. the gross lesions, visible endoscopically or at necropsy, consist of variably sized ( to mm) white foci located on the dorsolateral walls of the pharynx and extending into the openings of the guttural pouches and onto the soft palate. in severe cases, lesions may appear as pharyngeal polyps. microscopically, the lesions consist of large aggregates of lymphocytes and plasma cells in the pharyngeal mucosa. clinical signs consist of stertorous inspiration, expiration, or both. inflammation of guttural pouches. the guttural pouches of horses are large diverticula ( to ml) of the ventral portion of the auditory (eustachian) tubes. these diverticula are therefore exposed to the same pathogens as the pharynx and have drainage problems similar to the sinuses. although it is probable that various pathogens, including viruses, can infect them, the most common pathogens are fungi, which cause guttural pouch mycosis and guttural pouch empyema in the horse. eustachitis is the term used for inflammatory processes involving the eustachian (pharyngotympanic) tube. because of the close anatomic proximity of guttural pouches to the internal carotid arteries, cranial nerves (vii, ix, x, xi, and xii), and atlantooccipital joint, disease of these diverticula may involve these structures and cause a variety of clinical signs in horses. guttural pouch mycosis occurs primarily in stabled horses and is caused by aspergillus fumigatus and other aspergillus spp. infection is usually unilateral and presumably starts with the inhalation of spores from moldy hay. grossly, the mucosal surfaces of the dorsal and lateral walls of the guttural pouch mucosa are first covered by focal, rounded, raised plaques of diphtheritic (fibrinonecrotic) exudate, which with time can become confluent and grow into a large fibrinonecrotic mass ( fig. - ) . microscopically, the lesions are severe necrotic inflammation of the mucosa and submucosa with widespread vasculitis and intralesional fungal hyphae. necrosis of the mammomonogamus (syngamus) spp. mammomonogamus (syngamus) laryngeus is a nematode that is seen attached to the laryngeal mucosa of cattle in tropical asia and south america, and cats (gapeworm: mammomonogamus ierei) in the caribbean and southern united states. occasionally, human beings with a persistent cough or asthma-like symptoms have the parasite in the larynx or bronchi. oslerus (filaroides) osleri. see disorders of dogs. b a c empyema of guttural pouches is a sequela to suppurative inflammation of the nasal cavities, most commonly from streptococcus equi infection (strangles). in severe cases, the entire guttural pouch can be filled with purulent exudate ( fig. - ). the sequelae are similar to those of guttural pouch mycosis except that there is no erosion of the internal carotid artery. it is clinically characterized by nasal discharge, enlarged retropharyngeal lymph nodes, painful swelling of the parotid region, dysphagia, and respiratory distress. guttural pouch tympany develops sporadically in young horses when excessive air accumulates in the pouch from the one-way valve effect caused by inflammation or malformation of the eustachian tube. arabian and german warm-blooded horses are particularly susceptible to develop guttural pouch tympany. it is generally unilateral and characterized by nonpainful swelling of the parotid region. cattle. tracheal edema and hemorrhage syndrome of feeder cattle, also known as the honker syndrome or tracheal stenosis of feedlot cattle, is a poorly documented acute disease of unknown cause, most often seen during the summer months. severe edema and a few hemorrhages are present in the mucosa and submucosa of the dorsal surface of the trachea, extending caudally from the midcervical area as far as the tracheal bifurcation. on section, the tracheal mucosa is diffusely thickened and gelatinous. clinical signs include inspiratory wall of the guttural pouches can extend into the wall of the adjacent internal carotid artery causing hemorrhage into the lumen of the guttural pouch and recurrent epistaxis. invasion of the internal carotid artery causes arteritis, which can also lead to formation of an aneurysm and fatal bleeding into the guttural pouches. in other cases, the fungi may be angioinvasive, leading to the release of mycotic emboli into the internal carotid artery, generally resulting in multiple cerebral infarcts. dysphagia, another clinical sign seen in guttural pouch mycosis, is associated with damage to the pharyngeal branches of the vagus and glossopharyngeal nerves, which lie on the ventral aspect of the pouches. horner's syndrome results from damage to the cranial cervical ganglion and sympathetic fibers located in the caudodorsal aspect of the pouches. finally, equine laryngeal paralysis (hemiplegia) can result from damage to the laryngeal nerves as previously described in the section on laryngeal hemiplegia. pekingese, and others. the defects are a result of a mismatch of the ratio of soft tissue to cranial bone and the obstruction of airflow by excessive length of the palatine soft tissue. secondary changes, such as nasal and laryngeal edema caused by forceful inspiration, eventually lead to severe upper airway obstruction, respiratory distress, and exercise intolerance. tracheal hypoplasia. tracheal hypoplasia occurs most often in english bulldogs and boston terriers; the tracheal lumen is decreased in diameter throughout its length. canine infectious respiratory disease. canine infectious respiratory disease (cird), formerly called canine tracheobronchitis or kennel cough, is a highly contagious group of infectious diseases characterized clinically by an acute onset of coughing notably exacerbated by exercise. the term is nonspecific, much like the dyspnea that can progress to oral breathing, recumbency, and death by asphyxiation in less than hours. necrotic laryngitis. necrotic laryngitis (calf diphtheria, laryngeal necrobacillosis) is a common disease of feedlot cattle and cattle affected with other diseases, with nutritional deficiencies, or housed under unsanitary conditions. it also occurs sporadically in sheep and pigs. necrotic laryngitis, caused by fusobacterium necrophorum, is part of the syndrome termed necrotic stomatitis or laryngeal necrobacillosis, which can include lesions of the tongue, cheeks, palate, and pharynx. an opportunistic pathogen, fusobacterium necrophorum produces potent exotoxins and endotoxins after gaining entry either through lesions of viral infections, such as ibr and vesicular stomatitis in cattle, or after traumatic injury produced by feed or careless use of specula or balling guns. the gross lesions, regardless of location in the mouth or larynx (most common in the mucosa overlying the laryngeal cartilages), consist of well-demarcated, dry, yellow-gray, thick-crusted, and fibrinonecrotic exudate ( fig. - ) that in the early stages is bounded by a zone of active hyperemia. deep ulceration develops, and if the lesion does not result in death, healing is by granulation tissue formation. microscopically, the necrotic foci are first surrounded by congested borders, then by a band of leukocytes, and finally the ulcers heal by granulation tissue and collagen (fibrosis). the lesions can extend deep into the submucosal tissue. numerous bacteria are evident at the advancing edge. there are numerous and important sequelae to calf diphtheria; the most serious is death from severe toxemia or overwhelming fusobacteremia. sometimes, the exudate may be copious enough to cause laryngeal obstruction and asphyxiation or be aspirated and cause bronchopneumonia. the clinical signs of necrotic laryngitis are fever, anorexia, depression, halitosis, moist painful cough, dysphagia, and inspiratory dyspnea and ventilatory failure because of fatigue of the respiratory muscles (diaphragmatic and intercostal). laryngeal contact ulcers. ulcerative lesions in the larynx are commonly found in feedlot cattle. grossly, the laryngeal mucosa reveals circular ulcers (up to cm in diameter), which may be unilateral or bilateral and sometimes deep enough to expose the underlying arytenoid cartilages. the cause has not been established, but causal agents, such as viral, bacterial, and traumatic, have been proposed, along with increased frequency and rate of closure of the larynx (excessive swallowing and vocalization) when cattle are exposed to market and feedlot stresses such as dust, pathogens, and interruption of feeding. contact ulcers predispose a calf to diphtheria (fusobacterium necrophorum) and laryngeal papillomas. ulceration of the mucosa and necrosis of the laryngeal cartilages have also been described in calves, sheep, and horses under the term laryngeal chondritis. laryngeal abscesses involving the mucosa and underlying cartilage occur as a herd or flock problem in calves and sheep, presumably caused by a secondary infection with trueperella (arcanobacterium) pyogenes. anomalies brachycephalic airway syndrome. brachycephalic airway syndrome is a clinical term that refers to increased airflow resistance caused by stenotic nostrils and nasal meatuses and an excessively long soft palate. these abnormalities are present in brachycephalic canine breeds such as bulldogs, boxers, boston terriers, pugs, a "common cold" in human beings or bovine respiratory disease complex (brdc) in cattle. the infection occurs commonly as a result of mixing dogs from different origins such as occurs at commercial kennels, animal shelters, and veterinary clinics. between bouts of coughing, most animals appear normal, although some have rhinitis, pharyngitis, tonsillitis, or conjunctivitis; some with secondary pneumonia become quite ill. the pathogenesis of cird is complex, and many pathogens and environmental factors have been incriminated. bordetella bronchiseptica, canine adenovirus- (cav- ), and canine parainfluenza virus- (cpiv- ) are most commonly implicated. the severity of the disease is increased when more than one agent is involved or if there are extreme environmental conditions (e.g., poor ventilation). for example, dogs asymptomatically infected with bordetella bronchiseptica are more severely affected by superinfection with cav- than those not carrying the bacterium. other agents are sometimes isolated but of lesser significance and include canine adenovirus- (cav- : infectious canine hepatitis virus), reovirus type , canid herpesvirus- (cahv- ), canine respiratory coronavirus (crcov), and mycoplasma species. depending on the agents involved, gross and microscopic lesions are completely absent or they vary from catarrhal to mucopurulent tracheobronchitis, with enlargement of the tonsils and retropharyngeal and tracheobronchial lymph nodes. in dogs with bordetella bronchiseptica infection, the lesions are suppurative or mucopurulent rhinitis and tracheobronchitis, and suppurative bronchiolitis. in contrast, when lesions are purely viral, microscopic changes are focal necrosis of the tracheobronchial epithelium. sequelae can include spread either proximally or distally in the respiratory tract, the latter sometimes inducing chronic bronchitis and bronchopneumonia. oslerus (filaroides) osleri. oslerus (filaroides) osleri is a nematode parasite of dogs and other canidae that causes characteristic protruding nodules into the lumen at the tracheal bifurcation. they are readily seen on endoscopic examination or at necropsy. in severe cases, these nodules can extend cm cranially or caudally from the tracheal bifurcation and even into primary and secondary bronchi. the disease occurs worldwide, and oslerus osleri is considered the most common respiratory nematode of dogs. the gross lesions are variably sized, up to cm, submucosal nodules that extend up to cm into the tracheal lumen ( fig. - , a). microscopically, nodules contain adult parasites with a mild mononuclear cell reaction; with the death of the parasite, an intense foreign body reaction develops with neutrophils and giant cells b) . clinically, it can be asymptomatic, although it most often causes a chronic cough that can be exacerbated by exercise or excitement. severe infestations can result in dyspnea, exercise intolerance, cyanosis, emaciation, and even death in young dogs. neoplasms of the guttural pouches occur rarely in horses and are usually squamous cell carcinomas. laryngeal neoplasms are rare in dogs and extremely so in other species, although they have been reported in cats and horses. the most common laryngeal neoplasms in dogs are papillomas and squamous cell carcinomas. other less common tumors are laryngeal rhabdomyoma, previously referred to as laryngeal oncocytoma, and chondromas and osteochondromas. lymphoma involving the laryngeal tissue is sporadically seen in cats. when large enough to be obstructive, neoplasms may cause a change or loss of voice, cough, or respiratory distress with cyanosis, collapse, and syncope. other signs include dysphagia, anorexia, and exercise intolerance. the neoplasm is sometimes visible from the oral cavity and causes swelling of the neck. the prognosis is poor because most lesions recur after excision. tracheal neoplasms are even more uncommon than those of the larynx. the tracheal cartilage or mucosa can be the site of an osteochondroma, leiomyoma, osteosarcoma, mast cell tumor, and carcinoma. lymphoma in cats can extend from the mediastinum to involve the trachea. each lung is subdivided into various numbers of pulmonary lobes (see fig. - ). in the past, these were defined by anatomic fissures. however, in current anatomy, lobes are defined by the ramification of the bronchial tree. following this criterion, the left lung of all domestic species is composed of cranial and caudal lobes, whereas the right lung, depending on species, is composed of cranial, middle (absent in horse), caudal, and accessory lobes. each pulmonary lobe is further subdivided by connective tissue into pulmonary lobules, which in some species (cattle and pigs) are rather prominent and in others are much less conspicuous. from a practical standpoint, identification of the lungs among different species could be achieved by carefully observing the degree of lobation (external fissures) and the degree of lobulation (connective tissue between lobules). cattle and pigs have well-lobated and well-lobulated lungs; sheep and goats have well-lobated but poorly lobulated lungs; horses have both poorly lobated and poorly lobulated lungs and resemble human lungs; finally, dogs and cats have well-lobated but not well-lobulated lungs. the degree of lobulation determines the degree of air movement between the lobules. in pigs and cattle, movement of air between lobules is practically absent because of the thick connective tissue of the interlobular septa separating individual lobules. this movement of air between lobules and between adjacent alveoli (via the pores of kohn) constitutes what is referred to as collateral ventilation. this collateral ventilation is poor in cattle and pigs and good in dogs. the functional implications of collateral ventilation are discussed in the section on pulmonary emphysema. the lungs have an interconnecting network of interstitial stromal tissue supporting the blood and lymphatic vessels, nerves, bronchi, bronchioles, and alveoli. for purposes of simplicity, the pulmonary interstitium can be anatomically divided into three contiguous compartments: ( ) bronchovascular interstitium, where main bronchi and pulmonary vessels are situated; ( ) interlobular interstitium separating pulmonary lobules and supporting small blood and lymph vessels; and ( ) alveolar interstitium supporting the alveolar walls that contain pulmonary capillaries and alveolar epithelial cells (no lymphatic vessels here) (see discussion on the blood-air barrier in the section on alveoli). pulmonary changes, such as edema, emphysema, and inflammation, may affect one or more of these interstitial compartments. anomalies congenital anomalies of the lungs are rare in all species but are most commonly reported in cattle and sheep. compatibility with life largely depends on the type of structures involved and the proportion of functional tissue present at birth. accessory lungs are one of the most common anomalies and consist of distinctively lobulated masses of incompletely differentiated pulmonary tissue present in the thorax, abdominal cavity, or subcutaneous tissue virtually anywhere in the trunk. large accessory lungs can cause dystocia. ciliary dyskinesia (immotile cilia syndrome, kartagener's syndrome) is characterized by defective ciliary movement, which results in reduced mucociliary clearance because of a defect in the microtubules of all ciliated cells and, most important, in the ciliated respiratory epithelium and spermatozoa. primary ciliary dyskinesia often associated with situs inversus has been reported in dogs, which as a result usually have chronic recurrent rhinosinusitis, pneumonia, and infertility. pulmonary agenesis, pulmonary hypoplasia, abnormal lobulation, congenital emphysema, lung hamartoma, and congenital bronchiectasis are occasionally seen in domestic animals. congenital melanosis is a common incidental finding in pigs and ruminants and is usually seen at slaughter (fig. - ). it is characterized by black spots, often a few centimeters in diameter, in various organs, mainly the lungs, meninges, intima of the aorta, and caruncles of the uterus. melanosis has no clinical significance, and the texture of pigmented lungs remains unchanged. congenital emphysema is sporadically seen in dogs (e- fig. - ). pulmonary calcification ("calcinosis"). calcification of the lungs occurs in some hypercalcemic states, generally secondary to hypervitaminosis d or from ingestion of toxic (hypercalcemic) plants, such as solanum malacoxylon (manchester wasting disease), that contain vitamin d analogs. it is also a common sequela to uremia and hyperadrenocorticism in dogs and to pulmonary necrosis (dystrophic calcification) in most species. calcified lungs may fail to collapse when the thoracic cavity is opened and have a characteristic "gritty" texture ( fig. - ) . microscopically, lesions vary from calcification of the alveolar basement membranes (see by pathologists. recent investigations suggest that excessive lipid originates from the breakdown products of neoplastic cells. bronchial and bronchiolar obstructions such as those caused by lungworms can also cause alveolar lipidosis. the pathogenesis relates to the inability of alveolar macrophages that normally remove part of the surfactant lipids to exit the lung via the mucociliary escalator. exogenous lipid pneumonia. another form of lipid pneumonia occurs accidentally in cats or horses given mineral oil by their owners in an attempt to remove hairballs or treat colic (aspiration pneumonia). to achieve gaseous exchange, a balanced ratio of the volumes of air to capillary blood must be present in the lungs (ventilation/perfusion ratio), and the air and capillary blood must be in close proximity across the alveolar wall. a ventilation-perfusion mismatch occurs if pulmonary tissue is either collapsed (atelectasis) or overinflated (hyperinflation and emphysema). the term atelectasis means incomplete distention of alveoli and is used to describe lungs that have failed to expand with air at the time of birth (congenital or neonatal atelectasis) or lungs that have collapsed after inflation has taken place (acquired atelectasis or alveolar collapse) (figs. - and - ). during fetal life, lungs are not fully distended, contain no air, and are partially filled with a locally produced fluid known as fetal lung fluid. not surprisingly, lungs of aborted and stillborn fetuses sink when placed in water, whereas those from animals that have breathed float. at the time of birth, fetal lung fluid is rapidly reabsorbed and replaced by inspired air, leading to the normal distention of alveoli. congenital atelectasis occurs in newborns that fail to inflate their lungs after taking their first few breaths of air; it is caused by obstruction of airways, often as a result of aspiration of amniotic fluid and meconium (described in the section on meconium aspiration syndrome) (see fig. - ). congenital atelectasis also develops when alveoli cannot remain distended after initial aeration because of an alteration in quality and quantity of pulmonary surfactant produced by type ii pneumonocytes and club (clara) cells. this infant form of congenital atelectasis is referred to in human neonatology as infant respiratory distress syndrome (irds) or as hyaline membrane disease because of the clinical and microscopic features of the disease. it commonly occurs in babies who are premature or born to diabetic or alcoholic mothers and is occasionally found in animals, particularly foals and piglets. the pathetic, gasping attempts of affected foals and pigs to breathe have prompted the use of the name "barkers"; foals that survive may have brain damage from cerebral hypoxia (see chapter ) and are referred to as "wanderers" due to their aimless behavior and lack of a normal sense of fear. acquired atelectasis is much more common and occurs in two main forms: compressive and obstructive (see fig. - ). compressive atelectasis has two main causes: space-occupying masses in the pleural cavity, such as abscesses and tumors, or transferred pressures, such as that caused by bloat, hydrothorax, hemothorax, chylothorax, and empyema ( fig. - ). another form of compressive atelectasis occurs when the negative pressure in the thoracic cavity is lost because of pneumothorax. this form generally has massive atelectasis and thus is also referred to as lung collapse. obstructive (absorption) atelectasis occurs when there is a reduction in the diameter of the airways caused by mucosal edema and inflammation, or when the lumen of the airway is blocked by fig. - ) to heterotopic ossification of the lungs (e- fig. - ). in most cases, pulmonary calcification in itself has little clinical significance, although its cause (e.g., uremia or vitamin d toxicosis) may be very important. alveolar filling disorders are a heterogeneous group of lung diseases characterized by accumulation of various chemical compounds in the alveolar lumens. the most common are alveolar proteinosis, in which the alveoli are filled with finely granular eosinophilic material; pulmonary lipidosis, in which alveoli are filled with macrophages containing endogenous or exogenous lipid; and alveolar microlithiasis, in which the alveoli contain numerous concentric calcified "microliths" or "calcospherites." a similar but distinct concretion is known as corpora amylacea, which is an accumulation of laminated bodies composed of cellular debris, lipids, proteins, and possibly amyloid. for most alveolar filling disorders, there is little host response, and in many cases, it is an incidental finding. most of the alveolar filling disorders originate from inherited metabolic defects in which alveolar cells (epithelial or macrophages) cannot properly metabolize or remove lipids or proteins, whereas others result from an excessive synthesis of these substances in the lung. endogenous lipid (lipoid) pneumonia. endogenous lipid pneumonia is an obscure, subclinical pulmonary disease of cats and occasionally of dogs, which is unrelated to aspiration of foreign material. although the pathogenesis is not understood, it is presumed that lipids from pulmonary surfactant and from degenerated cells accumulate within alveolar macrophages. accumulation of surfactant lipids can occur in metabolic abnormalities of alveolar macrophages or in bronchial obstruction where surfactant-laden macrophages cannot exit the lungs via the mucociliary escalator. the gross lesions are multifocal, white, firm nodules scattered throughout the lungs (e- fig. - ) . microscopically, the alveoli are filled with foamy lipid-laden macrophages accompanied by interstitial infiltration of lymphocytes and plasma cells, fibrosis, alveolar epithelialization, and, in some cases, cholesterol clefts and lipid granulomas. lipid (lipoid) pneumonia occurs frequently in the vicinity of cancerous lung lesions in human beings, cats, and dogs. the reason for this association remains unknown and frequently unrecognized appearance of atelectasis is more common in species with poor collateral ventilation, such as cattle and pigs. the extent and location of obstructive atelectasis depends largely on the size of the affected airway (large vs. small) and on the degree of obstruction (partial vs. complete). atelectasis also occurs when large animals are kept recumbent for prolonged periods, such as during anesthesia (hypostatic atelectasis). the factors contributing to hypostatic atelectasis are a combination of blood-air imbalance, shallow breathing, airway obstruction because of mucus and fluid that has not been drained from bronchioles and alveoli, and from inadequate local production of surfactant. atelectasis can also be a sequel to paralysis of respiratory muscles and prolonged use of mechanical ventilation or general anesthesia in intensive care. in general, the lungs with atelectasis appear depressed below the surface of the normally inflated lung. the color is generally dark blue, and the texture is flabby or firm; they are firm if there is concurrent edema or other processes, such as can occur in ards or "shock" lungs (see the section on pulmonary edema). distribution and extent vary with the process, being patchy (multifocal) in congenital atelectasis, lobular in the obstructive type, and of various degrees in between in the compressive type. microscopically, the alveoli are collapsed or slitlike and the alveolar walls appear parallel and close together, giving prominence to the interstitial tissue even without any superimposed inflammation. pulmonary emphysema. pulmonary emphysema, often simply referred to as emphysema, is an extremely important primary disease in human beings, whereas in animals, it is always a secondary condition resulting from a variety of pulmonary lesions. in human medicine, emphysema is strictly defined as an abnormal permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of alveolar walls (alveolar emphysema). this definition separates it from simple airspace enlargement or hyperinflation, in which there is no destruction of alveolar walls and which can occur congenitally (down syndrome) or be acquired with age (aging lung, sometimes misnamed "senile emphysema"). the pathogenesis of emphysema in human beings is still controversial, but current thinking overwhelmingly suggests that destruction of mucus plugs, exudate, aspirated foreign material, or lungworms (see fig. - ). when the obstruction is complete, trapped air in the lung eventually becomes reabsorbed. unlike the compression type, obstructive atelectasis often has a lobular pattern as a result of blockage of the airway supplying that lobule. this lobular lungs are extremely well-vascularized organs with a dual circulation provided by pulmonary and bronchial arteries. disturbances in pulmonary circulation have a notable effect on gaseous exchange, which may result in life-threatening hypoxemia and acidosis. in addition, circulatory disturbances in the lungs can have an impact on other organs, such as the heart and liver. for example, impeded blood flow in the lungs because of chronic pulmonary disease results in cor pulmonale, which is caused by unremitting pulmonary hypertension followed by cardiac dilation, right heart failure, chronic passive congestion of the liver (nutmeg liver), and generalized edema (anasarca). hyperemia is an active process that is part of acute inflammation, whereas congestion is the passive process resulting from decreased outflow of venous blood, as occurs in congestive heart failure ( fig. - ). in the early acute stages of pneumonia, the lungs appear notably red, and microscopically, blood vessels and alveolar capillaries are engorged with blood from alveolar walls is largely the result of an imbalance between proteases released by phagocytes and antiproteases produced in the lung as a defense mechanism (the protease-antiprotease theory). the destructive process in human beings is markedly accelerated by defects in the synthesis of antiproteases or any factor, such as cigarette smoking or pollution, that increases the recruitment of macrophages and leukocytes in the lungs. this theory originated when it was found that human beings with homozygous α -antitrypsin deficiency were remarkably susceptible to emphysema and that proteases (elastase) inoculated intratracheally into the lungs of laboratory animals produced lesions similar to those found in the disease. more than % of the problem relates to cigarette smoking, and airway obstruction is no longer considered to play a major role in the pathogenesis of emphysema in human beings. primary emphysema does not occur in animals, and thus no animal disease should be called simply emphysema. in animals, this lesion is always secondary to obstruction of outflow of air or is agonal at slaughter. secondary pulmonary emphysema occurs frequently in animals with bronchopneumonia, in which exudate plugging bronchi and bronchioles causes an airflow imbalance where the volume of air entering exceeds the volume leaving the lung. this airflow imbalance is often promoted by the so-called one-way valve effect caused by the exudate, which allows air into the lung during inspiration but prevents movement of air out of the lung during expiration. depending on the localization in the lung, emphysema can be classified as alveolar or interstitial. alveolar emphysema characterized by distention and rupture of the alveolar walls, forming variably sized air bubbles in pulmonary parenchyma, occurs in all species. interstitial emphysema occurs mainly in cattle, presumably because of their wide interlobular septa, and lack of collateral ventilation in these species does not permit air to move freely into adjacent pulmonary lobules. as a result, accumulated air penetrates the alveolar and bronchiolar walls and forces its way into the interlobular connective tissue, causing notable distention of the interlobular septa. it is also suspected that forced respiratory movements predispose to interstitial emphysema when air at high pressure breaks into the loose connective tissue of the interlobular septa ( fig. - ). sometimes these bubbles of trapped air in alveolar or interstitial emphysema become confluent, forming large (several centimeters in diameter) pockets of air that are referred to as bullae (singular: bulla) (see e- fig. - ); the lesion is then called bullous emphysema. this lesion is not a specific type of emphysema and does not indicate a different disease process but, rather, is a larger accumulation of air at one focus. in the most severe cases, air moves from the interlobular septa into the connective tissue surrounding the main stem bronchi and major vessels (bronchovascular bundles), and from here it leaks into the mediastinum, causing pneumomediastinum first, and eventually exits via the thoracic inlet into the cervical and thoracic subcutaneous tissue causing subcutaneous emphysema. note that mild and even moderate alveolar emphysema is difficult to judge at necropsy and by light microscopy unless special techniques are used to prevent collapse of the lung when the thorax is opened. these techniques include plugging of the trachea or intratracheal perfusion of fixative ( % neutral-buffered formalin) before the thorax is opened to prevent collapse of the lungs. important diseases that cause secondary pulmonary emphysema in animals include small airway obstruction (e.g., heaves) in horses and pulmonary edema and emphysema (fog fever) in cattle (see fig. - ) and exudates in bronchopneumonia. congenital emphysema occurring secondary to bronchial cartilage hypoplasia with subsequent bronchial collapse is occasionally reported in dogs. severe and persistent cases of heart failure, the lungs fail to collapse because of edema and pulmonary fibrosis. terminal pulmonary congestion (acute) is frequently seen in animals euthanized with barbiturates and should not be mistaken for an antemortem lesion. hypostatic congestion is another form of pulmonary congestion that results from the effects of gravity and poor circulation on a highly vascularized tissue, such as the lung. this type of gravitational congestion is characterized by the increase of blood in the lower side of the lung, particularly the lower lung of animals in lateral recumbency, and is most notable in horses and cattle. the affected portions of the lung appear dark red and can have a firmer texture. in animals and human beings who have been prostrated for extended periods of time, hypostatic congestion may be followed by hypostatic edema, and hypostatic pneumonia as edema interferes locally with the bacterial defense mechanisms. pulmonary hemorrhage. pulmonary hemorrhages can occur as a result of trauma, coagulopathies, and disseminated intravascular coagulation (dic), vasculitis, sepsis, and pulmonary thromboembolism from jugular thrombosis or from embolism of exudate from a hepatic abscess that has eroded the wall and ruptured into the caudal vena cava (cattle). a gross finding often confused with intravital pulmonary hemorrhage is the result of severing both the trachea and the carotid arteries simultaneously at slaughter. blood is aspirated from the transected trachea into the lungs, forming a random pattern of irregular red foci ( to mm) in one or more lobes. these red foci are readily visible on both the pleural and the cut surfaces of the lung, and free blood is visible in the lumens of bronchi and bronchioles. rupture of a major pulmonary vessel with resulting massive hemorrhage occurs occasionally in cattle when a growing abscess in a lung invades and disrupts the wall of a major pulmonary artery or vein ( fig. - ). in most cases, animals die rapidly, often with spectacular hemoptysis, and on postmortem examination, bronchi are filled with blood (see fig. - ). pulmonary edema. in normal lungs, fluid from the vascular space slowly but continuously passes into the interstitial tissue, where it is rapidly drained by the pulmonary and pleural lymphatic vessels. clearance of alveolar fluid across the alveolar epithelium is also a major mechanism of fluid removal from the lung. edema develops when the rate of fluid transudation from pulmonary vessels into the interstitium or alveoli exceeds that of lymphatic and alveolar removal ( fig. - ). pulmonary edema can be physiologically classified as cardiogenic (hydrostatic; hemodynamic) and noncardiogenic (permeability) types. hydrostatic (cardiogenic) pulmonary edema develops when there is an elevated rate of fluid transudation because of increased hydrostatic pressure in the vascular compartment or decreased osmotic pressure in the blood. once the lymph drainage has been overwhelmed, fluid accumulates in the perivascular spaces, causing distention of the bronchovascular bundles and alveolar interstitium, and eventually leaks into the alveolar spaces. causes of hemodynamic pulmonary edema include congestive heart failure (increased hydrostatic pressure); iatrogenic fluid overload; and disorders in which blood osmotic pressure is reduced, such as with hypoalbuminemia seen in some hepatic diseases, nephrotic syndrome, and protein-losing enteropathy. hemodynamic pulmonary edema also occurs when lymph drainage is impaired, generally secondary to neoplastic invasion of lymphatic vessels. permeability edema (inflammatory) occurs when there is excessive opening of endothelial gaps or damage to the cells that constitute the blood-air barrier (endothelial cells or type i pneumonocytes). hyperemia. pulmonary congestion is most frequently caused by heart failure, which results in stagnation of blood in pulmonary vessels, leading to edema and egression of erythrocytes into the alveolar spaces. as with any other foreign particle, erythrocytes in alveolar spaces are rapidly phagocytosed (erythrophagocytosis) by pulmonary alveolar macrophages. when extravasation of erythrocytes is severe, large numbers of macrophages with brown cytoplasm may accumulate in the bronchoalveolar spaces. the brown cytoplasm is the result of accumulation of considerable amounts of hemosiderin; these macrophages filled with iron pigment (siderophages) are generally referred to as heart failure cells ( fig. - ). the lungs of animals with chronic heart failure usually have a patchy red appearance with foci of brown discoloration because of accumulated hemosiderin. in this type of edema is an integral and early part of the inflammatory response, primarily because of the effect of inflammatory mediators, such as leukotrienes, platelet-activating factor (paf), cytokines, and vasoactive amines released by neutrophils, macrophages, mast cells, lymphocytes, endothelial cells, and type ii pneumonocytes. these inflammatory mediators increase the permeability of the blood-air barrier. in other cases, permeability edema results from direct damage to the endothelium or type i pneumonocytes, allowing plasma fluids to move freely from the vascular space into the alveolar lumen ( fig. - and see fig. - ). because type i pneumonocytes are highly vulnerable to some pneumotropic viruses (influenza and brsv), toxicants (nitrogen dioxide [no ], sulfur dioxide [so ], hydrogen sulfide [h s], and -methylindole), and particularly to free radicals, it is not surprising that permeability edema commonly accompanies many viral or toxic pulmonary diseases. a permeability edema also occurs when endothelial cells in the lung are injured by bacterial toxins, sepsis, ards, dic, anaphylactic shock, milk allergy, paraquat toxicity, adverse drug reactions, and smoke inhalation (e- fig. - ) . the concentration of protein in edematous fluid is greater in permeability edema (exudate) than in hemodynamic edema (transudate); this difference has been used clinically in human medicine to differentiate one type of pulmonary edema from another. microscopically, because of the higher concentration of protein, edema fluid in lungs with inflammation or damage to the blood-air barrier tends to stain more intensely eosinophilic than that of the hydrostatic edema from heart failure. grossly, the edematous lungs-independent of the cause-are wet and heavy. the color varies, depending on the degree of congestion or hemorrhage, and fluid may be present in the pleural cavity. if edema is severe, the bronchi and trachea contain considerable amounts of foamy fluid, which originates from the mixing of edema fluid and air ( fig. - ). on cut surfaces, the lung parenchyma oozes fluid like a wet sponge. in cattle and pigs that have distinct lobules, the lobular pattern becomes rather accentuated because of edematous distention of lymphatic vessels in the interlobular septa and the edematous interlobular septum itself ( fig. - ). severe pulmonary edema may be impossible to differentiate from peracute pneumonia; (h&e)-stained sections (see fig. - ), particularly if a fixative such as zenker's solution, which precipitates protein, is used. acute respiratory distress syndrome. acute (adult) respiratory distress syndrome (ards; shock lung) is an important condition in human beings and animals characterized by pulmonary hypertension, intravascular aggregation of neutrophils in the lungs, acute lung injury, diffuse alveolar damage, permeability edema, and formation of hyaline membranes ( fig. - ) . these membranes are a mixture of plasma proteins, fibrin, surfactant, and cellular debris from necrotic pneumonocytes (see fig. - , b) . the pathogenesis of ards is complex and multifactorial but in general terms can be defined as diffuse alveolar damage that results from lesions in distant organs, from generalized systemic diseases, or from direct injury to the lung. sepsis, major trauma, aspiration of gastric contents, extensive burns, and pancreatitis are some of the disease entities known to trigger ards. all these conditions provoke "hyperreactive macrophages" to directly or indirectly generate overwhelming amounts of cytokines causing what is known as a "cytokine storm." the main cytokines that trigger ards are tnf-α, interleukin (il)- , il- , and il- , which prime neutrophils previously recruited in the lung capillaries and alveoli to release cytotoxic enzymes and free radicals. these substances cause severe and diffuse endothelial and alveolar damage that culminates in a fulminating pulmonary edema (see fig. - ). ards occurs in domestic animals and explains why pulmonary edema is one of the most common lesions found in many animals dying of sepsis, toxemia, aspiration of gastric contents, and pancreatitis, for example. a familial form of ards has been reported in dalmatians. the pulmonary lesions in this syndrome are further discussed in the sections on interstitial pneumonia and aspiration pneumonia in dogs. neurogenic pulmonary edema is another distinctive but poorly understood form of life-threatening lung edema in human beings that follows cns injury and increased intracranial pressure (i.e., head injury, brain edema, brain tumors, or cerebral hemorrhage). this type of pulmonary edema can be experimentally reproduced in laboratory animals by injecting fibrin into the fourth ventricle. it involves both hemodynamic and permeability pathways presumably from massive sympathetic stimulation and overwhelming release of catecholamines. neurogenic pulmonary edema has sporadically been reported in animals with brain injury or severe seizures or after severe stress and excitement. pulmonary embolism. with its vast vascular bed and position in the circulation, the lung acts as a safety net to catch emboli before they reach the brain and other tissues. however, this positioning is often to its own detriment. the most common pulmonary emboli in domestic animals are thromboemboli, septic (bacterial) emboli, fat emboli, and tumor cell emboli. pulmonary thromboembolism (pte) refers to both local thrombus formation and translocation of a thrombus present elsewhere in the venous circulation ( fig. - ). fragments released inevitably reach the lungs and become trapped in the pulmonary vasculature ( fig. - and see fig. - ). small sterile thromboemboli are generally of little clinical or pathologic significance because they can be rapidly degraded and disposed of by the fibrinolytic system. larger thromboemboli may cause small airway constriction, reduced surfactant production, pulmonary edema, and atelectasis resulting in hypoxemia, hyperventilation, and dyspnea. parasites (e.g., dirofilaria immitis and angiostrongylus vasorum), endocrinopathies (e.g., hyperadrenocorticism and hypothyroidism), glomerulopathies, and hypercoagulable states can be responsible for pulmonary arterial thrombosis and pulmonary thromboembolism in dogs (e- fig. - ) . pieces of this fact is not surprising because pulmonary edema occurs in the very early stages of inflammation (see e- fig. - ) . careful observation of the lungs at the time of necropsy is critical because diagnosis of pulmonary edema cannot be reliably performed microscopically. this is due in part to the loss of the edema fluid from the lungs during fixation with % neutral-buffered formalin and in part to the fact that the fluid itself stains very poorly or not at all with eosin because of its low protein content (hemodynamic edema). a protein-rich (permeability) edema is easier to visualize microscopically because it is deeply eosinophilic in hematoxylin and eosin fig. - ) . , normal alveolar capillary externally covered by type i and type ii pneumonocytes and internally by vascular endothelium (see fig. - for more detail). , at the early stages of sepsis, proinflammatory cytokines (interleukin [il- ] and tumor necrosis factor [tnf]) cause circulating neutrophils to adhere to the endothelial surface. following a "cytokine storm," the marginated neutrophils further activated by inflammatory mediators suddenly release their cytoplasmic granules (proteolytic enzymes and elastases myeloperoxidase) into the surrounding milieu (arrows). , enzymes released by these neutrophils cause injury to type i pneumonocytes (arrows) and endothelial cells (arrowheads), disrupting the blood-air barrier and causing permeability edema (curved arrows), alveolar hemorrhage (double-headed arrow), and exocytosis of neutrophils into the alveolar space (double-headed arrow). , extravasated plasma proteins admixed with surfactant and cell debris form thick hyaline membranes along the alveolar wall. , in the unlikely event that the animal survives, the healing process starts with alveolar macrophages removing cellular debris, reabsorption of edema, and hyperplasia of type ii pneumonocytes (double-headed curved arrow) that subsequently differentiate into type i pneumonocytes (see fig. b a recognized in the bovine lung after strong pneumatic stunning at slaughter (captive bolt) ( fig. - , a) . although obviously not important as an antemortem pulmonary lesion, brain emboli are intriguing as a potential risk for public health control of bovine spongiform encephalopathy (bse). fragments of hair can also embolize to the lung following intravenous injections (see fig. - , b). hepatic emboli formed by circulating pieces of fragmented liver occasionally become trapped in the pulmonary vasculature after severe abdominal trauma and hepatic rupture (see fig. - , c) . megakaryocytes trapped in alveolar capillaries are a common but incidental microscopic finding in the lungs of all species, particularly dogs (see fig. - , d) . tumor emboli (e.g., osteosarcoma and hemangiosarcoma in dogs and uterine carcinoma in cattle) can be numerous and striking and the ultimate cause of death in malignant neoplasia. in experimental studies, cytokines released during pulmonary inflammation are chemotactic for tumor cells and promote pulmonary metastasis. pulmonary infarcts. because of a dual arterial supply to the lung, pulmonary infarction is rare and generally asymptomatic. however, pulmonary infarcts can be readily caused when pulmonary thrombosis and embolism are superimposed on an already compromised pulmonary circulation such as occurs in congestive heart c d thrombi breaking free from a jugular, femoral, or uterine vein can cause pulmonary thromboembolism. pulmonary thromboembolisms occur in heavy horses after prolonged anesthesia (deep vein thrombosis), recumbent cows ("downer cow syndrome"), or in any animal undergoing long-term intravenous catheterization in which thrombi build up in the catheter and then break off (see fig. - ). septic emboli, pieces of thrombi contaminated with bacteria or fungi and broken free from infected mural or valvular thrombi in the heart and vessels, eventually become entrapped in the pulmonary circulation. pulmonary emboli originate most commonly from bacterial endocarditis (right side) and jugular thrombophlebitis in all species, hepatic abscesses that have eroded and discharged their contents into the caudal vena cava in cattle, and septic arthritis and omphalitis in farm animals (see fig. - ). when present in large numbers, septic emboli may cause unexpected death because of massive pulmonary edema; survivors generally develop pulmonary arteritis and thrombosis and embolic (suppurative) pneumonia, which may lead to pulmonary abscesses. bone marrow and bone emboli can form after bone fractures or surgical interventions of bone. these are not as significant a problem in domestic animals as they are in human beings. brain emboli (i.e., pieces of brain tissue) in the pulmonary vasculature reported in severe cases of head injury in human beings have recently been pulmonary macrophages (alveolar, intravascular, and interstitial), which have an immense biologic armamentarium, are the single most important effector cell and source of cytokines for all stages of pulmonary inflammation. these all-purpose phagocytic cells modulate the recruitment and trafficking of blood-borne leukocytes in the lung through the secretion of chemokines (see e- table - ). before reviewing how inflammatory cells are recruited in the lungs, three significant features in pulmonary injury must be remembered: ( ) leukocytes can exit the vascular system through the alveolar capillaries, unlike in other tissues, where postcapillary venules are the sites of leukocytic diapedesis (extravasation); ( ) the intact lung contains within alveolar capillaries a large pool of resident leukocytes (marginated pool); and ( ) additional neutrophils are sequestered within alveolar capillaries within minutes of a local or systemic inflammatory response. these three pulmonary idiosyncrasies, along with the enormous length of the capillary network in the lung, explain why recruitment and migration of leukocytes into alveolar spaces develops so rapidly. experimental studies with aerosols of endotoxin or gram-negative bacteria have shown that within minutes of exposure, there is a significant increase in capillary leukocytes, and by hours the alveolar lumen is filled with neutrophils. not surprisingly, the bal fluid collected from patients with acute pneumonia contains large amounts of inflammatory mediators such as tnf-α, il- , and il- . also, the capillary endothelium of patients with acute pneumonia has increased "expression" of adhesion molecules, which facilitate the migration of leukocytes from capillaries into the alveolar interstitium and from there into the alveolar lumen. in allergic pulmonary diseases, eotaxin and il- are primarily responsible for recruitment and trafficking of eosinophils in the lung. movement of plasma proteins into the pulmonary interstitium and alveolar lumen is a common but poorly understood phenomenon in pulmonary inflammation. leakage of fibrinogen and plasma proteins into the alveolar space occurs when there is structural damage to the blood-air barrier. this leakage is also promoted by some types of cytokines that enhance procoagulant activity, whereas others reduce fibrinolytic activity. excessive exudation of fibrin into the alveoli is particularly common in ruminants and pigs. the fibrinolytic system plays a major role in the resolution of pulmonary inflammatory diseases. in some cases, excessive plasma proteins leaked into alveoli mix with necrotic type i pneumonocytes and pulmonary surfactant, forming microscopic eosinophilic bands (membranes) along the lining of alveolar septa. these membranes, known as hyaline membranes, are found in specific types of pulmonary diseases, particularly in ards, and in cattle with acute interstitial pneumonias such as bovine pulmonary edema and emphysema and extrinsic allergic alveolitis (see pneumonias of cattle). in the past few years, nitric oxide has been identified as a major regulatory molecule of inflammation in a variety of tissues, including the lung. produced locally by macrophages, pulmonary endothelium, and pneumonocytes, nitric oxide regulates the vascular and bronchial tone, modulates the production of cytokines, controls the recruitment and trafficking of neutrophils in the lung, and switches on/off genes involved in inflammation and immunity. experimental work has also shown that pulmonary surfactant upregulates the production of nitric oxide in the lung, supporting the current view that pneumonocytes are also pivotal in amplifying and downregulating the inflammatory and immune responses in the lung (see e- table - ). as the inflammatory process becomes chronic, the types of cells making up cellular infiltrates in the lung change from mainly neutrophils to largely mononuclear cells. this shift in cellular composition is accompanied by an increase in specific cytokines, such as failure. it also occurs in dogs with torsion of a lung lobe (fig. - ) . the gross features of infarcts vary considerably, depending on the stage, and they can be red to black, swollen, firm, and cone or wedge shaped, particularly at the lung margins. in the early acute stage, microscopic lesions are severely hemorrhagic, and this is followed by necrosis. in or days, a border of inflammatory cells develops, and a few days later, a large number of siderophages are present in the necrotic lung. if sterile, pulmonary infarcts heal as fibrotic scars; if septic, an abscess may form surrounded by a thick fibrous capsule. in the past three decades, an information explosion has increased the overall understanding of pulmonary inflammation, with so many proinflammatory and antiinflammatory mediators described to date that it would be impossible to review them all here (see chapters and ). pulmonary inflammation is a highly regulated process that involves a complex interaction between cells imported from the blood (platelets, neutrophils, eosinophils, mast cells, and lymphocytes) and pulmonary cells (type i and ii pneumonocytes; endothelial and club [clara] cells; alveolar and intravascular macrophages; and stromal interstitial cells, such as mast cells, interstitial macrophages, fibroblasts, and myofibroblasts). blood-borne leukocytes, platelets, and plasma proteins are brought into the areas of inflammation by an elaborate network of chemical signals emitted by pulmonary cells and resident leukocytes. long-distance communication between pulmonary cells and blood cells is largely done by soluble cytokines; once in the lung, imported leukocytes communicate with pulmonary and vascular cells through adhesion and other inflammatory molecules. the best known inflammatory mediators are the complement system (c a, c b, and c a), coagulation factors (factors v and vii), arachidonic acid metabolites (leukotrienes and prostaglandins), cytokines (interleukins, monokines, and chemokines), adhesion molecules (icam and vcam), neuropeptides (substance p, tachykinins, and neurokinins), enzymes and enzyme inhibitors (elastase and antitrypsin), oxygen metabolites (o •, oh•, and h o ), antioxidants (glutathione), and nitric oxide (e -table - ). acting in concert, these and many other molecules send positive or negative signals to initiate, maintain, and, it is hoped, resolve the inflammatory process without causing injury to the lung. chapter respiratory system, mediastinum, and pleurae e- with several episodes of hemorrhage are characterized by large areas of dark brown discoloration, largely in the caudal lung lobes. microscopically, lesions are alveolar hemorrhages, abundant alveolar macrophages containing hemosiderin (siderophages), mild alveolar fibrosis, and occlusive remodeling of pulmonary veins. recurrent airway obstruction. recurrent airway obstruction (rao) of horses, also referred to as copd, heaves, chronic bronchiolitis-emphysema complex, chronic small airway disease, alveolar emphysema, and "broken wind," is a common clinically asthma-like syndrome of horses and ponies. rao is characterized by recurrent respiratory distress, chronic cough, poor athletic performance, airway neutrophilia, bronchoconstriction, mucus hypersecretion, and airway obstruction. the pathogenesis is still obscure, but genetic predisposition, t h (allergic) immune response, and the exceptional sensitivity of airways to environmental allergens (hyperreactive airway disease) have been postulated as the basic underlying mechanisms. what makes small airways hyperreactive to allergens is still a matter of controversy. epidemiologic and experimental studies suggest that it could be the result of preceding bronchiolar damage caused by viral infections; ingestion of pneumotoxicants ( -methylindole); or prolonged exposure to organic dust, endotoxin, and environmental allergens (molds). it has been postulated that sustained inhalation of dust particles, whether antigenic or not, upregulates the production of cytokines (tnf-α, il- , and monokine-inducible protein ) and neuropeptides (neurokinin a [nka], neurokinin b [nkb], and substance p), attracting neutrophils into the bronchioloalveolar region and promoting leukocyte-induced bronchiolar injury. summer pasture-associated obstructive pulmonary disease (spaopd) is a seasonal airway disease also reported in horses with similar clinical and pathologic findings. more recently, the term inflammatory airway disease (iad) has been introduced in equine medicine to describe rao-like syndrome in young horses to years old. the lungs of horses with heaves are grossly unremarkable, except for extreme cases in which alveolar emphysema may be present. microscopically, the lesions are often remarkable and include goblet cell metaplasia in bronchioles; plugging of bronchioles with mucus mixed with few eosinophils and neutrophils (see fig. - ); peribronchiolar infiltration with lymphocytes, plasma cells, and variable numbers of eosinophils; and hypertrophy of smooth muscle in bronchi and bronchioles. in severe cases, accumulation of mucus leads to the complete obstruction of bronchioles and alveoli and resultant alveolar emphysema characterized by enlarged "alveoli" from the destruction of alveolar walls. feline asthma syndrome. feline asthma syndrome, also known as feline allergic bronchitis, is a clinical syndrome in cats of any age characterized by recurrent episodes of bronchoconstriction, cough, or dyspnea. the pathogenesis is not well understood but is presumed to originate, as in human asthma, as a type i hypersensitivity (igemast cell reaction) to inhaled allergens. dust, cigarette smoke, plant and household materials, and parasitic proteins have been incriminated as possible allergens. this self-limited allergic disease responds well to steroid therapy; thus it is rarely implicated as a primary cause of death except when suppressed defense mechanisms allow a secondary bacterial pneumonia. bronchial biopsies from affected cats at the early stages reveal mild to moderate inflammation characterized by mucosal edema and infiltration of leukocytes, particularly eosinophils. increased numbers of circulating eosinophils (blood eosinophilia) are present in some but not all cats with feline asthma. il- , interferon-γ (ifn-γ), and interferon-inducible protein (ip- ), which are chemotactic for lymphocytes and macrophages. under appropriate conditions, these cytokines activate t lymphocytes, regulate granulomatous inflammation, and induce the formation of multinucleated giant cells such as in mycobacterial infections. inflammatory mediators locally released from inflamed lungs also have a biologic effect in other tissue. for example, pulmonary hypertension and right-sided heart failure (cor pulmonale) often follows chronic alveolar inflammation, not only as a result of increased pulmonary blood pressure but also from the effect of inflammatory mediators on the contractibility of smooth muscle of the pulmonary and systemic vasculature. cytokines, particularly tnf-α, that are released during inflammation are associated, both as cause and as effect, with the systemic inflammatory response syndrome (sirs), sepsis, severe sepsis with multiple organ dysfunction, and septic shock (cardiopulmonary collapse). as it occurs in any other sentinel system where many biologic promoters and inhibitors are involved (coagulation, the complement and immune systems), the inflammatory cascade could go into an "out-of-control" state, causing severe damage to the lungs. acute lung injury (ali), extrinsic allergic alveolitis, ards, pulmonary fibrosis, and asthma are archetypical diseases that ensue from an uncontrolled production and release of cytokines (cytokine storm). as long as acute alveolar injury is transient and there is no interference with the normal host response, the entire process of injury, degeneration, necrosis, inflammation, and repair can occur in less than days. on the other hand, when acute alveolar injury becomes persistent or when the capacity of the host for repair is impaired, lesions can progress to an irreversible stage in which restoration of alveolar structure is no longer possible. in diseases, such as extrinsic allergic alveolitis, the constant release of proteolytic enzymes and free radicals by phagocytic cells perpetuates alveolar damage in a vicious circle. in other cases, such as in paraquat toxicity, the magnitude of alveolar injury can be so severe that type ii pneumonocytes, basement membranes, and alveolar interstitium are so disrupted that the capacity for alveolar repair is lost. fibronectins and transforming growth factors (tgfs) released from macrophages and other mononuclear cells at the site of chronic inflammation regulate the recruitment, attachment, and proliferation of fibroblasts. in turn, these cells synthesize and release considerable amounts of ecm (collagen, elastic fibers, or proteoglycans), eventually leading to fibrosis and total obliteration of normal alveolar architecture. in summary, in diseases in which there is chronic and irreversible alveolar damage, lesions invariably progress to a stage of terminal alveolar and interstitial fibrosis. for pneumonia, see section species-specific pneumonia of domestic animals. exercise-induced pulmonary hemorrhage. exercise-induced pulmonary hemorrhage (eiph) is a specific form of pulmonary hemorrhage in racehorses that occurs after exercise and clinically is characterized by epistaxis. because only a small percentage of horses with bronchoscopic evidence of hemorrhage have clinical epistaxis, it is likely that eiph goes undetected in many cases. the pathogenesis is still controversial, but current literature suggests laryngeal paralysis, bronchiolitis, and extremely high pulmonary vascular and alveolar pressures during exercise, alveolar hypoxia, and preexisting pulmonary injury as possible causes. eiph is seldom fatal; postmortem lesions in the lungs of horses that have been affected disease may be known by different names. in pigs, for instance, enzootic pneumonia and mycoplasma pneumonia refer to the same disease caused by mycoplasma hyopneumoniae. the word pneumonitis has been used by some as a synonym for pneumonia; however, others have restricted this term to chronic proliferative inflammation generally involving the alveolar interstitium and with little or no evidence of exudate. in this chapter, the word pneumonia is used for any inflammatory lesion in the lungs, regardless of whether it is exudative or proliferative, alveolar, or interstitial. on the basis of texture, distribution, appearance, and exudation, pneumonias can be grossly diagnosed into four morphologically distinct types: bronchopneumonia, interstitial pneumonia, embolic pneumonia, and granulomatous pneumonia. by using this classification, it is possible at the time of a necropsy to predict with some degree of certainty the likely cause (virus, bacteria, fungi, or parasites), routes of entry (aerogenous vs. hematogenous), and possible sequelae. these four morphologic types allow the clinician or pathologists to predict the most likely etiology and therefore facilitate the decision as to what samples need to be taken and which tests should be requested to the diagnostic laboratory (i.e., histopathology, bacteriology, virology, or toxicology). however, overlapping of these four types of pneumonias is possible, and sometimes two morphologic types may be present in the same lung. the criteria used to classify pneumonias grossly into bronchopneumonia, interstitial pneumonia, embolic pneumonia, and granulomatous pneumonia are based on morphologic changes, including distribution, texture, color, and general appearance of the affected lungs (table - ). distribution of the inflammatory lesions in the lungs can be ( ) cranioventral, as in most bronchopneumonias; ( ) multifocal, as in embolic pneumonias; ( ) diffuse, as in interstitial pneumonias; or ( ) locally extensive, as in granulomatous in the most advanced cases, chronic bronchoconstriction and excess mucus production may result in smooth muscle hyperplasia and obstruction of the bronchi and bronchioles and infiltration of the airway mucosa by eosinophils. a syndrome known as canine asthma has been reported in dogs but is not as well characterized as the feline counterpart. few subjects in veterinary pathology have caused so much debate as the classification of pneumonias. historically, pneumonias in animals have been classified or named based on the following: . presumed cause, with names such as viral pneumonia, pasteurella pneumonia, distemper pneumonia, verminous pneumonia, chemical pneumonia, and hypersensitivity pneumonitis . type of exudation, with names such as suppurative pneumonia, fibrinous pneumonia, and pyogranulomatous pneumonia . morphologic features, with names such as gangrenous pneumonia, proliferative pneumonia, and embolic pneumonia . distribution of lesions, with names such as focal pneumonia, cranioventral pneumonia, diffuse pneumonia, and lobar pneumonia . epidemiologic attributes, with names such as enzootic pneumonia, contagious bovine pleuropneumonia, and "shipping fever" . geographic regions, with names such as montana progressive pneumonia . miscellaneous attributes, with names such as atypical pneumonia, cuffing pneumonia, progressive pneumonia, aspiration pneumonia, pneumonitis, farmer's lung, and extrinsic allergic alveolitis until a universal and systematic nomenclature for animal pneumonias is established, veterinarians should be acquainted with this heterogeneous list of names and should be well aware that one the parts of the face with the tip of your finger has been advocated by some pathologists. the texture of a normal lung is comparable to the texture of the center of the cheek. firm consolidation is comparable to the texture of the tip of the nose, and hard consolidation is comparable to the texture of the forehead. the term consolidation is frequently used to describe a firm or hard lung filled with exudate. pneumonias ( fig. - ) . texture of pneumonic lungs can be firmer or harder (bronchopneumonias), more elastic (rubbery) than normal lungs (interstitial pneumonias), or have a nodular feeling (granulomatous pneumonias). describing in words the palpable difference between the texture of a normal lung compared with the firm or hard texture of a consolidated lung can be a difficult undertaking. an analogy illustrating this difference based on touching changes in the gross appearance of pneumonic lungs include abnormal color, the presence of nodules or exudate, fibrinous or fibrous adhesions, and the presence of rib imprints on serosal surfaces (see fig. - ). on cut surfaces, pneumonic lungs may have exudate, hemorrhage, edema, necrosis, abscesses, bronchiectasis, granulomas or pyogranulomas, and fibrosis, depending on the stage. palpation and careful observation of the lungs are essential in the diagnosis of pneumonia. (for details, see the section on examination of the respiratory tract.) bronchopneumonia refers to a particular morphologic type of pneumonia in which injury and the inflammatory process take place primarily in the bronchial, bronchiolar, and alveolar lumens. bronchopneumonia is undoubtedly the most common type of pneumonia seen in domestic animals and is with few exceptions characterized grossly by cranioventral consolidation of the lungs (fig. - and see fig. - ). the reason why bronchopneumonias in animals are almost always restricted to the cranioventral portions of the lungs is not well understood. possible factors contributing to this topographic selectivity within the lungs include ( ) gravitational sedimentation of the exudate, ( ) greater deposition of infectious organisms, ( ) inadequate defense mechanisms, ( ) reduced vascular perfusion, ( ) shortness and abrupt branching of airways, and ( ) regional differences in ventilation. the term cranioventral in veterinary anatomy is the equivalent of "anterosuperior" in human anatomy. the latter is defined as "in front (ventral) and above (cranial)." thus, applied to the lung of animals, "cranioventral" means the ventral portion of the cranial lobe. however, by common usage in veterinary pathology, the term cranioventral used to describe the location of lesions in pneumonias has come to mean "cranial and ventral." thus it includes pneumonias affecting not only the ventral portion of the cranial lobe (true cranioventral) but also those cases in which the pneumonia has involved the ventral portions of adjacent lung lobes-initially the middle and then caudal on the right and the caudal lobe on the left side. bronchopneumonias are generally caused by bacteria and mycoplasmas, by bronchoaspiration of feed or gastric contents, or by improper tubing. as a rule, the pathogens causing bronchopneumonias arrive in the lungs via inspired air (aerogenous), either from infected aerosols or from the nasal flora. before establishing infection, pathogens must overwhelm or evade the pulmonary defense mechanisms. the initial injury in bronchopneumonias is centered on the mucosa of bronchioles; from there, the inflammatory process can spread downward to distal portions of the alveoli and upward to the bronchi. typically, for bronchopneumonias, the inflammatory exudates collect in the bronchial, bronchiolar, and alveolar lumina leaving the alveolar interstitium relatively unchanged, except for hyperemia and possibly edema. through the pores of kohn, the exudate can spread to adjacent alveoli until most or all of the alveoli in an individual lobule are involved. if the inflammatory process cannot control the inciting cause of injury, the lesions spread rapidly from lobule to lobule through alveolar pores and destroyed alveolar walls until an entire lobe or large portion of a lung is involved. the lesion tends to spread centrifugally, with the older lesions in the center, and exudate can be coughed up and then aspirated into other lobules, where the inflammatory process starts again. at the early stages of bronchopneumonia, the pulmonary vessels are engorged with blood (active hyperemia), and the bronchi, bronchioles, and alveoli contain some fluid (permeability edema). in cases in which pulmonary injury is mild to moderate, cytokines locally released in the lung cause rapid recruitment of neutrophils and alveolar macrophages into bronchioles and alveoli ( fig. - and see fig. - ). when pulmonary injury is much more severe, proinflammatory cytokines induce more pronounced vascular changes by further opening endothelial gaps, thus increasing vascular permeability resulting in leakage of plasma fibrinogen (fibrinous exudates) and sometimes hemorrhage in the alveoli. alterations in permeability can be further exacerbated by structural damage to pulmonary capillaries and vessels directly caused by microbial toxins. filling of alveoli, bronchioles, and small bronchi with inflammatory exudate progressively obliterates airspaces, and as a consequence of this process, portions of severely affected (consolidated) lungs sink to the bottom of the container when placed in fixative. the replacement of air by exudate also changes the texture of the lungs, and depending on the severity of bronchopneumonia, the texture varies from firmer to harder than normal. the term consolidation is used at gross examination when the texture of pneumonic lung becomes firmer or harder than normal as a result of loss of airspaces because of exudation and atelectasis. (for details, see the discussion of lung texture in the section on classification of pneumonias in domestic animals). inflammatory consolidation of the lungs has been referred to in the past as hepatization because the affected lung had the appearance and texture of liver. the process was referred to as red hepatization in acute cases in which ( ) congestion, ( ) red hepatization (liver texture), ( ) gray hepatization, and ( ) resolution. because of the use of effective antibiotics and prevention, pneumococcal pneumonia and its four classic stages are rarely seen; thus this terminology has been largely abandoned. currently, the term bronchopneumonia is widely used for both suppurative and fibrinous consolidation of the lungs because both forms of inflammation have essentially the same pathogenesis in which the pathogens reach the lung by the aerogenous route, injury occurs initially in the bronchial and bronchiolar regions, and the inflammatory process extends centrifugally deep into the alveoli. it must be emphasized that it is the severity of pulmonary injury that largely determines whether bronchopneumonia becomes suppurative or fibrinous. in some instances, however, it is difficult to discriminate between suppurative and fibrinous bronchopneumonia because both types can coexist (fibrinosuppurative bronchopneumonia), and one type can progress to the other. suppurative bronchopneumonia. suppurative bronchopneumonia is characterized by cranioventral consolidation of lungs (see figs. - and - ), with typically purulent or mucopurulent exudate present in the airways. this exudate can be best demonstrated by expressing intrapulmonary bronchi, thus forcing exudate out of the bronchi (see fig. - ). the inflammatory process in suppurative bronchopneumonia is generally confined to individual lobules, and as a result of this distribution, the lobular pattern of the lung becomes notably emphasized. this pattern is particularly obvious in cattle and pigs because these species have prominent lobulation of the lungs. the gross appearance often resembles an irregular checkerboard because of an admixture of normal and abnormal (consolidated) lobules (see fig. - ). because of this typical lobular distribution, suppurative bronchopneumonias are also referred to as lobular pneumonias. different inflammatory phases occur in suppurative bronchopneumonia where the color and appearance of consolidated lungs varies considerably, depending on the virulence of offending organisms and chronicity of the lesion. the typical phases of suppurative bronchopneumonia can be summarized as follows: . during the first hours when bacteria are rapidly multiplying, the lungs become hyperemic and edematous. . soon after, neutrophils start filling the airways, and by hours the parenchyma starts to consolidate and becomes firm in texture. . three to days later, hyperemic changes are less obvious, but the bronchial, bronchiolar, and alveolar spaces continue to fill with neutrophils and macrophages, and the affected lung sinks when placed in formalin. at this stage, the affected lung has a gray-pink color, and on cut surface, purulent exudate can be expressed from bronchi. . in favorable conditions where the infection is under control of the host defense mechanisms, the inflammatory processes begin to regress, a phase known as resolution. complete resolution in favorable conditions could take to weeks. . in animals in which the lung infection cannot be rapidly contained, inflammatory lesions can progress into a chronic phase. approximately to days after infection, the lungs become pale gray and take a "fish flesh" appearance. this appearance is the result of purulent and catarrhal inflammation, obstructive atelectasis, mononuclear cell infiltration, peribronchial and peribronchiolar lymphoid hyperplasia, and early alveolar fibrosis. complete resolution is unusual in chronic bronchopneumonia, and lung scars, such as pleural and pulmonary fibrosis; bronchiectasis as a consequence of chronic destructive bronchitis (see bronchiectasis [dysfunction/responses to injury and patterns of injury]); atelectasis; pleural adhesions; and lung abscesses may remain unresolved there was notable active hyperemia with little exudation of neutrophils; conversely, the process was referred to as gray hepatization in those chronic cases in which hyperemia was no longer present, but there was abundant exudation of neutrophils and macrophages. this terminology, although used for and applicable to human pneumonias, is rarely used in veterinary medicine primarily because the evolution of pneumonic processes in animals does not necessarily follow the red-to-gray hepatization pattern. bronchopneumonia can be subdivided into suppurative bronchopneumonia if the exudates are predominantly composed of neutrophils and fibrinous bronchopneumonia if fibrin is the predominant component of the exudates (see table - ). it is important to note that some veterinarians use the term fibrinous pneumonia or lobar pneumonia as a synonym for fibrinous bronchopneumonia, and bronchopneumonia or lobular pneumonia as a synonym for suppurative bronchopneumonia. human pneumonias for many years have been classified based on their etiology and morphology, which explains why pneumococcal pneumonia (streptococcus pneumoniae) has been synonymous with lobar pneumonia. in the old literature, four distinct stages of pneumococcal pneumonia were described as lumen of bronchiole capillary pulmonary defense mechanisms to allow them to colonize the lungs and establish an infection. suppurative bronchopneumonia can also result from aspiration of bland material (e.g., milk). pulmonary gangrene may ensue when the bronchopneumonic lung is invaded by saprophytic bacteria (aspiration pneumonia). fibrinous bronchopneumonia. fibrinous bronchopneumonia is similar to suppurative bronchopneumonia except that the predominant exudate is fibrinous rather than neutrophilic. with only a few exceptions, fibrinous bronchopneumonias also have a cranioventral distribution (fig. - and see fig. - ) . however, exudation is not restricted to the boundaries of individual pulmonary lobules, as is the case in suppurative bronchopneumonias. instead, the inflammatory process in fibrinous pneumonias involves numerous contiguous lobules and the exudate moves quickly through pulmonary tissue until the entire pulmonary lobe is rapidly affected. because of the involvement of the entire lobe and pleural surface, fibrinous bronchopneumonias are also referred to as lobar pneumonias or pleuropneumonias. in general terms, fibrinous bronchopneumonias are the result of more severe pulmonary injury and thus cause death earlier in the sequence of the inflammatory process than suppurative bronchopneumonias. even in cases in which fibrinous bronchopneumonia involves % or less of the total area, clinical signs and death can occur as a result of severe toxemia and sepsis. the gross appearance of fibrinous bronchopneumonia depends on the age and severity of the lesion and on whether the pleural surface or the cut surface of the lung is viewed. externally, early stages of fibrinous bronchopneumonias are characterized by severe congestion and hemorrhage, giving the affected lungs a characteristically intense red discoloration. a few hours later, fibrin starts to permeate and accumulate on the pleural surface, giving the pleura a ground glass appearance and eventually forming plaques of fibrinous exudate over a red, dark lung (see fig. - ). at this stage, a yellow fluid starts to accumulate in the thoracic cavity. the color of fibrin deposited over the pleural surface is also variable. it can be bright yellow when the exudate is formed primarily by fibrin, tan when fibrin is mixed with blood, and gray when a large number of leukocytes and fibroblasts are part of the fibrinous plaque in more chronic cases. because of the tendency of fibrin to deposit on the pleural surface, some pathologists use the term pleuropneumonia as a synonym for fibrinous bronchopneumonia. on the cut surface, early stages of fibrinous bronchopneumonia appear as simple red consolidation. in more advanced cases ( hours), fibrinous bronchopneumonia is generally accompanied by notable dilation and thrombosis of lymph vessels and edema of interlobular septa (see fig. - , b) . this distention of the interlobular septa gives affected lungs a typical marbled appearance. distinct focal areas of coagulative necrosis in the pulmonary parenchyma are also common in fibrinous bronchopneumonia such as in shipping fever pneumonia and contagious bovine pleuropneumonia. in animals that survive the early stage of fibrinous bronchopneumonia, pulmonary necrosis often develops into pulmonary "sequestra," which are isolated pieces of necrotic lung encapsulated by connective tissue. pulmonary sequestra result from extensive necrosis of lung tissue either from severe ischemia (infarct) caused by thrombosis of a major pulmonary vessel such as in contagious bovine pleuropneumonia or from the effect of necrotizing toxins released by pathogenic bacteria such as mannheimia haemolytica. sequestra in veterinary pathology should not be confused with "bronchopulmonary sequestration," a term used in human pathology to describe a congenital malformation in which whole lobes or parts of the lung develop without normal connections to the airway or vascular systems. for a long time. "enzootic pneumonias" of ruminants and pigs are typical examples of chronic suppurative bronchopneumonias. microscopically, acute suppurative bronchopneumonias are characterized by hyperemia, abundant neutrophils, macrophages, and cellular debris within the lumen of bronchi, bronchioles, and alveoli (see fig. - ). recruitment of leukocytes is promoted by cytokines, complement, and other chemotactic factors that are released in response to alveolar injury or by the chemotactic effect of bacterial toxins, particularly endotoxin. in most severe cases, purulent or mucopurulent exudates completely obliterate the entire lumen of bronchi, bronchioles, and alveoli. if suppurative bronchopneumonia is merely the response to a transient pulmonary injury or a mild infection, lesions resolve uneventfully. within to days, cellular exudate can be removed from the lungs via the mucociliary escalator, and complete resolution may take place within weeks. in other cases, if injury or infection is persistent, suppurative bronchopneumonia can become chronic with goblet cell hyperplasia, an important component of the inflammatory process. depending on the proportion of pus and mucus, the exudate in chronic suppurative bronchopneumonia varies from mucopurulent to mucoid. a mucoid exudate is found in the more chronic stages when the consolidated lung has a "fish flesh" appearance. hyperplasia of balt is another change commonly seen in chronic suppurative bronchopneumonias; it appears grossly as conspicuous white nodules (cuffs) around bronchial walls (cuffing pneumonia). this hyperplastic change merely indicates a normal reaction of lymphoid tissue to infection. further sequelae of chronic suppurative bronchopneumonia include bronchiectasis (see figs. - and - ), pulmonary abscesses, pleural adhesions (from pleuritis) ( fig. - ) , and atelectasis and emphysema from completely or partially obstructed bronchi or bronchioles (e.g., bronchiectasis). clinically, suppurative bronchopneumonias can be acute and fulminating but are often chronic, depending on the etiologic agent, stressors affecting the host, and immune status. the most common pathogens causing suppurative bronchopneumonia in domestic animals include pasteurella multocida, bordetella bronchiseptica, trueperella (arcanobacterium) pyogenes, streptococcus spp., escherichia coli, and several species of mycoplasmas. most of these organisms are secondary pathogens requiring a preceding impairment of the fulminating hemorrhagic bronchopneumonia can be caused by highly pathogenic bacteria such as bacillus anthracis. although the lesions in anthrax are primarily related to a severe septicemia and sepsis, anthrax should always be suspected in animals with sudden death and exhibiting severe acute fibrinohemorrhagic pneumonia, splenomegaly, and multisystemic hemorrhages. animals are considered good sentinels for anthrax in cases of bioterrorism. interstitial pneumonia refers to that type of pneumonia in which injury and the inflammatory process take place primarily in any microscopically, in the initial stage of fibrinous bronchopneumonia, there is massive exudation of plasma proteins into the bronchioles and alveoli, and as a result, most of the airspaces become obliterated by fluid and fibrin. leakage of fibrin and fluid into alveolar lumina is due to extensive disruption of the integrity and increased permeability of the blood-air barrier. fibrinous exudates can move from alveolus to alveolus through the pores of kohn. because fibrin is chemotactic for neutrophils, these types of leukocytes are always present a few hours after the onset of fibrinous inflammation. as inflammation progresses ( to days), fluid exudate is gradually replaced by fibrinocellular exudates composed of fibrin, neutrophils, macrophages, and necrotic debris ( fig. - ). in chronic cases (after days), there is notable fibrosis of the interlobular septa and pleura. in contrast to suppurative bronchopneumonia, fibrinous bronchopneumonia rarely resolves completely, thus leaving noticeable scars in the form of pulmonary fibrosis and pleural adhesions. the most common sequelae found in animals surviving an acute episode of fibrinous bronchopneumonia include alveolar fibrosis and bronchiolitis obliterans, in which organized exudate becomes attached to the bronchiolar lumen (see fig. - ) . these changes are collectively referred to as bronchiolitis obliterans organizing pneumonia (boop), a common microscopic finding in animals with unresolved bronchopneumonia. other important sequelae include pulmonary gangrene, when saprophytic bacteria colonize necrotic lung; pulmonary sequestra; pulmonary fibrosis; abscesses; and chronic pleuritis with pleural adhesions. in some cases, pleuritis can be so extensive that fibrous adhesions extend onto the pericardial sac. pathogens causing fibrinous bronchopneumonias in domestic animals include mannheimia (pasteurella) haemolytica (pneumonic mannheimiosis), histophilus somni (formerly haemophilus somnus), actinobacillus pleuropneumoniae (porcine pleuropneumonia), mycoplasma bovis, and mycoplasma mycoides ssp. mycoides small colony type (contagious bovine pleuropneumonia). fibrinous broncho- a b n alveolar epithelium. inhaled antigens, such as fungal spores, combine with circulating antibodies and form deposits of antigen-antibody complexes (type iii hypersensitivity) in the alveolar wall, which initiate a cascade of inflammatory responses and injury (allergic alveolitis). hematogenous injury to the vascular endothelium occurs in septicemias, sepsis, dic, larva migrans (ascaris suum), toxins absorbed in the alimentary tract (endotoxin) or toxic metabolites locally generated in the lungs ( -methylindole and paraquat), release of free radicals in alveolar capillaries (ards), and infections with endotheliotropic viruses (canine adenovirus and classical swine fever [hog cholera]). interstitial pneumonias in domestic animals and human beings are subdivided based on morphologic features into acute and chronic. it should be kept in mind, however, that not all acute interstitial pneumonias are fatal and that they do not necessarily progress to the chronic form. acute interstitial pneumonias. acute interstitial pneumonias begin with injury to either type i pneumonocytes or alveolar capillary endothelium, which provokes a disruption of the blood-air barrier and a subsequent exudation of plasma proteins into the alveolar space (see fig. - ) . this leakage of proteinaceous fluid into the alveolar lumen constitutes the exudative phase of acute interstitial pneumonia. in some cases of diffuse alveolar damage, exuded plasma proteins mix with lipids and other components of pulmonary surfactant and form elongated membranes that become partially attached to the alveolar basement membrane and bronchiolar walls. these membranes are referred to as hyaline membranes because of their hyaline appearance (eosinophilic, homogeneous, and amorphous) microscopically (see figs. - and - ). in addition to intraalveolar exudation of fluid, inflammatory edema and neutrophils accumulate in the alveolar interstitium and cause thickening of the alveolar walls. this acute exudative phase is generally followed a few days later by the proliferative phase of acute interstitial pneumonia, which is characterized by hyperplasia of type ii pneumonocytes to replace the lost type i pneumonocytes (see fig. - ). type ii pneumonocytes are in fact progenitor cells that differentiate and replace necrotic type i pneumonocytes (see fig. - ) . as a consequence, the alveolar walls become increasingly thickened. this process is in part the reason why lungs become rubbery on palpation, what prevents their normal collapse after the thorax is opened, and why the cut surface of the lung has a "meaty" appearance (see fig. - ). of the three layers of the alveolar walls (endothelium, basement membrane, and alveolar epithelium) and the contiguous bronchiolar interstitium (see fig. - ) . this morphologic type of pneumonia is the most difficult to diagnose at necropsy and requires microscopic confirmation because it is easily mistaken in the lung showing congestion, edema, hyperinflation, or emphysema. in contrast to bronchopneumonias, in which distribution of lesions is generally cranioventral, in interstitial pneumonias, lesions are more diffusely distributed and generally involve all pulmonary lobes, or in some cases, they appear to be more pronounced in the dorsocaudal aspects of the lungs (see fig. - ). three important gross features of interstitial pneumonia are ( ) the failure of lungs to collapse when the thoracic cavity is opened, ( ) the occasional presence of rib impressions on the pleural surface of the lung indicating poor deflation, and ( ) the lack of visible exudates in airways unless complicated with secondary bacterial pneumonia. the color of affected lungs varies from diffusely red in acute cases to diffusely pale gray to a mottled red, pale appearance in chronic ones. pale lungs are caused by severe obliteration of alveolar capillaries (reduced blood-tissue ratio), especially evident when there is fibrosis of the alveolar walls. the texture of lungs with uncomplicated interstitial pneumonia is typically elastic or rubbery, but definitive diagnosis based on texture alone is difficult and requires histopathologic examination. on a cut surface, the lungs may appear and feel more "meaty" (having the texture of raw meat) and have no evidence of exudate in the bronchi or pleura (fig. - ). in acute interstitial pneumonias, particularly in cattle, there is frequently pulmonary edema (exudative phase) and interstitial emphysema secondary to partial obstruction of bronchioles by edema fluid and strenuous air gasping before death. because edema tends to gravitate into the cranioventral portions of the lungs, and emphysema is often more obvious in the dorsocaudal aspects, acute interstitial pneumonias in cattle occasionally have a gross cranioventral-like pattern that may resemble bronchopneumonia, although the texture is different. lungs are notably heavy because of the edema and the infiltrative and proliferative changes. the pathogenesis of interstitial pneumonia is complex and can result from aerogenous injury to the alveolar epithelium (type i and ii pneumonocytes) or from hematogenous injury to the alveolar capillary endothelium or alveolar basement membrane. aerogenous inhalation of toxic gases (i.e., ozone and no ) or toxic fumes (smoke inhalation) and infection with pneumotropic viruses (influenza, herpesviruses, or canine distemper virus) can damage the figure - interstitial pneumonia, lung, feeder pig. a, the lung is heavy, pale, and rubbery in texture. it also has prominent costal (rib) imprints (arrows), a result of hypercellularity of the interstitium and the failure of the lungs to collapse when the thorax was opened. b, transverse section. the pulmonary parenchyma has a "meaty" appearance and some edema, but no exudate is present in airways or on the pleural surface. this type of lung change in pigs is highly suggestive of a viral pneumonia. (courtesy dr. a. lópez, atlantic veterinary college.) pneumonia are centered in the alveolar wall and its interstitium, a mixture of desquamated epithelial cells, macrophages, and mononuclear cells are usually present in the lumens of bronchioles and alveoli. ovine progressive pneumonia, hypersensitivity pneumonitis in cattle and dogs, and silicosis in horses are good veterinary examples of chronic interstitial pneumonia. pneumoconioses (silicosis and asbestosis), paraquat toxicity, pneumotoxic antineoplastic drugs (bleomycin), and extrinsic allergic alveolitis (farmer's lung) are well-known examples of diseases that lead to chronic interstitial pneumonias in human beings. massive pulmonary migration of ascaris larvae in pigs also causes interstitial pneumonia ( fig. - ). there is an insidious and poorly understood group of chronic idiopathic interstitial diseases, both in human beings and in animals, that eventually progress to terminal interstitial fibrosis. these were originally thought to be the result of repeated cycles of alveolar injury, inflammation, and fibroblastic/myoblastic response to an unknown agent. however, aggressive antiinflammatory therapy generally fails to prevent or reduce the severity of fibrosis. now, it is acute interstitial pneumonias are often mild and transient, especially those caused by some respiratory viruses, such as those responsible for equine and porcine influenza. these mild forms of pneumonia are rarely seen in the postmortem room because they are not fatal and do not leave significant sequelae (see the section on defense mechanisms/barrier systems). in severe cases of acute interstitial pneumonias, animals may die of respiratory failure, usually as a result of diffuse alveolar damage, a profuse exudative phase (leakage of proteinaceous fluid) leading to a fatal pulmonary edema. examples of this type of fatal acute interstitial pneumonia are bovine pulmonary edema and emphysema, and ards in all species. chronic interstitial pneumonia. when the source of alveolar injury persists, the exudative and proliferative lesions of acute interstitial pneumonia can progress into a morphologic stage referred to as chronic interstitial pneumonia. the hallmark of chronic interstitial pneumonia is fibrosis of the alveolar walls (with or without intraalveolar fibrosis) and the presence of lymphocytes, macrophages, fibroblasts, and myofibroblasts in the alveolar interstitium (figs. - and - ). in other cases, these chronic changes are accompanied by hyperplasia and persistence of type ii pneumonocytes, squamous metaplasia of the alveolar epithelium, microscopic granulomas, and hyperplasia of smooth muscle in bronchioles and pulmonary arterioles. it should be emphasized that although the lesions in interstitial the term bronchointerstitial pneumonia is used in veterinary pathology to describe cases in which microscopic lesions share some histologic features of both bronchopneumonia and interstitial pneumonia (e- fig. - ). this combined type of pneumonia is in fact frequently seen in many viral infections in which viruses replicate and cause necrosis in bronchial, bronchiolar, and alveolar cells. damage to the bronchial and bronchiolar epithelium causes an influx of neutrophils similar to that in bronchopneumonias, and damage to alveolar walls causes proliferation of type ii pneumonocytes, similar to that which takes place in the proliferative phase of acute interstitial pneumonias. it is important to emphasize that bronchointerstitial pneumonia is a microscopic not a gross diagnosis. examples include uncomplicated cases of respiratory syncytial virus infections in cattle and lambs, canine distemper, and influenza in pigs and horses. embolic pneumonia refers to a particular type of pneumonia in which gross and microscopic lesions are multifocally distributed in all pulmonary lobes. by definition, lung injury is hematogenous, and the inflammatory response is typically centered in pulmonary arterioles and alveolar capillaries. lungs act as a biologic filter for circulating particulate matter. sterile thromboemboli, unless extremely large, are rapidly dissolved and removed from the pulmonary vasculature by fibrinolysis, causing little, if any, ill effects. experimental studies have confirmed that most types of bacteria when injected intravenously (bacteremia) are phagocytosed by pulmonary intravascular macrophages, or they bypass the lungs and are finally trapped by macrophages in the liver, spleen, joints, or other organs. to cause pulmonary infection, circulating bacteria must first attach to the pulmonary endothelium with specific binding proteins or simply attach to intravascular fibrin and then evade phagocytosis by intravascular macrophages or leukocytes. septic thrombi facilitate entrapment of bacteria in the pulmonary vessels and provide a favorable environment to escape phagocytosis. once trapped in the pulmonary vasculature, usually in small arterioles or alveolar capillaries, offending bacteria disrupt endothelium and basement membranes, spread from the vessels to the interstitium and then to the surrounding lung, finally forming a new nidus of infection. embolic pneumonia is characterized by multifocal lesions randomly distributed in all pulmonary lobes (see fig. - and e-figs. - and - ). early lesions in embolic pneumonia are characterized grossly by the presence of very small ( to mm), white foci surrounded by discrete, red, hemorrhagic halos ( fig. - ). unless emboli arrive in massive numbers, causing fatal pulmonary edema, embolic pneumonia is seldom fatal; therefore these acute lesions are rarely seen at postmortem examination. in most instances, if unresolved, acute lesions rapidly progress to pulmonary abscesses. these are randomly distributed in all pulmonary lobes and are not restricted to the cranioventral aspects of the lungs, as is the case of abscesses developing from suppurative bronchopneumonia. the early microscopic lesions in embolic pneumonias are always focal or multifocal ( fig. - ) ; thus they differ from those of endotoxemia or septicemia, in which endothelial damage and interstitial reactions (interstitial pneumonia) are diffusely distributed in the lungs. when embolic pneumonia or its sequela (abscesses) is diagnosed at necropsy, an attempt should be made to locate the source of septic emboli. the most common sources are hepatic abscesses that have ruptured into the caudal vena cava in cattle, omphalophlebitis in farm animals, chronic bacterial skin or hoof infections, and a contaminated catheter in all species (see fig. - ) . valvular or mural endocarditis in the right heart is a common source of septic emboli and embolic pneumonia in all species. most frequently, bacterial proposed that a genetic mutation alters the cell-cell communication between epithelial and mesenchymal cells in the lung. this aberrant cellular communication leads to an overexpression of inflammatory and repair molecules (i.e., il- , il- , tgf-β , and caveolin), leading to increased apoptosis and interstitial deposition of extracellular matrix (ecm). the chronic interstitial (restrictive) diseases in human medicine include "idiopathic pulmonary fibrosis," "nonspecific interstitial pneumonia," "unusual interstitial pneumonia," and "cryptogenic organizing pneumonia," also referred to as idiopathic bronchiolitis obliterans organizing pneumonia (idiopathic boop). feline idiopathic pulmonary fibrosis is an example of this type of progressive interstitial disease in veterinary medicine. it has been reported that in rare cases, chronic alveolar remodeling and interstitial fibrosis can progress to lung cancer. the lung has numerous circular areas of hemorrhage distributed randomly throughout all lung lobes (embolic pattern [see fig. - ]). these foci arise from injury to the microvasculature in alveolar septa and the visceral pleura secondary to lodgment of bacterial or fungal emboli (septic emboli) from valvular or mural endocarditis in the right heart or from other bacterial or fungal diseases where the bacterium or fungus gains access to the circulatory system as occurs in many bacterial and fungal enteritides or pneumonias caused by salmonella spp., e. coli, or aspergillus spp. the pathogenesis of granulomatous pneumonia shares some similarities with that of interstitial and embolic pneumonias. not surprisingly, some pathologists group granulomatous pneumonias within one of these types of pneumonias (e.g., granulomatous interstitial pneumonia). what makes granulomatous pneumonia a distinctive type is not so much the portal of entry or site of initial injury in the lungs but, rather, the unique type of inflammatory response that results in the formation of granulomas, which can be easily recognized at gross and microscopic examination. as a rule, agents causing granulomatous pneumonias are resistant to intracellular killing by phagocytic cells and to the acute inflammatory response, allowing prolonged persistence of these agents in tissues. the most common causes of granulomatous pneumonia in animals include systemic fungal diseases, such as cryptococcosis (cryptococcus neoformans and cryptococcus gatti), coccidioidomycosis (coccidioides immitis), histoplasmosis (histoplasma capsulatum), and blastomycosis (blastomyces dermatitidis) (see fig. - ). in most of these fungal diseases, the port of entry is aerogenous, and from the lungs the fungi disseminate systemically to other organs, particularly the lymph nodes, liver, and spleen. filamentous fungi such as aspergillus spp. or mucor spp. can also reach the lung by the hematogenous route. granulomatous pneumonia is also seen in some bacterial diseases, such as tuberculosis (mycobacterium bovis) in all species and rhodococcus equi in horses. sporadically, aberrant parasites such as fasciola hepatica in cattle and aspiration of foreign bodies can also cause granulomatous pneumonia (e- fig. - granulomatous pneumonia is characterized by the presence of variable numbers of caseous or noncaseous granulomas randomly distributed in the lungs (see fig. - ). on palpation, lungs have a typical nodular character given by well-circumscribed, variably sized nodules that generally have a firm texture, especially if calcification has occurred ( fig. - ) . during postmortem examination, granulomas in the lungs occasionally can be mistaken for neoplasms. microscopically, pulmonary granulomas are composed of a center of necrotic tissue, surrounded by a rim of macrophages (epithelioid cells) and giant cells and an outer delineated layer of connective tissue commonly infiltrated by lymphocytes and plasma cells ( fig. - ). unlike other types of pneumonias, the causative agent in granulomatous pneumonia can, in many cases, be identified isolates from septic pulmonary emboli in domestic animals are trueperella (arcanobacterium) pyogenes (cattle), fusobacterium necrophorum (cattle, pigs, and human beings), erysipelothrix rhusiopathiae (pigs, cattle, dogs, and human beings), streptococcus suis (pigs), staphylococcus aureus (dogs and human beings), and streptococcus equi (horses). granulomatous pneumonia refers to a particular type of pneumonia in which aerogenous or hematogenous injury is caused by organisms or particles that cannot normally be eliminated by phagocytosis and that evoke a local inflammatory reaction with numerous alveolar and interstitial macrophages, lymphocytes, a few neutrophils, and sometimes giant cells. the term granulomatous is used here to describe an anatomic pattern of pneumonia typically characterized by the presence of granulomas. g g but yet unproven that viral infections may also predispose horses to airway hyperresponsiveness and recurrent airway obstruction (rao). equine influenza. equine influenza is an important and highly contagious flulike respiratory disease of horses characterized by high morbidity and low mortality and explosive outbreaks in susceptible populations. it is an oie-notifiable disease. two antigenically unrelated subtypes of equine influenza virus have been identified (h n [a/equi- ] and h n [a/equi- ]). the course of the disease is generally mild and transient, and its importance is primarily because of its economic impact on horse racing. the types of injury and host response in the conducting system are described in the section on disorders of the nasal cavity and paranasal sinuses of horses. uncomplicated lesions in the lungs are mild and self-limiting bronchointerstitial pneumonia. in fatal cases, the lungs are hyperinflated with coalescing areas of dark red discoloration. microscopically, there is a bronchointerstitial pneumonia characterized by necrotizing bronchiolitis that is followed by hyperplastic bronchiolitis, hyperplasia of type ii pneumonocytes, hyaline membranes in alveoli, and sporadic multinucleated giant cells. the microscopic changes are ards in severe and fatal cases. the influenza virus antigen can be readily demonstrated in ciliated cells and alveolar macrophages. clinical signs are characterized by fever, cough, abnormal lung sounds (crackles and wheezes), anorexia, and depression. secondary bacterial infections (streptococcus equi, streptococcus zooepidemicus, staphylococcus aureus, and escherichia coli) commonly complicate equine influenza. equine viral rhinopneumonitis. equine viral rhinopneumonitis (evr), or equine herpesvirus infection, is a respiratory disease of young horses that is particularly important in weanlings between and months of age and to a much lesser extent in young foals and adult horses. the causative agents are ubiquitous equine herpesviruses (ehv- and ehv- ) that in addition to respiratory disease can cause abortion in pregnant mares and neurologic disease (equine herpes myeloencephalopathy) (see the section on disorders of the nasal cavity and paranasal sinuses of horses). the respiratory form of evr is a mild and a transient bronchointerstitial pneumonia seen only by pathologists when complications with secondary bacterial infections cause a fatal bronchopneumonia microscopically in sections by pas reaction or grocott-gomori's methenamine silver (gms) stain for fungi or by an acid-fast stain for mycobacteria. viral infections of the respiratory tract, particularly equine viral rhinopneumonitis and equine influenza, are important diseases of horses throughout the world. the effects of these and other respiratory viruses on the horse can be manifested in three distinct ways. first, as pure viral infections, their severity may range from mild to severe, making them a frequent interfering factor in training and athletic performance. second, superimposed infections by opportunistic bacteria, such as streptococcus spp., escherichia coli, klebsiella pneumoniae, rhodococcus equi, and various anaerobes, can cause fibrinous or suppurative bronchopneumonias. third, it is possible equine henipavirus (hendra virus). fatal cases of a novel respiratory disease in horses and human beings suddenly appeared in approximately in hendra, a suburb of brisbane, australia. this outbreak was attributed to a newly recognized zoonotic virus that was tentatively named equine morbillivirus. now called hendra virus (hev), this emerging viral pathogen is currently classified as a member of the genus henipavirus (includes hendra virus and nipah virus), in the family paramyxoviridae. fruit bats (flying foxes) act as natural reservoirs and are involved in the transmission by poorly understood mechanisms. the lungs of affected horses are severely edematous with gelatinous distention of pleura and subpleural lymph vessels. microscopically, the lungs have diffuse alveolar edema associated with vasculitis, thrombosis, and the presence of multinucleated syncytial cells in the endothelium of small pulmonary blood vessels and alveolar capillaries. the lymphatic vessels are notably distended with fluid. the characteristic inclusion bodies seen in other paramyxovirus infections are not seen in horses; however, the virus can be easily detected by immunohistochemistry in pulmonary endothelial cells and alveolar epithelial cells (pneumonocytes). clinical signs are nonspecific and include fever, anorexia, respiratory distress, and nasal discharge. equine multinodular pulmonary fibrosis. equine multinodular pulmonary fibrosis is a lung disease characterized by well-demarcated fibrotic nodular lesions in the lung (e- fig. - ). until recently, the pathogenesis was unclear, but recent studies proposed equine herpesvirus (ehv- ) as the putative etiology. grossly, the lungs show multifocal to coalescing, firm tan nodules scattered in all pulmonary lobes, which resemble pulmonary neoplasia. microscopically, alveolar walls are thickened due to collagen deposition, infiltration of lymphocytes and macrophages, and cuboidal cells lining the alveolar walls. the alveolar lumens contain neutrophils and macrophages, some of which may contain a large eosinophilic intranuclear inclusion body. typical clinical signs include weight loss, low-grade fever, and progressive exercise intolerance. this condition has a poor prognosis. rhodococcus equi. rhodococcus equi is an important cause of morbidity and mortality in foals throughout the world. this facultative intracellular gram-positive bacterium causes two major forms of disease: the first involves the intestine, causing ulcerative enterocolitis, and the second severe and often fatal bronchopneumonia. although half of foals with pneumonia have ulcerative enterocolitis, it is rare to find animals with intestinal lesions alone. occasionally, infection disseminates to lymph nodes, joints, bones, the genital tract, and other organs. because rhodococcus equi is present in soil and feces of herbivores (particularly foals), it is common for the disease to become enzootic on farms ("hot spots") where the organism has been shed earlier by infected foals. serologic evidence of infection in horses is widespread, yet clinical disease is sporadic and largely restricted to young foals or to adult horses with severe immunosuppression. virulence factors encoded by plasmids (virulenceassociated protein a [vapa gene]) are responsible for the survival and replication of rhodococcus equi in macrophages, thus determining the evolution of the disease. this bacterium has also been sporadically incriminated with infections in cattle, goats, pigs, dogs, and cats, and quite often in immunocompromised human beings, for example, those infected with the aids virus, after organ transplantation, or undergoing chemotherapy. it is still debatable whether natural infection starts as a bronchopneumonia (aerogenous route) from which rhodococcus equi reaches the intestine via swallowed sputum or whether infection starts as an enteritis (oral route) with a subsequent bacteremia into the lungs. (streptococcus equi, streptococcus zooepidemicus, or staphylococcus aureus) . uncomplicated lesions in evr are seen only in aborted fetuses or in foals that die within the first few days of life. they consist of focal areas of necrosis ( . to mm) in various organs, including liver, adrenal glands, and lungs. in some cases, intranuclear inclusion bodies are microscopically observed in these organs. outbreaks of interstitial pneumonia in donkeys have been attributed to multiple strains of asinine herpesviruses (ahv- and - ). clinically, horses and donkeys affected with the respiratory form of evr exhibit fever, anorexia, conjunctivitis, cough, and nasal discharge. equine viral arteritis. equine viral arteritis (eva), a pansystemic disease of horses, donkeys, and mules caused by an arterivirus (equine arteritis virus [eav]), occurs sporadically throughout the world, sometimes as an outbreak. this virus infects and causes severe injury to macrophages and endothelial cells. gross lesions are hemorrhage and edema in many sites, including lungs, intestine, scrotum, and periorbital tissues and voluminous hydrothorax and hydroperitoneum. the basic lesion is fibrinoid necrosis and inflammation of the vessel walls (vasculitis), particularly the small muscular arteries (lymphocytic arteritis), which is responsible for the edema and hemorrhage that explain most of the clinical features. pulmonary lesions are those of interstitial pneumonia with hyperplasia of type ii pneumonocytes and vasculitis with abundant edema in the bronchoalveolar spaces and distended pulmonary lymphatic vessels. viral antigen can be detected by immunoperoxidase techniques in the walls and endothelial cells of affected pulmonary vessels and in alveolar macrophages. clinical signs are respiratory distress, fever, abortion, diarrhea, colic, and edema of the limbs and ventral abdomen. respiratory signs are frequent and consist of serous or mucopurulent rhinitis and conjunctivitis with palpebral edema. like most viral respiratory infections, eva can predispose horses to opportunistic bacterial pneumonias. african horse sickness. african horse sickness (ahs) is an arthropod-borne, oie-notifiable disease of horses, mules, donkeys, and zebras that is caused by an orbivirus (family reoviridae) and characterized by respiratory distress or cardiovascular failure. ahs has a high mortality rate-up to % in the native population of horses in africa, the middle east, india, pakistan, and, most recently, spain and portugal. although the ahs virus is transmitted primarily by insects (culicoides) to horses, other animals, such as dogs, can be infected by eating infected equine flesh. the pathogenesis of african horse sickness remains unclear, but this equine orbivirus has an obvious tropism for pulmonary and cardiac endothelial cells and, to a lesser extent, mononuclear cells. based on clinical signs (not pathogenesis), african horse sickness is arbitrarily divided into four different forms: pulmonary, cardiac, mixed, and mild. the pulmonary form is characterized by severe respiratory distress and rapid death because of massive pulmonary edema, presumably from viral injury to the pulmonary endothelial cells. grossly, large amounts of froth are present in the airways, lungs fail to collapse, subpleural lymph vessels are distended, and the ventral parts of the lungs are notably edematous (see fig. - ) . in the cardiac form, recurrent fever is detected, and heart failure results in subcutaneous and interfascial edema, most notably in the neck and supraorbital region. the mixed form is a combination of the respiratory and cardiac forms. finally, the mild form, rarely seen in postmortem rooms, is characterized by fever and clinical signs resembling those of equine influenza; it is in most cases transient and followed by a complete recovery. this mild form is most frequently seen in donkeys, mules, and zebras and in horses with some degree of immunity. detection of viral antigen for diagnostic purposes can be done by immunohistochemistry in paraffin-embedded tissues. chapter respiratory system, mediastinum, and pleurae clinically, rhodococcus equi infection can be acute, with rapid death caused by severe bronchopneumonia, or chronic, with depression, cough, weight loss, and respiratory distress. in either form, there may be diarrhea, arthritis, osteomyelitis, or subcutaneous abscess formation. parascaris equorum. parascaris equorum is a large nematode (roundworm) of the small intestine of horses; the larval stages migrate through the lungs as ascarid larvae do in pigs. it is still unclear whether migration of parascaris equorum larvae can cause significant pulmonary lesions under natural conditions. experimentally, migration of larvae results in coughing, anorexia, weight loss, and small necrotic foci and petechial hemorrhages in the liver, hepatic and tracheobronchial lymph nodes, and lungs. microscopically, eosinophils are prominent in the interstitium and airway mucosa during the parasitic migration and in focal granulomas caused by dead larvae in the lung. dictyocaulus arnfieldi. dictyocaulus arnfieldi is not a very pathogenic nematode, but it should be considered if there are signs of coughing in horses that are pastured together with donkeys. donkeys are considered the natural hosts and can tolerate large numbers of parasites without ill effects. dictyocaulus arnfieldi does not usually become patent in horses, so examination of fecal samples is not useful; bal is only occasionally diagnostic because eosinophils (but not parasites) are typically found in the lavage fluid. mature parasites (up to cm in length) cause obstructive bronchitis, edema, and atelectasis, particularly along the dorsocaudal lung. the microscopic lesion is an eosinophilic bronchitis similar to the less acute infestations seen in cattle and sheep with their dictyocaulus species. the results of experimental studies suggest that natural infection likely starts from inhalation of infected dust or aerosols. once in the lung, rhodococcus equi is rapidly phagocytosed by alveolar macrophages, but because of defective phagosome-lysosome fusion and premature lysosomal degranulation, bacteria survive and multiply intracellularly, eventually leading to the destruction of the macrophage. interestingly, rhodococcus equi appears to be easily killed by neutrophils but not macrophages. released cytokines and lysosomal enzymes and bacterial toxins are responsible for extensive caseous necrosis of the lungs and the recruitment of large numbers of neutrophils, macrophages, and giant cells containing intracellular gram-positive organisms in their cytoplasm. depending on the stage of infection and the immune status and age of affected horses, pulmonary lesions induced by rhodococcus equi can vary from pyogranulomatous to granulomatous pneumonia. in young foals, the infection starts as a suppurative cranioventral bronchopneumonia, which progresses within a few days into small variable-size pulmonary abscesses. these abscesses rapidly transform into pyogranulomatous nodules, some of which become confluent and form large masses of caseous exudate ( fig. - ). microscopically, the early lesion starts with neutrophilic infiltration, followed by an intense influx of alveolar macrophages into the bronchoalveolar spaces. this type of histiocytic inflammation persists for a long period of time because rhodococcus equi is a facultative intracellular organism that survives the bactericidal effects of equine alveolar macrophages. in the most chronic cases, the pulmonary lesions culminate with the formation of large caseonecrotic masses with extensive fibrosis of the surrounding pulmonary parenchyma. pcr analysis of tracheobronchial aspirates has successfully been used as an alternative to bacteriologic culture in the diagnosis of rhodococcus equi infection in live foals. b a rhinotracheitis (ibr)/bovine herpes virus (bohv- ), bovine parainfluenza virus (bpiv- ), and bovine respiratory syncytial virus (brsv); and noninfectious interstitial pneumonias, such as bovine pulmonary edema and emphysema, reinfection syndrome, and many others. bovine enzootic pneumonia. enzootic pneumonia, sometimes simply referred to as calf pneumonia, is a multifactorial disease caused by a variety of etiologic agents that produces an assortment of lung lesions in young, intensively housed calves. the hostmicrobial-environmental triad is central in the pathogenesis of this disease. morbidity is often high (up to %), but fatalities are uncommon (> %) unless management is poor or unless new, virulent pathogens are introduced by additions to the herd. enzootic pneumonia is also called viral pneumonia because it often begins with an acute respiratory infection with bpiv- , brsv, or possibly with one or more of several other viruses (adenovirus, bohv- , reovirus, bovine coronavirus [bcov] , and bovine rhinitis virus). mycoplasmas, notably mycoplasma dispar, mycoplasma bovis, ureaplasma, and possibly chlamydophila, may also be primary agents. following infection with any of these agents, opportunistic bacteria, such as pasteurella multocida, trueperella (arcanobacterium) pyogenes, histophilus somni, mannheimia haemolytica, and escherichia coli, can cause a secondary suppurative bronchopneumonia, the most serious stage of enzootic pneumonia. the pathogenesis of the primary invasion and how it predisposes the host to invasion by the opportunists are poorly understood, but it is likely that there is impairment of pulmonary defense mechanisms. environmental factors, including air quality (poor ventilation), high relative humidity, and animal crowding, have been strongly incriminated. the immune status of the calf also plays an important role in the development and severity of enzootic pneumonia. calves with bovine leukocyte adhesion deficiency (blad), which prevents the migration of neutrophils from the capillaries, are highly susceptible to bronchopneumonia. lesions are variable and depend largely on the agents involved and on the duration of the inflammatory process. in the acute phases, lesions caused by viruses are those of bronchointerstitial pneumonia, which are generally mild and transient, and therefore are seen only sporadically at necropsy. microscopically, the lesions are necrotizing bronchiolitis, necrosis of type i pneumonocytes with hyperplasia of type ii pneumonocytes, and mild interstitial and alveolar edema. in the case of bpiv- and brsv infection, intracytoplasmic inclusion bodies and the formation of large multinucleated syncytia, resulting from the fusion of infected bronchiolar and alveolar epithelial cells, can also be observed in the lungs (fig. - ) . airway hyperreactivity has been described in calves after brsv infection; however, the significance of this syndrome in relation to enzootic pneumonia of calves is still under investigation. the mycoplasmas also can cause bronchiolitis, bronchiolar and alveolar necrosis, and an interstitial reaction, but in contrast to viral-induced pneumonias, mycoplasmal lesions tend to progress to a chronic stage characterized by striking peribronchiolar lymphoid hyperplasia (cuffing pneumonia). when complicated by secondary bacterial infections (e.g., pasteurella multocida and trueperella pyogenes), viral or mycoplasmal lesions change from a pure bronchointerstitial to a suppurative bronchopneumonia (fig. - ) . in late stages of bronchopneumonia, the lungs contain a creamy-mucoid exudate in the airways and later often have pulmonary abscesses and bronchiectasis (see fig. - ) . note that the same viruses and mycoplasmas involved in the enzootic pneumonia complex can also predispose cattle to other diseases, such as pneumonic mannheimiosis (mannheimia aspiration pneumonia. aspiration pneumonia is often a devastating sequela to improper gastric tubing of horses, particularly exogenous lipid pneumonia from mineral oil delivered into the trachea in treatment of colic. gross and microscopic lesions are described in detail in the section on aspiration pneumonias of cattle. opportunistic infections. chlamydophila (chlamydia) spp., obligatory intracellular zoonotic pathogens, can cause systemic infection in many mammalian and avian species; in horses, they can also cause keratoconjunctivitis, rhinitis, pneumonia, abortion, polyarthritis, enteritis, hepatitis, and encephalitis. serologic studies suggest that infection without apparent disease is common in horses. horses experimentally infected with chlamydophila psittaci develop mild and transient bronchointerstitial pneumonia. there are unconfirmed reports suggesting a possible association between these organisms and recurrent airway obstruction in horses. detection of chlamydial organisms in affected tissue is not easy and requires special laboratory techniques such as pcr, immunohistochemistry, and fluorescent antibody tests. horses are only sporadically affected with mycobacteriosis (mycobacterium avium complex, mycobacterium tuberculosis, and mycobacterium bovis). the intestinal tract and associated lymph nodes are generally affected, suggesting an oral route of infection with subsequent hematogenous dissemination to the lungs. the tubercles (granulomas) differ from those in ruminants and pigs, being smooth, gray, solid, sarcoma-like nodules without grossly visible caseous necrosis or calcification (e- fig. - ) . microscopically, the tubercles are composed of macrophages, epithelioid cells, and multinucleated giant cells. fibrosis increases with time, accounting in part for the sarcomatous appearance. adenovirus infections occur commonly in arabian foals with combined immunodeficiency (cid), a hereditary lack of b and t lymphocytes. in cases of adenoviral infection, large basophilic or amphophilic inclusions are present in the nuclei of tracheal, bronchial, bronchiolar, alveolar, renal, and intestinal epithelial cells. as it occurs in other species, infection with a unique fungal pathogen known as pneumocystis carinii typically occurs in immunosuppressed or immunoincompetent individuals such as arabian foals with cid (see fig. - ). diagnosis of pneumocystis carinii requires microscopic examination of lungs and special stains. idiopathic interstitial pneumonia. interstitial and bronchointerstitial pneumonias of undetermined cause that can progress to severe pulmonary fibrosis have been reported in foals and young horses. the gross and microscopic lesions are reminiscent of those of bovine pulmonary edema and emphysema or ards. the lungs are notably congested and edematous and microscopically are characterized by necrosis of the bronchiolar epithelium, alveolar edema, hyperplasia of type ii pneumonocytes, and hyaline membranes. the cause of this form of equine interstitial pneumonia is not known, but toxic and particularly viral causes have been proposed. bovine respiratory disease complex (brdc) and acute undifferentiated respiratory disease are general terms often used by clinicians to describe acute and severe bovine respiratory illness of clinically undetermined cause. these terms do not imply any particular type of pneumonia and therefore should not be used in pathology reports. clinically, the brd complex includes bovine enzootic pneumonia (multifactorial etiology); pneumonic mannheimiosis (mannheimia haemolytica); respiratory histophilosis (histophilus somni), previously known as respiratory hemophilosis (haemophilus somnus); mycoplasma bovis; respiratory viral infections, such as infectious bovine .e chapter respiratory system, mediastinum, and pleurae pneumonic mannheimiosis (shipping fever) is the most important respiratory disease of cattle in north america, particularly in feedlot animals that have been through the stressful marketing and assembly processes. mannheimia haemolytica biotype a, serotype is the etiologic agent most commonly responsible for the severe pulmonary lesions. a few investigators still consider that pasteurella multocida and other serotypes of mannheimia haemolytica are also causes of this disease. even after many years of intense investigation, from the gross lesions to the molecular aspects of the disease, the pathogenesis of pneumonic mannheimiosis remains incompletely understood. experiments have established that mannheimia haemolytica a alone is usually incapable of causing disease because it is rapidly cleared by pulmonary defense mechanisms. these findings may explain why mannheimia haemolytica, despite being present in the nasal cavity of healthy animals, only sporadically causes disease. for mannheimia haemolytica to be established as a pulmonary infection, it is first required that stressors impair the defense mechanisms and allow the bacteria to colonize the lung (see section on impairment of defense haemolytica). clinically, enzootic pneumonia is usually mild, but fatal cases are occasionally seen even in farms with optimal health management. pneumonic mannheimiosis (shipping fever). shipping fever (transit fever) is a vague clinical term used to denote acute respiratory diseases that occur in cattle several days or weeks after shipment. the disease is characterized by a severe fibrinous bronchopneumonia, reflecting the fact that death generally occurs early or at an acute stage. because mannheimia haemolytica (formerly pasteurella haemolytica) is most frequently isolated from affected lungs, the names pneumonic mannheimiosis and pneumonic pasteurellosis have been used synonymously. it is known that pneumonic mannheimiosis can occur in animals that have not been shipped and that organisms other than mannheimia haemolytica can cause similar lesions. therefore the term shipping fever should be relinquished in favor of more specific names, such as pneumonic mannheimiosis or respiratory histophilosis. irregular areas of coagulative necrosis are typically bordered by a rim of elongated cells often referred to as oat-shaped cells or oat cells that are degenerating neutrophils mixed with a few alveolar macrophages (see fig. - ). in the early stages of necrosis, there is no evidence of vascular thrombosis, suggesting that necrosis is primarily caused by the cytotoxin of mannheimia haemolytica and is not the result of an ischemic change. the interlobular septa become distended with protein-rich edematous fluid, and the lymphatic vessels contain fibrin thrombi. the trachea and bronchi can have considerable amounts of blood and exudate, which are transported by the mucociliary escalator or coughed up from deep within the lungs, but the walls of the trachea and major bronchi may or may not be involved. because of the necrotizing process, sequelae to pneumonic mannheimiosis can be serious and can include abscesses, encapsulated sequestra (isolated pieces of necrotic lung), chronic pleuritis, fibrous pleural adhesions, and bronchiectasis. clinically, pneumonic mannheimiosis is characterized by a severe toxemia that can kill animals even when considerable parts of the lungs remain functionally and structurally normal. cattle usually become depressed, febrile ( ° to ° f [ ° to ° c]), and anorexic and have a productive cough, encrusted nose, mucopurulent nasal exudate, shallow respiration, or an expiratory grunt. hemorrhagic septicemia. pneumonic mannheimiosis should not be confused with hemorrhagic septicemia (septicemic pasteurellosis) of cattle and water buffalo (bubalus bubalis) caused by inhalation or ingestion of serotypes :b and :e of pasteurella multocida. this oie-notifiable disease does not occur in north america and currently is reported only from some countries in asia, africa, and recently in germany. in contrast to pneumonic mannheimiosis, in which lesions are always confined to the lower respiratory tract, the bacteria of hemorrhagic septicemia always disseminates hematogenously to other organs. at necropsy, typically, generalized petechiae are present on the serosal surfaces of the intestine, heart, and lungs and in skeletal muscles. superficial and visceral lymph nodes are swollen and hemorrhagic. variable lesions include edematous and hemorrhagic lungs with or without consolidation; hemorrhagic enteritis; blood-tinged fluid in the thorax and abdomen; and subcutaneous edema of the head, neck, and ventral abdomen. bacteria can be cultured from blood, and animals have high fever and die rapidly ( % case fatality). respiratory histophilosis (haemophilosis). respiratory histophilosis is part of the histophilus somni (haemophilus somnus) disease complex, which has at least eight different clinicopathologic forms, each one involving different organs. this complex includes septicemia, encephalitis (known as thrombotic meningoencephalitis [tme]), pneumonia (respiratory histophilosis), pleuritis, myocarditis, arthritis, ophthalmitis, conjunctivitis, otitis, and abortion. the portals of entry for the different forms of histophilosis have not been properly established. the respiratory form of bovine histophilosis is the result of the capacity of the bacterium to induce both suppurative and fibrinous bronchopneumonia (e- fig. - ). the latter is in some cases indistinguishable from that of pneumonic mannheimiosis. the pathogenesis of respiratory histophilosis is still poorly understood, and the disease cannot be reproduced consistently by administration of histophilus somni alone. like mannheimia haemolytica, it requires predisposing factors such as stress or a preceding viral infection. histophilus somni is often isolated from the lungs of calves with enzootic pneumonia. the capacity of histophilus somni to cause septicemia and localized infections in the lungs, brain, eyes, ear, heart, mammary gland, male and female genital organs, or placenta is perhaps attributable to specific virulence factors, such as immunoglobulin-binding proteins (igbps) and lipooligosaccharide (los). also, histophilus mechanisms). these stressors include weaning, transport, fatigue, crowding, mixing of cattle from various sources, inclement weather, temporary starvation, and viral infections. horizontal transmission of viruses and mannheimia haemolytica occurs during crowding and transportation of cattle. viruses that most commonly predispose cattle to pneumonic mannheimiosis include bohv- , bpiv- , and brsv. once established in the lungs, mannheimia haemolytica causes lesions by means of different virulence factors, which include endotoxin, lipopolysaccharide, adhesins, and outer membrane proteins; however, the most important is probably the production of a leukotoxin (exotoxin), which binds and kills bovine macrophages and neutrophils. the fact that this toxin exclusively affects ruminant leukocytes probably explains why mannheimia haemolytica is a respiratory pathogen in cattle and sheep but not in other species. during mannheimia haemolytica infection, alveolar macrophages, neutrophils, and mast cells release maximum amounts of proinflammatory cytokines, particularly tnf-α, il- , il- , adhesion molecules, histamine, and leukotrienes. by locally releasing enzymes and free radicals, leukocytes further contribute to the injury and necrosis of bronchiolar and alveolar cells. the gross lesions of acute and subacute pneumonic mannheimiosis are the prototypic fibrinous bronchopneumonia, with prominent fibrinous pleuritis ( fig. - and see fig. - ) and pleural effusion. lesions are always cranioventral and usually ventral to a horizontal line through the tracheal bifurcation. the interlobular septa are distended by yellow, gelatinous edema and fibrin. the "marbling" of lobules is the result of intermixing areas of coagulation necrosis, interlobular interstitial edema, and congestion ( fig. - ) . microscopically, lung lesions are evident hours after experimental infection in which neutrophils fill the bronchial, bronchiolar, and alveolar spaces. within to hours, the cytotoxic effect of mannheimia haemolytica is manifested by necrosis of individual alveolar cells and fibrin begins to exude into the alveoli from increased permeability of the air-blood barrier. these changes are exacerbated by endothelial swelling, altered platelet function, increased procoagulant activity, and diminished profibrinolytic activity in the lungs. by hours, alveolar macrophages start to appear in the bronchoalveolar space. at this time, large and the pulmonary defense mechanisms. lung lesions are typically those of a chronic bronchopneumonia with numerous well-delineated caseonecrotic nodules (fig. - and e-fig. - ) . microscopically, lesions are quite characteristic and consist of distinct areas of pulmonary necrosis centered on bronchi or bronchioles. the lesion is formed by a core of fine eosinophilic granular debris surrounded by a rim of neutrophils, macrophages, and fibroblasts (see fig. - ) . although the origin of the caseonecrotic lesions is under investigation, recent studies incriminate reactive oxygen species (ros) and reactive nitrogen species (rns) as the major contributors for cell injury in the lung. the diagnosis is confirmed by isolation or somni has the ability to undergo structural and antigenic variation, evade phagocytosis by promoting leukocytic apoptosis, inhibit intracellular killing, reduce transferrin concentrations, and induce endothelial apoptosis in the lungs of affected calves. mixed pulmonary infections of histophilus somni, mannheimia haemolytica, pasteurella multocida, trueperella pyogenes, and mycoplasmas are fairly common in calves. mycoplasma bovis pneumonia. mycoplasma bovis is the most common mycoplasma sp. isolated from pneumonic lungs of cattle in europe and north america. pulmonary infection is exacerbated by stress or any other adverse factor (e.g., viral infection) that depresses n control programs for infectious disease. it was eradicated from north america in and from australia in the s, but it is still enzootic in large areas of africa, asia, and eastern europe. the etiologic agent, mycoplasma mycoides ssp. mycoides small colony type, was the first mycoplasma isolated and is one of the most pathogenic of those that infect domestic animals. natural infection occurs in cattle and asian buffalo. the portal of entry is aerogenous, and infections occur when a susceptible animal inhales infected droplets. the pathogenic mechanisms are still inadequately understood but are suspected to involve toxin and galactan production, unregulated production of tnf-α, ciliary dysfunction, immunosuppression, and immune-mediated vasculitis. vasculitis and thrombosis of pulmonary arteries, arterioles, veins, and lymphatic vessels lead to lobular infarction. the name of the disease is a good indication of the gross lesions. it is a severe, fibrinous bronchopneumonia (pleuropneumonia) similar to that of pneumonic mannheimiosis (see figs. - and - ) but having a more pronounced "marbling" of the lobules because of extensive interlobular edema and lymphatic thrombosis. typically, % to % of lesions are in the caudal lobes (not cranioventrally), and pulmonary sequestra (necrotic lung encapsulated by connective tissue) are more frequent and larger than pneumonic mannheimiosis. unilateral lesions are common in this disease. microscopically, the appearance again is like that of pneumonic mannheimiosis, except that vasculitis and thrombosis of pulmonary arteries, arterioles, and capillaries are much more obvious and are clearly the major cause of the infarction and thrombosis of lymphatic vessels in interlobular septa. mycoplasma mycoides ssp. mycoides small colony type remains viable in the sequestra for many years, and under stress (e.g., starvation), the fibrous capsule may break down releasing mycoplasma into the airways, thus becoming a source of infection for other animals. clinical signs are those of severe sepsis, including fever, depression, and anorexia followed by severe respiratory signs such as opened-mouth breathing, dyspnea and coughing, and crepitation and pleural friction on thoracic auscultation. vaccination is highly effective in preventing the disease. bovine tuberculosis. tuberculosis is an ancient, communicable, worldwide, chronic disease of human beings and domestic animals. it continues to be a major problem in human beings in underdeveloped countries, and it is on the rise in some industrialized nations, largely because of the immunosuppressive effects of aids, immigration, and movement of infected animals across borders. the world health organization (who) estimates that more than million people die of tuberculosis and million new cases appear each year, mostly in developing countries. mycobacterium tuberculosis is transmitted between human beings, but where unpasteurized milk is consumed, mycobacterium bovis from the milk of cattle with mammary tuberculosis is also an important cause of human tuberculosis. mycobacterium bovis infections have also been reported in a number of domestic and wild mammalian species; in some countries, wildlife reservoirs exist and may act as a source of infection for cattle. bovine tuberculosis is primarily caused by mycobacterium bovis, but infection with mycobacterium tuberculosis, the pathogen of human tuberculosis, and mycobacterium caprae (formerly mycobacterium bovis ssp. caprae/mycobacterium tuberculosis ssp. caprae) can occur sporadically. tuberculosis can be acquired by several routes, but infection of the lungs by inhalation of mycobacterium bovis is the most common in adult cattle, whereas ingestion of infected milk is more predominant in young animals. organisms belonging to the mycobacterium avium complex can also infect cattle, but for infection caused by these organisms, the term atypical mycobacteriosis (not tuberculosis) is currently preferred. immunohistochemical labeling of tissue sections for mycoplasma antigens. mycoplasma bovis is also incriminated in arthritis, otitis, mastitis, abortion, and keratoconjunctivitis. contagious bovine pleuropneumonia. contagious bovine pleuropneumonia is an oie-notifiable disease of historic interest in veterinary medicine because it was the object of early national a b c than % of bovine cases, a chronic, moist cough can progress to dyspnea. enlarged tracheobronchial lymph nodes can contribute to the dyspnea by impinging on airways, and the enlargement of caudal mediastinal nodes can compress the caudal thoracic esophagus and cause bloating. interstitial pneumonias. atypical interstitial pneumonia (aip) is a vague clinical term well entrenched in veterinary literature but one that has led to enormous confusion among veterinarians. it was first used to describe acute or chronic forms of bovine pneumonia that did not fit in any of the "classic" forms because of the lack of exudate and lack of productive cough. microscopically, the criteria for diagnosis of aip in cattle were based on the absence of obvious exudate and the presence of edema, interstitial emphysema (see the section on pulmonary emphysema), hyaline membranes, hyperplasia of type ii pneumonocytes, and alveolar fibrosis with interstitial cellular infiltrates. at that time, any pulmonary disease or pulmonary syndrome that had a few of the previously mentioned lesions was traditionally diagnosed as aip, and grouping all these different syndromes together was inconsequential because their etiopathogenesis were then unknown. field and laboratory investigations have demonstrated that most of the bovine syndromes previously grouped under aip have rather different causes and pathogeneses ( fig. - ) . furthermore, what was "atypical" in the past has become so common that it is fairly routine nowadays to find "typical cases" of aip. for all these reasons, investigators, largely from britain, proposed that all these syndromes previously clustered into aip should be named according to their specific cause or pathogenesis. the most common bovine syndromes characterized by edema, emphysema, hyaline membranes, and hyperplasia of type ii pneumonocytes include bovine pulmonary edema and emphysema (fog fever), "extrinsic allergic alveolitis" (hypersensitivity pneumonitis), "reinfection syndromes" (hypersensitivity to dictyocaulus sp. or brsv), milk allergy, ingestion of moldy potatoes, paraquat toxicity, toxic silo gases, mycotoxins, and others. acute bovine pulmonary edema and emphysema (fog fever). acute bovine pulmonary edema and emphysema (abpee), known in britain as fog fever (no association with atmospheric conditions), occurs in cattle usually grazing "fog" pastures (i.e., aftermath or foggage, regrowth after a hay or silage has been cut). epidemiologically, abpee usually occurs in adult beef cattle in the fall when there is a change in pasture from a short, dry grass to a lush, green grass. it is generally accepted that l-tryptophan present in the pasture is metabolized in the rumen to -methylindole, which in turn is absorbed into the bloodstream and carried to the lungs. mixed function oxidases present in the nonciliated bronchiolar epithelial (club) cells metabolize -methylindole into a highly pneumotoxic compound that causes extensive and selective necrosis of bronchiolar cells and type i pneumonocytes (fig. - and see fig. - ) and increases alveolar permeability, leading to edema, thickening of the alveolar interstitium, and alveolar and interstitial emphysema. -methylindole also interferes with the lipid metabolism of type ii pneumonocytes. the gross lesions are those of a diffuse interstitial pneumonia with severe alveolar and interstitial edema and interlobular emphysema (see fig. - , a) . the lungs are expanded, pale, and rubbery in texture, and the lesions are most notable in the caudal lobes. microscopically, the lesions are alveolar and interstitial edema and emphysema, formation of characteristic hyaline membranes within alveoli (see fig. - , b) , and in those animals that survive for several days, hyperplasia of type ii pneumonocytes and alveolar interstitial fibrosis. respiratory infection usually starts when inhaled bacilli reach the alveoli and are phagocytosed by pulmonary alveolar macrophages. if these cells are successful in destroying the bacteria, infection is averted. however, mycobacterium bovis, being a facultative pathogen of the monocytic-macrophage system, may multiply intracellularly, kill the macrophage, and initiate infection. from this first nidus of infection, bacilli spread aerogenously via airways within the lungs and eventually via the lymph vessels to tracheobronchial and mediastinal lymph nodes. the initial focus of infection at the portal of entry (lungs) plus the involvement of regional lymph nodes is termed the primary (ghon) complex of tuberculosis. if the infection is not contained within this primary complex, bacilli disseminate via the lymph vessels to distant organs and other lymph nodes by the migration of infected macrophages. hematogenous dissemination occurs sporadically when a granuloma containing mycobacteria erodes the wall of a blood vessel, causes vasculitis, and allows the granuloma to discharge mycobacteria into the alveolar circulation. if dissemination is sudden and massive, mycobacteria are widely disseminated and numerous small foci of infection develop in many tissues and organs and the process is referred to as miliary tuberculosis (like millet seeds). the host becomes hypersensitive to the mycobacterium, which enhances the cell-mediated immune defenses in early or mild infections but can result in host-tissue destruction in the form of caseous necrosis. the evolution and dissemination of the pulmonary infection are closely regulated by cytokines and tnf-α production by alveolar macrophages. unlike abscesses that tend to grow rather fast, granulomas evolve slowly at the site of infection. the lesion starts with few macrophages and neutrophils ingesting the offending organism, but because mycobacterium organisms are resistant to phagocytosis, infected macrophages eventually die, releasing viable bacteria, lipids, and cell debris. cell debris accumulates in the center of the lesion, whereas viable bacteria and bacterial lipids attract additional macrophages and a few lymphocytes at the periphery of the lesion. some of these newly recruited macrophages are activated by local lymphocytes and become large phagocytic cells with abundant cytoplasm resembling epithelial cells, thus the term epithelioid macrophages. multinucleated giant cells (also macrophages) appear at the edges of the lesion, and finally the entire focus of inflammatory process becomes surrounded by fibroblasts and connective tissue (see fig. - ). it may take weeks or months for a granuloma to be grossly visible. bovine tuberculosis, the prototype for granulomatous pneumonia, is characterized by the presence of a few or many caseated granulomas (see fig. - ). the early gross changes are small foci (tubercles) most frequently seen in the dorsocaudal, subpleural areas. with progression, the lesions enlarge and become confluent with the formation of large areas of caseous necrosis. calcification of the granulomas is a typical finding in bovine tuberculosis. single nodules or clusters occur on the pleura and peritoneum, and this presentation has been termed pearl disease. microscopically, the tubercle is composed of mononuclear cells of various types. in young tubercles, which are noncaseous, epithelioid and langhans' giant cells are at the center, surrounded by lymphocytes, plasma cells, and macrophages. later, caseous necrosis develops at the center, secondary to the effects of cell-mediated hypersensitivity and enclosed by fibrosis at the periphery. acid-fast organisms may be numerous but more often are difficult to find in histologic section or smears. clinically, the signs of tuberculosis relate to the dysfunction of a particular organ system or to general debilitation, reduced milk production, and emaciation. in the pulmonary form, which is more grossly, the postmortem lesions vary from subtle, gray, subpleural foci (granulomatous inflammation) to severe lesions, in which the lungs are firm and heavy and have a "meaty appearance" because of interstitial pneumonia (e- fig. - ) with type ii pneumonocyte hyperplasia, lymphocytic infiltration, and interstitial fibrosis. characteristically, discrete noncaseous granulomas formed in response to the deposition of antigen-antibody complexes are scattered throughout the lungs. chronic cases of extrinsic allergic alveolitis can eventually progress to diffuse fibrosing alveolitis. clinically, it can be acute or chronic; the latter has a cyclical pattern of exacerbation during winter months. weight loss, coughing, and poor exercise tolerance are clinical features. full recovery can occur if the disease is recognized and treated early. reinfection syndrome. hypersensitivity to reinfection with larvae of dictyocaulus viviparus is another allergic syndrome manifested in the lungs that causes signs and lesions indistinguishable from abpee, with the exception of eosinophils and possibly larvae in the alveolar exudate. the hypersensitivity reaction in the lung causes diffuse alveolar damage and edema, necrosis of type i pneumonocytes, and hyperplasia of type ii pneumonocytes. in the later stages of the disease, there is formation of small granulomas with interstitial infiltrates of mononuclear cells. it has been suggested but not confirmed that emphysema with diffuse proliferative alveolitis and formation of hyaline membranes can also occur sporadically in the late stages of brsv infection in cattle. presumably, this disease shares many similarities with "atypical" infections occasionally seen in children with respiratory syncytial virus (rsv human strain), in which a hypersensitivity to the virus or virus-induced augmentation of the immune response results in hypersensitivity pneumonitis (see fig. - ). brsv infection is also known to enhance hypersensitivity to environmental allergens in cattle. other forms of bovine interstitial pneumonia. inhalation of manure ("pit") gases, such as nitrogen dioxide (no ), hydrogen interstitial cell infiltrates, fibrosis, emphysema acute proliferation phase hyperplasia of type ii pneumonocytes clinically, severe respiratory distress develops within days of the abrupt pasture change, and cattle develop expiratory dyspnea, oral breathing, and evidence of emphysema within the lungs and even subcutaneously along the back. experimentally, reducing ruminal conversion of l-tryptophan to -methylindole prevents the development of abpee. a number of other agents cause virtually the same clinical and pathologic syndrome as is seen in abpee. the pathogenesis is assumed to be similar, although presumably other toxic factors are specific for each syndrome. one of these pneumotoxic factors is -ipomeanol, which is found in moldy sweet potatoes contaminated with the fungus fusarium solani. mixed function oxidases in the lungs activate -ipomeanol into a potent pneumotoxicant capable of producing irreversible oxidative injury to type i pneumonocytes and bronchiolar epithelial cells, presumably through lipoperoxidation of cell membranes. similarly, purple mint (perilla frutescens), stinkwood (zieria arborescens), and rapeseed and kale (brassica species) also cause pulmonary edema, emphysema, and interstitial pneumonia. extrinsic allergic alveolitis. extrinsic allergic alveolitis (hypersensitivity pneumonitis), one of the most common allergic diseases in cattle, is seen mainly in housed adult dairy cows in the winter. this disease shares many similarities with its human counterpart known as farmer's lung, which results from a type iii hypersensitivity reaction to inhaled organic antigens, most commonly microbial spores, mainly of the thermophilic actinomycete, saccharopolyspora rectivirgula (micropolyspora faeni), commonly found in moldy hay. this is followed by an antibody response to inhaled spores and local deposition of antigen-antibody complexes (arthus reaction) in the lungs (see fig. - ). because it affects only a few animals of the herd or the sporadic person working in a farm, it is presumed that intrinsic host factors, such as dysregulation of dendritic cells, t lymphocytes, igg, interleukins, ifn-γ, and surfactant, are involved in the pathogenesis of the disease. chapter respiratory system, mediastinum, and pleurae e- figure - interstitial pneumonia, adult cow. note meaty appearance of the pulmonary parenchyma and mild edematous distention of the interlobular septa. inset, thick hyaline membranes (arrows) lining hypercellular alveolar walls. hypersensitivity pneumonia was suspected. (courtesy dr. a. lópez, atlantic veterinary college.) gases, inhalation of no (silo gas) also causes bronchiolitis, edema, and interstitial pneumonia and, in survivors, bronchiolitis obliterans ("silo filler's disease"). smoke inhalation resulting from barn or house fires is sporadically seen by veterinarians and pathologists. in addition to skin burns, animals involved in fire accidents suffer extensive thermal injury produced by the heat on the nasal and laryngeal mucosa, and severe chemical irritation caused by inhalation of combustion gases and particles in the lung. animals that survive or are rescued from fires frequently develop nasal, laryngeal, and tracheal edema, and pulmonary hemorrhage and alveolar edema, which are caused by chemical injury to the blood-air barrier or by ards caused by the excessive production of free radicals during the pulmonary inflammatory response (see e- fig. - ) . microscopic examination of the lungs often reveals carbon particles (soot) on mucosal surfaces of the conducting system. verminous pneumonia (dictyocaulus viviparus). pulmonary lesions in parasitic pneumonias vary from interstitial pneumonia caused by migrating larvae to chronic bronchitis from intrabronchial adult parasites, to granulomatous pneumonia, which is caused by dead larvae, aberrant parasites, or eggs of parasites. in many cases, an "eosinophilic syndrome" in the lungs is characterized by infiltrates of eosinophils in the pulmonary interstitium and bronchoalveolar spaces and by blood eosinophilia. atelectasis and emphysema secondary to the obstruction of airways by parasites and mucous secretions are also common findings in parasitic pneumonias. the severity of these lesions relates to the numbers and size of the parasites and the nature of the host reaction, which sometimes includes hypersensitivity reactions (see section on reinfection syndrome). a common general term for all of these diseases is verminous pneumonia, and the adult nematodes are often visible grossly in the airways ( fig. - ) . dictyocaulus viviparus is an important pulmonary nematode (lungworm) responsible for a disease in cattle referred to as verminous pneumonia or verminous bronchitis. adult parasites live in the bronchi of cattle, mainly in the caudal lobes, and cause severe bronchial irritation, bronchitis, and pulmonary edema, which in turn are responsible for lobular atelectasis and interstitial emphysema. atelectasis is confined to the lobules of the lungs ventilated by the obstructed bronchi (dorsocaudal). interstitial emphysema (interlobular) is caused by forced expiratory movements against a partially obstructed single bronchus. in addition to the inflammation of bronchial mucosa, bronchoaspiration of larvae and eggs also causes an influx of leukocytes into the bronchoalveolar space (alveolitis). verminous pneumonia is most commonly seen in calves during their first summer grazing pastures that are repeatedly used from year to year, particularly in regions of europe that have a moist cool climate. the parasite can overwinter in pastures, even in climates as cold as canada's, and older animals may be carriers for a considerable length of time. at necropsy, lesions appear as dark or gray, depressed, wedgeshaped areas of atelectasis involving few or many lobules usually along the dorsocaudal aspect of the lungs. on cut surface, edematous foam and mucus mixed with white, slender (up to -mm long) nematodes are visible in the bronchi (see fig. - ). in the most severe cases, massive numbers of nematodes fill the bronchial tree. microscopically, the bronchial lumens are filled with parasites admixed with mucus because of goblet cell hyperplasia, and there is squamous metaplasia of the bronchial and bronchiolar epithelium because of chronic irritation. there are also inflammatory infiltrates in the bronchial mucosa; alveolar edema; hyperplasia of balt sulfide (h s), and ammonia (nh ), from silos or sewage can be a serious hazard to animals and human beings. at toxic concentrations, these gases cause necrosis of bronchiolar cells and type i pneumonocytes and fulminating pulmonary edema that causes asphyxiation and rapid death (see fig. - ) . like other oxidant secretory granules released by club cells contain several proteins, such as surfactantlike protein, antiinflammatory protein (cc ), and bronchiolar lining proteins. b, ros produced by club cells are also absorbed into capillaries within the lamina propria and are transferred by the circulatory system to pulmonary capillaries where they disrupt the air-blood barrier, causing degeneration and necrosis of type i pneumonocytes. this process leads to leakage of plasma fluid (alveolar edema [pink color]) and extravasation of erythrocytes (alveolar hemorrhage) and neutrophils (inflammation). ingested pneumotoxicants can be metabolized by the liver, leading to release of ros into the circulatory system that then disrupts the air-blood barrier in a similar manner. fig. - ). microscopically, there are focal intraalveolar hemorrhages caused by larvae migrating through the alveolar walls. some larvae admixed with edematous fluid and cellular exudate (including eosinophils) may be visible in bronchioles and alveoli. the alveolar walls are thickened because of edema and a few inflammatory cells. clinical signs include cough and expiratory dyspnea to the point of oral breathing. hydatid cysts, the intermediate stage of echinococcus granulosus, can be found in the lungs and liver and other viscera of sheep and to a lesser extent in cattle, pigs, goats, horses, and human beings. the adult stage is a tapeworm that parasitizes the intestine of canidae. hydatidosis is still an important zoonosis in some countries, and perpetuation of the parasite life cycle results from animals being fed uncooked offal from infected sheep and consumption of uninspected meat. hydatid cysts are generally to cm in diameter, and numerous cysts can be found in the viscera of affected animals ( fig. - ). each parasitic cyst is filled with clear fluid; numerous daughter cysts attach to the wall, each containing several "brood capsules" with protoscolices inside. hydatid cysts have little clinical significance in animals but are economically important because of carcass condemnation. aspiration pneumonias. the inhalation of regurgitated ruminal contents or iatrogenic deposition of medicines or milk into the trachea can cause severe and often fatal aspiration pneumonia. bland substances, such as mineral oil, may incite only a mild suppurative or histiocytic bronchopneumonia, whereas some "home remedies" or ruminal contents are highly irritating and cause a fibrinous, necrotizing bronchopneumonia. the right cranial lung lobe tends to be more severely affected because the right cranial bronchus is the most cranial branch and enters the ventrolateral aspect of the trachea. however, the distribution may vary when animals aspirate while in lateral recumbency. in some severe cases, pulmonary necrosis can be complicated by infection with saprophytic organisms present in ruminal contents, causing fatal gangrenous pneumonia. aspiration pneumonia should always be considered in animals whose swallowing has been compromised-for example, those with cleft palate or hypocalcemia (milk fever). on the other hand, neurological diseases such as encephalitis (e.g., rabies) or encephalopathy (e.g., lead poisoning) should be investigated in animals in which the cause of aspiration pneumonia could not be caused by persistent immunologic stimuli; hypertrophy and hyperplasia of bronchiolar smooth muscle because of increased contraction and decreased muscle relaxation; and a few eosinophilic granulomas around the eggs and dead larvae. these granulomas, grossly, are gray, noncaseated nodules ( to mm in diameter) and may be confused with those seen at the early stages of tuberculosis. the clinical signs (coughing) vary with the severity of infection, and severe cases can be confused clinically with interstitial pneumonias. expiratory dyspnea and death can occur with heavy parasitic infestations when there is massive obstruction of airways. a different form of bovine pneumonia, an acute allergic reaction known as reinfection syndrome, occurs when previously sensitized adult cattle are exposed to large numbers of larvae (dictyocaulus viviparus). lesions in this syndrome are those of a hypersensitivity pneumonia as previously described. other lung parasites. ascaris suum is the common intestinal roundworm of pigs; larvae cannot complete their life cycle in calves, but the larvae can migrate through the lungs and cause severe pneumonia and death of calves within weeks of infection. infection is usually acquired from the soil on which infested pigs were previously kept. the gross lesions are a diffuse interstitial pneumonia with hemorrhagic foci, atelectasis, and interlobular edema and it also occurs in canada, europe, australia, and probably elsewhere. this disease has two major clinicopathologic forms: one involves the central nervous system of goat kids and young goats and is characterized by a nonsuppurative leukoencephalomyelitis; the other form involves the joints of adult goats and is characterized by a chronic, nonsuppurative arthritis-synovitis. in addition, infection with cae virus can cause chronic lymphocytic interstitial pneumonia. the lentivirus of cae, caprine arthritis and encephalitis virus (caev), is closely related to visna/maedi virus and, in fact, cross infection with cae virus in sheep has been achieved experimentally. similar to maedi, cae infection presumably occurs during the first weeks of life when the doe transmits the virus to her offspring through infected colostrum or milk. horizontal transmission between infected and susceptible goats via the respiratory route has also been described. after coming into contact with mucosal cells at the portal of entry, the virus is phagocytized by macrophages, which migrate to the regional lymph nodes. infected macrophages are disseminated hematogenously to the central nervous system, joints, lungs, and mammary glands. like maedi, there is some evidence that the recruitment of lymphocytic cells results from dysregulation of cytokine production by infected macrophages and lymphocytes in affected tissues. it can take several months before serum antibodies can be detected in infected goats. grossly, the interstitial pneumonia is diffuse and tends to be most severe in the caudal lobes. the lungs are gray-pink and firm in texture with numerous, -to -mm, gray-white foci on the cut surface. the tracheobronchial lymph nodes are consistently enlarged. microscopically, the alveolar walls are thickened by lymphocytes and conspicuous hyperplasia of type ii pneumonocytes ( fig. - ). one important difference between the pneumonias of cae and maedi is that in cae the alveoli are filled with proteinaceous eosinophilic material (alveolar proteinosis), which in electron micrographs has structural features of pulmonary surfactant. the pulmonary form of cae can be mistaken for parasitic pneumonia (muellerius capillaris) because these two diseases have lymphocytic interstitial pneumonia and can coexist in the same goat. explained otherwise. depending on the nature of the aspirated material, histopathologic evaluation generally reveals foreign particles such as vegetable cells, milk droplets, and large numbers of bacteria in bronchi, bronchioles, and alveoli (e- fig. - ). vegetable cells and milk typically induce an early neutrophilic response followed by a histiocytic reaction with "foreign body" multinucleated giant cells (see e- fig. - ). special stains are used for the microscopic confirmation of aspirated particles in the lung (e.g., pas for vegetable cells and oil red-o for oil or milk droplets). maedi (visna/maedi). maedi is an important, lifelong, and persistent viral disease of sheep and occurs in most countries, except australia and new zealand. maedi means "shortness of breath" in the icelandic language, and it is known as graaff-reinet disease in south africa, zwoegerziekte in the netherlands, la bouhite in france, and ovine progressive pneumonia (opp) in the united states. more recently, the disease has also been referred to as ovine lentivirusinduced lymphoid interstitial pneumonia or simply lymphoid interstitial pneumonia (lip). maedi is caused by visna/maedi virus (vmv), a nononcogenic small ruminant lentivirus (srlv) of the family retroviridae that is antigenically related to the lentivirus causing caprine arthritisencephalitis (cae). seroepidemiologic studies indicate that infection is widespread in the sheep population, yet the clinical disease seems to be rare. the pathogenesis is incompletely understood, but it is known that transmission occurs largely vertically, through ingestion of infected colostrum, and horizontally, via inhalation of infected respiratory secretions. once in the body, the ovine lentivirus causes lifelong infections within monocytes and macrophages, including alveolar and pulmonary intravascular macrophages; clinical signs do not develop until after a long incubation period of years or more. pulmonary lesions at the time of death are severe interstitial pneumonia and failure of the lungs to collapse when the thorax is opened. notable rib imprints, indicators of uncollapsed lungs, are often present on the pleural surface ( fig. - ). the lungs are pale, mottled, and typically heavy (two or three times normal weight), and the tracheobronchial lymph nodes are enlarged. microscopically, the interstitial pneumonia is characterized by balt hyperplasia and thickening of alveolar walls and peribronchial interstitial tissue by heavy infiltration of lymphocytes, largely t lymphocytes (see fig. - ). recruitment of mononuclear cells into the pulmonary interstitium is presumably the result of sustainable production of cytokines by retrovirus-infected pulmonary macrophages and lymphocytes. hyperplasia of type ii pneumonocytes is not a prominent feature of maedi, likely because in this disease there is no injury to type i pneumonocytes, but there is some alveolar fibrosis and smooth muscle hypertrophy in bronchioles. secondary bacterial infections often cause concomitant bronchopneumonia. enlargement of regional lymph nodes (tracheobronchial) is due to severe lymphoid hyperplasia, primarily of b lymphocytes. the virus can also infect many other tissues, causing nonsuppurative encephalitis (visna), lymphocytic arthritis, lymphofollicular mastitis, and vasculitis. maedi is clinically characterized by dyspnea and an insidious, slowly progressive emaciation despite good appetite. death is inevitable once clinical signs are present, but it may take many months. caprine arthritis-encephalitis. caprine arthritis-encephalitis (cae) is a retroviral disease of goats (small ruminant lentivirus) that has a pathogenesis remarkably similar to that of visna/maedi in sheep. it was first described in the united states in the s, but such as pasteurella multocida, pneumonia may progress to fibrinous or suppurative bronchopneumonia. one might expect some specific evidence pointing to the infectious agents (e.g., large intranuclear inclusion bodies in epithelial cells with adenoviral infection), but this is often not the case, either because examination is seldom done at the acute stage when the lesions are still present or because secondary bacterial infections mask the primary lesions. in the late stages, chronic enzootic pneumonia is characterized by hyperplastic bronchitis, atelectasis, alveolar and peribronchiolar fibrosis, and marked peribronchial lymphoid hyperplasia (cuffing pneumonia). ovine pneumonic mannheimiosis. ovine pneumonic mannheimiosis is one of the most common and economically significant diseases in most areas where sheep are raised. it is caused by mannheimia haemolytica and has a pathogenesis and lesions similar to those of pneumonic mannheimiosis of cattle. colonization and infection of lungs are facilitated by stressors such as changes in weather; handling; deworming; dipping; viral infections such as parainfluenza virus (piv ), respiratory syncytial virus (rsv), and adenovirus; and probably chlamydiae and bordetella parapertussis infections. lesions are characterized by a severe fibrinous bronchopneumonia (cranioventral) with pleuritis ( fig. - and e-fig. - ). subacute to chronic cases progress to purulent bronchopneumonia, and sequelae include abscesses and fibrous pleural adhesions. a similar form of pneumonic mannheimiosis has been reported with increased frequency in bighorn sheep. septicemic pasteurellosis. septicemic pasteurellosis, a common ovine disease, is caused by bibersteinia trehalosi (formerly pasteurella trehalosi or mannheimia haemolytica biotype t) in lambs months of age or older or by mannheimia haemolytica (biotype a) in lambs younger than months of age. both organisms are carried in the tonsils and oropharynx of clinically healthy sheep, and under abnormal circumstances (particularly under stress from dietary or environmental changes) bacteria can invade adjacent tissues, enter the bloodstream, and cause septicemia. gross lesions include a distinctive necrotizing pharyngitis and tonsillitis; ulcerative esophagitis (e- fig. - ) ; severe congestion and edema of the lungs; focal hepatic necrosis; and petechiae in the mucosa of the tongue, esophagus, and intestine and particularly in the lungs and pleura. clinically, goats are active and afebrile but progressively lose weight despite normal appetite. the encephalitic or arthritic signs tend to obscure the respiratory signs, which are only evident on exertion. secondary bacterial bronchopneumonia is common in affected animals. bacterial pneumonias. in the past, pasteurella haemolytica was incriminated in four major ovine diseases known as ( ) acute ovine pneumonic pasteurellosis (shipping fever), ( ) enzootic pneumonia (nonprogressive chronic pneumonia), ( ) fulminating septicemia, and ( ) mastitis. under the new nomenclature, mannheimia haemolytica is responsible for ovine pneumonia resembling shipping fever in cattle (ovine pneumonic mannheimiosis), septicemia in young lambs (younger than months of age), and ovine enzootic pneumonia and sporadic severe gangrenous mastitis in ewes. bibersteinia (pasteurella) trehalosi (formerly pasteurella haemolytica biotype t) is the agent incriminated in septicemia in lambs to months old. chronic enzootic pneumonia. in sheep, this entity is a multifactorial disease complex that, in contrast to ovine pneumonic mannheimiosis, causes only a mild to moderate pneumonia and it is rarely fatal. it generally affects animals younger than year of age. significant costs associated with chronic enzootic pneumonia include reduction of weight gain, labor costs, veterinary fees, and slaughterhouse waste. the modifier "chronic" is used here to avoid any confusion with pneumonic mannheimiosis ("acute enzootic pneumonia"). it is also sometimes called atypical pneumonia, chronic nonprogressive pneumonia, proliferative pneumonia, or other names. chronic enzootic pneumonia is a clinical epidemiologic term and does not imply a single causal agent but is the result of a combination of infectious, environmental, and managerial factors. the list of infectious agents involved in ovine enzootic pneumonia includes mannheimia haemolytica, pasteurella multocida, parainfluenza virus (pi- ), adenovirus, reovirus, respiratory syncytial virus (rsv), chlamydiae, and mycoplasmas (mycoplasma ovipneumoniae). in the early stages of enzootic pneumonia, a cranioventral bronchointerstitial pneumonia is characterized by moderate thickening of alveolar walls because of hyperplasia of type ii pneumonocytes. in some cases, when lungs are infected with secondary pathogens, viviparus of cattle. as seen in cattle with dictyocaulus viviparus, areas of atelectasis secondary to bronchiolar obstruction are present, particularly along the dorsal caudal aspects of the caudal lung lobes. microscopically, affected lungs are characterized by a catarrhal, eosinophilic bronchitis, with peribronchial lymphoid hyperplasia and smooth muscle hyperplasia of bronchi and bronchioles. bronchioles and alveoli can contain edematous fluid, eosinophils, and parasitic larvae and eggs. microscopic granulomas caused by aspirated eggs can be observed in the distal lung. the clinical signs (cough, moderate dyspnea, and loss of condition) and lesions relate mainly to obstruction of the small bronchi by adult worms and filaria. anemia of undetermined pathogenesis and secondary bacterial pneumonia are common in small ruminants with this parasitic disease. muellerius capillaris. muellerius capillaris, also called the nodular lungworm, occurs in sheep and goats in most areas of the world and is the most common lung parasite of sheep in europe and northern africa. it requires slugs or snails as intermediate hosts. the lesions in sheep are typically multifocal, subpleural nodules that tend to be most numerous in the dorsal areas of the caudal lung lobes ( fig. - , a) . these nodules are soft and hemorrhagic in the early stages but later become gray-green and hard or even calcified. microscopically, a focal, eosinophilic, and granulomatous reaction occurs in the microscopically, the hallmark lesion is a disseminated intravascular thrombosis often with bacterial colonies in the capillaries of affected tissues. the alveolar capillaries contain bacteria and microthrombi, and the alveolar lumens have fibrin and red blood cells. mannheimia haemolytica and bibersteinia trehalosi are readily isolated from many organs. affected animals usually die within a few hours of infection, and these animals only rarely have clinical signs such as dullness, recumbency, and dyspnea. contagious caprine pleuropneumonia. a number of mycoplasma spp., often referred to as the "mycoides cluster," can produce respiratory tract infections in goats; however, only mycoplasma capricolum ssp. capripneumoniae is considered to cause contagious caprine pleuropneumonia. this disease is the goat counterpart of contagious bovine pleuropneumonia in cattle; sheep do not have a corresponding disease. this oie-notifiable disease is important in africa, the middle east, and areas of asia, but it is also seen elsewhere. the gross lesions caused by mycoplasma capricolum ssp. capripneumoniae are similar to those of the bovine disease and consist of a severe, often unilateral fibrinous bronchopneumonia and pleuritis; however, distention of the interlobular septa (which are normally not as well developed in goats as in cattle) and formation of pulmonary sequestra are less obvious than in the bovine disease. clinically, contagious caprine pleuropneumonia is similar to contagious bovine pleuropneumonia, with high morbidity and mortality, fever, cough, dyspnea, and increasing distress and weakness. other small ruminant mycoplasmas. pneumonia, fibrinous polyarthritis, septicemia, meningitis, mastitis, peritonitis, and abortion are possible manifestations of disease caused by mycoplasma mycoides ssp. mycoides large colony type and mycoplasma mycoides ssp. capri. the pathogenicity of other mycoplasmas, such as mycoplasma ovipneumoniae, mycoplasma arginini, and mycoplasma capricolum ssp. capricolum, in sheep and goats is still being defined and specific description of the lesions would be premature. these organisms probably cause disease only in circumstances similar to those for enzootic pneumonia, where host, infectious, and environmental factors create a complex interaction in the pathogenesis of the disease. it has been suggested that igg antibodies directed against ovine mycoplasmal antigens cross-react with ciliary proteins, causing inflammation and ciliary dysfunction, a condition in lambs referred to as coughing syndrome. tuberculosis. although tuberculosis has generally been considered uncommon in sheep and goats, caprine tuberculosis has become a significant disease in areas of spain and europe. mycobacterium caprae (formerly mycobacterium bovis ssp. caprae/mycobacterium tuberculosis ssp. caprae) is the most common cause, but infection with mycobacterium bovis or with the mycobacterium avium complex does occur when the disease is prevalent in other species in the locality. the pulmonary form, similar to that seen in cattle, is characterized by a granulomatous pneumonia with multiple, large, caseous, calcified, and well-encapsulated granulomas scattered throughout the lungs. intralesional acid-fast organisms within macrophages are not as abundant as in bovine tuberculosis. staphylococcus aureus. young sheep ( to weeks old) are susceptible to staphylococcus aureus septicemia (tick pyemia). this bacterium causes disseminated inflammation and abscesses in the joints, heart, liver, kidneys, and cns, and in the lung it can also produce bronchopneumonia and pulmonary abscesses (e- fig. - ). dictyocaulus filaria. dictyocaulus filaria, also called the large lungworm, is a serious, worldwide, parasitic disease of the lungs, most commonly of lambs and goat kids but occurring in adults as well. the life cycle and lesions are similar to those of dictyocaulus epithelial cells spreads rapidly throughout the nasal, tracheal, and bronchial mucosa, with the more severe outbreaks reflecting more involvement of intrapulmonary airways and secondary infection with pasteurella multocida, trueperella (arcanobacterium) pyogenes, or haemophilus spp. although uncommon, human beings infected with swine influenza (h n ) can transmit the virus to pigs; therefore it is important that veterinarians or workers with influenza-like illness stay away from pig farms. natural transmission of h n and h n from human beings to ferrets (mustela putorius furo) and from human beings to cats and dogs has also been reported. pulmonary lesions caused by influenza virus alone are rarely seen in the postmortem room because this disease has a very low mortality rate unless complicated with secondary bacterial infections. grossly, a copious catarrhal to mucopurulent inflammation extends from the nasal passages to the bronchioles, with the volume of mucus being sufficient to plug small airways and cause a lobular or multilobular atelectasis in the cranioventral regions of the lungs. the appearance can be similar grossly, although not microscopically, to that of mycoplasma hyopneumoniae. fatal cases have severe alveolar and interstitial pulmonary edema. microscopically, the lesions in uncomplicated cases are typical of a virus-induced, necrotizing bronchitis-bronchiolitis, which in severe cases extends into the alveoli as bronchointerstitial pneumonia. it is characterized by necrosis of the bronchial/bronchiolar epithelium, thickening and infiltration of the alveolar wall with mononuclear cells and aggregates of macrophages, neutrophils, mucus, and some necrotic cells within the alveolar lumen. if these changes are extensive enough, the lumen of bronchioles can be occluded by exudate, causing lobular atelectasis. viral antigen can be demonstrated in infected epithelial cells by immunoperoxidase techniques. in the later stages of alveolar inflammation, neutrophils are progressively replaced by intraalveolar macrophages, unless the pneumonia is complicated by secondary bacterial infections. recent serologic surveys indicate that infection is also prevalent in wild pigs. clinically, a sudden onset of fever, nasal discharge, stiffness, labored breathing, weakness or even prostration, followed by painful and often paroxysmal coughing, is seen in animals of all age groups and may affect most of the herd. the outbreak subsides virtually without mortality within or weeks; the clinical appearance is much more alarming than the pathologic changes, unless the pigs have secondary infection with bacteria. infection can be confirmed using pcr in secretions collected with nasal swabs. the most important effect of most outbreaks of influenza is severe weight loss, but pregnant sows may abort or give birth to weak piglets. porcine reproductive and respiratory syndrome. a disease originally named mystery swine disease was first recognized in the united states in . in , it was seen in europe, and the disease now occurs worldwide in most major pig-raising countries. in , dutch investigators isolated a virus as the etiologic agent; porcine reproductive and respiratory syndrome virus (prrsv) is currently classified in the genus arterivirus of the family arteriviridae. as its name implies, prrs is characterized by late-term abortions and stillbirths and respiratory problems. the respiratory form is generally seen in nursery and grow/finish pigs. the pathogenesis has not been completely elucidated, but it is presumed that there is a mucosal portal of entry with virus replication in macrophages of the lymphoid tissue, followed by viremia and finally dissemination of infected macrophages to the lungs and other organs, such as the thymus, liver (kupffer cells), spleen, lymph nodes, and intestine. the pulmonary alveolar and intravascular macrophages are the major targets for prrs virus, which induces apoptosis of these cells. the virus also downregulates the innate immune response by subpleural alveoli where the adults, eggs, and coiled larvae reside ( fig. - , b) . clinical signs are usually not apparent. goats differ from sheep by having diffuse interstitial rather than focal lesions, and the reaction to the parasites seen microscopically varies from almost no lesions to a severe interstitial pneumonia with heavy infiltrates of mononuclear cells in alveolar walls resembling cae or mycoplasmal infections. secondary effects of muellerius capillaris infection in sheep and goats include decreased weight gain and possibly secondary bacterial infections. protostrongylus rufescens. protostrongylus rufescens is a worldwide parasite of sheep, goats, and wild ruminants. it requires an intermediate snail as a host. infection is usually subclinical, but protostrongylus rufescens can be pathogenic for lambs and goat kids and can cause anorexia, diarrhea, weight loss, and mucopurulent nasal discharge. the adult parasite lives in bronchioles as dictyocaulus spp., but it causes pulmonary nodules similar to those of muellerius capillaris. porcine pneumonias are unequivocally a major obstacle for the contemporary swine industry. the incidence, prevalence, and mortality rates of pneumonias in pigs depend on a series of complex, multifactorial interactions. among the most commonly recognized elements linked to porcine pneumonias are the following: • host (age, genetic makeup, immune status) • infectious agents (viruses, bacteria) • environmental determinants (humidity, temperature, ammonia concentrations) • management practices (crowding, mixing of animals, air quality, nutrition, stress) because of the nature of these multifactorial interactions, it will become obvious in the following paragraphs that more often than not a specific type of pneumonia frequently progresses to or coexists with another. the term porcine respiratory disease complex (prdc) has been introduced in clinical practice to describe pigs with signs of respiratory infection involving combined bacterial and viral infections. commonly implicated microbes include porcine reproductive and respiratory syndrome virus (prrsv), swine influenza virus (siv), porcine circovirus (pcv ), porcine respiratory coronavirus (prcov), mycoplasma hyopneumoniae, and pasteurella multocida. swine influenza (swine flu). swine influenza is a highly contagious acute respiratory viral disease of swine that is caused by swine influenza virus (siv), a type a influenza virus of the family orthomyxoviridae. it is generally accepted that swine influenza resulted from adaptation of the type a influenza virus that caused the human influenza pandemic during world war i. the most common subtypes of siv currently circulating in pigs are h n , h n , and h n . swine influenza is enzootic worldwide and is known to infect human beings who are in close contact with sick pigs. in , an outbreak of swine-human influenza (h n ), presumably transmitted from pigs to human beings, emerged in mexico and rapidly spread to many countries throughout the world. this new "pandemic" was attributed to a triple-reassortant of influenza a virus containing gene segments of swine, eurasian avian, and human strains. human infection with this novel strain affected mainly children and young adults, as well as individuals of any age with an underlying debilitating condition. transmission between influenza-infected and susceptible pigs occurs mainly by aerosol or oral route. siv attaches to and replicates within epithelial cells of the upper respiratory tract; the infection of similar inclusions are occasionally seen in bronchial glandular and renal epithelial cells. the lungs show thickening of the alveolar walls because of hyperplasia of type ii pneumonocytes and interstitial infiltrates of mononuclear cells, peribronchiolar fibrous hyperplasia, and necrotizing bronchitis/bronchiolitis. circovirus can be confirmed in affected tissue by immunohistochemical or pcr techniques. dual infections with pcv and prrsv frequently occur in pigs, and secondary infections with pneumocystis carinii are commonly seen in pigs with this coinfection. characteristically, alveoli are filled with a distinctive foamy exudate that contains the organism, which is not visible in h&e-stained sections but is easily demonstrated with gomori's methenamine silver stain (see fig. - ) . in human beings, pneumocystis (carinii) jirovecii pneumonia (pneumocystosis) is one of the most common and often fatal complications in aids patients. as in aids patients, abnormal populations of cd + and cd + t lymphocytes have been incriminated as the underlying mechanism leading to pneumocystosis in foals and pigs. nipah virus. nipah virus belongs to the paramyxoviridae family and shares a genus (henipavirus) with the closely related hendra virus (see section on pneumonias of horses). another emerging zoonotic disease, nipah virus caused a major epidemic with significant human mortality in southeast asia in and . people handling pigs were primarily affected. similar to hendra virus, fruit bats (flying foxes) act as natural reservoir and are involved in the transmission to pigs by poorly understood mechanisms. in pigs, this virus infects the respiratory system resulting in pneumonia with syncytial cells occurring in the vascular endothelium and in the respiratory epithelium at all levels of the lung. disease is spread to human beings via the respiratory route. human-to-human transmission of this virus has been reported in more recent outbreaks. other viral pneumonias of pigs. porcine respiratory coronavirus (prcov) is sporadically incriminated in pneumonia in pigs. this viral pneumonia is generally mild, and most pigs fully recover if the pneumonia is not complicated with other infections. lesions in the lung are those of bronchointerstitial pneumonia with necrotizing bronchiolitis. interestingly, infections with porcine and other respiratory coronaviruses have been used to investigate the pathogenesis of severe acute respiratory syndrome (sars), an emerging and highly contagious condition in human beings that is attributed to a novel human coronavirus (sars-cov). the relationship between sars-cov and animal coronavirus is still under investigation. other viruses rarely incriminated in porcine respiratory disease complex (prdc) include paramyxovirus, encephalomyocarditis virus, hemagglutinating encephalomyocarditis virus, and adenovirus. petechial hemorrhages in the lung and pulmonary edema may be seen with african swine fever, classical swine fever, and pseudorabies virus infections. porcine enzootic pneumonia. porcine enzootic pneumonia, a highly contagious disease of pigs caused by mycoplasma hyopneumoniae, is grossly characterized by suppurative or catarrhal bronchopneumonia ( fig. - and e- fig. - ). when its worldwide prevalence and deleterious effect on feed conversion are taken into account, this disease is probably the most economically significant respiratory disease of pigs. although an infectious disease, it is very much influenced by immune status and management factors, such as crowding (airspace and floor space), ventilation (air exchange rate), concentrations of noxious gases in the air (ammonia and hydrogen sulfide), relative humidity, temperature fluctuations, and mixing of stock from various sources. it has been demonstrated with inhibiting interferons and deregulates the adaptive immune response, thus interfering with the normal defense mechanisms predisposing pigs to septicemia and bacterial pneumonia. the most common opportunistic organisms are streptococcus suis, salmonella choleraesuis, mycoplasma hyopneumoniae, haemophilus parasuis, bordetella bronchiseptica, pasteurella multocida, and pneumocystis carinii. dual viral infections with prrsv and porcine circovirus (pcv ), siv, and porcine respiratory coronavirus (prcov) are commonly found in pigs, and such coinfections increase the severity of disease. on postmortem examination, pulmonary lesions vary from very mild changes characterized by failure of the lung to collapse when the thorax is opened and the presence of rib imprints (see fig. - ) to severe changes manifested by consolidation of the lung in cases that have been complicated with bacterial pneumonia. tracheobronchial and mediastinal lymph nodes are typically enlarged. microscopically, pulmonary changes are those of interstitial pneumonia characterized by thickening of alveolar walls by infiltrating macrophages and lymphocytes and mild hyperplasia of type ii pneumonocytes. necrotic cells are scattered in the alveolar lumens. unlike some other viral infections, bronchiolar epithelium does not appear to be affected. diagnosis of prrs in tissue collected at necropsy can be confirmed by immunohistochemistry and pcr techniques. infected pigs may become carriers and transmit the infection through body fluids and semen. clinically, prrs in nursery and young growing animals is characterized by sneezing, fever, anorexia, dyspnea, cough, and occasional death. some piglets develop severe cyanosis of the abdomen and ears, which explains why this syndrome was named blue ear disease when first described in europe. porcine circovirus-associated disease. another emerging porcine syndrome, characterized clinically by progressive emaciation in weaned pigs, was originally described in the s in canada, the united states, and europe. since then, it has disseminated to many countries, causing economic devastation in pig farms worldwide. because of the clinical signs and lesions in many organs, this syndrome was named postweaning multisystemic wasting syndrome (pmws). porcine circovirus (pcv ) has been incriminated as the etiologic agent and is a member of the circoviridae family. pcv has been associated with a number of syndromes in pigs, including systemic pcv infection (the preferred term for pmws because it may also affect mature pigs), pcv -associated pneumonia, pcv -associated enteritis, porcine dermatitis and nephropathy syndrome (pdns), pcv -associated reproductive failure, and, most recently, pcv -associated cerebellar vasculitis. the diseases caused by pcv are now collectively known as porcine circovirus-associated disease (pcvad); the most common manifestations are systemic pcv infection (pmws) and pcv -associated pneumonia as part of the porcine respiratory disease complex. all of these manifestations affect more than one organ, and there is substantial overlap between the syndromes. at necropsy, pigs with systemic pcv infection (pmws) and pcv -associated pneumonia are often in poor body condition, and the most remarkable changes, not considering other possible secondary infections, are enlargement of the superficial and visceral lymph nodes and a mild interstitial pneumonia characterized by failure of the lungs to collapse when the thorax is opened. jaundice is occasionally observed. microscopically, the lymphoid tissues show lymphoid depletion, histiocytic replacement of follicles, and notable proliferation of parafollicular histiocytes, some of which fuse and form syncytial cells (granulomatous lymphadenitis); necrosis of the lymphoid follicles is seen less often. in some cases, large basophilic inclusion bodies are present singly or as grapelike clusters (botryoid inclusions) within the cytoplasm of macrophages, particularly in peyer's patches, spleen, and lymph nodes (e- fig. - ). chapter respiratory system, mediastinum, and pleurae peribronchial, bronchiolar, and alveolar interstitium. additional virulence factors include the ability of mycoplasma hyopneumoniae to cause immunosuppression, reduce the phagocytic activity of neutrophils in the lung, and change the chemical composition of mucus. all of these functional alterations can predispose the lung to secondary bacterial infections. the lesions caused by mycoplasma hyopneumoniae start as a bronchointerstitial pneumonia and progress to a suppurative or mucopurulent bronchopneumonia once secondary pathogens are involved (commonly seen at necropsy). in most pigs, gross lesions affect only portions of the cranial lobes, but in more severely affected pigs, lesions involve % or more of the cranioventral portions of the lungs (see fig. - ). the affected lungs are dark red in the early stages but have a homogeneous pale-gray ("fish flesh") appearance in the more chronic stages of the disease. on cut surface, exudate can easily be expressed from airways, and depending on the stage of the lesions and secondary infections, the exudate varies from purulent to mucopurulent to mucoid. microscopic lesions are characterized by an influx of macrophages and neutrophils into the bronchi, bronchioles, and alveoli, and with time there is also notable balt hyperplasia (see fig. - , b) . in some cases, accumulation of exudate can be severe enough to cause occlusion of bronchioles and atelectasis of the corresponding lobules. the suppurative bronchopneumonia may be accompanied by a mild fibrinous pleuritis, which is often more severe if other organisms, such as mycoplasma hyorhinis, pasteurella multocida, or actinobacillus pleuropneumoniae, are also involved. abscesses and fibrous pleural adhesions are sequelae of chronic complicated infections. clinically, enzootic pneumonia occurs as a herd problem in two disease forms. a newly acquired infection of a previously clean herd causes disease in all age groups, resulting in acute respiratory distress and low mortality. in a chronically infected herd, the mature animals are immune and clinical signs are usually apparent only in growing pigs at times of particular stress such as at weaning. in such herds, coughing and reduced rate of weight gain are the most notable signs. porcine pasteurellosis. porcine pasteurellosis is an infectious disease complex with unclear pathogenesis that includes primary infections by pasteurella multocida alone (primary pasteurellosis) or, more frequently, after the defense mechanisms are impaired and a secondary bacterium colonizes the lung (porcine pneumonic pasteurellosis). in rare cases, pasteurella multocida causes acutely fatal septicemias in pigs (primary septicemic pasteurellosis). it is important to remember that pasteurella multocida serotypes a and d are both part of the normal nasal flora and are also causative agents of bronchopneumonia, pleuritis, and atrophic rhinitis in pigs. pasteurella multocida is one of the most common secondary pathogens isolated from the lungs of pigs with swine influenza virus (siv), porcine reproductive and respiratory syndrome virus (prrsv), porcine circovirus (pcv ), pseudorabies (suhv- ), classical swine fever (hog cholera), enzootic pneumonia, and porcine pleuropneumonia. secondary infections with pasteurella multocida notably change the early and mild bronchointerstitial reaction of enzootic and viral pneumonias into a severe suppurative bronchopneumonia with multiple abscesses and sometimes pleuritis. the other important role of pasteurella multocida in porcine pneumonias is as a cause of a fulminating, cranioventral, fibrinous bronchopneumonia (pleuropneumonia) after influenza virus infection or stress from inadequate ventilation resulting in high levels of ammonia in the air. the nature of the lesion and the predisposing factors of poor management or coexisting viral infections suggest that fulminating porcine pasteurellosis has a pathogenesis similar to that of pneumonic mannheimiosis of cattle. pharyngitis with subcutaneous cervical edema, fibrinohemorrhagic polyarthritis, and focal lymphocytic pcr that mycoplasma hyopneumoniae is present in the air of infected farms. the causative agent, mycoplasma hyopneumoniae, is a fastidious organism and very difficult to grow; thus the final diagnosis is frequently based on interpretation of lesions alone or supported by ancillary tests to detect this mycoplasma in affected lungs by immunohistochemistry, immunofluorescence, or pcr. the bronchopneumonic lesions of porcine enzootic pneumonia are in most cases mild to moderate, and thus mortality is low unless complicated with secondary pathogens, such as pasteurella multocida, trueperella (arcanobacterium) pyogenes, bordetella bronchiseptica, haemophilus spp., mycoplasma hyorhinis, and other mycoplasmas and ureaplasmas. although the pathogenesis of porcine enzootic pneumonia is not completely elucidated, it is known that mycoplasma hyopneumoniae first adheres to the cilia of the bronchi by means of a unique adhesive protein, produces ciliostasis, and finally colonizes the respiratory system by firmly attaching to the ciliated epithelial cells of the trachea and the bronchi of the cranioventral regions of the lungs. once attached to the respiratory epithelium, it provokes an influx of neutrophils into the tracheobronchial mucosa; causes extensive loss of cilia (deciliation); stimulates an intense hyperplasia of lymphocytes in the balt; and attracts mononuclear cells into the factors have been identified. these factors allow actinobacillus pleuropneumoniae to attach to cells; produce pores in cell membranes; damage capillaries and alveolar walls, resulting in vascular leakage and thrombosis; impair phagocytic function; and elicit failure of clearance mechanisms. the gross lesions in the acute form consist of a fibrinous bronchopneumonia characterized by severe consolidation and a fibrinous exudate on the pleural surface. although all lobes can be affected, a common site is the dorsal area of the caudal lobes. in fact, a large area of fibrinous pleuropneumonia involving the caudal lobe of a pig's lung is considered almost diagnostic for this disease (fig. - ) . on cut surface, consolidated lungs have notably dilated interlobular septa and irregular but well-circumscribed areas of necrosis caused by potent cytotoxins produced by actinobacillus pleuropneumoniae. except for the distribution, pulmonary lesions of porcine pleuropneumonia are identical to those of pneumonic mannheimiosis of cattle. the microscopic lesions are also very similar and include areas of coagulative necrosis surrounded by a thick cluster of "streaming (oat-shaped/oat cell) leukocytes" and notable distention of the interlobular septa because of severe edema and lymphatic thrombosis. bronchioles and alveoli are filled with edematous fluid, fibrin, neutrophils, and few macrophages (see fig. - ). pigs with the chronic form have multiple pulmonary abscesses and large ( to cm) pieces of necrotic lung encapsulated by connective tissue (sequestra)-changes frequently seen in slaughterhouses. interstitial nephritis are also present in porcine pneumonic pasteurellosis. sequelae of porcine pneumonic pasteurellosis include fibrous pleuritis and pericarditis, pulmonary abscesses, so-called sequestra, and usually death. in contrast to ruminants, mannheimia haemolytica is not a respiratory pathogen for pigs, but in some instances, it can cause abortion in sows. porcine pleuropneumonia. porcine pleuropneumonia is a highly contagious, worldwide disease of pigs caused by actinobacillus (haemophilus) pleuropneumoniae (app), which is characterized by a severe, often fatal, fibrinous bronchopneumonia with extensive pleuritis (pleuropneumonia). survivors generally develop notable residual lesions and become carriers of the organisms. porcine pleuropneumonia is an increasingly important cause of acute and chronic pneumonias, particularly in intensively raised pigs ( to months old). transmission of actinobacillus pleuropneumoniae occurs by the respiratory route, and the disease can be reproduced experimentally by intranasal inoculation of the bacterium. considered a primary pathogen, actinobacillus pleuropneumoniae can sporadically produce septicemia in young pigs and otitis media and otitis interna with vestibular syndrome in weaned pigs. two biovars and serotypes of the organism have been identified; all serotypes can cause the disease, but differences in virulence exist. the pathogenesis is not yet well understood, but specific virulence factors, such as rtx toxins (hemolytic/cytolytic toxins apx i to apx iv), capsular factors, fimbriae and adhesins, lipopolysaccharide, and permeability tuberculosis. tuberculosis is an important disease in domestic and wild pigs that has a much greater prevalence in pigs than in cattle or other domestic mammals in many countries. porcine tuberculosis is attributed to infection with mycobacterium bovis and porcine mycobacteriosis to infection with mycobacterium avium complex. a common scenario in small mixed-farming operations is the diagnosis of avian tuberculosis at the time that pigs are slaughtered, and the source is ingestion of tuberculous chickens or contaminated litter. as would be expected, granulomas are found in the mesenteric, mandibular, and retropharyngeal lymph nodes; to a lesser extent in the intestine, liver, and spleen; and only in rare cases in the lung. the route of infection in pulmonary tuberculosis and mycobacteriosis of pigs is most often hematogenous after oral exposure and intestinal infection. lung lesions are those of a granulomatous pneumonia. the microscopic lesions are basically those of tubercles (granulomas), but the degree of encapsulation, caseation, and calcification varies with the type of mycobacterium, age of the lesion, and host immune response. other bacterial pneumonias of pigs. septicemias in pigs often cause petechial hemorrhages in the lung and pulmonary edema. salmonellae, escherichia coli, and listeria monocytogenes can cause severe interstitial pneumonia in very young animals. salmonella choleraesuis causes a necrotizing fibrinous pneumonia similar to porcine pleuropneumonia, and salmonella typhisuis causes a chronic suppurative bronchopneumonia. in high health herds, actinobacillus suis may cause fibrinohemorrhagic pleuropneumonia and is easily confused with porcine pleuropneumonia. metastrongylosis. metastrongylus apri (elongatus), metastrongylus salmi, and metastrongylus pudendotectus (lungworms) of domestic and feral pigs occur throughout most of the world and require earthworms as intermediate hosts for transmission. the incidence of disease has therefore decreased with development of confinement housing. the importance of pig lungworms is mainly because infection results in growth retardation of the host. clinical signs include coughing because of parasitic bronchitis. the gross lesions, when noticeable, consist of small gray nodules, particularly along the ventral borders of the caudal lobes. the adult worms are grossly visible in bronchi, and microscopically, the parasites cause a catarrhal bronchitis with infiltration of eosinophils and lobular atelectasis ( fig. - ) . ascaris suum. the larvae of ascaris suum can cause edema, focal subpleural hemorrhages, and interstitial inflammation (see fig. - ). along their larval migration tracts, hemorrhages also occur in the liver and, after fibrosis, become the large white "milk spots" seen so frequently as incidental findings at necropsy. it has been reported that ascaris suum may cause immunosuppression in severely affected pigs. pigs can be killed if exposed to an overwhelming larval migration. other causes of pneumonia. foreign body granulomatous pneumonia occurs frequently in pigs after inhalation of vegetable material (starch pneumonia), presumably from dusty (nonpelleted) feed. lesions are clinically silent but are often mistaken for other pneumonic processes during inspection at slaughterhouses. microscopically, pulmonary changes are typical of foreign body granulomatous inflammation in which variably sized feed particles are surrounded by macrophages and neutrophils, and often have been phagocytosed by multinucleated giant cells. feed (vegetable) particles appear as thick-walled polygonal cells that stain positive with pas because of their rich carbohydrate (starch) content (see e- fig. - ) . clinically, porcine pleuropneumonia can vary from an acute form with unexpected death and blood-stained froth at the nostrils and mouth to a subacute form characterized by coughing and dyspnea accompanied by clinical signs of sepsis such as high fever, hypoxemia, anorexia, and lethargy (e- fig. - ) . a chronic form is characterized by decreased growth rate and persistent cough. animals that survive often carry the organism in the tonsils, shed the organism, and infect susceptible pigs. haemophilus pneumonia. in addition to glasser's disease characterized by polyserositis (pericarditis, pleuritis, peritonitis, polyarthritis, and meningitis) (e- fig. - ) , some serotypes of haemophilus parasuis (originally haemophilus influenzae suis) can also cause suppurative bronchopneumonia that in severe cases can be fatal. the causal organism, haemophilus parasuis, is usually carried in the nasopharynx of normal pigs and requires abnormal circumstances such as those following stress (weaning and cold weather) or viral infections (swine influenza or pcv ). specific pathogen-free (spf) pigs seem to be particularly susceptible to glasser's disease (arthritis and serositis) but not to pulmonary infection (bronchopneumonia). streptococcal pneumonia. streptococcus suis is a common cause of porcine disease worldwide and a serious zoonosis capable of causing death by septic shock or meningitis and residual deafness in butchers, veterinarians, and pig farmers. typically, streptococcus suis gains entrance to the susceptible young pig through the oropharyngeal mucosa and is carried in the tonsils, nasal mucosa, and mandibular lymph nodes of healthy animals, particularly in survivors of an outbreak. infected sows can abort or vertically transmit the infection to their offspring. some serotypes of streptococcus suis cause neonatal septicemia, and this can result in suppurative meningitis, otitis, arthritis, polyserositis, myocarditis, valvular endocarditis, and embolic pneumonia ( fig. - ). other serotypes of streptococcus suis can reach the lung by the aerogenous route and cause a suppurative bronchopneumonia, in combination with pasteurella multocida, escherichia coli, or mycoplasma hyopneumoniae, or in combination with actinobacillus pleuropneumoniae, which causes a fibrinous bronchopneumonia. coinfections of streptococcus suis with pcv and prrsv are also frequently seen in some farms. gross lesions in the acute stages include serous to catarrhal to mucopurulent nasopharyngitis and conjunctivitis. the lungs are edematous and have a diffuse interstitial pneumonia ( fig. - ) microscopically characterized by necrotizing bronchiolitis, necrosis and exfoliation of pneumonocytes, mild alveolar edema, and, several hours later, thickening of the alveolar walls because of interstitial mononuclear cell infiltrates and hyperplasia of type ii pneumonocytes. secondary infections with bordetella bronchiseptica and mycoplasmas are common and induce life-threatening suppurative bronchopneumonia. the thymus may be small relative to the age of the animal because of viral-induced lymphocytolysis. microscopically, eosinophilic inclusions are present in the epithelial cells of many tissues, in the nuclei or cytoplasm, or in both (see fig. - ). they appear early in the bronchiolar epithelium but are most prominent in the epithelium of the lung, stomach, renal pelvis, and urinary bladder, making these tissues good choices for diagnostic examination. viral inclusions are rarely seen in the later stages of this disease. the suppurative secondary bronchopneumonias often hinder the detection of viral lesions in the lung, particularly because bronchiolar cells containing inclusion bodies exfoliate and mix with the neutrophils recruited by the bacterial infection. distemper virus antigens can be readily demonstrated in infected cells by the immunoperoxidase technique (see fig. - ), which can also be used in skin biopsies for the antemortem diagnosis of canine distemper. distemper virus also has a tendency to affect developing tooth buds and ameloblasts, causing enamel hypoplasia in dogs that recover from infection. of all distemper lesions, demyelinating encephalomyelitis, which develops late, is the most devastating (see chapter ). sequelae to distemper include the nervous and pneumonic complications mentioned previously and various systemic infections, such as toxoplasmosis and sarcocystosis, because of depressed immunity. persistent viral infection occurs in some dogs that survive the disease, and they may become carriers and the source of infection for other susceptible animals. clinical signs consist of biphasic fever, diarrhea, vomiting, weight loss, mucopurulent oculonasal discharge, coughing, respiratory distress, and possible loss of vision. weeks later, hyperkeratosis of the foot pads ("hard pad") and the nose are observed, along with nervous signs, including ataxia, paralysis, convulsions, or residual myoclonus (muscle twitches, tremors, and "tics"). in general, inflammatory diseases of the lungs are less of a problem in dogs than in food-producing species and can be subdivided in two major groups, infectious and noninfectious pneumonias. "canine infectious respiratory disease" (cird) is the term currently used by clinicians to describe a heterogeneous group of respiratory infections in dogs; these diseases were previously clustered under the name of infectious tracheobronchitis or "kennel cough." cird is the canine counterpart of brd and prd complexes in cattle and pigs, respectively. the most common viruses in cird include canine parainfluenza virus (cpiv), canid herpesvirus (cahv- ), canine adenovirus- (cav- ), canine respiratory coronavirus (crcov), canine distemper virus (cdv), and canine influenza virus (civ). bordetella bronchiseptica, streptococcus equi ssp. zooepidemicus, and mycoplasma spp. are the most frequent bacterial isolates in cird. it has been recently recognized that animal shelters are an important source of viral and bacterial infections for dogs and cats. uremia and paraquat toxicity are perhaps the two most notable noninfectious causes of canine respiratory disease. canine distemper. canine distemper is an important and ubiquitous infectious disease of dogs, other canidae, wild felidae, mustelidae, and marine mammals throughout the world. it is caused by a morbillivirus that is antigenically related to the human measles, rinderpest (officially eradicated in ), "peste de petit ruminants," and phocine distemper viruses. canine distemper virus (cdv) is transmitted to susceptible puppies through infected body fluids. the virus invades through the upper respiratory tract and conjunctiva, proliferates in regional lymph nodes, becomes viremic, and in dogs with an inadequate antibody response, infects nearly all body tissues (pantropic), particularly the epithelial cells. distemper virus hampers the immune response, downregulates cytokine production, and persists for a long time in some tissues. cdv can target the lungs either directly as a viral pneumonia or indirectly by its immunosuppressive effects rendering the lungs susceptible to secondary bacterial and protozoal infections, or as a coinfection with other viruses such as canine adenovirus- and canid herpesvirus . : - , .) inclusion bodies occur within epithelial cells in early lesions. cahv- has also been identified as a cause of ulcerative keratoconjunctivitis in older dogs. canine influenza (canine flu). canine influenza is an emerging contagious respiratory infection of dogs that was first described in the united states and subsequently in other countries. it has a high morbidity (close to %), but the mortality, as with most other influenza infections, is relatively low (less than %). this disease, first diagnosed in greyhounds, is caused by a novel influenza-a virus (canine influenza virus or civ), a mutation from a previously recognized h n strain of equine influenza virus. dog-to-dog transmission does occur and therefore this infection must be distinguished from other viruses of the canine infectious respiratory disease (cird) group. pulmonary lesions are generally mild and transient, but infected dogs are susceptible to secondary bacterial bronchopneumonia. the most relevant lesions in dogs dying unexpectedly from canine influenza are pleural and pulmonary hemorrhages. microscopically, there is necrotizing tracheitis, bronchitis, and bronchiolitis with exudation of neutrophils and macrophages. in severe cases, hemorrhagic interstitial or bronchointerstitial pneumonia may be accompanied by vasculitis and thrombosis. influenza antigen can be demonstrated by immunohistochemistry in airway epithelium and alveolar macrophages. clinically, dogs with canine influenza are lethargic, inappetent, and hyperthermic and frequently cough and show nasal discharge. these signs resemble those seen in dogs with kennel cough or secondary bacterial pneumonia. in addition, there are confirmed cases of canine influenza caused by the porcine h n presumably transmitted from infected pet owners. bacterial pneumonias. dogs generally develop bacterial pneumonias when the pulmonary defense mechanisms have been impaired. pasteurella multocida, streptococcus spp., escherichia coli, klebsiella pneumoniae, and bordetella bronchiseptica can be involved in pneumonia secondary to distemper or after aspiration of gastric contents ( fig. - and e- fig. - ). streptococcus zooepidemicus can cause acute and fatal hemorrhagic pleuropneumonia with canine adenovirus type infection. cav- infection is a common but transient contagious disease of the respiratory tract of dogs, causing mild fever, oculonasal discharge, coughing, and poor weight gain. the portal of entry is generally by inhalation of infected aerosols followed by viral replication in the surface cells of the upper respiratory tract, mucous cells of the trachea and bronchi, nonciliated bronchiolar epithelial cells, and type ii pneumonocytes. pulmonary lesions are initially those of bronchointerstitial pneumonia, with necrosis and exfoliation of bronchiolar and alveolar epithelium, edema, and, a few days later, proliferation of type ii pneumonocytes, mild infiltration of neutrophils and lymphocytes in the alveolar interstitium, and hyperplastic bronchitis and bronchiolitis. large basophilic intranuclear viral inclusions are typically seen in bronchiolar and alveolar cells ( fig. - ) . infection with cav- is clinically mild unless complicated with a secondary bacterial infection or coinfections with other viruses such as distemper virus. experimental work suggests cav- reinfection may lead to hyperreactive airways, a nonspecific condition in which the bronchial mucosa becomes highly "responsive" to irritation such as that caused by cold air, gases, or cigarette smoke. however, it is not clear if this outcome is true in natural infections. canid herpesvirus . canid herpesvirus (cahv- ) can cause fatal systemic disease in newborn puppies and is probably a contributing factor in "fading puppy syndrome." hypothermia has been suggested as a pivotal component in the pathogenesis of fatal infections in puppies. many dogs are seropositive, suggesting that transient or subclinical infections are more common than realized; the virus remains latent in the trigeminal and other ganglia and can be reactivated after stress, resulting in asymptomatic transmission of cahv- virus to offspring via the placenta, thus resulting in abortion or stillbirths. in puppies, cahv- causes ulcerative tracheitis, interstitial pneumonia (e- fig. - ) , and focal necrosis and inflammation in the kidneys, liver, and brain. eosinophilic intranuclear aspiration pneumonia starts as an acute necrotizing bronchitis and bronchiolitis caused by aspiration of irritant materials such as gastric acid or a caustic material administered by mouth. the aspirate also contains potentially pathogenic bacteria, and because the mucociliary apparatus is damaged and these bacteria are not removed, they settle into the ventral portions of the lung (from gravity) and provoke a fibrinosuppurative and necrotizing bronchopneumonia. b, bronchoalveolar spaces are filled with neutrophils, macrophages, and bacteria (arrows). h&e stain. inset, large colonies of bacteria (arrows). h&e stain. (courtesy dr. a. lópez, atlantic veterinary college.) a b infection; thus it most frequently affects outdoor and hunting dogs. from the lung, infection is disseminated hematogenously to other organs, mainly bone, skin, brain, and eyes. pulmonary lesions are characterized by multifocal to coalescing pyogranulomatous pneumonia, generally with firm nodules scattered throughout the lungs (fig. - ) . microscopically, nodules are pyogranulomas with numerous macrophages (epithelioid cells), some neutrophils, multinucleated giant cells, and thick-walled yeasts (see fig. - , c). yeasts are to µm in diameter and are much better visualized when they are stained with pas reaction or gomori's methenamine silver stain. nodules can also be present in other tissues, chiefly lymph nodes, skin, spleen, liver, kidneys, bones, testes, prostate, and eyes. this fungus can be easily identified in properly prepared and stained transtracheal washes or lymph node aspirates. clinical signs can reflect involvement of virtually any body tissue; pulmonary effects include cough, decreased exercise tolerance, and terminal respiratory distress. coccidioidomycosis. coccidioidomycosis (san joaquin valley fever), caused by the dimorphic fungus coccidioides immitis, occurs mainly in animals living in arid regions of the southwestern united states, mexico, and central and south america. it is a primary respiratory tract (aerogenous) infection commonly seen at slaughterhouses in clinically normal feedlot cattle. in dogs, coccidioidomycosis also has an aerogenous portal of entry and then a b hemorrhagic pleural effusion in dogs. death is generally a consequence of severe sepsis and septic shock or from β-hemolytic streptococcal bacteremia causing emboli in the lungs, liver, brain, and lymph nodes. the primary source of the infection cannot be determined in most cases. dental disease in dogs may be a source of systemic and pulmonary infection, a concept wellrecognized in human medicine for many years. the role of mycoplasmas in canine pneumonia is still uncertain because these organisms are frequently isolated from normal nasopharyngeal flora. tuberculosis is uncommon in dogs because these animals appear to be quite resistant to infection; most cases occur in immunocompromised dogs or in dogs living with infected human beings. dogs are susceptible to the infection with mycobacterium tuberculosis, mycobacterium bovis, and mycobacterium avium complex, and therefore canine infection presupposes contact with human or animal tuberculosis. the clinicopathologic manifestation is pulmonary after inhalation or alimentary after oral exposure, but in most cases infection is disseminated to lymph nodes and visceral organs. the gross lesions are multifocal, firm nodules with necrotic centers, most often seen in the lungs, lymph nodes, kidneys, and liver. diffuse granulomatous pleuritis and pericarditis with copious serofibrinous or sanguineous effusion are common. microscopically, granulomas are formed by closely packed macrophages but with very little connective tissue. mycotic pneumonias. mycotic pneumonias are serious diseases seen commonly in animals in some regions. there are two main types: those caused by opportunistic fungi and those caused by a group of fungi associated with systemic "deep" mycoses. all of these fungi affect human beings and most domestic animals but are probably not transmitted between species. aspergillosis. opportunistic fungi, such as aspergillus spp. (particularly aspergillus fumigatus), are important in birds, but in domestic animals, they mainly affect immunosuppressed individuals or those on prolonged antibiotic therapy. the pulmonary lesion is a multifocal, nodular, pyogranulomatous, or granulomatous pneumonia. microscopically, there is necrosis and infiltrates of neutrophils, macrophages, and lymphocytes, with proliferation of fibroblasts eventually leading to encapsulation of the granuloma. fungal hyphae are generally visible in the core of the lesion and in the walls of blood vessels. systemic mycoses (dimorphic fungal infections) . systemic (deep) mycoses are caused by blastomyces dermatitidis, histoplasma capsulatum, coccidioides immitis, and cryptococcus neoformans/ cryptococcus gatti (see fig. - ). blastomycosis mainly affects dogs and is discussed here, whereas cryptococcosis is discussed in the section on pneumonias of cats. in contrast to other fungi, such as aspergillus spp., organisms of the systemic mycosis group are all primary pathogens of human beings and animals and thus do not necessarily require a preceding immunosuppression to cause disease. these fungi have virulence factors that favor hematogenous dissemination and evasion of immune and phagocytic responses. systemic dissemination is often exacerbated by the administration of immunosuppressant drugs such as corticosteroids. these fungi are usually detected by cytological evaluation of affected tissues. blastomycosis. blastomycosis occurs in many countries of the north american continent, africa, the middle east, and occasionally in europe. in the united states, it is most prevalent in the atlantic, st. lawrence, and ohio-mississippi river valley states, compared with the mountain-pacific region. blastomyces dermatitidis is a dimorphic fungus (mycelia-yeast) seen mainly in young dogs and occasionally in cats and horses. this fungus is present in the soil, and inhalation of spores is considered the principal route of from the alveolar interstitium associated with larvae or dead worms because little reaction develops to the live adults. crenosoma vulpis. crenosoma vulpis is a lungworm seen commonly in foxes and sporadically in dogs with access to the intermediate hosts-slugs and snails. the adult lungworms live in small bronchi and bronchioles in the caudal lobes, causing eosinophilic and catarrhal bronchitis manifested grossly as gray areas of inflammation and atelectasis. in some animals, crenosoma vulpis causes bronchiolar goblet cell metaplasia and mucous obstruction, resulting in lobular atelectasis due to the valve effect of the mucous plug. eucoleus aerophilus. eucoleus aerophilus (capillaria aerophila) is a nematode parasite typically found in the trachea and bronchi of wild and domestic carnivores. in some cases, this parasite may also involve the nasal passages and sinuses. although generally asymptomatic, some dogs cough because of the local irritation caused by the parasites on the tracheal or bronchial mucosa. paragonimus spp. paragonimus kellicotti in north america and paragonimus westermani in asia are generally asymptomatic fluke infections in fish-eating species. the life cycle involves two intermediate hosts, the first a freshwater snail and the second a freshwater crab or crayfish; in north america, cats and dogs acquire infection by eating crayfish. gross lesions include pleural hemorrhages where the metacercariae migrate into the lungs. later, multifocal eosinophilic pleuritis, and subpleural cysts up to mm long containing pairs of adult flukes, are found along with eosinophilic granulomas around clusters of eggs. like many other parasitic pneumonias, lesions and scars are more frequent in the caudal lobes. pneumothorax can occur if a cyst that communicates with an airway ruptures to the pleural surface. other parasitic infections. angiostrongylus vasorum and dirofilaria immitis are parasites of the pulmonary arteries and right ventricle and, depending on the stage, can produce different forms of pulmonary lesions. adult parasites can cause chronic arteritis that leads to pulmonary hypertension, pulmonary arterial thrombosis, interstitial (eosinophilic) granulomatous pneumonia, pulmonary interstitial fibrosis, congestive right-sided cardiac failure, and eventually caudal vena caval syndrome. other lesions include pleural petechial hemorrhages and, in later stages, diffuse pulmonary hemosiderosis and multifocal pulmonary infarcts. larvae and eggs also cause alveolar injury, thickening of the alveolar walls with eosinophils and lymphocytes (interstitial pneumonia), and multifocal or coalescing granulomas with giant cells (parasitic granulomas). pneumocystis carinii has been reported as a sporadic cause of chronic interstitial pneumonia in dogs with a compromised immune system (see pneumonias of horses; also see fig. - ). aspiration pneumonia. aspiration pneumonia is an important form of pneumonia that occurs in dogs when vomit or regurgitated materials are aspirated into the lungs, or when drugs or radiographic contrast media are accidentally introduced into the airways (e- fig. - ) . as in other animal species, aspiration pneumonia may be unilateral or may more often affect the right cranial lobe ( fig. - ). the severity of lesions depends very much on the chemical and microbiologic composition of the aspirated material. in general, aspiration in monogastric animals, particularly in dogs and cats, is more severe because of the low ph of the gastric contents (chemical pneumonitis). in severe cases, dogs and cats die rapidly from septic shock and ards (see fig. - ), which is microscopically characterized by diffuse alveolar damage, protein-rich pulmonary edema, neutrophilic alveolitis, and formation of typical hyaline membranes along the alveolar walls (see fig. - ). in animals that survive the acute stages of aspiration, pulmonary lesions progress to bronchopneumonia. aspiration pneumonia is a common sequela to disseminates systemically to other organs. clinical signs relate to the location of lesions, so there can be respiratory distress, lameness, generalized lymphadenopathy, or cutaneous lesions, among others. the lesions caused by coccidioides immitis consist of focal granulomas or pyogranulomas that can have suppurative or caseated centers. the fungal organisms are readily seen in histologic or cytologic preparation as large ( to µm in diameter), double-walled, and highly refractile spherules containing numerous endospores (see fig. - , d) . histoplasmosis. histoplasmosis is a systemic infection that results from inhalation and, in dogs, possibly ingestion of another dimorphic fungus, histoplasma capsulatum. histoplasmosis occurs sporadically in dogs and human beings and, to a lesser extent, in cats and horses. bats often eliminate histoplasma capsulatum in the feces, and droppings from bats and birds, particularly pigeons, heavily promote the growth and survival of this fungus in the soil of enzootic areas. pulmonary lesions are grossly characterized by variably sized, firm, poorly encapsulated granulomas and, sometimes, more diffuse involvement of the lungs. microscopically, granulomatous lesions typically have many macrophages filled with small ( to µm), punctiform, intracytoplasmic, dark oval bodies (yeasts) (see fig. - , a) that are best demonstrated with pas reaction or gomori's methenamine silver stain. similar nodules or diffuse involvement can be present in other tissues, chiefly lymph nodes, spleen, intestine, and liver. toxoplasmosis. toxoplasmosis is a worldwide disease caused by the obligate intracellular, protozoal parasite toxoplasma gondii. cats and other felidae are the definitive hosts in which the mature parasite divides sexually in the intestinal mucosa. human beings, dogs, cats, and many wild mammals can become intermediate hosts after accidental ingestion of fertile oocysts shed in cat feces or ingestion of undercooked or raw meat containing tissue cysts, and fetuses can be infected transplacentally from an infected dam. in most instances, the parasite infects many cells of different tissues and induces an antibody response (seropositive animals) but does not cause clinical disease. toxoplasmosis is often triggered by immunosuppression, such as that caused by canine distemper virus. toxoplasmosis is characterized by focal necrosis around the protozoan. pulmonary lesions are severe, multifocal necrotizing interstitial pneumonia with notable proliferation of type ii pneumonocytes and infiltrates of macrophages and neutrophils. other lesions in disseminated toxoplasmosis include multifocal necrotizing hepatitis, myocarditis, splenitis, myositis, encephalitis, and ophthalmitis. the parasites appear microscopically as small ( to µm) basophilic cysts that can be found free in affected tissues or within the cytoplasm of many epithelial cells and macrophages (see e- fig. - ) . similar findings can be seen sporadically in dogs infected with neospora caninum and sarcocystis canis, and immunohistochemistry would be required to differentiate those protozoal organisms from toxoplasma gondii. filaroides hirthi. filaroides hirthi, a lungworm of the alveoli and bronchioles of dogs, has long been known as a cause of mild subclinical infection in large colonies of beagle dogs in the united states. however, it can on occasion cause severe and even fatal disease in individual pets, presumably as a result of immunosuppression. clinical signs may include coughing and terminal respiratory distress. grossly, the lesions are multifocal subpleural nodules, often with a green hue because of eosinophils, scattered throughout the lungs. microscopically, these nodules are eosinophilic granulomas arising .e chapter respiratory system, mediastinum, and pleurae other pneumonias. idiopathic pulmonary fibrosis is a rare condition of uncertain etiology reported in the west highland white terrier breed that shares similarities with human and feline idiopathic pulmonary fibrosis. microscopically, there is diffuse interstitial pneumonia and progressive alveolar fibrosis with capillary obliteration, hyperplasia of type ii cells, some of which exhibit cellular atypia, and finally hypertrophy and hyperplasia of smooth muscle. the interstitial fibrosis eventually spills over alveolar spaces causing conspicuous intraalveolar fibrosis. although upper respiratory tract infections are common and important in cats, pneumonias are uncommon except when there is immunosuppression or aspiration of gastric contents. viral infections such as feline rhinotracheitis and calicivirus may cause lesions in the lungs, but unless there is secondary invasion by bacteria, they do not usually cause a fatal pneumonia. feline rhinotracheitis. feline rhinotracheitis is an important viral disease of cats caused by the ubiquitous felid herpesvirus (fehv- ). this infection affects primarily young or debilitated cats causing inflammation in the nasal, ocular, and tracheal mucosa and, to a much lesser extent, the lung (see species-specific diseases of the nasal cavity and paranasal sinuses). when lungs are affected, fehv- causes bronchointerstitial pneumonia with necrosis of bronchiolar and alveolar epithelium, thickening of the alveolar walls, and extensive permeability edema. eosinophilic intranuclear inclusion bodies may be seen in infected epithelial cells early in infection. feline calicivirus. feline calicivirus (fcv) causes upper respiratory disease, stomatitis, conjunctivitis, and, to a lesser extent, interstitial pneumonia. microscopically, affected lungs exhibit the typical pattern of bronchointerstitial pneumonia with necrotizing bronchiolitis, thickening of alveolar walls, occasionally hyaline membranes, hyperplasia of type ii pneumonocytes, and macrophages admixed with cellular debris in the alveolar lumens. because pulmonary lesions are similar to those caused by fehv- , isolation or in situ detection is required for final diagnosis. feline infectious peritonitis. feline infectious peritonitis (fip) is caused by fip virus (fipv), a mutated form of feline enteric cleft palate, and in dogs with megaesophagus secondary to either myasthenia gravis or persistent right aortic arch. it is also an important complication of general anesthesia or neurologic diseases affecting laryngeal function. paraquat. paraquat, a broad-spectrum herbicide widely used in gardening and agriculture, can cause severe and often fatal toxic interstitial pneumonia (pneumonitis) in dogs, cats, human beings, and other species. after ingestion or inhalation, this herbicide selectively accumulates in the lung where paraquat toxic metabolites are produced by club (clara) cells. these metabolites promote local release of free radicals in the lung, which causes extensive injury to club cells and to the blood-air barrier, presumably through lipid peroxidation of type i and ii pneumonocytes and alveolar endothelial cells (see fig. - ). paraquat toxicity has been used experimentally as a model of oxidant-induced alveolar injury and pulmonary fibrosis. soon after poisoning, the lungs are heavy, edematous, and hemorrhagic because of extensive necrosis of epithelial and endothelial cells in the alveolar walls. the lungs of animals that survive acute paraquat toxicosis are pale, fail to collapse when the thorax is opened, and have interstitial emphysema, bullous emphysema, and occasionally pneumomediastinum. microscopic findings in the acute and subacute phases include necrosis of type i pneumonocytes, interstitial and alveolar edema, intraalveolar hemorrhages, and proliferation of type ii pneumonocytes. in the chronic stages ( to weeks later), the lesions are typically characterized by severe interstitial and intraalveolar fibrosis. uremic pneumopathy. uremic pneumonopathy (pneumonitis) is one of the many extrarenal lesions seen in dogs with chronic uremia. lesions are characterized by a combination of pulmonary edema and calcification of vascular smooth muscle and alveolar basement membranes. in severe cases, alveolar calcification prevents lung collapse when the thorax is opened. in the more advanced cases, the lungs appear diffusely distended, pale red or brown in color, and show a rough pleural surface with rib imprints (see fig. - ). on palpation, the pulmonary parenchyma has a typical "gritty" texture because of mineralization of the alveolar and vascular walls, which are best visualized microscopically by using special stains such as von kossa (see fig. - ). because this is not primarily an inflammatory lesion, the term pneumonitis should not be used. fig. - ) . a, note that the lungs did not collapse when the thorax was opened (loss of negative pressure) and as a result fill almost the entire thoracic cavity. the cranioventral aspects of the lung are consolidated with hemorrhage. b, alveolar capillary congestion, thick hyaline membranes along the alveolar septa (arrows), and intraalveolar hemorrhage. these microscopic changes are typical of the diffuse alveolar damage seen in lungs with ards. h&e stain. (courtesy dr. a. lópez, atlantic veterinary college.) feline calicivirus has removed chlamydophila felis from its previously overstated importance as a lung pathogen. tuberculosis. cats are susceptible to three types of mycobacterial infections: classic tuberculosis, feline leprosy, and atypical mycobacteriosis. classic tuberculosis in cats is rare and generally caused by mycobacterium bovis and mycobacterium microti but also, to a lesser extent, by mycobacterium tuberculosis. nosocomial tuberculosis (mycobacterium bovis) in cats has been reported with increased frequency. the usual route of infection for feline tuberculosis is oral, through infected rodents/meat or unpasteurized milk, so the granulomatous lesions are mainly in the intestine and mesenteric lymph nodes where they may disseminate through infected phagocytes to other organs. the solid and noncaseated appearance of tuberculous nodules is grossly similar to that of neoplasms, so they must be differentiated from pulmonary neoplasms (e.g., lymphoma). classic tuberculosis with dermal lesions in cats should be differentiated from feline leprosy (localized skin granulomas) caused by mycobacterium lepraemurium and other nonculturable species of acid-fast bacilli. atypical mycobacteriosis is caused by contamination of a skin wound with saprophytic and nonsaprophytic mycobacteria such as those of the mycobacterium avium complex. advances in pcr techniques have notably reduced the time required for etiologic diagnosis of mycobacteriosis in veterinary diagnostic laboratories. cryptococcosis. cryptococcosis (pulmonary cryptococcus neoformans or cryptococcus gatti) is the most frequent systemic mycosis in cats, and lesions are akin to those discussed in the section on mycotic pneumonias of dogs. it occurs worldwide in all species but is diagnosed most frequently in cats, horses, dogs, and human beings. some healthy dogs and cats harbor cryptococcus in the nasal cavity and become asymptomatic carriers. clinical infection may occur in immunocompetent cats and in cats that are immunologically compromised, such as by felv, fiv, malnutrition, or corticosteroid treatment. lesions can occur in nearly any tissue, resulting in a wide c coronavirus (fecv), and is one of a few viral infections of domestic animals that result in pyogranulomatous pneumonia. this disease is microscopically characterized by a vasculitis affecting many tissues and organs ( fig. - ) . other viral pneumonias. other viruses sporadically incriminated in feline interstitial pneumonia are cowpox virus (cpxv) and influenza a h n . pasteurellae. bacteria from the nasal flora such as pasteurella multocida and pasteurella-like organisms are occasionally associated with secondary bronchopneumonia in cats ( fig. - ) . pasteurella multocida also causes otitis media and meningitis, but its role as a respiratory pathogen is mainly associated with pyothorax. interestingly, there are reports of pasteurella multocida pneumonia in older or immunosuppressed human beings acquired through contact with domestic cats. mycoplasmas. mycoplasmas are often isolated from the lungs of cats with pulmonary lesions but are not definitively established as primary pathogens in feline pneumonias. feline pneumonitis. the term feline pneumonitis is a misnomer because the major lesions caused by chlamydophila felis (formerly chlamydia psittaci) are severe conjunctivitis and rhinitis (see species-specific diseases of the nasal cavity and paranasal sinuses). the elucidation of the importance of feline viral rhinotracheitis and organism infects erythrocytes in the erythrocytic stage of disease and multiplies in intravascular macrophages/monocytes, including those in the alveolar capillaries (e- fig. - ) , during the leukocytic stage of disease. aspiration pneumonia. aspiration pneumonias are common in cats as a result of vomiting, regurgitation, dysphagia, or anesthetic complication or after accidental administration of food, oral medicaments, or contrast media into the trachea (iatrogenic). pulmonary lesions are similar to those described for dogs, and the type of lung lesion depends on the chemical and bacterial composition of the aspirated material (see the section on aspiration pneumonia of dogs). feline idiopathic pulmonary fibrosis. feline idiopathic pulmonary fibrosis is a rare, progressive, and fatal disease of cats of uncertain etiology characterized by multifocal fibrotic nodules subpleurally and randomly in the lung making the pleural surface resemble nodular cirrhosis of the liver ( fig. - ) . microscopically, the affected alveolar and peribronchiolar interstitium is thickened by excessive fibrosis, abundant deposition of extracellular matrix, and hypertrophy of smooth muscle. some investigators suggest an intrinsic cellular defect in type ii pneumonocytes as the underlying cause. the alveolar walls are diffusely lined by cuboidal hyperplastic type ii pneumonocytes, and the alveolar lumens often contain exfoliated cells and necrotic debris. this feline condition has morphologic features similar to "equine multinodular pulmonary fibrosis" and "cryptogenic pulmonary fibrosis" in human beings. fetal pneumonias. pneumonia is one of the most frequent lesions found in fetuses submitted for postmortem examination, particularly in foals and food-producing animals. because of autolysis, lack of inflation, and the lungs being at various stages of development, fetal lesions are often missed or misdiagnosed. in the nonaerated fetal lung, the bronchoalveolar spaces are filled with a viscous, locally produced fluid known as lung fluid or lung liquid. it has been estimated that an ovine fetus produces approximately . ml of "lung fluid" per kilogram of body weight per hour. in the variety of clinical signs. however, granulomatous rhinitis, sinusitis, otitis media and interna, pneumonia, ulcerative dermatitis, and meningoencephalitis are most common. the pulmonary lesion in cryptococcosis is a multifocal granulomatous pneumonia and, like those occurring in other internal organs, they are small, gelatinous, white foci. the gelatinous appearance is due to the broad mucous capsule around the yeast (see fig. - , b) . microscopically, lesions contain great numbers of fungal organisms ( to µm in diameter without the capsule) and only a few macrophages, lymphocytes, and multinucleated giant cells. this thick polysaccharide capsule does not stain well with h&e, and thus there is a large empty space or halo around the yeast. feline lungworm. aelurostrongylus abstrusus, known as feline lungworm, is a parasite that occurs in cats wherever the necessary slug and snail intermediate hosts are found. it can cause chronic respiratory disease with coughing and weight loss and, sometimes, severe dyspnea and death, particularly if there are secondary bacterial infections. the gross lesions are multifocal, amber, and subpleural granulomatous nodules up to cm in diameter throughout the lungs. on incision, these nodules may contain viscous exudate. microscopically, the adult parasites, eggs, and coiled larvae are in the bronchioles and alveoli, where they cause catarrhal bronchiolitis, hyperplasia of submucosal glands, and, later, granulomatous alveolitis, alveolar fibrosis, and fibromuscular hyperplasia ( fig. - ) . during routine examination of feline lungs, it is quite common to find fibromuscular hyperplasia in bronchioles and arterioles in otherwise healthy cats. it was alleged in the past that this fibromuscular hyperplasia was a long-term sequela of subclinical infection with aelurostrongylus abstrusus. however, this view has been challenged; thus the pathogenesis and significance of pulmonary fibromuscular hyperplasia in healthy cats remains uncertain. in severe cases, fibromuscular hyperplasia is grossly visible in the lungs as white subpleural nodules. other parasitic pneumonias. toxoplasma gondii, paragonimus kellicotti, and dirofilaria immitis can also affect cats (see the section on parasitic pneumonias of dogs). cytauxzoon felis is an apicomplexan hemoparasite that affects domestic and wild felidae. the diseases that cause fetal pneumonia in farm animals. gross lesions in the lungs are generally undetected, but microscopic lesions include focal necrotizing interstitial pneumonia and focal necrosis in the liver, spleen, or brain. fetal bronchointerstitial pneumonia also occurs in some viral abortions, such as those caused by infectious bovine rhinotracheitis (ibr) virus and bovine parainfluenza virus (bpiv- ) in cattle and equine viral rhinopneumonitis (evr) in horses. fetal pneumonias in dogs and cats are infrequently described, perhaps because aborted puppies and kittens are rarely submitted for postmortem examination. with advancements in molecular biology techniques, the etiologic diagnosis of abortions and their association with pulmonary fetal lesions is rapidly improving. neonatal pneumonias and septicemias. these entities are rather common in newborn animals lacking passive immunity because of the lack of either ingestion or absorption of maternal colostrum (failure of passive transfer or hypogammaglobulinemia). in addition to septicemias causing interstitial pneumonia, farm animals with hypogammaglobulinemia can develop bronchopneumonia by inhalation of bacterial pathogens. these include histophilus somni and pasteurella multocida in calves; streptococcus spp. in foals; and escherichia coli, listeria monocytogenes, and streptococcus suis in pigs. meconium aspiration syndrome. meconium aspiration syndrome (mas) is an important but preventable condition in human babies that originates when amniotic fluid contaminated with meconium is aspirated during labor or immediately after birth. the pathogenesis of mas is basically the same as in those of fetal bronchopneumonia (see fig. - ) . fetal hypoxia, a common event during dystocia or prolonged parturition, causes the fetus to relax the anal sphincter and release meconium into the amniotic fluid. aspiration of meconium can occur directly from aspirating contaminated amniotic fluid before delivery (respiratory movements with an open glottis) or immediately after delivery when the meconium lodged in the nasopharynx is carried into the lung with the first breath of air. this latter form of aspiration is prevented in delivery rooms by routine suction of the nasopharynx in meconium-stained babies. mas is well known in human babies, but the occurrence and significance in animals remains largely unknown. mas has been reported in calves, foals, piglets, and puppies. although pulmonary lesions are generally mild and transient, aspiration of meconium can be life-threatening for newborn babies and animals because it typically occurs in compromised neonates already suffering from intrauterine hypoxia and acidosis. neonatal acidosis is known to impair colostrum absorption in calves. common mas sequelae are lobular atelectasis, pulmonary hypertension, and possibly airway hyperreactivity. in the most severe cases of mas, focal (patchy) atelectasis can be observed grossly in the lung, indicating failure of the lungs to be fully aerated because of the mechanical obstruction and the chemical effect of meconium on pulmonary surfactant (see fig. - ). microscopically, meconium and keratin exfoliated from skin of the fetus into the amniotic fluid are present in bronchi, bronchioles, and alveoli and accompanied by mild alveolitis characterized by infiltration of leukocytes followed by alveolar macrophages and occasional giant cells (e- fig. - ) . lung cancer in animals is rare, unlike in human beings, in which the incidence is alarming and continues to be the number one cause of death due to cancer in canada, the united states, and europe. interestingly, prostatic and breast cancers, so much feared by men fetus, this fluid normally moves along the tracheobronchial tree, reaching the oropharynx, where a fraction is swallowed into the gastrointestinal tract, and a small portion is released into the amniotic fluid. at the time of birth, the lung fluid is rapidly reabsorbed from the lungs by alveolar absorption and lymphatic drainage. aspiration of amniotic fluid contaminated with meconium and bacteria from placentitis is the most common route by which microbial pathogens reach the fetal lungs. this form of pneumonia is secondary to fetal hypoxia and acidosis ("fetal distress"), which cause the fetus to relax the anal sphincter, release meconium into the amniotic fluid, and, in the terminal stages, inspire deeply with open glottis, resulting in the aspiration of contaminated fluid ( fig. - ). gross lesions are only occasionally recognized, but microscopic changes are similar to those of a bronchopneumonia. microscopically, bronchoalveolar spaces contain variable numbers of neutrophils, macrophages, epidermal squames, and pieces of meconium that appear as bright yellow material because of its bile content. in contrast to postnatal bronchopneumonia, lesions in fetuses are not restricted to the cranioventral aspects of the lungs but typically involve all pulmonary lobes. in cattle, brucella abortus and trueperella (arcanobacterium) pyogenes are two of the most common bacteria isolated from the lungs of aborted fetuses. these bacteria are usually present in large numbers in the amniotic fluid of cows with bacterial placentitis. inflammation of the placenta interferes with oxygen exchange between fetal and maternal tissue, and the resultant fetal hypoxia induces the fetus to "breathe" with an open glottis and aspirate the amniotic fluid. aspergillus spp. (mycotic abortion) and ureaplasma diversum cause sporadic cases of placentitis, which results in fetal pneumonia and abortion. in addition to the respiratory route (aspiration), pathogens, such as bacteria and viruses, can also reach the lungs via fetal blood and cause interstitial pneumonia. listeriosis (listeria monocytogenes), salmonellosis (salmonella spp.), and chlamydiosis (chlamydophila abortus [c. psittaci]) are the best known examples of blood-borne primary benign neoplasms of the lungs, such as pulmonary adenomas, are highly unusual in domestic animals. most primary neoplasms are malignant and appear as solitary masses of variable size that, with time, can metastasize to other areas of the lungs and to distant organs. it is sometimes difficult on gross and microscopic examination to differentiate primary lung cancer from pulmonary metastasis resulting from malignant neoplasms elsewhere in the body. it is often difficult to determine the precise topographic origin of a neoplasm within the lungs-for example, whether it originates in the conducting system (bronchogenic carcinoma), transitional system (bronchiolar carcinoma), exchange system (alveolar carcinoma), or bronchial glands (bronchial gland carcinoma). according to the literature, pulmonary carcinomas in animals arise generally from club (clara) cells or type ii pneumonocytes of the bronchioloalveolar region, in contrast to those in human beings, which are mostly bronchogenic. tumors located at the hilus generally arise from major bronchi and tend to be a solitary large mass with occasional small metastasis to the periphery of the lung. in contrast, tumors arising from the bronchioloalveolar region are often multicentric with numerous peripheral metastases in the lung parenchyma. because of histologic architecture and irrespective of the site of origin, many malignant epithelial neoplasms are classified by the all-encompassing term of pulmonary adenocarcinomas. dogs and cats are the species most frequently affected with primary pulmonary neoplasms, largely carcinomas, generally in older animals. the mean age for primary lung tumors is years for dogs and years for cats. pulmonary carcinomas in other domestic animals, except for retrovirus-induced pulmonary carcinoma in sheep, are less common, possibly because fewer farm animals are allowed to reach their natural life span. these neoplasms can be invasive or expansive, vary in color (white, tan, or gray) and texture (soft or firm), and often have areas of necrosis and hemorrhage, which result in a "craterous" or "umbilicate" appearance. this umbilicate appearance is frequently seen in rapidly growing carcinomas in which the center of the tumoral mass undergoes necrosis as a result of ischemia. some lung neoplasms resemble pulmonary consolidation or large granulomas. cats with moderately differentiated neoplasms had significantly longer survival time (median, days) than cats with poorly differentiated neoplasms (median, days). dogs with primary lung neoplasms, grades i, ii, and iii, had survival times of , , and days, respectively. ovine pulmonary adenocarcinoma (ovine pulmonary carcinoma). ovine pulmonary adenocarcinoma, also known as pulmonary adenomatosis and jaagsiekte (from the south african afrikaans word for "driving sickness"), is a transmissible, retrovirus-induced neoplasia of ovine lungs caused by jaagsiekte sheep retrovirus (jsrv). it occurs in sheep throughout the world, with the notable exception of australia and new zealand; its incidence is high in scotland, south africa, and peru and unknown but probably low in north america. this pulmonary carcinoma behaves very much like a chronic pneumonia, and jsrv shares many epidemiologic similarities with the ovine lentivirus responsible for maedi and the retrovirus responsible for enzootic nasal carcinoma in small ruminants. pulmonary adenomatosis has been transmitted to goats experimentally but is not known to be a spontaneous disease in that species. ovine pulmonary adenocarcinoma affects mainly mature sheep but can occasionally affect young stock. intensive husbandry probably facilitates horizontal transmission by the copious nasal discharge and explains why the disease occurs as devastating epizootics with % to % mortality when first introduced into a flock. differential diagnosis between maedi and pulmonary adenomatosis can prove difficult because both diseases often coexist in the same flock and women, are a distant second. to say that cigarette smoking is responsible for this epidemic of lung cancer is unnecessary. although dogs have been proposed as valuable "sentinels" for environmental hazards, such as exposure to passive smoking, asbestos, dyes, and insecticides, it is not known if the prevalence of canine lung tumors has increased in geographical areas with high contamination. alterations in genes (oncogenes) and chromosomes and changes in biologically active molecules have been linked to lung cancer in recent years. as with many other forms of cancer, epidemiologic studies indicate that the incidence of pulmonary neoplasms increases with age, but there are still insufficient data to confirm that particular canine or feline breeds have a higher predisposition to spontaneous lung neoplasms. a standard nomenclature of pulmonary neoplasms in domestic animals is lacking, and as a consequence, multiplicity of names and synonyms occur in the veterinary literature. some classifications are based on the primary site, whereas others emphasize more the histomorphologic type. the most common types of benign and malignant pulmonary neoplasms in domestic mammals are listed in box - . clinically, the signs of pulmonary neoplasia vary with the degree of invasiveness, the amount of parenchyma involved, and locations of metastases. signs may be vague, such as cough, lethargy, anorexia, weight loss, and perhaps dyspnea. in addition, paraneoplastic syndromes, such as hypercalcemia, endocrinopathies, and pulmonary hypertrophic osteoarthropathy, have been associated with pulmonary neoplasms. primary neoplasms of the lungs. primary neoplasms of the lungs arise from cells normally present in the pulmonary tissue and can be epithelial or mesenchymal, although the latter are rare. any malignant tumor metastatic from another body location (e.g., osteosarcoma in dogs, uterine carcinoma in cows, and malignant melanoma in horses) box - classification of pulmonary neoplasms .e chapter respiratory system, mediastinum, and pleurae abundant cytoplasm containing numerous acidophilic granules, which are positive for pas and for s- protein using immunohistochemistry. although this tumor can cause bronchial obstruction and respiratory signs, in most cases, it is an incidental finding in older horses submitted for postmortem examination. lymphomatoid granulomatosis. lymphomatoid granulomatosis is a rare but interesting pulmonary disease of human beings, dogs, cats, and possibly horses and donkeys characterized by nodules or large solid masses in one or more lung lobes. these frequently metastasize to lymph nodes, kidneys, and liver. microscopically, tumors are formed by large pleomorphic mononuclear (lymphomatoid) cells with a high mitotic rate and frequent formation of binucleated or multinucleated cells. tumor cells have a distinct tendency to grow around blood vessels and invade and destroy the vascular walls. lymphomatoid granulomatosis has some resemblance to lymphoma and is therefore also referred to as angiocentric lymphoma; phenotypic marking confirms that neoplastic cells are a mixed population of plasma cells, b and t lymphocytes, and histiocytes. cerebral and cutaneous forms of lymphomatoid granulomatosis have also reported in human beings, dogs, and cats. secondary neoplasms of the lungs. secondary neoplasms of the lungs are all malignant by definition because they are the result of metastasis to the lungs from malignant neoplasms elsewhere. because the pulmonary capillaries are the first filter met by tumor emboli released into the vena cava or pulmonary arteries, secondary neoplasms in the lung are relatively common in comparison to primary ones. also, secondary tumors can be epithelial or mesenchymal in origin. common metastatic tumors of epithelial origin are mammary, thyroid ( fig. - ) , and uterine carcinomas. tumors of mesenchymal origin are osteosarcoma ( fig. - , a) ; hemangiosarcoma ( fig. - , b) ; malignant melanoma in dogs; lymphoma in cows, pigs, dogs, and cats ( fig. - ) ; and vaccineassociated sarcoma in cats. usually, secondary pulmonary neoplasms are multiple; scattered throughout all pulmonary lobes (hematogenous dissemination); of variable size; and, according to the growth pattern, can be nodular, diffuse, or radiating (e- fig. - ) . the appearance of metastatic neoplasms differs according to the type of neoplasm. for example, dark red cystic nodules containing blood indicate hemangiosarcoma, dark black solid nodules indicate melanoma, and hard solid nodules (white, yellow, or tan color) with bone spicules indicate osteosarcoma. the gross appearances of or in the same animal. death is inevitable after several months of the initial onset of respiratory signs, and a specific humoral immune response to jsrv is undetectable in affected sheep. during the early stages of ovine pulmonary carcinoma, the lungs are enlarged, heavy, and wet and have several firm, gray, variably sized nodules that in some cases can be located in the cranioventral lobes mimicking a bronchopneumonic lesion ( fig. - , a) . in the later stages, the nodules become confluent, and large segments of both lungs are diffusely, but not symmetrically, infiltrated by neoplastic cells. on cross section, edematous fluid and a copious mucoid secretion are present in the trachea and bronchi ( fig. - , b) . microscopically, the nodules consist of cuboidal or columnar epithelial cells lining airways and alveoli and forming papillary or acinar (glandlike) structures (see fig. - , a) . because the cells have been identified ultrastructurally as originating from both type ii alveolar epithelial cells and club (clara) cells, the neoplasm is considered a "bronchioloalveolar" carcinoma. sequelae often include secondary bronchopneumonia, abscesses, and fibrous pleural adhesions. metastases occur to tracheobronchial and mediastinal lymph nodes and, to a lesser extent, to other tissues such as pleura, muscle, liver, and kidneys. neoplastic cells stain strongly positive for jsrv using immunohistochemistry. clinically, ovine pulmonary adenocarcinoma is characterized by a gradual loss of condition, coughing, and respiratory distress, especially after exercise (e.g., herding or "driving"). appetite and temperature are normal, unless there are secondary bacterial infections. an important differentiating feature from maedi (interstitial pneumonia) can be observed if animals with pulmonary adenomatosis are raised by their hind limbs; copious, thin, mucoid fluid, produced by neoplastic cells in the lungs, pours from the nostrils of some animals. carcinoid (neuroendocrine) tumor of the lungs. carcinoid tumor of the lungs is a neoplasm presumably arising from neuroendocrine cells and is sporadically seen in dogs as multiple, large, firm pulmonary masses close to the mainstem bronchi. it has also been reported in the nasal cavity of horses. tumor cells are generally polygonal with finely granular, pale, or slightly eosinophilic cytoplasm. nuclei are small, and mitotic figures are absent or rare. granular cell tumor. granular cell tumor is a rare and locally invasive tumor that has been reported mainly in human beings and older horses. the cell origin of this tumor was thought to be the myoblast, but it is currently presumed to be schwann cells, which are normally present in the bronchovascular bundles of the lung. microscopically, neoplastic cells are large, polyhedron-shaped with metastatic carcinomas are generally similar to the primary neoplasm and sometimes have umbilicated centers. proper diagnoses of pulmonary neoplasms in live animals require history, clinical signs, radiographs, cytologic analysis of bal fluid, and, when necessary, a lung biopsy. identification of a specific lineage of neoplastic cells in biopsy or postmortem specimens is often difficult and requires electron microscopy or immunohistochemical techniques. electron microscopy allows identification of distinctive cellular components such as osmiophilic lamellar phospholipid nephritic bodies in alveolar type ii epithelial cells or melanosomes in melanomas. immunohistochemical staining is also helpful in identifying tumor cells. the thoracic wall, diaphragm, and mediastinum are lined by the parietal pleura, which reflects onto the lungs at the hilum and continues as the visceral pleura, covering the entire surface of the lungs, except at the hilus where the bronchi and blood vessels enter. the space between the parietal and visceral pleura (pleural space) is only minimal and under normal conditions contains only traces of clear fluid, which is a lubricant, and a few exfoliated cells. samples of this fluid are obtained by thoracocentesis, a simple procedure in which a needle is passed into the pleural cavity. volumetric, biochemical, and cytologic changes in this fluid are routinely used in veterinary diagnostics. anomalies congenital defects are rare and generally of little clinical significance. cysts within the mediastinum of dogs and, less often, cats in severe cases, the amount of fluid present in the thoracic cavity can be considerable. for instance, a medium-size dog can have l of fluid, and a cow may accumulate l or more. excessive fluid in the thorax causes compressive atelectasis resulting in respiratory distress (see fig. - ). hydrothorax is most commonly seen in cattle with right-sided heart failure or cor pulmonale (hydrostatic) (e- fig. - ); dogs with congestive heart failure (hydrostatic), chronic hepatic disease (hepatic hydrothorax) ( fig. - ) , or nephrotic syndrome (hypoproteinemia); pigs with mulberry heart disease (increased vascular permeability); and horses with african horse sickness (increased vascular permeability). hemothorax. blood in the thoracic cavity is called hemothorax, but the term has been used for exudate with a sanguineous component. causes include rupture of a major blood vessel as a result of severe thoracic trauma (e.g., hit by car); erosion of a vascular wall by malignant cells or inflammation (e.g., aortitis caused by spirocerca lupi); ruptured aortic aneurysms; clotting defects, including coagulopathies; warfarin toxicity; disseminated intravascular coagulation (consumption coagulopathy); and thrombocytopenia. hemothorax is generally acute and fatal. on gross examination, the thoracic cavity can be filled with blood, and the lungs are partially or completely atelectatic ( fig. - ). chylothorax. the accumulation of chyle (lymph rich in triglycerides) in the thoracic cavity ( fig. - ) is a result of the rupture of major lymph vessels, usually the thoracic duct or the right lymphatic duct. the clinical and pathologic effects of chylothorax are similar to those of the other pleural effusions. causes include thoracic neoplasia (the most common cause in human beings but a distant second to idiopathic cases in dogs), trauma, congenital lymph vessel anomalies, lymphangitis, dirofilariasis, and iatrogenic rupture of the thoracic duct during surgery. the source of the leakage of chyle is rarely found at necropsy. when the leakage of chyle occurs in the abdominal cavity, the condition is referred to as chyloabdomen. cytologic and biochemical examination of fluid collected by thoracocentesis typically reveals large numbers of lymphocytes, lipid droplets, few neutrophils in chronic cases, and high triglyceride content. can be large enough to compromise pulmonary function or mimic neoplasia in thoracic radiographs. these cysts may arise from the thymus (thymic branchial cysts), bronchi (bronchogenic cysts), ectopic thyroid tissue (thyroglossal duct cysts), or from remnants of the branchial pouches, and they are generally lined by epithelium and surrounded by a capsule of stromal tissue. anomalies of the thoracic duct cause some cases of chylothorax. pleural calcification. pleural calcification is commonly found in dogs and less often in cats with chronic uremia. lesions appear as linear white streaks in parietal pleura, mainly over the intercostal muscles of the cranial part of the thoracic cavity. the lesions are not functionally significant but indicate a severe underlying renal problem. vitamin d toxicity (hypervitaminosis d) and ingestion of hypercalcemic substances, such as vitamin d analogs, can also cause calcification of the pleura and other organs. pneumothorax. pneumothorax is the presence of air in the thoracic cavity where there should normally be negative pressure to facilitate inspiration. human beings have a complete and strong mediastinum so that pneumothorax is generally unilateral and thus not a serious problem. in dogs, the barrier varies, but in general it is not complete, so often some communication exists between left and right sides. there are two main forms of pneumothorax. in spontaneous (idiopathic) pneumothorax, air leaking into the pleural cavity from the lungs occurs without any known underlying disease or trauma. in secondary pneumothorax, movement of air into the pleural cavity results from underlying pulmonary or thoracic wall disease. the most common causes of secondary pneumothorax in veterinary medicine are penetrating wounds to the thoracic wall, perforated esophagus, iatrogenic trauma to the thorax and lung during a transthoracic lung biopsy or thoracoscopy, tracheal rupture from improper intubation, and rupture of emphysematous bullae or parasitic pulmonary cysts (paragonimus spp.) that communicate with the thoracic cavity. pneumothorax and pneumomediastinum caused by high air pressure (barotrauma) are also well documented in cats after equipment failure during anesthesia. clinical signs of pneumothorax include respiratory distress, and the lesion is simply a collapsed, atelectatic lung. the air is readily reabsorbed from the cavity if the site of entry is sealed. pleural effusion. pleural effusion is a general term used to describe accumulation of any fluid (transudate, modified transudate, exudate, blood, lymph, or chyle) in the thoracic cavity. cytologic and biochemical evaluations of pleural effusions taken by thoracocentesis are helpful in determining the type of effusion and possible pathogenesis. based on protein concentration and total numbers of nucleated cells, pleural effusions are cytologically divided into transudates, modified transudates, and exudates. hydrothorax. when the fluid is serous, clear, and odorless and fails to coagulate when exposed to air, the condition is referred to as hydrothorax (transudate). causes of hydrothorax are the same as those involved in edema formation in other organs: increased hydrostatic pressure (heart failure), decreased oncotic pressure (hypoproteinemia, as in liver disease), alterations in vascular permeability (inflammation), or obstruction of lymph drainage (neoplasia). in cases in which the leakage is corrected, if the fluid is a transudate, it is rapidly reabsorbed. if the fluid persists, it irritates the pleura and causes mesothelial hyperplasia and fibrosis, which thickens the pleura. from a perforated esophagus. chronic injury typically results in serosal fibrosis and tight adhesions between visceral and parietal pleurae (see fig. - ). when extensive, these adhesions can obliterate the pleural space. pleuritis or pleurisy. inflammation of the visceral or parietal pleurae is called pleuritis, and according to the type of exudate, it can be fibrinous, suppurative, granulomatous, hemorrhagic, or a combination of exudates. acute fibrinous pleuritis can progress with time to pleural fibrosis ( fig. - ). when suppurative pleuritis results in accumulation of purulent exudate in the cavity, the lesion is called pyothorax or thoracic empyema ( fig. - ) . clinically, pleuritis causes considerable pain, and in addition, empyema can result in severe toxemia. pleural fibrous adhesions (between parietal and visceral pleura) and fibrosis are the most common sequelae of chronic pleuritis and can significantly interfere with inflation of the lungs. pleuritis can occur as an extension of pneumonia, particularly in fibrinous bronchopneumonias (pleuropneumonia), or it can occur alone, without pulmonary involvement ( fig. - ). bovine and ovine pneumonic mannheimiosis and porcine and bovine pleuropneumonia are good examples of pleuritis associated with fibrinous bronchopneumonias. polyserositis in pigs and pleural empyema, particularly in cats and horses, are examples of pleural inflammation in pleural tissue is readily susceptible to injury caused by direct implantation of an organism through a penetrating thoracic or diaphragmatic wound; by hematogenous dissemination of infectious organisms in septicemias; or by direct extension from an adjacent inflammatory process, such as in fibrinous bronchopneumonia or in contrast to those with the effusive ("wet") form, in which thoracic involvement is primarily that of a pleural effusion. cytologic evaluation of the effusion typically shows a low to moderate cellularity with degenerated leukocytes, lymphocytes, macrophages, and mesothelial cells, and a pink granular background as a result of the high protein content. pleuritis is also an important problem in horses. nocardia spp. can cause fibrinopurulent pneumonia and pyothorax with characteristic sulfur granules. although mycoplasma felis can be isolated from the respiratory tract of normal horses, it is also isolated from horses with pleuritis and pleural effusion, particularly during the early stages of infection. the portal of entry of this infection is presumably aerogenous, first to the lung and subsequently to the pleura. the pleural surface of the lung is often involved in neoplasms that have metastasized from other organs to the pulmonary parenchyma and ruptured the visceral pleura to seed the pleural cavity. mesothelioma is the only primary neoplasm of the pleura. which involvement of the lungs may not accompany the pleuritis. pleural inflammation is most frequently caused by bacteria, which cause polyserositis reaching the pleura hematogenously. these bacteria include haemophilus parasuis (glasser's disease) (see , streptococcus suis, and some strains of pasteurella multocida in pigs; streptococcus equi ssp. equi and streptococcus equi ssp. zooepidemicus in horses; escherichia coli in calves; and mycoplasma spp. and haemophilus spp. in sheep and goats. contamination of pleural surfaces can be the result of extension of a septic process (e.g., puncture wounds of the thoracic wall and, in cattle, traumatic reticulopericarditis) and ruptured pulmonary abscesses (e.g., trueperella pyogenes). in dogs and cats, bacteria (e.g., nocardia, actinomyces, and bacteroides) can cause pyogranulomatous pleuritis, characterized by accumulation of blood-stained pus ("tomato soup") in the thoracic cavity. this exudate usually contains yellowish flecks called sulfur granules ( fig. - ), although these are less common in nocardial empyema in cats. many species of bacteria, such as escherichia coli, trueperella pyogenes, pasteurella multocida, and fusobacterium necrophorum, can be present in pyothorax of dogs and cats. these bacteria occur alone or in mixed infections. the pathogenesis of pleural empyema in cats is still debatable, but bite wounds or penetration of foreign material (migrating grass awns) are likely. pyogranulomatous pleuritis with empyema occurs occasionally in dogs, presumably associated with inhaled small plant material and penetrating (migrating) grass awns. because of their physical shape (barbed) and assisted by the respiratory movement, aspirated grass awns can penetrate airways, move through the pulmonary parenchyma, and eventually perforate the visceral pleura causing pyogranulomatous pleuritis. cats with the noneffusive ("dry") form of feline infectious peritonitis (fip) frequently have focal pyogranulomatous pleuritis, mesothelioma is a rare neoplasm of the thoracic, pericardial, and peritoneal mesothelium of human beings that is seen most commonly in calves, in which it can be congenital. in human beings, it has long been associated with inhalation of certain types of asbestos fibers (asbestos mining and ship building) alone or with cigarette smoking as a probable cocarcinogen; no convincing association between the incidence of mesothelioma and exposure to asbestos has been made in domestic animals. in animals, there may be pleural effusion with resulting respiratory distress, cough, and weight loss. mesothelioma initially causes a thoracic effusion, but cytologic diagnosis can be difficult because of the morphologic resemblance of malignant and reactive mesothelial cells. during inflammation, mesothelial cells become reactive and not only increase in number but also become pleomorphic and form multinucleated cells that may be cytologically mistaken for those of a carcinoma. grossly, mesothelioma appears as multiple, discrete nodules or arborescent, spreading growths on the pleural surface ( fig. - ) . microscopically, either the mesothelial covering cells or the supporting tissue can be the predominant malignant component, so the neoplasm can microscopically resemble a carcinoma or a sarcoma. figure - nocardiosis. a, chronic pleuritis (nocardia asteroides), pleural cavity, cat. the pleural cavity is covered with abundant red-brown ("tomato soup") exudate" (syringe). once considered to be pathognomonic of nocardia spp. infection, it is no longer regarded as being diagnostic of nocardiosis. the fluid contains abundant protein, erythrocytes, granulomatous inflammatory cells, and sulfur granules. b, chronic pleuritis (nocardia asteroides), visceral pleura, dog. the thickened pleura has a granular pink-gray appearance because of granulomatous inflammation and the proliferation of fibrovascular tissue of the pleura. c, chronic pleuritis (nocardia asteroides), dog. the pleura has been thrown up into villous-like projections composed of abundant fibrovascular tissue and granulomatous inflammation. leakage from the neocapillaries of the fibrovascular tissue is responsible for the hemorrhagic appearance of the pleural exudate. h&e stain. d, chronic pleuritis (nocardia asteroides), thoracic cage, parietal pleura, cat. large pieces of exudate, which contain yellow sulfur granules, are present on the thickened pleura. although considered malignant, mesotheliomas rarely metastasize to distant organs. secondary neoplasms of the pleura. secondary tumors may also spread into the visceral and parietal pleura. thymomas are rare neoplasms that grow in the cranial mediastinum of adult or aged dogs, cats, pigs, cattle, and sheep. thymomas are composed of thymic epithelium and lymphocytes (see chapter ). old age, both in human beings and in animals, is known to be a risk factor for pulmonary infections, but the precise mechanisms involved in this increased susceptibility are still under investigation. some studies have shown that in aged individuals the antibacterial properties provided by surfactant proteins, proinflammatory cytokines, and complement are altered. pulmonary hyperinflation (often referred to as senile emphysema) has been reported as an age-related change in human and canine lungs. other age-related changes described in canine lungs include mineralization of bronchial cartilage, pleural and alveolar fibrosis, and heterotopic bone formation (so-called "pulmonary osteomas"). we thank all pathologists at the atlantic veterinary college, university of prince edward island for providing case material. suggested readings are available at www.expertconsult.com. lung section showing a distended and partially occluded blood vessel (center of figure) containing large granular cells. these large cells are macrophages, and their cytoplasm is filled with myriad merozoites isolation of porcine circoviruslike viruses from pigs with a wasting disease in the usa and europe exercise-induced pulmonary hemorrhage effect of mucociliary transport relies on efficient regulation of ciliary beating epidemiology, diagnosis, and treatment of blastomycosis in dogs and cats canine h n influenza virus infection in dogs and mice failure of respiratory defenses in the pathogenesis of bacterial pneumonia in cattle the respiratory system advances in diagnosis of respiratory diseases of small ruminants canine nasal disease transmission of equine influenza virus to dogs dear jd: bacterial pneumonia in dogs and cats acute respiratory distress syndrome in dogs and cats: a review of clinical findings and pathophysiology inflammatory response to infectious pulmonary injury laryngeal paralysis: a study of cases in a mixed-breed population of horses stem cells of the respiratory tract exudative pleural disease in small animals bovine respiratory disease research pulmonary thromboembolism coccidioidomycosis in dogs and cats: a review cousens c: pathology and pathogenesis of ovine pulmonary adenocarcinoma prognosis factors for survival in cats after removal of a primary lung tumor: cases ( - ) the acute respiratory distress syndrome: from mechanism to translation endogenous lipid pneumonia in cats: cases ( - ) retroviral infections in sheep and goats: small ruminant lentiviruses and host interaction canine and feline nasal neoplasia the acute respiratory distress syndrome equine respiratory medicine and surgery canine pleural and mediastinal effusions: a retrospective study of cases a review of histiocytic diseases of dogs and cats estimation of nasal shedding and seroprevalence of organisms known to be associated with bovine respiratory disease in australian live export cattle polymicrobial respiratory disease in pigs current state of knowledge on porcine circovirus type -associated lesions common and emerging infectious diseases in the animal shelter chronic rhinitis in the cat advances in the understanding of pathogenesis, and diagnosis and therapeutics of feline allergic asthma mannheimia haemolytica and bovine respiratory disease detection of respiratory viruses and bordetella bronchiseptica in dogs with acute respiratory tract infections current perspectives on the diagnosis and epidemiology of mycoplasma hyopneumoniae infection mannheimia haemolytica: bacterialhost interactions in bovine pneumonia acute lung injury review rhodococcus equi: the many facets of a pathogenic actinomycete tumors of the respiratory system key: cord- -skavefji authors: choi, sang-ho; hong, sang-bum; hong, hyo-lim; kim, sung-han; huh, jin won; sung, heungsup; lee, sang-oh; kim, mi-na; jeong, jin-yong; lim, chae-man; kim, yang soo; woo, jun hee; koh, younsuck title: usefulness of cellular analysis of bronchoalveolar lavage fluid for predicting the etiology of pneumonia in critically ill patients date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: skavefji background: the usefulness of bronchoalveolar lavage (bal) fluid cellular analysis in pneumonia has not been adequately evaluated. this study investigated the ability of cellular analysis of bal fluid to differentially diagnose bacterial pneumonia from viral pneumonia in adult patients who are admitted to intensive care unit. methods: bal fluid cellular analysis was evaluated in adult patients who underwent bronchoscopic bal following less than hours of antimicrobial agent exposure. the abilities of bal fluid total white blood cell (wbc) counts and differential cell counts to differentiate between bacterial and viral pneumonia were evaluated using receiver operating characteristic (roc) curve analysis. results: bacterial pneumonia (n = ) and viral pneumonia (n = ) were frequently associated with neutrophilic pleocytosis in bal fluid. bal fluid median total wbc count ( , /µl vs. /µl, p< . ) and percentage of neutrophils ( . % vs. . %, p = . ) were significantly higher in the bacterial pneumonia group than in the viral pneumonia group. in roc curve analysis, bal fluid total wbc count showed the best discrimination, with an area under the curve of . ( % ci, . – . ). bal fluid total wbc count ≥ /µl had a sensitivity of . %, specificity of . %, positive likelihood ratio (plr) of . , and negative likelihood ratio (nlr) of . . when analyzed in combination with serum procalcitonin or c-reactive protein, sensitivity was . %, specificity was . %, plr was . , and nlr was . . bal fluid total wbc count ≥ /µl was an independent predictor of bacterial pneumonia with an adjusted odds ratio of . in multiple logistic regression analysis. conclusions: cellular analysis of bal fluid can aid early differential diagnosis of bacterial pneumonia from viral pneumonia in critically ill patients. severe pneumonia requiring intensive care unit (icu) admission is associated with high rates of morbidity and mortality. delays in the provision of adequate antimicrobial therapy have been reported to be associated with excess mortality [ ] [ ] [ ] ; therefore, rapid and accurate etiologic diagnosis of severe pneumonia is essential for successful treatment. in recent years, bronchoscopic bronchoalveolar lavage (bal) has been established as a useful technique for collecting lower respiratory tract specimens from the alveolar level, and can thus be used to accurately define the causative organisms of pneumonia [ ] [ ] [ ] . however, a conventional culture usually takes at least a few days, and microbiological yield is often compromised by prior empirical usage of antimicrobial agents. in addition, identification of viruses and atypical organisms requires a separate etiologic work-up. cellular analysis of bal fluid, including total and differential cell counts and the cd +:cd + t-lymphocyte ratio, is useful for the diagnosis of various interstitial lung diseases [ ] [ ] [ ] . under an appropriate clinical setting, bal fluid analysis can provide highly suggestive or even diagnostic information for specific interstitial lung diseases in the absence of a lung biopsy [ ] . however, only a few previous studies with limited patient populations [ ] [ ] [ ] have evaluated the role of cellular analysis of bal fluid in patients with suspected pneumonia. most of these studies focused on the differential diagnosis of pneumonia from non-infectious pulmonary diseases, not on the prediction of pneumonia etiology. bal fluid analysis can be performed within several hours. therefore, such analysis would be useful for guiding early treatment if it could predict the etiology of pneumonia, similar to the role of cerebrospinal fluid cellular analysis, which can reliably differentiate among meningitis etiologies. therefore, this study investigated whether analysis of the cellular profile of bal fluid can predict the etiology of pneumonia in critically ill patients admitted to the medical icu. this study was based on data from a prospective observational cohort study conducted from march to may . all patients admitted to the medical icu of asan medical center, a , -bed tertiary care university-affiliated hospital in seoul, republic of korea, with suspected severe pneumonia were prospectively identified and monitored until discharged [ ] . the data collected included patient demographics, underlying diseases or conditions, illness severity scores including acute physiological and chronic health evaluation (apache) ii and sequential organ failure assessment (sofa), type of pneumonia, laboratory data including microbiological tests, length of icu stay, and outcome. the prospectively collected data were retrospectively analyzed. this study was approved by the institutional review board of asan medical center and the requirement for informed consent was waived because of the observational nature of the study. all patients information was anonymized and deidentified prior to analysis. inclusion criteria were as follows: ( ) patients aged $ years with a clinical diagnosis of pneumonia (see below for definition), and ( ) patients who underwent bronchoscopic bal for etiologic diagnosis of pneumonia. exclusion criteria were as follows: ( ) patients in whom the pathogen was not identified, ( ) patients in whom bal fluid analysis was impossible (due to severe neutropenia or clotting of specimen) or not performed, ( ) patients with a mixed infection (identification of bacteria and virus), ( ) patients who were treated with antimicrobial agents for more than hours before bronchoscopic bal, ( ) patients with invasive pulmonary aspergillosis, ( ) patients with mycobacterial infection, and ( ) patients with pneumocystis jirovecii pneumonia. pneumonia was defined as the presence of an acute infiltrate on a chest radiograph and at least one of the following: fever (temperature $ . uc) or hypothermia (temperature , . uc), cough, pleuritic chest pain, dyspnea, and altered breath sounds on auscultation [ ] . pneumonia was categorized as communityacquired pneumonia (cap), healthcare-associated pneumonia (hcap), or hospital-acquired pneumonia (hap), as defined previously [ , ] . fiberoptic bronchoscopy with bal was performed following a standardized protocol as previously described [ ] . briefly, bal was performed by instillation of three consecutive aliquots of sterile saline solution ( - - ml) into the bronchial tree at the area that was most abnormal on the chest radiography. the right middle lobe or lingual segment was chosen in patients with bilateral diffuse infiltration. bal fluid that was first retrieved was discarded, and bal fluid that was subsequently retrieved was collected. the total cell count was determined using a hemocytometer. the corresponding amount of bal fluid for cells was centrifuged onto a microscope slide using a thermo shandon cytospin (thermo fisher scientific inc., waltham, ma, usa), at rpm for minutes at room temperature. the slide was airdried and stained with wright-giemsa stain. differential cell counts that included percentages of neutrophils, lymphocytes, alveolar macrophages, and eosinophils were determined. bacterial, fungal, and mycobacterial cultures of endotracheal aspirates and bal fluid were performed. respiratory viruses were tested by a multiplex reverse-transcription polymerase chain reaction (pcr) assay using a seeplex rv ace detection kit (seegene inc., seoul, korea) and/or shell vial culture. pcr to detect mycoplasma pneumoniae, chlamydophila pneumoniae, and legionella pneumophila, and a urinary antigen test to detect streptococcus pneumoniae and l. pneumophilia serogroup species were also performed. data were expressed as mean standard deviation or median and - % interquartile range according to data distribution. categorical variables were compared using the chi-square test or fisher's exact test as appropriate. receiver operating characteristic (roc) curves were constructed to determine the performances of bal fluid cellular components, serum procalcitonin concentration, and c-reactive protein concentration for predicting bacterial pneumonia. youden's index (sensitivity + specificity- ) [ ] was used to select the optimal cutoff points of the roc curve. area under the curve (auc), sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were calculated. for positiveand negative predictive values, the prevalence of bacterial pneumonia in severe pneumonia patients admitted to the medical icu was assumed to be . %, based on our previous study [ ] . multivariable logistic regression analysis was used to identify independent predictors of bacterial pneumonia. variables with p values less than . in the univariate analysis were included in the multivariate analysis. the correlation between bal fluid white blood cell (wbc) count and apache ii score was determined by calculating pearson's correlation coefficient. significance was accepted at p # . . all tests were performed using spss (version . ; spss, inc.) and graphpad prism (version ; graphpad, inc.) software. pneumonia underwent bronchoscopic bal ( with cap, with hcap, and with hap). of these patients, were excluded because the pathogen was not identified, were excluded because bal fluid analysis was not possible (due to severe neutropenia or specimen clotting) or not performed, were excluded because two or more types of pathogens were identified, and were excluded because they received antimicrobial therapy for more than hours before bronchoscopic bal. ten patients with pneumocystis jirovecii pneumonia, patients with invasive pulmonary aspergillosis, and patients with mycobacterial pneumonia were also excluded. finally, patients ( with bacterial pneumonia and with viral pneumonia) were included. the characteristics of the patients are shown in table . thirty-two patients ( . %) were men and the mean age was . years. structural lung disease was the most common underlying disease ( . %), followed by diabetes mellitus ( . %), and hematologic malignancy/solid cancer (both . %). sixteen patients ( . %) had cap, ( . %) had hcap, and ( . %) had hap. most baseline characteristics did not significantly differ between the bacterial pneumonia and viral pneumonia groups. by contrast, mean apache ii ( . . vs. . . , p = . ) and sofa ( . . vs. . . , p = . ) scores were significantly higher in the bacterial pneumonia group than in the viral pneumonia group. however, mortality rates, including -day mortality, did not significantly differ between the groups. pathogens that were identified in patients are summarized in table . twenty-eight bacterial pathogens were identified in patients. in patients, two different bacteria were identified. staphylococcus aureus (n = ) was the most common bacteria, followed by legionella pneumophila (n = ), and streptococcus pneumoniae (n = ). bacteria were identified from bal fluid cultures or pcrs in patients, from endotracheal aspirates or sputum cultures in patients, from blood cultures in patients, and from urinary antigen tests in patients (two patients with pneumococcal antigens and two patients with legionella antigens). eleven patients had two or more positive tests. twenty-six viruses were identified in patients. in three patients, two different viruses were identified. rhinovirus was the most common virus (n = ), followed by influenza virus (n = ), and respiratory syncytial virus (n = ). viruses were identified from bal fluid specimens in patients and from nasopharyngeal specimens in patients. viruses were detected in both in bal fluid and nasopharyngeal samples in patients. cellular bal fluid profiles and distributions of bal fluid cell counts in the two groups are shown in table and figure . detailed data of each patient are summarized in table s . the median total wbc count ( , /ml vs. /ml, p, . ), percentage of neutrophils ( . % vs. . %, p = . ), and absolute neutrophil count ( , /ml vs. /ml, p, . ) of bal fluid were significantly higher in the bacterial pneumonia group than in the viral pneumonia group. the median serum procalcitonin concentration was also higher in the bacterial pneumonia group than in the viral pneumonia group ( . ng/ml vs. . ng/ml, p = . ), and the c-reactive protein concentration tended to be higher in the bacterial pneumonia group than in the viral pneumonia group ( . mg/dl vs. . mg/dl, p = . ). of the pathogen-identified patients who had received antimicrobial agent for more than hours prior to bronchoscopic bal (figure ) , had bacterial pneumonia, had viral pneumonia, and had invasive pulmonary aspergillosis. of the patients with bacterial pneumonia or viral pneumonia, the median duration of antimicrobial therapy before bronchoscopic bal was days (interquartile range, - days). the median total wbc count ( /ml vs. /ml, p = . ) and percentage of neutrophils ( . % vs. . %, p = . ) were not significantly different between these two groups. figure s shows the changes recorded in the bal fluid total wbc count and percentage of neutrophils according to the duration of exposure to antimicrobial agents. diagnostic performances of bal fluid cellular components, serum procalcitonin concentration, and serum c-reactive protein concentration for the prediction of bacterial pneumonia the ability of bal fluid cellular analysis to distinguish between bacterial pneumonia and viral pneumonia was assessed using roc analysis (table last the sensitivities, specificities, positive predictive values, negative predictive values, positive likelihood ratios, and negative likelihood ratios are summarized in table . when the cutoff value of bal fluid total wbc count was $ /ml, which was selected using youden's index, sensitivity was . % ( % ci; . - . ), specificity was . % ( % ci; . - . ), positive predictive value was . % ( % ci; . - . ), negative predictive value was . % ( % ci; . - . ), positive likelihood ratio was . ( % ci; . - . ), and negative likelihood ratio was . ( % ci; . - . ). a combination of bal fluid total wbc count $ /ml or serum procalcitonin concentration $ . ng/ml had a sensitivity of . % ( % ci; . - . ) and a negative likelihood ratio of . ( % ci; . - . ), whereas bal fluid total wbc count $ /ml and serum c-reactive protein concentration $ . mg/dl had specificity of . % ( % ci, . - . ) and a positive likelihood ratio of . ( % ci, . - . ). when a cutoff value of bal fluid total wbc count $ /ml was applied to pathogen-identified patients who had received antimicrobial agent for more than hours, sensitivity was . % ( % ci; . - . ), specificity was . % ( % ci; . - . ), positive predictive value was . % ( % ci; . - . ), negative predictive value was . % ( % ci; . - . ), positive likelihood ratio was . ( % ci; . - . ), and negative likelihood ratio was . ( % ci; . - . ). multiple logistic regression analysis revealed that bal fluid total wbc count $ /ml was an independent predictor of bacterial pneumonia with an adjusted odds ratio of . ( % ci; . - . ) ( table ). there was a modest but significant positive correlation between the degree of bal leukocytosis and the apache ii score (r = . , p = . ) (figure ) . table . bronchoalveolar lavage total and differential cell counts (%) in patients with pneumonia. this study analyzed the usefulness of cellular analysis of bal fluid for predicting the etiology of pneumonia in critically ill adult patients. neutrophilic pleocytosis in bal fluid was frequently found in patients with bacterial-and viral pneumonia. the degree of pleocytosis, which was higher in the bacterial pneumonia, was useful for differential diagnosis of bacterial pneumonia. total wbc count had the best diagnostic accuracy for predicting bacterial pneumonia, and its diagnostic performances was better than those of serum procalcitonin and c-reactive protein concentrations. combinations of bal fluid total wbc count, serum procalcitonin concentration, and serum c-reactive protein concentration provided the best diagnostic yields. the data suggest that cellular analysis of bal fluid is a rapid and useful technique for differentiating bacterial pneumonia from viral pneumonia, and can be used to direct early appropriate treatment. information about the role of cellular profiles of bal fluid for differential diagnosis of bacterial pneumonia in adult patients is limited. stolz et al [ ] . evaluated potential markers of bacterial infection in a cohort of immunocompromised patients with pulmonary complications. they reported that the percentage of neutrophils in bal fluid and the serum procalcitonin concentration are independent predictors of bacterial infection. they suggested that the optimal cutoff value of the percentage of neutrophils in bal fluid is % (sensitivity %; specificity %), which is much lower than the cutoff value in the current study. sternberg et al. [ ] investigated the usefulness of bal in assessing pneumonia in renal transplant patients, and suggested that the optimal cutoff value of the percentage of neutrophils in bal fluid is . % for predicting bacterial pneumonia. however, neither of these previous studies included patients with severe pneumonia caused by respiratory viruses alone, and both compared bal findings between patients with bacterial pneumonia and those with non-infectious diseases. in the current study, patients with viral pneumonia were included by using the newly developed multiplex respiratory virus rt-pcr. this showed that cases of viral pneumonia were frequently associated with neutrophilia in bal fluid (median . %). we speculate that this underlies why the optimal cutoff value of percentage of neutrophils in bal fluid for predicting bacterial pneumonia is much higher in the current study ( %, table ) than in previous studies. several authors of the current study previously investigated the diagnostic utility of soluble triggering receptor expressed on myeloid cells- (strem- ) in bal fluid of various patient populations with bilateral lung infiltrates. a cutoff value of $ % neutrophils in bal fluid is useful for differential diagnosis of bacterial or fungal pneumonia from other causes of pneumonia or non-infectious diseases (auc = . , % ci; . - . , p = . ) [ ] . in comparison to this previous study, the current study did not include patients with non-infectious diseases or fungal pneumonia, included much more cases of severe viral pneumonia, and analyzed the counts of various cell types. among the currently available inflammatory markers, serum procalcitonin is one of the best indicators of bacterial infections, including lower respiratory tract infections [ ] . the usefulness of serum procalcitonin measurements has been validated in the diagnosis, severity assessment, and follow-up of patients with lower respiratory tract infections [ ] [ ] [ ] . in the current study, the auc of serum procalcitonin concentration for predicting bacterial pneumonia (auc = . ) was smaller than those of total wbc (auc = . ) and neutrophil (auc = . ) counts. the combination of bal fluid wbc counts and serum procalcitonin concentration tended to improve the diagnostic accuracy of the roc model. this indicates that combinations of these markers can be useful to rule-out (bal fluid total wbc count $ /ml or serum procalcitonin concentration $ . ng/ml with a sensitivity of . % and negative likelihood ratio of . ) or rule-in (bal fluid total wbc count $ /ml and serum c-reactive protein concentration $ . mg/dl with a specificity of . % and positive likelihood ratio of . ) bacterial pneumonia. diagnostic accuracy could be further improved if bal fluid cellular profiles are interpreted alongside clinical presentations, radiographic studies, and other relevant test results. using this approach, it might be possible to identify patients who can be managed without antibacterial agents or those who require antiviral agents. although not included in the current study, strem- in bal fluid is another notable biomarker for the diagnosis of pneumonia. strem- is reportedly a potent discriminator of bacterial pneumonia from non-infectious lung infiltrations [ , [ ] [ ] [ ] [ ] [ ] . however, the proposed cutoff values of strem- concentration vary widely ( - pg/ml) and some studies have questioned the reliability of bal fluid strem- [ ] [ ] [ ] . studies on bal fluid strem- have mainly been confined to patients with ventilator-associated pneumonia. therefore, the usefulness of strem- for etiologic diagnosis of pneumonia, especially differential diagnosis of viral pneumonia, has not been elucidated yet. the current study directly compared patients with bacterial and viral pneumonia, and therefore differs from previous studies of strem- . bal fluid strem- concentration in combination with the bal fluid cellular profile might exhibit better diagnostic performance, although this warrants further studies. a strength of the current study is the relatively strict enrollment criteria used. to minimize bias associated with antimicrobial therapy, all patients who received antimicrobial therapy for more than hours were excluded, regardless of the adequacy of prior antimicrobial therapy. by using strict enrollment criteria, however, only a small proportion of pneumonia patients who underwent bronchoscopic bal was finally included (figure ), which might have influenced on the results. however, positive likelihood and negative likelihood ratio, which are not influenced by disease prevalence, were good, which supports the validity of the data. in clinical practice, the results might be applied to patients who have received antimicrobial therapy more than hours. that is, if bal fluid cellular analysis shows evident pleocytosis even after antimicrobial therapy for more than hours, it would be a strong suggestion for bacterial etiology. the study has several limitations. first, the small sample size of the select critically ill patient population analyzed limits the general applicability of our findings. moreover, since our study included critically ill patients with acute respiratory failure secondary to pneumonia who were not receiving antimicrobial therapy, our results may not be applicable to the majority of severe pneumonia patients in clinical practice. second, the impact of antimicrobial therapy on the both bal fluid cellular profiles and other inflammation markers such as procalcitonin, remains to be further elucidated. third, cases of invasive pulmonary aspergillosis, pneumocystis jirovecii pneumonia, and mycobacterial pneumonia, were not included, mainly because few patients had these types of pneumonia. fourth, patients with non-infectious causes of pulmonary infiltrates that can often mimic infectious causes, such as acute respiratory distress syndrome, cryptogenic organizing pneumonia, eosinophilic pneumonia, and drug-induced pneumonitis, were also excluded from our analyses. the inclusion of those cases may have caused a marked decrease in the specificity of our bal fluid criteria. finally, all the pathogens were not directly identified from bal fluid. some patients were included in whom pathogens were identified by other means, such as blood culture, endotracheal aspirates culture, urinary pneumococcal antigen test, and pcr from nasopharyngeal samples, as long as clinically and radiographically compatible and no other etiology was demonstrated. therefore, patients with coincidental upper respiratory infections or colonization may have been included. in conclusion, the data indicate that cellular analysis of bal fluid, alone or in combination with serum procalcitonin and creactive protein concentrations, may rapidly provide valuable diagnostic information for the early differential diagnosis of pneumonia in critically ill adult patients. timing of antibiotic administration and outcomes for medicare patients hospitalized with 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usefulness of procalcitonin levels in community-acquired pneumonia according to the patients outcome research team pneumonia severity index effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial pneumonitis-associated hyperprocalcitoninemia soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia combined measurement of procalcitonin and soluble trem- in the diagnosis of nosocomial sepsis triggering receptors expressed on myeloid cells in pulmonary aspiration syndromes diagnostic implications of soluble triggering receptor expressed on myeloid cells- in patients with acute respiratory distress syndrome and abdominal diseases: a preliminary observational study diagnostic implications of soluble triggering receptor expressed on myeloid cells- in bal fluid of patients with pulmonary infiltrates in the icu soluble triggering receptor expressed on myeloid cells- in bronchoalveolar lavage fluid is not predictive for ventilator-associated pneumonia soluble triggering receptor expressed on myeloid cells- (strem- ) as a diagnostic marker of ventilator-associated pneumonia soluble triggering receptor expressed on myeloid cell- is increased in patients with ventilator-associated pneumonia: a preliminary report key: cord- -ashjw xs authors: guo, lingxi; wei, dong; zhang, xinxin; wu, yurong; li, qingyun; zhou, min; qu, jieming title: clinical features predicting mortality risk in patients with viral pneumonia: the mulbsta score date: - - journal: front microbiol doi: . /fmicb. . sha: doc_id: cord_uid: ashjw xs objective: the aim of this study was to further clarify clinical characteristics and predict mortality risk among patients with viral pneumonia. methods: a total of patients with viral pneumonia at ruijin hospital in shanghai from may to may were recruited. multiplex real-time rt-pcr was used to detect respiratory viruses. demographic information, comorbidities, routine laboratory examinations, immunological indexes, etiological detections, radiological images and treatment were collected on admission. results: ( . %) patients died within days in hospital. a predictive mulbsta score was calculated on the basis of a multivariate logistic regression model in order to predict mortality with a weighted score that included multilobular infiltrates (or = . , % ci . – . , p = . ; points), lymphocyte ≤ . (∗) ( )/l (or = . , % ci . – . , p < . ; points), bacterial coinfection (or = . , % ci . – . , p < . ; points), acute-smoker (or = . , % ci . – . , p = . ; points), quit-smoker (or = . , % ci . – . , p = . ; points), hypertension (or = . , % ci . – . , p = . ; points) and age ≥ years (or = . , % ci . – . , p = . ; points). points was used as a cut-off value for mortality risk stratification. this model showed sensitivity of . , specificity of . and a better predictive ability than curb- (auroc = . vs. . , p < . ). conclusion: here, we designed an easy-to-use clinically predictive tool for assessing -day mortality risk of viral pneumonia. it can accurately stratify hospitalized patients with viral pneumonia into relevant risk categories and could provide guidance to make further clinical decisions. statement viral infections could present with severe pneumonia, acute respiratory distress syndrome or are complicated by bacterial super-infections in many patients. influenza and other respiratory viruses are common reasons of acute pneumonia which can result in significant morbidity or mortality in the setting of high-risk factors such as extremes of age, pregnancy, obesity or chronic pre-existing conditions. cytokines and chemokines, on the other hand, are regarded as possible hallmarks of severe disease and many of them reach high serum levels in the setting of severe infection. although a variety of clinical prediction rules for pneumonia such as crb- and curb- are widely used in the assessment of community acquired pneumonia, no standard rule for the calculation of viral pneumonia severity scores has been established to our knowledge. here, we designed a easy-touse clinically predictive score for assessing mortality risk of viral pneumonia. this model showed better predictive ability with a c-index of . , sensitivity of . and specificity of . . a cut-off value of points could be used for mortality risk stratification. background viral infections, in spite of their common manifestations as mild illnesses, present with severe pneumonia, acute respiratory distress syndrome (ards) or bacterial coinfections in many patients (shorr et al., ) . in recent years, the dissemination of pcr has increased the ability to detect respiratory viruses in both upper and lower-respiratory tract samples (das et al., ) . influenza and other respiratory viruses are common reasons of acute respiratory infection. patients predisposed to bacterial infections have greater morbidity and mortality levels (hanada et al., ) . during natural infection, both the adaptive and innate immune responses play important roles in controlling respiratory virus infection (nussing et al., ) . adaptive t and b cells maintain immunological memory and provide protection against subsequent virus infections. cytokines and chemokines, on the other hand, are regarded as possible hallmarks of severe disease and many of them reach high serum levels in the setting of severe infections (la gruta et al., ) . such variables also could guide clinical decision making as well as infectious disease management. although a variety of clinical prediction rules for pneumonia such as crb- and curb- are widely used in the assessment of community acquired pneumonia (cap) (viasus et al., ; uranga et al., ) , most remain not applicable in the setting of viral infection. other reported risk factors for influenza pneumonia such as po /fio , lymphocyte count, and antigen-specific t cells are likewise useful in predicting mortality and deciding on appropriate management (viasus et al., ; shi et al., ) . to our knowledge, no standard rule for the calculation of viral pneumonia severity scores has been established. here, we aimed to further elucidate the potential risk factors and attempt to predict the probability of mortality among patients infected with respiratory viruses. a retrospective single-center observational study was conducted from may to may in ruijin hospital, shanghai, china. the study was approved by ruijin hospital ethics committee and written informed consent was obtained from all patients involved before enrolment. we retrospectively studied all hospitalized patients with positive result of multiplex real-time reverse-transcription polymerase chain reaction (rt-pcr, tib respiratory kit, roche, switzerland) aiming to detect respiratory viruses. the time period of this study was selected because of the introduction of the viral test panel. patients who were diagnosed pneumonia according to the infectious diseases society of american (idsa)/american thoracic society (ats) guidelines (charles et al., ) were enrolled in this study. patients were excluded if: ) age < years; ) had a clear alternative final diagnosis as lung cancer or other non-pneumonia illness; ) long hospitalization > months before death. hospitalized patients had initial positive rt-pcr results and of them were enrolled with pneumonia. a total of cases were excluded: final diagnosis of non-pneumonia illness (n = ), children or adolescent patient (n = ). pneumonia patients with positive viral detection were finally included in this analysis (figure ). infections due to influenza a (flua), adenovirus (adv), bocavirus, human rhinovirus (hrv), influenza b (flub), parainfluenza (piv), coronavirus (cov), respiratory syncytial virus a (rsva), respiratory syncytial virus b (rsvb), enterovirus (ev) and human metapneumovirus (hmpv) were confirmed using rt-pcr via nasal wash products. data were collected on admission including demographic information, comorbidities, routine laboratory examinations, chest radiography or ct scanning, immunological and etiological detections. we used positive bacterial culture of blood and sputum samples as the criteria for bacterial growth. the use of antiviral therapy and steroids was recorded, including the drug, start date, duration and dosage. patients were evaluated as deemed clinically appropriate at any time when pneumonia was suspected. curb- score of each patient was calculated (barlow et al., ) . length of stay and outcome state of each patient were recorded. those improved patients with hospital stay < days were followed up by a phone call to determine survival status if they were not seen in the outpatient clinic. finally, the outcome of mortality was defined as overall mortality within days. viral pneumonia patients were classified into two groups: survival group and -day death group. univariate analysis was initially used to compare risk factors for mortality separately among patients with viral pneumonia. proportions or means with sd were used to characterize the patient sample. continuous variables were compared using t-tests or one-way anova while χ or fisher exact tests were used for categorical dependent data analysis, as appropriate. the percentages of missing values of variables in our cohort were lower than %. we imputed missing data of the covariates by using multiple imputations (sterne et al., ) . conclusions of univariate logistic regression analyses with or without imputed data were unchanged. continuous variables were categorized and retained for multivariate testing. cut-off points were identified following youden's index of receiver operator characteristic (roc) curve or a clinically relevant cut-off. variables with p < . were regarded as potential risk factors and included in multivariate regression analysis against overall mortality reduced by a backward elimination procedure (conditional likelihood ratio test and elimination if p ≥ . ). data of patients was partitioned randomly into two complementary subsets: the training set of ( %) was used to establish the model; the testing set of ( %) was used to validate the analysis. for pragmatic reasons, scores for each predictors were assigned as integer values relative to the regression coefficient. cut-off points were identified following youden's index of roc. survival analysis was performed using univariate approach with kaplan-meier analysis between lowrisk and high-risk group according to the cut-off value. performance of the score was assessed by measuring the area under roc curve (auroc) while sensitivity and specificity were calculated. internal validation was assessed by auroc of bootstrapped samples. the cross-validation was assessed by calculating auroc of the testing set. roc curve and net reclassification improvement (nri) (leening et al., ) analyses were used to assess the improvement in risk predicting capacity compared with curb- . statistical analysis was performed using spss version . and r . . . all tests were two-sided and a p-value < . was considered significant. baseline characteristics of complete cases and different groups are described in table . the mean age of viral pneumonia patients was . (sd . ) years and . % were male. immune examinations between survival and dead patients are described in table lower serum levels of t-lymphocyte subtypes were noted in death group (p < . ). moreover, patients from death group were found to possess lower serum levels of t-lymphocyte subtypes (p < . ) and elevated levels of the cytokines il- r (p = . ), il- (p < . ) and il- (p = . ). we further analyzed these same immunological indices in patient subgroups with or without bacterial infections. lower levels of cd + (p < . ), cd + (p = . ) and cd + (p = . ) t-lymphocyte counts were found in the group suffering bacterial infections. as for interleukins, elevated levels of the cytokines il- r (p = . ), il- (p = . ) and il- (p = . ) were also found in bacterial group. there were no statistically significant differences in cd + /cd + , il- , il- and tnf-α in both comparisons. (figure ) . we compared the curb- score, severity and prognoses among patients with or without bacterial co-infection (table ) . patients with bacterial infections revealed striking differences in curb- scores, use of either non-invasive or invasive ventilation, icu admission rate, length of hospitalization and treatment cost as compared with those who simply suffered viral infections. multiple imputation of missing data was performed for: serum interleukins ( . % missing); pao /fio ( . % missing); t lymphocyte subsets levels ( . % missing); body mass index (bmi) and lymphocyte count (all < % missing). according to the methods and analyses above, the following categorical variables were entered in a backward stepwise logistic regression analysis: male; age ≥ years; smoking history; hypertension; lymphocyte ≤ . * /l; po /fio ≤ ; il- ≥ pg/ml; il- r ≥ pg/ml; positive sputum or sanguine culture for bacteria; fungi infection; multilobular infiltration ( table ) . in order to develop a simple and useful clinical predicting tool, relative weights were assigned according to the regression coefficient of each categorical variable (β). figure shows coefficient, odd ratio (or), % ci and calculation of the multilobular infiltration, hypo-lymphocytosis, bacterial coinfection, smoking history, hyper-tension and age (mulbsta) score. auroc of the training set was . ( % ci . to . ), and auroc of the testing set was . ( % ci . - . ). for the total patients, auroc was . ( % ci . - . ). sensitivity, specificity and corresponding risk of death of mulbsta are shown in table . patients were divided in to high-risk and low-risk groups considering the cut-off value of . the kaplan-meier survival curves for high-risk and low-risk groups are shown in figure . continuous parameters presented as mean ± sd, categorical data as n (%). in comparison, the nomogram of the full regression model in original form is shown in supplemental figure . compared with the mulbsta score, there was no difference between the auroc for the original regression model ( . vs. . , p = . ). in our cohort, mulbsta was a significantly stronger predictor of overall mortality than curb- (auroc = . vs. . , p = . , n = ) (figure ) . the average auroc of bootstrapped (n = ) mulbsta model and curb- score were . and . separately. nri of mulbsta was also improved than curb- (nri . , % ci . - . , p = . ). as curb- was commonly used to predict -day mortality, we also assessed the use of mulbsta score in -day mortality which tended to be a stronger predictor than curb- (auroc = . vs. . , p < . , n = ). in patients hospitalized with viral pneumonia, a simple prognostic tool was made for overall mortality which is useful for prediction several days after admission upon obtaining culture results. this score predicts prognoses with greater accuracy than curb- . pneumonia is a global cause of death with high shortterm and long-term mortality. though short-term mortality rates are high in this acute disease, long-term mortality within days, year and years are also noteworthy in previous studies (mortensen et al., ; uranga et al., ) . nowadays, the survival time for patients with severe lung failure with the progress of radiological image, new drugs and supporting techniques like extracorporeal membrane oxygenation (ecmo) (pappalardo et al., ) . a prospective research on viral pneumonia showed a higher -day mortality rate than overall mortality as length of hospital stay was between to days (zhou et al., ) . during hospitalization, patients in our study died between and days of hospital stay, among them ( . %) lived longer than days, which makes -day mortality worthy of attention. as immune deficiency is a close relative of mortality, evaluating immune condition could be conductive to monitor patient's general condition and estimate prognosis. in our study, all t-lymphocyte subtypes were reduced in death group reflecting the deficiency of adaptive immune response. prior research on viral infection indicated that adaptive t cells provide broader and more lasting cross-reactive cellular immunity with less limitations of strain-specific restriction, especially cd + t cells (bender et al., ). besides, the higher level of proinflammatory cytokines had been documented to attribute to severe disease and lung damage (das et al., ) . accordingly, il- r and il- , which appeared to significantly correlate with illness severity by complementing cd + t cell function (nussing et al., ) , presented with significantly higher serum levels in death group. il- r and il- were also found related to mortality in univariate regression. meanwhile, il- secreted along with adoptive transfer of th cd + t cell clones, but it was associated with delayed viral clearance and failed to cause protective effect (la gruta et al., ) . although the test of interleukin is not yet widely available, we suggest that patients could be stratified by il- r and il- regarding mortality risk. bacterial coinfection in the setting of viral pneumonia is known as another major cause of mortality. acinetobacter baumannii is one of the most commonly encountered pathogens both in prior studies and in our investigation (gao et al., ) . we further compared patients with or without bacterial infection. bacterial co-infection not only manifested with worsened outcomes but also prolonged hospital stay and significantly increased the cost of hospital care. bacterial infection is an independent predictor without other driving forces. viral pneumonia further deteriorates when bacterial infection occurs spontaneously. this process is considered to be associated with the dysregulation of t-cell, antigen-specific t cell and plasma cytokine levels (li and cao, ) . levels of inflammatory cytokines, such as il- and il- , were found to be higher in patients suffering bacterial and influenza virus co-infections than in patients infected by a sole pathogen (li et al., ) . as such, the remarkably increased il- in patients co-infected with bacteria demonstrated its predictive potential once again. despite intense efforts, the development of antiviral therapy to prevent or treat respiratory virus infections is under limitation. influenza antivirals as oseltamivir or zanamivir were commonly used on the basis of international recommendations (jefferson et al., ) . however, oral oseltamivir has a relatively strict time window and several secondary effects like nausea and renal syndromes, and it's hard to use for unconscious patients (lee et al., ) . there is no effective listed antiviral or vaccine approved for the prevention or treatment of non-influenza viruses (heylen et al., ) . in our study, oseltamivir was commonly used as antiviral therapy; while acyclovir, ganciclovir or foscarnet were used for cytomegalovirus or herpes simplex virus. nevertheless, early antiviral treatment did not prevent progression to pneumonia consistent with earlier studies (elizaga et al., ; chemaly et al., ) . the confused choice of respiratory virus therapy makes it urgent to predict mortality more accurately. to date, a variety of studies concerning respiratory viruses were found to demonstrate risk factors by multivariate regression. consistent with previous report, po /fio ≤ in combination with lymphopenia (peripheral blood lymphocyte count < . * / l) were reported to be simple and reliable predictors of influenza (shi et al., ) . multilobular infection was also noted in our study, which was also a remarkable factor in prior report (jennings et al., ) . in our study, po /fio was also statistically significant mortality predictors according to univariate analysis, while the cut-off was adjusted to . moreover, younger age, chronic comorbid conditions, morbid obesity, high-dose steroid use, hematopoietic stem cell therapy, lower levels of cd + t specific cells and a lack of early antiviral therapy were also regarded as independent risk factors for severe disease, according to prior reports (viasus et al., ; chemaly et al., ; li and cao, ) . however, none of these were significant in our study. the idsa/ats guidelines had recommended curb- (confusion, urea, respiratory rate, blood pressure, age ≥ year) as one of cap severity score (charles et al., ). however, it had a low mortality rate among patients categorized as low risk (mandell et al., ) . several studies argued that increasing age had worse predicting ability due to the fact that influenza a virus had been reported to occur in younger individuals (riquelme et al., ; bjarnason et al., ) . meanwhile, the relative mortality rate of virus infectious diseases in the elderly are reported more than twice those of the young (pawelec et al., ) . early study suggested that a high cd + t cell count and low nk activity correlated significantly with survival of infectious diseases in the elderly (ogata et al., ) , suggesting that aging could lead to increasing immunity deficiency and mortality. in our population of hospitalized viral pneumonia patients, age ≥ years was statistically associated with mortality while the weight coefficient was relatively small. it is not reasonable to completely deny the importance of age, but appropriate weight adjustment may enhance the predictive capacity of the model. all parameters identified in the mulbsta score are easy to get clinically and all examinations are recommended to be done on admission of hospitalization. roc and nri analysis suggests that our new score has better predictive capacity in comparison with curb- . moreover, the mulbsta score shows promise for the risk stratification of patients hospitalized with viral pneumonia. the death rates for each grade ( table ) suggest the following risk categories: mulbsta - ('low-risk' , mortality = . %); mulbsta - ('high-risk' , mortality = . %). a higher mulbsta score might be used as a good predictor of prognosis. some limitations of this study should also be acknowledged. the retrospective single-center design leads to missing data and unavoidable biases in identifying and recruiting participants. the sample size was relatively small in order to build up a predicting score. despite these limitations, the study was designed to reflect the 'real life' clinical situation. clinical information was meticulously gathered using standard protocols by admitted medical team. this score might assist clinicians in making appropriate decisions and optimizing the use of hospital resources. we found that the mulbsta score, based on six parameters routinely available in hospital, has a strong predictive ability for -day mortality. it can accurately stratify hospitalized patients with viral pneumonia into relevant risk categories and could provide guidance to make further clinical decisions. the datasets analyzed for this study can be found in the figshare. link: https://figshare.com/articles/dataset_for_the_ mulbsta_score_xlsx/ . the curb pneumonia severity score outperforms generic sepsis and early warning scores in predicting mortality in community-acquired pneumonia transgenic mice lacking class i major histocompatibility complex-restricted t cells have delayed viral clearance and increased mortality after influenza virus challenge severity of influenza a (h n ) pneumonia is underestimated by routine prediction rules. results from a prospective, population-based study rocket science and the infectious diseases society of america the characteristics and outcomes of parainfluenza virus 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of influenza: systematic review and meta-analysis net reclassification improvement: computation, interpretation, and controversies: a literature review and clinician's guide pandemic and avian influenza a viruses in humans: epidemiology, virology, clinical characteristics, and treatment strategy type i interferon induction during influenza virus infection increases susceptibility to secondary streptococcus pneumoniae infection by negative regulation of gammadelta t cells infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults assessment of mortality after long-term follow-up of patients with community-acquired pneumonia innate and adaptive t cells in influenza disease association between natural killer cell activity and infection in immunologically normal elderly people predicting mortality risk in patients undergoing venovenous ecmo for ards due to influenza a (h n ) pneumonia: the ecmonet score t cells and aging predicting mortality in hospitalized patients with h n influenza pneumonia mortality prediction to hospitalized patients with influenza pneumonia: po /fio combined lymphocyte count is the answer viruses are prevalent in non-ventilated hospital-acquired pneumonia multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls predicting -year mortality after hospitalization for communityacquired pneumonia biomarkers for predicting short-term mortality in community-acquired pneumonia: a systematic review and meta-analysis factors associated with severe disease in hospitalized adults with pandemic (h n ) in spain disease severity and clinical outcomes of community-acquired pneumonia caused by non-influenza respiratory viruses in adults: a multicentre prospective registry study from the cap-china network this study was approved by the coordinating ethics committee of ruijin hospital affiliated to shanghai jiao tong university school of medicine (no. - ) . written informed consents were obtained from all patients involved before enrolment. in our study, patients from to years old were included. the consent obtained from the participants was both informed and written. mz and xz conceived or designed the work. lg, dw, and yw collected the data. lg, dw, and ql analyzed and interpreted the data.lg, dw, ql, and jq drafted the manuscript. all authors critically revised the manuscript and approved the final version of the manuscript to be published. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fmicb. . /full#supplementary-material key: cord- -x ddi wg authors: li, wanli; an, xinjiang; fu, mingyu; li, chunli title: emergency treatment and nursing of children with severe pneumonia complicated by heart failure and respiratory failure: case reports date: - - journal: exp ther med doi: . /etm. . sha: doc_id: cord_uid: x ddi wg pneumonia refers to lung inflammation caused by different pathogens or other factors, and is a common pediatric disease occurring in infants and young children. it is closely related to the anatomical and physiological characteristics of infants and young children and is more frequent during winter and spring, or sudden changes in temperature. pneumonia is a serious disease that poses a threat to children's health and its morbidity and mortality rank first, accounting for . – . % of pediatric inpatients. due to juvenile age, severe illness and rapid changes, children often suffer acute heart failure, respiratory failure and even toxic encephalopathy at the same time. the concurrence in different stages of the process of emergency treatment tends to relapse, which directly places the lives of these children at risk. severe pneumonia constitutes one of the main causes of infant mortality. in the process of nursing children with severe pneumonia, intensive care was provided, including condition assessment and diagnosis, close observation of disease, keeping the airway unblocked, rational oxygen therapy, prevention and treatment of respiratory and circulatory failure, support of vital organs, complications, and health education. the inflammatory response was proactively controlled, to prevent suffocation and reduce mortality. in summary, positive and effective nursing can promote the rehabilitation of children patients, which can be reinforced with adequate communication with the parents and/or caretakers. severe pneumonia is a common life-threatening disease, particularly for children, and is more common in infants and young children ( , ) . the estimated worldwide incidence of severe pneumonia in children less than years of age is - per , person-years and the mortality is . - . per , person-years ( ) ( ) ( ) . it often occurs in the winter and spring, with acute onset, complex clinical manifestations and fast-changing condition, which usually involves the circulation, nervous and digestive systems ( ) ( ) ( ) . as a result, severe pneumonia produces corresponding clinical symptoms, such as respiratory failure, heart failure, toxic encephalopathy and intestinal paralysis, which endanger the lives of children in the short term, and is the first cause of death of pediatric inpatients ( , ) . it is listed as the one of the four diseases requiring prevention and treatment in children by the ministry of health ( , ) . pneumonia may occur at any point of the year, but is more common in the months of winter and spring or during the time of climate variability. the disease may be the primary illness, or secondary one after an acute infectious disease, such as bronchitis and measles, upper respiratory tract infections and whooping cough, and has a high morbidity and mortality rate in china ( ) . as reported by several studies, the number of annual pneumonia patients in china is ≤ million individuals, and among the children with pneumonia, - % cases are of severe pneumonia, which ranks fifth amongst various diseases leading to death ( ) ( ) ( ) ( ) ( ) ( ) . the aim of this study was to conduct a retrospective analysis of the clinical data of cases of children presenting with severe pneumonia at the xuzhou children's hospital between january and june , retrieve and review the literature, and summarize emergency treatment and nursing experience. general information. ten cases of children diagnosed with severe pneumonia according to the guidelines of the world health organization were included in the present study ( ) . in this group, there were males and females, aged month to years. the children patients were hospitalized due to fever, cough, asthma, dry and wet rales could be heard in lung auscultation, and a chest x-ray showed thickened lung markings with visible punctate and flake-like shadows. the children patients refused any intake of dairy products or food. there was one case of concurrent toxic encephalopathy, case of gastrointestinal bleeding, and case of toxic intestinal paralysis. the physical examination showed a body temperature of . - ˚c, pulse rate of - beats/min, breathing of - beats/min, and dry and wet rales could be heard in lung. the x-ray examination showed thickened lung markings, and flake-like shadows, and abdominal palpation showed enlarged liver and spleen. respiratory or circulatory functions were at different levels of exhaustion. treatment. after admission, comprehensive emergency treatment measures were taken, such as improving the ventilation function, oxygen uptake, maintaining airway patency, administration of cardiac and diuretic drugs, reduction of intracranial pressure, and conducting anti-infection and symptomatic support measures. nine cases were successfully treated, case succumbed to respiratory failure, and the success rate was %. condition assessment and diagnosis. a detailed inquiry of the medical history was carried out to determine whether the children patients had a history of recurrent respiratory tract infection, and whether they had measles, whooping cough and other respiratory diseases prior to onset, as well as whether the children patients had a full-term birth or asphyxia, and if the growth and development of children patients after birth was normal ( ) ( ) ( ) . conditions such as fever, cough, extent of choked asthma, the presence or absence of breathing, faster heart rate, pulmonary rales, orthopnea, nose flap, three depression signs and cyanosis, as well as clinical manifestations of infected circulatory, digestive, and nervous system were assessed. evaluation of blood routine examination, chest x-ray, and etiology test results were conducted. psychological and social conditions of children and parents were also assessed ( ) . common condition assessment and diagnostic criteria included: i) air exchange impairment, related to lung inflammation; ii) invalid airway clearance, related to excessive and sticky respiratory secretions, frail children patients, and inability to expectorate; iii) hyperthermia, related to lung infection; and iv) malnutrition, related to inadequate intake, increased consumption. close observation of the condition. attention was paid to changes in total peripheral resistance blood pressure (bp), the presence of double suction, such as nodding-like breathing, apnea and other conditions indicating respiratory failure. the presence of exacerbation of dyspnea, dysphoria, quickening heart rate, and an enlarged liver in a short period of time suggested heart failure ( ) ( ) ( ) . children patients with severe wheezing often suffered respiratory acidosis due to retention of carbon dioxide. drowsiness, convulsions or coma in sick children suggested an occurrence of toxic encephalopathy. medicines such as antibiotics, antiasthmatic drugs, cardiac drugs and other medications were administered to patients at the appropriate dosage, the appropriate time and in an accurate manner. side effects of various drugs were observed, and if children patients showed signs of dysphoria, quickening heart rate, worsening asthma, or enlarged liver in a short period of time, indicating heart failure, then the infusion rate was reduced. in our study, close observation of consciousness, pupil changes and muscle tension was carried out, and if manifestations of intracranial pressure such as drowsiness, convulsions, irregular breathing and increased muscle tension appeared, immediate rescue steps were taken. abdominal distension and decreased or disappearing bowel sounds were observed, in order to detect toxic intestinal paralysis in time ( ) . emergency treatment and therapy for respiratory failure. type i respiratory failure refers to the lone presence of hypoxemia and absence of hypercapnia, featuring ventilation dysfunctions, blood change of pao ≤ mmhg, and paco which can be maintained at normal level or reduced ( ) . type i respiratory failure also refers to the coexistence of hypoxemia and hypercapnia, impairment of ventilatory function and gas exchange functions, severe lung lesion, obstruction of trachea and bronchia caused by sticky secretions, blood change of pao < mmhg, and paco > mmhg. main clinical manifestations of children patients with type i pneumonia with respiratory failure include, poor mental state or dysphoria, polypnea, cyanosis of lips, dyspnea, nasal flaring and three depression signs. these symptoms are difficult to distinguish from type ii respiratory failure, and can be observed only by blood gas analysis, which shows a marked difference between type i and ii. type ii respiratory failure shows symptoms of type i respiratory failure and in addition more often than not, it also has symptoms such as shallow breathing, irregular rhythm, slow breathing, drowsiness or coma and even jaw breathing in some patients ( , ) . in our study, changes in condition and changes in blood were closely observed, and where required, a tracheal intubation ventilator was employed to improve the cure rate. oxygen uptake. nasal catheter is easily blocked by secretions, leading to failure of effective uptake oxygen, and is therefore difficult to utilize. we employed the conventional oxygen mask inhalation method, which is comfortable and without stimulation, and was easily accepted by children ( , ) . after using oxygen, once hypoxia was improved, timely adjustment of the oxygen flow or deactivation of oxygen was needed, because inadequate oxygen concentration such as excessive or overtime concentration may lead to changes such as lung tissue edema atelectasis and proliferation of alveolar capillary. the humidification bottle contained % alcohol, aiming to reduce the alveolar surface tension and help improve ventilation. maintenance of airway patency and administration of various aerosol inhalation therapies. i) this group of children patients took appropriate clinostatism according to the state of disease. under normal conditions, the children were placed in a horizontal position, with neck raised high, in order that airways would be unblocked. for children patients with severe heart failure and wheezing, semi-recumbent position was taken to reduce the burden on the heart and lungs ( , ) . for children patients with increased respiratory secretions, the lateral position was useful to expectorate and prevent aspiration. ii) patients received daily routine aerosol inhalation, turning drugs into aerialfog-like fine particles, inhaled to the bronchioles or alveoli, which diluted secretions and had an anti-inflammatory and anti-allergic function and reduced local inflammatory exudates, in addition to reducing airway resistance and improving ventilation. aerosol inhalation time was - min and afterwards sputum suction was carried out immediately in order to clear respiratory secretions. commonly used drugs included: , units of gentamicin, - mg of α-chymotrypsin, - mg of dexamethasone, and ml of saline. the dual role of the aforementioned ultrasonic aerosol inhalation was useful to reinforce treatment of children with severe pneumonia. according to the disease, aerosol inhalation was conducted every or h, with sputum suction ensuing, which produced a good suction effect for children patients with many sticky respiratory secretions. it should be noted that if patients had excessive sputum, the sputum suction was also carried out once prior to using ultrasound aerosol inhalation therapy, followed by thorough sputum suction. in the whole process of aerosol inhalation, providing oxygen inhalation or enhancing oxygen concentration effectively prevented the occurrence of hypoxemia ( ) . iii) hypocalcemia may produce laryngospasm and tongue tenesmus, which causes obstruction and sudden suffocation. first, the child patient's tongue tip was pulled outside the mouth, and then artificial respiration was conducted, with most patients being able to relieve themselves spontaneously. pressurized oxygen was given, endotracheal intubation was carried out if necessary and calcium was replenished immediately. iv) when nasal obstruction caused breathing difficulties, % ephedrine drops were used after clearing away nasal secretions with a cotton swab, to maintain the airway patency. v) the diet of children with severe pneumonia was affected due to high fever, vomiting, diarrhea and other factors. when children patients were unable to eat, it was appropriate to supplement water, electrolytes, vitamins, and give them high-calorie, high protein, digestible food, that was eaten in small amounts but frequently, to prevent satiety from interfering with respiratory function. vi) previous findings showed that, ambroxol and low-dose heparin coupled with aerosol inhalation significantly shortened the time of the disappearance of all the clinical signs and improved overall efficiency of the clinical treatment ( , ) . there was no bleeding and other adverse reactions involved in the clinical treatment process, which had advantages such as easy administration, safe use, inexpensiveness, a significant effect, and less adverse effects in the treatment of children with severe pneumonia, and was thus worthy of wider application. since the application of mechanical ventilation is prone to cause ventilator-related complications, to improve the successful rescue rate of children with severe pneumonia and shorten the course of treatment, the use of ncpap may be considered a priority. for severe pneumonia, ncpap can support cardiopulmonary function, and its early application can improve timely oxygenation, stabilize disease, prevent disease progression, reduce ventilator application and average hospitalization time in pediatric intensive care unit as well as avoid the adverse effects caused by intubation ( ) . however, two points are important when applying it to infants: i) grasp indications and standard of respiratory failure that the children comply with; ii) over ncpap application process, nasal and oral secretions should be immediately removed, raising the neck high, to strengthen expectoration in order to maintain airway patency. operating parameters of using the ncpap oxygen therapy machine in our department: i) oxygen concentration inhaled (fio ) or %; ii) the oxygen flow - l/min; and iii) the beginning pressure was maintained at - cm h o. after observing - h, the adjustment of pressure was determined by clinical symptoms, signs and blood gas analysis. ncpap is an effective treatment for severe pneumonia with respiratory and heart failure, and can quickly correct hypoxemia, reduce endotracheal intubation and mechanical ventilation demand ( ) . it has a positive effect and can reduce the stimulation of children, thus decreasing any occurrence of ventilator pneumonia. in addition, parents readily accepted this treatment ( ) . short-term intubation ventilator was utilized when there was: i) respiratory arrest or respiratory and cardiac arrest; ii) sputum congestion, dyspnea, serious cyanosis; and iii) blood paco > mmhg, in order to accelerate the discharge of paco and reduce respiratory acidosis. emergency treatment and treatment of heart failure. when children patients coughed, their body temperature increased to ≤ ˚c and was accompanied by dyspnea, dysphoria, pale face, cyanosis, drowsiness, fixed moist rales in lung, respiratory rate of ≥ beats/min, heart rate of ≥ - beats/min in quiet state, low and blunt heart sound, gallop rate, and a progressively enlarged liver, cm beyond the ribs or an increase of ≥ . cm in a short period of time. the above, as well as cold extremities and weak pulse, constituted clinical manifestations of a heart failure. in this situation, oxygen inhalation and tranquilizers were given immediately, . µg/(kg x min) and milrinone, a second generation of phosphodiesterase Ⅲ (pde-Ⅲ) inhibitor, which acts on the β receptor accessory pathway, was administered to maintain heart function. by selectively inhibiting pde-Ⅲ in myocardial cells, increasing intracellular cyclic adenosine monophosphate levels, promoting calcium influx, enhancing calcium concentration in myocardial cytolymph, milrinone strengthens myocardial contractility, increases cardiac output, and exerts direct relaxation on vascular smooth muscle, dilates blood vessels and reduces cardiac preload and afterload. milrinone demonstrates a better clinical efficacy in the treatment of children with pneumonia complicated by heart failure than catecholamines ( ) . emergency treatment and treatment of toxic encephalopathy and intestinal paralysis. when children show signs of exhaustion, dysphoria, coma, increased muscle tension, irregular breathing, and increased cerebrospinal fluid pressure, toxic encephalopathy should be considered. timely administration of sedatives, oxygen and mannitol are important in order to ease cerebral edema. decrease in intracranial pressure. in the present study, any changes including children' pupillary light reflex, headache, vomiting, consciousness, breathing, pulse, temperature, and fluctuation in bp were closely observed. the head was raised - ˚ to facilitate the intracranial venous return, leading to a corresponding reduction in intracranial pressure. precaution was taken when using dehydrating agent as well as to prevent it from leaking from blood vessels, and to prevent tissue necrosis. when administering furosemide, its effect and adverse drug reactions were observed. if intracranial pressure increased, lumbar puncture was avoided as much as possible, but if it had to be carried out then rescue preparation was performed. cerebrospinal fluid flow is not be in excess to avoid the formation of hernia. control of fever and convulsions. an increase in body temperature leads to an increased oxygen consumption in brain tissue, and aggravating cerebral hypoxia, which causes cerebral edema and nerve cell damage ( ) . immediate measures must be taken to control hyperpyrexia by combining the use of artificial hibernation to decrease the temperature, lower metabolism and protect the central nervous system. the drug of choice is the application of cold compressors of chlorpromazine to the head, wearing ice caps and decreasing the temperature with drugs, thereby reducing hyperpyrexia-induced damage to brain tissue. for children patients in the study, when intracranial pressure increased, the motor cortex wass stimulated, causing convulsions and exacerbating cerebral hypoxia and brain edema, thereby aggravating intracranial pressure. the ward was kept quiet and visitors were avoided. treatment and care were performed simultaneously, as much as possible, and operating and any negative stimuli were reduced to prevent convulsions. seizures required the focus of intensive nursing, a dental pad was placed between the upper and lower teeth to prevent tongue bite, and extra gear was added to prevent any fall damage during sleep. drugs, such as phenobarbital and diazepam were administered to control fear. restless children were guarded by specially-assigned persons to prevent scratches and fall damage. heads of children in a coma were leaned to one side, to facilitate the discharge of secretions. should be given. for any child having a seizure, it was considered improper for the fright-checking agent to forcibly press the child's body, in order not to cause fractures. treatment of abdominal distention. abdominal distention often occurs in children with pneumonia, leading to children feeling uncomfortable and unrest, which hinders normal breathing. a hot water bag was placed on the abdomen, to facilitate venting. anal venting was also used and children became quiet after venting. if abdominal distention did not improve, it suggested the presence of toxic intestinal paralysis, and a poor prognosis. anti-infective therapy. after a clear diagnosis of severe pneumonia, collecting blood for bacterial culture and sensitivity test was performed prior to the use of antibiotics when conditions permitted. a separate venous access for antibiotics was established as much as possible, to rationalize the use of antimicrobial drugs and avoid side effects. in principle, the application of antimicrobial drugs was carried out on the basis of evidence-based medicine, but a majority of them are classified as empirical treatment. as the therapeutic window of children with severe pneumonia was very small, the initial drugs for treatment covered an antibacterial spectrum as broad as possible, as well as all the pathogens. there were sufficient data displaying that the inappropriate choice of anti-infective drugs for initial therapy and untimely appropriate treatment (effective therapy of antigens) had adverse consequences on the prognosis. the main indicators of efficacy were a decrease in body temperature, improvement in poisoning symptoms and ability to drink water or conduct breast-feeding or food intake. in general, - days after the body temperature became stable, the drug dosage was reduced and gradually discontinued. intravenous injection of immune globulin is considered a safe and effective method for the treatment of children with severe pneumonia. it can rapidly improve immunoglobulin g (igg) levels in the patient's blood; enhance the body's resistance to infection and immune function. by passively accepting lgg, the body acquires resistance to a variety of microbial infections. high-dose intravenous igg infusion can increase the igg concentration -to -fold in circulating blood compared to a normal person. therefore it has the ability to prevent infections. using igg infusion concurrently with antibiotics can be used to treat bacterial infections and has a broad anti-bacterial and viral spectrum, as well as a dual function of anti-bacterial antigens and viral antigens. in summary, positive and effective nursing can promote the rehabilitation of children patients, reduce the incidence of complications and children's mortality, thus play an important role in the rehabilitation of children with severe pneumonia. psychological counseling may also be strengthened. children feel a sense of inadaptation with regard to unfamiliar environment by instinct. they cried and even refused infusion in the face of examination and treatment by strangers. therefore, nurses must be careful and gentle to children patients. for older children, they were able to explain to them the importance of the infusion and blood tests for the treatment of the disease, and increase their sense of trust in the medical staff. health education is also essential, nurses should communicate more with parents and acquaint them with relevant knowledge and inform them regarding the prevention and treatment of diseases, such as that children usually need to do exercise, enhance nutrition, bask more in sunshine and engage in outdoor activities, ensure adequate sleep, pay attention to personal health, and get vaccinated for the prevention of pneumonia and influenza if necessary. global burden of childhood pneumonia and diarrhoea epidemiology and etiology of childhood pneumonia in : estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for countries epidemiology and etiology of childhood pneumonia incidence and risk factors of childhood pneumonia-like episodes in biliran island, philippines -a community-based study global estimate of the incidence of clinical pneumonia among children under five years of age severe pneumonia caused by nocardia farcinica and complicated by staphylococcus haemoliticus superinfection trimethoprim-sulfamethoxazole-associated severe hypoglycaemia: a sulfonylurea-like effect in-hospital mortality due to infectious disease in an internal medicine department. epidemiology and risk factors people's medical publishing house respiratory rate and signs in roentgenographically confirmed pneumonia among children in china viral and mycoplasma pneumoniae community-acquired pneumonia and novel clinical outcome evaluation in ambulatory adult patients in china effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial etiology of severe community-acquired pneumonia during the hajj-part of the mers-cov surveillance program management of severe community-acquired pneumonia: a survey on the attitudes of physicians in iberia and south america severe pneumonia due to cytomegalovirus in chronic obstructive pulmonary disease poor adherence to the world health organization guidelines of treatment of severe pneumonia in children at khartoum, sudan childhood anemia at high altitude: risk factors for poor outcomes in severe pneumonia zinc as an adjunct to the treatment of severe pneumonia in ecuadorian children: a randomized controlled trial severe pneumonia in intensive care: cause, diagnosis, treatment and management: a review of the literature levels of serum brain natriuretic peptide in children with congestive heart failure or with severe pneumonia two severe cases of h n pneumonia patients with immunoneuroendocrine axis dysfunction and vitamin d insufficiency severe forms of acute pneumonia with a protracted course accompanied by liver and intestinal dysfunction and dysbacteriosis in young children association of bacterial pneumonia and respiratory failure in children with community-acquired influenza infection chronic obstructive pulmonary disease severity is associated with severe pneumonia childhood very severe pneumonia and meningitis-related hospitalization and death in yemen, before and after introduction of h. influenzae type b (hib) vaccine severe pneumonia mortality in elderly patients is associated with downregulation of toll-like receptors and on monocytes hospital-acquired pneumonia is an independent predictor of poor global outcome in severe traumatic brain injury up to years after discharge the management of severe community acquired pneumonia in the intensive care unit effect of semirecumbent sleep position on severity of obstructive sleep apnea in patients with heart failure oxygen-driving and atomized mucosolvan inhalation combined with holistic nursing in the treatment of children severe bronchial pneumonia atomization inhalation of ambroxol as an auxiliary therapy for severe pneumonia in neonates high incidence of pulmonary tuberculosis in children admitted with severe pneumonia in uganda moderate-dose glucocorticoids as salvage therapy for severe pneumonia in renal transplant recipients: a single-center feasibility study noninvasive ventilation in children: a review milrinone combined with dopamine for child pneumonia complicated with heart failure experimental study of relation of fever to cerebral edema key: cord- -c d nk x authors: mikasa, keiichi; aoki, nobuki; aoki, yosuke; abe, shuichi; iwata, satoshi; ouchi, kazunobu; kasahara, kei; kadota, junichi; kishida, naoki; kobayashi, osamu; sakata, hiroshi; seki, masahumi; tsukada, hiroki; tokue, yutaka; nakamura-uchiyama, fukumi; higa, futoshi; maeda, koichi; yanagihara, katsunori; yoshida, koichiro title: jaid/jsc guidelines for the treatment of respiratory infectious diseases: the japanese association for infectious diseases/japanese society of chemotherapy – the jaid/jsc guide to clinical management of infectious disease/guideline-preparing committee respiratory infectious disease wg date: - - journal: journal of infection and chemotherapy doi: . /j.jiac. . . sha: doc_id: cord_uid: c d nk x nan the japanese association for infectious diseases (jaid) and japanese society of chemotherapy (jsc) announced the "guide for the use of antimicrobial drugs" in and the "guidelines for the use of antimicrobial drugs" in . subsequently, the "the jaid/ jsc guide to clinical management of infectious diseases " was published. with its revision, guidelines were newly prepared. concerning respiratory infectious diseases, in japan, the japanese respiratory society published guidelines for the management of community-acquired pneumonia, hospital-acquired pneumonia, respiratory tract infection, and -/nursing and healthcare-associated pneumonia. furthermore, the japanese society of pediatric pulmonology and japanese society for pediatric infectious diseases announced the "guidelines for the management of respiratory infectious diseases in children in japan". internationally, many guidelines, including those established by the american thoracic society and infectious diseases society of america, have been published from various countries. thereafter, clinical research on respiratory infectious diseases has advanced, leading to the accumulation of many outcomes regarding epidemiology, clinical diagnosis, and treatment. however, the types of microorganisms that cause respiratory infectious diseases have increased with the number of resistant bacteria. in addition, conditions have also varied with causative microorganisms through the recent compromised host's severe status. the place of treatment varies: from the outpatient clinic to the icu. physicians responsible for treatment also vary: practitioners, hospital doctors, pulmonologists, emergency physicians, board certified member of jaid, japanese antimicrobial chemotherapy physician. there are a large number of options of antimicrobial drugs that are available, including new drugs; therapeutic strategies are confused. on the other hand, recently, the entity of pk-pd has been commonly recognized, and the importance of scientifically using antimicrobial drugs has been emphasized. in addition, the japanese society of chemotherapy established a system for antimicrobial chemotherapy-certified physicians, and promoted the widespread, adequate use of antimicrobial drugs. based on these, the two societies prepared the jaid/jsc guidelines for the treatment of respiratory infectious diseases. if specific treatment guidelines can be presented, this may contribute to an improvement in the treatment responses of respiratory infectious diseases, a reduction in health expenditure, and the prevention of resistant bacteria. the guidelines were prepared based on the ebm so that they reflected the management of respiratory infectious diseases in japan and covered all such diseases in adults and children. to prepare the guidelines, a committee was established in , and a draft was published on homepage based on an approval from the boards of directors at the two societies through a review-based consensus. opinions were collected from the two societies' members. in japan, there have been no such guidelines covering respiratory infectious diseases. in the future, with further advances in research, the contents of the guidelines must be revised. however, we successfully provided treatment guidelines that are the most advanced at present. the guidelines were prepared for all clinicians to understand the treatment of respiratory infectious diseases and manage them with antimicrobial drugs adequately. they do not limit treatment by individual physicians or affect their rights to select it. the guidelines may be commonly applied for respiratory infectious disease management/research/education in japan, improving the quality of respiratory infectious disease management, preventing an increase in the number of resistant bacteria, and contributing to national health. we hope that the guidelines will be utilized by a large number of clinicians in respiratory infectious disease management. lastly, we thank the committee members and secretariat staff for their cooperation. . descriptions on the recommendation grade and evidence level . definition of firstand second-choice drugs . precautions -in this article, with respect to the administration method (especially doses) of antimicrobial drugs, they are recommended based on sufficient doses. considering the products adopted at each medical institution, antibiograms, severity, underlying disease, age, and presence or absence of organ disorder, the dose should be increased or decreased if necessary. -the spectra of third-generation cephems for intravenous injection, ctx and ctrx, are similar, but ctx, which is excreted in the kidney, should be primarily used when liver dysfunction is present, and ctrx, which is excreted in bile, should be primarily used when renal dysfunction is present. -as quinolones exhibit antitubercular actions, patients with pulmonary tuberculosis should be excluded for use. . a list of antimicrobial drug abbreviations and doses for neonates are presented at the end of this volume. . . community-acquired pneumonia . . . empiric therapy ---executive summary---patient with bacterial pneumonia should be treated primarily with high-dose penicillin (aii). in elderly patients and those with underlying lung diseases, the use of respiratory quinolones may be considered positively (bii). in case of atypical pneumonia, a macrolide or tetracycline is the first choice. respiratory quinolones should be reserved as alternative drugs (bii), but may be used depending on local circumstances about drug resistance (ciii). in case of whether pneumonia or atypical pneumonia dose not diagnose, comobination with high-dose penicillin and a macrolide or tetracycline should be attempted first (bii). respiratory quinolones should be reserved as alternative drugs (bii). in severer cases requiring treatment in the icu, a macrolide or new quinolone should be used aggressively in combination with a broad spectrum b-lactam such as high-dose penicillin from the beginning of treatment (aii). ---explanation---community-acquired pneumonia refers to hospital-acquired pneumonia that develops h or more after admission or pneumonia that develops in healthy adults on social activities other than medical practice-/nursing-associated pneumonia [ e ] . as signs and symptoms, cough, sputum, thoracic pain, and dyspnea appear, and this disease acutely occurs with systemic symptoms such as fever and general malaise [ e ] . however, these symptoms are not marked in some elderly patients. furthermore, atypical pneumonia including mycoplasma is characterized by a small amount of sputum, and can be differentiated (tables and ) [ , ] . concerning examination, gram staining and culture of sputum are used to identify causative microorganisms and select subsequent treatment strategies [ , ] (aii). kits for rapid diagnosis with urine or nasal swab are also used for auxiliary diagnosis [ , ] (aii). a blood test shows inflammatory findings such as leukocytosis and an increase in the crp level, facilitating a certain assessment of the disease [ , ] . on thoracic imaging, consolidation or a ground glasslike shadow is observed [ e ] (ii). when patients are in an immunosuppressive state related to an underlying disease, a causative microorganism test should be performed, considering the possibility of opportunistic infection [ e , , ] (a). in elderly patients, aspiration pneumonia is frequently observed, and the management of this disorder is necessary (refer to the section " . aspiration pneumonia" on page. ). in the presence of renal dysfunction, the type and dose of an antimicrobial drug must be carefully selected [ , ] (aii). bacterial pneumonia should be differentiated from atypical pneumonia in accordance with "the jrs guidelines for the management of community-acquired pneumonia in adults in " (edited by the committee to prepare guidelines regarding respiratory infectious diseases, japanese respiratory society) (tables and ) [ ] . although legionella pneumonia is routinely classified as atypical pneumonia, various types of atypical pneumonia do not include legionella pneumonia in this differentiation method. a. bacterial pneumonia ( ) outpatient treatment bacterial pneumonia is primarily caused by sterptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis [ e , , ] (ii). basically, these types of pneumonia should be treated by orally administering high-dose penicillin [ e ] (aii). in japan, macrolide-resistant s. pneumoniae is detected in most cases; therefore, macrolides are not recommended as the first choice, differing form those in europe and the united states [ , , , , ] (aii). for outpatient treatment, b-lactamase inhibitorcontaining penicillin is commonly used. therapy with cva/ampc or sbtpc ( tablets/ e times a day) is recommended with respect to the efficacy and suppression of resistant bacteria [ , , ] (aii). however, such high-dose prescriptions are not always accepted by health insurance system in japan, and the following prescriptions (examples) should also be considered. in elderly patients or those with underlying lung diseases such as copd/old pulmonary tuberculosis, the use of respiratory quinolones should be considered positively from the perspective of the effects on penicillin-resistant pneumococcus and tissue transfer [ , , ] (bii). however, many new quinolones also have antimicrobial activities against mycobacterium tuberculosis; therefore, the presence or absence of active tuberculosis must be strictly checked before administration [ ] (aii). ( ) hospital treatment for hospital treatment, injection is primarily used. however, basic concepts for drug selection are similar to those at the outpatient clinic. considering s. pneumoniae, h. influenzae, and m. catarrhalis, high-dose penicillin or cephems, which are effective for these microorganisms, should be selected [ e ] (aii). if more potent treatment is required, respiratory quinolone injection should be used [ , ] (bii). ---drugs to be recommended---( ) outpatient treatment a first choices -cva/ampc, oral ( / mg), tablets/ e times a day -sbtpc, oral ( mg), tablets/ e times a day * concerning cva/ampc and sbtpc, up to mg of ampc or up to mg of abpc are approved dosage in japan. combination therapy with ampc (oral preparation) should also be considered. [example] cva/ampc, oral ( / mg), tablet/ times a day þ ampc, oral ( mg), tablet/ times a day <> second choices -lvfx, oral, mg/once a day -grnx, oral, mg/once a day -stfx, oral, mg/ e times a day -mflx, oral, mg/once a day -tflx, oral, mg/twice a day ( ) hospital treatment a first choices -sbt/abpc, intravenous drip, g/ e times a day -ctx, intravenous drip, e g/ e times a day -ctrx, intravenous drip, g/once a day or g/twice a day <> second choice -lvfx, intravenous drip, mg/once a day b. atypical pneumonia ( ) outpatient treatment atypical pneumonia is primarily caused by mycoplasma pneumoniae, chlamydophila pneumoniae, and legionella pneumophila [ e , , , , ] (ii). the oral administration of a macrolide or tetracycline is the first choice [ , , , ] (aii). to suppress resistant bacteria, respiratory quinolones should be reserved as alternative drugs [ , , , , ] (bii). however, recently, the appearance of macrolideresistant m. pneumoniae in adults has raised an issue in japan. respiratory quinolones must be used as the first choice depending on local circumstances about drug resistance [ ] (ciii). ( ) hospital treatment for hospital treatment, injection is primarily used. however, basic concepts for drug selection are similar to those at the outpatient clinic. if more potent treatment is required, new quinolone injection should be used [ e , , , ] (bii). ---drugs to be recommended---( ) outpatient treatment a first choices -azm sustained-release preparation, oral, g/single dose -cam, oral, mg/twice a day -mino, oral, mg twice a day <> second choices -lvfx, oral, mg/once a day -grnx, oral, mg/once a day -stfx, oral, mg/ e times a day -mflx, oral, mg/once a day table items used to differentiate between bacterial and atypical pneumonia [ ] . . under years of age . no or minor underlying diseases . stubborn cough . poor chest auscultatory findings . no sputum, or no identified aetiological agent by rapid diagnosis . a peripheral white blood cell count below , /ml table criteria for differentiation [ ] . in cases using the items in -tflx, oral, mg/twice a day ( ) hospital treatment -azm, intravenous drip, mg/once a day -mino, intravenous drip, mg/twice a day -lvfx, intravenous drip, mg/once a day -cpfx, intravenous drip, mg/twice a day. -pzfx, intravenous drip, to mg/twice a day c. cases in which whether the disease is bacterial pneumonia or atypical pneumonia is unclear ( ) outpatient treatment in this case, combination therapy with high-dose penicillin and a macrolide or tetracycline should be selected as the first choice to cover both bacterial and atypical pneumonia [ e , , , , , ] (bii). as respiratory quinolones cover both bacterial and atypical pneumonia, they are convenient, but should be reserved as alternative drugs from the perspective of suppression of resistant bacteria [ e , , , , ] (bii). however, in elderly patients or those with underlying lung diseases such as copd/old pulmonary tuberculosis, the use of respiratory quinolones should be considered positively from the perspective of the effects on penicillin-resistant pneumococcus and tissue transfer [ , , ] (bii). recently, the appearance of macrolideresistant m. pneumoniae in adults has raised an issue. respiratory quinolones may be used as the first choice depending on local circumstances about drug resistance [ ] (ciii). ( ) hospital treatment for hospital treatment, injection is primarily used. however, basic concepts for drug selection are similar to those at the outpatient clinic. if more potent treatment is required, new quinolone injection should be used [ e , , ] (bii). ( ) severer cases requiring treatment in the icu in severer cases requiring treatment in the icu, s. pneumoniae should be initially considered, and a macrolide or new quinolone should be used aggressively in combination with a broad spectrum b-lactam such as high-dose penicillin from the beginning of treatment primarily to cover latent atypical bacteria (in particular, when l. pneumophila is not covered, the condition may become fatal) [ e , , , ] (aii). in particular, combination therapy with a macrolide is recommended from immunological aspects to suppress excessive inflammation related to cytokines [ ] (cii). as the possibility that causative microorganisms may be enteric bacteria including esbl-producing bacteria cannot be ruled out, carbapenem injection should be used as a first-choice drug in patients with a background factor for which esbl-producing bacteria are frequently detected [ , ] (bii). the sensitivity of a urinary antigen kit to s. pneumoniae and legionella spp. is approximately %. therefore, even when the patient is negative for these bacteria in the initial phase, the possibility of pneumonia related to these bacteria should not be ruled out [ e , , ] (ii). ---drugs to be recommended---( ) outpatient treatment a first choices -cva/ampc, oral ( / mg), tablets/ e times a day -sbtpc, oral ( mg), tablets/ e times a day * concerning cva/ampc and sbtpc, up to mg of ampc or up to mg of abpc are approved dosage in japan. combination therapy with ampc (oral preparation) should also be considered. [example] cva/ampc, oral ( / mg), tablet/ times a day þ ampc, oral ( mg), tablet/ times a day þ one of the followings: -azm sustained-release preparation, oral, g/single dose -cam, oral, mg/twice a day -mino, oral, mg/twice a day <> second choices -lvfx, oral, mg/once a day -grnx, oral, mg/once a day -stfx, oral, mg/ e times a day -mflx, oral, mg/once a day -tflx, oral, mg/twice a day ( ) hospital treatment a first choices -sbt/abpc, intravenous drip, g/ e times a day -ctx, intravenous drip, e g/ e times a day -ctrx, intravenous drip, g/once a day or g/twice a day þ one of the followings: -azm, intravenous drip, mg/once a day -mino, intravenous drip, mg/twice a day -cam, oral, mg/twice a day <> second choices -lvfx, intravenous drip, mg/once a day -pzfx, intravenous drip, to mg/twice a day ( ) severer cases requiring treatment in the icu -taz/pipc, intravenous drip, . g/ e times a day -ipm/cs, intravenous drip, . e g/ e times a day -mepm, intravenous drip, g/ e times a day -bipm, intravenous drip, . e . g/ e times a day -drpm, intravenous drip, . e g/ times a day þ one of the followings: -azm, intravenous drip, mg/once a day -lvfx, intravenous drip, mg/once a day -cpfx, intravenous drip, mg/twice a day -pzfx, intravenous drip, to mg/twice a day -mino, intravenous drip, mg/twice a day ---executive summary----when causative microorganisms are identified based on the results of microbial examination of good-quality sputum, blood culture, and urinary antigen (s. pneumoniae, l. pneumophila) tests and drug susceptibility testing of the causative agents, definitive therapy should be performed if possible [ , ] (biii). -the place of treatment and drugs should be selected in accordance with the severity of the disease [ , ] (aii). -antimicrobial drugs should be selected in reference to the susceptibility of isolated bacteria to antimicrobial drugs or a drugsusceptibility tendency in the area [ , , , ] when these data are available (aii). -the administration period of an antimicrobial drug is determined in accordance with the improvement of symptoms and laboratory data, with a target of e days [ , ] (biii). -when the patient is infected with l. pneumophila or c. pneumoniae, the optimal administration period is about days [ ] (biv). a. streptococcus pneumoniae -the clinical and laboratory standards institute (clsi) has established higher criteria for breakpoints for penicillin susceptibility on the administration of parenteral antimicrobial drugs for s. pneumoniae infections other than meningitis [ ] , based on the following findings: patients with severe pneumonia due to s. pneumoniae with a low pcg susceptibility (mic: . e mg/ml) showed no difference in responses to pcg and outcome [ , ] (ii). for the treatment of pneumococcal pneumonia, the dose of penicillin should be increased [ , ] (a). -in japan, most s. pneumoniae isolates are macrolide resistant [ , ] . -respiratory quinolones have potent anti-pneumococcal activities (iii). the clinical effects of such quinolones are similar to those of high-dose ampc [ ] (ii). -in japan, quinolone-resistant s. pneumoniae is detected in e % of the isolates [ ] . as quinolone resistance may be readily induced by point mutations of dna gyrase or topoisomerase genes [ ] , quinolones must be used adequately (aiii). b. haemophilus influenzae -the abpc-resistant mechanism of h. influenzae involves blactamase production and/or pbp mutation. previously, blactamase production was primarily involved, but, recently, pbp mutation-mediated b-lactamase-negative abpc-resistant (blnar) strains have been increasingly detected. abpcresistant strains with both b-lactamase production and pbp mutation are classified as b-lactamase-positive cva/abpcresistant (blpacr) strains. -according to a national survey in japan, ( . %) and ( . %) of h. influenzae strains were blnar and b-lactamase-producing strains, respectively [ ] . -blnar strains are also resistant to firstand secondgeneration cephems. -pipc exhibits an antimicrobial activity against blnar strains. however, it is ineffective for blpacr strains. c. klebsiella spp., escherichia coli, proteus spp. -the proportion of extended spectrum b-lactamase (esbl)producing bacteria has slightly increased among isolates from respiratory samples. -according to a national survey in japan, esbl-producing bacteria account for . e . % of respiratory sample-derived klebsiella spp. strains [ , ] . -most esbl-producing strains are simultaneously resistant to quinolones [ ] . antimicrobials should be selected according to the drug susceptibility of isolated bacteria. -in japan, carbapenemase-producing strains are extremely rare. d. mycoplasma pneumoniae -in the field of pediatrics, the detection rate of macrolideresistant m. pneumoniae has markedly increased. in adults, that of macrolide-resistant m. pneumoniae also increase [ , ] . -tetracyclines exhibit potent clinical effects on macrolideresistant m. pneumoniae [ ] . -respiratory quinolones have good activities against m. pneumoniae [ , ] . e. legionella spp. -it should be noted that pneumonia related to legionella spp. other than l. pneumophila sg cannot be diagnosed using legionella urinary antigen testing. -as neither b-lactams nor aminoglycosides have antimicrobial activities against legionella spp., which proliferates within host cells, they are clinically ineffective. -quinolones, macrolides, and tetracyclines have been confirmed to exhibit clinical effects on legionella spp. previously, em was the first choice for this infection, but many recent studies have showed the clinical efficacies of lvfx and azm [ , ] . -rfp is effective when combined with em. the combination of em and rfp is useful. a study suggested the effects of combination therapy with lvfx and a macrolide [ ] (ciii). -although there are no marked differences in antimicrobial drug susceptibility among legionella spp., clinical reviews to verify this are limited [ ] . f. chlamydophila pneumoniae -only a few studies have supported the clinical effects of antimicrobial drugs against c. pneumoniae pulmonary infections. -tetracyclines, macrolides, and quinolones may be effective. these drugs are recommended primarily based on the results of basic studies [ , ] . g. staphylococcus aureus -with respect to staphylococcus aureus in japan, there has been an increase in the number of methicillin-resistant strains even in patients with community-acquired pneumonia. in particular, recently, municipal-onset-type mrsa (ca-mrsa) with panton-valentine-leucocidine (pvl) has been detected in japan, raising an issue [ ] . -in cases of mssa infection (bacteremia), the clinical effects of cez are superior to those of vcm [ ] . -as the susceptibility of mrsa to oral antimicrobial drugs differs among isolates, drugs should be selected according to its drug susceptibility results. h. streptococcus spp. -among various types of streptococcus, the streptococcus anginosus group is frequently detected, and characterized by strong abscess-forming features [ ] . streptococcus pyogenes and streptococcus agalactiae may also cause pneumonia. the former may lead to serious pulmonary infection [ ] (v). -there is no penicillin resistance, but macrolide resistance is observed at a low frequency [ ] . -the anti-streptococcus activities of quinolones vary. among quinolones, grnx, mflx, and stfx have relatively potent antimicrobial activities [ , ] . i. moraxella catarrhalis -the number of b-lactamaseproducing strains has increased since the 's. currently, most strains produce b-lactamase [ , ] . b-lactamase produced by m. catarrhalis decomposes penicillin. -in japan, macrolide-or quinolone-resistance have not been reported [ ] . j. anaerobes -most anaerobes that cause pneumonia exist in the oral cavity. peptostreptococcus spp., prevotella spp., and fusobacterium spp. are involved. mixed infection with microaerophilic streptococci is often observed. -in many cases, infection with anaerobes may be associated with aspiration. -most oral anaerobes (prevotella spp., fusobacterium spp., and porphyromonas spp.) are susceptible to combination drugs consisting of penicillin and a b-lactamase inhibitor, cldm and mnz [ ] . k. pseudomonas aeruginosa -in patients with chronic respiratory tract infection, pseudomonas aeruginosa colonizes in the airway, and may cause community-acquired pneumonia [ ] . -as the susceptibility of p. aeruginosa to antimicrobial drugs differs among clinical isolates, drugs should be selected according to its drug susceptibility results. ---drugs to be recommended----the drug susceptibility of each clinical isolate should be classified in accordance with the clsi criteria [ ] . -establishment of prescriptions recommended in this article * antimicrobials have been approved for specific diseases and specific causative agents by japanese ministry of health and welfare. the approvals are based on the results of clinical studies with good clinical practice. as a general rule, the recommendations in this section refer to this (aii). however, recent trends in drug susceptibility are also considered. * the recent drug susceptibility results of the nationwide studies in japan were referred [ , ] . * the recommendations without the approvals by japanese ministry are graded by evidence levels. [ -when the susceptibility of identified causative microorganisms is clarified, or after the treatment responsiveness is evaluated, whether or not de-escalation is possible should be reviewed [ e ] (aii). ---explanation---definition: hospital-acquired pneumonia is defined as "pneumonia that newly develops h or more after admission". in many cases, treatment is difficult due to unfavorable patient conditions such as the presence of an underlying disease, immune capacity, and general condition [ e ]. laboratory findings: patients meeting of items, fever, an abnormal leukocyte count, and purulent secretes, in addition to the appearance of an abnormal shadow of the chest should be diagnosed with hospital-acquired pneumonia [ e ]. ) ventilator-associated pneumonia (vap): vap refers to pneumonia that newly develops h or more after endotracheal intubation/ventilator initiation. its onset within e days after endotracheal intubation is classified as early-type, and its subsequent onset as late-type [ , , , ] . ) hospital-acquired pneumonia other than vap: several types of hospital-acquired pneumonia other than vap include ( ) immunodeficiency (for example, neutropenia during anticancer therapy, cell-mediated immunodeficiency related to the administration of steroids or immunosuppressive drugs) and ( ) aspiration pneumonia including latent aspiration (refer to the section " . aspiration pneumonia" on page ). appropriate management and selection of antimicrobial drugs in accordance with individual conditions are necessary [ ] . with respect to microorganisms that are expected, refer to the section " . hospital-acquired pneumonia--- . . empiric therapy: cases in which gram staining is available" (p. ). ---drugs to be recommended--a. cases in which there is no risk of resistant bacteria antimicrobial drugs should be selected, targeting streptococcus pneumoniae, h. influenzae, and klebsiella spp. as causative microorganisms [ e ] (biii). although it is difficult to estimate/identify causative microorganisms using sputum samples, bacteria that are not isolated/cultured from goodquality sputum may not be causative microorganisms. if resistant bacteria such as mrsa and p. aeruginosa are not detected on sputum culture and there is no deterioration of clinical symptoms, an initial drug should be continued [ ] (biii). in patients in whom aspiration episodes are clear, those in whom oral hygiene is not maintained, or those with consciousness disorder, drugs with anti-anaerobe activities should be selected, considering the involvement of anaerobes [ ] (biii). if an adequate antimicrobial drug is administered, the treatment period may be e days, excluding mrsa and p. aeruginosa [ , ] (bii). a first choices -sbt/abpc, intravenous drip, g/ e times a day -ctx, intravenous drip, e g/ times a day -ctrx, intravenous drip, g/once a day or g/twice a day * if the involvement of anaerobes is suspected, sbt/abpc should be selected. <> second choice -lvfx, intravenous drip, mg/once a day (as its antimicrobial activity against anaerobes is weak, monotherapy with this drug should be avoided in patients with aspiration pneumonia.). b. cases in which there is a risk of multi-drug-resistant bacteria (table ) [ ] to cover multi-drug-resistant bacteria including p. aeruginosa, broad-spectrum antimicrobial drugs with anti-p. aeruginosa activities should be selected [ e ] (aiii). considering the frequency of esbl in each institution, carbapenems should be considered even when enteric bacteria, including klebsiella spp. and escherichia coli, are suspected (biv). if p. aeruginosa is not isolated on good-quality sputum culture, a treatment option should be de-escalated to drugs for cases in which there is no risk of resistant bacteria [ e ] (aii). if aspiration is suspected, or if the involvement of grampositive bacteria is suggested, combination therapy with cldm must be considered (biv). if there is a risk of mrsa carrier (table ) , combination therapy with anti-mrsa drugs should also be considered. the mean administration period of antimicrobial drugs with respect to causative bacteria in patients with an improvement was approximately days. however, that for resistant bacteria such as p. aeruginosa and mrsa was approximately days [ ] (bii). if appropriate antimicrobial drugs can be administered after clarifying causative bacteria, a treatment period of approximately days is recommended [ , , ] (bii). a first choices -taz/pipc, intravenous drip, . g/ e times a day -ipm/cs, intravenous drip, . g/ times a day or g/ times a day -mepm, intravenous drip, g/ times a day -drpm, intravenous drip, . e g/ times a day -bipm, intravenous drip, . e . g/ e times a day <> second choices -cfpm, intravenous drip, e g/ e times a day -cpfx, intravenous drip, mg/twice a day -pzfx, intravenous drip, to mg/twice a day if the involvement of anaerobes is suspected, one of the following options should be combined with one of the above regimens: -cldm, intravenous drip, mg/ e times a day -sbt/abpc, intravenous drip, g/ e times a day c. severe cases one of the following options must be combined with one of the regimens for cases in which there is a risk of multi-drugresistant bacteria. when comparing the results between patients undergoing appropriate and inappropriate treatments, the prognosis of the latter was significantly poorer [ , ] (bii). however, a study reported that the prognosis in a group with compliance with recommended drug selection was significantly poorer than in a non-compliance group in patients in whom infection with drug-resistant bacteria in the icu was suspected even among those in whom the etiology was bacteriologically investigated [ ] (bii). therefore, it must be considered that, even when resistant bacteria are etiologically involved, the administration of an appropriate antimicrobial drug that covers them does not always improve the prognosis. -taz/pipc, intravenous drip, . g/ e times a day -ipm/cs, intravenous drip, . g/ times a day or g/ times a day -mepm, intravenous drip, g/ times a day -drpm, intravenous drip, . e g/ times a day -bipm, intravenous drip, . e . g/ e times a day one of the following options should be combined with one of the above regimens: should be estimated based on the results of the clinical microbiological culture (cmc: gram staining and culture) of a lower airway sample immediately before the start of treatment, and not based on bacteria isolated on active surveillance culture (asc), which was conducted as a strategy to prevent/ control infection prior to onset [ ] . -microorganisms that cause pneumonia or (colonization of) the lower airway should be estimated based on the presence or absence of neutrophils or phagocytosis (excluding those patients with neutropenia or functional impairment of neutrophil) [ ] (bii). ---explanation---[gram staining] diagnostic accuracy of hospital-acquired pneumonia is improved by confirming neutrophils and bacterial cells using gram staining of airway samples. this observation has also been confirmed through an increase in the likelihood ratio of hospital-acquired pneumonia in patients with a clinical pulmonary infection score (cpis) of points or higher [ ] . as bacteria isolated from the lower airways of inpatients are common colonizers in many cases, gram staining is also useful for discerning colonization from infection by evaluating the presence or absence of neutrophil and phagocytosis. therefore, it is desirable to combine bacterial culture with gram staining [ , e ] . antimicrobial-drug selection based on gram staining findings leads to appropriate empiric therapy in two-thirds of patients with hospital-acquired pneumonia, and it can be continued as definitive therapy in many cases [ ] . if there are no bacterial cells on gram staining of lower airway sample in whom an antimicrobial regimen was not changed within the past h, it is unlikely that the focus of infection/inflammation is within the lungs (lower airway) [ ] . in this case, the possibility of pneumonia mimic, such as pleural effusion, atelectasis, and pulmonary edema, is suggested if the lung field opacity still remains in chest x-ray. if there is no other infectious focus, the discontinuation of an antimicrobial drug may be warranted [ , , ] . a study has reported that the culture results of asc performed as a strategy of routine infection control measure prior to the development of nosocomial pneumonia accurately predicted the causative pathogen in only % of cases [ ] . therefore, it is necessary to submit airway samples for clinical microbiological culture (cmc) immediately before the start of presumptive treatment. [causative microorganisms and their origin] microorganisms that cause hospital-acquired pneumonia are derived from the oropharynx, airway (including the nasal cavity and nasal sinus), digestive tract, and environment. gastrointestinal tract-derived causative microorganisms are enteric bacteria (primarily, klebsiella spp., e. coli and others such as proteus spp., enterobacter spp., serratia spp., morganella spp., and citrobacter spp.). those derived from the upper airway include s. pneumoniae, h. influenzae, moraxella catarrhalis, s. aureus (namely methicillin sensitive strain), and oral anaerobes. those derived from the environment include methicillin-sensitive s. aureus, pseudomonas spp., acinetobacter spp., and stenotrophomonas spp. [ , , , ] . as the above bacteria derived from the airway and gastrointestinal tract basically exert strong virulence to the airway, they can be considered a core pathogen group of hospital-acquired pneumonia. their potential for developing airway inflammatory response is generally believed stronger than those caused by environmental pathogen [ , ] . table risk factors for multi-drug-resistant bacteria. . previous use of antimicrobial drugs within days . interval of days or more from admission . admission from an area/hospital in which resistant bacteria are frequent . immunosuppressive state or treatment table risk factors for carrying mrsa [ ] . conditions under which anti-mrsa drug therapy should be considered (including gram stain) mrsa---" (p. ). ( ) diplococcus consisting of a pair of two cocci (gpdc: grampositive diplococci) s. pneumoniae should initially be suspected. enterococcus is also a gpdc in microscopic appearance, but is basically considered a non-pulmonary pathogen [ ] . <> cases in which there have been no previous treatment with antimicrobial drugs or risks of penicillin-resistant pneumococcus -pcg, intravenous drip, , , to , , units/ e times a day -abpc, intravenous drip, g/ e times a day <> cases in which previous treatment with antimicrobial drugs or a risk of prsp is present -ctrx, intravenous drip, g/twice a day or g/once a day -ctx, intravenous drip, e g/ e times a day -lvfx, intravenous drip, mg/once a day -vcm, intravenous drip, g/twice a day (tdm should be conducted so that a trough is e mg/ml [ ] .) ( ) gram-positive coccus in either short or long chain (gpc in chain) aor b-hemolytic streptococci is indicated. -pcg, intravenous drip, , , to , , units/ e times a day -abpc, intravenous drip, g/ e times a day ( ) gram-positive bacillus with a rod-like morphology (gpr: gram-positive rod) corynebacterium spp. may be indicated. -vcm, intravenous drip, g/twice a day (tdm should be conducted so that a trough is e mg/ml [ ] .) c. gram-negative bacteria ---executive summary----when gram-negative bacteria are observed, h. influenzae, m. catarrhalis, enterobacteriaceae, p. aeruginosa, acinetobacter spp., and stenotrophomonas spp. may be indicated [ e , , ] (bii). -it is difficult to estimate the type of bacteria based on the morphology on gram staining in comparison with grampositive bacteria. -gram-negative bacteria frequently detected as causative microorganisms include enteric bacteria and p. aeruginosa. -it is encouraged important to recognize the basic antimicrobial drug susceptibility pattern of each type (group) of bacteria to make sure that the empiric antimicrobial therapy is appropriate (table ). ---drugs to be recommended--- ( ) cases of early-onset hospital-acquired pneumonia in which there have been no previous administration of antimicrobial drugs or risk of resistant bacteria aero-respiratory pathogen, such as h. influenzae and m. catarrhalis, and enteric bacteria, such as klebsiella spp., are indicated. -sbt/abpc, intravenous drip, g/ e times a day -ctrx, intravenous drip, g/twice a day or g/once a day -ctx, intravenous drip, e g/ e times a day -lvfx, intravenous drip, mg/once a day ( ) cases of late-onset hospital-acquired pneumonia or ventilator-associated pneumonia in which the risk of resistant bacteria is high an antimicrobial drug with anti-pseudomonal activity that targets non-glucose-fermentative gram-negative rod should be administered [ , , ] -to treat polymicrobial infection, the administration of an antimicrobial drug with an activity against obligate anaerobe is not always necessary [ , ] . -in non-severe cases, the administration of antimicrobial agents with anti-mrsa activity may be withheld in the initial phase even when staphylococcus-like bacterial cells are observed [ ] . ---explanation---when several types of bacteria differing in gram staining and morphology are observed, the condition is commonly interpreted as aspiration pneumonia, suggesting the involvement of anaerobes. however, the number of hospital-acquired pneumonia (including vap) caused by anaerobes have been reported relatively smaller than generally anticipated. [ ] , polymicrobial infection does not always require the prompt antimicrobial therapy that covers anaerobes. even though when aspiration pneumonia is suspected, sbt/abpc is frequently prescribed assuming anaerobic infection, which actually works good on many occasions, it has to be acknowledged that sbt/abpc exert good antimicrobial activity not solely against anaerobes, but also aero-enteric pathogen of pneumonia such as streptococcus pneumonia, oral streptococci, h. influenzae, m. catarrhalis, and klebsiella pneumonia. inpatients are often exposed to gram-negative bacteria residing in the hospital environment. furthermore, there are many opportunities to undergo antimicrobial drug therapy that affects the indigenous microflora. for such reasons, gram-negative bacillus (enteric bacteria or p. aeruginosa) frequently colonize within the oropharyngeal region of the elderly patients or long-term bedbound patients, many of whom need airway suctioning or have tracheostomy that may serve as portal of entry of environmental pathogen. oropharyngeal microflora primarily consisting of these gram-negative bacteria can be aspirated into the airway after surgery requiring sedation or anesthesia, or during or after endoscopic examination [ , , ] . briefly, anaerobes may be an occasional pathoen in polymicrobial infection as seen on gram staining of patients with suspected aspiration pneumonia, but s. pneumoniae, h. influenzae, s. aureus, klebsiella spp., p. aeruginosa, and acinetobacter spp. are more commonly involved in many cases, being similar to the microorganisms that are thought to be the major pathogen of hospital-acquired pneumonia. this is in contrast with the community-onset aspiration pneumonia, represented by lung abscess, in that anaerobes are primarily involved [ , ] . anaerobes involved in hospital-acquired pneumonia include facultative anaerobic a-hemolytic streptococci in the oral cavity and obligate anaerobes. oral obligate anaerobes include grampositive coccus (peptostreptococcus sp.), gram-negative coccus (veillonella sp.), and gram-negative bacillus "oral pigmented" bacteroides (bacteroides melaninogenicus), prevotella sp., porphyromonas sp., and fusobacterium sp.). many of these types of bacteria are susceptible to b-lactams that do not contain a b-lactamase inhibitor, new quinolones, macrolides, and tetracyclines. therefore, patients with hospital-acquired pneumonia may be basically treated by standard empiric therapy for hospital-acquired pneumonia even when aspiration pneumonia related to several types of bacteria is suspected [ ] . ---drugs to be recommended---( ) cases in which it is not necessary to consider the involvement of multi-drug-resistant bacteria, or early hospitalacquired pneumonia the involvement of oral streptococcus, oral anaerobes, s. pneumoniae, h. influenzae, and enteric bacteria should be considered. -sbt/abpc, intravenous drip, g/ e times a day -ctrx, intravenous drip, g/once a day or g/twice a day -ctx, intravenous drip, e g/ e times a day -lvfx, intravenous drip, mg/once a day ( ) late-onset hospital-acquired pneumonia or cases in which there is a risk of multi-drug-resistant bacteria in addition to the above pathogens, the involvement of non-glucose-fermentative gram negative bacteria or esblproducing enteric bacteria must be considered. -cfpm, intravenous drip, e g/ e times a day -czop, intravenous drip, e g/ e times a day -taz/pipc, intravenous drip, . g/ e times a day table basic susceptibility of various pathogen groups to antimicrobial drugs. ---explanation---if drug susceptibility test is not conducted for some reasons after the identification of causative microorganisms, an antimicrobial drug should be selected with reference to the susceptibility pattern (local sensitivity) of the identified bacteria at each institution. if the local sensitivity is not obtained, a drug should be selected based on the basic susceptibility of various pathogens to antimicrobial drugs (table ) [ ] . in the treatment of hospital-acquired pneumonia, the duration of antimicrobial therapy generally tends to be longer than required for the following reasons: opacity on chest x-ray often remains for reasons other than pneumonia even after the start of antimicrobial drug treatment; and there may be a large number of latent nonpneumonia (or non-infectious-disease) factors that may cause increase in body temperature or crp level in inpatients [ ] . however, if appropriate antimicrobial drug treatment is performed, it is possible to complete treatment in week [ ] . in strains such as enterobacter spp., serratia spp., citrobacter spp., and morganella spp. (table gnr b ), the expression of intrinsic antimicrobial-drugresistance genes encoded in chromosome genes is induced during antimicrobial drug treatment, a phenomenon which is basically rarely seen in e. coli, klebsiella spp., h. influenzae, and m. catarrhalis (table gnr a ) ( table ) [ , , ] . therefore, if adequately chosen treatment parameters are improved, antimicrobial treatment could be completed with careful follow up of patients' condition. although it is useful to recognize these pathogens, abbreviated as space (serratia, pseudomonas, acinetobacter, citrobacter, and enterobacter), as a representative microorganism group that causes hospital-acquired pneumonia, the space group is essentially a common colonizer. therefore it is important to bear in mind that antimicrobial drug is not always indicated upon the isolation of space to avoid selection of antimicrobial resistant bacteria related to unnecessary or long-term antimicrobial therapy [ , ] . lzd should be selected [ , ] (ai). the therapeutic efficacy of lzd is similar to those of glycopeptides [ , ] . the penetration of lzd into the alveolar epitheliumlining fluid and intra-alveolar sputum is more favorable. therefore, use of lzd should be encouraged in cases of restricted sputum expectoration, such as vap [ ] (bii). exclusive use of a single drug may accelerate the acquisition of resistance to the agent [ e ] (ci). as dap is inactivated by pulmonary surfactants, its use should be avoided for mrsa pneumonia. -glycopeptides should be selected as first-line drug for pneumonia caused by corynebacterium sp [ ] (aii). ---explanation---there is no significant difference in the therapeutic efficacy for mrsa pneumonia between glycopeptides and lzd. several studies reported that the overall clinical efficacy of lzd, including the incidence of side effects, was superior to vcm in patients with hospital-acquired pneumonia caused by mrsa [ , ] . however, since the dosing of vcm in these studies have been considered suboptimal, further study is needed [ , ] . some investigators have recommended that, when mrsa is susceptible to cldm or mino on a susceptibility test, lzd, a protein synthesis inhibitor should be administered given the possible involvement of the panton-valentine leukocidin [ , ] . if a prompt improvement is achieved by the intravenous drip of lzd mg q h, or if the patient's condition is not critical, switch from the intravenous administration to an oral preparation of lzd, which shows high bioavailability [ ] , is encouraged. as dap is inactivated by pulmonary surfactants, it should not be used to treat mrsa pneumonia. this may not apply to the treatment of septic pulmonary embolism [ ] . ---drugs to be recommended---( ) mrsa a first choices -vcm, intravenous drip, g/twice a day -teic, intravenous drip, mg for the first days/ twice a day for loading, mg/once a day from day * tdm should be conducted so that the trough levels of vcm and teic range from to mg/ml [ ] . -lzd, intravenous drip or oral administration, mg/ twice a day <> second choices -abk, intravenous drip, mg/once a day (a trough level was established as mg/ml using tdm.) -st combination drug (smx at mg/tmp at mg), oral administration, tablets/twice a day or intravenous drip, mg/twice a day -cldm, intravenous drip, mg/ e times a day (the results of drug susceptibility testing must be confirmed). [non-extended-spectrum b-lactamase (esbl)-producing bacteria] ( ) hospital treatment " (p. ). ( ) e. coli, klebsiella spp., proteus mirabilis (esbl-producing bacteria) refer to the section " . community-acquired pneumonia--- . . definitive therapy--- [ ] klebsiella spp. [esbl-producing bacteria] ( ) hospital treatment" (p. ). ( ) enterobacter spp., serratia spp., citrobacter spp., morganella spp., proteus vulgaris a third-generation cephems or quinolones should be administered [ , , ] (aii). -ctrx, intravenous drip, g/once a day or g/twice a day -ctx, intravenous drip, e g/ e times a day -lvfx, intravenous drip, mg/once a day -cpfx, intravenous drip, mg/twice a day -pzfx, intravenous drip, mg/twice a day <> if a strain is estimated to constantly express cephalosporinase (highly resistant to b-lactamase inhibitorcontaining b-lactams, oxyimino [¼ rd generation] cephalosporin and cephamycin, through plasmid genes) on an antimicrobial drug susceptibility test, fourthgeneration cephems or carbapenems should be administered. -cfpm, intravenous drip, e g/ times a day -czop, intravenous drip, e g/ times a day -mepm, intravenous drip, g/ times a day -drpm, intravenous drip, . e g/ times a day ( ) p. aeruginosa anti-pseudomonal penicillins, third-generation or later cephems, carbapenems, or new quinolones should be administered [ , ] refer to the section " . community-acquired pneumonia--- . . definitive therapy--- [ ] h. influenza (abpcsusceptible), [ ] h. influenza (b-lactamase-producing), [ ] h. influenza (b-lactamase-negative ampicillin-resistant (blnar), and [ ] h. influenza (b-lactamase-positive amoxicillin clavulanate-resistant (blpacr)" (p. e ). ---explanation---according to some investigators, enteric bacteria are classified into types: sensitive, gram-negative rods, such as e. coli, klebsiella pneumoniae, and p. mirabilis, which are susceptible to first-generation cephalosporin, and resistant, gram-negative rods, such as enterobacter spp., serratia spp., and citrobacter spp., which show an intrinsic or inducible resistance to third-generation cephalosporin through chromosomal ampc genes [ , , ] . in addition, the number of extended spectrum of b-lactamase (esbl)-producing strains of e. coli, klebsiella, and proteus sp. that are resistant to all cephalosporin has increased. among resistant gnrs, such as enterobacter spp., strains that constantly produce ampctype b-lactamase (cephalosporinase) (plasmid type) must also be considered [ , ] . concerning non-fermentative bacteria, their intrinsic susceptibility to antimicrobial agents differs among p. aeruginosa, stenotrophomonas spp., and acinetobacter spp. a study indicated that, in patients with p. aeruginosa pneumonia, monotherapy with a new quinolone might show unfavorable bacteria-eradicating effects or lead to recrudescence [ ] . in some patients, combination therapy with a b-lactam (pipc, caz, cfpm, or carbapenems), which has an anti-pseudomonal activity, and aminoglycoside or new quinolone may be considered [ , , ] . most strains of stenotrophomonas spp. are susceptible to mino or an st combination drug. m. catarrhalis and acinetobacter spp. are the frequent types of gram-negative coccus detected in patients with early and late hospital-acquired pneumonia, respectively. many strains of the former produce b-lactamase. the latter is a gnr existing in the hospital environment, and may be resistant to many antimicrobial drugs. however, in japan, the multi-drug resistance of this type of bacteria has not widely distributed. carbapenems and new quinolones should be selected. however, the vast majority of acinetobaccter strains are susceptible to sbt/abpc. in particular, sbt has an antimicrobial activity against this type of bacteria, and their susceptibility to sbt/abpc should routinely be confirmed. primary test drugs for an antimicrobial susceptibility of this type of bacteria (drugs appropriate for a routine examination panel) are sbt/abpc, caz, ipm/cs, mepm, gm, tob, lvfx, and cpfx [ ] . pan-sensitive strains of h. influenzae are b-lactamase (bl)-negative, abpc-sensitive (blnas) strains. however, there are various resistance patterns: bl-producing, abpcresistant (blpar), bl-negative, abpc-resistant (blnar), and bl-producing, ampc/cva-resistant (blpacr) strains. blnas strains can be treated with abpc, but sbt/abpc therapy is required to control blpar strains. the administration of ctrx or new quinolones is necessary for blnar or blpacr. a randomized-controlled trial with multivariate analysis has shown that factors for favorable bacteriological effects included the absence of p. aeruginosa-related pneumonia (< . ), a higher body weight (< . ), a low apache ii score (severity) ( . ), and cpfx therapy ( . ) [ ] . conditions suggesting the use of new quinolones include allergy to b-lactams, the presence of or concern for nephropathy (an aminoglycoside cannot be combined with a b-lactam), necessity of covering obligate intracellular pathogen, or situations in which switching to an oral preparation is indicated [ ] . an in vitro study indicated that the alveolar epithelial lining fluid (elf) concentration of lvfx reached as high as its serum concentration. furthermore, a prospective open-label study reported that switching of intravenous drip to oral administration decreased the elf concentration, but it was within the range at which many pathogens are deemed sensitive based on the cumulative data of minimum inhibitory concentrations for causative microorganisms [ ] . ---executive summary----nursing and healthcare-associated pneumonia (nhcap) is a category independently defined in japan based on medical circumstances. -the attending physician proposes a treatment category (groups a to d) by evaluating what treatment is necessary as the most important item based on the patient's and his/her family's will ( fig. ) [ ] . -risk factors for resistant bacteria are categorized into two items, and initial treatment options are recommended, assuming target causative microorganisms (civ). -in patients in whom the general condition is unfavorable due to complications or in terminal-stage patients, initial treatment options are recommended considering side effects from the perspective of innocent properties (civ). -in group d, in which intensive care is required, combination therapy with broad-spectrum (involving resistant bacteria and legionella) and potent antimicrobial drugs is recommended (bi). ---explanation--- in , the japanese respiratory society issued the "guidelines for the management of nursing and healthcare-associated pneumonia (nhcap)" [ ] , considering medical circumstances in japan with reference to the entity of healthcare-associated pneumonia (hcap) proposed in the untied states [ ] . the definition of nhcap is shown in table . as this committee has no objection to the entity itself, the selection of drugs will be explained based on evidence to avoid duplications with the above guidelines. the mortality rate and frequency of resistant bacteria in patients with nhcap are intermediate between community-acquired pneumonia (cap) and hospital-acquired pneumonia (hap). however, nhcap may be primarily regarded as being similar to geriatric pneumonia [ , ] . there is no fact that the rate at which resistant bacteria are isolated increases with severity [ ] . even when pneumonia is not severe, the host's activities of daily living (adl) and an underlying disease/immunodeficiency reduce the prognosis in many cases [ ] . as this type of pneumonia develops in a variety of uneven populations, it is difficult to simply determine severity classification. therefore, considering various conditions, the entity of "treatment category", involving the ethical aspects of geriatric care, was introduced based on evaluation by the attending physician who knows the patient well ( fig. ). frequent basic conditions or concomitant diseases for nhcap in japan include an advanced age, central nervous diseases, aspiration, a reduction in adl, and tubal feeding. their factors are aspiration pneumonia itself or risk factors, and hcap in japan may overlap with aspiration pneumonia [ ] . on the other hand, in nhcap patients, mrsa, p. aeruginosa, and anaerobes are more frequently isolated in comparison with cap patients. it is necessary to switch therapeutic strategies, considering these causative microorganisms. refer to the next section " . aspiration pneumonia" (p. ). [type and frequency of causative microorganisms] concerning causative microorganisms in nhcap patients, resistant bacteria are frequently detected, differing from cap patients. however, with respect to microorganisms that cause hcap, the distribution and frequency of streptococcus pneumoniae and h. influenzae, which are frequently isolated in cap patients, as well as mrsa, p. aeruginosa, and gram-negative bacillus, which are frequently detected in hap patients, differ among countries, areas, and institutions due to their variety (iii). concerning causative microorganisms, a study reported that there was no marked difference between nhcap and cap [ ] . on the other hand, a study in the united states indicated that s. aureus was frequently detected [ ] , and another study in italy, where the rapid aging of society is advanced, as described for japan, reported that aspiration pneumonia, h. influenzae, s. aureus, and gram-negative bacillus were more frequent than in patients with cap [ ] . as a result, the rate of resistant bacteria increased, and inappropriate antimicrobial drugs were selected in a high proportion of patients. in addition, the mortality rate was higher than in cap patients, suggesting the association between the two factors. representative causative microorganisms with respect to the presence or absence of risk factors for resistant bacteria are presented in table [ ] . of these, resistant bacteria, which are not targeted in cap patients, were isolated in approximately %. however, the value was lower than in hap patients. this is a current status of japan (iii). however, we must consider that patients in whom isolated bacteria are unclear account for approximately %, with the involvement of aspiration as a background factor [ ] . in addition to bacteria commonly isolated in cap patients, the frequency of enteric bacteria and anaerobes has increased [ ] . [rules of antimicrobial drug therapy] risk factors for resistant bacteria in nhcap patients include "the previous use of antimicrobial drugs for days or more within days" and "tubal feeding" ( [ ] . risk factors for involvement by drug-resistant pathogens. -if no antibiotic therapy in the preceding days or current tube feeding, the patient can be assumed to have no risk of involvement by drug-resistant pathogens. -however, if past medical history indicates isolation of mrsa, the patient should be assumed to have risk of involvement by mrsa. * ) inappropriate when aspiration pneumonia is suspected, because it has insufficient activity against anaerobic bacteria. * ) because of insufficient activity against anaerobic bacteria, when used to treat suspected aspiration pneumonia, it should be used in combination with an antibiotic that has activity against anaerobic bacteria (e.g., mnz, cldm, sbt/abpc). definition of nhcap [ ] . . pneumonia diagnosed in a resident of an extended care facility or nursing home . pneumonia diagnosed in a person who has been discharged from a hospital within the preceding days . pneumonia diagnosed in an elderly or disable d person who is receiving nursing care . pneumonia diagnosed in a person who is receiving regular endovascular treatment as an outpatient (dialysis, antibiotic therapy, chemotherapy, immunosuppressant therapy) standards for nursing care patients whose performance statues is ps (capable of only limited self-care, confined to bed or a chair more than % of their waking hours) or more. item incudes patients on psychiatric wards. not isolated in those who had made favorable daily life activities without a history of antimicrobial drug therapy [ ] . another study indicated that tubal feeding was an independent risk factor for infection with p. aeruginosa (odds ratio: . ) [ ] (ii). this is the reason why treatment category c was established in the guidelines. briefly, patients who do not meet the above two items are regarded as having no risk factor for resistant bacteria, and assigned to group b. patients meeting or items or those in whom mrsa was previously isolated are assigned to group c. respective drugs to be recommended were separately established. patients in whom outpatient treatment is considered to be appropriate are assigned to group a, and those in whom the attending physician considers ventilator or icu management necessary to group d. drugs to be recommended were added, and a treatment category algorithm ( fig. ) [ ] was prepared. concerning hcap treatment in europe and the united states, there is a gap between drugs used in clinical practice and those recommended in guidelines [ ] (ii). therefore, treatment category-based empiric therapy in japan may be acceptable in clinical practice; future investigation is necessary. there is no evidence regarding the administration period of antimicrobial drugs. an administration period of e days, which is routinely adopted in the highest percentage of patients, is appropriate (biv). when administering antimicrobial drugs for a longer period, equivalent-spectrum antimicrobial drugs should be selected, or de-escalation of antimicrobial drugs should be performed. in this case, fever, crp, and leukocyte counts are often used as indices of the treatment response. in cases of aspiration pneumonia in which aspiration recurs during treatment despite the efficacy of antimicrobial drugs, it is necessary to evaluate whether the effects of antimicrobial drugs are not obtained or recurrence occurs. ---drugs to be recommended--a. empiric therapy ( fig. ) [ ] ( ) cases in which there is no risk of resistant bacteria and outpatient treatment is performed (group a) according to a study, chlamydophila spp. and m. pneumoniae accounted for . and . % of patients in whom the type of microorganisms that cause nhcap was clarified in japan, respectively [ ] . the results suggested that chlamydophila spp. is a target of treatment, as described for cap. therefore, in group a, combination therapy with a b-lactam and macrolide or monotherapy with a respiratory quinolone should be performed (bii). in group d, an anti-p. aeruginosa drug should be combined with cpfx, pzfx, or azm for injection, considering legionella or chlamydophila spp. pneumonia. however, concerning combination therapy with a macrolide (cii) in patients without "severe pneumonia requiring intensive care", as described below, the evidence level is not always high from the perspectives of medical economics, side effects, and resistant bacteria [ ] . some studies examined the mortality rate with respect to the presence or absence of treatment covering atypical pathogens, and reported that the mortality rate was significantly lower in the presence of such treatment [ ] . a recent meta-analysis also showed a difference [ ] . respiratory quinolones were established as an option (bii) based on many references describing that their effects are similar to or more potent than those of combination therapy with a b-lactam and macrolide. however, this must be further examined, considering factors such as severity and the presence or absence of concomitant sepsis [ ] . furthermore, the prevalence of penicillinresistant pneumococcus, which has been internationally emphasized as an issue, and macrolide-resistant pneumococcus, which has been markedly observed in japan, was also a background factor for establishing respiratory quinolones as an option [ ] . the previous use of antimicrobial drugs, which is often observed in patients with nhcap, is considered to be a risk factor for resistant pneumococcus [ ] . a study reported that penicillin or em resistance in hcap patients was more advanced than in cap patients [ ] . a study indicated that the efficacy of oral therapy with lvfx was similar to that of ctrx injection therapy in patients with cap [ ] . another study reported that, among patients with non-severe hcap, oral lvfx was useful in those with no description of causative microorganisms [ ] . however, when aspiration pneumonia is suspected, grnx or mflx should be selected, because the effects of lvfx on anaerobes are weak. furthermore, several studies suggested the usefulness of mflx, which is not influenced by the kidney function and does not require dose regulation, in elderly patients with nhcap [ , ] . as treatment is completed with a single, high dose, compliance is favorable. azm sustained-release preparations [ e ], which simultaneously cover bacteria and atypical pathogens, and stfx, which shows a favorable mic for anaerobes, may also be recommended [ ] . a first choices -cva/ampc, oral ( / mg), tablets/ e times a day -sbtpc, oral ( mg), tablets/ e times a day table risk factors for involvement by drug-resistant pathogens a in nhcap [ ] . history of antibiotic therapy for or more days in the preceding days current tube feeding the risk of mrsa should be taken into account whenever there is past history of mrsa isolation. when attempting to predict the isolation of drug-resistant pathogens based on the presence of these risk factors, it should be borne in mind that their sensitivity and negative predictive value are high, but their specificity and positive predictive value are low. a drug-resistant pathogens include pseudomonas aeruginosa, mrsa, acinetobacter, esbl-producing enteric bacteria, and stenotrophomonas maltophilia. table possible pathogens isolated from nhcap patients [ ] . when an nhcap patient has no risk factors for involvement by drug-resistant pathogens pneumococcus mssa gram-negative enteric bacteria (including klebsiella and e. coli) haemophilus influenzae oral streptococci atypical pathogens (particularly chlamydophila) when an nhcap patient has a risk factor for involvement by drug-resistant pathogens (the following will be considered in addition to the above-mentioned pathogens) pseudomonas aeruginosa mrsa acinetobacter esbl-producing enteric bacteria þ one of the followings: -azm sustained-release preparation, oral, g/single dose -cam, oral, mg/twice a day <> second choices -mflx, oral, mg/once a day -grnx, oral, mg/once a day -stfx, oral, mg/l to times a day or -ctrx * , intravenous drip, g/once a day or g/twice a day -ctx * , intravenous drip, e g/ e times a day þ one of the followings: -azm sustained-release preparation, oral, g/single dose -cam, oral, mg/twice a day * ) as the antimicrobial activity of the drug against anaerobes is insufficient, it is inappropriate under a tentative diagnosis of aspiration pneumonia. ( ) cases in which there is no risk of resistant bacteria and hospital treatment is performed (group b) in this category, we recommend monotherapy from the perspectives of causative microorganisms resembling those for cap and side effect-based "innocent properties". a study reported that initial treatment with narrow-spectrum antimicrobial drugs did not always lead to a poor prognosis [ ] . in particular, according to two articles [ , ] , it is not necessary to consider resistant bacteria in hcap patients in whom causative microorganisms are unclear; treatment in accordance with cap treatment is sufficient (bii). however, an advanced age, central nervous diseases, aspiration, and a reduction in adl are the clinical characteristics of aspiration pneumonia. the condition of nhcap in japan overlaps with aspiration pneumonia [ ] . therefore, in group b, to which patients admitted for the first time, with no recent use of antimicrobial drugs, correspond, antimicrobial therapy with b-lactamase inhibitor-containing penicillins is appropriate, as described for cap. however, when aspiration pneumonia is suspected, ctrx and lvfx should be avoided (biv). for the management of enteric bacteria, candidate drugs for group b, papm/bp, may be selected. actually, it is not necessary to consider p. aeruginosa in patients with cap or non-icu hap. a study indicated that ertapenem, which is not effective for p. aeruginosa, was useful [ ] , as demonstrated for papm/bp. however, another study reported that the widespread use of ertapenem induced the cross resistance of p. aeruginosa to other carbapenems; the use of papm/bp alone should be avoided [ ] (biv). in elderly persons, with a high risk of aspiration, who are repeatedly admitted and discharged, klebsiella is often involved. taz/pipc is more useful according to a study [ ] (bii). in patients in whom gram-negative bacillus is detected on gram staining of sputum or those in whom the involvement of enteric bacteria is suspected, papm/bp or taz/pipc should be selected (biv). -sbt/abpc, intravenous drip, g/ e times a day -ctrx * , intravenous drip, g/once a day or g/twice a day -ctx * , intravenous drip, e g/ e times a day -lvfx * , intravenous drip, mg/once a day -papm/bp, intravenous drip, . e g/ e times a day * ) as the antimicrobial activity of the drug against anaerobes is insufficient, it is inappropriate under a tentative diagnosis of aspiration pneumonia. ( ) cases in which there is a risk of resistant bacteria and hospital treatment is performed (group c) the target microorganisms include p. aeruginosa, mrsa, and acinetobacter spp. in addition to frequent microorganisms that cause respiratory infection [ , , , ] . as antimicrobial drugs, taz/pipc, with an antimicrobial activity against p. aeruginosa, fourth-generation cephems, carbapenems, and quinolones (cpfx, pzfx) are recommended. taz/ pipc exhibits effects similar to those of ipm/cs and mepm in patients with nursing and healthcare-associated pneumonia [ ] (bii). pzfx also has an antimicrobial activity against s. pneumoniae when used at a high dose ( g/day). when pneumonia related to atypical pathogens such as chlamydophila spp. is suggested, quinolones should be selected. as the antimicrobial activities of fourth-generation cephems and quinolones against anaerobes are weak, these drugs should be combined with mnz, cldm, or sbt/abpc. recently, the resistance of the bacteroides fragilis group to cldm has advanced [ ] . therefore, in europe and the united states, mnz is selected as a first-choice antimicrobial drug against anaerobes. however, the rate at which the b. fragilis group is involved in oral anaerobes is low, and combination therapy with cldm may be selected [ , ] . therefore, for combination therapy with fourth-generation cephems, we recommend the two drugs. when there is a risk of mrsa, such as previous admission, they should be combined with vcm, teic, or lzd. if there is no abscess formation, abk is also effective. a first choices -taz/pipc, intravenous drip, . g/ e times a day -ipm/cs, intravenous drip, . e g/ e times a day -mepm, intravenous drip, g/ e times a day -drpm, intravenous drip, . e g/ times a day <> second choices -cfpm* , intravenous drip, e g/ e times a day -cpr * , intravenous drip, e g/ e times a day þ one of the followings: -cldm, intravenous drip, mg/ e times a day -mnz, intravenous drip, mg/ times a day or -cpfx * , intravenous drip, mg/twice a day -pzfx * , intravenous drip, mg/twice a day þ one of the followings: -cldm, intravenous drip, mg/ e times a day -sbt/abpc, intravenous drip, g/ e times a day *in addition to the above drugs, if mrsa infection is suspected, antimicrobial drugs should be added in accordance with the section "mrsa pneumonia". * ) as the antimicrobial activity of the drug against anaerobes is insufficient, it should be combined with a drug with an antimicrobial activity against anaerobes (mnz, cldm, or sbt/abpc) under a tentative diagnosis of aspiration pneumonia. ( ) severe cases requiring intensive care (group d) to cover l. pneumophila and atypical pathogens, which are rare as causative microorganisms but may cause severe conditions, group-c antimicrobial drugs should be combined with cpfx, pzfx, or azm injection (bi). concerning the usefulness of combination therapy with a b-lactam and macrolide injection for severe pneumonia, evidence has been accumulated [ ] . a study indicated that, in severe community-acquired pneumonia patients with sepsis or requiring icu management, combination therapy with a blactam and macrolide led to a more favorable prognosis compared to that with a quinolone (i), suggesting that antiinflammatory actions are involved in the mechanism [ ] . in addition, another study reported that, among pneumonia patients with acute pulmonary disorder, both the ventilator withdrawal and survival rates in a macrolide-treated group were higher than in a non-macrolide-treated group [ ] (i). several meta-analyses also support them [ , ] . a first choices -taz/pipc, intravenous drip, . g/ e times a day -ipm/cs, intravenous drip, . e g/ e times a day -mepm, intravenous drip, g/ e times a day -drpm, intravenous drip, . e g/ times a day þ one of the followings: -cpfx * , intravenous drip, mg/twice a day -pzfx * , intravenous drip, mg/twice a day -azm, intravenous drip, mg/once a day <> second choices -cfpm * , intravenous drip, e g/ e times a day -cpr * , intravenous drip, e g/ e times a day þ one of the followings: -cldm, intravenous drip, mg/ e times a day -mnz, intravenous drip, mg/ times a day þ one of the followings: -cpfx * , intravenous drip, mg/twice a day -pzfx * , intravenous drip, mg/twice a day -azm, intravenous drip, mg/once a day in addition to the above drugs, *if mrsa infection is suspected, antimicrobial drugs should be added in accordance with the section "mrsa pneumonia". * ) as the antimicrobial activity of the drug against anaerobes is insufficient, it should be combined with a drug with an antimicrobial activity against anaerobes (mnz, cldm, or sbt/abpc) under a tentative diagnosis of aspiration pneumonia. antimicrobial drugs against identified causative microorganisms should be selected in accordance with the section " . hospital-acquired pneumonia" (p. ). ---executive summary----as oral indigenous bacteria, including anaerobes, cause aspiration pneumonia, b-lactamase inhibitor-containing penicillins are appropriate (bii). -in cases of nosocomial onset, it is necessary to cover gramnegative bacillus, including p. aeruginosa. -in cases of severe ventilator-associated pneumonia (vap), the selection of broad-spectrum antimicrobial drugs or combination therapy with them should not be hesitated (ai). -the detection rate of esbl-producing gram-negative bacillus has increased, and antimicrobial drugs should be carefully selected. -it is important to prevent subclinical aspiration through oral care and the prevention of gastroesophageal reflux, such as head lifting (bii). -to prevent aspiration pneumonia, it is also important to improve the nutritional status and avoid the overuse of sleeping pills/ sedatives (bii). ---explanation---[characteristic and classification of diseases] aspiration pneumonia occurs with a background factor, dysphagia, which is frequently observed in the presence of a reduction in adl or systemic functions, especially cerebrovascular disorder. its onset is associated with dietary ingestion in elderly persons [ ] . currently, aspiration pneumonia is accurately defined only in the guidelines for the management of hospitalacquired pneumonia (hap) in adults, which were prepared by the japanese respiratory society [ ] . the guidelines present conditions that may cause dysphagia, which were proposed by the japanese study group on aspiration pulmonary disease (table , modified) [ ] . in our guidelines, we primarily explain antimicrobial drugs to be selected for patients with such conditions. the above definition is also adopted in the guidelines for the management of nursing and healthcare-associated pneumonia (nhcap) [ ] . in elderly persons admitted to long-term care beds or nursing homes, risk factors include dysphagia and tubal feeding according to international data on pneumonia that develops in nursing homes [ e ]. in japan, frequent underlying diseases in patients with nhcap also include central nervous diseases and dementia, which are closely associated with aspiration. the proportion of patients after percutaneous endoscopic gastrostomy (peg) is high [ ] . however, among various types of community-acquired pneumonia, a diagnosis of aspiration pneumonia is made based on onset factor-based classification, and is not equal to nhcap diagnosed primarily based on the place of onset or grade of nursing. according to data in spain, aspiration pneumonia accounts for . % of patients with healthcareassociated pneumonia (hcap) requiring admission. this percentage was markedly higher than in those with communityacquired pneumonia (cap) requiring admission ( . %), but corresponded to no more than / [ ] . on the other hand, a multicenter cooperative study involving inpatients with pneumonia in japan, where the rapid aging of society is advanced, reported that . % of patients who were admitted with cap had aspiration pneumonia. even in patients with cap, which is not classified as nhcap, the involvement of aspiration cannot be ignored [ ] . furthermore, the study indicated the involvement of aspiration in . % of patients, aged over years, with cap/ hap [ ] . in the future, the significance of distinguishing aspiration pneumonia among patients with nhcap or hap and changing therapeutic strategies should be examined. however, nhcap more markedly affects adl compared to cap, and the aspect of elderly pneumonia is emphasized; it may be significant to positively diagnose aspiration pneumonia and establish therapeutic strategies different from those for cap [ ] . concerning hap, a reduction in the immune function is a background factor. hap has two aspects: pneumonia with a high risk of resistant bacteria and that in which central nervous diseaserelated aspiration is involved. in the guidelines for the management of hospital-acquired pneumonia in adults, which were prepared by the japanese respiratory society, mendelson syndrome and vap are categorized as a group, and classifications, involving diffuse deglutition-related bronchiolitis, in which there are no findings of pneumonia, are proposed. in addition, a flow chart for diagnosis is presented [ ] (fig. ) . with respect to the condition and treatment of vap, refer to a review described by chastre et al. [ ] management other than antimicrobial drug therapy should also be considered, and bundle (table )-based prevention should be performed [ ] (aii). [type and frequency of causative microorganisms] streptococcus pneumoniae, s. aureus, and enterobacteriacae have been reported. a study indicated that k. pneumoniae was frequent [ ] . the involvement of oral indigenous bacteria, such as streptococcus anginosus group. and anaerobes, has been suggested [ , ] . in cases of nosocomial onset, gram-negative bacillus, including p. aeruginosa, must also be considered. concerning e. coli, klebsiella spp., and proteus spp., the number of esbl-producing strains may increase in the future. [rules of antimicrobial drug therapy] if appropriate antimicrobial drug therapy is not selected under a diagnosis of aspiration-related pneumonia, insufficient treatment may lead to a fatal condition, or excessive treatment may increase the number of resistant bacteria, showing negative effects. there may be differences in options for empiric therapy between patients with vap (most patients show severe conditions) and those with diffuse deglutition-related bronchiolitis, in whom the start of treatment is not accelerated. on the other hand, approaches to prevent pneumonia after aspiration or avoid aspiration are important. oral care, head lifting, and improvement in the nutritional status must be considered, and the overuse of sleeping pills/ sedatives should be avoided (bii). the best option for standard-type aspiration pneumonia is an antimicrobial drug that exists an antimicrobial activity against both aerobes and anaerobes. sbt/abpc and taz/pipc are effective for anaerobes frequently isolated in the respiratory system, such as fusobacterium spp., prevotella spp., and peptostreptococcus spp. [ , ] . as the resistance rates of these types of bacteria to the two regimens are low, these regimens are also recommended as first choices in the guidelines established by the japanese association for anaerobic infection research [ ] . however, a study reported that the previous administration of antimicrobial drugs and adl were correlated with the frequency of enterobacteriacae-or p. aeruginosa-related pneumonia [ ] . a retrospective study involving patients with aspiration pneumonia showed that the frequency of k. pneumoniae-related pneumonia was % [ ] . based on these studies, drugs to be selected should be changed in accordance with the previous administration of antimicrobial chemotherapeutic drugs in patients admitted to general or medical wards. among patients with hospital-acquired pneumonia, broad-spectrum drugs should be selected in those with severe aspiration pneumonia or vap (bii). when causative microorganisms are identified and an improvement in the condition is achieved, de-escalation should be performed. ---drugs to be recommended--a. empiric therapy ➀ no risk of resistant bacteria drugs with potent antimicrobial activities against oral anaerobes are presented. however, no article has provided high-level evidence regarding aspiration pneumonia. as the following drugs affect the intestinal flora, antimicrobial drugassociated diarrhea may occur. if symptom improvement is delayed, patients must be promptly admitted, and drip table conditions that may cause dysphagia [ ] [ ] . bundles for the prevention of ventilator-associated pneumonia. ( ) upper body lifting the head should be lifted at e . ( ) discontinuation of sedatives a sedative should be discontinued once a day to evaluate whether or not extubation is possible. ( in addition to the above items, methods to prevent aspiration pneumonia include oral care, the administration of drugs that improve the deglutition function, such as ace inhibitors and cilostazol, improvement in the nutritional status, eating/swallowing rehabilitation, and anti-pneumococcus vaccination. infusion therapy should be performed (outpatient treatment should not be prolonged). ( ) outpatient treatment a first choices -cva/ampc, oral ( / mg), tablets/ e times a day -sbtpc, oral ( mg), tablets/ e times a day <> second choices -mflx, oral, mg/once a day -stfx, oral, mg/ e times a day -grnx, oral, mg/once a day ( ) hospital treatment when a diagnosis of aspiration pneumonia is made, sbt/abpc is most frequently used in japan [ ] . kaneko et al. reported that the sensitivity of oral anaerobes that may cause aspiration pneumonia, such as peptostreptococcus spp., prevotella spp., and fusobacterium spp., to sbt/abpc was %, similar to that to taz/pipc [ ] . the effects of cldm on aspiration pneumonia or a pulmonary abscess are similar to those of sbt/abpc (bi) [ ] . sbt/abpc and cldm showed similar effects and tolerance on aspiration pneumonia ( . and . %, respectively) [ ] . oral anaerobes, excluding bacteroides spp., are still susceptible to cldm. a randomized clinical trial (rct) indicated that cldm was more potent than cephems [ ] . a first choice -sbt/abpc, intravenous drip, g/ e times a day <> second choice -cldm, intravenous drip, mg/ e times a day ➁ cases in which there is a risk of resistant bacteria or severe cases in cases in which there is a risk of resistant bacteria or severe cases, drugs should be selected in accordance with options for group c for nhcap. tubal feeding is a risk factor for aspiration, and is also a risk factor for resistant bacteria [ ] . when the involvement of enterobacteriacae, such as k. pneumoniae and e. coli, is suggested, empiric therapy should be selected in accordance with cases in which there is a risk of resistant bacteria [ ] . in japan, the proportion of esbl-producing bacteria on sputum culture in patients with respiratory infectious diseases is % or less [ ] , but the number of esbl-producing bacteria has slightly increased; this must be considered in the future [ , ] . a study reported that the clinical effects of taz/pipc on non-esblproducing k. pneumoniae were more potent than those of sbt/abpc; caution is needed [ ] . it must be considered that, in cases of aspiration pneumonia classified as hcap, enterobacteriacae is isolated at a frequency that cannot be ignored. concerning aspiration pneumonia that occurs in hospitals, some reviews proposed that antimicrobial drugs should be selected, regarding the condition as hospitalacquired pneumonia; empiric therapy may be selected in accordance with the guidelines for the management of hospital-acquired pneumonia, which were published by the japanese respiratory society [ , ] . according to a study, bipm, which does not cause kidney dysfunction in elderly patients, is also effective (civ); therefore, it is presented as an option for cases in which there is a risk of resistant bacteria [ ] . the mortality rate in patients with vap is high. if causative microorganisms cannot be initially covered, the mortality rate may increase [ ] . therefore, drugs should be selected, regarding the condition as severe aspiration pneumonia. three studies reported that, in a group in which taz/pipc was selected as a drug to be combined with aminoglycosides for vap treatment, the mortality rate was lower than in a group in which caz was selected [ e ]. in particular, when pneumonia was caused by p. aeruginosa, the clinical effects of taz/pipc were more potent than those of ipm/cs (bii). for monotherapy, information on the culture of protected specimen brush (psb) samples or broncho-alveolar lavage (bal) fluid is strongly recommended [ , ] . on the other hand, an observational study indicated that threedrug therapy (two anti-p. aeruginosa drugs þ an anti-mrsa drug) deteriorated the prognosis; an rct should be conducted in the future [ ] . therefore, if there is a risk of resistant bacteria, at least broad-spectrum antimicrobial drugs must be used for empiric therapy. however, assuming causative microorganisms with reference to gram staining reactions, minimum necessary antimicrobial drugs should be selected based on local factors (antimicrobial drug susceptibility pattern of each type of bacteria in each hospital). recently, the entity of ventilator-associated tracheobronchitis (vat) was proposed, and the disadvantages of aggressive treatment have been discussed [ ] . in a multicenter cooperative study, patients with vat, which occurred in the icu, were divided into two groups with and without antimicrobial drug therapy, and the results were compared. in the former, the incidence of vap was significantly lower, and the mechanical ventilation-free period was significantly longer. in addition, the icu mortality rate was significantly lower. on the other hand, there was no significant difference in the appearance of resistant bacteria between the two groups [ ] . a first choices -taz/pipc, intravenous drip, . g/ e times a day -ipm/cs, intravenous drip, . e g/ e times a day -mepm, intravenous drip, g/ e times a day -drpm, intravenous drip, . e g/ times a day -bipm, intravenous drip, . e . g/ e times a day <> second choices -cfpm, intravenous drip, e g/ e times a day -cpr, intravenous drip, e g/ e times a day þ one of the followings: -cldm, intravenous drip, mg/ e times a day -mnz, intravenous drip, mg/ times a day or -lvfx, intravenous drip, mg/once a day -cpfx, intravenous drip, mg/twice a day -pzfx, intravenous drip, to mg/twice a day þ one of the followings: -cldm, intravenous drip, mg/ e times a day -mnz, intravenous drip, mg/ times a day -sbt/abpc, intravenous drip, . e g/ e times a day *if mrsa infection is suspected, antimicrobial drugs should be administered in accordance with the section "mrsa pneumonia" in addition to the above drugs. [administration period of antimicrobial drugs] it is recommended that the treatment period of hospitalacquired pneumonia should be e days. however, the treatment period should be days in patients with pneumonia related to non-glucose-fermenting bacteria such as p. aeruginosa [ ] (bii). concerning vap, a study reported that there was no difference in the clinical effects between and days [ ] . to control identified causative microorganisms, antimicrobial drugs should be selected in accordance with the section "hospital-acquired pneumonia". if mrsa infection is suspected, antimicrobial drugs should be selected in accordance with the section "mrsa pneumonia". (bii). -in severe or refractory cases in which the efficacy of initial treatment is not sufficient, combination therapy with an antifungal drug should also be considered [ e ] (bii). -as the effects of combination therapy with an azole and amph-b preparation antagonize in some strains, a combination of these drugs should be avoided [ ] (aiii). -for the target treatment of this disease, an antifungal drug of which the class is different from that of a drug used for preventive administration should be used (biii). ---explanation---[characteristics of the disease] -symptoms: this disease develops in severe immunocompromised hosts such as patients received chemotherapy for leukemia or hematopoietic stem cell/organ transplantation. symptoms such as fever that does not respond to broadspectrum antimicrobial drugs, cough, dyspnea, sputum, and bloody sputum/hemoptysis are observed. -laboratory findings: chest x-ray shows an infiltrative shadow (typically, a wedge shadow involving the pleura as the base). on thoracic ct, infiltrative and nodular shadows (with a halo sign in some cases) are observed. in the recovery phase of neutrophils, an air crescent sign is noted. an increase in the inflammatory marker such as the crp level, aspergillus galactomannan antigen-positive reactions, and an increase in the ( / )-b-d-glucan level are useful for diagnosis. however, neither the sensitivity nor specificity is sufficient. the results should be carefully evaluated. -causative microorganisms: aspergillus fumigatus is frequently detected, but, recently, an increase in the number of patients with non-fumigatus aspergillus-related ipa has been indicated. -specific condition: lesions are sometimes formed in the nasal sinus and brain; caution is needed. -early diagnosis: early treatment is important for successful treatment for this disease. ---drugs to be recommended---a study reported that, in a group in which vrcz was used for the initial treatment of ipa, the results of treatment were more favorable than in a group in which d-amph was used [ ] . furthermore, another study indicated that therapy with l-amb at mg/kg/day was safer than that at mg/kg/ day, although there was no significant difference in the clinical efficacy [ ] . cpfg, mcfg, and itcz also have anti-aspergillus activities, and can be used. it is important to consider different strategies in accordance with the appearance of the host's allergy or adverse events and interactions with drugs used to treat an underlying disease. b. chronic progressive pulmonary aspergillosis (cppa) ---executive summary----in japan, various disease types such as aspergilloma with infiltration and enlargement of an existing cavity are included. cppa includes various diseases such as chronic necrotizing pulmonary aspergillosis (cnpa), chronic cavitary pulmonary aspergillosis (ccpa), and chronic fibrosing pulmonary aspergillosis (cfpa). it refers to a series of syndrome for which the administration of antifungal drugs is essential. -treatment should be started with injection. if symptoms and findings are stabilized, injection should be switched to oral drugs. -initial treatment with mcfg or cpfg should be performed [ , ] (ai). -initial treatment with itcz, vrcz, or l-amb can also be selected in accordance with the host's underlying disease or drugs used to treat the underlying disease. -for maintenance therapy, itcz and vrcz oral preparations are recommended (aiii). ---explanation---[characteristics of the disease] -symptoms: this disease develops in hosts with organic diseases such as a cavity or cystic disease of the lung or bronchus. symptoms such as fever, sputum, bloody sputum/ hemoptysis, and dyspnea are observed. -laboratory findings: chest x-ray and ct show an infiltrative shadow, enlargement of a cavity, thickening of the cavity wall/pleura, and a niveau in the cavity. there is an increase in the crp level in many patients. most patients are positive for anti-aspergillus precipitating antibody. neither aspergillus galactomannan antigen nor b-d-glucan is a clue to diagnosis. -causative microorganisms: a. fumigatus is frequently detected. non-fumigatus aspergillus-related cppa is also often observed. ---drugs to be recommended---a clinical study in japan indicated that there was no marked difference in the efficacy of treatment between mcfg-and vrcz-treated groups, whereas mcfg was safer [ ] . another study reported that there was no difference in treatment results between mcfg and cpfg [ ] . in the phase of severe symptoms such as fever and bloody sputum, treatment should be started using these injections. -pulmonary aspergilloma is classified into two types: simple and complex aspergilloma based on the grade of difficulty in resection. the former refers to aspergilloma formation in a focus with a thin wall, such as a cyst, without accessory lesions at the periphery. the latter refers to aspergilloma formation in a cavity derived from a strongly destructed existing structure of the lung, such as old pulmonary tuberculosis and bronchiectasis, with marked destructive lesions or pleural adhesion at the periphery of the cavity. ---drugs to be recommended---resection should be selected as a first choice. when resection is impossible, medical treatment can be considered. in preparation, such as l-amb, and -fc should be performed for weeks or more. subsequently, treatment should be continued using flcz or f-flcz. -in japan, cryptococcus gattii infection has also been reported. if possible, causative fungus must be isolated/identified. ---explanation---[characteristics of the disease] -symptoms: this disease is often asymptomatic, and is detected on a health checkup in many cases. -laboratory findings: chest x-ray and ct show solitary or multiple nodular and infiltrative shadows. -some cavities are observed in a lot of cases. there is no enhancement of the inflammatory marker in many cases, but glucuronoxylomannan antigen-positive reactions are detected. -causative microorganisms: this disease is caused by cryptococcus neoformans. recently, infection with c. gattii has been reported in vancouver, canada and the north area of the west coast of the united states of america; caution is needed. -c. gattii is primarily distributed in the tropical and subtropical zones. infection in humans has been considered to be rare. however, since , patients infected with c. gattii have been reported in the pacific coast of north america. even healthy adults are infected with c. gattii, and the mortality rate is high. ---drugs to be recommended---although there is no evidence regarding pulmonary cryptococcosis, flcz tablets, which have a potent activity against cryptococcus, are frequently selected when the patient's condition is stable in the absence of an underlying disease. azoles other than this drug can also be selected. [ ] (aii). -if the lesion is localized, resection should be considered. -combination therapy with an iron chelating agent and l-amb should be avoided [ ] (ai). ---explanation--- recently, an increase in the incidence of infection with cunninghamella has also been indicated. -specific condition: nasal/brain-type, dermal, and disseminated zygomycosis is observed. ---drugs to be recommended---currently, only amph preparations may be clinically useful for treating zygomycosis among antifungal drugs that are available in clinical practice in japan. as high-dose therapy must be started as early as possible, not d-amph but l-amb should be selected. -l-amb, intravenous drip, mg/kg/once a day precautions for the use of antifungal drugs (confirm the package inserts.) ➀ vrcz vision disorder, liver dysfunction, and neurological/ mental adverse events may occur. combination therapy with rfp, rbt, efavirenz, ritonavir, carbamazepine, long-acting barbiturate, pimozide, quinidine sulfate, ergot alkaloid, or triazolam is contraindicated. this drug is also contraindicated for pregnant women. as a rule, it is contraindicated for patients with a ccr of < ml/ min (injection only). as the blood concentration of vrcz may vary, tdm should be conducted. in patients with mild to moderate liver dysfunction, the dose should be regulated. ➁ itcz hepatopathy and congestive heart failure may occur. combination therapy with pimozide, quinidine, bepridil, simvastatin, triazolam, azelnidipine, ergotamine, nisoldipine, dihydroergotamine, vardenafil, eplerenone, blonanserin, sildenafil, tadalafil, aliskiren, dabigatran(itcz oral only), rivaroxaban, ergometrine, or methylergometrine is contraindicated. this drug is contraindicated for patients with severe liver diseases, pregnant women. patients with a ccr of < ml/min are also contraindicated (injection only). ➂ flcz hepatopathy and a prolongation of qt may occur. combination therapy with triazolam, ergotamine, dihydroergotamine, quinidine, or pimozide is contraindicated. this drug is also contraindicated for pregnant women. ➃ f-flcz combination therapy with triazolam, ergotamine, dihydroergotamine, quinidine, or pimozide is contraindicated. this drug is also contraindicated for pregnant women. ➄ l-amb adverse events such as nephropathy, hypopotassiumemia, and fever may occur. this drug is contraindicated during leukocyte transfusion. ➅ cpfg this drug is safe, but hepatopathy may occur. caution is needed for combination therapy with cyclosporin, tacrolimus, rfp, efavirenz, nevirapine, phenytoin, dexamethasone, or carbamazepine. ➆ mcfg this drug is safe, but hepatopathy may occur. ➇ -fc anorexia and myelopathy may occur. combination therapy with tegafur-/gimeracil-/oteracil potassium-containing drugs is contraindicated. even after the discontinuation of tegafur-/gimeracil-/oteracil potassium-containing drugs, combination therapy should be avoided within days. this drug is also contraindicated for pregnant women. ---drugs to be recommended---st combination drugs are used as a gold standard of pcp treatment. however, there have been a large number of patients in whom treatment was discontinued due to their side effects. recently, atovaquone also became available in japan as a second-choice drug. in patients with mild pcp, atovaquone tablets were as effective as st combination drugs. in those with moderate pcp, st combination drugs were more effective, but there was no significant difference due to a small number of subjects. in atovaquone-treated patients, the incidence of adverse events for which administration was discontinued was lower than in st combination drug-treated patients, suggesting that the tolerance is high [ ] . the administration period should be days in hivinfected patients and days in non-hiv-infected patients. a target daily dose of trimethoprim should be e mg/kg. -st combination drug, oral, to tablets/ times a day -st combination drug, intravenous drip, e mg as trimethoprim/ times a day (infused over e h) <> second choices -pentamidine, intravenous drip, mg/kg/once a day (infused over e h) -atovaquone oral suspension, ml ( mg as atovaquone)/twice a day for days (orally administered after meals) * adjuvant therapy in patients with a pao of < mmhg or a-ado of > mmhg in room air, one of the above drugs should be combined with a corticosteroid from the start of treatment. however, the dose may be reduced or administration may be discontinued in the early phase in accordance with symptoms. when the respiratory state is extremely unfavorable, pulse therapy should also be considered. prednisolone days e : oral, e mg/twice a day days e : oral, e mg/twice a day days e : oral, . e mg/twice a day ---precautions for each drug---(confirm the package inserts.) ➀ st combination drug (baktar tablets) fever, exanthema, digestive symptoms, hepatopathy, nephropathy, and blood disorder may occur. this drug may interact with methotrexate, sulfadoxine, pyrimethamine, diaphenylsulfone, sulfonyl amide/sulfonylurea oral drugs for diabetes, warfarin, phenytoin, cyclosporin, zidovudine, digoxin, tricyclic antidepressants, and lamivudine. this drug is contraindicated for neonates, low-birthweight infants, pregnant women, and patients with g- -pd deficiency. in patients with renal dysfunction, dose reduction must be considered. side effects such as hypoglycemia, hypotension, nephropathy, taste disorder, numbness of the tongue/lips, ventricular arrhythmia, exanthema, and fever may occur. combination therapy with zalcitabine, pfa, or amiodarone is contraindicated. this drug is contraindicated for patients with severe ventilatory disturbance. ➂ atovaquone nausea/vomiting, exanthema, and diarrhea may occur. this drug should be carefully administered to patients with severe kidney or liver dysfunction. this drug may interact with rfp, rbt, tetracycline, metoclopramide, zidovudine, acetaminophen, benzodiazepines, aciclovir, opioid analgesic drugs, cephalosporin antibiotics, antidiarrheal drugs/laxatives, and indinavir. h. cytomegalovirus (cmv) pneumonia ---executive summary----in the field of transplantation, preemptive treatment with gcv should be conducted through cmv antigenemia test monitoring. -the efficacy of preemptive treatment with vgcv or pfa is similar to that of gcv. -if a diagnosis of cmv pneumonia is made, treatment with gcv should be promptly started [ ] (aii). -vgcv and pfa are recognized as alternative drugs for gcv [ , ] (bii). -combination therapy with an antiviral drug and high-dose immunoglobulin should be performed [ ] (aiii). ---explanation--- ---antimicrobial drugs to be recommended---a first-choice drug for cmv pneumonia treatment is gcv, which has been frequently used. pfa has been used to treat cmv infection in aids patients, but experience on its use is limited in patients after hematopoietic stem cell transplantation. ( ) initial administration a first choice -gcv, intravenous drip, mg/kg (over h or more)/ every h for e weeks þ anti-cmv high-titer gamma globulin, intravenous drip, . e g/once a day for the first days <> second choices -pfa, intravenous drip, mg/kg (over h or more)/ times a day, every h for e weeks or more þ anti-cmv high-titer gamma globulin, intravenous drip, . e g/once a day for the first days or -pfa, intravenous drip, mg/kg (over h or more)/ twice a day, every h for e weeks or more þ anti-cmv high-titer gamma globulin, intravenous drip, . e g/once a day for the first days ( ) maintenance administration a first choices -gcv, intravenous drip, mg/kg (over h or more)/once a day, days a week or -gcv, intravenous drip, mg/kg (over h or more)/once a day, days a week * this regimen should be completed after confirming the disappearance of clinical symptoms and negative reactions on two consecutive cmv antigenemia tests. <> second choice -pfa, intravenous drip, e mg/kg (over h or more)/once a day (in clinical practice in japan, there have been few case reports on once-a-day administration at mg/ kg as maintenance therapy. a dose exceeding mg/ kg should be avoided. for administration at mg/kg, twice-a-day administration at mg/kg is commonly selected.) * this regimen should be completed after confirming the disappearance of clinical symptoms and negative reactions on two consecutive cmv antigenemia tests. ---precautions for each drug---(confirm the package inserts.) ➀ gcv severe leukopenia, neutropenia, anemia, thrombopenia, pancytopenia, aplastic anemia, and bone marrow suppression may occur. an animal experiment showed that this drug induced transient or irreversible spermatogenic dysfunction and reduced fertility. in humans, this drug may cause spermatogenic dysfunction. an animal experiment demonstrated the teratogenicity, mutagenicity, and carcinogenicity of this drug. in the presence of renal hypofunction, it is necessary to regulate the dose. this drug is contraindicated for patients with marked bone marrow suppression (neutrophil count: < /mm or platelet count: < , /mm ) and pregnant women. it may interact with didanosine, zidovudine, ipm/cs, bone marrow-suppressing and kidney function-affecting drugs, zalcitabine, st combination drugs, cyclosporin, probenecid, and mycophenolate mofetil. ➁ vgcv this is a prodrug of gcv. ➂ pfa acute renal failure, shock, heart failure, thrombophlebitis, and convulsion may occur. it is necessary to regulate the dose in accordance with the kidney function. combination therapy with pentamidine is contraindicated. this drug is contraindicated for patients with a ccr of < . ml/min/kg. ---executive summary---for the treatment of community-acquired pneumonia in children, antimicrobial drugs should be selected, considering age and severity. ---explanation--- patients with acute respiratory infectious disease symptoms, such as fever, nasal discharge, pharyngeal pain, and cough, and the appearance of a new infiltrative shadow in the lung on imaging examinations such as chest x-ray and ct are regarded as having pneumonia [ ] . in patients with pneumonia, thoracic auscultation findings often include accessory murmurs and the attenuation of respiratory sounds. most patients with respiratory infectious diseases consult hospitals with fever and cough. the lesion site of the airway is estimated based on symptoms and physical findings (fig. ) [ ] . in addition to thoracic findings, it is necessary to check the presence or absence of dyspnea signs, such as tachypnea, nasal alar breathing, retractive breathing, shoulder breathing, orthopnea, groaning, and cyanosis. to consider the need of antimicrobial-drug administration and options of antimicrobial drugs, pneumonia is classified into three types: bacterial, viral, and atypical pneumonia based on causative microorganisms [ ] . [type and frequency of causative microorganisms] microorganisms that cause childhood community-acquired pneumonia differ among ages. according to the data on investigation of causative microorganisms based on lavage sputum culture in japan, bacterial and viral pneumonia is frequent in infants/children aged year or younger. in those aged e years, the incidences of bacterial, viral, and atypical pneumonia are similar. in those aged over years, the incidence of atypical pneumonia is the highest [ ] (fig. ) insufficient. however, a review reported similar findings [ ] ( table ) [ ] . in children, it is not easy to investigate causative microorganisms. in institutions in which it is impossible to investigate causative microorganisms, treatment must be performed based on the statistical frequency of causative microorganisms described below. however, in those in which investigation is possible, the etiology should be investigated if possible. [rules of antimicrobial drug therapy] it is important to improve the efficacy of treatment by accurately predicting causative microorganisms and selecting an appropriate antimicrobial drug and its administration method. whether or not an antimicrobial drug should be indicated must be comprehensively evaluated by differentiating bacterial, viral, and atypical pneumonia with reference to age, severity, clinical symptoms, physical findings, laboratory data, and x-ray findings [ ] . as a rule, a single antimicrobial drug should be selected. when the type of microorganisms that caused pneumonia is identified, an antimicrobial drug should be selected through de-escalation, considering drug susceptibility and pharmacokinetics. [clinical symptoms, physical findings] wet cough and tachypnea are frequently observed in children with bacterial pneumonia. the proportion of labored breathingfree patients is high in children with mycoplasma pneumonia [ , ] . auscultation findings include intermittent accessory murmurs (rales) regardless of the type of pneumonia. in children with mycoplasma pneumonia, the proportion of those in whom auscultation findings are not marked is significantly higher than in other groups. in children with chlamydia pneumonia, fever is mild, and cough is protracted. thus, clinical symptoms and physical findings show characteristics related to causative microorganisms, but it is difficult to identify causative microorganisms based on clinical symptoms and physical findings alone in individual patients [ e ] . concerning laboratory findings on admission in children with bacterial and viral pneumonia, there are significant differences in the leukocyte count, crp level, and erythrocyte sedimentation rate between the two groups (p < . ). however, measurements overlapping in about one-third of patients are presented [ ] (fig. ) . briefly, it is impossible to accurately differentiate bacterial from viral pneumonia based on inflammatory responses reflected by the leukocyte count, crp level, and erythrocyte sedimentation rate. mycoplasma pneumonia is characterized by increases in the crp level and erythrocyte sedimentation rate, but many patients show normal leukocyte counts or a slight decrease in this parameter. furthermore, it is difficult to differentiate mycoplasma from viral pneumonia based on laboratory data [ ] . [chest x-ray] chest x-ray findings show characteristics related to causative microorganisms to some degree, but it is difficult to identify causative microorganisms in individual patients [ ] . it is important to evaluate the severity of pneumonia, for selecting outpatient or hospital treatment and reviewing the necessity of antimicrobial drugs and route of administration (oral or intravenous). the classification of severity in the guidelines for the management of respiratory infectious diseases in children in japan is presented [ ] (table ) . causative microorganisms with respect to age in children with community-acquired pneumonia [ ] . the severity classification of childhood pneumonia has not been reached in japan or internationally. this should be examined in the future. [standards for outpatient/hospital treatment] as a rule, outpatient treatment should be performed in mildstatus patients evaluated according to the severity classification, and hospital treatment in mild-status patients with dehydration. in addition, it is necessary to determine admission when outpatient treatment does not lead to an improvement in symptoms or considering social adaptation [ ] (table ) . [initial antimicrobial drug therapy] when examining children with pneumonia, treatment must be started without any precise information about causative microorganism in many cases. basically, empiric therapy should be performed, considering the severity of pneumonia and causative microorganisms. -the type of causative microorganisms depends on age and severity. therefore, the necessity of antimicrobial drugs should be examined, and selected, considering age and severity. in addition, bacterial, viral, or atypical pneumonia should be differentiated, and comprehensively evaluated in reference to clinical symptoms, physical findings, laboratory findings, and xray findings [ ] . in particular, acute bronchitis/pneumonia related to intermediately susceptible h. influenzae (mic: mg/ml) can be managed with oral ampc or abpc intravenous injection therapies [ ] . recently, the number of abpc-susceptible strains has annually decreased [ , ] . the proportion of blnar strains (mic: mg/ table age-related distribution of microorganisms that cause pneumonia in children [ ] . immediately after birth to . inflammatory response on admission in children with pneumonia [ ] . ml or more) has increased, raising an issue with respect to drug selection. when the involvement of blnar strains is suspected, high-dose ampc or new oral cephems may be necessary at outpatient clinics [ ] . the efficacy of outpatient antimicrobial drugs for blnar strains, which will increase in the future, should be carefully monitored. concerning hospital treatment, the clinical effects of abpc intravenous injection for e days until the results of a susceptibility test were clarified were investigated, and approximately % of patients responded to this therapy. there was no exacerbation in any patient [ ] . in non-responders or patients in whom clinical effects are insufficient, it is necessary to switch the antimicrobial drug. pipc, ctx, and ctrx have stable antimicrobial activities. when reviewing the clinical effects of pipc on childhood bronchopulmonary infection, the response rate was %; the results were satisfactory [ ] . -concerning treatment for m. catarrhalis pneumonia, m. catarrhalis produces b-lactamase. however, when examining the clinical course, ampc is effective [ , ] . this is because the enzymatic activity of b-lactamase produced by m. catarrhalis is low [ ] . (table ) . [evaluation of the treatment response and administration period] the administration period of antimicrobial drugs is shown in table [ ] . classification of the severity of community-acquired pneumonia in children [ ] . moderate severe . increases in the number of resistant strains of s. pneumoniae and h. influenzae derived from respiratory infectious diseases [ ] . to treat community-acquired pneumonia, antimicrobial drugs should be administered for e days. the treatment response should be evaluated after e days. in children, disease progression is often prompt, and the first evaluation should be performed after days in younger and severe-status children, and not after days [ ] . if an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until an appropriate antimicrobial drug and drug susceptibility are clarified. with respect to the administration period of antimicrobial drugs, factors such as the type of causative microorganisms and patient background differ among individual patients; therefore, it is difficult to establish standardized criteria. as m. pneumoniae and c. pneumoniae slowly proliferate, the treatment period is prolonged (table ). in patients infected with general bacteria, the administration of antimicrobial drugs can be discontinued days after pyretolysis [ ] . however, further antimicrobial drug therapy is necessary to treat s. aureus pneumonia. [management for non-responders to antimicrobial drugs] when there are no therapeutic effects of antimicrobial drugs on pneumonia, whether or not a diagnosis of pneumonia is correct should be initially investigated [ ] . the possibility of diseases other than pneumonia, with a pneumonia-like shadow, must be reviewed (table ). if it can be ruled out, whether or not the expected type of pathogenic microorganisms is correct should be examined. if the type of causative microorganisms is the same as expected, the possibility of resistant microorganisms should be considered. new therapeutic strategies should be devised carefully and promptly. when the condition further exacerbates despite treatment switching, additional examination should be conducted. [ ] . concepts regarding the diagnosis and treatment of childhood mycoplasma pneumonia [ ] . . as it is often difficult to make a diagnosis of mycoplasma pneumoniae infection based on serum antibody titer-positive findings in the acute stage alone, the mycoplasma pneumoniae nucleic acid identification test (lamp method) should be conducted to make a definitive diagnosis in the acute stage. . as first-choice drugs for mycoplasma pneumonia, macrolides should be used. . the effects of macrolides can be evaluated based on pyretolysis within e days after administration. . to treat pneumonia that does not respond to macrolides, the administration of tosufloxacin or tetracyclines should be considered if necessary. however, as a rule, tetracyclines are contraindicated for children aged years or younger. . these antimicrobial drugs should be administered in accordance with administration periods recommended for individual drugs. . in patients with severe pneumonia, systemic steroid therapy must be considered. however, easy steroid administration should be avoided. however, mycoplasma pneumoniae is not included in bacterial types for which this preparation may be indicated. ---drugs to be recommended--- a first choices ) cases in which there is no risk of resistant bacteria -ampc, oral, e mg/kg/ times a day -sbtpc, oral, mg/kg/ times a day -cdtr-pi, oral, mg/kg/ times a day -cfpn-pi, oral, mg/kg/ times a day -cftm-pi, oral, mg/kg/ times a day ) cases in which infection with resistant bacteria is suspected i) two years or younger, ii) pretreatment with an antimicrobial drug (within weeks), iii) concomitant development of otitis media, iv) history of pneumonia/repeated otitis media -ampc, oral, e mg/kg/ times a day -cva/ampc ( : preparation), oral, . mg/ kg/twice a day -cdtr-pi, oral, mg/kg/ times a day -cfpn-pi, oral, mg/kg/ times a day -cftm-pi, oral, mg/kg/ times a day ) cases in which onset/recurrence/recrudescence is observed despite previous treatment ) -tbpm-pi, oral, e mg/kg/twice a day -tflx, oral, mg/kg/twice a day <> second choices -azm, oral, mg/kg/once a day for days -cam, oral, . mg/kg/twice a day ( ) admission (moderate, general ward) a first choices -abpc, intravenous injection or drip, mg/kg/ times a day -pipc, intravenous injection or drip, mg/kg/ times a day -sbt/abpc, intravenous injection or drip, mg/kg/ times a day * when m. pneumoniae, chlamydia trachomatis, or c. pneumoniae infection is strongly suspected, one of the above regimens should be combined with a macrolide [with respect to the administration method/ dose, refer to the section "➁ six years or older---( ) outpatient clinic (mild)".]. <> second choices -ctx, intravenous injection or drip, mg/kg/ times a day -ctrx, intravenous injection or drip, e mg/kg/ once to twice a day ( e mg/kg/day) ( ) admission (severe, icu) -papm/bp, intravenous drip, mg/kg/ times a day -mepm, intravenous drip, mg/kg/ times a day -taz/pipc, intravenous drip, . mg/kg/ times a day * when legionellosis cannot be ruled out, one of the above regimens should be combined with a macrolide [with respect to the administration method/dose, refer to the section "➁ six years or older---( ) admission (moderate, general ward)".]. ➁ six years or older ( ) outpatient clinic (mild) a first choices -azm, oral, mg/kg/once a day for days -cam, oral, . mg/kg/twice a day <> second choices -ampc, oral, e mg/kg/ times a day -sbtpc, oral, mg/kg/ times a day -cdtr-pi, oral, mg/kg/ times a day -cfpn-pi, oral, mg/kg/ times a day -cftm-pi, oral, mg/kg/ times a day -mino, oral, e mg/kg/twice a day (in children aged years or younger, the use of this drug is limited to those in whom other drugs cannot be used or nonresponders to other drugs.) ( a first choices ) cases in which bacterial pneumonia is suspected -abpc, intravenous injection or drip, mg/kg/ times a day -pipc, intravenous injection or drip, mg/kg/ times a day -sbt/abpc, intravenous injection or drip, mg/ kg/ times a day -ctx, intravenous injection or drip, mg/kg/ times a day -ctrx, intravenous injection or drip, e mg/ kg/once to twice a day ( e mg/kg/day) ) cases in which atypical pneumonia is suspected -azm, oral, mg/kg/once a day for days -cam, oral, . mg/kg/twice a day -em, intravenous drip, mg/kg/ e times a day -mino, oral or intravenous drip, e mg/kg/twice a day (in children aged years or younger, the use of this drug is limited to those in whom other drugs cannot be used or non-responders to other drugs.) ) cases in which it is impossible to differentiate bacterial from atypical pneumonia one drug each should be selected from choices ) and ), and combined. -em, oral, e mg/kg/ times a day -azm, oral, mg/kg/once a day for days -cam, oral, . mg/kg/twice a day -em, intravenous drip, mg/kg/ e times a day -mino, oral or intravenous drip, e mg/kg/twice a day (in children aged years or younger, the use of this drug is limited to those in whom other drugs cannot be used or non-responders to other drugs.) ---executive summary---for the treatment of hospital-acquired pneumonia in children, antimicrobial drugs should be selected, considering severity and the involvement of resistant bacteria. empiric therapy should be started by combining two drugs if necessary, considering various resistant microorganisms, differing from that for communityacquired pneumonia (biii). hospital-acquired pneumonia is defined as pneumonia that newly develops h or more after admission. ventilator-associated pneumonia is defined as pneumonia that develops h or more after endotracheal intubation [ ] . these conditions may become severe due to an underlying disease, reduced immune capacity, or the deterioration of the general condition, and are caused by drugresistant microorganisms in many cases; treatment is difficult in most cases. not only microorganisms acquired in the community but also those existing in the hospital environment cause hospital-acquired pneumonia in children, as reported in the adult field. bacteria that cause community-acquired pneumonia (s. pneumoniae, h. influenzae), enteric bacteria (e. coli, k. pneumoniae), s. aureus, non-glucose-fermenting bacteria, such as p. aeruginosa, and acinetobacter spp., and anaerobes cause hospital-acquired pneumonia [ ] . in addition, not only general bacteria but also fungus and viruses sometimes cause hospital-acquired pneumonia in patients with immunodeficiency. among patients with nosocomial infection, causative microorganisms differ, and drug-resistant microorganisms are involved in many cases. in children, it is not easy to investigate causative microorganisms, but, if drug susceptibility is clarified, it contributes to successful treatment. therefore, lavage or aspiration sputum culture should be conducted to investigate the etiology, if possible [ , ] . [rules of antimicrobial drug therapy] basically, empiric therapy should be performed, considering the severity of pneumonia, an underlying disease, and causative microorganisms. in particular, the involvement of drug-resistant microorganisms, such as mrsa, extended-spectrum b-lactamase (esbl)-producing bacteria, and multi-drug-resistant p. aeruginosa (mdrp), must always be considered for treatment. empiric therapy should be started by combining two drugs if necessary, considering various resistant microorganisms, differing from that for community-acquired pneumonia [ ] . as the state of resistant bacteria differs among institutions, antimicrobial drug options should be customized based on records on antimicrobial drug susceptibility (antibiograms) at each institution. a consensus regarding the administration period of antimicrobial drugs has not been reached. with respect to the administration period of antimicrobial drugs, factors such as the type of causative microorganisms and patient background differ among individual patients with nosocomial infection; therefore, it is difficult to establish standardized criteria. however, when complications such as severe immunodeficiency, pulmonary suppuration, lung abscess, and pleuritis are absent, antimicrobial drugs should be administered for days after pyretolysis ( e days) [ ] . considering an underlying disease or the immune state, flexible management must be performed. in children, disease progression is often prompt, and the first evaluation should be performed after days in younger and severe-status children, and not after days [ ] . if an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until an appropriate antimicrobial drug and drug susceptibility are clarified. when the type of microorganisms that caused pneumonia is identified, a target-focused antimicrobial drug should be selected through de-escalation, considering drug susceptibility and pharmacokinetics [ ] . concerning multi-drug-resistant microorganisms, it is important to promote standard preventive strategies and those to control nosocomial infection, such as the prevention of droplet/contact infection, thoroughly. furthermore, oral care and devised postures (if there is no medical contraindication, the head should be lifted at e .) are necessary to prevent vap [ ] . in this article, the classification of severity (table , p. ) in the guidelines for the management of respiratory infectious diseases in children in japan was used [ ] (refer to the section " . pneumonia (children), . community-acquired pneumonia".). ---drugs to be recommended--- a first choices -caz, intravenous injection or drip, mg/kg/ times a day -czop, intravenous injection or drip, mg/kg/ e times a day -cpr, intravenous injection or drip, mg/kg/ e times a day if necessary, one of the above regimens should be combined with one of the following drugs: ) cases in which anaerobe infection is suspected (such as aspiration pneumonia) -cldm, intravenous drip, in children with immunodeficiency-/blood disease-related pneumonia, antimicrobial drugs should be selected, considering an underlying disease, the grade of immunodeficiency, and involvement of various causative microorganisms. initial antimicrobial drug therapy should be started by combining two drugs if necessary, considering various causative microorganisms, differing from that for community-acquired pneumonia (biii). [characteristics and classification of the disease] as immunodeficiency-/blood disease-related pneumonia in children often develops in hospitals, it has the characteristics of hospital-acquired pneumonia in many cases. it may become severe due to the patient's unfavorable conditions, such as an underlying disease, reduced immune capacity, and the deterioration of the general condition. even non-pathogenic microorganisms may cause pneumonia in many cases. furthermore, drug-resistant microorganisms often cause pneumonia; treatment is difficult in many cases [ , ] . to achieve multidisciplinary, comprehensive treatment to save children, it is necessary to cooperate with other special fields. [type and frequency of causative microorganisms] not only microorganisms acquired in the community in the presence of various immunodeficiency states but also nonpathogenic microorganisms existing in the hospital environment cause immunodeficiency-/blood disease-related pneumonia in children. bacteria that cause community-acquired pneumonia (s. pneumoniae, h. influenzae), enteric bacteria (e. coli, k. pneumoniae), s. aureus, non-glucose-fermenting bacteria, such as p. aeruginosa, and acinetobacter spp., and anaerobes cause this type of pneumonia. in addition, not only general bacteria but also fungus and viruses often cause this type of pneumonia. furthermore, drugresistant microorganisms are involved in many cases, as indicated for hospital-acquired pneumonia [ , ] . [type of immunodeficiency, causative microorganisms to be monitored, and precautions for diagnosis] ➀ humoral immunodeficiency: as bacterial opsonization and complement activation are affected, patients with humoral immunodeficiency are prone to be infected with general bacteria. among immunodeficiency patients with hyper-igm-emia, pneumocystis pneumonia should be considered in those with conditions related to cd ligand abnormalities. ➁ cellular immunodeficiency: in addition to infection with general bacteria, infection with intracellular parasitic bacteria, fungus, or protozoa may become severe, and be protracted. as the differentiation and induction of b and killer t cells by cd -positive lymphocytes are affected, the eradication of virus-infected cells is inhibited (table ) [ ] . ➂ neutrophil abnormalities: neutrophil abnormalities are classified into two types: neutropenia and neutrophil functional disorders. patients with a peripheral blood absolute neutrophil count (anc) of < /ml or those in whom the anc is estimated to reach < /ml within h are regarded as having neutropenia [ ] . of these, the risk is higher in patients with an anc of /ml or less in whom the period is estimated to exceed days. many patients with neutropenia do not show purulent sputum or abnormal findings on chest x-ray even in the presence of pneumonia. therefore, when fever persists, thoracic ct should be performed in the early stage. all microorganisms including general bacteria (gram-positive bacteria, gramnegative bacteria), fungus, and viruses may cause pneumonia. in particular, in addition to neutropenia early after homologous hematopoietic stem cell transplantation, infection-prone features associated with humoral/cellular immunodeficiency related to the administration of immunosuppressives persist over a long period. furthermore, the concomitant development of acute/chronic graft-versus-host disease (gvhd) is a risk factor for the onset of pneumonia. in addition, non-infectious pulmonary disorder related to drugs/radiation for pretreatment may occur, and it is important to differentiate it from infectious diseases (fig. ) [ , ] . a representative neutrophil functional disorder, chronic granulomatosis, induces active oxygen production disorder of neutrophils, affecting bactericidal actions. therefore, patients with this disorder are prone to be infected with non-h o -producing catalase-positive bacteria (s. aureus, k. pneumoniae, e. coli, candida spp., aspergillus spp.). ➃ complement deficiency: patients with complement deficiency are prone to be infected with bacteria with capsules, such as s. pneumoniae, h. influenzae (capsule strains), and neisseria meningitidis [ ] . in children, it is not easy to investigate causative microorganisms, but, if drug susceptibility is clarified, it contributes to successful treatment. therefore, various cultures should be conducted to investigate the etiology, if possible. in addition, testing of various antigens, such as urinary s. pneumoniae/legionella antigens, b-dglucan, aspergillus antigen, cryptococcus antigen, candida antigen, and cytomegalovirus antigen, and tests using nucleic acid amplification methods, such as the pcr method, should be utilized, if possible. [rules of antimicrobial drug therapy] initial antimicrobial drug therapy should be performed, considering the severity of pneumonia and an underlying disease. for the treatment of immunodeficiency-/blood disease-related pneumonia in children, antimicrobial drug therapy should also be basically selected, considering causative microorganisms. as described for nosocomial infection, the involvement of drugresistant microorganisms, such as mrsa, extended-spectrum blactamase (esbl)-producing bacteria, and multi-drug-resistant p. aeruginosa (mdrp), must always be considered for treatment. initial antimicrobial drug therapy should be started by combining two drugs, if necessary, considering various resistant microorganisms, differing from that for community-acquired pneumonia [ , ] . as the state of resistant bacteria differs among institutions, antimicrobial drug options should be customized based on records on antimicrobial drug susceptibility (antibiograms) at each institution. a consensus regarding the administration period of antimicrobial drugs has not been reached. with respect to the administration period of antimicrobial drugs, factors such as the type of causative microorganisms and patient background differ among individual patients with nosocomial infection; therefore, it is difficult to establish standardized criteria. in children, disease progression is often prompt, and the first evaluation should be performed after days in younger and severe-status children, and not after days. if an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until an appropriate antimicrobial drug and drug susceptibility are clarified. when the type of microorganisms that caused pneumonia is identified, a target-focused antimicrobial drug should be selected through de-escalation, considering drug susceptibility and pharmacokinetics [ ] . monitoring culture of the airway is useful for treating immunodeficiency-/blood disease-related pneumonia in children [ ] . general preventive methods are presented in table [ ] . in addition, long-term low-dose macrolide therapy or the intermittent administration of b-lactams to prevent p. aeruginosa fixation is effective in some patients with chronic bronchitis [ , ] . in those with chronic granulomatosis, the oral administration of itcz ( e mg/kg/day, maximum: mg/day) or subcutaneous injection of ifn-g ( , domestic standard units/m , e times a week) is useful for preventing infection [ ] . in this article, the classification of severity (table , p. ) in the guidelines for the management of respiratory infectious diseases in children in japan was used (refer to the section " . pneumonia (children), . community-acquired pneumonia".). ---drugs to be recommended--- ( ) pneumonia related to mild immunodeficiency in the initial phase after admission -sbt/abpc, intravenous injection or drip, mg/kg/ e times a day -ctx, intravenous injection or drip, mg/kg/ e times a day -ctrx, intravenous injection or drip, mg/kg/twice a day ( ) pneumonia related to moderate/severe immunodeficiency -caz, intravenous injection or drip, mg/kg/ e times a day -czop, intravenous injection or drip, mg/kg/ e times a day -cpr, intravenous injection or drip, mg/kg/ e times a day in severe cases, -papm/bp, intravenous drip, mg/kg/ times a day -mepm, intravenous drip, mg/kg/ times a day -drpm, intravenous drip, mg/kg/ times a day -taz/pipc, intravenous drip, . mg/kg/ times a day -vcm, intravenous drip, mg/kg/ times a day -abk, intravenous drip, e mg/kg/once a day -teic, intravenous drip, mg/kg/every h, times, subsequently: e mg/kg/once a day when there is no response, -amk, intravenous drip, e . mg/kg/twice a day -tob, intravenous drip, . mg/kg/ times a day if necessary, an antifungal drug (mcfg) and st combination drug should be additionally administered. when aspergillus infection is suspected, treatment should be started with vrcz or l-amb instead of mcfg. in patients with cellular immunodeficiency, one of the above drugs should be combined with mcfg and an st combination drug in the early stage. in those with neutrophil abnormalities, one of the above drugs should be combined with mcfg in the early stage. when legionellosis cannot be ruled out in the severest cases, one of the above regimens should be combined with a macrolide (with respect to the administration method/dose, refer to the section " . community-acquired pneumonia---➁ six years or older---( ) admission (moderate, general ward)" (p. ).). in the presence of gcv resistance, the intravenous drip of pfa (foscarnet), mg/kg/ times a day should be performed. ---executive summary---in the treatment of neonatal pneumonia, antimicrobial drugs should be selected after differentiating congenital from acquired pneumonia. initial antimicrobial drug therapy should be started by combining two drugs, regarding the condition as severe systemic infection and considering various causative microorganisms. the administration method and dose should be selected based on the age (days) and birth weight (biii). [characteristics and classification of the disease] the incidence of neonatal pneumonia is not high. according to sakata, pneumonia occurred in only ( . %) of approximately , neonates who were admitted during a -year period [ ] . neonatal pneumonia is frequently observed as a portion of systemic infection represented by sepsis, and not as a single condition. it is classified into two types: congenital and acquired pneumonia [ ] . in most cases, neonatal pneumonia does not cause any typical symptoms such as fever or cough in comparison with infantile/ childhood pneumonia. the neonatal protective capacity against infection is physiologically immature, often leading to a severe condition. in the neonatal phase, artificial respiration management is performed in many cases, and ventilator-associated pneumonia (vap) is frequently observed [ e ]. in addition, many neonates are admitted to the neonatal intensive care unit (nicu) for a long period; therefore, the incidence of nosocomial infection is high. [type and frequency of causative microorganisms] several types of congenital pneumonia include transplacental infection, intrauterine infection related to aspiration of infected amniotic fluid on premature rupture, and birth canal infection with vaginal discharge on delivery. these types of congenital pneumonia are primarily caused by various viruses (cytomegalovirus, herpes simplex virus), bacteria (streptococcus agalactiae (gbs), e. coli, listeria monocytogenes), chlamydia, and fungus. the clinical onset of perinatal pneumonia is frequently observed immediately to days after birth [ ] . postnatal pneumonia usually develops weeks or more after birth. it is caused by viruses and bacteria. viral infection may occur when rs virus, parainfluenza virus, or adenovirus prevails in the ward. however, it rarely leads to the onset of pneumonia. frequent causative bacteria include s. aureus, e. coli, p. aeruginosa, acinetobacter spp., enterobacter spp., and legionella spp., which exist in the environment. these often cause nosocomial infection [ ] . in premature babies, gram staining of tracheal aspirate samples is useful for selecting antimicrobial drugs to be administered in the initial phase [ ] . in children, it is not easy to investigate causative microorganisms, but, if drug susceptibility is clarified, it contributes to successful treatment. therefore, blood or bronchial lavage fluid culture should be conducted to investigate the etiology, if possible. [rules of antimicrobial drug therapy] as many neonates have systemic infection in an immunodeficiency state, the same administration method and dose as selected for the treatment of sepsis should be used [ ] . therefore, the severity of pneumonia is not considered. when bacterial pneumonia is suspected, combination therapy with abpc and ctx is commonly selected as initial treatment. considering l. monocytogenes infection, combination therapy with abpc is recommended. after causative microorganisms are identified, antimicrobial drugs should be selected with reference to their drug susceptibility. in cases of vap, antimicrobial drug options should be customized based on records on the drug susceptibility (antibiograms) of microorganisms that cause nosocomial infection at each institution. in neonates, there are marked age-related differences in the pharmacokinetics of antimicrobial drugs; therefore, these drugs must be carefully administered in the neonatal phase. concretely, the same dose as established in the field of pediatrics should be used, and the administration interval should be prolonged in accordance with age [ ] . in cases of severe asphyxia or acute renal failure, the administration interval must be further prolonged. it should be shortened with an improvement in the kidney function [ e ] . a consensus regarding the administration period of antimicrobial drugs has not been reached. however, the standard administration period is days. with respect to the administration method/dose, refer to the section "xi. doses for neonates". in neonates, disease progression is often prompt, and the treatment response should be evaluated after days, and not after days. if an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until an appropriate antimicrobial drug and drug susceptibility are clarified. when the type of microorganisms that caused pneumonia is identified, a target-focused antimicrobial drug should be selected through de-escalation, considering drug susceptibility and pharmacokinetics [ ] . ---drugs to be recommended--- ---executive summary----pyothorax refers to a condition in which pus accumulates in the thoracic cavity. usually, pleural effusion puncture is performed, and a diagnosis of pyothorax is made based on the results of various examinations, such as (macroscopic) purulent pleural effusion, microorganisms detected on gram staining or culture of pleural effusion, or pleural effusion ph: < . (biii). -in patients with acute pyothorax related to community-acquired pneumonia, treatment should be performed in accordance with that for community-acquired pneumonia, considering microorganisms that cause community-acquired pneumonia, such as streptococcus pneumoniae (biii). -in patients with slowly progressing pyothorax, mixed infection with oral aerobes/anaerobes is frequently observed. combination therapy with pcg or abpc and cldm or mnz, which show anti-anaerobe activities, or therapy with a single antimicrobial drug with an anti-anaerobe activity, such as sbt/abpc, should be selected (biii). -when there is a risk of multi-drug-resistant bacteria, monotherapy with a carbapenem, combination therapy with a fourthgeneration cephalosporin and cldm or mnz, and combination therapy with a quinolone and cldm or mnz should be considered, assuming esbl-producing enteric bacteria, resistant p. aeruginosa, anaerobes, and acinetobacter (biii). -if the results of culture/susceptibility tests are clarified, antimicrobial drugs should be changed in accordance with them (aiii). -the penetration of aminoglycosides to the thoracic cavity is poor, and their activities reduce when the ph is low. therefore, the use of aminoglycosides should be avoided as a rule (biii). -if a diagnosis of pyothorax is made, the administration of an appropriate antimicrobial drug should be started, and drainage must be performed (aii). if possible, the attending physician should consult a surgeon in the early stage (aiii). -in some patients with marked pleural thickening or multilocular pleural effusion, thoracoscopic debridement is necessary (biii). in addition, a fibrinolytic drug, such as streptokinase, is administered through a thoracic drain, or surgical interventions such as thoracotomy or decortication is performed in some cases (biii). ---explanation--- [diagnosis] -pyothorax is defined as a condition in which pus accumulates in the thoracic cavity, but this definition has no diagnostic objectivity. for this reason, usually, pleural effusion puncture is performed, and a diagnosis of pyothorax is made based on the results of various examinations, such as (macroscopic) purulent pleural effusion, microorganisms detected on gram staining or culture of pleural effusion, or pleural effusion ph: < . [ , ] . [causative microorganisms] -pleural effusion appears in e % of patients with bacterial pneumonia, but leads to pyothorax in . e %. other etiological factors for pyothorax include surgery, trauma, and esophageal perforation. -microorganisms that cause pyothorax depend on its etiology and course. in the presence of bacterial pneumonia, pyothorax is caused by the same microorganisms as caused bacterial pneumonia. furthermore, acute pyothorax is frequently caused by s. pneumoniae and s. aureus. however, in many patients with chronic pyothorax, mixed infection primarily with anaerobes is involved. among anaerobes, fusobacterium spp. (especially fusobacterium nucleatum), prevotella spp., peptostreptococcus spp., and bacteroides spp. are frequently detected [ e ]. according to recent studies, the detection rate of the streptococcus anginosus group is high [ , ] . -in many cases, pyothorax with a relatively slow course is associated with m. tuberculosis. it must be considered that pulmonary lesions do not always concurrently exist with tuberculous pleuritis. [treatment] -no randomized comparative study regarding antimicrobial drug treatment for pyothorax has been conducted. an antimicrobial drug with an activity against microorganisms expected or obtained on culture should be selected and administered. in acuteonset patients in whom there is no risk of resistant bacteria, for example, those with pyothorax accompanying communityacquired pneumonia, antimicrobial drugs such as pcg and abpc should be initially selected, considering s. pneumoniae. these drugs simultaneously cover fusobacterium, peptostreptococcus, and the viridans streptococcus group. however, prevotella and bacteroides produce b-lactamase; therefore, when the results of culture are not obtained, combination therapy with antimicrobial drugs with activities against anaerobes, such as cldm and mnz, or therapy with such a single drug, such as sbt/abpc, should be selected. -when there is a risk of multi-drug-resistant bacteria, monotherapy with a carbapenem should be selected as a first choice, assuming esbl-producing enteric bacteria, resistant p. aeruginosa, and acinetobacter. a fourth-generation cephalosporin should be combined with cldm, or a quinolone should be combined with cldm or sbt/abpc. -if the results of culture/susceptibility tests are clarified, antimicrobial drugs should be changed in accordance with them. however, the culture of anaerobes is difficult, or is not conducted in some cases. therefore, this should be confirmed to the laboratory. when only one type of bacteria are detected on a culture test despite several types of bacteria detected on gram staining of pleural effusion, anaerobes must also be considered. -the penetration of aminoglycosides to the thoracic cavity is poor, and their activities reduce when the ph is low. therefore, for pyothorax treatment, the use of aminoglycosides should be generally avoided [ e ]. [treatment period] -the pyothorax treatment period has not been established. however, when pneumonia promptly responds to treatment and thoracic drainage is successfully achieved in patients with pneumonia-related pyothorax, a treatment period of e days is required. in patients in whom drainage is unsuccessful, those with marked pleural thickening, or those with encapsulated/septum-like pyothorax, a treatment period of about weeks is often required. [treatments other than antimicrobial drug therapy] -after a diagnosis of pyothorax is made, the administration of an appropriate antimicrobial drug should be promptly started, and drainage is necessary. when the pleural fluid is purulent and viscous in the absence of a multilocular pattern, chest-tube insertion is routinely performed. the position of insertion should be confirmed using thoracic ct within h after insertion. wozniak et al. performed multivariate analysis involving patients with pyothorax and indicated that failure in the first drainage was strongly correlated with mortality, suggesting the necessity of early consultation with surgeons [ ] . -in some patients with marked pleural thickening or multilocular pleural effusion, thoracoscopic debridement is necessary. in addition, a fibrinolytic drug, such as streptokinase, is administered through a thoracic drain, or surgerical interventions such as thoracotomy or decortication is performed in some cases [ ] . ---drugs to be recommended--- a first choice -sbt/abpc, intravenous drip, g/ e times a day <> second choices -pcg, intravenous drip, , , to , , units/ times a day -abpc, intravenous drip, g/ e times a day þ one of the followings: -cldm, intravenous drip, mg/ e times a day -mnz, intravenous drip, mg/ times a day ➁ cases in which there is a risk of multi-drug-resistant bacteria a first choices -taz/pipc, intravenous drip, . g/ e times a day -ipm/cs, intravenous drip, . e g/ e times a day -mepm, intravenous drip, g/ e times a day -drpm, intravenous drip, . e g/ times a day <> second choices (i) -cfpm, intravenous drip, e g/ e times a day -czop, intravenous drip, e g/ e times a day -cpr, intravenous drip, e g/ e times a day þ one of the followings: -cldm, intravenous drip, mg/ e times a day -mnz, intravenous drip, mg/ times a day <> second choices (ii) -lvfx, intravenous drip, mg/once a day -cpfx, intravenous drip, mg/twice a day -pzfx, intravenous drip, to mg/twice a day þ one of the followings: -cldm, intravenous drip, mg/ e times a day -sbt/abpc, intravenous drip, g/ e times a day -mnz, intravenous drip, mg/ times a day * with respect to the risk of multi-drug-resistant bacteria, refer to the section " . hospital-acquired pneumonia" table (p. ). * in particular, mrsa infection must be considered in patients with nosocomial onset or the previous administration of antimicrobial drugs. when staphylococcus infection is suspected on gram staining of pleural effusion, an anti-mrsa drug should be used as an empiric therapy. if mssa is identified as causative bacteria, deescalation should be performed. . definitive therapy -antimicrobial drugs against causative microorganisms identified should be selected in accordance with the section " . ---executive summary---for the treatment of pyothorax in children, antimicrobial drugs should be administered after investigating the etiology using thoracentesis or blood culture, if possible. in addition to antimicrobial drug therapy, treatment for retention fluid (pleural effusion drainage, continuous drainage) must also be considered (biii). [characteristics and classification of the disease] pleuritis refers to inflammation of the pleura. fluid (pleural effusion) is retained in the pleural cavity. pleuritis is classified into types: fibrinous (dry) pleuritis, exudative (wet) pleuritis, and purulent pleuritis (pyothorax) based on conditions [ ] . on auscultation, the attenuation of respiratory sounds, as well as pleural friction rubs, are heard. percussion dullness is noted. in the chronic stage, localized pleural thickening in various shapes is observed. when pus is obtained on thoracentesis, a definitive diagnosis of pyothorax is made. when the protein level in nonpurulent pleural effusion is high, tuberculous pleuritis should be differentiated [ ] . [type and frequency of causative microorganisms] previously, pyothorax was associated with s. aureus in many cases. however, recently, such cases have been rare. according to data form a national survey in the former half of the 's, there were only a few patients with s. pneumoniae-or anaeroberelated pyothorax [ ] . in many cases, pleuritis follows m. pneumoniae-or virus-related pneumonia. decubitus-view imaging shows the retention of pleural effusion in approximately % of patients with mycoplasma pneumonia [ ] . if the drug susceptibility of causative microorganisms is clarified, it contributes to successful treatment. therefore, pleural effusion obtained by thoracentesis should be cultured to investigate the etiology, if possible. when bacterial infection-related pyothorax is suspected, the intravenous injection or drip of sbt/abpc, ctx, or ctrx should be selected in community-onset patients without an underlying disease. on the other hand, combination therapy with sbt/abpc (intravenous injection or drip) and cldm (intravenous drip) or carbapenem therapy (intravenous drip) should be started in those with an underlying disease or nosocomial onset, considering s. pneumoniae, anaerobes, h. influenzae, and s. aureus [ ] . based on the gram staining reactions of pleural effusion, causative microorganisms should be estimated, and antimicrobial drugs must be reviewed. if necessary, tuberculosis should also be investigated. the administration period of antimicrobial drugs must be longer than that for pneumonia. as the type of causative microorganisms, patient background, and state of retention-fluid drainage differ among individual patients, it is difficult to establish standardized criteria. however, target administration periods for s. pyogenes (gas)-, s. pneumoniae-, and s. aureus-related pyothorax are , , and days or more, respectively. the treatment response should be evaluated e days after the start of administration. if an improvement in clinical symptoms or laboratory data is achieved, the same antimicrobial drug should be continued until causative microorganisms and their drug susceptibility are clarified. when the type of microorganisms that caused pneumonia is identified, a targetfocused antimicrobial drug should be selected through deescalation, considering drug susceptibility and pharmacokinetics [ ] . for the treatment of pyothorax, treatment for retention fluid (pleural effusion drainage) is also a basic procedure in addition to antimicrobial drug therapy. if necessary, continuous drainage should be performed (table ) [ ] . if pleural thickening leads to underexpanded lung, decortication should be indicated. the widespread application of thoracoscopic surgery has facilitated minimally invasive surgery [ ] . ---drugs to be recommended--- ( ) community onset (without an underlying disease) -sbt/abpc, intravenous injection or drip, mg/kg/ times a day -ctx, intravenous injection or drip, mg/kg/ e times a day -ctrx, intravenous injection or drip, mg/kg/twice a day ( ) community-acquired infection (with an underlying disease), nosocomial onset -cldm, intravenous drip, mg/kg/ times a day þ -sbt/abpc, intravenous injection or drip, mg/kg/ times a day or one of the following drugs alone should be administered: -taz/pipc, intravenous drip, . mg/kg/ times a day -papm/bp, intravenous drip, mg/kg/ times a day -mepm, intravenous drip, mg/kg/ times a day -drpm, intravenous drip, mg/kg/ times a day . definitive therapy refer to the section " . community-acquired pneumonia--- . . definitive therapy" (p. ) or " . hospital-acquired pneumonia--- . . definitive therapy" (p. ). table indications for continuous drainage [ ] . ➀ cases in which pleural effusion obtained on thoracentesis is purulent ➁ cases in which clinical effects are not achieved by antimicrobial drug therapy alone (within h) ➂ cases in which retention fluid affects the respiratory function ---executive summary----as initial treatment, four drugs (inh, rfp, and pza þ eb or sm) should be administered for months. subsequently, as a rule, standard treatment (a), in which two drugs, inh and rfp, are administered for months, should be performed as maintenance treatment (ai). -when pza cannot be used for initial treatment for some reason, inh, rfp, and eb or sm, should be administered for months as initial treatment. subsequently, standard treatment (b), in which two drugs, inh and rfp, are administered for months, should be performed as maintenance treatment (aii). -in patients in whom chest x-ray shows a cavity on initial consultation to during initial treatment and the septum culture is still positive at the completion of initial treatment, maintenance treatment should be prolonged over months. in addition, the prolongation of maintenance treatment should also be considered in patients with severe tuberculosis, such as military tuberculosis and tuberculosis of the central nervous system, those with immune depression, and those with relapse of tuberculosis (aii). -for the treatment of latent tuberculosis infection, inh should be administered for or months (ai). when m. tuberculosis, as the source of infection, is resistant to inh, or when the oral administration of inh is difficult due to side effects, rfp should be used as a second-choice drug for or months (ai). ---explanation--- [ , ] . in particular, this method is named "standard treatment (a)" in the guidelines for the management of tuberculosis in in japan. in this article, this name is also used. -the secondary assessment of a study examining the efficacy of rifapentine and inh showed that factors for unsuccessful treatment/recurrence included a cavity on chest x-ray at the start of treatment and positive findings on culture at the completion of initial treatment for months [ ] . similarly, when the treatment period was extended from to months in patients with silicotuberculosis, in whom the unsuccessful treatment/recurrence rates are high, the recurrence rate decreased from to %. therefore, various guidelines recommend that maintenance treatment should be prolonged over months in patients with a cavity and those showing positive findings on septum culture at the completion of initial treatment [ , ] . -in , combs et al. compared the results of treatment between a group treated with inh, rfp, and pza for months and, then, with inh and rfp for months and that treated with inh and rfp for months, and reported that the efficacy and incidence of side effects were similar [ ] . based on such a study, the following regimen is recommended as standard treatment (b) in the guidelines for the management of tuberculosis in in japan: when pza cannot be used for some reason, inh, rfp, and eb or sm, are administered for the first months, and, subsequently, two drugs, inh and rfp, are administered for months. -patients who are infected with m. tuberculosis, but do not develop tuberculosis are regarded as having latent tuberculosis infection (ltbi). inh administration for ltbi decreases the incidence of tuberculosis by e % [ ] . previously, this was called preventive therapy, but is currently termed ltbi treatment. the decrease in the incidence of tuberculosis is correlated with compliance with inh, and more marked preventive effects may be achieved when compliance is higher [ e ]. in a study involving inh administration to ltbi patients with an old shadow on chest x-ray, this therapy inhibited the onset of tuberculosis in and % of patients treated for and months, respectively (there was no significant difference between the two groups) [ ] . based on the data, some studies recommended that the period of standard inh administration for ltbi should be months [ e ]. however, a consensus regarding an effective administration period ( or months) has not been reached from various aspects including the efficacy, compliance, expenses, and incidence of side effects. actually, the administration period should be determined based on compliance and the incidence of side effects. -in ltbi treatment, rfp should be used for or months as an alternative drug when the oral administration of inh is impossible for some reason. the preventive effects of rfp on the onset of tuberculosis in ltbi patients may be similar to those of inh. furthermore, the incidence of liver dysfunction is lower than that related to inh [ e ]. however, for the use of rfp, drug interactions must be considered. ---drugs to be recommended---a first choice -inh, oral, mg/kg/once a day (maximum: mg/ day) þ rfp, oral, mg/kg/once a day (maximum: mg/ day, orally administered before meals as a rule) þ pza, oral, mg/kg/once a day (maximum: mg/day) þ eb, oral, mg/kg/once a day (maximum: mg/day) or sm, intramuscular injection, mg/kg/once a day (maximum: mg/day)/ e times a week. * the above drugs should be administered for months, and, subsequently, two drugs, inh and rfp, should be administered for months. <> second choice -inh, oral, mg/kg/once a day (maximum: mg/ day) þ rfp, oral, mg/kg/once a day (maximum: mg/ day, orally administered before meals as a rule) þ eb, oral, mg/kg/once a day (maximum: mg/day) or sm, intramuscular injection, mg/kg/once a day (maximum: mg/day)/ e times a week. * the above drugs should be administered for months, and, subsequently, two drugs, inh and rfp, should be administered for months. [ ] . in japan, tanaka et al. conducted combination therapy with cam ( mg/kg) and eb/rfp/km in patients, and indicated that . % of those who underwent initial treatment became negative for mac [ ] . concerning cam, many studies have reported a correlation between the in vitro drug susceptibility and treatment response [ e ]. furthermore, a study indicated that azm was as effective as cam [ ] . -rbt, which was published in the drug price in nhi scheme in japan in , was also approved for tuberculosis and non-tuberculous mycobacterium infection, including pulmonary mac infection. the drug interactions of rbt are less marked than those of rfp, and rbt is used as a first-choice drug for disseminated mac infection in hiv-infected patients [ ] . on the other hand, rbt induces side effects such as uveitis. in elderly patients, in whom pulmonary mac infection frequently develops, various side effects, such as gastrointestinal disorder, make long-term therapy difficult [ ] . in addition, no study has indicated that rbt is more effective than rfp for pulmonary mac infection in non-hiv-infected patients. therefore, rfp should be selected as a first-choice drug for pulmonary mac infection in non-hiv-infected patients. -kobashi et al. divided patients with pulmonary mac infection into two groups: a group treated with cam, rfp, eb, and sm (intramuscularly injected at mg/kg times a week for months) and a group treated with saline, and conducted a randomized, double-blind, comparative study [ ] . in the sm-treated group, the rate at which the culture of sputum became negative was higher than in the salinetreated group ( . vs. . %, respectively). there has been no high-quality study demonstrating the usefulness of combination therapy with aminoglycosides other than their study. however, various guidelines recommend that combination therapy with sm, amk, or km should be performed for e months in the initial phase of treatment in patients with a cavity or severe nodular/bronchodilatation type infection based on experience [ , , ] . guidelines in the united states recommend sm or amk, and comment that no study has showed which of two drugs, sm and amk, is more effective, although sm has been more frequently used [ ] . in japan, sm or km is recommended [ ] . -based on the results of these studies, the non-tuberculous mycobacterium infection control committee, japanese society for tuberculosis recommends the following doses and administration methods for chemotherapy for pulmonary mac infection in the "opinions regarding chemotherapy for pulmonary non-tuberculous mycobacterium infection---revision in ": rfp: mg/kg (up to mg)/day, once a day, eb: mg/kg (up to mg)/day, once a day, cam: e mg/day ( e mg/kg), once a day or two divided doses ( mg: two divided doses), and sm or km: mg/kg or less (up to mg), intramuscularly injected or times a week [ ] . -a cooperative statement on non-tuberculous mycobacterium infection by the american thoracic society/infectious diseases society of america recommends therapy with cam at to mg/day or azm at mg/day, eb at mg/kg/day, and rfp at mg/kg/day (up to mg) for patients with a cavity or severe nodular/bronchodilatation type infection. in addition, it is recommended that combination therapy with sm or amk ( e mg/kg, e times a week, patients aged over years: mg or less) for e months in the initial phase should be considered [ , ] . -the treatment period is established as about year after the culture becomes negative in the above guidelines, but this is not based on evidence. in the guidelines for the management of non-tuberculous mycobacterium infection, which were published by the british thoracic society, the treatment period of pulmonary mac infection is established as years. in the future, an optimal treatment period should be investigated. ---drugs to be recommended----cam, oral, mg/ times a day or mg/twice a day þ rfp, oral, mg/kg/once a day (maximum: mg/ day, orally administered before meals as a rule) þ eb, oral, mg/kg/once a day (maximum: mg/day) * severe-status patients and those with cavity-type lesions in addition to the above regimen, the intramuscular injection of sm or km should be added. abscessus is sometimes susceptible to lzd, tgc (tigecycline), and ketolides, but it is unclear whether there is a correlation between the drug susceptibility and clinical effects [ , ] . -combination therapy with cam and several intravenous antimicrobial drugs (amk, cfx, and ipm/cs) may control the symptoms and progression of pulmonary infection with m. abscessus [ , ] . however, actually, hospitalization is required to administer these intravenous antimicrobials, and the administration period is limited to e months. subsequently, treatment with oral drugs is performed, but cam is the only reliable oral drug, as described above. on the other hand, monotherapy with cam should be avoided from the perspective of resistance induction. although some studies reported combination therapy with lzd or quinolones, its efficacy has not been established. -based on such a background, a combination of surgical resection of the lesion and combination chemotherapy is the only treatment that is expected to achieve the complete cure of pulmonary infection with m. abscessus in which the lesion is localized [ , , ] . ---drugs to be recommended--- a first choice based on the results of a drug susceptibility test, the following antimicrobial drugs should be combined: -cam, oral, mg/ times a day or mg/twice a day þ amk, intravenous drip, mg/kg/once a day þ ipm/cs, intravenous drip, . g/ times a day or g/ times a day * surgery must be considered. the treatment period should be at least months after culture becomes negative. ---executive summary----for the treatment of childhood tuberculosis, several drugs should be combined, and administered for a specific period (aii). -for the treatment of non-tuberculous mycobacterium infection, several drugs should be combined, and administered for a specific period. however, mycobacterium often resists treatment. if there is no treatment response, surgery must be considered (ciii). ---explanation--- [characteristics and classification of the disease] in japan, tuberculosis is still an important infectious disease. when encountering patients with chronic infection who do not respond to general antimicrobial drugs, tuberculosis should be considered for differential diagnosis. mycobacteria that can be cultured are classified into two types: m. tuberculosis complex and non-tuberculous mycobacteria (ntm) [ ] . m. tuberculosis is a major type of m. tuberculosis complex, and has a strong infectivity from humans to humans. childhood tuberculosis is classified into two types based on age [ ] . briefly, primary tuberculosis represented by hilar lymph node tuberculosis and meningitis, which develop following primary infection, is characteristic of infants and children. the interval from infection until onset is short, and the morbidity rate is high. in addition, this disease may lead to a severe condition. pulmonary/hilar lymph node tuberculosis in infants and children is asymptomatic, or the general condition is favorable even in the presence of fever or cough in many cases. when primary tuberculosis is detected based on dyspnea or an unfavorable general condition in addition to fever or cough, many infants/children have military tuberculosis or meningitis. on the other hand, secondary tuberculosis with a cavity lesion or nodular shadow in the lung field is frequent in junior high school students or older. symptoms such as cough, sputum, fever, and thoracic pain are often observed. in most children, the source of infection can be clarified through detailed peripheral contact screening at the time of onset. usually, the source of infection is clarified in / to / of children. it is often their fathers/mothers or grandfathers/grandmothers [ e ]. as childhood tuberculosis does not form a cavity in the lung field, the m. tuberculosis level in the focus is lower than in adults. in many cases, it is difficult to bacteriologically or histologically make a definitive diagnosis in comparison with adult tuberculosis. usually, it is possible to make a definitive diagnosis by comprehensively evaluating epidemiological/clinical information such as opportunities for the source of infection to contact with tuberculosis patients, tuberculin reaction-or quantiferon tb (qft)-based verification of infection, imaging findings suggestive of tuberculosis, such as chest x-ray findings, verification of m. tuberculosis from sputum or gastric juice, and individuals' resistance including the grade of bcg vaccination-acquired immunity and age, as well as by considering treatment responses in some cases. qft is a very useful testing method to quantitatively measure ifn-g and diagnose tuberculosis infection without being influenced by bcg. however, assessment in infants/children should be further examined in the future [ ] . when a definitive diagnosis of pulmonary tuberculosis cannot be made based on chest x-ray findings alone, thoracic ct, which facilitates the detailed evaluation of the presence or absence and extent of tuberculous lesions, is useful for diagnosis. furthermore, imaging findings of tuberculosis do not change in a short period in many cases. non-tuberculous mycobacterium belongs to mycobacterium, the same category as reported for m. tuberculosis. therefore, it is often detected as a mycobacterium-positive smear of sputum, that is, gaffky's positive reaction. initially, some patients are regarded as having infectious tuberculosis, and admitted to a tuberculosis ward. symptoms and imaging findings are also similar between nontuberculous mycobacterium-and m. tuberculosis-infected patients. unless detected bacteria are identified, or unless either gene is detected using the nucleic acid amplification method, it is difficult to differentiate the two types of bacteria. however, it is important to recognize that tuberculosis and non-tuberculous mycobacterium infection are different diseases [ , ] . the most important point is that non-tuberculous mycobacterium infection does not transmit from humans to humans, differing from tuberculosis, an infectious disease in humans. therefore, it is not necessary to isolate the patient, and, as a rule, patients requiring admission should be managed in a general ward. as there are no public hygieneassociated problems, it is not necessary to submit a report to a health center. [type and frequency of causative microorganisms] in japan, the number of patients with childhood tuberculosis has markedly decreased. the number of newly registered patients with tuberculosis decreased from , ( ) to ( ) in children aged e years [ e ]. however, a decrease in the incidence of smear-positive pulmonary tuberculosis, which is important as the source of infection, is not marked in great urban areas. we cannot conclude that the opportunity of infection in children is favorably decreasing; caution is needed. the number of patients who newly develop non-tuberculous mycobacterium infection in japan is estimated to be approximately . in the adult field, it accounts for about / of that of patients who newly develop tuberculosis. however, it is relatively low in children. approximately % of patients with non-tuberculous mycobacterium infection are infected with m. avium complex (m. avium and mycoboterium intracellulare, pulmonary mac infection), and approximately % are infected with m. cansasii. [rules of antimicrobial drug therapy] -the characteristics of antitubercular chemotherapy in children are that children are tolerable to a relatively high dose per body weight in comparison with adults with respect to pharmacokinetics, and that the incidence of side effects is low [ ] . in the pediatric field, -month treatment with inh, rfp, and pza for childhood pulmonary tuberculosis is internationally selected as standard chemotherapy: three drugs, inh, rfp, and pza, are administered every day for the first months, and inh and rfp every day for the subsequent months. when drug resistance is suspected, these drugs should be combined with sm or eb in the initial phase until the results of a resistance test are clarified. in patients with secondary tuberculosis, -drug combination therapy with inh, rfp, pza, and sm (or eb) should be initially performed. in addition, as a rule, follow-up must be continued for years after the completion of treatment [ e ]. on the other hand, drug resistance, referral to another hospital, and discontinued treatment are present among patients who drop out of treatment, although the number of such patients is small. it is necessary to support the resistance and continuation of treatment. in particular, recently, the number of patients in whom it is difficult to continue treatment has increased. potent compliance support must be considered in connection with direct observed therapy (dot) by health centers and welfare activities [ ] . side effects during treatment include liver dysfunction. however, if the maximum ast or alt levels are approximately , administration should be carefully continued without discontinuing treatment. if these levels exceed , treatment should be transiently discontinued, and additional administration at a low dose should be conducted after confirming the normalization of the liver function. the dose should be gradually increased. liver dysfunction requiring a change of treatment is not frequent. furthermore, there is an increase in the serum uric acid level, but continuous treatment leads to normalization. there have been few patients with arthralgia. -prevention of tuberculosis: to prevent the onset of tuberculosis in uninfected persons, bcg vaccination should be performed. concerning its efficacy, a consensus regarding its potent preventive effects on severe disseminated tuberculosis, such as tuberculous meningitis and military tuberculosis, has been reached. considering the importance of tuberculous meningitis prevention, bcg vaccination in the early phase of infancy ( e months after birth, or earlier in accordance with the state of peripheral tuberculosis prevalence) is still necessary in japan [ ] . -treatment for latent tuberculosis: to prevent the onset of tuberculosis in persons with a history of tuberculosis, treatment for latent tuberculosis (conventional chemoprevention) should be conducted. a large-scale controlled study reported that inh therapy decreased the incidence of tuberculosis by approximately e %. for drug administration, the risk of tuberculosis onset should be concretely and flexibly evaluated based on the tuberculin reaction, opportunity of infection, age, and state of bcg vaccination in individual patients [ ] . -treatment for non-tuberculous mycobacterium infection: nontuberculous mycobacterium infection is refractory despite combination therapy with antitubercular drugs. in particular, there is no evidence regarding treatment in children [ ] . the effects of monotherapy are weak, and monotherapy with cam may lead to the appearance of cam-resistant bacteria within a few months [ ] ; therefore, this therapy should be avoided. the responses of m. kansasii to antitubercular drugs are relatively favorable, and cure may be achieved. however, pulmonary mac infection is often resistant to treatment. if there is no response, surgery must be considered. recurrence after the completion of treatment is also often observed. ---drugs to be recommended--- * as the administration period is longer than that for tuberculosis patients, the development of vision disorder should be considered even at these doses. * if there is no response, surgery must be considered. ---explanation---acute bronchitis is characterized by cough that persists for days or more. in most cases, cough persists for e weeks, but spontaneously subsides [ , ] . sputum is present in some cases, but is absent in others. sputum may be purulent even when viral infection is etiologically involved. neither chest x-ray nor ct shows the appearance of a new abnormal shadow, differing from pneumonia. viruses . there is no evidence that infection with other bacteria directly causes acute bronchitis in adults without an underlying disease [ ] . however, in a study using the transtracheal aspiration method in japan, h. influenzae, s. pneumoniae, and m. catarrhalis were primarily isolated in patients diagnosed with bacterial acute bronchitis in the absence of a chronic lower respiratory infectious disease as an underlying disease [ ] . in cases of pertussis, cough persists particularly over a long period, and paroxysmal coughing, inspiratory whooping, and vomiting after coughing may occur [ ] . acute bronchitis caused by m. pneumoniae also induces severe, persistent cough. in cases of influenza, fever, headache, general malaise, and arthralgia are observed. furthermore, acute viral bronchitis may lead to acute bacterial exacerbation in patients with chronic respiratory lesions as underlying diseases; fever and an increase in the amount of purulent sputum are observed. as a rule, when an underlying disease or complication is absent, the routine administration of antimicrobial drugs for acute bronchitis is not recommended [ , ] . to control symptoms such as cough, symptomatic therapy should be performed if necessary. on the other hand, antimicrobial drug treatment with macrolides is indicated for patients with pertussis. treatment after the catarrhal period does not reduce the degree or duration of cough, but antimicrobial drugs are necessary to prevent infection to peripheral persons [ , ] . when performing antimicrobial drug treatment for acute bronchitis caused by m. pneumoniae or c. pneumoniae, macrolides should be selected as first-choice drugs. however, an increase in macrolide-resistant m. pneumoniae must be considered [ ] . in cases of influenza, anti-influenza therapy should be conducted within h after onset [ ] . in patients with underlying diseases or elderly persons with complications, bacterial (e.g., s. pneumoniae) infection may occur following viral infection, although this is not frequent in healthy adults. when acute bronchitis related to bacterial infection, including secondary infection, is strongly suspected based on cough/sputum, fever, leukocytosis, or findings suggestive of the presence of causative microorganisms on gram staining of sputum despite the absence of a new infiltrative shadow on chest x-ray, antimicrobial drug treatment is considered in accordance with treatment for community-acquired bacterial pneumonia [ , ] . ---drugs to be recommended--- when there are no complications such as chronic respiratory diseases, the administration of antimicrobial drugs for acute bronchitis are not recommended as a rule (with respect to the selection of antimicrobial drugs for acute bronchitis complicated by chronic respiratory diseases with secondary bacterial infection, refer to the section " . miller & jones classification of purulent sputum. m : saliva, complete mucous sputum m : mucous sputum containing a small volume of purulent sputum p : sputum in which the purulent area comprises / or smaller p : sputum in which the purulent area comprises / to / p : sputum in which the purulent area comprises / or greater fever and shortness of breath, in addition to bacterial infection-related respiratory symptoms, such as increases in the frequency of cough, volume of purulent sputum, and degree of purulence, from the chronic, stable conditions of underlying diseases, such as copd, bronchiectasis, and old pulmonary tuberculosis. concerning laboratory data, inflammatory responses involving the leukocyte count and crp level are enhanced, and pao is often reduced on blood gas analysis. [imaging findings] imaging findings are necessary to differentiate chronic respiratory disease-related airway infection from pneumonia. the absence of a shadow must be confirmed. ct should also be performed to evaluate underlying diseases such as pulmonary emphysema and bronchiectasis. [estimation of causative microorganisms and gram staining] it is possible to collect sputum in many patients. gram staining is useful for predicting causative microorganisms or differentiating respiratory tract infection in the presence of chronic respiratory disease from persistent infection. according to a study, the tone of sputum suggests the presence of pathogenic microorganisms rather than the degree of purulence; macroscopic examination is also necessary [ ] . sputum involves much information, and is the most important sample. samples should be collected before the administration of antimicrobial drugs. those collected on waking-up early in the morning are ideal. to evaluate the degree of sputum purulence, the miller & jones classification [ ] (table ) is used, but, if samples are evaluated as p or higher, causative microorganisms may be predicted using gram staining. on gram staining, an area where the number of inflammatory cells is large should be initially searched at a low magnification, and detailed observation should be conducted at a high magnification. before the administration of antimicrobial drugs, sputum should always be submitted for a susceptibility test. as causative microorganisms, h. influenzae, p. aeruginosa, m. catarrhalis, and s. pneumoniae are frequently detected. persistent infection with p. aeruginosa is often observed, but it must be differentiated from acute exacerbation based on clinical symptoms and laboratory data. in addition, s. aureus and k. pneumoniae should be considered [ ] . the involvement of atypical pathogens such as c. pneumoniae or mixed infection with viruses and bacteria must also be considered. [treatment] the purpose of treatment is to reduce clinical symptoms, prevent recurrence, prolong the interval until subsequent exacerbation, and inhibit lung tissue damage. the administration of appropriate antimicrobial drugs relieves clinical symptoms, and maintains the respiratory function [ ] . on the other hand, inappropriate antimicrobial drugs may deteriorate the prognosis, inducing recurrence. in japan, the resistance of s. pneumoniae and h. influenzae to macrolides and b-lactams is advanced [ , ] . several studies have reported that new quinolones are more useful than b-lactams [ , e ] . respiratory quinolones have potent antimicrobial activities against all types of causative microorganisms, and against resistant bacteria [ e ]. concerning the administration period, a study indicated that the efficacy of administration for days was similar to that for days, and that the former was safer than the latter. the administration period should be shortened [ ] . ---drugs to be recommended--a. empiric therapy internationally, some studies have supported the usefulness of b-lactams [ , ] . however, in japan, the resistance of s. pneumoniae and h. influenzae to macrolides and b-lactams is advanced, and p. aeruginosa is also sometimes isolated. therefore, the use of b-lactams and macrolides is limited to patients without risk factors. an international comparative study reported that the efficacy of azm sustained-release preparations was similar to that of new quinolones [ ] . however, in japan, the long-term administration of macrolides is performed in many patients; therefore, circumstances differ. beta-lactamase-producing strains are detected in approximately e % of h. influenzae strains. beta-lactamasenegative, ampicillin-resistant (blnar) strains account for approximately %. therefore, when drug susceptibility is unclear, new quinolones should be selected as first-choice oral antimicrobial drugs. if drug susceptibility is clarified, they should be switched to effective and narrow-spectrum drugs. as injection, penicillins should be initially selected, followed by b-lactamase inhibitor-containing penicillins, carbapenems, and new quinolones. ➁ m. catarrhalis beta-lactamase-producing strains account for % of m. catarrhalis strains. as oral antimicrobial drugs, macrolides should be initially selected, followed by b-lactamase inhibitor-containing penicillins, second-/third-generation cephems, and new quinolones. as injection, b-lactamase inhibitor-containing penicillins, second-/third-generation cephems, new quinolones, or carbapenems should be selected. ➂ p. aeruginosa as oral drugs, new quinolones should be selected. as injection, anti-p. aeruginosa penicillins, cephems, monobactums, carbapenems, or new quinolones should be selected. as the drug susceptibility of this type of bacteria markedly differs among strains, drugs should be selected based on the results of culture tests. ➃ s. pneumoniae as oral drugs, penicillins should be initially selected, followed by new quinolones. in patients with a risk of resistant bacteria, respiratory quinolones such as lvfx and grnx should be selected. as injection, penicillins or ctrx should be selected, but carbapenems must be considered in severestatus patients. ---explanation---[characteristics/classification of the disease] dpb is a chronic inflammatory disease of the respiratory tract, which is frequently observed in east asians including japanese. there is no gender difference, and this disease frequently develops in persons aged e years. it is often detected in patients with a history of chronic sinusitis or in those with the concomitant development of chronic sinusitis. this disease is classified as the category of sinobronchial syndrome. [symptoms] the most typical symptoms of dpb are persistent cough and purulent sputum. symptoms such as exertional shortness of breath and dyspnea appear in accordance with disease progression. in patients with a complication of chronic sinusitis, purulent nasal discharge and nasal obstruction are observed. chest x-ray shows pulmonary overexpansion or a diffuse scattered nodular shadow. thoracic hrct reveals a diffuse centrilobular nodular shadow. furthermore, obstructive respiratory dysfunction, hypoxemia, and an increase in the cold agglutinin value ( -fold or more on the hemagglutination method) are observed. [type and frequency of causative microorganisms] in patients with dpb, persistent respiratory tract infection with h. influenzae, s. pneumoniae, or m. catarrhalis is often observed. however, the incidence of persistent infection with p. aeruginosa increases with progression. [long-term macrolide therapy] previously, the prognosis of dpb was unfavorable; respiratory failure gradually progressed through repeated acute exacerbation related to respiratory tract infection, leading to a fatal outcome; however, the prognosis of dpb has been markedly improved since long-term macrolide therapy with low-dose administration of em or other -membered ring macrolides was established [ e ]. early diagnosis/treatment have facilitated the complete cure of dpb. therefore, if once a diagnosis of dpb is made, long-term macrolide therapy should be started promptly. ---drugs to be recommended---➀ persistent infection -the oral administration of em at e mg/day should be continued for months to be evaluated its clinical effects [ ] . -in many cases, an improvement in symptoms (such as a decrease in the volume of sputum) will be achieved within e months after the start of administration. -in addition, an improvement in imaging findings or the respiratory function will be achieved after e months of treatment. croup syndrome is characterized by acute laryngeal stenosisassociated respiratory disturbance such as barking cough, hoarseness, and inspiratory stridor. most lesions involve not only the larynx but also the trachea/bronchus. this disease is sometimes called laryngotracheobronchitis [ ] . etiological factors are classified into two types: infectious and non-infectious (allergy-/ foreign body-related) factors [ , ] . the incidence of infectious croup syndrome is high in infants/children aged monthse years [ , ] . [type and frequency of causative microorganisms] croup syndrome is primarily caused by viruses. parainfluenza virus type is the most common virus [ ] . in addition, parainfluenza virus type / , influenza a/b virus, rs virus, human metapneumovirus, coronavirus, adenovirus, and measles virus are relatively frequently isolated [ , ] . [rules of antimicrobial drug therapy] in most cases, croup syndrome is caused by viruses, and antimicrobial drugs are not necessary. therefore, no study has evaluated the efficacy of antimicrobial drugs in patients with croup syndrome. there are no treatment guidelines regarding croup syndrome in which antimicrobial drugs are recommended [ , ] . ---executive summary---bronchiolitis is caused by viruses, and the administration of antimicrobial drugs is not necessary (ai). ---explanation--- bronchiolitis is an acute, inflammatory, obstructive disease involving the bronchiole. narrowing of the bronchiolar lumen related to mucosal epithelial injury, inflammatory-cell infiltration, interstitial edema, or an increase in mucus secretion causes air trapping in the peripheral respiratory tract, leading to obstructive respiratory disorder. this disease frequently develops in children aged years or younger. however, infants aged months or younger account for % or more [ ] . [type and frequency of causative microorganisms] bronchiolitis is primarily caused by viruses. rs virus accounts for e %. in addition, parainfluenza virus, human metapneumovirus, adenovirus, and influenza virus are relatively frequently isolated [ e ]. [rules of antimicrobial drug therapy] in most cases, bronchiolitis is caused by viruses, and antimicrobial drugs are not necessary. basic treatment is symptomatic therapy. in double-blind comparative studies involving abpc and non-treated groups [ ] , azm and non-treated groups [ ] , and abpc intravenous injection/oral em and non-treated groups [ ] , respectively, there were no significant differences in the admission period or symptom improvement. however, a small-scale doubleblind comparative study reported that the interval until recovery in the cam-treated group was shorter than in the non-treated group [ ] . according to another study, the incidence of secondary bacterial infection during the course of rs virus-related bronchiolitis was . %, and there was no difference between antimicrobial drug-treated and non-treated groups [ ] . therefore, it is not necessary to administer antimicrobial drugs to children with bronchiolitis for routine treatment or the prevention of secondary bacterial infection. however, follow-up must be carefully continued during the course of bronchiolitis. when a diagnosis of secondary bacterial infection-related pneumonia or otitis media is made, antimicrobial drug therapy should be started. ---executive summary---bacterial tracheitis is a bacterial disease with the rapid progression of dyspnea. if symptoms are progressive, antimicrobial drugs should be used even when a definitive diagnosis is not made (aiii). ---explanation--- fever and croup syndrome-like cough/stridor initially appear, and respiratory disorder rapidly progresses, but there is no specific posture, salivation, or dysphagia, which are characteristic of acute epiglottitis. a definitive diagnosis can be made based on characteristic clinical features and purulent secretion in the respiratory tract. in some cases, a lateral view of the larynx on x-ray shows stenosis below the larynx [ ] . this disease frequently develops in children aged e years [ ] . [type and frequency of causative microorganisms] s. aureus-related tracheitis accounts for approximately %, followed by that related to m. catarrhalis, h. influenzae, streptococcus pneumoniae, and streptococcus pyogenes [ e ]. mixed infection with viruses and bacteria is frequent, and parainfluenza virus type i [ ] and influenza a virus [ ] are often detected. [rules of antimicrobial drug therapy] antimicrobial drugs should be intravenously administered for the following reasons: this disease rapidly progresses, and oral administration is difficult in many cases. as empiric therapy, combination therapy with vcm, which may be effective for infection with s. aureus (including mrsa), and third-generation cephems (ctrx, ctx), which have potent antimicrobial activities against m. catarrhalis, h. influenzae, s. pneumoniae, and s. pyogenes, should be performed. the administration period is e days [ ] . ---drugs to be recommended---refer to the section " . pneumonia (children)---drugs to be recommended . definitive therapy---" (p. ). ---executive summary---acute bronchitis is primarily caused by viruses, and the necessity of antimicrobial drug administration is low (ai). when acute bronchitis is caused by m. pneumoniae, c. pneumoniae, or b. pertussis, antimicrobial drugs should be administered if necessary (aiii). secondary infection with s. pneumoniae or h. influenzae may occur, although its incidence is unclear. therefore, when there is no improvement, the administration of antimicrobial drugs should be considered (aiii). ---explanation---[characteristics and classification of the disease] bronchitis causes symptoms such as cough, fever, and general malaise. various causative microorganisms induce inflammation of the epithelial tracheobronchial tissue, leading to the onset of bronchitis. clinically, there are no special findings on auscultation, or only rough respiratory sounds (intermittent accessory murmurs) are heard. chest x-ray does not also show any marked infiltrative shadow. usually, patients in whom the interval after onset is less than weeks are regarded as having acute bronchitis [ ] . however, bronchitis diagnosed in japan slightly differs from that in europe and the united states. the latter primarily causes persistent cough. in japan, patients in whom there are no findings on chest x-ray despite clinical signs of pneumonia or those in whom chest x-ray is not performed are often diagnosed with bronchitis; the disease entity must be arranged. [type and frequency of causative microorganisms] viruses, such as rhinovirus, influenza virus, rs virus, adenovirus, parainfluenza virus, human metapneumovirus, and human bocavirus, account for % of causative microorganisms. m. pneumoniae, c. pneumoniae, and b. pertussis also cause bronchitis, although such cases are relatively rare [ , ] . [rules of antimicrobial drug therapy] acute bronchitis is primarily caused by viruses, and the administration of antimicrobial drugs is not necessary. a metaanalysis compared adults to whom antimicrobial drugs were administered for bronchitis treatment with non-treated adults, and indicated that there was no difference in the efficacy [ ] . few reports on clinical studies involving children have been published, and the scale is small; objective data are insufficient, but no study has reported that antimicrobial drugs are effective [ e ]. however, if secondary bacterial infection following viral infection causes fever, purulent sputum, leukocytosis, or an increase in the crp level, antimicrobial drugs should be administered, considering s. pneumoniae and h. influenzae. other indications for antimicrobial drug administration include m. pneumoniae-, c. pneumoniae-, or b. pertussis-related bronchitis with protracted cough. as m. pneumoniae-or c. pneumoniae-related bronchitis tends to show spontaneous cure, the administration of antimicrobial drugs is not always necessary, but the necessity of administration should be evaluated, considering the severity of symptoms and course (with respect to indications and administration methods, refer to the section " . pneumonia (children)".). first-choice drugs for m. pneumoniae-, c. pneumoniae-, or b. pertussis-related bronchitis are macrolides. in patients with b. pertussis-related bronchitis, antimicrobial drugs relieve symptoms only during the catarrhal period, but, if b. pertussis-related bronchitis is suspected based on clinical symptoms, previous vaccination, lymphocyte-predominant leukocytosis, an anti-pt antibody titer, and lamp findings, antimicrobial drugs should be used. however, -membered ring macrolides are ineffective for b. pertussis-related bronchitis. symptoms are similar to those of pneumonia, but, when chest x-ray does not show any abnormalities, or, when it is impossible to strictly differentiate bronchitis from pneumonia due to difficulty in chest x-ray, treatment should be performed in accordance with pneumonia. ---drugs to be recommended--- secondary bacterial infection after viral infection (cases in which fever, purulent sputum, leukocytosis, or an increase in the crp level is observed) a first choices -ampc, oral, e mg/kg/ times a day -sbtpc, oral, mg/kg/ times a day -cdtr-pi, oral, mg/kg/ times a day -cfpn-pi, oral, mg/kg/ times a day -cftm-pi, oral, mg/kg/ times a day <> second choices -azm, oral, mg/kg/once a day, days -cam, oral, . mg/kg/twice a day . definitive therapy ➀ b. pertussis -em, oral, e mg/kg/ times a day -cam, oral, . mg/kg/twice a day -azm, oral, mg/kg/once a day, days ➁ m. pneumoniae ▪ macrolide-sensitive strains -em, oral, e mg/kg/ times a day -azm, oral, mg/kg/once a day, days -cam, oral, . mg/kg/twice a day ▪ macrolide-resistant strains -mino, oral or intravenous drip, e mg/kg/twice a day (in children aged years or younger, the use of this drug is limited to those in whom other drugs cannot be used or non-responders.) -tflx, oral, mg/kg/twice a day (administration is limited to children aged years or younger in whom mino cannot be used.) ➂ chlamydia (c. pneumoniae, c. psittaci, c. trachomatis) -em, oral, e mg/kg/ times a day -azm, oral, mg/kg/once a day, days -cam, oral, . mg/kg/twice a day . influenza ---executive summary----both m protein inhibitors and neuraminidase inhibitors (nais) are commercially available as anti-influenza drugs as of july . -influenza viruses a (h n ) and a (h n ) pdm (seasonal influenza) have been reported to be resistant to amantadine, an m protein inhibitor which can be used in japan. the use of this drug as an anti-influenza drug should be avoided for a while [ , ] . -during the influenza outbreak period, anti-influenza therapy should be promptly started based on a clinical diagnosis even when patients with influenza-like symptoms show negative results on a rapid diagnosis kits (because influenza cannot be completely ruled out) [ ] (ai). -nais significantly improve influenza survival, and nai administration within days after onset significantly reduces the rate at which the condition becomes severe [ , ] (ai). -currently, the following nais can be selected in japan. during the outbreak period, an appropriate drug should be selected based on the patient background and latest information on a prevalent influenza strain: -oseltamivir (oral), efficacy: a (h n ) pdm , a (h n ), b, resistance: h y mutant -zanamivir (inhalation), efficacy: type a/b -laninamivir (inhalation), efficacy: type a/b -peramivir (intravenous drip), efficacy: type a/b ---drugs to be recommended---there is no meta-analysis of anti-influenza drugs other than oseltamivir and zanamivir as of july . however, it has been shown that the early introduction of anti-influenza therapy for influenza significantly inhibits not only the mortality and admission rates but also the incidences of influenza-associated pneumonia, otitis media, and ischemic heart disease in comparison with symptomatic therapy. nais such as laninamivir and peramivir have also been confirmed to be as effective as oseltamivir at the time of development [ ] (ai). <>outpatient treatment -oseltamivir, oral, mg/twice a day, days (as a rule, administration to children/adolescents aged e years should be avoided.) -zanamivir, inhalation, mg/twice a day, days -laninamivir, inhalation, mg/single dose -peramivir, intravenous drip, mg/single dose <>hospital treatment ➀ patients with severe, life-threatening influenza in patients with severe, life-threatening influenza requiring admission, respiratory failure or encephalopathy is present. in either case, the complication must be treated, but, as a rule, nais should be introduced within h after the onset of influenza to obtain their effects. -oseltamivir, oral, mg/twice a day, days (as a rule, administration to children/adolescents aged e years should be avoided.) -peramivir, intravenous drip, mg/single dose (this drug can be repeatedly administered every day in accordance with symptoms.) ➁ non-life-threatening influenza patients with pneumonia -oseltamivir, oral, mg/twice a day, days (as a rule, administration to children/adolescents aged e years should be avoided.) -peramivir, intravenous drip, mg ( mg for patients in whom the condition may become severe)/single dose (this drug can be repeatedly administered every day in accordance with symptoms.) ➂ non-life-threatening influenza patients without pneumonia -oseltamivir, oral, mg/twice a day, days (as a rule, administration to children/adolescents aged e years should be avoided.) -zanamivir, inhalation, mg/twice a day, days -laninamivir, inhalation, mg/single dose -peramivir, intravenous drip, mg/single dose (this drug can be repeatedly administered every day in accordance with symptoms.) * patients with a (h n ) -basic treatment is the early administration of anti-influenza drugs [ ] . -according to an article, there were no significant differences in the viral level or mortality rate days after the start of administration between double-and standard-dose oseltamivir therapies [ ] . however, treatment was not started within h after onset in all patients in the article. ---executive summary---influenza is caused by influenza virus. antimicrobial drugs are not necessary. it is recommended that neuraminidase inhibitors should be administered within h after onset (ai). if pneumonia or otitis media occurs through secondary bacterial infection, the administration of antimicrobial drugs must be considered (biii). ---explanation---[characteristics and classification of the disease] influenza often appears with sudden fever and shivering/ headache/general malaise/muscular pain/dry cough, followed by marked respiratory or digestive symptoms. in underlying diseasefree children, recovery is achieved after e days [ , ] . however, during the outbreak period, even underlying disease-free children are often admitted with serious symptoms such as encephalopathy, myocarditis, and pneumonia requiring artificial respiration. although the outbreak period is from december until march every year, outbreaks are observed in the summer in some areas [ , ] . [type and frequency of causative microorganisms] since influenza a (h n ) pdm prevailed in , the outbreaks of types of influenza, a (h n ) pdm , a (h n ), and b, have been repeated. their incidences differ among years. [rules of antimicrobial drug therapy] no antimicrobial drug is indicated for influenza. it is recommended that neuraminidase inhibitors should be administered within h after onset [ ] . the doses of neuraminidase inhibitors approved in japan are presented in table . during the course of influenza, bacterial infection such as pneumonia and otitis media may occur. previously, the incidence of secondary bacterial infection in children exceeded % [ ] , but it has been % or less since neuraminidase inhibitors were developed [ , ] . however, bacterial infection is observed in e % of severe-status patients requiring intensive care [ , ] . streptococcus pneumoniae, s. aureus, and h. influenzae are frequently detected as causative microorganisms [ , , , ] . no study has demonstrated that the prophylactic administration of antimicrobial drugs at the onset of influenza prevents secondary bacterial infection. among children with influenza, antimicrobial drug therapy should be considered in those in whom signs of pneumonia or otitis media do not subside despite the administration of a neuraminidase inhibitor. . parasitic diseases of the respiratory system ---executive summary----parasitic diseases are widely distributed throughout the world. in addition to domestic infection, japanese travelers may be infected in overseas endemic areas. furthermore, parasitic diseases always considered in foreign patients from endemic areas [ ] (biv). -when peripheral blood eosinophilia is observed in addition to respiratory symptoms and abnormal findings of the chest imaging, examinations should be performed to differentiate parasitic diseases [ ] (biv). -parasitic diseases of the respiratory system are caused by paragonimus spp., ascaris lumbricoides, ancylostoma duodenale, necator americanus, strongyloides stercoralis, toxocara canis, toxocara cati, wuchereria bancrofti, brugia malayi, or dirofilaria immitis. -there are two major diagnostic tests for parasitic diseases: ( ) detection of parasite eggs or larvae in sputum or stools, and ( ) detection of parasite-specific antibodies using serum or pleural effusion samples (immunodiagnosis). -an anti-parasite antibody screening test against species of parasite is commercially available; paragonimus spp., strongyloides sp., t. canis, d. immitis, ascaris suum, anisakis simplex, gnathostoma spp., fasciola hepatica, clonorchis sinensis, spirometra erinaceieuropaei, and cysticercus cellulosae. -diagnosis/treatment consultations regarding parasitic diseases by the japanese society of parasitology are available (as of ). refer to the homepage (http://jsp.tm.nagasaki-u.ac.jp). ---explanation----paragonimus spp. several paragonimus species are known to cause human infection. paragonimus westermani and p. miyazakii are distributed in japan. infection occurs through the consumption of freshwater crabs (intermediate host: eriocheir japonica, e. sinensis, geothelphusa dehaani) or wild boars (paratenic host:sus scrofa) contaminated with metacercaria (infective larvae) as a raw or insufficiently cooked food [ ] . typical symptoms are cough, sputum, thoracic pain, and exertional dyspnea. in patients with such symptoms, the presence of peripheral blood eosinophilia suggests this disease. in many cases, a diagnosis is made based on the peripheral blood eosinophilia, a history taking of food and table standard doses of neuraminidase inhibitors in children. oseltamivir a oral mg/kg, twice a day, days (the use of this drug should be avoided in children/adolescents aged e years.) zanamivir b inhalation mg, twice a day, days laninamivir inhalation years or older: mg years or younger: mg, single dose peramivir intravenous drip mg/kg, once a day a the preventive administration of this drug at mg/kg (once a day) for days was approved, but is not covered by health insurance. b the preventive administration of this drug at mg (once a day) for days was approved, but is not covered by health insurance. immunodiagnosis. some of paragonimiasis patients are asymptomatic, and the presence of lung lesions is detected on a health checkup. extrapulmonary paragonimiasis such as cutaneous and cerebral paragonimiasis are classically known form of the ectopic infection with paragonimus spp. in cases of cutaneous paragonimiasis, a slowly moving nodular lesion in the subcutaneous tissue is a characteristic symptom. the worms may migrate through mediastinal soft tissues to the brain, causing eosinophilic meningitis or cerebral paragonimiasis in some cases [ ] . since paragonimus spp. is widely distributed around the world, japanese travel to endemic area such as china, korea, thailand, and philippines possible to infect with paragonimus spp. as well as foreign patients from endemic areas, this disease always is considered when a patient has respiratory symptoms and/or lung lesions with eosinophilia [ ] . chest x-ray findings vary: not only pulmonary parenchymal lesions, such as nodular (±cavity formation) and infiltrative shadows, but also pleural lesions, such as the retention of pleural effusion and pneumothorax, are sometimes observed [ ] . many patients show peripheral blood eosinophilia and/or elevated serum total ige. immunodiagnosis to detect parasite-specific antibody has been proven as the most useful and reliable tool. not only patient's serum but also pleural effusion could examine by immunological test. commercially available anti-parasite antibody screening test is including paragomimus spp. in japan, egg-detection rate among paragonimiasis patients nowadays is low; for example . % in sputum and . % in balf [ ] , . % in bronchoscopic aspirate [ , ] . after a definitive diagnosis is made, oral treatment should be started. the type of treatment to be selected, outpatient or hospital treatment, depends on the patient's general condition. however, usually, outpatient treatment is possible. in patients having pleural effusion, pleural fluid must be extensively drained off before starting chemotherapy [ ] (biii). in patients with chronically encapsulated pleural effusion, surgery is required [ ] (ciii). ---drugs to be recommended---a first choice (same dose for adults and children) -praziquantel, oral, mg/kg/ times a day, e days [ ] (aiii) -a. lumbricoides, a. duodenale, n. americanus the larvae of these parasites pass through the lung in the human body, causing asthma-or pneumonia-like symptoms such as transient fever, cough, and dyspnea. on chest x-ray, transient nodular/infiltrative shadows are observed. many patients show peripheral blood eosinophilia and/or elevated serum total ige. previously, the condition was called loffler syndrome. currently, it is classified as simple pulmonary eosinophilia in the category of pie syndrome [ ] . symptoms appear e weeks after the oral ingestion of a. lumbricoides embryonated eggs. the latency period of percutaneous infection with n. americanus larvae or percutaneous/oral infection with a. duodenale larvae is approximately days. larvae appeared in the small intestine penetrate the intestinal wall, enter the portal vein, migrate through liver to heart/lung. larvae penetrate the human skin transfer to the lung with blood flow. then these larvae migrate up the bronchi and trachea, over the epiglottis, down the esophagus/stomach, and reach the small intestine. in the intestine the larvae develop into mature adults [ ] . simple pulmonary eosinophilia related to parasites spontaneously resolved in a few weeks. in many cases, a definitive diagnosis is made based on parasite eggs detected on a stool examination, although larvae are sometimes detected in sputum [ ] . ---drugs to be recommended---a first choice (same dose for adults and children) -pyrantel pamoate, oral, mg/kg/single-dose administration * dry syrup for children is available. * this drug is effective for adult worms in the intestinal tract, but not for larvae migrating in the human body. therefore, a stool examination should be performed weeks after oral administration. if parasite eggs are detected, additional administration should be conducted. <> second choices (same dose for adults and children) -albendazol, oral, mg/single-dose administration -mebendazole, oral, mg/twice a day, days, or mg/single-dose administration -ivermectin, oral, e mg/kg/single-dose administration (after fasting) -s. stercoralis in japan, s. stercoralis is distributed in nansei islands, chain of islands extending from southwestern kyushu to northern taiwan. there are few young persons newly infected with s. stercoralis, but the incidence of infection is high in elderly persons [ ] . internationally, s. stercoralis is widely distributed in tropical/subtropical areas. not only domestic infection but also japanese travel to endemic area possible to infect with this parasite. foreign patients from endemic areas, strongyloidiasis always considered when a patient has respiratory symptoms and/or lung lesions with eosinophilia. s. stercoralis percutaneously infects humans. larvae penetrate the human skin transfer to the lung with blood flow. then these larvae migrate up the bronchi and trachea, over the epiglottis, down the esophagus/stomach, and reach the small intestine. in the intestine the larvae develop into mature adults. parasite eggs delivered by adults are hatched while descending the intestinal tract, and larvae excreted in stools. some larvae developed to infective form again invade/transfer through the mucosa around the anus, maintaining a life cycle in the human body. such a mode of infection is termed autoinfection. with the transfer of larvae to the lung, asthma-or pneumonia-like symptoms, such as transient fever, cough, and dyspnea, appear, as indicated for simple pulmonary eosinophilia related to a. lumbricoides, a. duodenale, or n. americanus. on chest x-ray, transient nodular/infiltrative shadows are observed. many patients show peripheral blood eosinophilia and/or an increase in the total ige level. in immunocompromised patients, suppressing the cellmediated immunity such as atl patients, hiv/aids patients, those receiving immunosuppressive drugs, the number of s. stercoralis increases through acceleration of autoinfection, and larvae are disseminated in various organs, leading to a severe condition (disseminated strongyloidiasis). in such cases, stridor, bloody sputum, tachypnea, protein-losing gastroenteritis, ileus, and mobile exanthema are observed. furthermore, severe pneumonia related to enteric bacteria disseminated with larvae, lung abscess, or bacterial meningitis concomitantly occurs [ ] . a diagnosis is made based on s. stercoralis larvae detected in stools/sputum. immunological diagnosis is also useful [ ] . ---drugs to be recommended---a first choice (same dose for adults and children) -ivermectin, oral, mg/kg/single-dose administration (after fasting), additional administration at the same dose after weeks (ai) * repeated administration must be considered in cases of disseminated strongyloidiasis [ ] . * a study reported that transrectal or percutaneous administration was useful in patients in whom oral administration was difficult due to digestive symptoms [ ] . <> second choice (same dose for adults and children) -albendazol, oral, mg/twice a day, days (bi) -t. canis, t. cati infection to humans occurs through the oral ingestion of the embryonated eggs of t. canis or t. cati [ ] . it also occurs through the consumption of beef/chicken liver or meat contaminated with larvae as a raw or insufficiently heated food. this is considered to be a dominant route of infection in japan [ ] . as humans are not definitive host for t. canis and t. cati, they do not become adults in the human body [ ] . larvae invading the human body transfer to various organs with blood flow through the intestinal mucosa. target organs are the lung, liver, eyes, and central nervous system including spinal cord. toxocariasis is a typical larva migrans. lesions are often observed in the lung/liver (visceral larva migrans). there are few symptoms, or nonspecific symptoms are present. in many cases, a diagnosis is made based on peripheral blood eosinophilia and multiple nodular shadows of the lung or liver on ct. ocular or central nervous symptoms appear in some patients. it is impossible to make a diagnosis on a stool examination due to larva migrans. immunological diagnosis is useful. after a definitive diagnosis is made, treatment should be started. when visceral larva migrans is asymptomatic, follow-up may be continued. ---drugs to be recommended---a first choice (same dose for adults and children) -albendazol, oral, mg/kg/ or times a day, e weeks [ ] (biii) * this drug should be taken with meals for days. a -day period of discontinuation should be established and then restarted drug if required. <> second choices (same dose for adults and children) -albendazol, oral, mg/twice a day, days [ ] (biii) -mebendazole, oral, e mg/twice a day, days [ ] (ciii) -w. bancrofti, b. malayi w. bancrofti and b. malayi are called lymphatic filaria. infection occurs when these parasites are transmitted to humans through mosquitoes. the pathogenesis of lymphatic filariasis is relate to structural and functional abnormality of lymphatic channels induced by parasitized adult worms. infection with w. bancrofti is characterized by febrile attacks, lymphedema/elephantiasis, hydrocele, and chyluria. in patients infected with b. malayi, neither hydrocele nor chyluria is observed, and lymphedema of the lower limbs/ elephantiasis are localized in the lower thighs. microfilaria produced by adult worms is not pathogenic, but rarely induces allergic reactions in the lung, contributing to tropical pulmonary eosinophilia (tpe) [ ] . this condition shows a chronic course, differing from simple pulmonary eosinophilia. cough, dyspnea, and stridor with exacerbation at night are observed. fever, malaise, and weight loss are noted in some patients. on chest x-ray, bilateral reticular nodular lesions are detected. peripheral blood eosinophilia and an increase in the anti-filaria antibody titer are observed. in case of tpe, no microfilaria is detected [ ] . if treatment is not performed, the condition may gradually exacerbate. it is important to adequately make a diagnosis for the differentiation of this disease. in the world, , , persons are infected with lymphatic filaria, but tpe occurs in less than . % of these. the risk of this disease in travelers is unclear, and most patients consist of foreign persons from endemic areas [ ] . ---drugs to be recommended---a first choice (same dose for adults and children) -diethylcarbamazine, mg/kg/ times a day, days * in cases of malayan filariasis, marked side effects, such as digestive symptoms, fever, lymphangitis/ lymphadenitis, and orchitis/epididymitis, may appear. therefore, a half dose ( mg/kg) should be administered times a day for days [ ] . -d. immitis d. immitis parasitize in the dog right ventricle and pulmonary artery, where mature female worms produce microfilaria that circulate in peripheral blood. infection to humans is mediated by microfilaria-ingesting mosquitoes. d. immitis larvae in human subcutaneous tissue inserted by mosquito bite, some larvae migrate to the heart and die. dead worms produce infarcts then they lodge in pulmonary vessels. there are few symptoms [ ] . in patients with symptoms, thoracic pain, cough, bloody sputum, stridor, and fever have been reported. typical chest x-ray findings include solitary coin lesions. in many cases, an abnormal shadow of the chest x-ray is indicated on a health checkup, and d. immitis infection is pathologically diagnosed from a tissue specimen extirpated under a tentative diagnosis of lung cancer. at this point, peripheral blood eosinophilia is rarely observed [ ] . ---drugs to be recommended (same dose for adults and children)----as a diagnosis is made using pathological specimens in many patients, oral treatment is not necessary. -if necessary, diethylcarbamazine at mg/kg should be orally administered times a day for days. ---precautions for each drug--- in the japanese package inserts, it is described that this drug at mg/kg/day should be orally administered twice a day for days for the treatment of paragominiasis. however, we recommend administration at mg/kg/day ( times a day) for e days based on reference no. . the incidence of side effects is low, but fever, abdominal discomfort, nausea, diarrhea, and headache are sometimes observed. masahumi seki: speaker's honorarium from shionogi & co., ltd., and taisho toyama pharmaceutical co., ltd dolin r, editors. mandell, douglas, and bennett's principles and practice of infectious diseases infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults the committee for the japanese respiratory society guidelines for the management of respiratory infections. the japanese 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immunodeficiency virus-negative patients in the era of effective azole therapy primary treatment of zygomycosis with liposomal amphotericin b: analysis of cases the deferasirox-ambisome therapy for mucormycosis (defeat mucor) study: a randomized, double-blinded, placebo-controlled trial pneumocystis pneumonia the national institute of health-university of california expert panel for corticosteroids as adjunctive therapy for pneumocystis pneumonia. consensus statement on the use of corticosteroids as adjunctive therapy for pneumocystis pneumonia in the acquired immunodeficiency syndrome comparison of atovaquone ( c ) with trimethoprim-sulfamethoxazole to treat pneumocystis carinii pneumonia in patients with aids international consensus guidelines on the management of cytomegalovirus in solid organ transplantation oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients forscarnet vs ganciclovir for cytomegalovirus (cmv) antigenemia after allogeneic hemopoietic stem cell transplantation (hsct): a randomised study treatment of interstitial pneumonitis due to cytomegalovirus with ganciclovir and intravenous immune globulin: experience of european bone marrow transplant group committee to prepare the guidelines for the management of respiratory infectious diseases in children. pneumonia. the guidelines for the management of respiratory infectious diseases in children in japan limitations of the etiological diagnosis of bronchopulmonary infectious diseases---appearance of emb community-acquired pneumonia in children fifth pediatric respiration seminar. review of chest x-ray findings of pneumonia, childhood pneumonia with respect to causative pathogens world health organization: programme for the control of acute respiratory infections: technical bases for the who recommendations on the management of pneumonia in children at first-level health facilities pneumonia in pediatric 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informational supplement. performance standards for antimicrobial susceptibility testing annual change of ampicillin susceptibility of h. influenzae and the clinical efficacy of penicillins in bronchopulmonary infections caused by b-lactamase negative h. influenzae with an ampicillin-minimum inhibitory concentration (mic) of mg/ml clinical effects of piperacillin and tazobactam/piperacillin on haemophilus influenzae lower respiratory tract infection in pediatric patients clinical studies on lower respiratory tract infections caused by moraxella catarrhalis in childhood ( st report) clinical studies on lower respiratory tract infections caused by moraxella catarrhalis in childhood ( nd report)-indirect pathogenicity of moraxella catarrhalis increased prevalence of penicillin-resistant viridans group streptococci in japanese children with upper respiratory infection treated by beta-lactam agents and in those with oncohematologic diseases strong macrolide resistance in children/ pandemic of mycoplasma pneumoniae infection macrolide resistance of mycoplasma pneumoniae in primary hospitals committee to prepare the guidelines for the management of respiratory infectious diseases in children, vaccination/infectious disease control committee of the japan pediatric society. supplement revision ( ) of the guidelines for the management of respiratory infectious diseases in children in regarding the diagnosis and treatment of pneumonia with mycoplasma pneumoniae in children ventilator-associated pneumonia in neonatal and pediatric intensive care unit patients committee to prepare the guidelines for the management of respiratory infectious diseases in children. pneumonia in the presence of an underlying disease . blood disease. guidelines for the management of respiratory infectious diseases in children committee to prepare the guidelines for the management of respiratory infectious diseases in children. pneumonia in the presence of an underlying disease . immunodeficiency. guidelines for the management of respiratory infectious diseases in children clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: update by the infectious diseases society of america indicative therapy during blood disease treatment experience on long-term therapy with macrolides in the field of pediatrics refractory respiratory infectious diseases. tokyo: van medical co itraconazole to prevent fungal infections in chronic granulomatous disease special issue---respiratory infectious disease---neonatal pneumonia committee to prepare the guidelines for the management of respiratory infectious diseases in children. pneumonia in the presence of an underlying disease . neonates. guidelines for the management of respiratory infectious diseases in children nosocomial infection in a newborn intensive care unit (nicu), south korea a -year prospective surveillance of nosocomial infections in neonatal intensive care units risk factors and outcomes 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anaerobic empyema and update of bacteriology anaerobic microbiology in cases of pleural empyema: a bulgarian study thoracic empyema in patients with community-acquired pneumonia controlled trial of intrapleural streptokinase for pleural infection antibiotic therapy of pleural empyema pharmacokinetics and therapeutic efficacy of gentamicin in an experimental pleural empyema rabbit model amikacin concentrations in uninfected post thoracotomy pleural fluid and in serum after intravenous and intrapleural injection penetration of aminoglycosides in uninfected pleural exudates and in pleural empyemas choice of first intervention is related to outcomes in the management of empyema; discussion d management of pleural infection in adults: british thoracic society pleural disease guideline committee to prepare the guidelines for the management of respiratory infectious diseases in children. pleuritis/pyothorax. guidelines for the management of respiratory infectious diseases in children pleural tuberculosis radiological study of mycoplasma pneumonia in children principle and practice of pediatric surgery committee to prepare the guidelines for the management of respiratory infectious diseases in children. primary diseases for which vaccination should be performed . tuberculosis. guidelines for the management of respiratory infectious diseases in children controlled clinical trial of four short-course ( -month) regimens of chemotherapy for treatment of pulmonary tuberculosis controlled clinical trial of four short-course ( -month) regimens of chemotherapy for treatment of pulmonary tuberculosis controlled trial of , , and months of pyrazinamide in -month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, and pyrazinamide. results at months a controlled trial of months' chemotherapy in pulmonary tuberculosis. final report: results during the months after the end of chemotherapy and beyond short-course antituberculous chemotherapy for pulmonary and pleural disease: years' experience in clinical practice joint tuberculosis committee of the british thoracic society. chemotherapy and management of tuberculosis in the united kingdom: recommendations infectious diseases society of america: treatment of tuberculosis the japanese society for tuberculosis. guidelines for the management of tuberculosis rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in hiv-negative patients: a randomised clinical trial usphs tuberculosis short-course chemotherapy trial :effectiveness, toxicity, and acceptability. the report of final results controlled chemoprophylaxis trials in tuberculosis. a general review prophylactic effect of isoniazid in young tuberculin reactors isoniazid chemoprophylaxis of tuberculosis international union against tuberculosis committee on prophylaxis. efficacy of various 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paragonimiasis: experimental and clinical experience with praziquantel in korea parasitic infections of the lung:a guide for the respiratory physician current status of strongyloides infection in okinawa pulmonary strongyloidiasis: the varied clinical presentations non-oral treatment with ivermectin for disseminated strongyloidiasis how common is human toxocariasis? towards standardizing our knowledge toxocariasis in japan lessons from eight cases of adult pulmonary toxocariasis :abridged republication thiabendazole vs. albendazole in treatment of toxocariasis: a clinical trial a case of adult hepatic toxocariasis tropical pulmonary eosinophilia: a case series in a setting of nonendemicity study group regarding the establishment of medical management by appropriate treatment with rare-disease drugs for imported tropical diseases/parasitosis. guidelines for drug therapy for parasitosis. study group regarding drugs for tropical diseases drug to be contraindicated for combination therapy: rfp precautions for combination therapy: decrease in the blood concentration: dexamethasone, phenytoin, carbamazepine, chloroquine increase in the blood concentration: cimetidine ➁ pyrantel pamoate patients can take this drug regardless of meals. there are few side effects. ➂ albendazol this drug should be taken with meals for days. a day period of discontinuation should be established and then restarted drug if required.as liver dysfunction is frequently observed, caution is needed during the administration period. bone marrow suppression and stevens-johnson syndrome must also be considered.precautions for combination therapy: decrease in the blood concentration: ritonavir, phenytoin, carbamazepine, phenobarbital increase in the blood concentration: praziquantel ➃ mebendazolealthough this drug has been used in few children, the same dose as established for adults is used. in children weighing kg or less, a half dose should be used. this drug is contraindicated for pregnant women or those who may be pregnant. combination therapy with cimetidine may increase the blood concentration of mebendazole. combination therapy with metronidazole may cause toxic epidermal necrolysis (ten) and stevens-johnson syndrome. after fasting, this drug should be taken with water. the incidence of side effects is low, but nausea/vomiting and mild hepatic disorder are sometimes observed. the safety of this drug in pregnant women or children weighing less than kg has not been established. to these patients, this drug should be administered only when its therapeutic advantage is considered to exceed its risk. ➅ diethylcarbamazine as side effects, fever, lymphangitis/lymphadenitis, and orchitis/epididymitis, which result from anti-parasitic actions, are observed in addition to abdominal discomfort, nausea, and abdominal pain. the safety of this drug in pregnant women has not been established. upper row: dose (mg/kg), lower row: frequency of administration per day key: cord- - hjeaf s authors: liu, yen-lin; wu, ping-sheng; tsai, li-ping; tsai, wen-hsin title: pediatric round pneumonia date: - - journal: pediatr neonatol doi: . /j.pedneo. . . sha: doc_id: cord_uid: hjeaf s “round pneumonia” or “spherical pneumonia” is a well-characterized clinical entity that seems to be less addressed by pediatricians in taiwan. we herein report the case of a -year-old boy who presented with prolonged fever, cough, and chest x-rays showing a well-demarcated round mass measuring . × . × . cm in the left lower lung field, findings which were typical for round pneumonia. the urinary pneumococcal antigen test was positive, and serum anti-mycoplasma pneumoniae antibody titer measurement using a microparticle agglutination method was : (+). after oral administration of antibiotics including azithromycin and amoxicillin/clavulanate, which was subsequently replaced by ceftibuten due to moderate diarrhea, the fever subsided days later and the round patch had completely resolved on the th day after the diagnosis. recent evidence suggests treating classical round pneumonia with antibiotics first and waiving unwarranted advanced imaging studies, while alternative etiologies such as abscesses, tuberculosis, nonbacterial infections, congenital malformations, or neoplasms should still be considered in patients with atypical features or poor treatment response. children; lobar pneumonia; pneumonia; radiology; round pneumonia; spherical pneumonia "round pneumonia" or "spherical pneumonia" is a well-characterized clinical entity that seems to be less addressed by pediatricians in taiwan. we herein report the case of a year-old boy who presented with prolonged fever, cough, and chest x-rays showing a welldemarcated round mass measuring .  .  . cm in the left lower lung field, findings which were typical for round pneumonia. the urinary pneumococcal antigen test was positive, and serum anti-mycoplasma pneumoniae antibody titer measurement using a microparticle agglutination method was : (þ). after oral administration of antibiotics including azithromycin and amoxicillin/clavulanate, which was subsequently replaced by ceftibuten due to moderate diarrhea, the fever subsided days later and the round patch had completely resolved on the th day after the diagnosis. recent evidence suggests treating classical round pneumonia with antibiotics first and waiving unwarranted advanced imaging studies, while alternative etiologies such as abscesses, tuberculosis, nonbacterial infections, congenital malformations, or neoplasms should still be considered in patients with atypical features or poor treatment response. copyright ª , taiwan pediatric association. published by elsevier taiwan llc. all rights reserved. pneumonia is a common disease in children that has caused much burden to patients, families, and health-care systems. in taiwan, the average annual incidence of patients hospitalized with pneumonia was with . mortalities per , children younger than years of age, costing nt$ , , , (about us$ million) per year. occasionally, a child may develop an opaque pulmonary consolidation with unusually round shape, which raises the concern of a tumor in the chest, causing anxiety to the pediatrician and parents. herein, we report the case of a patient with so-called "round pneumonia", whose initial chest x-ray (cxr) findings mimicked those of a lung mass, but subsequently showed complete response to oral antibiotics alone. recent findings and recommendations in the literature are also reviewed. a -year-old boy was referred to the emergency room (er) of a regional hospital due to intermittent fever for days. he had had dry cough for weeks, intermittent abdominal pain in the periumbilical area for days, and vomiting once on the day of arrival. he also had decreased appetite but with excellent activity. there was no history of systemic diseases. the patient's weight was kg ( rd %; dropped kg during the recent year), and his height was . cm ( e th %). on examination, this child had intact throat and tympanic membranes, several small and soft lymph nodes over bilateral anterior cervical triangles, clear lung sound, regular heart beat with no murmurs, epigastric tenderness, and warm extremities with prompt capillary refilling. cxrs showed a round-shaped opacity with clear margins in the left lower lobe (lll) and the retrocardiac region, measuring .  .  . cm in size (width  height  depth). there were also mild streaking infiltrates in bilateral lower lung fields, especially the perihilar regions, while no pleural effusion was noted (figures and a) . laboratory data showed a white blood cell count of /ml with left shift (metamyelocyte %, band-form %, segmented neutrophils %, lymphocytes %, atypical lymphocytes %, and monocytes %), a hemoglobin level of . g/dl, platelets count of  /ml, a c-reactive protein level of . mg/dl, with normal electrolytes, blood sugar, lactate dehydrogenase, and uric acid levels, renal and liver function tests, and peripheral blood smear. under the working diagnosis of round pneumonia, the patient was suggested to be hospitalized and undergo antimicrobial therapy. however, due to family reasons, his mother requested that he be treated as an outpatient. his subjective abdominal pain had improved after an enema and intravenous administration of metoclopramide, and he was discharged and given oral amoxicillin/ clavulanate ( . mg amoxicillin/kg/day) and azithromycin ( mg/kg/day). two days later, the patient had become afebrile, but was still coughing badly and developed moderate diarrhea at home. on the th day after diagnosis, the lll opacity had become smaller and less dense ( figure b ). further results of laboratory tests obtained at the er showed serum anti-mycoplasma pneumoniae antibody titer measurement to be : (þ), rapid urinary antigen test for streptococcus pneumoniae to be positive, and no bacterial growth on blood culture. azithromycin was extended to a -day course, and amoxicillin/clavulanate was replaced with cefibuten due to antibiotic-associated diarrhea. three days later, or on the th day after the first er visit, the patient reported that both his cough and diarrhea had improved. ceftibuten was continued to complete a -day course. on the th day after his first er visit, follow-up cxrs showed complete resolution of the lll lesion ( figure c ), and serum anti-m. pneumoniae antibody titer figure chest x-rays at presentation showed a well-demarcated round opacity in the left lower lung field (arrowheads). note the apparent air bronchogram on the posteroanterior view (arrow). measurement remained at : (þ). a follow-up complete blood count test showed that the white blood cell count had decreased to /ml, with neutrophils constituting . %, lymphocytes . %, and monocytes . %. round pneumonia, also called spherical pneumonia, has been recognized since the s as a clinical entity that usually occurs in children. young children are predisposed to round pneumonia because of their underdeveloped pores of kohn and lambert's channels that may cause the centrifugal spread of fluid or bacteria. in a recent large study involving children with round pneumonia, the consolidations tended to be solitary, have well-defined borders, and were located posteriorly and in bilateral lower lobes ( %), which exactly matched the initial radiographic findings in our patient ( figure ). although the exact term "round pneumonia" does not seem to be widely used by pediatricians in taiwan, a previous study identified typical imaging features in % ( / ) of children with mycoplasmal pneumonia, whose lesions had been described as "nodular or mass-like opacification". the diagnosis of classical round pneumonia in children should be kept straightforward. in comparison to that in adults, in whom neoplastic diseases such as bronchogenic carcinoma are more common and pneumonia only comprises less than % of "coin lesions", round pneumonia in children is likely to represent a benign process. with the typical clinical presentation and radiographic appearance, misdiagnosis of round pneumonia is unlikely, and unwarranted additional imaging should be avoided. computerized tomography (ct) of the chest is recommended when ( ) the clinical features are not consistent with pneumonia, ( ) the round opacity does not resolve after appropriate antibiotic treatment, or ( ) there are radiographic signs of a nonpulmonary origin on cxr. round pneumonia is most commonly caused by s. pneumoniae and may rarely be caused by other bacteria, while viral etiology such as severe acute respiratory syndrome has also been seen in adults. in our patient, although the initial blood culture was negative, results of a urinary antigen test revealed the presence of s. pneumoniae. as taiwanese children's nasopharyngeal carriage rate of pneumococcus has decreased to approximately % with the advent of conjugate vaccines, urinary antigen positivity nowadays may serve as a reliable indicator of recent pneumococcal disease. by contrast, mycoplasmal pneumonia is prevalent in children older than e years of age, and its diagnosis in most clinical laboratories relies solely on serology. the patient's sera were tested with a microparticle agglutination assay (fti serodia myco ii; fujirebio taiwan inc., taoyuan, taiwan), which detects both igg and igm simultaneously. the test was considered positive when the acuteand convalescent-phase sera showed a fourfold or higher increase in antibody titer, or when one sera had an antibody titer measurement of at least : (þ), , as was the case in our patient. the test kit had a sensitivity of . % and specificity of . %, thereby indicating a high likelihood of concomitant m. pneumoniae infection in this child. however, neither imaging studies nor laboratory data can perfectly distinguish these two pathogens, and mixed infections are not uncommon in children with community-acquired pneuonia. , therefore, combination therapy was given to treat both pathogens. the differential diagnoses of pediatric round pneumonia include fungal infection, lung abscess, tuberculosis, pulmonary malformations (sequestration, congenital cystic adenomatoid malformation, and bronchogenic cyst), neoplasms (lymphoma, neuroblastoma, and chest wall tumors), and diaphragmatic hernia. their clinical and radiographic characteristics have been thoroughly reviewed. , the normal results of lactate dehydrogenase, uric acid, liver function tests, and peripheral blood smear in our patient suggested a very low likelihood of malignancy. meanwhile, the patient's good clinical condition permitted a therapeutic trial with oral antibiotics. as the lesion resolved completely after oral antibiotic use (figure ), the diagnosis of round pneumonia was confirmed, and therefore a chest ct was not indicated. of note, with the recent emergence of macrolide-resistant m. pneumoniae, mutation analysis may be considered in patients with poor improvement despite adequate antibiotic treatment. in conclusion, we have presented a typical case of pediatric round pneumonia with probable s. pneumoniae and m. pneumoniae infections. recent evidence suggests treating classical round pneumonia with antibiotics first and waiving unwarranted advanced imaging studies, while abscesses, tuberculosis, nonbacterial infections, congenital malformations, or neoplasms should still be considered in patients with atypical features or poor treatment response. epidemiology and impacts of children hospitalized with pneumonia from to in taiwan spherical pneumonias in children simulating pulmonary and mediastinal masses imaging of round pneumonia and mimics in children round pneumonia: imaging findings in a large series of children mycoplasma pneumonia: clinical and radiographic features in children radiologic manifestations of round pneumonia in adults eight cases of severe acute respiratory syndrome presenting as round pneumonia the impact of the heptavalent pneumococcal conjugate vaccine on risk factors for streptococcus pneumoniae carriage in children taiwan pediatric working group for guideline on the management of cap in children. guidelines for the management of communityacquired pneumonia in children mycoplasma pneumoniae and its role as a human pathogen microparticle agglutination versus antibody-capture enzyme immunoassay for diagnosis of community-acquired mycoplasma pneumoniae pneumonia diagnosis of mycoplasma pneumoniae infection by microparticle agglutination and antibody-capture enzyme-immunoassay comparative clinical and laboratory features of children with pneumococcal vs mycoplasmal pneumonia congenital pulmonary malformations in pediatric patients: review and update on etiology, classification, and imaging findings life-threatening pneumonia caused by macrolideresistant mycoplasma pneumoniae key: cord- - b preq authors: morgan, carrie i.; shah, samir s. title: pneumonia date: - - journal: pediatric critical care medicine doi: . / - - - - _ sha: doc_id: cord_uid: b preq respiratory diagnoses continue to make up a large number of admissions to the pediatric intensive care unit (picu), most notably lower respiratory infections including pneumonia. this chapter will focus on pediatric community-acquired pneumonia (cap), immunocompromised pneumonia, and aspiration pneumonia. the pathogenesis for developing pneumonia varies; it can occur by direct inhalation of infectious particles in the air or aspiration, direct extension from the upper airways, and hematogenous spread. there are multiple levels of defense against pathogen invasion including anatomic barriers, as well as innate and adaptive immunity, which may be compromised in picu patients. the etiologies of pediatric pneumonia vary depending on age, host condition, and environmental factors like time of year and location. viruses remain the most common form of lower respiratory tract infection in children, especially in neonates. community-acquired bacterial pneumonia continues to be most prevalent in younger children as well, most often affecting children less than years of age who are otherwise healthy. despite immunizations and public health initiatives, the most common bacterial causes of cap have remained largely unchanged over the last several decades and include: streptococcus pneumoniae, staphylococcus aureus, haemophilus influenzae (including non-typable strains) and moraxella catarrhalis. pulmonary infection in an immunocompromised host provides a much broader differential and must be aggressively treated without delay. this chapter will also address various imaging modalities and typical findings with pediatric pneumonia. methods for pathogen identification are broad and range from non-specific markers of illness to invasive techniques for culture. the mainstay of therapy continues to be antibiotics tailored to the patient and presumed etiology; more novel therapies may include corticosteroids or macrolide antibiotics for immune modulation. in those patients with pneumonia with effusion or empyema, drainage therapies with thoracostomy tubes or a vats procedure may be indicated. respiratory diagnoses continue to make up a large number of admissions to the pediatric intensive care unit (picu) [ ] . lower respiratory tract infections are considered to be any infection beneath the anatomic level of the vocal cords, including bronchitis, bronchiolitis, tracheitis, and pneumonia [ ] . pneumonia remains an important cause of pediatric morbidity and mortality. there are nearly two million pneumoniarelated deaths worldwide each year among children years of age and younger [ , ] . in the u.s., pneumonia causes over three million outpatient visits and more than , hospitalizations each year [ , ] . in the developed world, early recognition and availability of antimicrobial therapies and respiratory support have lessened the mortality of pneumonia, but its morbidities remain. while widespread use of the heptavalent pneumococcal conjugate vaccine in was associated with fewer pneumonia-associated complications in infants < year of age, complications remained unchanged or increased in school-age children and adolescents [ ] . thus, despite our best efforts at prevention through vaccination, morbidities continue to plague our patients and pneumonia remains a common cause of pediatric hospital admission. this chapter will focus on pediatric community-acquired pneumonia (cap), immunocompromised pneumonia, and aspiration pneumonia. hospital acquired pneumonia is an important type of lower respiratory infection found in the picu, but it is discussed extensively in the chapter on hospital-acquired infections elsewhere in this textbook. the defi nition of pneumonia is generally accepted to be a lower respiratory illness with fever, respiratory symptoms including tachypnea, and often, radiologic evidence of parenchymal infi ltrates [ ] . the world health organization (who) has defi ned pneumonia solely based on clinical fi ndings due to the lack of radiologic studies in many parts of the world [ ] . determining the type of pneumonia can help guide clinical management. previously healthy children presenting with the signs and symptoms of a lower respiratory tract infection are generally considered to have cap. aspiration involves inhaling foreign material beyond the vocal cords, often causing aspiration pneumonitis (chemical pneumonitis) or pneumonia (an infectious process secondary to the aspiration) [ , ] . commonly aspirated materials in children include oropharyngeal secretions, gastric contents, water, hydrocarbon, lipid, and foreign bodies [ ] . guidelines for admission to the icu are available for both young children and adults, and are summarized in table . [ , ] . pneumonia can occur by direct inhalation of infectious particles in the air or aspiration, direct extension from the upper airways, and hematogenous spread. anatomic and cellular protection serves as the fi rst line of defense against potential pathogens. airway mucus traps inhaled toxins and microbes and helps to transport them up and out of the respiratory tract via ciliary beating and cough, a mechanism referred to clinically as mucociliary clearance [ ] . when the microbe burden or virulence of the organism surpasses the abilities of these simple mechanical protections, the innate immune response is activated. the innate immunity is responsible for immediate recognition and control of microbial invasion. in mammals, conserved receptors enable rapid recognition of pathogens to begin elimination of the infection as well as initiate the adaptive immune response. activating the innate immune receptors in the airway epithelium leads to mobilization and activation of dendritic cells, t cells, and b cells that amplify antigen recognition, antibody production, and further cellular recruitment and infl ammation [ ] . the specifi cs of these interactions and signaling cascades are beyond the scope of this chapter, but are further discussed in other chapters within this text. the lower respiratory tract remains generally clear of pathogens [ ] . the mechanisms by which microbes are able adapted from refs. [ , ] to overwhelm defensive measures and result in pneumonia vary and depend on host conditions. the most common mechanism of pathogen entry is via inhalation of infectious particles, particularly in the case of specifi c organisms that spread via respiratory droplets such as mycobacterium tuberculosis. many viruses that cause lower respiratory tract infections are also spread utilizing aerosolized modes of transmission, including respiratory syncytial virus (rsv), infl uenza, and rhinoviruses. due to their smaller size compared with bacteria, viruses consolidate more effi ciently on smaller particles [ , ] . hematogenous spread results in pneumonia when bacteria in the bloodstream directly deposit in lung tissue. pulmonary aspiration can occur as a result of swallowing dysfunction, gastroesophageal refl ux, anatomic anomalies such as tracheoesophageal fi stulas, or an inability to protect the airway from oropharyngeal secretions. in the picu, many patients have neurologic diseases that coexist with one, if not several, of these aforementioned mechanisms. furthermore, impaired consciousness, as may occur with head injury, intoxication, sedation, and tracheal intubation, can also impair the ability to protect the airway, diminish the cough refl ex, and exploit the patency of the anatomical connection between the larynx and trachea [ , , ] . direct aspiration of a large inoculum of infectious organisms can result when there is impairment of the host's anatomic defense, usually the gag and cough refl ex. this most commonly occurs in children with profound neurologic impairment or during tracheal intubation [ , ] . viruses still remain the most common cause of lower respiratory tract infection, especially in infants [ ] . the occurrence of primary viral infections and co-infections with bacterial pneumonia are receiving more attention in recent years due to advances in detection methods to improve the reliability and sensitivity in diagnosis [ ] . viruses have been found in approximately % of sampled patients with a range of - %, although this prevalence is diffi cult to compare across studies that utilize different identifi cation techniques [ - ] . the most commonly noted infectious viruses were rhinovirus, human bocavirus, human metapneumovirus (hmpv), and respiratory syncytial virus (rsv). human metapneumovirus causes signifi cant respiratory infection, accounting for - % of viral pneumonia cases [ , ] . human bocavirus, fi rst described in , is detected in up to % of children with respiratory infections [ ] . however, co-infection with another virus occurs in more than half of human bocavirus infected children, making its role as a predominant respiratory pathogen unclear. one possible explanation for the high prevalence of viral coinfection with human bocavirus is that this virus is shed in respiratory tract secretions for a longer period of time than other viruses [ - ] . other important respiratory tract pathogens include adenovirus, parainfl uenza viruses, and infl uenza a or b, all of which vary in prevalence based on season and epidemic periods. the most common complication of viral pneumonia is a secondary bacterial infection. bacterial co-infection occurs in about - % of pediatric patients hospitalized with a lower respiratory tract infection [ ] . the most often occurring combination was rhinovirus and streptococcus pneumoniae , though it remains diffi cult to interpret the causal role of rhinovirus in lower respiratory tract infections [ , ] . rsv remains an important cause of bronchiolitis in infants and can often progress to pneumonia. a recent study noted that % of children admitted to the picu with rsv bronchiolitis had bacterial co-infection [ ] . community-acquired bacterial pneumonia continues to be most prevalent in younger children as well, most often affecting children less than years of age who are otherwise healthy. despite immunizations and public health initiatives, the most common bacterial causes of cap have remained largely unchanged over the last several decades and include: streptococcus pneumoniae , staphylococcus aureus , haemophilus infl uenzae (including non-typable strains) and moraxella catarrhalis [ , , , ] . in developing countries, other bacterial and viral etiologies must be considered, including mycobacterium tuberculosis, h. infl uenzae type b (in unvaccinated areas of the world), and the measles virus [ ] . in infants under - weeks of life, the most common etiologic agents include group b streptococcus, listeria monocytogenes, and gram-negative enteric bacteria. mycoplasma pneumoniae and chlamydophila pneumoniae (formerly chlamydia pneumoniae ), once considered to occur primarily among adolescents and young adults, are increasing being recognized as a cause of cap in younger children, including those less than years of age [ ] . there are many causes of immunodefi ciency in pediatrics including congenital, acquired (hiv/aids), or iatrogenic (during chemotherapy or after solid organ or stem cell transplant). these states can result in defi ciencies in humoral immunity, cellular immunity, and neutrophil availability or function, making the host susceptible to not only typical pneumonia etiologies, but many opportunistic agents. thus, the approach to an immunocompromised patient must be altered to consider the type and severity of immunodeficiency, as well as the temporal pattern after chemotherapy or transplant. other considerations that are important in immunocompromised patients include neutropenia, where a low white blood cell count can hinder the patient's ability to exhibit cxr fi ndings and the lack of infl ammation can alter the clinical presentation, and environmental factors and exposures that can cause geographic and temporal clustering of pathogens [ ] . the causes of pneumonia following solid organ and stem cell transplant may follow a predictable temporal relationship. in the early post-transplant period (< month), infections from nosocomial or iatrogenic sources are most common. in the middle post-transplant period ( - months), donor-associated and opportunistic infections, including reactivation of latent infections, predominate; specifi c causes include cytomegalovirus (cmv), epstein-barr virus (ebv) or human herpes virus (hhv ). late post-transplant period (> months) etiologies include community-acquired infections as well as infections associated with profound immunosuppression [ , ] . in an effort to diminish the risk associated with post-transplant immunosuppression, immunosuppressive agents (e.g., calcineurin inhibitors, high-dose corticosteroids) are used sparingly when possible and most protocols include anti-viral (especially cmv), anti-fungal, and pneumocystis jiroveci (pcp) prophylaxis [ ] . still, many common infections continue to pose a great risk. for example, viral infections (e.g., rsv, infl uenza, adenovirus) cause greater virulence following solid organ or stem cell transplantation immediately after transplant when cellular immunity is profoundly low. later in the course of transplantation, fungi such as aspergillus spp. and candida spp. become more prevalent causes of pneumonia with long-term steroid therapy [ , ] . thus, when a pulmonary process is suspected, aggressive treatment with broad-spectrum antibiotics, antifungals, and antivirals must be employed. immunocompromised patients with pulmonary infi ltrates may rapidly progress to respiratory failure and, thus, often require icu care. infection must be aggressively treated without delay, but other conditions must also be sought including pulmonary hemorrhage, malignancy, idiopathic pneumonitis, or cardiac disease [ , ] . the clinical presentation of aspiration pneumonitis or pneumonia can vary and like other pneumonia etiologies, aspiration can result in acute lung injury (ali) or acute respiratory distress syndrome (ards) manifested by severe pulmonary infl ammation and alveolar-capillary permeability injury. it is estimated that approximately one-third of patients with aspiration pneumonitis develop ali/ards [ ] . etiologies of aspiration pneumonia depend if the aspiration is community acquired or hospital acquired. bacteriologic studies in aspiration patients have shown that community acquired aspiration pneumonias are generally the same bacterium as cap, including h. infl uenzae , s. pneumoniae , s. aureus , and enterobacteriaceae species. in those patients who aspirated in a hospital setting, the most common organisms cultured were gram-negative enteric bacteria including pseudomonas aeruginosa . these recent studies failed to grow any anaerobic organisms, refuting the prior studies that endorsed anaerobes as common etiologies [ ] . the role for imaging in pediatric pneumonia is to detect the presence of pneumonia, determine the location and extent, and identify complications such as effusion or empyema. modalities include chest radiographs (cxr), ultrasound (us), and computed tomography (ct) [ ] . the presence of an infi ltrate on cxr, combined with clinical and other laboratory fi ndings can aid in the diagnosis of pneumonia. however, these modalities are not suffi ciently sensitive or specifi c to reliably differentiate between viral, bacterial, and atypical bacterial causes [ ] . the main use for us is to identify and characterize a parapneumonic effusion or empyema and provide image guidance for chest tube placement. this modality is limited by availability of equipment and operators. chest ct is helpful to further evaluate diffi cult cases, particularly immunocompromised children with ill-defi ned infi ltrates on cxr, complex empyema or effusion, or recurrent or chronic pneumonia [ ] . imaging fi ndings in pneumonia can be non-specifi c, but when combined with other factors such as patient age, immune status, and historical information, they may help to narrow the differential diagnosis. in viral pneumonia, the most common fi ndings are bilateral symmetrical parahilar and bronchial opacities with or without atelectasis and air trapping; pleural effusions are rare ( fig. . ). this is in contrast to bronchopneumonia, a form of bacterial pneumonia that begins as peribronchiolar infl ammation and spreads to the lung parenchyma. bacterial pneumonia is characterized by consolidation and fi lling of the alveolar air spaces with exudate, infl ammation, and fi brin. bronchopneumonia is typical of many bacteria including s. pneumoniae , h. infl uenzae , s. aureus , and gram-negative enteric bacteria. the cxr often reveals fl uffy lobar consolidation or diffuse bilateral opacities extending peripherally, with or without associated pleural effusion. in aspiration pneumonia, the cxr may reveal ground-glass or consolidative opacities predominantly involving the middle and lower (dependent) lobes [ ] . finally, atypical pneumonia etiologies include mycoplasma pneumoniae , chlamydophila pneumoniae and, less commonly, legionella species. the cxr fi ndings for these atypical causes are varied. diffuse interstitial infi ltrates are characteristic though other fi ndings include lobar consolidation, small bilateral pleural effusions, perihilar and peribronchial opacities that resemble butterfl y wings, or a bi-lobar reticular pattern ( fig. . ) [ , ] . the etiology of pneumonia in the immunocompromised patient can be diffi cult to determine though further imaging can help elucidate the cause. respiratory failure in an immunocompromised child frequently necessitates a chest ct to better visualize the pattern and extent of disease, aid in diagnosis of the etiology, determine the need for more invasive procedures, and to increase the sensitivity of assessing treatment response [ ] . fungal infections are more diffi cult to diagnose; classic fi ndings include pulmonary nodules on chest ct (fig. . ). the "gold standard" diagnosis of pneumonia is microbiological identifi cation of a pathogen from the lower respiratory tract [ ] . obtaining a lrt specimen can be diffi cult, especially in children, as it may require an invasive procedure and can be contaminated with oropharyngeal bacteria. most children younger than years of age cannot produce a suffi cient sputum sample, defi ned as < squamous or epithelial cells and > polymorphonuclear white blood cells per low power fi eld. therefore, most samples are obtained through either an endotracheal tube via aspiration or bronchoalveolar lavage [ ] . other laboratory tests helpful in identifying the causative agent in cap can include blood cultures, viral polymerase chain reaction (pcr) tests, and bacterial serologies. commonly used diagnostic methods available for an individual microorganism may be found in table . [ ] . the clinician may also be limited by the capabilities of the laboratory in their institution for performing these tests. because of the diffi culties in determining the etiology of pneumonia, non-microbiologic approaches have been sought to differentiate serious bacterial infections from nonbacterial pneumonia [ ] . many studies have evaluated markers including serum c-reactive protein (crp), blood white cell count (wbc), serum procalcitonin (pct), and erythrocyte sedimentation rate (esr), attempting to fi nd a test, or combination of tests, that would differentiate viral pneumonia from serious bacterial pneumonia necessitating antibiotic therapy [ , - ] . all of the aforementioned tests have limited utility in reliably differentiating viral from bacterial pneumonia, but when one or more of the markers are signifi cantly elevated, a bacterial etiology is more likely. thus, taken together with the clinical examination and radiologic fi ndings, these tests can aid the clinician in deciding which patients require antibiotic therapy. pct levels appear to be more sensitive than wbc, esr, and crp in identifying children with bacterial pneumonia and have been used to identify children who may benefi t from a longer duration of antibiotic therapy [ ] . when non-invasive identifi cation techniques are inadequate, or when identifying the cause is especially important, such as when treating an immunocompromised host, invasive diagnostic procedures may be necessary. fiberoptic bronchoscopy with bronchoalveolar lavage (bal) is the preferred diagnostic procedure in an immunocompromised host with an unknown pathogen [ ] . the sensitivity for diagnosis varies and depends on the host, pathogen, and the post-collection microbiologic detection methods employed. while many atypical organisms may be diffi cult to culture, p. jiroveci and mycobacterium infections are more easily detected in bal because of high organism burden in the lungs. the diagnosis of aspiration pneumonia is mainly clinical, often based on historical or witnessed events or conditions, and thus can be diffi cult to ascertain. if a bal is performed in suspected aspiration, the presence of lipid-laden macrophages can help diagnose the aspiration of lipophilic foods such as formula [ ] . a lipid-laden macrophage index can be obtained using the oil red o stain and when high, can be very sensitive and specifi c for aspiration [ ] . other invasive procedures include transbronchial biopsy if diffuse infi ltrates are present but the bal is negative, or ct-guided needle biopsy of a focal lesion. the improved diagnosis with these invasive procedures must be balanced against the risks to critically ill patients [ ] . important noninfectious etiologies to rule out with these invasive procedures include lung rejection (if transplanted), post-engraftment syndrome, idiopathic pneumonitis, graft versus host disease, and bronchiolitis obliterans. children with severe pneumonia requiring admission to the picu are likely to receive intravenous antimicrobial therapy even if only until the possibility of bacterial infection can be excluded. in critically ill children with respiratory failure from pneumonia, prompt initiation of broad-spectrum antimicrobials is crucial. one study in pediatric patients with cap showed that longer delays in receipt of antibiotics were independently associated with adverse outcomes [ ] . however, antibiotic resistance is increasing and the principles of appropriate antibiotic utilization must be adhered to: use of drug with narrowest spectrum, aiming for high tissue penetration, short half-life, and abiding to a short, intense duration of therapy [ ] . the duration of therapy is typically - days, with days being the best studied. a -day course may be reasonable in non-severe cases of pneumonia [ ] . the choice of antimicrobial agent is based on many things including the patient's age, the type of pneumonia, and clinical and epidemiologic factors. recent guidelines published by the pediatric infectious diseases society and the infectious diseases society of america offer guidance for empiric antibiotic selection in children hospitalized with cap (table . ) [ ] . pneumonia causes a profound infl ammatory response in the lungs and it has long been postulated that regulating this infl ammation with steroid therapy may help to modulate local tissue damage and accelerate recovery for the patient. in addition, steroids are frequently utilized in other pulmonary infl ammatory conditions such as reactive airway a b the fi nding of at least a quadrupling of serum antibody levels between the acute phase and convalescence the fi nding of igm antibody in serum late in the acute phase or early in convalescence is helpful, as is a positive pcr assay of secretions from a throat or a nasopharyngeal swab rapid igm assays can provide results within min. in younger children, an elevated igm titer is often diagnostic; in older children, the fi nding of at least a quadrupling of serum antibody levels between the acute phase and convalescence is diagnostic. cold agglutinin titers lack sensitivity and specifi city and thus are no longer recommended separate serum specimen because some agents (e.g., piperacillintazobactam) may cross-react with the assay. if invasive aspergillosis is suspected in high-risk patients, serial sampling is recommended. the false positive rate is higher in children than adults [ , ] adapted from mcintosh [ ] . with permission from massachusetts medical society disease (rad) and acute respiratory distress syndrome (ards) [ ] . the infl ammatory responses in pneumonia and ards are similar with increases in pro-infl ammatory cytokines concurrent with illness severity; severe pneumonia can often progress to acute lung injury (ali) or ards [ - ] . while preclinical data support the use of steroids, current studies have not demonstrated a reduction in mortality among corticosteroid recipients compared with non-recipients. several trials, however, have shown some secondary benefi ts of steroids, including reduced length of hospital stay and reduced infl ammatory markers [ , ] . in contrast, a multi-center, retrospective cohort study using administrative data found that among patients not receiving concomitant beta-agonist therapy (used as a proxy for wheezing), corticosteroid recipients had a longer los and higher readmission rate compared with non-recipients [ ] . at present, the lack of high quality data supporting the effi cacy of corticosteroids prevents the recommendation for the use of steroids in most patients with severe pneumonia. however, corticosteroids may provide benefi t to certain subgroups of patients such as those with acute onset of wheezing and those who meet the criteria for ali/ards [ ] . macrolide antibiotics have important anti-microbial as well as anti-infl ammatory properties, though the relative importance of these two mechanisms in children with pneumonia is unknown. in adult studies, macrolides have recently been touted for their immunomodulatory effects and clinical benefi t in multiple chronic pulmonary conditions such as asthma, chronic obstructive pulmonary disease (copd), and cystic fi brosis (cf). the specifi c immunomodulatory effects are vast and include inhibition of intracellular signaling to suppress the production of transcription factors such as nf-κb and decrease production of infl ammatory cytokines that recruit neutrophils [ , ] . several recent studies in adult patients with severe cap and sepsis have shown a benefi t in survival in patients treated with macrolide antibiotics in addition to the recommended antibiotics based on pathogen [ , - ] . the role of macrolides in children with pneumonia is unclear. in pediatrics, several small retrospective studies have shown that among children with atypical cap, those treated with macrolides were less likely to have persistence of signs and symptoms after days of therapy [ , ] . among children with m. pneumoniae infection, lu et al. found a shorter duration of fever among macrolide recipients compared with non-recipients [ ] . finally, a large multi-center study of patients with m. pneumoniae infection defi ned by discharge diagnosis codes, the median length of hospital stay was days (interquartile range, - days); macrolide recipients had a % shorter length of stay compared with non-recipients [ ] . pneumonia-associated complications such as empyema affect . - % of children hospitalized with pneumonia [ , - ] . the progression from simple parapneumonic effusion to empyema occurs in stages that represent a continuous spectrum (table . ) [ ] . in the fi rst stage, there is a rapid infl ux of exudative fl uid into the pleural space as a result of increased pulmonary interstitial fl uid traversing the pleura and an increase in vascular permeability due to pro-infl ammatory cytokines. the pleural fl uid is marked by the absence of bacteria, fl uid ph > . , normal glucose, and ldh < times the upper limit of normal. at this stage, drainage is not generally required for resolution but if the effusion becomes large and piperacillin-tazobactam if concern for gram negative enteric bacteria iv cefotaxime if > days of age adapted from refs. [ , ] impairs respiratory mechanics, drainage might become necessary. the fl uid in the pleural space can fl ow freely and often layers along the lateral chest wall in decubitus fi lms or along the posterior chest wall in supine fi lms [ , ] ( fig. . a , b) . if left untreated, exudative effusions can progress to fi bropurulent effusions characterized by the new presence of bacteria or positive microbial cultures. cellular lysis and phagocytosis in the fl uid can result in ph < . , higher ldh, and low glucose. loculations begin to develop, causing these effusions to now be referred to as "complicated." a chest radiograph may be diffi cult to interpret with respect to evidence of complicated effusions. thoracic us is more accurate than chest radiographs in distinguishing simple from complicated pleural effusions. complicated effusions are associated with fl oating debris and echogenic material or septations. ultrasound is also useful in guiding pleural aspiration and drainage. chest computed tomography (ct) may be indicated to better defi ne pulmonary and pleural anatomy. thickening of the parietal pleura on a contrasted ct scan is suggestive of empyema, even if the effusions are small in size ( fig. . c ) . finally, stage three is the organizing phase where fi broblasts grow into the pleural space and eventually results in a pleural peel, restricting chest mechanics. this stage often necessitates surgical decortication, especially if there is restrictive impairment [ ] . the typical organisms responsible for the development of an empyema include s. pneumoniae and s. aureus . pleural fl uid cultures identify an organism in only - % of children with empyema. blood cultures are positive in - % of children with empyema [ - ] . s. aureus is most often identifi ed in pleural fl uid culture. however, molecular identifi cation techniques reveal that most culture-negative cases are attributable to s. pneumoniae [ , ] . regardless of the type of effusion present, antibiotic coverage based on treatment guidelines for pneumonia are essential. a recent study on the impact of early antibiotic therapy on the laboratory analysis of pleural fl uid found that pre-treatment signifi cantly hindered a bacterial diagnosis but did not alter the biochemical parameters of the fl uid [ ] . however, delaying antibiotic treatment for a thoracentesis would not be recommended in a critically ill child with respiratory failure secondary to pneumonia. the treatment of complicated effusions and empyema remains controversial but recent studies have better defi ned protocols. a complete list of the available treatments for effusions and empyema is found in table . . small, uncomplicated pleural effusions do not routinely require drainage. moderate or large pleural effusions as well as those with evidence of septations or loculations usually require drainage. the medical options include appropriate antimicrobials and chest tube insertion with or without fi brinolytic therapy. surgical options include video-assisted thoracoscopic surgery (vats) or open thoracotomy and decortication. recent guidelines concluded that chest tube drainage with the addition of fi brinolytic agents and vats are equivalent methods of treatment and emphasize the importance of local expertise in determining the optimal approach for individual patients [ , ] . vats has gained popularity over conservative medical therapy as a way to directly visualize the pleural space, mechanically disrupt the adhesions, and strategically place the chest tube for optimal drainage [ , ] . the higher cost and risk of anesthesia with vats must be balanced against the more frequent requirement for additional drainage procedures for those undergoing primary chest tube placement. thoracotomy and decortication are rarely needed. the argument of medical management versus surgical management remains controversial. to date, at least two prospective trials in pediatrics have been completed directly comparing these methods. both trials failed to show any outcome superiority with surgical management [ , ] . certainly children who have a very high white blood cell count in their pleural fl uid (> , ), poor output drainage by chest tube, low pleural ph, the presence of bacteria in the pleural fl uid and/or bloodstream, or failure of medical therapy alone may benefi t from early vats [ ] . patients who underwent vats required fewer adapted from refs. [ , , ] additional drainage procedures, but had no difference in hospital length of stay [ ] . however, one study of adults with empyema found that patients treated with a combination of tpa and recombinant human dnase required fewer surgical interventions and had a shorter length of hospital stay [ ] . cost-effectiveness, balance of risks, and availability of resources also plays a role in considerations for surgical management. a comparison of multiple strategies for pediatric empyema noted that the most cost effective method was insertion of a chest tube with fi brinolytic therapy [ ] . abscesses develop in localized areas of parenchymal infection that becomes necrotic and cavitates ( fig. . a , b ) . primary lung abscesses can develop either in previously healthy children or in children with underlying lung disease such as congenital cystic lesions, cystic fi brosis, or immunodefi ciency. mechanisms for abscess development can include direct aspiration of infectious material, embolic phenomena, hematogenous spread from septicemia, or local extension from abdominal or oropharyngeal processes. the most common organisms include gram-positive bacteria such as streptococci, staphylococcus aureus or anaerobes. most abscesses resolve with intravenous antibiotics alone, but aspiration or drainage with a pigtail catheter may be necessary [ ] . vaccines against specifi c bacteria that predominantly cause pneumonia in children, specifi cally pneumococcal conjugate vaccine (pcv- ) and h. infl uenzae vaccine (hib) have drastically lowered the prevalence of infections causes by these strains. since the introduction of pcv- , several studies have documented its effi cacy, and the decrease in cases of h. infl uenzae are equally striking [ , ] . however, while pcv- has decreased the prevalence of invasive pneumococcal disease, the incidence of empyema is rising, the reason for which is unclear [ ] . the licensure of pneumococcal conjugate vaccines that include even more serotypes (e.g., -valent) may further change the epidemiology of childhood pneumonia. other vaccines, such as for measles (mmr) and infl uenza, can also aid to reduce these viral infections that so commonly lead to secondary bacterial pneumonia. while vaccines appear to be our greatest effort toward preventing pneumonia in children, more work needs to be done to increase their microbial coverage and availability throughout the world. operative technique in which a small camera and instruments are inserted into the pleural space through - small ( - cm) incisions of the skin and muscle on the lateral chest wall to mechanically remove purulent material and pleural adhesions. a thoracostomy tube is placed through one of the existing incisions following completion of the procedure open thoracotomy operative technique where instruments are inserted into the pleural space through a single - cm incision of the skin and muscle on the posterolateral chest wall to mechanically remove purulent material and pleural adhesions. a thoracostomy tube is placed through a second smaller - cm incision following completion of the procedure general anesthesia reprinted from swami and shah [ ] . with permission from mcgraw-hill three decades of pediatric intensive care: who was admitted, what happened in intensive care, and what happened afterward defi ning pneumonia in critically ill infants and children world health organization (who) childhood pneumonia mortality-a permanent global emergency national hospitalization trends for pediatric pneumonia and associated complications ambulatory visit rates and antibiotic prescribing for children with pneumonia pneumonia and other respiratory infections community-acquired pneumonia in children pulmonary complications of pediatric neurological diseases aspiration pneumonitis and aspiration pneumonia pneumonia in normal and immunocompromised children: an overview and update the management of community-acquired pneumonia in infants and children older than months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults airway mucus function and dysfunction beyond infl ammation: airway epithelial cells are at the interface of innate and adaptive immunity the role of particle size in aerosolised pathogen transmission: a review distribution of airborne infl uenza virus and respiratory syncytial virus in an urgent care medical clinic aspiration lung disease the impact of tracheal intubation on host defenses and risks for nosocomial pneumonia feeding the disabled child community-acquired pneumonia: a review and recent advances viruses in community-acquired pneumonia in children aged less than years old: high rate of viral coinfection viruses and bacteria in sputum samples of children with community-acquired pneumonia viral pneumonia induced sputum in the diagnosis of childhood community-acquired pneumonia etiology of community-acquired pneumonia in hospitalized children etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections etiology of community-acquired pneumonia in hospitalized children based on who clinical guidelines the changing face of pediatric respiratory tract infections: how human metapneumovirus and human bocavirus fi t into the overall etiology of respiratory tract infections in young children population-based incidence of human metapneumovirus infection among hospitalized children human bocavirus human bocavirus in children with acute lymphoblastic leukemia frequent and prolonged shedding of bocavirus in young children attending daycare human bocavirus: passenger or pathogen in acute respiratory tract infections? high incidence of pulmonary bacterial coinfection in children with severe respiratory syncytial virus (rsv) bronchiolitis infection in solid-organ transplant recipients respiratory infections: pneumonia, lung abscess, and empyema approach to the immunocompromised host with infection in the intensive care unit aspiration-induced lung injury community-acquired pneumonia in children: what's old? what's new? lipoid pneumonia: spectrum of clinical and radiologic manifestations pulmonary infections pediatric practice: infectious diseases murray and nadel's textbook of respiratory medicine value of the c-reactive protein test in the differentiation of bacterial and viral pneumonia serum procalcitonin, c-reactive protein and interleukin- for distinguishing bacterial and viral pneumonia in children differentiation of bacterial and viral communityacquired pneumonia in children white blood cells, c-reactive protein and erythrocyte sedimentation rate in pneumococcal pneumonia in children non-specifi c host response markers in the differentiation between pneumococcal and viral pneumonia: what is the most accurate combination? procalcitonin measurements for guiding antibiotic treatment in pediatric pneumonia role of fl exible bronchoscopy in immunocompromised patients with lung infi ltrates chronic pulmonary aspiration in children lipid-laden macrophages in induced sputum are a marker of oropharyngeal refl ux and possible gastric aspiration open lung biopsy in pediatric bone marrow transplant patients timing of correct parenteral antibiotic initiation and outcomes from severe bacterial community-acquired pneumonia in children activation and regulation of systemic infl ammation in ards: rationale for prolonged glucocorticoid therapy understanding the infl ammatory cytokine response in pneumonia and sepsis: results of the genetic and infl ammatory markers of sepsis (genims) study infl ammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis steroids in severe pneumonia: a literature review dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study adjunct corticosteroids in children hospitalized with community-acquired pneumonia immunomodulatory agents in the treatment of community-acquired pneumonia: a systematic review mechanisms of action and clinical application of macrolides as immunomodulatory medications combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia combination antibiotic therapy with macrolides improves survival in intubated patients with communityacquired pneumonia role of mycoplasma pneumoniae and chlamydia pneumoniae in children with community-acquired lower respiratory tract infections characteristics of streptococcus pneumoniae and atypical bacterial infections in children - years of age with community-acquired pneumonia macrolide use shortens fever duration in mycoplasma pneumoniae infection in children: a -year experience macrolide therapy and outcomes in a multicenter cohort of children hospitalized with mycoplasma pneumoniae pneumonia primary operative versus nonoperative therapy for pediatric empyema: a meta-analysis comparative effectiveness of pleural drainage procedures for the treatment of complicated pneumonia in childhood primary early thoracoscopy and reduction in length of hospital stay and additional procedures among children with complicated pneumonia: results of a multicenter retrospective cohort study empyema hospitalizations increased in us children despite pneumococcal conjugate vaccine parapneumonic effusions and empyema parapneumonic pleural effusion and empyema blood cultures in the emergency department evaluation of childhood pneumonia thoracoscopic decortication vs tube thoracostomy with fi brinolysis for empyema in children: a prospective, randomized trial impact of the pneumococcal conjugate vaccine on pneumococcal parapneumonic empyema an epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations the changing face of pleural empyemas in children: epidemiology and management molecular analysis improves pathogen identification and epidemiologic study of pediatric parapneumonic empyema impact of antibiotic therapy on laboratory analysis of parapneumonic pleural fl uid in children management of parapneumonic empyema pediatric respiratory diseases: update for the rogers' textbook of pediatric intensive care comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema intrapleural use of tissue plasminogen activator and dnase in pleural infection cost-effectiveness of competing strategies for the treatment of pediatric empyema diagnostic aspects of invasive aspergillus infections in allogeneic bmt recipients diagnostic potential of nested pcr, galactomannan eia, and beta-d-glucan for invasive aspergillosis in pediatric patients medical and surgical treatment of parapneumonic effusions : an evidence-based guideline key: cord- -e o j authors: bénet, thomas; sylla, mariam; messaoudi, mélina; sánchez picot, valentina; telles, jean-noël; diakite, abdoul-aziz; komurian-pradel, florence; endtz, hubert; diallo, souleymane; paranhos-baccalà, gláucia; vanhems, philippe title: etiology and factors associated with pneumonia in children under years of age in mali: a prospective case-control study date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: e o j background: there are very limited data on children with pneumonia in mali. the objective was to assess the etiology and factors associated with community-acquired pneumonia in hospitalized children < years of age in mali. methods: a prospective hospital-based case-control study was implemented in the pediatric department of gabriel touré university hospital at bamako, mali, between july -december . cases were children with radiologically-confirmed pneumonia; controls were hospitalized children without respiratory features, matched for age and period. respiratory specimens, were collected to identify viruses and bacteria. whole blood was collected from cases only. factors associated with pneumonia were assessed by multivariate logistic regression. results: overall, cases and controls were analyzed; . % were female, median age was months. among pneumonia cases, . % were hypoxemic at admission, mortality was . %. pneumonia cases differed from the controls regarding clinical signs and symptoms but not in terms of past medical history. multivariate analysis of nasal swab findings disclosed that s. pneumoniae (adjusted odds ratio [aor] = . , % confidence interval [ % ci]: . – . ), human metapneumovirus (aor = . , % ci: . – . ), respiratory syncytial virus [rsv] (aor = . , % ci: . – . ), and influenza a virus (aor = . , % ci: . – . ) were associated with pneumonia, independently of patient age, gender, period, and other pathogens. distribution of s. pneumoniae and rsv differed by season with higher rates of s. pneumoniae in january-june and of rsv in july-september. pneumococcal serotypes and were more frequent in pneumonia cases than in the controls (p = . , and p = . , respectively). conclusions: in this non-pcv population from mali, pneumonia in children was mainly attributed to s. pneumoniae, rsv, human metapneumovirus, and influenza a virus. increased pneumococcal conjugate vaccine coverage in children could significantly reduce the burden of pneumonia in sub-saharan african countries. pneumonia is the leading cause of child mortality from infectious diseases, accounting for an estimated million deaths annually, and mainly affecting children in developing countries [ , ] . mortality attributed to pneumonia has decreased since , but remains a major public health concern [ , ] . the main known causative pathogens reported are streptococcus pneumoniae, haemophilus influenzae type b, and respiratory syncytial virus (rsv) [ ] . however, their distribution varies by season and location. data on the etiology and epidemiology of pneumonia in children in developing countries are still insufficient, particularly in sub-saharan africa [ ] . mali is one of the poorest countries in the world, with a under-five year mortality rate of per , live births in according to the un inter-agency group for child mortality estimation. it has been estimated that among its . million inhabitants, each year more than , pneumonia episodes occur in children under years of age, leading to almost , deaths annually [ ] . a previous descriptive study reported that pneumonia was the most frequent cause of admission, representing % of total hospital admissions [ ] . however, detailed information was not available on clinical presentation and on the etiology of suspected pneumonia cases [ ] . moreover, no control group was included. the presence of a control group of children without pneumonia would allow better interpretation of microbiological findings, particularly with nasal sampling [ ] . in march , mali included pneumococcal vaccination (pcv ) in a routine immunization program; but vaccine coverage is still low [ ] . the study objective was to assess the etiology and factors associated with communityacquired pneumonia in hospitalized children in mali. the gabriel touré university hospital is a -bed tertiary-care general hospital located in bamako. it is a primary care hospital for people living in bamako and a national reference centre for other patients. various medical and surgical specialities, including pediatrics, are located in the hospital. the pediatrics department, with a capacity of beds, includes a general pediatrics unit and a neonatal/emergency unit. it receives sick children for primary care and severe cases referred from other healthcare settings. on average, , consultations and , hospital admissions occur in the pediatrics department annually. acute respiratory infections represent % of admissions in children, and % of child hospitalizations. pneumonia cases were hospitalized children who fulfilled the following criteria: -cough and/or dyspnea, and -tachypnea, as characterized by the world health organization (who) in children between and months of age: breathing rate ! cycles per minute; in children between and months of age: breathing rate ! cycles per minute) [ ] , and -absence of wheezing at auscultation, and -first symptoms appearing within the last days, and -radiological confirmation of pneumonia as per who guidelines [ ] . the exclusion criterions for cases were presence of wheezing at auscultation, or minors whose parents or legal guardian declined to sign the informed consent statement. controls were patients hospitalized for surgery or in a routine outpatient practice environment, aged between and months, without any symptoms suggestive of respiratory illness; suspicion of infection of other site was not an exclusion criteria. cases and controls were matched for age (± year) and calendar date of hospital admission (± month) to take seasonality into account. thus, % of patients were recruited during the rainy season (may to october) while % were recruited during the dry season (november to april). samples were collected in the first hours of patient hospitalization. nasal swabs were taken from all pneumonia cases and controls. to document antibiotic usage history, urine was sampled from cases for broad spectrum antibiotic detection. whole blood and pleural effusions (in applicable cases) were collected from cases only. whole blood was distributed in ethylenediaminetetraacetic acid (edta) vials for preservation and in dry tubes for serum specimens. edta-whole blood samples allowed complete blood count, blood culture and real-time multiplex polymerase chain reaction (pcr) assay for the identification of staphylococcus aureus, streptococcus pneumoniae and haemophilus influenzae type b. c reactive protein (crp) and procalcitonin (pct) were measured quantitatively in serum. respiratory specimens from nasal swabs and pleural effusions were characterized by ftd respiratory pathogens plus (fast-track diagnostics, luxembourg) based on rt-pcr which included a panel of demographic characteristics, underlying diseases, medical history, clinical examination at enrollment, radiological findings, vaccinations, and outcome were recorded prospectively for each patient on a standardized form. continuous variables were described as median and interquartile range (iqr), categorical variables as number and percentage. pneumonia cases we compared to the controls by the mann-whitney u test for continuous covariates, and by the chi test for categorical variables. univariate and multivariate logistic regression analyses were performed to assess factors associated with pneumonia. multivariate analyses were adjusted for gender, age, period per quarter, and other pathogens significantly associated with increased risk of pneumonia. concordance between serotypes detected in nasopharyngeal samples and blood was tested by kendall rank correlation. crude population attributable fraction (paf) was calculated after univariate logistic regression analysis to quantify the contribution of the each microorganism to pneumonia occurrence. conceptuality, paf permits the estimation of the proportional reduction in pneumonia occurrence that would occur if the pathogen was absent (alternative ideal scenario). the formula was the following: with : pr c ¼ prevalence of microorganim detection in controls; or ¼ crude odds ratio: no patient was excluded because of missing data. p< . was considered significant; all tests were bilateral, and statistical analysis was conducted with stata version . (stata corp.). with at least cases and controls, analyses had % power to detect odds ratios (or)! with ! % prevalence of control exposure, whatever the prevalence of case exposure. the study protocol, informed consent statement, clinical research form, any amendments and all other study documents were submitted to and approved by the institutional ethics committee (comité national d'ethique pour la santé et les sciences de la vie). written informed consent was obtained from all participants. among the enrolled cases, conformed with the inclusion criteria and were all sampled. one patient without radiological confirmation was excluded from the analysis. among the included controls, were excluded because of missing data. overall, patient, accounting for ( . %) pneumonia cases and ( . %) controls, were analyzed. among them, ( . %) were female. the male/female gender ratio was . , and median age was months (iqr: - months). among the patients with pneumonia, ( . %) were referred from another health center; median length of hospital stay was days (iqr: - days) for a total of days of hospitalization ( table ). the median time period between first symptoms and hospitalization was days (iqr: - days). four ( . %) pneumonia cases presented a ventricular septal defect. none had previous tuberculosis or underlying lung disease. among cases with pulmonary crackles, ( . %) were unilateral and ( . %) were bilateral. other signs or medical history of pneumonia cases included sickle-cell anaemia (n = ), dehydration (n = ), epilepsy (n = ), goiter (n = ), edema (n = ), pallor (n = ), and trisomy (n = ). among the patients who took antibiotics before hospitalization, ( . %) received amoxicillin, ( . %) ceftriaxone, ( . %) amoxicillin/clavulanic acid, and ( . %) cotrimoxazole. among the cases tested for antibiotic detection testing in urine, ( . %) were positive; in this population, sensitivity of declared antibiotic use compared with urine detection was low (sensitivity = . %, % confidence interval: . - . %). median crp level at admission was mg/l (iqr: - , mean: . mg/l), median pct level was . ng/ml (iqr: . - . , mean: . ng/ml). median crp and pct levels were higher in hypoxemic compared with non-hypoxemic pneumonia cases (p = . and p = . , respectively). median white blood cell count was , à cells/l (iqr: , - , , mean: , à cells/l), and median neutrophil percentage was . % (iqr: - , mean: . %). x-rays showed generalized, dense, homogeneous opacification in ( . %) patients, interstitial syndrome in ( . %), and alveolar infiltrate in ( . %), without significant differences according to the pattern of infection (viral, bacterial or mixed). no patient had abscess or pneumothorax, but ( . %) had pleural effusion. during hospital stay, pneumonia cases received the following antibiotics: amoxicillin (n = , . %), ceftriaxone (n = , . %), amoxicillin/clavulanic acid (n = , . %), ciprofloxacin (n = , . %), and vancomycin (n = , . %). fifty-one ( . %) received oxygen for a median length of days (iqr: - days), and ( . %) had blood transfusions. three patients with pleural effusions were tested for microbial detection. five patients died (lethality: . %); death was directly related to pneumonia in patients ( table ). table compares the clinical signs and symptoms at admission between cases and controls, underlying conditions and biological findings. pneumonia cases differed from controls regarding clinical signs and symptoms as well as vital signs at admission, but not in terms of demographic factors or past medical history. pneumonia cases were more frequently hypoxemic (defined as oxygen saturation< %) at admission than the controls ( . % vs. %, p< . ). pcv coverage was zero in both groups. at least microorganism was detected on nasal swabs in . % of cases and . % of controls (crude or = . , % confidence interval [ % ci]: . - . , p< . ). overall, . % of cases and . % of controls were co-infected or co-colonized (crude or = . , % ci: . - . , p< . ). co-detection on nasal swab of s. pneumoniae and rsv was more frequent in cases than in controls (respectively, between cases and controls (respectively, . % [n = ] vs. . % [n = ], p = . ). a doseresponse relationship was apparent between the number of microorganisms found in nasal swabs and the risk of being a case (fig ) . distribution of s. pneumoniae and rsv differed by season with higher rates of s. pneumoniae in january-june and of rsv in july-september (fig ) . univariate analysis revealed that s. pneumoniae, human metapneumovirus, rsv, and influenza a virus detection in nasal swabs were significantly associated with pneumonia in mali (table ) . multivariate analysis reinforced linkage of these pathogens with pneumonia, independently of patient age, gender, period per quarter and the presence of other pathogens significantly coupled with increased risk of pneumonia (table ) . paf was the highest for s. pneumoniae (paf = %, % ci: - %). contribution of human metapneumovirus, rsv, and influenza a were lower, with pafs of % ( % ci: - %), % ( % ci: - %) and, % ( % ci: - %), respectively. fig reports the distribution of pneumococcal serotypes detected in nasal swabs from cases and controls. the most prevalent serotype in pneumonia cases and controls was serotype a/b ( . % vs. . %, p = . ). serotypes and were more frequent in pneumonia cases than in the controls: . % vs. %, p = . , and . % vs. %, p = . , respectively. in pneumonia cases, s. pneumoniae was positive in ( . %) patients, s. aureus in ( . %) patients and h. influenza in ( . %) patients by pcr blood sample detection. most patients with s. pneumoniae detection by pcr had also s. pneumoniae nasal carriage ( . %, / ), while only . % ( / ) of patients with s. pneumoniae nasal carriage had positive detection by pcr (p = . ). concordance of serotype detected in nasal swabs and blood in pneumonia cases was high (κ = . , p< . ). coronavirus was identified from pleural effusion in patient. microbiological findings, including s. pneumoniae serotypes distribution, from pcr nasal swab or blood sample were not different in pneumonia cases according to the result of urine antibiotic testing (data not shown). blood culture was positive in ( . %) pneumonia cases; most microorganisms were probably related to contamination of samples. the following bacteria were detected: coagulase-negative staphyloccoci (n = ), salmonella spp. (n = ), gram-positive bacilli (n = ), acinetobacter baumannii (n = ), aerococcus viridans (n = ), enterococcus faecium (n = ), granulicatella elegans (n = ), and staphylococcus aureus (n = ). the primary objective of this prospective case-control study was to assess the etiology and factors associated with community-acquired pneumonia in hospitalized children in mali. in this non-pcv population, we observed that s. pneumoniae, human metapneumovirus, rsv, and influenza a were the main microbial agents associated with pneumonia among children in mali, independently of patient age, gender, period, and other pathogens. h. influenzae was not associated with pneumonia, but the vaccination rate against this bacteria, at least for the first dose, was above % in both cases and controls. in addition, while most patients with s. pneumoniae by pcr in blood had also nasal carriage, frequently with the same serotype, positive s. pneumoniae test from nasal sample was not highly predictive of s. pneumoniae detection in blood, meaning that the bacteria was frequently not the cause of pneumonia. few studies have assessed the etiology of pneumonia in sub-saharan africa. howie et al. recently investigated pneumonia etiology in children in gambia, observing that s. pneumoniae was the leading cause with a high rate of microbial agent co-detection [ ] . conversely, they found that viral pneumonia was not predominant whereas we observed that viruses, namely human metapneumovirus, rsv, and influenza a virus, were associated with pneumonia in mali. major differences between the studies were sample type (lung aspirates vs. nasal swabs in our investigation) and the lack of a comparative group in the study by howie et al. which did not permit comparison of microbial prevalence in pneumonia patients and healthy subjects [ ] . in a western kenya case-control study, s. pneumoniae, rsv, and influenza a virus were the predominant causes of pneumonia in children [ ] . we noted almost similar results in mali. thus, s. pneumoniae and rsv could still be considered as the primary causes of pneumonia in several sub-sharan african countries. all patients who died had severe pneumonia, according to who criteria, with significant dyspnea, very marked chest indrawing and severe hypoxia. two patients had confirmed pneumococcal pneumonia. two patients had acute malnutrition linked with pneumonia. in cases, death occurred within hours of admission. despite active treatment with antibiotics and oxygen, the management of severe respiratory distress is often difficult in this context because the hospital does not have assisted ventilatory support. mortality was higher than in a recent birth cohort in south africa [ ] , but was similar to what was reported previously in other developing countries [ , ] . some invasive serotypes were detected selectively in pneumonia cases but not in the controls (i.e., serotypes and were associated with the risk of pneumonia). a previous study of serotypes involved in invasive pneumococcal disease in mali found that serotype was the most prevalent ( %) [ ] . it was also linked with pneumonia in our series. in other sub-saharan african countries, serotype was described as the most prevalent serotype of invasive pneumococcal disease [ ] . it was the second serotype significantly associated with pneumonia in children in mali. thus, the introduction of pcv in routine immunization programs in mali would substantially reduce pneumonia caused by s. pneumoniae because most serotypes eliciting pneumonia would be covered by the vaccine [ ] . in addition, pneumococcal pneumonia seasonality was similar to that observed previously in burkina faso, a neighbouring country, in - with higher incidence during the dry season between january and may [ ] . interestingly, among the microbial agents associated with pneumonia, were viruses: human metapneumovirus, rsv, and influenza a virus. self et al. recently observed, in a pneumonia cases-control study implemented in hospitals of utah, that detection respiratory syncytial virus, human metapneumovirus and influenza from nasopharyngeal or oropharyngeal sample of patients with pneumonia probably indicates an etiologic role [ ] . we observed similar results in a different context. despite the dearth of vaccination against pneumococcus in our population, viral pneumonia is a major segment of the pneumonia burden. treatment of these infections is often problematic because the empirical use of antibiotics or antivirals is not consensual [ ] . vaccine development, particularly against rsv, is warranted to prevent pneumonia in children. moreover, the impact of influenza vaccine policies in developing countries should be evaluated because this virus often causes pneumonia [ ] . rhinovirus was detected in almost % of pneumonia cases of our series, but the detection rate was not different between cases and controls. however, this observation does formally excludes that rhinovirus could play a role in the etiology of pneumonia. jain et al. recently observed that rhinovirus was detected in % of u.s. children with community-pneumonia requiring hospitalization [ ]; this large study had however no control group, it was also not possible to estimate the prevalence of respiratory detection in children without pneumonia. growing evidence suggests the role of rhinovirus in the etiology of viral pneumonia [ ] or related to the risk of secondary bacterial pneumonia [ ] . other viruses, such as bocavirus or adenovirus were also equally prevalent in cases and controls. again, this finding does not exclude completely their implication in pneumonia etiology in children from mali. however these viruses were poorly described as causative agents of pneumonia in children from other sub-saharan african countries. several microorganisms have been detected in most pneumonia cases but also in the controls. the clinical significance of microbial detection by pcr is problematic at the individual level because most detected pathogens are not causes of pneumonia. however, number of pathogens is predictive of the risk of pneumonia, suggesting that simple quantification of species detected would permit the evaluation of pneumonia risk. at the population level, nasal samples are interesting because the prevalence of carriage in the controls is considered. the main strengths of our study were its prospective design with the inclusion of controls that permitted us to assess pneumonia etiologies while taking into account the prevalence of pathogen detection in non-infected patients. ours is the first case-control investigation of pneumonia etiology in children from mali (s strobe checklist). the results should serve to better manage pneumonia not only in these children but also in those from neighboring countries. data quality was enhanced by centralized microbiological analysis in the emerging pathogens laboratory (lyon, france). in addition, this analysis should serve to better focus multicentric pneumonia studies that will permit us to assess the global etiologies of pneumonia and to compare etiologic agents between countries and continents. some limitations should be underlined. first, microbiological diagnosis of pneumonia is difficult due to the lack of single reliable test. then, at the individual level, it is difficult to establish if a positive nasal swab denotes etiology or nasopharyngeal colonization; particularly for bacterial agents such as s. pneumoniae because of the high asymptomatic carriage. however, at the population level, addition of a control group permits to evaluate and control for the prevalence of carriage in asymptomatic children. in a pneumonia etiology study, it would be interesting to correlate the threshold cycle (ct) values obtained from rt-pcr with lower airway specimens to establish more precisely the relationship between positive nasal swab and etiology of pneumonia, according to the microorganism [ ] . second, because the study was implemented in one hospital in mali, external validity might be limited. however, gabriel touré university hospital is a reference center in the country, and then source population is not limited to the city of bamako. third, study power was confined to detecting some linkages (i.e. serotypes associated with the risk of pneumonia). community-acquired pneumonia was mainly attributable to s. pneumoniae, human metapneumovirus, rsv or influenza a among children in mali. increased pneumococcal conjugate vaccine coverage in children would significantly reduce the burden of pneumonia in this country. the addition of a control group to assess etiologies of pneumonia in children is critical to properly interpret the microbiological results of diagnostic testing with high sensitivity. supporting information s strobe checklist. (doc) s global burden of childhood pneumonia and diarrhoea global health observatory data repository global, regional, and national causes of child mortality: an updated systematic analysis for with time trends since global, regional, and national causes of child mortality in : a systematic analysis community-acquired pneumonia in children epidemiology and etiology of childhood pneumonia in : estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for countries the causes of hospital admission and death among children in bamako, mali identification and selection of cases and controls in the pneumonia etiology research for child health project the impact of introducing new vaccines on the health system: case studies from six low-and middleincome countries enhancing research capacities in infectious diseases: the gabriel network, a joint approach to major local health issues in developing countries multicenter case-control study protocol of pneumonia etiology in children: global approach to biological research, infectious diseases and epidemics in low-income countries (gabriel network) case management of childhood pneumonia in developing countries standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies etiology of severe childhood pneumonia in the gambia, west africa, determined by conventional and molecular microbiological analyses of lung and pleural aspirate samples viral and bacterial causes of severe acute respiratory illness among children aged less than years in a high malaria prevalence area of western kenya incidence and severity of childhood pneumonia in the first year of life in a south african birth cohort: the drakenstein child health study variations in mortality in children admitted with pneumonia to kenyan hospitals risk factors for mortality in community acquired pneumonia among children aged - months admitted in a referral hospital invasive pneumococcal infections among hospitalized children in bamako, mali molecular typing of the pneumococcus and its application in epidemiology in sub-saharan africa licensure of a -valent pneumococcal conjugate vaccine (pcv ) and recommendations for use among children-advisory committee on immunization practices (acip) streptococcus pneumoniae invasive infections in burkina faso respiratory viral detection in children and adults: comparing asymptomatic controls and patients with community-acquired pneumonia strategic priorities for respiratory syncytial virus (rsv) vaccine development global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. the lancet community-acquired pneumonia requiring hospitalization among u.s. children rhinovirus associated with severe lower respiratory tract infections in children viral and bacterial interactions in the upper respiratory tract respiratory virus detection in nasopharyngeal aspirate versus bronchoalveolar lavage is dependent on virus type in children with chronic respiratory symptoms this protocol was developed on behalf of members of the global approach to biological research, infectious diseases and epidemics in low-income countries (gabriel) network: http://gabriel.globe-network.org. key: cord- -vmsdhccp authors: mandell, lionel a.; wunderink, richard g.; anzueto, antonio; bartlett, john g.; campbell, g. douglas; dean, nathan c.; dowell, scott f.; file, thomas m.; musher, daniel m.; niederman, michael s.; torres, antonio; whitney, cynthia g. title: infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults date: - - journal: clin infect dis doi: . / sha: doc_id: cord_uid: vmsdhccp nan improving the care of adult patients with communityacquired pneumonia (cap) has been the focus of many different organizations, and several have developed guidelines for management of cap. two of the most widely referenced are those of the infectious diseases society of america (idsa) and the american thoracic society (ats). in response to confusion regarding differences between their respective guidelines, the idsa and the ats convened a joint committee to develop a unified cap guideline document. the guidelines are intended primarily for use by emergency medicine physicians, hospitalists, and primary care practitioners; however, the extensive literature evaluation suggests that they are also an appro-reprints or correspondence: dr. lionel a. mandell priate starting point for consultation by specialists. substantial overlap exists among the patients whom these guidelines address and those discussed in the recently published guidelines for health care-associated pneumonia (hcap). pneumonia in nonambulatory residents of nursing homes and other long-term care facilities epidemiologically mirrors hospital-acquired pneumonia and should be treated according to the hcap guidelines. however, certain other patients whose conditions are included in the designation of hcap are better served by management in accordance with cap guidelines with concern for specific pathogens. . locally adapted guidelines should be implemented to improve process of care variables and relevant clinical outcomes. (strong recommendation; level i evidence.) it is important to realize that guidelines cannot always account for individual variation among patients. they are not intended to supplant physician judgment with respect to particular patients or special clinical situations. the idsa considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. enthusiasm for developing these guidelines derives, in large part, from evidence that previous cap guidelines have led to improvement in clinically relevant outcomes. consistently beneficial effects in clinically relevant parameters (listed in table ) followed the introduction of a comprehensive protocol (including a combination of components from table ) that increased compliance with published guidelines. the first recommendation, therefore, is that cap management guidelines be locally adapted and implemented. documented benefits. . cap guidelines should address a comprehensive set of elements in the process of care rather than a single element in isolation. (strong recommendation; level iii evidence.) . development of local cap guidelines should be directed toward improvement in specific and clinically relevant outcomes. (moderate recommendation; level iii evidence.) almost all of the major decisions regarding management of cap, including diagnostic and treatment issues, revolve around the initial assessment of severity. site-of-care decisions (e.g., hospital vs. outpatient, intensive care unit [icu] vs. general ward) are important areas for improvement in cap management. hospital admission decision. . severity-of-illness scores, such as the curb- criteria (confusion, uremia, respiratory rate, low blood pressure, age years or greater), or prognostic models, such as the pneumonia severity index (psi), can be used to identify patients with cap who may be candidates for outpatient treatment. (strong recommendation; level i evidence.) . objective criteria or scores should always be supplemented with physician determination of subjective factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. (strong recommendation; level ii evidence.) . for patients with curb- scores у , more-intensive treatment-that is, hospitalization or, where appropriate and available, intensive in-home health care services-is usually warranted. (moderate recommendation; level iii evidence.) physicians often admit patients to the hospital who could be well managed as outpatients and who would generally prefer to be treated as outpatients. objective scores, such as the curb- score or the psi, can assist in identifying patients who may be appropriate for outpatient care, but the use of such scores must be tempered by the physician's determination of additional critical factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. icu admission decision. . direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. (strong recommendation; level ii evidence.) . direct admission to an icu or high-level monitoring unit is recommended for patients with of the minor criteria for severe cap listed in table . (moderate recommendation; level ii evidence.) in some studies, a significant percentage of patients with cap are transferred to the icu in the first - h after hospitalization. mortality and morbidity among these patients appears to be greater than those among patients admitted directly to the icu. conversely, icu resources are often overstretched in many institutions, and the admission of patients with cap who would not directly benefit from icu care is also problematic. unfortunately, none of the published criteria for severe cap adequately distinguishes these patients from those for whom icu admission is necessary. in the present set of guidelines, a new set of criteria has been developed on the basis of data on individual risks, although the previous ats criteria format is retained. in addition to the major criteria (need for mechanical ventilation and septic shock), an expanded set of minor criteria (respiratory rate, breaths/min; arterial oxygen pressure/fraction of inspired oxygen (pao /fio ) ratio, ! ; multilobar infiltrates; confusion; blood urea nitrogen level, mg/dl; leukopenia resulting from infection; thrombocytopenia; hypothermia; or hypotension requiring aggressive fluid resuscitation) is proposed (table ). the presence of at least of these criteria suggests the need for icu care but will require prospective validation. . in addition to a constellation of suggestive clinical features, a demonstrable infiltrate by chest radiograph or other imaging technique, with or without supporting microbiological data, is required for the diagnosis of pneumonia. (moderate recommendation; level iii evidence.) recommended diagnostic tests for etiology. . patients with cap should be investigated for specific pathogens that would significantly alter standard (empirical) management decisions, when the presence of such pathogens is suspected on the basis of clinical and epidemiologic clues. (strong recommendation; level ii evidence.) recommendations for diagnostic testing remain controversial. the overall low yield and infrequent positive impact on clinical care argue against the routine use of common tests, such as blood and sputum cultures. conversely, these cultures may have a major impact on the care of an individual patient and are important for epidemiologic reasons, including the antibiotic susceptibility patterns used to develop treatment guidelines. a list of clinical indications for more extensive diagnostic testing (table ) was, therefore, developed, primarily on the basis of criteria: ( ) when the result is likely to change individual antibiotic management and ( ) when the test is likely to have the highest yield. . routine diagnostic tests to identify an etiologic diagnosis are optional for outpatients with cap. (moderate recommendation; level iii evidence.) . pretreatment blood samples for culture and an expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized patients with the clinical indications listed in table but are optional for patients without these conditions. (moderate recommendation; level i evidence.) . pretreatment gram stain and culture of expectorated sputum should be performed only if a good-quality specimen can be obtained and quality performance measures for collection, transport, and processing of samples can be met. (moderate recommendation; level ii evidence.) . patients with severe cap, as defined above, should at least have blood samples drawn for culture, urinary antigen tests for legionella pneumophila and streptococcus pneumoniae performed, and expectorated sputum samples collected for culture. for intubated patients, an endotracheal aspirate sample should be obtained. (moderate recommendation; level ii evidence.) the most clear-cut indication for extensive diagnostic testing is in the critically ill cap patient. such patients should at least have blood drawn for culture and an endotracheal aspirate obtained if they are intubated; consideration should be given to more extensive testing, including urinary antigen tests for l. pneumophila and s. pneumoniae and gram stain and culture of expectorated sputum in nonintubated patients. for inpatients without the clinical indications listed in table , diagnostic testing is optional (but should not be considered wrong). empirical antimicrobial therapy. empirical antibiotic recommendations (table ) have not changed significantly from those in previous guidelines. increasing evidence has strengthened the recommendation for combination empirical therapy for severe cap. only recently released antibiotic has been added to the recommendations: ertapenem, as an acceptable b-lactam alternative for hospitalized patients with risk factors for infection with gram-negative pathogens other than pseudomonas aeruginosa. at present, the committee is awaiting further evaluation of the safety of telithromycin by the us food and drug administration before making its final recommendation regarding this drug. recommendations are generally for a class of antibiotics rather than for a specific drug, unless outcome data clearly favor one drug. because overall efficacy remains good for many classes of agents, the more potent drugs are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance. . a b-lactam plus a macrolide (strong recommendation; level i evidence) (preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline [level iii evidence] as an alternative to the macrolide. a respiratory fluoroquinolone should be used for penicillin-allergic patients.) increasing resistance rates have suggested that empirical therapy with a macrolide alone can be used only for the treat-ment of carefully selected hospitalized patients with nonsevere disease and without risk factors for infection with drug-resistant pathogens. however, such monotherapy cannot be routinely recommended. inpatient, icu treatment . a b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level ii evidence) or a fluoroquinolone (level i evidence) (strong recommendation) (for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) . for pseudomonas infection, use an antipneumococcal, antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin ( -mg dose) or the above b-lactam plus an aminoglycoside and azithromycin or the above b-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone (for penicillin-allergic patients, substitute aztreonam for the above b-lactam). (moderate recommendation; level iii evidence.) . for community-acquired methicillin-resistant staphylococcus aureus infection, add vancomycin or linezolid. (moderate recommendation; level iii evidence.) infections with the overwhelming majority of cap pathogens will be adequately treated by use of the recommended empirical regimens. the emergence of methicillin-resistant s. aureus as a cap pathogen and the small but significant incidence of cap due to p. aeruginosa are the exceptions. these pathogens occur in specific epidemiologic patterns and/or with certain clinical presentations, for which empirical antibiotic coverage may be warranted. however, diagnostic tests are likely to be of high yield for these pathogens, allowing early discontinuation of empirical treatment if results are negative. the risk factors are included in the table recommendations for indications for increased diagnostic testing. risk factors for other uncommon etiologies of cap are listed in table , and recommendations for treatment are included in table . pathogen-directed therapy. definitions and classification. . the use of a systematic classification of possible causes of failure to respond, based on time of onset and type of failure (table ) , is recommended. (moderate recommendation; level ii evidence.) as many as % of patients with cap may not respond appropriately to initial antibiotic therapy. a systematic approach to these patients (table ) will help to determine the cause. because determination of the cause of failure is more accurate if the original microbiological etiology is known, risk factors for nonresponse or deterioration (table ) figure prominently in the list of situations in which more aggressive and/ or extensive initial diagnostic testing is warranted ( [ ] . despite advances in antimicrobial therapy, rates of mortality due to pneumonia have not decreased significantly since penicillin became routinely available [ ] . groups interested in approaches to the management of cap include professional societies, such as the american thoracic society (ats) and the infectious diseases society of america (idsa); government agencies or their contract agents, such as the center for medicare and medicaid services and the department of veterans affairs; and voluntary accrediting agencies, such as the joint commission on accreditation of healthcare organizations. in addition, external review groups and consumer groups have chosen cap outcomes as major quality indicators. such interest has resulted in numerous guidelines for the management of cap [ ] . some of these guidelines represent truly different perspectives, including differences in health care systems, in the availability of diagnostic tools or therapeutic agents, or in either the etiology or the antibiotic susceptibility of common causative microorganisms. the most widely referenced guidelines in the united states have been those published by the ats [ , ] and the idsa [ ] [ ] [ ] . differences, both real and imagined, between the ats and idsa guidelines have led to confusion for individual physicians, as well as for other groups who use these published guidelines rather than promulgating their own. in response to this concern, the idsa and the ats convened a joint committee to develop a unified cap guideline document. this document represents a consensus of members of both societies, and both governing councils have approved the statement. purpose and scope. the purpose of this document is to update clinicians with regard to important advances and controversies in the management of patients with cap. the committee chose not to address cap occurring in immunocompromised patients, including solid organ, bone marrow, or stem cell transplant recipients; patients receiving cancer chemotherapy or long-term ( days) high-dose corticosteroid treatment; and patients with congenital or acquired immunodeficiency or those infected with hiv who have cd cell counts ! cells/mm , although many of these patients may be infected with the same microorganisms. pneumonia in children (р years of age) is also not addressed. substantial overlap exists among the patients these guidelines address and those discussed in the recently published guidelines for health care-associated pneumonia (hcap) [ ] . two issues are pertinent: ( ) an increased risk of infection with drugresistant isolates of usual cap pathogens, such as streptococcus pneumoniae, and ( ) an increased risk of infection with less common, usually hospital-associated pathogens, such as pseudomonas and acinetobacter species and methicillin-resistant staphylococcus aureus (mrsa). pneumonia in nonambulatory residents of nursing homes and other long-term care facilities epidemiologically mirrors hospital-acquired pneumonia and should be treated according to the hcap guidelines. however, certain other patients whose conditions are included under the designation of hcap are better served by management in ac-cordance with cap guidelines with concern for specific pathogens. for example, long-term dialysis alone is a risk for mrsa infection but does not necessarily predispose patients to infection with other hcap pathogens, such as pseudomonas aeruginosa or acinetobacter species. on the other hand, certain patients with chronic obstructive pulmonary disease (copd) are at greater risk for infection with pseudomonas species but not mrsa. these issues will be discussed in specific sections below. the committee started with the premise that mortality due to cap can be decreased. we, therefore, have placed the greatest emphasis on aspects of the guidelines that have been associated with decreases in mortality. for this reason, the document focuses mainly on management and minimizes discussions of such factors as pathophysiology, pathogenesis, mechanisms of antibiotic resistance, and virulence factors. the committee recognizes that the majority of patients with cap are cared for by primary care, hospitalist, and emergency medicine physicians [ ] , and these guidelines are, therefore, directed primarily at them. the committee consisted of infectious diseases, pulmonary, and critical care physicians with interest and expertise in pulmonary infections. the expertise of the committee and the extensive literature evaluation suggest that these guidelines are also an appropriate starting point for consultation by these types of physicians. although much of the literature cited originates in europe, these guidelines are oriented toward the united states and canada. although the guidelines are generally applicable to other parts of the world, local antibiotic resistance patterns, drug availability, and variations in health care systems suggest that modification of these guidelines is prudent for local use. methodology. the process of guideline development started with the selection of committee cochairs by the presidents of the idsa [ ] and ats [ ] , in consultation with other leaders in the respective societies. the committee cochairs were charged with selection of the rest of the committee. the idsa members were those involved in the development of previous idsa cap guidelines [ ] , whereas ats members were chosen in consultation with the leadership of the mycobacteria tuberculosis and pulmonary infection assembly, with input from the chairs of the clinical pulmonary and critical care assemblies. committee members were chosen to represent differing expertise and viewpoints on the various topics. one acknowledged weakness of this document is the lack of representation by primary care, hospitalist, and emergency medicine physicians. the cochairs generated a general outline of the topics to be covered that was then circulated to committee members for input. a conference phone call was used to review topics and to discuss evidence grading and the general aims and expectations of the document. the topics were divided, and committee members were assigned by the cochairs and charged with presentation of their topic at an initial face-to-face meeting, as well as with development of a preliminary document dealing with their topic. controversial topics were assigned to committee members, from each society. an initial face-to-face meeting of a majority of committee members involved presentations of the most controversial topics, including admission decisions, diagnostic strategies, and antibiotic therapy. prolonged discussions followed each presentation, with consensus regarding the major issues achieved before moving to the next topic. with input from the rest of the committee, each presenter and committee member assigned to the less controversial topics prepared an initial draft of their section, including grading of the evidence. iterative drafts of the statement were developed and distributed by e-mail for critique, followed by multiple revisions by the primary authors. a second face-to-face meeting was also held for discussion of the less controversial areas and further critique of the initial drafts. once general agreement on the separate topics was obtained, the cochairs incorporated the separate documents into a single statement, with substantial editing for style and consistency. the document was then redistributed to committee members to review and update with new information from the literature up to june . recommended changes were reviewed by all committee members by e-mail and/or conference phone call and were incorporated into the final document by the cochairs. this document was then submitted to the societies for approval. each society independently selected reviewers, and changes recommended by the reviewers were discussed by the committee and incorporated into the final document. the guideline was then submitted to the idsa governing council and the ats board of directors for final approval. grading of guideline recommendations. initially, the committee decided to grade only the strength of the evidence, using a -tier scale (table ) used in a recent guideline from both societies [ ] . in response to reviewers' comments and the maturation of the field of guideline development [ ] , a separate grading of the strength of the recommendations was added to the final draft. more extensive and validated criteria, such as grade [ ] , were impractical for use at this stage. the -tier scale similar to that used in other idsa guideline documents [ ] and familiar to many of the committee members was therefore chosen. the strength of each recommendation was graded as "strong," "moderate," or "weak." each committee member independently graded each recommendation on the basis of not only the evidence but also expert interpretation and clinical applicability. the final grading of each recommendation was a composite of the individual committee members' grades. for the final document, a strong recommendation required у (of ) of the members to consider it to be strong and the majority of the others to grade it as moderate. the implication of a strong recommendation is that most patients should receive that intervention. significant variability in the management of patients with cap is well documented. some who use guidelines suggest that this variability itself is undesirable. industrial models suggesting that variability per se is undesirable may not always be relevant to medicine [ ] . such models do not account for substantial variability among patients, nor do they account for variable end points, such as limitation of care in patients with end-stage underlying diseases who present with cap. for this reason, the committee members feel strongly that % compliance with guidelines is not the desired goal. however, the rationale for variation from a strongly recommended guideline should be apparent from the medical record. conversely, moderate or weak recommendations suggest that, even if a majority would follow the recommended management, many practitioners may not. deviation from guidelines may occur for a variety of reasons [ , ] . one document cannot cover all of the variable settings, unique hosts, or epidemiologic patterns that may dictate alternative management strategies, and physician judgment should always supersede guidelines. this is borne out by the finding that deviation from guidelines is greatest in the treatment of patients with cap admitted to the icu [ ] . in addition, few of the recommendations have level i evidence to support them, and most are, therefore, legitimate topics for future research. subsequent publication of studies documenting that care that deviates from guidelines results in better outcomes will stimulate revision of the guidelines. the committee anticipates that this will occur, and, for this reason, both the ats and idsa leaderships have committed to the revision of these guidelines on a regular basis. we recognize that these guidelines may be used as a measure of quality of care for hospitals and individual practitioners. although these guidelines are evidence based, the committee strongly urges that deviations from them not necessarily be considered substandard care, unless they are accompanied by evidence for worse outcomes in a studied population. . locally adapted guidelines should be implemented to improve process of care variables and relevant clinical outcomes. (strong recommendation; level i evidence.) enthusiasm for developing this set of cap guidelines derives, in large part, from evidence that previous cap guidelines have led to improvement in clinically relevant outcomes [ , [ ] [ ] [ ] . protocol design varies among studies, and the preferable randomized, parallel group design has been used in only a small minority. confirmatory studies that use randomized, parallel groups with precisely defined treatments are still needed, but a consistent pattern of benefit is found in the other types of level i studies. documented benefits. published protocols have varied in primary focus and comprehensiveness, and the corresponding benefits vary from one study to another. however, the most impressive aspect of this literature is the consistently beneficial effect seen in some clinically relevant parameter after the introduction of a protocol that increases compliance with published guidelines. a decrease in mortality with the introduction of guidelinebased protocols was found in several studies [ , ] . a -year study of , patients with pneumonia who were admitted during implementation of a pneumonia guideline demonstrated that the crude -day mortality rate was . % lower with the guideline (adjusted or, . ; % ci, . - . ) [ ] , compared with that among patients treated concurrently by nonaffiliated physicians. after implemention of a practice guideline at one spanish hospital [ ] , the survival rate at days was higher (or, . ; % ci, . - . ) than at baseline and in comparison with other hospitals without overt protocols. lower mortality was seen in other studies, although the differences were not statistically significant [ , ] . studies that documented lower mortality emphasized increasing the number of patients receiving guideline-recommended antibiotics, confirming results of the multivariate analysis of a retrospective review [ ] . when the focus of a guideline was hospitalization, the number of less ill patients admitted to the hospital was consistently found to be lower. using admission decision support, a prospective study of emergency department (ed) visits in hospitals randomized between pathway and "conventional" management found that admission rates among low-risk patients at pathway hospitals decreased (from % to % of patients in pneumonia severity index [psi] classes i-iii; p ! ) without differences in patient satisfaction scores or rate of . readmission [ ] . calculating the psi score and assigning the risk class, providing oral clarithromycin, and home nursing follow-up significantly ( ) decreased the number of low-p p . mortality-risk admissions [ ] . however, patient satisfaction among outpatients was lower after implementation of this guideline, despite survey data that suggested most patients would prefer outpatient treatment [ ] . of patients discharged from the ed, % required hospitalization within days, although another study showed lower readmission rates with the use of a protocol [ ] . admission decision support derived from the ats guideline [ ] recommendations, combined with outpatient antibiotic recommendations, reduced the cap hospitalization rate from . % to . % [ ] , and admission rates for other diagnoses were unchanged. not surprisingly, the resultant overall cost of care decreased by half ( ). p p . protocols using guidelines to decrease the duration of hospitalization have also been successful. guideline implementation in connecticut hospitals decreased the mean length of hospital stay (los) from to days ( ) [ ] . an ed-p ! . based protocol decreased the mean los from . to . days ( ), with the benefits of guideline implementation p ! . maintained years after the initial study [ ] . a -site trial, randomized by physician group, of guideline alone versus the same guideline with a multifaceted implementation strategy found that addition of an implementation strategy was associated with decreased duration of intravenous antibiotic therapy and los, although neither decrease was statistically significant [ ] . several other studies used guidelines to significantly shorten the los, by an average of . days [ , ] . markers of process of care can also change with the use of a protocol. the time to first antibiotic dose has been effectively decreased with cap protocols [ , , ] . a randomized, parallel group study introduced a pneumonia guideline in of small oklahoma hospitals [ ] , with the identical protocol implemented in the remaining hospitals in a second phase. serial measurement of key process measures showed significant improvement in time to first antibiotic dose and other variables, first in the initial hospitals and later in the remaining hospitals. implementing a guideline in the ed halved the time to initial antibiotic dose [ ] . . cap guidelines should address a comprehensive set of elements in the process of care rather than a single element in isolation. (strong recommendation; level iii evidence.) common to all of the studies documented above, a com- prehensive protocol was developed and implemented, rather than one addressing a single aspect of cap care. no study has documented that simply changing metric, such as time to first antibiotic dose, is associated with a decrease in mortality. elements important in cap guidelines are listed in table . of these, rapid and appropriate empirical antibiotic therapy is consistently associated with improved outcome. we have also included elements of good care for general medical inpatients, such as early mobilization [ ] and prophylaxis against thromboembolic disease [ ] . although local guidelines need not include all elements, a logical constellation of elements should be addressed. in instituting cap protocol guidelines, the outcomes most relevant to the individual center or medical system should be addressed first. unless a desire to change clinically relevant outcomes exists, adherence to guidelines will be low, and institutional resources committed to implement the guideline are likely to be insufficient. guidelines for the treatment of pneumonia must use approaches that differ from current practice and must be successfully implemented before process of care and outcomes can change. for example, rhew et al. [ ] designed a guideline to decrease los that was unlikely to change care, because the recommended median los was longer than the existing los for cap at the study hospitals. the difficulty in implementing guidelines and changing physician behavior has also been documented [ , ] . clinically relevant outcome parameters should be evaluated to measure the effect of the local guideline. outcome parameters that can be used to measure the effect of implementation of a cap guideline within an organization are listed in table . just as it is important not to focus on one aspect of care, studying more than one outcome is also important. improvements in one area may be offset by worsening in a related area; for example, decreasing admission of low-acuity patients might increase the number of return visits to the ed or hospital readmissions [ ] . almost all of the major decisions regarding management of cap, including diagnostic and treatment issues, revolve around the initial assessment of severity. we have, therefore, organized the guidelines to address this issue first. hospital admission decision. the initial management decision after diagnosis is to determine the site of care-outpatient, hospitalization in a medical ward, or admission to an icu. the decision to admit the patient is the most costly issue in the management of cap, because the cost of inpatient care for pneumonia is up to times greater than that of outpatient care [ ] and consumes the majority of the estimated $ . -$ billion spent yearly on treatment. other reasons for avoiding unnecessary admissions are that patients at low risk for death who are treated in the outpatient setting are able to resume normal activity sooner than those who are hospitalized, and % are reported to prefer outpatient therapy [ , ] . hospitalization also increases the risk of thromboembolic events and superinfection by more-virulent or resistant hospital bacteria [ ] . . severity-of-illness scores, such as the curb- criteria (confusion, uremia, respiratory rate, low blood pressure, age years or greater), or prognostic models, such as the psi, can be used to identify patients with cap who may be candidates for outpatient treatment. (strong recommendation; level i evidence.) significant variation in admission rates among hospitals and among individual physicians is well documented. physicians often overestimate severity and hospitalize a significant number of patients at low risk for death [ , , ] . because of these issues, interest in objective site-of-care criteria has led to attempts by a number of groups to develop such criteria [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the relative merits and limitations of various proposed criteria have been carefully evaluated [ ] . the most interesting are the psi [ ] and the british thoracic society (bts) criteria [ , ] . the psi is based on derivation and validation cohorts of , and , hospitalized patients with cap, respectively, plus an additional combined inpatients and outpatients [ ] . the psi stratifies patients into mortality risk classes, and its ability to predict mortality has been confirmed in multiple subsequent studies. on the basis of associated mortality rates, it has been suggested that risk class i and ii patients should be treated as outpatients, risk class iii patients should be treated in an observation unit or with a short hospitalization, and risk class iv and v patients should be treated as inpatients [ ] . yealy et al. [ ] conducted a cluster-randomized trial of low-, moderate-, and high-intensity processes of guideline implementation in eds in the united states. their guideline used the psi for admission decision support and included recommendations for antibiotic therapy, timing of first antibiotic dose, measurement of oxygen saturation, and blood cultures for admitted patients. eds with moderate-to high-intensity guideline implementation demonstrated more outpatient treatment of low-risk patients and higher compliance with antibiotic recommendations. no differences were found in mortality rate, rate of hospitalization, median time to return to work or usual activities, or patient satisfaction. this study differs from those reporting a mortality rate difference [ , ] in that many hospitalized patients with pneumonia were not included. in addition, eds with low-intensity guideline implementation formed the comparison group, rather than eds practicing nonguideline, usual pneumonia care. the bts original criteria of have subsequently been modified [ , ] . in the initial study, risk of death was increased -fold if a patient, at the time of admission, had at least of the following conditions: tachypnea, diastolic hypotension, and an elevated blood urea nitrogen (bun) level. these criteria appear to function well except among patients with underlying renal insufficiency and among elderly patients [ , ] . the most recent modification of the bts criteria includes easily measurable factors [ ] . multivariate analysis of patients identified the following factors as indicators of increased mortality: confusion (based on a specific mental test or disorientation to person, place, or time), bun level mmol/l ( mg/dl), respiratory rate у breaths/min, low blood pressure (systolic, ! mm hg; or diastolic, р mm hg), and age у years; this gave rise to the acronym curb- . in the derivation and validation cohorts, the -day mortality among patients with , , or factors was . %, . %, and . %, respectively. mortality was higher when , , or factors were present and was reported as . %, %, and %, respectively. the authors suggested that patients with a curb- score of - be treated as outpatients, that those with a score of be admitted to the wards, and that patients with a score of у often required icu care. a simplified version (crb- ), which does not require testing for bun level, may be appropriate for decision making in a primary care practitioner's office [ ] . the use of objective admission criteria clearly can decrease the number of patients hospitalized with cap [ , , , ] . whether the psi or the curb- score is superior is unclear, because no randomized trials of alternative admission criteria exist. when compared in the same population, the psi classified a slightly larger percentage of patients with cap in the lowrisk categories, compared with the curb or curb- criteria, while remaining associated with a similar low mortality rate among patients categorized as low risk [ ] . several factors are important in this comparison. the psi includes different variables and, therefore, relies on the availability of scoring sheets, limiting its practicality in a busy ed [ ] . in contrast, the curb- criteria are easily remembered. however, curb- has not been as extensively studied as the psi, especially with prospective validation in other patient populations (e.g., the indigent inner-city population), and has not been specifically studied as a means of reducing hospital admission rates. in eds with sufficient decision support resources (either human or computerized), the benefit of greater experience with the psi score may favor its use for screening patients who may be candidates for outpatient management [ , [ ] [ ] [ ] . . objective criteria or scores should always be supplemented with physician determination of subjective factors, including the ability to safely and reliably take oral medication and the availability of outpatient support resources. (strong recommendation; level ii evidence.) studies show that certain patients with low psi or curb- scores [ , , ] require hospital admission, even to the icu [ , , ] . both scores depend on certain assumptions. one is that the main rationale for admission of a patient with cap is risk of death. this assumption is clearly not valid in all cases. another is that the laboratory and vital signs used for scoring are stable over time rather than indicative of transient abnormalities. this is also not true in all cases. therefore, dynamic assessment over several hours of observation may be more accurate than a score derived at a single point in time. although advantageous to making decisions regarding hospital admission, sole reliance on a score for the hospital admission decision is unsafe. reasons for the admission of low-mortality-risk patients fall into categories: ( ) complications of the pneumonia itself, ( ) exacerbation of underlying diseases(s), ( ) inability to reliably take oral medications or receive outpatient care, and/or ( ) multiple risk factors falling just above or below thresholds for the score [ ] . use of the psi score in clinical trials has demonstrated some of its limitations, which may be equally applicable to other scoring techniques. a modification of the original psi score was needed when it was applied to the admission decision. an arterial saturation of ! % or an arterial oxygen pressure (pao ) of ! mm hg as a complication of the pneumonia, was added as a sole indicator for admission for patients in risk classes i-iii as an added "margin of safety" in one trial [ ] . in addition to patients who required hospital admission because of hypoxemia, a subsequent study identified patients in low psi risk classes (i-iii) who needed hospital admission because of shock, decompensated coexisting illnesses, pleural effusion, inability to maintain oral intake, social problems (the patient was dependent or no caregiver was available), and lack of response to previous adequate empirical antibiotic therapy [ ] . of patients in low psi risk classes who were treated as inpatients, ( %) presented with at least of these factors. other medical or psychosocial needs requiring hospital care include intractable vomiting, injection drug abuse, severe psychiatric illness, homelessness, poor overall functional status [ ] , and cognitive dysfunction [ , ] . the psi score is based on a history of diseases that increase risk of death, whereas the curb- score does not directly address underlying disease. however, pneumonia may exacerbate an underlying disease, such as obstructive lung disease, congestive heart failure, or diabetes mellitus, which, by themselves, may require hospital admission [ , ] . atlas et al. [ ] were able to reduce hospital admissions among patients in psi risk classes i-iii from % in a retrospective control group to % in a psi-based intervention group. ten of patients in the latter group (compared with patients in the control population) were subsequently admitted, several for reasons unrelated to their pneumonia. also, the presence of rare illnesses, such as neuromuscular or sickle cell disease, may require hospitalization but not affect the psi score. the necessary reliance on dichotomous predictor variables (abnormal vs. normal) in most criteria and the heavy reliance on age as a surrogate in the psi score may oversimplify their use for admission decisions. for example, a previously healthy -year-old patient with severe hypotension and tachycardia and no additional pertinent prognostic factors would be placed in risk class ii, whereas a -year-old man with a history of localized prostate cancer diagnosed months earlier and no other problems would be placed in risk class iv [ ] . finally, patient satisfaction was lower among patients treated outside the hospital in one study with a psi-based intervention group [ ] , suggesting that the savings resulting from use of the psi may be overestimated and that physicians should consider additional factors not measured by the psi. . for patients with curb- scores у , more-intensive treatment-that is, hospitalization or, where appropriate and available, intensive in-home health care services-is usually warranted. (moderate recommendation; level iii evidence.) although the psi and curb- criteria are valuable aids in avoiding inappropriate admissions of low-mortality-risk patients, another important role of these criteria may be to help identify patients at high risk who would benefit from hospitalization. the committee preferred the curb- criteria because of ease of use and because they were designed to measure illness severity more than the likelihood of mortality. patients with a curb- score у are not only at increased risk of death but also are likely to have clinically important physiologic derangements requiring active intervention. these patients should usually be considered for hospitalization or for aggressive in-home care, where available. in a cohort of ∼ patients, the mortality with a curb- score of was only . %, whereas - points were associated with % mortality [ ] . because the psi score is not based as directly on severity of illness as are the curb- criteria, a threshold for patients who would require hospital admission or intensive outpatient treatment is harder to define. the higher the score, the greater the need for hospitalization. however, even a patient who meets criteria for risk class v on the basis of very old age and multiple stable chronic illnesses may be successfully managed as an outpatient [ ] . . direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. (strong recommendation; level ii evidence.) the second-level admission decision is whether to place the patient in the icu or a high-level monitoring unit rather than on a general medical floor. approximately % of hospitalized patients with cap require icu admission [ ] [ ] [ ] , but the indications vary strikingly among patients, physicians, hospitals, and different health care systems. some of the variability among institutions results from the availability of high-level monitoring or intermediate care units appropriate for patients at increased risk of complications. because respiratory failure is the major reason for delayed transfer to the icu, simple cardiac monitoring units would not meet the criteria for a highlevel monitoring unit for patients with severe cap. one of the most important determinants of the need for icu care is the presence of chronic comorbid conditions [ ] [ ] [ ] [ ] [ ] . however, approximately one-third of patients with severe cap were previously healthy [ ] . the rationale for specifically defining severe cap is -fold: • appropriate placement of patients optimizes use of limited icu resources. • transfer to the icu for delayed respiratory failure or delayed onset of septic shock is associated with increased mortality [ ] . although low-acuity icu admissions do occur, the major concern is initial admission to the general medical unit, with subsequent transfer to the icu. as many as % of patients with cap who ultimately require icu admission were initially admitted to a non-icu setting [ ] . many delayed transfers to the icu represent rapidly progressive pneumonia that is not obvious on admission. however, some have subtle findings, including those included in the minor criteria in table , which might warrant direct admission to the icu. • the distribution of microbial etiologies differs from that of cap in general [ ] [ ] [ ] [ ] , with significant implications for diagnostic testing and empirical antibiotic choices. avoidance of inappropriate antibiotic therapy has also been associated with lower mortality [ , ] . • patients with cap appropriate for immunomodulatory treatment must be identified. the systemic inflammatory response/severe sepsis criteria typically used for generic sepsis trials may not be adequate when applied specifically to severe cap [ ] . for example, patients with unilateral lobar pneumonia may have hypoxemia severe enough to meet criteria for acute lung injury but not have a systemic response. several criteria have been proposed to define severe cap. most case series have defined it simply as cap that necessitates icu admission. objective criteria to identify patients for icu admission include the initial ats definition of severe cap [ ] and its subsequent modification [ , ] , the curb criteria [ , ] , and psi severity class v (or iv and v) [ ] . however, none of these criteria has been prospectively validated for the icu admission decision. recently, these criteria were retrospectively evaluated in a cohort of patients with cap admitted to the icu [ ] . all were found to be both overly sensitive and nonspecific in comparison with the original clinical decision to admit to the icu. revisions of the criteria or alternative criteria were, therefore, recommended. for the revised criteria, the structure of the modified ats criteria for severe cap was retained [ ] . the major criteriamechanical ventilation with endotracheal intubation and septic shock requiring vasopressors-are absolute indications for admission to an icu. in contrast, the need for icu admission is less straightforward for patients who do not meet the major criteria. on the basis of the published operating characteristics of the criteria, no single set of minor criteria is adequate to define severe cap. both the ats minor criteria [ ] and the curb criteria [ ] have validity when predicting which patients will be at increased risk of death. therefore, the ats minor criteria and the curb variables were included in the new proposed minor criteria (table ) . age, by itself, was not felt to be an appropriate factor for the icu admission decision, but the remainder of the curb- criteria [ ] were retained as minor criteria (with the exception of hypotension requiring vasopressors as a major criterion). rather than the complex criteria for confusion in the original curb studies, the definition of confusion should be new-onset disorientation to person, place, or time. three additional minor criteria were added. leukopenia (white blood cell count, ! cells/mm ) resulting from cap has consistently been associated with excess mortality, as well as with an increased risk of complications such as acute respiratory distress syndrome (ards) [ , , [ ] [ ] [ ] [ ] [ ] . in addition, leukopenia is seen not only in bacteremic pneumococcal disease but also in gram-negative cap [ , ] . when leukopenia occurs in patients with a history of alcohol abuse, the adverse manifestations of septic shock and ards may be delayed or masked. therefore, these patients were thought to benefit from icu monitoring. the coagulation system is often activated in cap, and development of thrombocytopenia (platelet count, ! , cells/mm ) is also associated with a worse prognosis [ , [ ] [ ] [ ] . nonexposure hypothermia (core temperature, ! Њc) also carries an ominous prognosis in cap [ , ] . the committee felt that there was sufficient justification for including these additional factors as minor criteria. other factors associated with increased mortality due to cap were also considered, including acute alcohol ingestion and delirium tremens [ , , ] , hypoglycemia and hyperglycemia, occult metabolic acidosis or elevated lactate levels [ ] , and hyponatremia [ ] . however, many of these criteria overlap with those selected. future studies validating the proposed criteria should record these factors as well, to determine whether addition or substitution improves the predictive value of our proposed criteria. with the addition of more minor criteria, the threshold for icu admission was felt to be the presence of at least minor criteria, based on the mortality association with the curb criteria. selecting criteria appears to be too nonspecific, as is demonstrated by the initial ats criteria [ ] . whether each of the criteria is of equal weight is also not clear. therefore, prospective validation of this set of criteria is clearly needed. . in addition to a constellation of suggestive clinical features, a demonstrable infiltrate by chest radiograph or other imaging technique, with or without supporting microbiological data, is required for the diagnosis of pneumonia. (moderate recommendation; level iii evidence.) the diagnosis of cap is based on the presence of select clinical features (e.g., cough, fever, sputum production, and pleuritic chest pain) and is supported by imaging of the lung, usually by chest radiography. physical examination to detect rales or bronchial breath sounds is an important component of the evaluation but is less sensitive and specific than chest radiographs [ ] . both clinical features and physical exam findings may be lacking or altered in elderly patients. all patients should be screened by pulse oximetry, which may suggest both the presence of pneumonia in patients without obvious signs of pneumonia and unsuspected hypoxemia in patients with diagnosed pneumonia [ , , ] . a chest radiograph is required for the routine evaluation of patients who are likely to have pneumonia, to establish the diagnosis and to aid in differentiating cap from other common causes of cough and fever, such as acute bronchitis. chest radiographs are sometimes useful for suggesting the etiologic agent, prognosis, alternative diagnoses, and associated conditions. rarely, the admission chest radiograph is clear, but the patient's toxic appearance suggests more than bronchitis. ct scans may be more sensitive, but the clinical significance of these findings when findings of radiography are negative is unclear [ ] . for patients who are hospitalized for suspected pneumonia but who have negative chest radiography findings, it may be reasonable to treat their condition presumptively with antibiotics and repeat the imaging in - h. microbiological studies may support the diagnosis of pneumonia due to an infectious agent, but routine tests are frequently falsely negative and are often nonspecific. a history of recent travel or endemic exposure, if routinely sought, may identify specific potential etiologies that would otherwise be unexpected as a cause of cap (see table ) [ ] . . patients with cap should be investigated for specific pathogens that would significantly alter standard (empirical) management decisions, when the presence of such pathogens is suspected on the basis of clinical and epidemiologic clues. (strong recommendation; level ii evidence.) the need for diagnostic testing to determine the etiology of cap can be justified from several perspectives. the primary reason for such testing is if results will change the antibiotic management for an individual patient. the spectrum of antibiotic therapy can be broadened, narrowed, or completely altered on the basis of diagnostic testing. the alteration in therapy that is potentially most beneficial to the individual is an escalation or switch of the usual empirical regimen because of unusual pathogens (e.g., endemic fungi or mycobacterium tuberculosis) or antibiotic resistance issues. broad empirical coverage, such as that recommended in these guidelines, would not provide the optimal treatment for certain infections, such as psittacosis or tularemia. increased mortality [ ] and increased risk of clinical failure [ , ] are more common with inappropriate antibiotic therapy. management of initial antibiotic failure is greatly facilitated by an etiologic diagnosis at admission. de-escalation or narrowing of antibiotic therapy on the basis of diagnostic testing is less likely to decrease an in- dividual's risk of death but may decrease cost, drug adverse effects, and antibiotic resistance pressure. some etiologic diagnoses have important epidemiologic implications, such as documentation of severe acute respiratory syndrome (sars), influenza, legionnaires disease, or agents of bioterrorism. diagnostic testing for these infections may affect not only the individual but also many other people. although pneumonia etiologies that should be reported to public health officials vary by state, in general, most states' health regulations require reporting of legionnaires disease, sars, psittacosis, avian influenza (h n ), and possible agents of bioterrorism (plague, tularemia, and anthrax). in addition, specific diagnostic testing and reporting are important for pneumonia cases of any etiology thought to be part of a cluster or caused by pathogens not endemic to the area. there are also societal reasons for encouraging diagnostic testing. the antibiotic recommendations in the present guidelines are based on culture results and sensitivity patterns from patients with positive etiologic diagnoses [ ] . without the accumulated information available from these culture results, trends in antibiotic resistance are more difficult to track, and empirical antibiotic recommendations are less likely to be accurate. the main downside of extensive diagnostic testing of all patients with cap is cost, which is driven by the poor quality of most sputum microbiological samples and the low yield of positive culture results in many groups of patients with cap. a clear need for improved diagnostic testing in cap, most likely using molecular methodology rather than culture, has been recognized by the national institutes of health [ ] . the cost-benefit ratio is even worse when antibiotic therapy is not streamlined when possible [ , ] or when inappropriate escalation occurs [ ] . in clinical practice, narrowing of antibiotic therapy is, unfortunately, unusual, but the committee strongly recommends this as best medical practice. the possibility of polymicrobial cap and the potential benefit of combination therapy for bacteremic pneumococcal pneumonia have complicated the decision to narrow antibiotic therapy. delays in starting antibiotic therapy that result from the need to obtain specimens, complications of invasive diagnostic procedures, and unneeded antibiotic changes and additional testing for false-positive tests are also important considerations. the general recommendation of the committee is to strongly encourage diagnostic testing whenever the result is likely to change individual antibiotic management. for other patients with cap, the recommendations for diagnostic testing focus on patients in whom the diagnostic yield is thought to be greatest. these priorities often overlap. recommendations for patients in whom routine diagnostic testing is indicated for the above reasons are listed in retrospective studies of outpatient cap management usually show that diagnostic tests to define an etiologic pathogen are infrequently performed, yet most patients do well with empir-ical antibiotic treatment [ , ] . exceptions to this general rule may apply to some pathogens important for epidemiologic reasons or management decisions. the availability of rapid point-of-care diagnostic tests, specific treatment and chemoprevention, and epidemiologic importance make influenza testing the most logical. influenza is often suspected on the basis of typical symptoms during the proper season in the presence of an epidemic. however, respiratory syncytial virus (rsv) can cause a similar syndrome and often occurs in the same clinical scenario [ ] . rapid diagnostic tests may be indicated when the diagnosis is uncertain and when distinguishing influenza a from influenza b is important for therapeutic decisions. other infections that are important to verify with diagnostic studies because of epidemiologic implications or because they require unique therapeutic intervention are sars and avian (h n ) influenza, disease caused by agents of bioterrorism, legionella infection, community-acquired mrsa (ca-mrsa) infection, m. tuberculosis infection, or endemic fungal infection. attempts to establish an etiologic diagnosis are also appropriate in selected cases associated with outbreaks, specific risk factors, or atypical presentations. . pretreatment blood samples for culture and an expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized patients with the clinical indications listed in the only randomized controlled trial of diagnostic strategy in cap has demonstrated no statistically significant differences in mortality rate or los between patients receiving pathogendirected therapy and patients receiving empirical therapy [ ] . however, pathogen-directed therapy was associated with lower mortality among the small number of patients admitted to the icu. the study was performed in a country with a low incidence of antibiotic resistance, which may limit its applicability to areas with higher levels of resistance. adverse effects were significantly more common in the empirical therapy group but may have been unique to the specific antibiotic choice (erythromycin). the lack of benefit overall in this trial should not be interpreted as a lack of benefit for an individual patient. therefore, performing diagnostic tests is never incorrect or a breach of the standard of care. however, information from cohort and observational studies may be used to define patient groups in which the diagnostic yield is increased. patient groups in which routine diagnostic testing is indicated and the recommended tests are listed in table . blood cultures. pretreatment blood cultures yielded positive results for a probable pathogen in %- % in large series of nonselected patients hospitalized with cap [ , , [ ] [ ] [ ] . the yield of blood cultures is, therefore, relatively low (although it is similar to yields in other serious infections), and, when management decisions are analyzed, the impact of positive blood cultures is minor [ , ] . the most common blood culture isolate in all cap studies is s. pneumoniae. because this bacterial organism is always considered to be the most likely pathogen, positive blood culture results have not clearly led to better outcomes or improvements in antibiotic selection [ , ] . false-positive blood culture results are associated with prolonged hospital stay, possibly related to changes in management based on preliminary results showing gram-positive cocci, which eventually prove to be coagulasenegative staphylococci [ , ] . in addition, false-positive blood culture results have led to significantly more vancomycin use [ ] . for these reasons, blood cultures are optional for all hospitalized patients with cap but should be performed selectively (table ). the yield for positive blood culture results is halved by prior antibiotic therapy [ ] . therefore, when performed, samples for blood culture should be obtained before antibiotic administration. however, when multiple risk factors for bacteremia are present, blood culture results after initiation of antibiotic therapy are still positive in up to % of cases [ ] and are, therefore, still warranted in these cases, despite the lower yield. the strongest indication for blood cultures is severe cap. patients with severe cap are more likely to be infected with pathogens other than s. pneumoniae, including s. aureus, p. aeruginosa, and other gram-negative bacilli [ - , , , ] . many of the factors predictive of positive blood culture results [ ] overlap with risk factors for severe cap (table ) . therefore, blood cultures are recommended for all patients with severe cap because of the higher yield, the greater possibility of the presence of pathogens not covered by the usual empirical antibiotic therapy, and the increased potential to affect antibiotic management. blood cultures are also indicated when patients have a host defect in the ability to clear bacteremia-for example, as a result of asplenia or complement deficiencies. patients with chronic liver disease also are more likely to have bacteremia with cap [ ] . leukopenia is also associated with a high incidence of bacteremia [ , ] . respiratory tract specimen gram stain and culture. the yield of sputum bacterial cultures is variable and strongly influenced by the quality of the entire process, including specimen collection, transport, rapid processing, satisfactory use of cytologic criteria, absence of prior antibiotic therapy, and skill in interpretation. the yield of s. pneumoniae, for example, is only %- % from sputum cultures from patients with bacteremic pneumococcal pneumonia in studies performed a few decades ago [ , ] . a more recent study of cases of bacteremic pneumococcal pneumonia found that sputum specimens were not submitted in % of cases and were judged as inadequate in another % of cases [ ] . when patients receiving antibiotics for h were excluded, gram stain showed pneumococci in % of sputum specimens, and culture results were positive in %. for patients who had received no antibiotics, the gram stain was read as being consistent with pneumococci in % of cases, and sputum culture results were positive in %. although there are favorable reports of the utility of gram stain [ ] , a meta-analysis showed a low yield, considering the number of patients with adequate specimens and definitive results [ ] . recent data show that an adequate specimen with a predominant morphotype on gram stain was found in only % of hospitalized patients with cap [ ] . higher psi scores did not predict higher yield. however, a positive gram stain was highly predictive of a subsequent positive culture result. the benefit of a sputum gram stain is, therefore, -fold. first, it broadens initial empirical coverage for less common etiologies, such as infection with s. aureus or gram-negative organisms. this indication is probably the most important, because it will lead to less inappropriate antibiotic therapy. second, it can validate the subsequent sputum culture results. forty percent or more of patients are unable to produce any sputum or to produce sputum in a timely manner [ , ] . the yield of cultures is substantially higher with endotracheal aspirates, bronchoscopic sampling, or transthoracic needle aspirates [ ] [ ] [ ] [ ] [ ] [ ] [ ] , although specimens obtained after initiation of antibiotic therapy are unreliable and must be interpreted carefully [ , , ] . interpretation is improved with quantitative cultures of respiratory secretions from any source (sputum, tracheal aspirations, and bronchoscopic aspirations) or by interpretation based on semiquantitative culture results [ , , ] . because of the significant influence on diagnostic yield and cost effectiveness, careful attention to the details of specimen handling and processing are critical if sputum cultures are obtained. because the best specimens are collected and processed before antibiotics are given, the time to consider obtaining expectorated sputum specimens from patients with factors listed in table is before initiation of antibiotic therapy. once again, the best indication for more extensive respiratory tract cultures is severe cap. gram stain and culture of endotracheal aspirates from intubated patients with cap produce different results than expectorated sputum from non-icu patients [ , ] . many of the pathogens in the broader microbiological spectrum of severe cap are unaffected by a single dose of antibiotics, unlike s. pneumoniae. in addition, an endotracheal aspirate does not require patient cooperation, is clearly a lower respiratory tract sample, and is less likely to be contaminated by oropharyngeal colonizers. nosocomial tracheal colonization is not an issue if the sample is obtained soon after intubation. therefore, culture and gram stain of endotracheal aspirates are recommended for patients intubated for severe cap. in addition to routine cultures, a specific request for culture of respiratory secretions on buffered charcoal yeast extract agar to isolate legionella species may be useful in this subset of patients with severe cap in areas where legionella is endemic, as well as in patients with a recent travel history [ ] . the fact that a respiratory tract culture result is negative does not mean that it has no value. failure to detect s. aureus or gram-negative bacilli in good-quality specimens is strong evidence against the presence of these pathogens. growth inhibition by antibiotics is lower with these pathogens than with s. pneumoniae, but specimens obtained after initiation of antibiotic therapy are harder to interpret, with the possibility of colonization. necrotizing or cavitary pneumonia is a risk for ca-mrsa infection, and sputum samples should be obtained in all cases. negative gram stain and culture results should be adequate to withhold or stop treatment for mrsa infection. severe copd and alcoholism are major risk factors for infection with p. aeruginosa and other gram-negative pathogens [ ] . once again, gram stain and culture of an adequate sputum specimen are usually adequate to exclude the need for empirical coverage of these pathogens. a sputum culture in patients with suspected legionnaires disease is important, because the identification of legionella species implies the possibility of an environmental source to which other susceptible individuals may be exposed. localized community outbreaks of legionnaires disease might be recognized by clinicians or local health departments because у patients might be admitted to the same hospital. however, outbreaks of legionnaires disease associated with hotels or cruise ships [ ] [ ] [ ] are rarely detected by individual clinicians, because travelers typically disperse from the source of infection before developing symptoms. therefore, a travel history should be actively sought from patients with cap, and legionella testing should be performed for those who have traveled in the weeks before the onset of symptoms. urinary antigen tests may be adequate to diagnose and treat an individual, but efforts to obtain a sputum specimen for culture are still indicated to facilitate epidemiologic tracking. the availability of a culture isolate of legionella dramatically improves the likelihood that an environmental source of legionella can be identified and remediated [ ] [ ] [ ] . the yield of sputum culture is increased to %- % when associated with a positive urinary antigen test result [ , ] . attempts to obtain a sample for sputum culture from a patient with a positive pneumococcal urinary antigen test result may be indicated for similar reasons. patients with a productive cough and positive urinary antigen test results have positive sputum culture results in as many as %- % of cases [ ] [ ] [ ] [ ] . in these cases, not only can sensitivity testing confirm the appropriate choice for the individual patient, but important data regarding local community antibiotic resistance rates can also be acquired. other cultures. patients with pleural effusions cm in height on a lateral upright chest radiograph [ ] should undergo thoracentesis to yield material for gram stain and culture for aerobic and anaerobic bacteria. the yield with pleural fluid cultures is low, but the impact on management decisions is substantial, in terms of both antibiotic choice and the need for drainage. nonbronchoscopic bronchoalveolar lavage (bal) in the ed has been studied in a small, randomized trial of intubated patients with cap [ ] . a high percentage ( %) of nonbronchoscopic bal culture results were positive, even in some patients who had already received their first dose of antibiotics. unfortunately, tracheal aspirates were obtained from only a third of patients in the control group, but they all were culture positive. therefore, it is unclear that endotracheal aspirates are inferior to nonbronchoscopic bal. the use of bronchoscopic bal, protected specimen brushing, or transthoracic lung aspiration has not been prospectively studied for initial management of patients with cap [ ] . the best indications are for immunocompromised patients with cap or for patients with cap in whom therapy failed [ , ] . antigen tests. urinary antigen tests are commercially available and have been cleared by the us food and drug administration (fda) for detection of s. pneumoniae and l. pneumophila serogroup [ , , [ ] [ ] [ ] [ ] . urinary antigen testing appears to have a higher diagnostic yield in patients with more severe illness [ , ] . for pneumococcal pneumonia, the principal advantages of antigen tests are rapidity (∼ min), simplicity, reasonable specificity in adults, and the ability to detect pneumococcal pneumonia after antibiotic therapy has been started. studies in adults show a sensitivity of %- % and a specificity of % [ , , ] . this is an attractive test for detecting pneumococcal pneumonia when samples for culture cannot be obtained in a timely fashion or when antibiotic therapy has already been initiated. serial specimens from patients with known bacteremia were still positive for pneumococcal urinary antigen in % of cases after days of therapy [ ] . comparisons with gram stain show that these rapidly available tests often do not overlap, with only % concordance ( of ) among patients when results of either test were positive [ ] . only ∼ % of binax pneumococcal urinary antigen-positive patients can be diagnosed by conventional methods [ , ] . disadvantages include cost (approximately $ per specimen), although this is offset by increased diagnosis-related group-based reimbursement for coding for pneumococcal pneumonia, and the lack of an organism for in vitro susceptibility tests. falsepositive results have been seen in children with chronic respiratory diseases who are colonized with s. pneumoniae [ ] and in patients with an episode of cap within the previous months [ ] , but they do not appear to be a significant problem in colonized patients with copd [ , ] . for legionella, several urinary antigen assays are available, but all detect only l. pneumophila serogroup . although this particular serogroup accounts for %- % of communityacquired cases of legionnaires disease [ , ] in many areas of north america, other species and serogroups predominate in specific locales [ , ] . prior studies of culture-proven legionnaires disease indicate a sensitivity of %- % and a specificity of nearly % for detection of l. pneumophila serogroup . the urine is positive for antigen on day of illness and continues to be positive for weeks [ , ] . the major issue with urinary bacterial antigen detection is whether the tests allow narrowing of empirical antibiotic therapy to a single specific agent. the recommended empirical antibiotic regimens will cover both of these microorganisms. results of a small observational study suggest that therapy with a macrolide alone is adequate for hospitalized patients with cap who test positive for l. pneumophila urinary antigen [ ] . further research is needed in this area. in contrast, rapid antigen detection tests for influenza, which can also provide an etiologic diagnosis within - min, can lead to consideration of antiviral therapy. test performance varies according to the test used, sample type, duration of illness, and patient age. most show a sensitivity of %- % in adults and a specificity approaching % [ ] [ ] [ ] . advantages include the high specificity, the ability of some assays to distinguish between influenza a and b, the rapidity with which the results can be obtained, the possibly reduced use of antibacterial agents, and the utility of establishing this diagnosis for epidemiologic purposes, especially in hospitalized patients who may require infection control precautions. disadvantages include cost (approximately $ per specimen), high rates of false-negative test results, false-positive assays with adenovirus infections, and the fact that the sensitivity is not superior to physician judgment among patients with typical symptoms during an influenza epidemic [ , , ] . direct fluorescent antibody tests are available for influenza and rsv and require ∼ h. for influenza virus, the sensitivity is better than with the point-of-care tests ( %- %). they will detect animal subtypes such as h n and, thus, may be preferred for hospitalized patients [ , ] . for rsv, direct fluorescent antibody tests are so insensitive (sensitivity, %- %) in adults that they are rarely of value [ ] . acute-phase serologic testing. the standard for diagnosis of infection with most atypical pathogens, including chlamydophila pneumoniae, mycoplasma pneumoniae, and legionella species other than l. pneumophila, relies on acute-and convalescent-phase serologic testing. most studies use a microimmunofluorescence serologic test, but this test shows poor reproducibility [ ] . management of patients on the basis of a single acute-phase titer is unreliable [ ] , and initial antibiotic therapy will be completed before the earliest time point to check a convalescent-phase specimen. a new pcr test (bd probetec et legionella pneumophila; becton dickinson) that will detect all serotypes of l. pneumophila in sputum is now cleared by the fda, but extensive published clinical experience is lacking. most pcr reagents for other respiratory pathogens (except mycobacterium species) are "home grown," with requirements for use based on compliance with nccls criteria for analytical validity [ ] . despite the increasing use of these tests for atypical pathogens [ , ] , a review by the centers for disease control and prevention (cdc) of diagnostic assays for detection of c. pneumoniae indicated that, of the pcr reagents, only satisfied the criteria for a validated test [ ] . the diagnostic criteria defined in this review are particularly important for use in prospective studies of cap, because most prior reports used liberal criteria, which resulted in exaggerated rates. for sars, several pcr assays have been developed, but these tests are inadequate because of high rates of false-negative assays in early stages of infection [ , ] . a major goal of therapy is eradication of the infecting organism, with resultant resolution of clinical disease. as such, antimicrobials are a mainstay of treatment. appropriate drug selection is dependent on the causative pathogen and its antibiotic susceptibility. acute pneumonia may be caused by a wide variety of pathogens (table ) . however, until more accurate and rapid diagnostic methods are available, the initial treatment for most patients will remain empirical. recommendations for therapy (table ) apply to most cases; however, physicians should consider specific risk factors for each patient (table ) . a syndromic approach to therapy (under the assumption that an etiology correlates with the presenting clinical manifestations) is not specific enough to reliably predict the etiology of cap [ ] [ ] [ ] . even if a microbial etiology is identified, debate continues with regard to pathogen-specific treatment, because recent studies suggest coinfection by atypical pathogens (such as c. pneumoniae, legionella species, and viruses) and more traditional bacteria [ , ] . however, the importance of treating multiple infecting organisms has not been firmly established. the majority of antibiotics released in the past several decades have an fda indication for cap, making the choice of antibiotics potentially overwhelming. selection of antimicrobial regimens for empirical therapy is based on prediction of the most likely pathogen(s) and knowledge of local susceptibility patterns. recommendations are generally for a class of antibiotics rather than a specific drug, unless outcome data clearly favor one drug. because overall efficacy remains good for many classes of agents, the more potent drugs are given preference because of their benefit in decreasing the risk of selection for antibiotic resistance. other factors for consideration of specific antimicrobials include pharmacokinetics/pharmacodynamics, compliance, safety, and cost. although cap may be caused by a myriad of pathogens, a limited number of agents are responsible for most cases. the emergence of newly recognized pathogens, such as the novel sars-associated coronavirus [ ] , continually increases the challenge for appropriate management. table lists the most common causes of cap, in decreasing order of frequency of occurrence and stratified for severity of illness as judged by site of care (ambulatory vs. hospitalized). s. pneumoniae is the most frequently isolated pathogen. other bacterial causes include nontypeable haemophilus influenzae and moraxella catarrhalis, generally in patients who have underlying bronchopulmonary disease, and s. aureus, especially during an influenza outbreak. risks for infection with enterobacteriaceae species and p. aeruginosa as etiologies for cap are chronic oral steroid administration or severe underlying bronchopulmonary disease, alcoholism, and frequent antibiotic therapy [ , ] , whereas recent hospitalization would define cases as hcap. less common causes of pneumonia include, but are by no means limited to, streptococcus pyogenes, neisseria meningitidis, pasteurella multocida, and h. influenzae type b. the "atypical" organisms, so called because they are not detectable on gram stain or cultivatable on standard bacteriologic media, include m. pneumoniae, c. pneumoniae, legionella species, and respiratory viruses. with the exception of legionella species, these microorganisms are common causes of pneumonia, especially among outpatients. however, these pathogens are not often identified in clinical practice because, with a few exceptions, such as l. pneumophila and influenza virus, no specific, rapid, or standardized tests for their detection exist. although influenza remains the predominant viral cause of cap in adults, other commonly recognized viruses include rsv [ ] , adenovirus, and parainfluenza virus, as well as less common viruses, including human metapneumovirus, herpes simplex virus, varicella-zoster virus, sars-associated coronavirus, and measles virus. in a recent study of immunocompetent adult patients admitted to the hospital with cap, % had evidence of a viral etiology, and, in %, a respiratory virus was the only pathogen identified [ ] . studies that include outpatients find viral pneumonia rates as high as % [ ] . the frequency of other etiologic agents-for example, m. tuberculosis, chlamydophila psittaci (psittacosis), coxiella burnetii (q fever), francisella tularensis (tularemia), bordetella pertussis (whooping cough), and endemic fungi (histoplasma capsulatum, coccidioides immitis, cryptococcus neoformans, and blastomyces hominis)-is largely determined by the epidemiologic setting (table ) but rarely exceeds %- % total [ , ] . the exception may be endemic fungi in the appropriate geographic distribution [ ] . the need for specific anaerobic coverage for cap is generally overestimated. anaerobic bacteria cannot be detected by diagnostic techniques in current use. anaerobic coverage is clearly indicated only in the classic aspiration pleuropulmonary syndrome in patients with a history of loss of consciousness as a result of alcohol/drug overdose or after seizures in patients with concomitant gingival disease or esophogeal motility disorders. antibiotic trials have not demonstrated a need to specifically treat these organisms in the majority of cap cases. smallvolume aspiration at the time of intubation should be adequately handled by standard empirical severe cap treatment [ ] and by the high oxygen tension provided by mechanical ventilation. resistance to commonly used antibiotics for cap presents another major consideration in choosing empirical therapy. resistance patterns clearly vary by geography. local antibiotic prescribing patterns are a likely explanation [ ] [ ] [ ] . however, clonal spread of resistant strains is well documented. therefore, antibiotic recommendations must be modified on the basis of local susceptibility patterns. the most reliable source is state/provincial or municipal health department regional data, if available. local hospital antibiograms are generally the most accessible source of data but may suffer from small numbers of isolates. drug-resistant s. pneumoniae (drsp). the emergence of drug-resistant pneumococcal isolates is well documented. the incidence of resistance appears to have stabilized somewhat in the past few years. resistance to penicillin and cephalosporins may even be decreasing, whereas macrolide resistance continues to increase [ , ] . however, the clinical relevance of drsp for pneumonia is uncertain, and few well-controlled studies have examined the impact of in vitro resistance on clinical outcomes of cap. published studies are limited by small sample sizes, biases inherent in observational design, and the relative infrequency of isolates exhibiting high-level resistance [ ] [ ] [ ] . current levels of b-lactam resistance do not generally result in cap treatment failures when appropriate agents (i.e., amoxicillin, ceftriaxone, or cefotaxime) and doses are used, even in the presence of bacteremia [ , ] . the available data suggest that the clinically relevant level of penicillin resistance is a mic of at least mg/l [ ] . one report suggested that, if cefuroxime is used to treat pneumococcal bacteremia when the organism is resistant in vitro, the outcome is worse than with other therapies [ ] . other discordant therapies, including penicillin, did not have an impact on mortality. data exist suggesting that resistance to macrolides [ ] [ ] [ ] and older fluoroquinolones (ciprofloxacin and levofloxacin) [ , , ] results in clinical failure. to date, no failures have been reported for the newer fluoroquinolones (moxifloxacin and gemifloxacin). risk factors for infection with b-lactam-resistant s. pneumoniae include age ! years or years, b-lactam therapy within the previous months, alcoholism, medical comorbidities, immunosuppressive illness or therapy, and exposure to a child in a day care center [ , [ ] [ ] [ ] . although the relative predictive value of these risk factors is unclear, recent treatment with antimicrobials is likely the most significant. recent therapy or repeated courses of therapy with b-lactams, macrolides, or fluoroquinolones are risk factors for pneumococcal resistance to the same class of antibiotic [ , , , ] . one study found that use of either a b-lactam or macrolide within the previous months predicted an increased likelihood that, if pneumococcal bacteremia is present, the organism would be penicillin resistant [ ] . other studies have shown that repeated use of fluoroquinolones predicts an increased risk of infection with fluoroquinolone-resistant pneumococci [ , ] . whether this risk applies equally to all fluoroquinolones or is more of a concern for less active antipneumococcal agents (levofloxacin and ciprofloxacin) than for more active agents (moxifloxacin and gemifloxacin) is uncertain [ , , ] . recommendations for the use of highly active agents in patients at risk for infection with drsp is, therefore, based only in part on efficacy considerations; it is also based on a desire to prevent more resistance from emerging by employing the most potent regimen possible. although increasing the doses of certain agents (penicillins, cephalosporins, levofloxacin) may lead to adequate outcomes in the majority of cases, switching to more potent agents may lead to stabilization or even an overall decrease in resistance rates [ , ] . ca-mrsa. recently, an increasing incidence of pneumonia due to ca-mrsa has been observed [ , ] . ca-mrsa appears in patterns: the typical hospital-acquired strain [ ] and, recently, strains that are epidemiologically, genotypically, and phenotypically distinct from hospital-acquired strains [ , ] . many of the former may represent hcap, because these earlier studies did not differentiate this group from typical cap. the latter are resistant to fewer antimicrobials than are hospitalacquired mrsa strains and often contain a novel type iv sccmec gene. in addition, most contain the gene for panton-valentine leukocidin [ , ] , a toxin associated with clinical features of necrotizing pneumonia, shock, and respiratory failure, as well as formation of abscesses and empyemas. the large majority of cases published to date have been skin infections in children. in a large study of ca-mrsa in communities, % of ca-mrsa infections were pneumonia [ ] . however, pneumonia in both adults [ ] and children has been reported, often associated with preceding influenza. this strain should also be suspected in patients who present with cavitary infiltrates without risk factors for anaerobic aspiration pneu-monia (gingivitis and a risk for loss of consciousness, such as seizures or alcohol abuse, or esophogeal motility disorders). diagnosis is usually straightforward, with high yields from sputum and blood cultures in this characteristic clinical scenario. ca-mrsa cap remains rare in most communities but is expected to be an emerging problem in cap treatment. outpatient treatment. the following regimens are recommended for outpatient treatment on the basis of the listed clinical risks. the most common pathogens identified from recent studies of mild (ambulatory) cap were s. pneumoniae, m. pneumoniae, c. pneumoniae, and h. influenzae [ , ] . mycoplasma infection was most common among patients ! years of age without significant comorbid conditions or abnormal vital signs, whereas s. pneumoniae was the most common pathogen among older patients and among those with significant underlying disease. hemophilus infection was found in %mostly in patients with comorbidities. the importance of ther-apy for mycoplasma infection and chlamydophila infection in mild cap has been the subject of debate, because many infections are self-limiting [ , ] . nevertheless, studies from the s of children indicate that treatment of mild m. pneumoniae cap reduces the morbidity of pneumonia and shortens the duration of symptoms [ ] . the evidence to support specific treatment of these microorganisms in adults is lacking. macrolides have long been commonly prescribed for treatment of outpatients with cap in the united states, because of their activity against s. pneumoniae and the atypical pathogens. this class includes the erythromycin-type agents (including dirithromycin), clarithromycin, and the azalide azithromycin. although the least expensive, erythromycin is not often used now, because of gastrointestinal intolerance and lack of activity against h. influenzae. because of h. influenzae, azithromycin is preferred for outpatients with comorbidities such as copd. numerous randomized clinical trials have documented the efficacy of clarithromycin and azithromycin as monotherapy for outpatient cap, although several studies have demonstrated that clinical failure can occur with a resistant isolate. when such patients were hospitalized and treated with a b-lactam and a macrolide, however, all survived and generally recovered without significant complications [ , ] . most of these patients had risk factors for which therapy with a macrolide alone is not recommended in the present guidelines. thus, for patients with a significant risk of drsp infection, monotherapy with a macrolide is not recommended. doxycycline is included as a cost-effective alternative on the basis of in vitro data indicating effectiveness equivalent to that of erythromycin for pneumococcal isolates. the use of fluoroquinolones to treat ambulatory patients with cap without comorbid conditions, risk factors for drsp, or recent antimicrobial use is discouraged because of concern that widespread use may lead to the development of fluoroquinolone resistance [ ] . however, the fraction of total fluoroquinolone use specifically for cap is extremely small and unlikely to lead to increased resistance by itself. more concerning is a recent study suggesting that many outpatients given a fluoroquinolone may not have even required an antibiotic, that the dose and duration of treatment were often incorrect, and that another agent often should have been used as firstline therapy. this usage pattern may promote the rapid development of resistance to fluoroquinolones [ ] . comorbidities or recent antimicrobial therapy increase the likelihood of infection with drsp and enteric gram-negative bacteria. for such patients, recommended empirical therapeutic options include ( ) a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [ mg daily]) or ( ) combination therapy with a b-lactam effective against s. pneumoniae plus a macrolide (doxycycline as an alternative). on the basis of present pharmacodynamic principles, high-dose amox-icillin (amoxicillin [ g times daily] or amoxicillin-clavulanate [ g times daily]) should target % of s. pneumoniae and is the preferred b-lactam. ceftriaxone is an alternative to highdose amoxicillin when parenteral therapy is feasible. selected oral cephalosporins (cefpodoxime and cefuroxime) can be used as alternatives [ ] , but these are less active in vitro than highdose amoxicillin or ceftriaxone. agents in the same class as the patient had been receiving previously should not be used to treat patients with recent antibiotic exposure. telithromycin is the first of the ketolide antibiotics, derived from the macrolide family, and is active against s. pneumoniae that is resistant to other antimicrobials commonly used for cap (including penicillin, macrolides, and fluoroquinolones). several cap trials suggest that telithromycin is equivalent to comparators (including amoxicillin, clarithromycin, and trovafloxacin) [ ] [ ] [ ] [ ] . there have also been recent postmarketing reports of life-threatening hepatotoxicity [ ] . at present, the committee is awaiting further evaluation of the safety of this drug by the fda before making its final recommendation. inpatient, non-icu treatment. the following regimens are recommended for hospital ward treatment. level i evidence) . a b-lactam plus a macrolide (strong recommendation; level i evidence) (preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients; with doxycycline [level iii evidence] as an alternative to the macrolide. a respiratory fluoroquinolone should be used for penicillin-allergic patients.) the recommendations of combination treatment with a blactam plus a macrolide or monotherapy with a fluoroquinolone were based on retrospective studies demonstrating a significant reduction in mortality compared with that associated with administration of a cephalosporin alone [ ] [ ] [ ] [ ] . multiple prospective randomized trials have demonstrated that either regimen results in high cure rates. the major discriminating factor between the regimens is the patient's prior antibiotic exposure (within the past months). preferred b-lactams are those effective against s. pneumoniae and other common, nonatypical pathogens without being overly broad spectrum. in january , the clinical laboratory standards institute (formerly the nccls) increased the mic breakpoints for cefotaxime and ceftriaxone for nonmeningeal s. pneumoniae infections. these new breakpoints acknowledge that nonmeningeal infections caused by strains formerly considered to be intermediately susceptible, or even resistant, can be treated successfully with usual doses of these b-lactams [ , , ] . two randomized, double-blind studies showed ertapenem to be equivalent to ceftriaxone [ , ] . it also has excellent activity against anaerobic organisms, drsp, and most enterobacteriaceae species (including extended-spectrum b-lactamase producers, but not p. aeruginosa). ertapenem may be useful in treating patients with risks for infection with these pathogens and for patients who have recently received antibiotic therapy. however, clinical experience with this agent is limited. other "antipneumococcal, antipseudomonal" b-lactam agents are appropriate when resistant pathogens, such as pseudomonas, are likely to be present. doxycycline can be used as an alternative to a macrolide on the basis of scant data for treatment of legionella infections [ , , ] . two randomized, double-blind studies of adults hospitalized for cap have demonstrated that parenteral azithromycin alone was as effective, with improved tolerability, as intravenous cefuroxime, with or without intravenous erythromycin [ , ] . in another study, mortality and readmission rates were similar, but the mean los was shorter among patients receiving azithromycin alone than among those receiving other guideline-recommended therapy [ ] . none of the patients with erythromycin-resistant s. pneumoniae infections died or was transferred to the icu, including who received azithromycin alone. another study showed that those receiving a macrolide alone had the lowest -day mortality but were the least ill [ ] . such patients were younger and were more likely to be in lower-risk groups. these studies suggest that therapy with azithromycin alone can be considered for carefully selected patients with cap with nonsevere disease (patients admitted primarily for reasons other than cap) and no risk factors for infection with drsp or gramnegative pathogens. however, the emergence of high rates of macrolide resistance in many areas of the country suggests that this therapy cannot be routinely recommended. initial therapy should be given intravenously for most admitted patients, but some without risk factors for severe pneumonia could receive oral therapy, especially with highly bioavailable agents such as fluoroquinolones. when an intravenous b-lactam is combined with coverage for atypical pathogens, oral therapy with a macrolide or doxycycline is appropriate for selected patients without severe pneumonia risk factors [ ] . inpatient, icu treatment. the following regimen is the minimal recommended treatment for patients admitted to the icu. . a b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin (level ii evidence) or a fluoroquinolone (level i evidence) (strong recommendation) (for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam are recommended.) a single randomized controlled trial of treatment for severe cap is available. patients with shock were excluded; however, among the patients with mechanical ventilation, treatment with a fluoroquinolone alone resulted in a trend toward inferior outcome [ ] . because septic shock and mechanical ventilation are the clearest reasons for icu admission, the majority of icu patients would still require combination therapy. icu patients are routinely excluded from other trials; therefore, recommendations are extrapolated from nonsevere cases, in conjunction with case series and retrospective analyses of cohorts with severe cap. for all patients admitted to the icu, coverage for s. pneumoniae and legionella species should be ensured [ , ] by using a potent antipneumococcal b-lactam and either a macrolide or a fluoroquinolone. therapy with a respiratory fluoroquinolone alone is not established for severe cap [ ] , and, if the patient has concomitant pneumococcal meningitis, the efficacy of fluoroquinolone monotherapy is uncertain. in addition, prospective observational studies [ , ] and retrospective analyses [ ] [ ] [ ] have found that combination therapy for bacteremic pneumococcal pneumonia is associated with lower mortality than monotherapy. the mechanism of this benefit is unclear but was principally found in the patients with the most severe illness and has not been demonstrated in nonbacteremic pneumococcal cap studies. therefore, combination empirical therapy is recommended for at least h or until results of diagnostic tests are known. in critically ill patients with cap, a large number of microorganisms other than s. pneumoniae and legionella species must be considered. a review of studies that included patients with cap who were admitted to the icu demonstrates that the most common pathogens in the icu population were (in descending order of frequency) s. pneumoniae, legionella species, h. influenzae, enterobacteriaceae species, s. aureus, and pseudomonas species [ ] . the atypical pathogens responsible for severe cap may vary over time but can account collectively for у % of severe pneumonia episodes. the dominant atypical pathogen in severe cap is legionella [ ] , but some diagnostic bias probably accounts for this finding [ ] . the recommended standard empirical regimen should routinely cover the most common pathogens that cause severe cap, all of the atypical pathogens, and most of the relevant enterobacteriaceae species. treatment of mrsa or p. aeruginosa infection is the main reason to modify the standard empirical regimen. the following are additions or modifications to the basic empirical regimen recommended above if these pathogens are suspected. pseudomonal cap requires combination treatment to prevent inappropriate initial therapy, just as pseudomonas nosocomial pneumonia does [ ] . once susceptibilities are known, treatment can be adjusted accordingly. alternative regimens are provided for patients who may have recently received an oral fluoroquinolone, in whom the aminoglycoside-containing regimen would be preferred. a consistent gram stain of tracheal aspirate, sputum, or blood is the best indication for pseudomonas coverage. other, easier-to-treat gram-negative microorganisms may ultimately be proven to be the causative pathogen, but empirical coverage of pseudomonas species until culture results are known is least likely to be associated with inappropriate therapy. other clinical risk factors for infection with pseudomonas species include structural lung diseases, such as bronchiectasis, or repeated exacerbations of severe copd leading to frequent steroid and/or antibiotic use, as well as prior antibiotic therapy [ ] . these patients do not necessarily require icu admission for cap [ ] , so pseudomonas infection remains a concern for them even if they are only hospitalized on a general ward. the major risk factor for infection with other serious gram-negative pathogens, such as klebsiella pneumoniae or acinetobacter species, is chronic alcoholism. (moderate recommendation; level iii evidence.) the best indicator of s. aureus infection is the presence of gram-positive cocci in clusters in a tracheal aspirate or in an adequate sputum sample. the same findings on preliminary results of blood cultures are not as reliable, because of the significant risk of contamination [ ] . clinical risk factors for s. aureus cap include end-stage renal disease, injection drug abuse, prior influenza, and prior antibiotic therapy (especially with fluoroquinolones [ ] ). for methicillin-sensitive s. aureus, the empirical combination therapy recommended above, which includes a b-lactam and sometimes a respiratory fluoroquinolone, should be adequate until susceptibility results are available and specific therapy with a penicillinase-resistant semisynthetic penicillin or first-generation cephalosporin can be initiated. both also offer additional coverage for drsp. neither linezolid [ ] nor vancomycin [ ] is an optimal drug for methicillin-sensitive s. aureus. although methicillin-resistant strains of s. aureus are still the minority, the excess mortality associated with inappropriate an-tibiotic therapy [ ] would suggest that empirical coverage should be considered when ca-mrsa is a concern. the most effective therapy has yet to be defined. the majority of ca-mrsa strains are more susceptible in vitro to non-b-lactam antimicrobials, including trimethoprim-sulfamethoxazole (tmp-smx) and fluoroquinolones, than are hospital-acquired strains. previous experience with tmp-smx in other types of severe infections (endocarditis and septic thrombophlebitis) suggests that tmp-smx is inferior to vancomycin [ ] . further experience and study of the adequacy of tmp-smx for ca-mrsa cap is clearly needed. vancomycin has never been specifically studied for cap, and linezolid has been found to be better than ceftriaxone for bacteremic s. pneumoniae in a nonblinded study [ ] and superior to vancomycin in retrospective analysis of studies involving nosocomial mrsa pneumonia [ ] . newer agents for mrsa have recently become available, and others are anticipated. of the presently available agents, daptomycin should not be used for cap, and no data on pneumonia are available for tigecycline. a concern with ca-mrsa is necrotizing pneumonia associated with production of panton-valentine leukocidin and other toxins. vancomycin clearly does not decrease toxin production, and the effect of tmp-smx and fluoroquinolones on toxin production is unclear. addition of clindamycin or use of linezolid, both of which have been shown to affect toxin production in a laboratory setting [ ] , may warrant their consideration for treatment of these necrotizing pneumonias [ ] . unfortunately, the emergence of resistance during therapy with clindamycin has been reported (especially in erythromycinresistant strains), and vancomycin would still be needed for bacterial killing. clinicians should be aware of epidemiologic conditions and/ or risk factors that may suggest that alternative or specific additional antibiotics should be considered. these conditions and specific pathogens, with preferred treatment, are listed in tables and . pathogen-directed therapy . once the etiology of cap has been identified on the basis of reliable microbiological methods, antimicrobial therapy should be directed at that pathogen. (moderate recommendation; level iii evidence.) treatment options may be simplified (table ) if the etiologic agent is established or strongly suspected. diagnostic procedures that identify a specific etiology within - h can still be useful for guiding continued therapy. this information is often available at the time of consideration for a switch from parenteral to oral therapy and may be used to direct specific oral antimicrobial choices. if, for example, an appropriate culture reveals penicillin-susceptible s. pneumoniae, a narrowspectrum agent (such as penicillin or amoxicillin) may be used. this will, hopefully, reduce the selective pressure for resistance. the major issue with pathogen-specific therapy is management of bacteremic s. pneumoniae cap. the implications of the observational finding that dual therapy was associated with reduced mortality in bacteremic pneumococcal pneumonia [ ] [ ] [ ] [ ] [ ] are uncertain. one explanation for the reduced mortality may be the presence of undiagnosed coinfection with an atypical pathogen; although reported to occur in %- % of cap cases in some studies [ , ] , much lower rates of undiagnosed coinfection are found in general [ ] and specifically in severe cases [ ] . an alternative explanation is the immunomodulatory effects of macrolides [ , ] . it is important to note that these studies evaluated the effects of initial empirical therapy before the results of blood cultures were known and did not examine effects of pathogen-specific therapy after the results of blood cultures were available. the benefit of combination therapy was also most pronounced in the more severely ill patients [ , ] . therefore, discontinuation of combination therapy after results of cultures are known is most likely safe in non-icu patients. oseltamivir or zanamivir is recommended for influenza a. (strong recommendation; level i evidence.) . use of oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for h (level i evidence), but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia. (moderate recommendation; level iii evidence.) studies that demonstrate that treatment of influenza is effective only if instituted within h of the onset of symptoms have been performed only in uncomplicated cases [ ] [ ] [ ] [ ] . the impact of such treatment on patients who are hospitalized with influenza pneumonia or a bacterial pneumonia complicating influenza is unclear. in hospitalized adults with influenza, a minority of whom had radiographically documented pneumonia, no obvious benefit was found in one retrospective study of amantadine treatment [ ] . treatment of antigen-or culture-positive patients with influenza with antivirals in addition to antibiotics is warranted, even if the radiographic infiltrate is caused by a subsequent bacterial superinfection. because of the longer period of persistent positivity after infection, the appropriate treatment for patients diagnosed with only of the rapid diagnostic tests is unclear. because such patients often have recoverable virus (median duration of days) after hos-pitalization, antiviral treatment seems reasonable from an infection-control standpoint alone. because of its broad influenza spectrum, low risk of resistance emergence, and lack of bronchospasm risk, oseltamivir is an appropriate choice for hospitalized patients. the neuraminidase inhibitors are effective against both influenza a and b viruses, whereas the m inhibitors, amantadine, and rimantadine are active only against influenza a [ ] . in addition, viruses recently circulating in the united states and canada are often resistant to the m inhibitors on the basis of antiviral testing [ , ] . therefore, neither amantadine nor rimantadine should be used for treatment or chemoprophylaxis of influenza a in the united states until susceptibility to these antiviral medications has been reestablished among circulating influenza a viruses [ ] . early treatment of influenza in ambulatory adults with inhaled zanamivir or oral oseltamivir appears to reduce the likelihood of lower respiratory tract complications [ ] [ ] [ ] . the use of influenza antiviral medications appears to reduce the likelihood of respiratory tract complications, as reflected by reduced usage rates of antibacterial agents in ambulatory patients with influenza. although clearly important in outpatient pneumonia, this experience may also apply to patients hospitalized primarily for influenza. parenteral acyclovir is indicated for treatment of varicellazoster virus infection [ ] recent human infections caused by avian influenza a (h n ) in vietnam, thailand, cambodia, china, indonesia, egypt, and turkey raise the possibility of a pandemic in the near future. the severity of h n infection in humans distinguishes it from that caused by routine seasonal influenza. respiratory failure requiring hospitalization and intensive care has been seen in the majority of the recognized cases, and mortality is ∼ % [ , ] . if a pandemic occurs, deaths will result from primary influenza pneumonia with or without secondary bacterial pneumonia. this section highlights issues for consideration, recognizing that treatment recommendations will likely change as the pandemic progresses. more specific guidance can be found on the idsa, ats, cdc, and who web sites as the key features of the pandemic become clearer. additional guidance is available at http://www.pandemicflu.gov. the who has delineated phases of an influenza pandemic, defined by increasing levels of risk and public health response [ ] . during the current pandemic alert phase (phase : cases of novel influenza infection without sustained person-to-person transmission), testing should be focused on confirming all suspected cases in areas where h n infection has been documented in poultry and on detecting the arrival of the pandemic strain in unaffected countries. early clinical features of h n infection include persistent fever, cough, and respiratory difficulty progressing over - days, as well as lymphopenia on admission to the hospital [ , , ] . exposure to sick and dying poultry in an area with known or suspected h n activity has been reported by most patients, although the recognition of poultry outbreaks has sometimes followed the recognition of human cases [ ] . rapid bedside tests to detect influenza a have been used as screening tools for avian influenza in some settings. throat swabs tested by rt-pcr have been the most sensitive for confirming h n infection to date, but nasopharyngeal swabs, washes, and aspirates; bal fluid; lung and other tissues; and stool have yielded positive results by rt-pcr and viral culture with varying sensitivity. convalescent-phase serum can be tested by microneutralization for antibodies to h antigen in a small number of international reference laboratories. specimens from suspected cases of h n infection should be sent to public health laboratories with appropriate biocontainment facilities; the case should be discussed with health department officials to arrange the transfer of specimens and to initiate an epidemiologic evaluation. during later phases of an ongoing pandemic, testing may be necessary for many more patients, so that appropriate treatment and infection control decisions can be made, and to assist in defining the extent of the pandemic. recommendations for such testing will evolve on the basis of the features of the pandemic, and guidance should be sought from the cdc and who web sites (http://www.cdc.gov and http://www.who.int). patients with confirmed or suspected h n influenza should be treated with oseltamivir. most h n isolates since have been susceptible to the neuraminidase inhibitors oseltamivir and zanamivir and resistant to the adamantanes (amantidine and rimantidine) [ , ] . the current recommendation is for a -day course of treatment at the standard dosage of mg times daily. in addition, droplet precautions should be used for patients with suspected h n influenza, and they should be placed in respiratory isolation until that etiology is ruled out. health care personnel should wear n- (or higher) respirators during medical procedures that have a high likelihood of generating infectious respiratory aerosols. bacterial superinfections, particularly pneumonia, are important complications of influenza pneumonia. the bacterial etiologies of cap after influenza infection have included s. pneumoniae, s. aureus, h. influenzae, and group a streptococci. legionella, chlamydophila, and mycoplasma species are not important causes of secondary bacterial pneumonia after influenza. appropriate agents would therefore include cefotaxime, ceftriaxone, and respiratory fluoroquinolones. treatment with vancomycin, linezolid, or other agents directed against ca-mrsa should be limited to patients with confirmed infection or a compatible clinical presentation (shock and necrotizing pneumonia). because shortages of antibacterials and antivirals are anticipated during a pandemic, the appropriate use of diagnostic tests will be even more important to help target antibacterial therapy whenever possible, especially for patients admitted to the hospital. time to first antibiotic dose for cap has recently received significant attention from a quality-of-care perspective. this emphasis is based on retrospective studies of medicare beneficiaries that demonstrated statistically significantly lower mortality among patients who received early antibiotic therapy [ , ] . the initial study suggested a breakpoint of h [ ] , whereas the subsequent analysis found that h was associated with lower mortality [ ] . studies that document the time to first antibiotic dose do not consistently demonstrate this difference, although none had as large a patient population. most importantly, prospective trials of care by protocol have not demonstrated a survival benefit to increasing the percentage of patients with cap who receive antibiotics within the first - h [ , ] . early antibiotic administration does not appear to shorten the time to clinical stability, either [ ] , although time of first dose does appear to correlate with los [ , ] . a problem of internal consistency is also present, because, in both studies [ , ] , patients who received antibiotics in the first h after presentation actually did worse than those who re- temperature р . ؇c heart rate р beats/min respiratory rate р breaths/min systolic blood pressure у mm hg arterial oxygen saturation у % or po у mm hg on room air ability to maintain oral intake a normal mental status a note. criteria are from [ , , ] . po , oxygen partial pressure. a important for discharge or oral switch decision but not necessarily for determination of nonresponse. ceived antibiotics - h after presentation. for these and other reasons, the committee did not feel that a specific time window for delivery of the first antibiotic dose should be recommended. however, the committee does feel that therapy should be administered as soon as possible after the diagnosis is considered likely. conversely, a delay in antibiotic therapy has adverse consequences in many infections. for critically ill, hemodynamically unstable patients, early antibiotic therapy should be encouraged, although no prospective data support this recommendation. delay in beginning antibiotic treatment during the transition from the ed is not uncommon. especially with the frequent use of once-daily antibiotics for cap, timing and communication issues may result in patients not receiving antibiotics for h after hospital admission. the committee felt that the best and most practical resolution to this issue was that the initial dose be given in the ed [ ] . data from the medicare database indicated that antibiotic treatment before hospital admission was also associated with lower mortality [ ] . given that there are even more concerns regarding timing of the first dose of antibiotic when the patient is directly admitted to a busy inpatient unit, provision of the first dose in the physician's office may be best if the recommended oral or intramuscular antibiotics are available in the office. with the use of a potent, highly bioavailable antibiotic, the ability to eat and drink is the major consideration for switching from intravenous to oral antibiotic therapy for non-icu patients. initially, ramirez et al. [ ] defined a set of criteria for an early switch from intravenous to oral therapy (table ). in general, as many as two-thirds of all patients have clinical improvement and meet criteria for a therapy switch in the first days, and most non-icu patients meet these criteria by day . subsequent studies have suggested that even more liberal criteria are adequate for the switch to oral therapy. an alternative approach is to change from intravenous to oral therapy at a predetermined time, regardless of the clinical response [ ] . one study population with nonsevere illness was randomized to receive either oral therapy alone or intravenous therapy, with the switch occurring after h without fever. the study population with severe illness was randomized to receive either intravenous therapy with a switch to oral therapy after days or a full -day course of intravenous antibiotics. time to resolution of symptoms for the patients with nonsevere illness was similar with either regimen. among patients with more severe illness, the rapid switch to oral therapy had the same rate of treatment failure and the same time to resolution of symptoms as prolonged intravenous therapy. the rapid-switch group required fewer inpatient days ( vs. ) , although this was likely partially a result of the protocol, but the patients also had fewer adverse events. the need to keep patients in the hospital once clinical stability is achieved has been questioned, even though physicians commonly choose to observe patients receiving oral therapy for у day. even in the presence of pneumococcal bacteremia, a switch to oral therapy can be safely done once clinical stability is achieved and prolonged intravenous therapy is not needed [ ] . such patients generally take longer (approximately half a day) to become clinically stable than do nonbacteremic patients. the benefits of in-hospital observation after a switch to oral therapy are limited and add to the cost of care [ ] . discharge should be considered when the patient is a candidate for oral therapy and when there is no need to treat any comorbid illness, no need for further diagnostic testing, and no unmet social needs [ , , ] . although it is clear that clinically stable patients can be safely switched to oral therapy and discharged, the need to wait for all of the features of clinical stability to be present before a patient is discharged is uncertain. for example, not all investigators have found it necessary to have the white blood cell count improve. using the definition for clinical stability in table , halm et al. [ ] found that . % of patients were discharged from the hospital with у instability. death or readmission occurred in . % of patients with no instability on discharge, in . % of patients with instability, and in . % with у instabilities. in general, patients in higher psi classes take longer to reach clinical stability than do patients in lower risk classes [ ] . this finding may reflect the fact that elderly patients with multiple comorbidities often recover more slowly. arrangements for appropriate follow-up care, including rehabilitation, should therefore be initiated early for these patients. in general, when switching to oral antibiotics, either the same agent as the intravenous antibiotic or the same drug class should be used. switching to a different class of agents simply because of its high bioavailability (such as a fluoroquinolone) is probably not necessary for a responding patient. for patients who received intravenous b-lactam-macrolide combination therapy, a switch to a macrolide alone appears to be safe for those who do not have drsp or gram-negative enteric pathogens isolated [ ] . most patients with cap have been treated for - days or longer, but few well-controlled studies have evaluated the optimal duration of therapy for patients with cap, managed in or out of the hospital. available data on short-course treatment do not suggest any difference in outcome with appropriate therapy in either inpatients or outpatients [ ] . duration is also difficult to define in a uniform fashion, because some antibiotics (such as azithromycin) are administered for a short time yet have a long half-life at respiratory sites of infection. in trials of antibiotic therapy for cap, azithromycin has been used for - days as oral therapy for outpatients, with some reports of single-dose therapy for patients with atypical pathogen infections [ ] [ ] [ ] . results with azithromycin should not be extrapolated to other drugs with significantly shorter half-lives. the ketolide telithromycin has been used for - days to treat outpatients, including some with pneumococcal bacteremia or psi classes уiii [ ] . in a recent study, highdose ( mg) levofloxacin therapy for days was equally successful and resulted in more afebrile patients by day than did the -mg dose for - days ( . % vs. . %; p p ) [ ] . on the basis of these studies, days appears to be . the minimal overall duration of therapy documented to be effective in usual forms of cap. as is discussed above, most patients become clinically stable within - days, so longer durations of therapy are rarely necessary. patients with persistent clinical instability are often readmitted to the hospital and may not be candidates for shortduration therapy. short-duration therapy may be suboptimal for patients with bacteremic s. aureus pneumonia (because of the risk of associated endocarditis and deep-seated infection), for those with meningitis or endocarditis complicating pneumonia, and for those infected with other, less common pathogens (e.g., burkholderia pseudomallei or endemic fungi). an -day course of therapy for nosocomial p. aeruginosa pneumonia led to relapse more commonly than did a -day course of therapy [ ] . whether the same results would be applicable to cap cases is unclear, but the presence of cavities or other signs of tissue necrosis may warrant prolonged treatment. studies of duration of therapy have focused on patients receiving empirical treatment, and reliable data defining treatment duration after an initially ineffective regimen are lacking. drotrecogin alfa activated is the first immunomodulatory therapy approved for severe sepsis. in the united states, the fda recommended the use of drotrecogin alfa activated for patients at high risk of death. the high-risk criterion suggested by the fda was an acute physiologic and chronic health assessment (apache) ii score у , based on a subgroup analysis of the overall study. however, the survival advantage (absolute risk reduction, . %) of drotrecogin alfa activated treatment of patients in the cap subgroup was equivalent to that in the subgroup with apache ii scores у [ , , ] . the greatest reduction in the mortality rate was for s. pneumoniae infection (relative risk, . ; % ci, . - . ) [ ] . subsequent data have suggested that the benefit appears to be greatest when the treatment is given as early in the hospital admission as possible. in the subgroup with severe cap caused by a pathogen other than s. pneumoniae and treated with appropriate antibiotics, there was no evidence that drotrecogin alfa activated affected mortality. although the benefit of drotrecogin alfa activated is clearly greatest for patients with cap who have high apache ii scores, this criterion alone may not be adequate to select appropriate patients. an apache ii score у was selected by a subgroup analysis of the entire study cohort and may not be similarly calibrated in a cap-only cohort. two-organ failure, the criterion suggested for drotrecogin alfa activated use by the european regulatory agency, did not influence the mortality benefit for patients with cap [ ] . therefore, in addition to patients with septic shock, other patients with severe cap could be considered for treatment with drotrecogin alfa activated. those with sepsis-induced leukopenia are at extremely high risk of death and ards and are, therefore, potential candidates. conversely, the benefit of drotrecogin alfa activated is not as clear when respiratory failure is caused more by exacerbation of underlying lung disease rather than by the pneumonia itself. other minor criteria for severe cap proposed above are similar to organ failure criteria used in many sepsis trials. consideration of treatment with drotrecogin alfa activated is appropriate, but the strength of the recommendation is only level ii. . hypotensive, fluid-resuscitated patients with severe cap should be screened for occult adrenal insufficiency. (moderate recommendation; level ii evidence.) a large, multicenter trial has suggested that stress-dose ( - mg of hydrocortisone per day or equivalent) steroid treatment improves outcomes of vasopressor-dependent patients with septic shock who do not have an appropriate cortisol response to stimulation [ ] . once again, patients with cap made up a significant fraction of patients entered into the trial. in addition, small pilot studies have suggested that there is a benefit to corticosteroid therapy even for patients with severe cap who are not in shock [ ] [ ] [ ] . the small sample size and baseline differences between groups compromise the conclusions. although the criteria for steroid replacement therapy remain controversial, the frequency of intermittent steroid treatment in patients at risk for severe cap, such as those with severe copd, suggests that screening of patients with severe cap is appropriate with replacement if inadequate cortisol levels are documented. if corticosteroids are used, close attention to tight glucose control is required [ ] . patients who do not require immediate intubation but who have either hypoxemia or respiratory distress should receive a trial of niv [ , , ] . patients with underlying copd are most likely to benefit. patients with cap who were ran-domized to receive niv had a % absolute risk reduction for the need for intubation [ ] . the use of niv may also improve intermediate-term mortality. inability to expectorate may limit the use of niv [ ] , but intermittent application of niv may allow for its use in patients with productive cough unless sputum production is excessive. prompt recognition of a failed niv trial is critically important, because most studies demonstrate worse outcomes for patients who require intubation after a prolonged niv trial [ , ] . within the first - h of niv, failure to improve respiratory rate and oxygenation [ , , ] or failure to decrease carbon dioxide partial pressure (pco ) in patients with initial hypercarbia [ ] predicts niv failure and warrants prompt intubation. niv provides no benefit for patients with ards [ ] , which may be nearly indistinguishable from cap among patients with bilateral alveolar infiltrates. patients with cap who have severe hypoxemia (pao /fio ratio, ! ) are also poor candidates for niv [ ] . . low-tidal-volume ventilation ( cm /kg of ideal body weight) should be used for patients undergoing ventilation who have diffuse bilateral pneumonia or ards. (strong recommendation; level i evidence.) distinguishing between diffuse bilateral pneumonia and ards is difficult, but it may not be an important distinction. results of the ardsnet trial suggest that the use of low-tidalvolume ventilation provides a survival advantage [ ] . pneumonia, principally cap, was the most common cause of ards in that trial, and the benefit of the low-tidal-volume ventilatory strategy appeared to be equivalent in the population with pneumonia compared with the entire cohort. the absolute risk reduction for mortality in the pneumonia cohort was %, indicating that, in order to avoid death, patients must be treated [ ] . other aspects of the management of severe sepsis and septic shock in patients with cap do not appear to be significantly different from those for patients with other sources of infection. recommendations for these aspects of care are reviewed elsewhere [ ] . because of the limitations of diagnostic testing, the majority of cap is still treated empirically. critical to empirical therapy is an understanding of the management of patients who do not follow the normal response pattern. although difficult to define, nonresponse is not uncommon. overall, %- % of hospitalized patients with cap do not respond to the initial antibiotic treatment [ , , , ] . the incidence of treatment failure among patients with cap who are not hospitalized is not well known, because population-based studies are required. almirall et al. [ ] described an overall hospitalization rate of % in a population-based study, but the rate of failure among the % of patients who initially presented to their primary care physician was not provided. the frequency of prior antibiotic therapy among medicare patients admitted to the hospital with cap is %- % [ , ] , but the percentage who received prior antibiotic therapy for the acute episode of pneumonia itself versus other indications is unclear. for patients initially admitted to the icu, the risk of failure to respond is already high; as many as % will experience deterioration even after initial stabilization in the icu [ ] . mortality among nonresponding patients is increased several-fold in comparison with that among responding patients [ ] . overall mortality rates as high as % have been reported for an entire population of nonresponding hospitalized patients with cap [ , , ] , and the mortality rate reported in one study of early failure was % [ ] . apache ii score was not the only factor independently associated with mortality in the nonresponding group, suggesting that the excess mortality may be due to factors other than severity of illness at presentation [ ] . . the use of a systematic classification of possible causes of failure to respond, based on time of onset and type of failure (table ) , is recommended. (moderate recommendation; level ii evidence.) the term "nonresponding pneumonia" is used to define a situation in which an inadequate clinical response is present despite antibiotic treatment. lack of a clear-cut and validated definition in the literature makes nonresponse difficult to study. lack of response also varies according to the site of treatment. lack of response in outpatients is very different from that in patients admitted to the icu. the time of evaluation is also important. persistent fever after the first day of treatment differs significantly from fever persisting (or recurring) at day of treatment. table provides a construct for evaluating nonresponse to antibiotic treatment of cap, based on several studies addressing this issue [ , , , ] . two patterns of unacceptable response are seen in hospitalized patients [ ] . the first is progressive pneumonia or actual clinical deterioration, with acute respiratory failure requiring ventilatory support and/or septic shock, usually occurring within the first h of hospital admission. as is noted above, as many as % of patients with cap who ultimately require icu admission are initially admitted to a non-icu setting and are transferred because of deterioration [ ] . deterioration and development of respira-tory failure or hypotension h after initial treatment is often related to intercurrent complications, deterioration in underlying disease, or development of nosocomial superinfection. the second pattern is that of persistent or nonresponding pneumonia. nonresponse can be defined as absence of or delay in achieving clinical stability, using the criteria in table [ , ] . when these criteria were used, the median time to achieve clinical stability was days for all patients, but a quarter of patients took у days to meet all of these criteria for stability [ ] . stricter definitions for each of the criteria and higher psi scores were associated with longer times to achieve clinical stability. conversely, subsequent transfer to the icu after achieving this degree of clinical stability occurred in ! % of [ ] . given these results, concern regarding nonresponse should be tempered before h of therapy. antibiotic changes during this period should be considered only for patients with deterioration or in whom new culture data or epidemiologic clues suggest alternative etiologies. finally, nonresolving or slow-resolving pneumonia has been used to refer to the conditions of patients who present with persistence of pulmonary infiltrates days after initial pneumonia-like syndrome [ ] . as many as % of these patients will be found to have diseases other than cap when carefully evaluated [ ] . two studies have evaluated the risk factors for a lack of response in multivariate analyses [ , ] , including those amenable to medical intervention. use of fluoroquinolones was independently associated with a better response in one study [ ] , whereas discordant antimicrobial therapy was associated with early failure [ ] . in table , the different risk and protective factors and their respective odds ratios are summarized. specific causes that may be responsible for a lack of response in cap have been classified by arancibia et al. [ ] (table ) . this classification may be useful for clinicians as a systematic approach to diagnose the potential causes of nonresponse in cap. although in the original study only ( %) of cases could not be classified [ ] , a subsequent prospective multicenter trial found that the cause of failure could not be determined in % [ ] . management of nonresponding cap. nonresponse to antibiotics in cap will generally result in у of clinical responses: ( ) transfer of the patient to a higher level of care, ( ) further diagnostic testing, and ( ) escalation or change in treatment. issues regarding hospital admission and icu transfer are discussed above. an inadequate host response, rather than inappropriate antibiotic therapy or unexpected microorganisms, is the most common cause of apparent antibiotic failure when guidelinerecommended therapy is used. decisions regarding further diagnostic testing and antibiotic change/escalation are intimately intertwined and need to be discussed in tandem. information regarding the utility of extensive microbiological testing in cases of nonresponding cap is mainly retrospective and therefore affected by selection bias. a systematic diagnostic approach, which included invasive, noninvasive, and imaging procedures, in a series of nonresponding patients with cap obtained a specific diagnosis in % [ ] . in a different study, mortality among patients with microbiologically guided versus empirical antibiotic changes was not improved (mortality rate, % vs. %, respectively) [ ] . however, no antibiotic changes were based solely on sputum smears, suggesting that invasive cultures or nonculture methods may be needed. mismatch between the susceptibility of a common causative organism, infection with a pathogen not covered by the usual empirical regimen, and nosocomial superinfection pneumonia are major causes of apparent antibiotic failure. therefore, the first response to nonresponse or deterioration is to reevaluate the initial microbiological results. culture or sensitivity data not available at admission may now make the cause of clinical failure obvious. in addition, a further history of any risk factors for infection with unusual microorganisms (table ) should be taken if not done previously. viruses are relatively neglected as a cause of infection in adults but may account for %- % of cases [ ] . other family members or coworkers may have developed viral symptoms in the interval since the patient was admitted, increasing suspicion of this cause. the evaluation of nonresponse is severely hampered if a microbiological diagnosis was not made on initial presentation. if cultures were not obtained, clinical decisions are much more difficult than if the adequate cultures were obtained but negative. risk factors for nonresponse or deterioration (table ) , therefore, figure prominently in the list of situations in which more aggressive initial diagnostic testing is warranted (table ) . blood cultures should be repeated for deterioration or progressive pneumonia. deteriorating patients have many of the risk factors for bacteremia, and blood cultures are still high yield even in the face of prior antibiotic therapy [ ] . positive blood culture results in the face of what should be adequate antibiotic therapy should increase the suspicion of either antibiotic-resistant isolates or metastatic sites, such as endocarditis or arthritis. despite the high frequency of infectious pulmonary causes of nonresponse, the diagnostic utility of respiratory tract cultures is less clear. caution in the interpretation of sputum or tracheal aspirate cultures, especially of gram-negative bacilli, is warranted because early colonization, rather than superinfection with resistant bacteria, is not uncommon in specimens obtained after initiation of antibiotic treatment. once again, the absence of multidrug-resistant pathogens, such as mrsa or pseudomonas, is strong evidence that they are not the cause of nonresponse. an etiology was determined by bronchoscopy in % of patients with cap, mainly in those not responding to therapy [ ] . despite the potential benefit suggested by these results, and in contrast to ventilator-associated pneumonia [ , ] , no randomized study has compared the utility of invasive versus noninvasive strategies in the cap population with nonresponse. rapid urinary antigen tests for s. pneumoniae and l. pneumophila remain positive for days after initiation of antibiotic therapy [ , ] and, therefore, may be high-yield tests in this group. a urinary antigen test result that is positive for l. pneumophila has several clinical implications, including that coverage for legionella should be added if not started empirically [ ] . this finding may be a partial explanation for the finding that fluoroquinolones are associated with a lower incidence of nonresponse [ ] . if a patient has persistent fever, the faster response to fluoroquinolones in legionella cap warrants consideration of switching coverage from a macrolide [ ] . stopping the b-lactam component of combination therapy to exclude drug fever is probably also safe [ ] . because one of the major explanations for nonresponse is poor host immunity rather than incorrect antibiotics, a positive pneumococcal antigen test result would at least clarify the probable original pathogen and turn attention to other causes of failure. in addition, a positive pneumococcal antigen test result would also help with interpretation of subsequent sputum/tracheal aspirate cultures, which may indicate early superinfection. nonresponse may also be mimicked by concomitant or subsequent extrapulmonary infection, such as intravascular catheter, urinary, abdominal, and skin infections, particularly in icu patients. appropriate cultures of these sites should be considered for patients with nonresponse to cap therapy. in addition to microbiological diagnostic procedures, several other tests appear to be valuable for selected patients with nonresponse: • chest ct. in addition to ruling out pulmonary emboli, a ct scan can disclose other reasons for antibiotic failure, including pleural effusions, lung abscess, or central airway obstruction. the pattern of opacities may also suggest alternative noninfectious disease, such as bronchiolitis obliterans organizing pneumonia. • thoracentesis. empyema and parapneumonic effusions are important causes of nonresponse [ , ] , and thoracentesis should be performed whenever significant pleural fluid is present. • bronchoscopy with bal and transbronchial biopsies. if the differential of nonresponse includes noninfectious pneumonia mimics, bronchoscopy will provide more diagnostic information than routine microbiological cultures. bal may reveal noninfectious entities, such as pulmonary hemorrhage or acute eosinophilic pneumonia, or hints of infectious diseases, such as lymphocytic rather than neutrophilic alveolitis pointing toward virus or chlamydophila infection. transbronchial biopsies can also yield a specific diagnosis. antibiotic management of nonresponse in cap has not been studied. the overwhelming majority of cases of apparent nonresponse are due to the severity of illness at presentation or a delay in treatment response related to host factors. other than the use of combination therapy for severe bacteremic pneumococcal pneumonia [ , , , ] , there is no documentation that additional antibiotics for early deterioration lead to a better outcome. the presence of risk factors for potentially untreated microorganisms may warrant temporary empirical broadening of the antibiotic regimen until results of diagnostic tests are available. vaccines targeting pneumococcal disease and influenza remain the mainstay for preventing cap. pneumococcal polysaccharide vaccine and inactivated influenza vaccine are recommended for all older adults and for younger persons with medical conditions that place them at high risk for pneumonia morbidity and mortality (table ) [ , ] . the new live attenuated influenza vaccine is recommended for healthy persons - years of age, including health care workers [ ] . postlicensure epidemiologic studies have documented the effectiveness of pneumococcal polysaccharide vaccines for prevention of invasive infection (bacteremia and meningitis) among elderly individuals and younger adults with certain chronic medical conditions [ ] [ ] [ ] [ ] . the overall effectiveness against invasive pneumococcal disease among persons у years of age is %- % [ , , ] , although efficacy may decrease with advancing age [ ] . the effectiveness of the vaccine against pneumococcal disease in immunocompromised persons is less clear, and results of studies evaluating its effectiveness against pneumonia without bacteremia have been mixed. the vaccine has been shown to be cost effective for general populations of adults - years of age and у years of age [ , ] . a second dose of pneumococcal polysaccharide vaccine after a у -year interval has been shown to be safe, with only slightly more local reactions than are seen after the first dose [ ] . because the safety of a third dose has not been demonstrated, current guidelines do not suggest repeated revaccination. the pneumococcal conjugate vaccine is under investigation for use in adults but is currently only licensed for use in young children [ , ] . however, its use in children ! years of age has dramatically reduced invasive pneumococcal bacteremia among adults as well [ , ] . the effectiveness of influenza vaccines depends on host factors and on how closely the antigens in the vaccine are matched with the circulating strain of influenza. a systematic review demonstrates that influenza vaccine effectively prevents pneumonia, hospitalization, and death [ , ] . a recent large observational study of adults у years of age found that vaccination against influenza was associated with a reduction in the risk of hospitalization for cardiac disease ( % reduction), cerebrovascular disease ( %- % reduction), and pneumonia or influenza ( %- % reduction) and a reduction in the risk of death from all causes ( %- % reduction) [ ] . in longterm-care facilities, vaccination of health care workers with influenza vaccine is an important preventive health measure [ , , ] . because the main virulence factors of influenza virus, a neuraminidase and hemagglutinin, adapt quickly to selective pressures, new vaccine formulations are created each year on the basis of the strains expected to be circulating, and annual revaccination is needed for optimal protection. many people who should receive either influenza or pneumococcal polysaccharide vaccine have not received them. according to a survey, only % of adults у years of age had received influenza vaccine in the past year, and only % had ever received pneumococcal polysaccharide vaccine [ ] . coverage levels are lower for younger persons with vaccine indications. among adults - years of age with diabetes, % had received influenza vaccine, and % had ever received pneumococcal vaccine [ ] . studies of vaccine delivery methods indicate that the use of standing orders is the best way to improve vaccination coverage in office, hospital, or long-term care settings [ ] . hospitalization of at-risk patients represents an underutilized opportunity to assess vaccination status and to either provide or recommend immunization. ideally, patients should be vaccinated before developing pneumonia; therefore, admissions for illnesses other than respiratory tract infections would be an appropriate focus. however, admission for pneumonia is an important trigger for assessing the need for immunization. the actual immunization may be better provided at the time of outpatient follow-up, especially with the emphasis on early discharge of patients with cap. patients with an acute fever should not be vaccinated until their fever has resolved. confusion of a febrile reaction to immunization with recurrent/superinfection pneumonia is a risk. however, immunization at discharge for pneumonia is warranted for patients for whom outpatient follow-up is unreliable, and such vaccinations have been safely given to many patients. the best time for influenza vaccination in north america is october and november, although vaccination in december and later is recommended for those who were not vaccinated earlier. influenza and pneumococcal vaccines can be given at the same time in different arms. chemoprophylaxis can be used as an adjunct to vaccination for prevention and control of influenza. oseltamivir and zanamivir are both approved for prophylaxis; amantadine and rimantadine have fda indications for chemoprophylaxis against influenza a infection, but these agents are currently not recommended because of the frequency of resistance among strains circulating in the united states and canada [ , ] . developing an adequate immune response to the inactivated influenza vaccine takes ∼ weeks in adults; chemoprophylaxis may be useful during this period for those with household exposure to influenza, those who live or work in institutions with an influenza outbreak, or those who are at high risk for influenza complications in the setting of a community outbreak [ , ] . chemoprophylaxis also may be useful for persons with contraindications to influenza vaccine or as an adjunct to vaccination for those who may not respond well to influenza vaccine (e.g., persons with hiv infection) [ , ] . the use of influenza antiviral medications for treatment or chemoprophylaxis should not affect the response to the inactivated vaccine. because it is unknown whether administering influenza antiviral medications affects the performance of the new live attenuated intranasal vaccine, this vaccine should not be used in conjunction with antiviral agents. other types of vaccination can be considered. pertussis is a rare cause of pneumonia itself. however, pneumonia is one of the major complications of pertussis. concern over waning immunity has led the acip to emphasize adult immunization for pertussis [ ] . one-time vaccination with the new tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine-adsorbed (tdap) product, adacel (sanofi pasteur)is recommended for adults - years of age. for most adults, the vaccine should be given in place of their next routine tetanus-diphtheria booster; adults with close contact with infants ! months of age and health care workers should receive the vaccine as soon as possible, with an interval as short as years after their most recent tetanus/diphtheria booster. smoking is associated with a substantial risk of pneumococcal bacteremia; one report showed that smoking was the strongest of multiple risks for invasive pneumococcal disease in immunocompetent nonelderly adults [ ] . smoking has also been identified as a risk for legionella infection [ ] . smoking cessation should be attempted when smokers are hospitalized; this is particularly important and relevant when these patients are hospitalized for pneumonia. materials for clinicians and patients to assist with smoking cessation are available online from the us surgeon general (http://www.surgeongeneral.gov/tobacco), the centers for disease control and prevention (http://www.cdc.gov/ tobacco), and the american cancer society (http://www .cancer.org). the most successful approaches to quitting include some combination of nicotine replacement and/or bupropion, a method to change habits, and emotional support. given the increased risk of pneumonia, the committee felt that persons unwilling to stop smoking should be given the pneumococcal polysaccharide vaccine, although this is not currently an aciprecommended indication. . cases of pneumonia that are of public health concern should be reported immediately to the state or local health department. (strong recommendation; level iii evidence.) public health interventions are important for preventing some forms of pneumonia. notifying the state or local health department about a condition of interest is the first step to getting public health professionals involved. rules and regulations regarding which diseases are reportable differ between states. for pneumonia, most states require reporting for legionnaires disease, sars, and psittacosis, so that an investigation can determine whether others may be at risk and whether control measures are necessary. for legionnaires disease, reporting of cases has helped to identify common-source outbreaks caused by environmental contamination [ ] . for sars, close observation and, in some cases, quarantine of close contacts have been critical for controlling transmission [ ] . in addition, any time avian influenza (h n ) or a possible terrorism agent (e.g., plague, tularemia, or anthrax) is being considered as the etiology of pneumonia, the case should be reported immediately, even before a definitive diagnosis is obtained. in addition, pneumonia cases that are caused by pathogens not thought to be endemic to the area should be reported, even if those conditions are not typically on the list of reportable conditions, because control strategies might be possible. for other respiratory diseases, episodes that are suspected of being part of an outbreak or cluster should be reported. for pneumococcal disease and influenza, outbreaks can occur in crowded settings of susceptible hosts, such as homeless shelters, nursing homes, and jails. in these settings, prophylaxis, vaccination, and infection control methods are used to control further transmission [ ] . for mycoplasma, antibiotic prophylaxis has been used in schools and institutions to control outbreaks [ ] . . respiratory hygiene measures, including the use of hand hygiene and masks or tissues for patients with cough, should be used in outpatient settings and eds as a means to reduce the spread of respiratory infections. (strong recommendation; level iii evidence.) in part because of the emergence of sars, improved respiratory hygiene measures ("respiratory hygiene" or "cough etiquette") have been promoted as a means for reducing transmission of respiratory infections in outpatient clinics and eds [ ] . key components of respiratory hygiene include encouraging patients to alert providers when they present for a visit and have symptoms of a respiratory infection; the use of hand hygiene measures, such as alcohol-based hand gels; and the use of masks or tissues to cover the mouth for patients with respiratory illnesses. in a survey of the us population, the use of masks in outpatient settings was viewed as an acceptable means for reducing the spread of respiratory infections [ ] . for hospitalized patients, infection control recommendations typically are pathogen specific. for more details on the use of personal protective equipment and other measures to prevent transmission within health care settings, refer to the healthcare infection control practices advisory committee [ ] . performance indicators are tools to help guideline users measure both the extent and the effects of implementation of guidelines. such tools or measures can be indicators of the process itself, outcomes, or both. deviations from the recommendations are expected in a proportion of cases, and compliance in %- % of cases is generally appropriate, depending on the indicator. four specific performance indicators have been selected for the cap guidelines, of which focus on treatment issues and of which deals with prevention: • initial empirical treatment of cap should be consistent with guideline recommendations. data exist that support the role of cap guidelines and that have demonstrated reductions in cost, los, and mortality when the guidelines are followed. reasons for deviation from the guidelines should be clearly documented in the medical record. • the first treatment dose for patients who are to be admitted to the hospital should be given in the ed. unlike in prior guidelines, a specific time frame is not being recommended. initiation of treatment would be expected within - h of presentation whenever the admission diagnosis is likely cap. a rush to treatment without a diagnosis of cap can, however, result in the inappropriate use of antibiotics with a concomitant increase in costs, adverse drug events, increased antibiotic selection pressure, and, possibly, increased antibiotic resistance. consideration should be given to monitoring the number of patients who receive empirical antibiotics in the ed but are admitted to the hospital without an infectious diagnosis. • mortality data for all patients with cap admitted to wards, icus, or high-level monitoring units should be collected. although tools to predict mortality and severity of illness exist-such as the psi and curb- criteria, respectivelynone is foolproof. overall mortality rates for all patients with cap admitted to the hospital, including general medical wards, should be monitored and compared with severity-adjusted norms. in addition, careful attention should be paid to the percentage of patients with severe cap, as defined in this document, who are admitted initially to a non-icu or a high-level monitoring unit and to their mortality rate. • it is important to determine what percentage of at-risk patients in one's practice actually receive immunization for influenza or pneumococcal infection. prevention of infection is clearly more desirable than having to treat established infection, but it is clear that target groups are undervaccin-ated. trying to increase the number of protected individuals is a desirable end point and, therefore, a goal worth pursuing. this is particularly true for influenza, because the vaccine data are more compelling, but it is important to try to protect against pneumococcal infection as well. coverage of % of adults у years of age should be the target. the burden of 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the guidelines. supplement sponsorship. this article was published as part of a supplement entitled "infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults," sponsored by the infectious diseases society of america. key: cord- -lwki rzc authors: sekeroglu, boran; ozsahin, ilker title: detection of covid- from chest x-ray images using convolutional neural networks date: - - journal: slas technol doi: . / sha: doc_id: cord_uid: lwki rzc the detection of severe acute respiratory syndrome coronavirus (sars cov- ), which is responsible for coronavirus disease (covid- ), using chest x-ray images has life-saving importance for both patients and doctors. in addition, in countries that are unable to purchase laboratory kits for testing, this becomes even more vital. in this study, we aimed to present the use of deep learning for the high-accuracy detection of covid- using chest x-ray images. publicly available x-ray images ( healthy, pneumonia, and confirmed covid- ) were used in the experiments, which involved the training of deep learning and machine learning classifiers. thirty-eight experiments were performed using convolutional neural networks, experiments were performed using five machine learning models, and experiments were performed using the state-of-the-art pre-trained networks for transfer learning. images and statistical data were considered separately in the experiments to evaluate the performances of models, and eightfold cross-validation was used. a mean sensitivity of . %, mean specificity of . %, mean accuracy of . %, and mean receiver operating characteristics–area under the curve scores of . % are achieved. a convolutional neural network without pre-processing and with minimized layers is capable of detecting covid- in a limited number of, and in imbalanced, chest x-ray images. at the end of , humankind was faced with an epidemic-severe acute respiratory syndrome coronavirus (sars cov- )-related pneumonia, referred to as coronavirus disease (covid- )-that people did not expect to encounter in the current era of technology. while the covid- outbreak started in wuhan, china, the significant spread of the epidemic around the world has meant that the amount of equipment available to doctors fighting the disease is insufficient. at the time of writing (september , ), there have been more than , , confirmed cases and more than , confirmed deaths worldwide. considering the time required for diagnosis and the financial costs of the laboratory kits used for diagnosis, artificial intelligence (ai) and deep learning research and applications have been initiated to support doctors who aim to treat patients and fight the illness. although rapid point-of-care covid- tests are expected to be used in clinical settings at some point, for now, turnaround times for covid- test results range from to more than hours, and probably not all countries will have access to those test kits that give results rapidly. according to a recently published multinational consensus statement by the fleischner society, one of the main recommendations is to use chest radiography for patients with covid- in a resource-constrained environment when access to computed tomography (ct) is limited. the financial costs of the laboratory kits used for diagnosis, especially for developing and underdeveloped countries, are a significant issue when fighting the illness. using x-ray images for the automated detection of covid- might be helpful in particular for countries and hospitals that are unable to purchase a laboratory kit for tests or that do not have a ct scanner. this is significant because, currently, no effective treatment option has been found, and therefore effective diagnosis is critical. ai tools have produced stable and accurate results in the applications that use either image-based or other types of data. , [ ] [ ] [ ] apostolopoulos and mpesiana performed one of the first studies on covid- detection using x-ray images. in their study, they considered transfer learning using pre-trained networks such as vgg , mobilenet v , inception, xception, and inception resnet v , which are the most frequently used. several evaluation metrics were used to evaluate the results obtained from two different datasets. mobilenet v and vgg achieved . % and . % accuracy, respectively, for two-class experiments (covid- /normal and covid- /pneumonia), and . % and . % for three-class experiments (covid- /pneumonia/normal). the final conclusion was made by the authors using the obtained confusion matrices, not the accuracy results because of the imbalanced data. ozsahin et al. used the average pixel per node (appn) approach, which is also considered in this study, and image pre-processing techniques to detect alzheimer's disease in positron emission tomography (pet) images. dai et al. modeled vehicle interactions using long short-term memory neural networks and predicted the trajectory for the vehicles. yilmaz et al. applied several machine learning classification models to classify student performance, using a numerical dataset whose implemented logistic regression (lr) and decision trees are considered in this study. all these and similar studies obtained high-accuracy results using ai techniques. for that reason, it has been widely used in the past two decades. ai, which aims to imitate human nature, can learn and makes decisions from data and images. deep learning, which takes its name from the number of its hidden layers, has gained a special place in the field of ai by providing successful results for both image-based classification applications and regression problems during the past years. , the frequent use of deep convolutional neural networks (convnet, or cnns) has enabled imagebased applications to reach their peak in the past years. generally, cnns that try to simulate biological aspects of human beings on computers required pre-processing of images or data before feeding them to the network. when the convnet was first invented, however, it was described as a neural network that requires minimal pre-processing of images before feeding them to the network, and a system that is capable of extracting the features from images to optimize the learning performance of the neural network. the convnet comprises both feature extraction and classification phases in a single network. a traditional convnet consists of three layers: convolution, pooling, and fully connected layers. feature extraction is performed in the convolutional layer by applying masks, which is the process of dividing images into a predefined dimension of segments and using filters to extract features from the image. then a feature map, which is the projection of features on the d map, is created by applying an activation function to the values obtained by the masks. the activation function activates the most knowledgeable neurons in a nonlinear way and reduces the computational cost of the neural network. several activation functions are available in cnns, and the rectified linear unit (relu) is the most commonly used activation function; it does not activate all the neurons at the same time, and therefore provides a faster convergence when the weights find the optimal values to produce the trained response during the training. a pooling operation is performed on the produced feature map to reduce the dimensions of the images. finally, the feature map is flattened into a vector and sent to the fully connected layer. the convergence of the neural network and the classification of the input patterns are performed in the fully connected layer, and its principles are based on error backpropagation to update the weights within this layer. deep convnets were applied in several image recognition applications with high accuracy, and this increased its reliability for future research. [ ] [ ] [ ] roy et al. explored cnns for hyperspectral image classification, and hartenstein et al. used deep learning to determine prostate cancer positivity from ct imaging. yoon et al. used a cnn for tumor identification in colorectal histology images. these and similar studies motivated researchers to investigate whether ai and convnets can be used effectively in covid- research, particularly in diagnostic applications. recently, apostolopoulos and mpesiana performed a study on the classification of novel covid- . they considered two different, publicly available chest x-ray images. the training process was performed by using convnet with transfer learning with pre-trained networks. they concluded that vgg and mobilenet-v outperformed other pre-trained convnets. each trained neural network gains knowledge for the particular task that is considered. while the main principle of artificial neural networks is to simulate human behavior and intelligence, the transfer learning in artificial neural networks is used to apply the stored knowledge of a particular task for another related task. deep learning for image recognition applications is capable of learning millions of images, and several huge models were trained with different architectures. [ ] [ ] [ ] [ ] [ ] these pre-trained models have been publicly shared so that all researchers can make use of the stored knowledge. the state-of-the-art pre-trained publicly available networks, namely, vgg , vgg , resnet , inceptionv , mobilenet-v , and densenet , were considered in comparison. when we consider the incidence rates of covid- , it is obvious that the data we can encounter in real life will be imbalanced. therefore, it is important to evaluate which methods and convnet architectures can be used on imbalanced data, and, if efficient, which pre-processing methods. in this study, normal, pneumonia-infected ( bacterial and viral), and covid- -infected original and pre-processed public x-ray images were considered for the diagnosis of covid- using the different architectures of the most widely used image recognition convnet networks. the classification was performed between covid- and normal images, covid- and pneumonia images, and covid- , pneumonia, and normal images to provide high-efficiency detection of covid- in chest x-ray images and to differentiate covid- from both normal and pneumonia-infected images. the receiver operating characteristics (roc) area under the curve (auc) scores and macro-averaged f score of the pre-processed and original images were examined. in addition, five machine learning classifiers-support vector machines (svms), lr, naive bayes (nb), decision tree (dt), and k-nearest neighbor (knn)-were implemented with statistical data attributes obtained from the images, and the image-based and statistically based results were compared. finally, six state-of-theart pre-trained convnets-vgg , vgg , inceptionv , mobilenet-v , resnet , and densenet -were considered for the comparison. according to their previously mentioned statement, the fleischner society recommends that medical practitioners use chest x-ray and ct in the management of covid- . in the end, the choice of imaging modality is left to the judgment of clinical teams at the point of care, accounting for the differing attributes of chest radiography and ct, local resources, and expertise. in this study, we propose the use of chest x-ray images over ct of the thorax, considering the latter's required diagnostic time. a ct scan of the thorax takes significantly more time than a chest x-ray scan does, and this means more contact duration with suspected or confirmed covid- patients. a total of covid- chest x-ray images were obtained from cohen; they can be accessed from github. the average age for the covid- group was . ± . years, and it comprised male patients and female patients. note that some patients' information is missing; this is because the dataset used in this study does not have accompanying complete metadata, because this is the very first publicly available covid- x-ray image collection, and it was created in a limited time. in addition, normal and pneumonia chest x-ray images were obtained from kermany et al. all images were in different dimensions, so they were resized to × . several categorized experiments were performed to evaluate the efficiency of the convnet on the considered image database and to compare convnet with other models using the basic statistical characteristics of the images, which can provide effective information for classification. experiments were divided into three categories: convnet experiments, statistical measurement experiments, and transfer learning experiments. convnet experiments were performed on three subcategories: covid- /normal, covid- / pneumonia, and covid- /pneumonia/normal. they included the use of four different network architectures with varying numbers of convolutional and fully connected layers, and basic image pre-processing techniques to test the results using various structures and pre-processing methods. the first structure (convnet# ) consisted of two convolutional layers with and filters, respectively, with two fully connected (dense) layers with and neurons. it was the lightest architecture considered in this study. the second and third convnet structures (convnet# and convnet# ) included three convolutional layers with , , and , , filters, respectively, and two fully connected layers were implemented with and neurons. convnet# , which was the deepest architecture in this study, consisted of four convolutional layers ( , , , and filters) and three fully connected layers ( , , and neurons). the filter sizes were considered as × for all structures, and . dropout was used for each layer. pooling was applied as maximum pooling, and × pooling was considered for each layer except the last convolutional layer of each structure. the pooling was applied as × in the last convolutional layer of each structure, to not minimize the features extracted by convolutional layers. table and table show the architectural properties of four considered convnets. a total of experiments were performed in this category, each of covid- /normal and covid- / pneumonia, to evaluate and analyze the performance of convnets under different conditions to achieve an optimal classification of covid- images. the covid- / pneumonia/normal experiments were performed by considering the optimal results obtained in the other two categories, and four experiments were performed. convnet# was not implemented on the images because the total filters of convolutional layers and pooling operations exceeded the input image dimensions. when the blurred appearance of x-ray images was considered, image sharpening using a laplacian filter (sigma = . ) was applied to improve the visual appearance of the images and to test the convnets with different input data. the appn approach, which is widely and efficiently used in image pre-processing for classification tasks, was applied to the x-ray images to obtain statistically resized images. appn is based on dividing the image into segments with predetermined sizes, and taking the mean of the pixels within the corresponding segment. thus, statistically reduced dimensions of images are obtained. in this research, × x-ray images were resized to × , and then appn with × segment sizes was applied. as a result, × x-ray images were produced. figure presents the original, sharpened, and appn-applied x-ray images. in addition to these, original images were sent to convnets without any pre-processing. all experiments were performed on four different convnet architectures with two different image dimensions. table shows the properties of convnet experiments. each image hides basic statistical information that is useful for machine learning models. consideration of the limited number of values instead of images decreases the computational time while achieving reasonable results. in this research, basic statistical information and the pre-processed characteristics were obtained from the images. a threshold value was determined as half of the maximum pixel value within the image, and the number of pixels greater and smaller than this value were counted. then, the image was divided into three segments vertically, and the center one was the widest so as not to divide the region of interest. the mean values of each segment were calculated separately. this process was performed to eliminate the corners and borders within the image. the mean values of laplacian filter, sharpened image, and histogram equalization applied images were calculated separately to provide different information to the machine learning models for the same image at the same time. besides these measurements, the minimum and maximum pixel values within the image, image entropy, standard deviation, variance, and the mode were calculated. table shows the created statistical and fundamental properties of the images in detail. a feature vector with attributes, described above, was created and fed to five machine learning classifiers: svm, lr, nb, dt, and knn. transfer learning experiments. the images that gave the best results with the convnet experiments and statistical measurement experiments, which were the unprocessed images, were compared with the pre-trained networks mentioned in the previous section. vgg is a cnn architecture that has layers with weights and uses × filters. after convolutional layers, it has two fully connected layers, followed by a softmax for output. it has approximately million parameters for the network. vgg is similar to vgg , but it has layers with weights, and this provides approximately million parameters for the network. resnet has residual layers, which aim to solve problems such as time consumption when the network becomes deeper. its principle is based on skip connections between layers called identity function, and this increases the accuracy of the model and decreases the training time. it has more than million trainable parameters. inception v has layers and million parameters. it factorizes convolutions to reduce the number of parameters without decreasing the network efficiency. in addition, novel downsizing was proposed in inception v to reduce the number of features. mobilenet-v has layers and more than . million trainable parameters. it consists of residual connections and expansion, depthwise, and projection convolutions. the expansion convolutions convert the input tensor into a higher-channel tensor; depthwise convolutions apply filters to the converted tensors; and, finally, the projection convolutions project the higher channels to a smaller number of tensors. densenet connects each layer to every other layer in a feedforward fashion. the initial convolutional layer is followed by a fully connected layer, and the rest of the convolutional layers are followed by the pooling and a fully connected layer. it has layers and more than million trainable parameters. each x-ray image was sent to the considered networks with the minimum dimensions required. the pre-processing pixel value that is the most frequent within the image was performed on the considered models' pre-processing steps to provide consequent images to the models. after training of each model with pre-trained weights, maximum pooling was applied, and features were sent to the fully connected layer ( ). similar to previous experiments, the eightfold cross-validation method was used for all experiments. model evaluation criteria. models can be evaluated using different criteria, such as classification accuracy, sensitivity (true positive rate), specificity, and roc auc. using only an accuracy or a sensitivity/specificity criterion is not enough, however, especially for imbalanced data; while higher scores can be obtained in one metric, lower scores can be produced by other metrics. therefore, considering all the above-mentioned criteria, roc auc was used to evaluate the model performance for the statistical measurement, covid- /normal, and covid- /pneumonia experiments, which had two output classes (labels). roc auc is used to measure the performance of a model. in medical applications, the model with the higher roc auc score is more capable of distinguishing between patients with covid- and without covid- . "positive" and "negative" results are the responses of the outputs (classification predictions) obtained from the model. "true" and "false" are the actual data. the accuracy, sensitivity, and specificity are calculated as given in equation ( ), equation where tp and tn denote the true-positive and true-negative values, respectively; and fp and fn represent false-positive and false-negative values, respectively. macro-averaged f score is a measure of model performance for multiclass (multilabel) problems that have more than two output classes, if the data are imbalanced, and the accuracy is not reliable. it considers the harmonic mean of recall and precision scores of all classes separately, and measures the capacity of the model for the correct detection of samples. all experiments were performed by k-fold cross-validation, which is based on dividing all the data into a predefined number of folds, k, and using onefold for testing and the remaining for training. the training step is repeated k times until all folds are used for the test set. in this study, eightfold cross-validation was used for testing. therefore, . % and . % of the data were used for testing and training, respectively. four randomly selected images for both healthy and coronavirus-infected patients were assigned as the validation set. the number of images within the validation set was limited so as not to reduce the number of images in the infected class. at the end of statistical measurement, covid- / normal, and covid- /pneumonia experiments, the mean accuracy, mean specificity, mean sensitivity, and the mean roc auc scores were calculated, and all the evaluations were performed on the mean scores. the mean roc auc scores were, however, used as the primary evaluation criteria. for covid- /pneumonia/normal experiments, the macro-averaged f score was used for the model evaluation. all experiments were performed on an ubuntu . . lts -bit operating system, intel core i - cpu @ . ghz × , gb ram, nvidia geforce rtx gpu. this section presents the results obtained from convnet experiments, statistical measurement experiments, and transfer learning experiments. as mentioned above, experiments were performed for the convnet experiments in three groups separately. in this group, a total of images ( covid- and normal) were trained in each experiment without the data augmentation procedure, which artificially increases the training samples. sharpened images with different image sizes and by using different architecture produced consistent results for all experiments (exp. through exp. ). the highest mean accuracy of experiments - was obtained in exp. ( . %). the highest mean sensitivity, highest mean specificity, and highest mean roc auc score, which is the primary indicator for an imbalanced dataset, however, were obtained in exp. ( . , . , and . %, respectively). exp. and experiments - could not achieve higher rates than exp. and exp. in all evaluation metrics. in the appn-applied experiments (exp. , exp. , and exp. ), while the higher mean accuracy, higher mean sensitivity, and higher roc auc score were obtained in exp. ( . , . , and . %, respectively), the higher mean specificity was achieved in exp. ( . %). exp. , which was implemented using the deepest convnet architecture for appn, produced the lowest results within these three experiments. in exp. through exp. , in which original images were used with different dimensions in different convnet architectures, consistent rates were obtained for mean accuracy and mean specificity. changes in the rates of mean sensitivity and mean roc auc scores (between and %, respectively) were, however, obtained using the different architectures. the highest mean accuracy and highest mean specificity were obtained in exp. ( . and . %), and these were the highest scores obtained in the convnet experiments for the covid- /normal group. the highest mean sensitivity and highest mean roc auc scores for the covid- /normal group were achieved in exp. with . and . %, respectively. table shows the results obtained in the experiments for covid- /normal classification. in the second group of convnet experiments, a total of images ( covid- and pneumonia) were trained in each experiment; as with the covid- /normal experiments, the data augmentation procedure was not applied. even though the number of training images was increased, and the second training set (pneumonia set) is a challenging dataset for detecting covid- , similar results to those in the covid- /normal experiments were obtained. in sharpening applied experiments (experiments - ), the mean roc auc scores fluctuated up to . %, and the highest mean roc auc score ( . %), highest mean sensitivity ( . %), and highest mean accuracy ( . %) were obtained in exp. that was implemented using convnet# . but the highest mean specificity achieved was . % in exp. . in appn-applied experiments (experiments - ), similar results were obtained; however, the lightest architecture achieved the highest mean roc auc score. when the images fed convnets directly (experiments - ), we observed that the increment of the convolutional layer number of convnets reduces the scores obtained by the neural network up to %, similar to covid- /normal results. the highest mean accuracy, mean sensitivity, mean specificity, and mean roc auc scores were obtained in exp. : . , . , . , and . %, respectively. table shows the results obtained in the experiments for the covid- /pneumonia classification. in the last group of convnet experiments, a total of images ( covid- , pneumonia, and normal) were trained in each experiment for three output classes as covid- , normal, and pneumonia. because superior results were obtained without image pre-processing in covid- /normal and covid- /pneumonia experiments, the experiments in this group were performed using only the unprocessed images with × dimensions with four considered convnet architectures. convnet# could not achieve the highest scores in any metrics in terms of recall and precision for each class, and it produced . % for a macro-averaged f score in covid- / pneumonia/normal experiments. convnet# , which was the lightest structure and produced the optimal results in two-class five experiments were performed for covid- /normal classification by considering features obtained from the images and using five machine learning classifiers: svm, lr, nb, dt, and knn. inconsistent results were obtained for knn and nb. knn achieved the highest mean specificity rate ( . %), but it also produced the lowest mean sensitivity and lowest mean roc auc score ( . and . %, respectively). similarly, nb produced the highest mean sensitivity rate and mean roc auc score ( . and . %, respectively), but it produced the lowest mean accuracy and mean specificity rates ( . and . %, respectively). svm achieved the highest mean accuracy result ( . %). none of these models, however, was capable of outperforming the convnet for any of the evaluation metrics using the obtained statistical data. table presents the results obtained in statistical measurement experiments. the same machine learning classifiers and features were considered for the classification of covid- /pneumonia. similar results were obtained in the experiments, and nb produced the highest mean roc auc, mean sensitivity, and mean accuracy scores ( . , . , and . %, respectively) for statistical measurement experiments of covid- /pneumonia classification. the highest mean specificity was obtained by nb and svm ( . % each). the lowest scores of statistical measurements for covid- /pneumonia classification were obtained by lr. even though similar results were obtained in covid- /normal and covid- /pneumonia experiments, the decrement in the classification levels was observed for all machine learning algorithms. this might be caused by both image classes having disease and the increment of the number of training images. comparisons were performed for all groups of experiments. pre-processing methods were not applied to the images because the original images achieved the highest results in convnet experiments. similar to convnet experiments, transfer learning experiments were also performed in three groups as covid- /normal, covid- /pneumonia, and covid- /pneumonia/normal. the two models that would produce superior results in the covid- /normal and covid- /pneumonia groups were considered in covid- /pneumonia/normal experiments. in the covid- /normal group, vgg and mobilenet-v produced the worst results. they were only able to learn one class and could not classify covid- x-ray images. resnet- and vgg produced comparatively better results than vgg and mobilenet-v . the mean roc auc scores of resnet- and vgg were calculated as . and . %, respectively. inception-v produced higher results than other pre-trained networks; however, the highest mean roc auc score in transfer learning experiments was obtained by densenet ( . %). table presents the results obtained using transfer learning for the covid- /normal group. in the covid- /pneumonia group, similar results were obtained. even though the vgg , mobilenet-v , and resnet increased their scores, they were not able to reach the scores of densenet and inception v . the highest mean roc auc score of covid- /pneumonia classification in the transfer learning experiment was achieved by densenet ( . %), and it was followed by inception v ( . %). table presents the results obtained using transfer learning for the covid- /pneumonia group. after considering the results obtained in the first two groups, we implemented densenet and inception v for the classification of covid- /pneumonia/normal. even though fluctuating results were observed for precision and recall scores for the covid- , pneumonia, and normal classes, densenet outperformed inception v in transfer learning experiments by obtaining a macro-averaged f score of . %, while inception v achieved . %. table shows the results obtained in covid- / pneumonia/normal experiments with the results obtained in convnet experiments of the same group. in covid- /normal classification, the highest mean specificity (when the . % scores of pre-trained networks are not considered because of not learning another class) and the highest mean accuracy results were obtained in exp. ( . and . %, respectively), which consisted of the deepest architecture in convnet experiments ( table ). this failed, however, to produce higher results in terms of mean sensitivity, and this reduced the performance of the considered convnet in the primary performance indicator for both classes, mean roc auc score. the highest mean sensitivity was achieved by densenet ( . %) ( table ) , but other obtained scores were not high enough to outperform other models in other metrics. densenet 's mean roc auc score was . %. even though convnet# could not produce the optimal results in sensitivity, specificity, and accuracy results, its stability produced consistent results, and the highest mean roc auc score was achieved by convnet# with . % ( table ) . machine learning classifiers could not produce satisfactory results using the extracted statistical information to classify covid- in this experimental group. in covid- /pneumonia classification, similarly to the previous experiments, the highest mean roc auc score was obtained in exp. ( . %) with convnet# (table ) , followed by densenet ( . %) ( table ) . besides, the highest mean sensitivity and mean accuracy results were also obtained in exp. ( . and . %, respectively). the highest mean specificity was achieved in transfer learning experiments by resnet ( %); however, the other table shows the total tp, tn, fp, and fn results obtained for exp. and densenet for all folds in covid- / normal and covid- /pneumonia classification. figure demonstrates the architecture of convnet# , which obtained the highest classification results, and figure shows some of the highest roc auc scores obtained in convnet, statistical measurement, and transfer learning experiments. for three-class experiments (covid- /pneumonia/ normal), the macro-averaged f scores were between . and . % (table ) . densenet , however, achieved higher results than convnet# , convnet# , convnet# , and inception v . but the optimal results were obtained by convnet# , which had a macro-averaged f score of . %, followed by densenet with . %, as shown in table . figure shows the macro-averaged f scores obtained in covid- /normal/pneumonia experiments. the performed experiments should be analyzed separately to evaluate the performance of the applied techniques and considered models. as mentioned above, the final evaluation process was performed by the eightfold cross-validation method and roc auc score because of the imbalanced database. in two-class experiments, a variety of image pre-processing methods were applied with different image sizes and four convnet architectures to provide the highest detection accuracy of covid- in chest x-ray images. in covid- /normal classification experiments, it was relatively easier to classify covid- because the normal x-ray images do not contain any abnormalities. the performed experiments showed that the considered image preprocessing steps produced similar results to convnets fed with original images; however, none of these considered techniques were able to increase the performance of convnets in terms of mean roc auc score. the maximum mean roc auc score using an image pre-processing technique was . %, which was obtained in exp. with convnet# and appn. the use of the images with reduced dimensions caused the mean roc auc scores of the experiments to decrease by approximately . % (max. . % and min. . %) compared to the experiments with higher dimensions. a possible solution is feeding the convnet with images with increased dimensions. four architectures were also considered for all experiments to evaluate the model performance with different numbers of layers. experimental results showed that the use of more convolutional and fully connected layers could not improve the model performance for the image database considered, because the differences between the mean roc auc scores of the convnet with minimized layers and the convnet with more layers were more than . - %, depending on the pre-processing technique. the minimum mean roc auc score of convnet with more layers in appnapplied images was . %, while convnet# achieved . %. the number of images used in the experiments has a direct effect on the number of layers and the architecture of the convnet, but the obtained results suggest that the use of minimized layer numbers can enhance detection of covid- within the normal images. the highest result was obtained by using two convolutional layers and two dense layers with × image dimensions. then, statistical measurements and covid- detection using several machine learning models were considered. the determination of the specific statistical measurements to be used is vital for this kind of classification approach; however, there are basic measurements that can be obtained from the images. in addition to the above-mentioned statistical measurements, the image pre-processing techniques were applied, and additional measurements were obtained from the images to make the knowledge for the machine learning models as similar as possible to that for the convnets. the machine learning models, however, could not achieve mean roc auc scores as high as those of the convnets, and there was a % difference between the highest mean roc auc score in convnet experiments and nb, which produced the highest result in statistical measurement experiments. the use of transfer learning with the state-of-the-art pretrained convnets was also considered in covid- / normal classification experiments. six pre-trained networks were considered, and the results showed that two of them, inceptionv and densenet , were able to correctly detect the x-ray images. densenet produced similar results to the highest results obtained in exp. ; however, it could not outperform exp. in terms of mean specificity, mean accuracy, and mean roc auc scores. the other classification type in this study was the detection of covid- within the pneumonia images (covid- /pneumonia). the same experiments were performed as with covid- /normal experiments, and similar results were obtained. the lightest convnet outperformed the other considered convnet structures and pre-trained models, even though the number of training samples increased because of the number of images in the dataset. similarly, machine learning classifiers were not able to produce higher results than convnets obtained, but general reduction was observed in the classification performance of machine learning models. this was caused by the complexity of images, the difficulty of differentiating covid- from pneumonia images, and the increased number of training samples. it should be noted, however, that additional measured characteristics of images or significant statistical measurements, such as contrast level, brightness level, kurtosis, and so on, may help to improve the scores obtained by machine learning models. in three-class experiments (covid- /normal/pneumonia), the increment of the class number and the training samples caused convnet# to not produce optimal results. even the deepest structure (convnet# ) could not achieve superior results; it was observed that the deeper structure was more effective than convnet# at detecting covid- between pneumonia and normal images. although the success of the recognition ability of the models strongly depends on the image or dataset characteristics, we can conclude that the use of lighter convnets for a smaller number of output classes for a limited number of images performs better convergence. the increment of the number of output classes and training samples, however, requires a deeper structure for effective learning. it should also be noted that the characteristics of the images have a direct effect on convergence; therefore, different architectures should be analyzed for each application to improve the recognition capacity of the model. pre-trained networks have very deep architectures, they have been trained by using millions of different kinds of images, and the saved final weights are intended to be transferred to similar or different applications. recent research, [ ] [ ] [ ] however, aimed to develop light convnets to reduce the computational cost of pre-trained networks; and, as mentioned above, networks with less deep architectures become preferable for classification problems, even with a huge number of images and a high number of output classes. the obtained results also demonstrate that architectures may begin to deepen more in connection with the increased number of images and output classes. for this reason, some pre-trained neural networks have been found to have difficulties in learning one class successfully while learning another class with high accuracy. similar results were obtained in apostolopoulos and mpesiana. covid- data used in this study have been collected by pulling images from publications and websites. therefore, they have come from different institutions and different scanners. x-ray imaging parameters might be different for some of the scans, which might result in different image quality, and this is common when multisite studies are mixed, or one database has multiple characteristic flaws like different imaging protocols. therefore, pre-processing of the data to make the radiographic images more similar and uniform is important in terms of providing more efficient analysis and consistency. this is a complex procedure, however, including co-registration, standardization, and so on to obtain the same image size and pixel size along the same spatial orientation and to make the images' resolution uniform and isotropic. we believe that, as more pre-processed datasets on covid- become publicly available, more accurate studies will be conducted. nevertheless, the current limited dataset has led researchers around the globe to develop methods to aid in facilitating the diagnosis of covid- . although this study shows that cnns can be used for automated detection of covid- and for distinguishing it from pneumonia, we believe applying artificial neural networks to covid- detection more accurately requires clinical trials. another limitation of this study is the small sample size of covid- images, which restricts the appropriate cohort selection and might result in a biased conclusion. at the time of writing, there is no other reliable publicly available dataset. to have a more accurate and robust model, a larger covid- dataset is needed. furthermore, because of the use of a relatively small number of covid- images, clinical information about the patients, such as risk factors and medical history, is not available at this time. detection of covid- from chest x-ray images is of vital importance for both doctors and patients to decrease the diagnostic time and reduce financial costs. artificial intelligence and deep learning are capable of recognizing images for the tasks taught. in this study, several experiments were performed for the high-accuracy detection of covid- in chest x-ray images using convnets. various groups-covid- /normal, covid- /pneumonia, and covid- /pneumonia/normalwere considered for the classification. different image dimensions, different network architectures, state-of-the-art pre-trained networks, and machine learning models were implemented and evaluated using images and statistical data. when the number of images in the database and the detection time of covid- (average testing time = . s/image) are considered using convnets, it can be suggested that the considered architectures reduce the computational cost with high performance. the results showed that the convolutional neural network with minimized convolutional and fully connected layers is capable of detecting covid- images within the two-class, covid- /normal and covid- / pneumonia classifications, with mean roc auc scores of . and . %, respectively. in addition, the second proposed architecture, which had the second-lightest architecture, is capable of detecting covid- in three-class, covid- /pneumonia/normal images, with a macro-averaged f score of . %. therefore, the use of ai-based automated high-accuracy technologies may provide valuable assistance to doctors in diagnosing covid- . further studies, based on the results obtained in this study, would provide more information about the use of cnn architectures with covid- chest x-ray images and improve on the results of this study. world health organization. who coronavirus disease (covid- ) dashboard covid- : automatic detection from x-ray images utilizing transfer learning with convolutional neural networks the role of chest imaging in patient management during the covid- pandemic: a multinational consensus statement from the fleischner society the use of back propagation neural networks and f-florbetapir pet for early detection of alzheimer's disease using alzheimer's disease neuroimaging initiative database modeling vehicle interactions via modified lstm models for trajectory prediction student performance classification using artificial intelligence techniques webcam-based eye movement analysis using cnn joint hand detection and rotation estimation using cnn object recognition with gradient-based learning: shape, contour and grouping in computer vision exploring -d- -d cnn feature hierarchy for hyperspectral image classification prostate cancer nodal staging: using deep learning to predict ga-psma-positivity from ct imaging alone tumor identification in colorectal histology images using a convolutional neural network very deep convolutional networks for large-scale image recognition deep residual learning for image recognition rethinking the inception architecture for computer vision mobilenets: efficient convolutional neural networks for mobile vision applications covid- image data collection identifying medical diagnoses and treatable diseases by image-based deep learning area under the roc curve deep convolutional network method for automatic sleep stage classification based on neurophysiological signals cross-validation using polar expression features and nonlinear machine learning classifier for automated parkinson's disease screening a light cnn for deep face representation with noisy labels a normalized light cnn for face recognition wasnet: a neural network-based garbage collection management system the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the authors received no financial support for the research, authorship, and/or publication of this article. key: cord- -qr gdmbc authors: grief, samuel n.; loza, julie k. title: guidelines for the evaluation and treatment of pneumonia date: - - journal: prim care doi: . /j.pop. . . sha: doc_id: cord_uid: qr gdmbc pneumonia is a common cause of respiratory infection, accounting for more than , hospitalizations in the united states annually. presenting symptoms of pneumonia are typically cough, pleuritic chest pain, fever, fatigue, and loss of appetite. children and the elderly have different presenting features of pneumonia, which include headache, nausea, abdominal pain, and absence of one or more of the prototypical symptoms. knowledge of local bacterial pathogens and their antibiotic susceptibility and resistance profiles is the key for effective pharmacologic selection and treatment of pneumonia. pneumonia is a leading cause of hospitalization among both adults and children in the united states, accounting for more than , hospitalizations and more than , emergency department visits in . , it is among the most expensive conditions treated in us hospitals with national aggregate costs of $ . billion in . a causal pathogen is often not identified. a prospective, multi-center study by the centers for disease control and prevention identified a responsible pathogen in only % of cases of community-acquired pneumonia (cap) in adults requiring hospitalization. cap is an infection of the lung parenchyma that is acquired outside of hospitals or extended-care facilities. viral pathogens were identified in % of cases and bacterial pathogens in % of cases. in adults of all ages, human rhinovirus and influenza were the most frequently identified viruses. streptococcus pneumoniae is the most common causal bacterium. staphylococcus aureus and enterobacteriaceae were significantly more common among patients requiring intensive care unit (icu) level care. other bacteria identified in cap include mycoplasma pneumoniae, chlamydophila pneumoniae, and haemophilus influenzae. less common bacterial causes include mycobacterium tuberculosis, legionella sp, and pseudomonas aeruginosa. these and other bacteria may be considered more likely in patients with certain risk factors ( table ) . diagnosis a diagnosis of pneumonia should be considered in patients presenting with acute onset fever or chills and cough. the cough may be described as productive. additional symptoms frequently seen include fatigue, anorexia, and pleuritic chest pain. important components of a history include recent travel, history of underlying lung disease, and smoking history. , a study by diehr and colleagues found that history of alcoholism or bloody sputum have relative risk of , so the presence of these findings is not predictive of pneumonia. physical examination findings frequently appreciated in patients with pneumonia include decreased breath sounds, rales, tactile fremitus, and crackles. , tachypnea and hypotension are more worrisome symptoms that may also be seen and require urgent evaluation. it is imperative to maintain a high level of suspicion in immunocompromised or elderly and nursing home patients, because they frequently display fewer overt symptoms of pneumonia when compared with the general population. , no individual component of the history or physical examination is useful in diagnosing pneumonia, but the presence of multiple findings is required ( table ). in adults presenting with acute cough, the baseline probability of pneumonia is only %. absence of any vital sign abnormality (blood pressure, heart rate, respiratory rate) reduces the predicted probability of pneumonia to %. a chest radiograph should be ordered for any patient with abnormal vital signs defined as temperature higher than f, heart rate higher than bpm, or respiratory rate higher than bpm. imaging should also be obtained for physical examination abnormalities of crackles or decreased breath sounds in a patient without asthma. infectious disease society of america guidelines recommend imaging with a demonstrable infiltrate to confirm the diagnosis of pneumonia and to exclude other causes of cough and fever such as acute bronchitis. although x-ray imaging is a mainstay of diagnosis of pneumonia, the british thoracic society recommends the entire clinical picture should be considered when making a decision to treat. a systematic review found that among patients who are sick enough to be admitted with a clinical diagnosis of cap but have a normal initial chest radiograph, approximately in will develop radiographic evidence of pneumonia within hours. in such cases, it is appropriate to treat the patient empirically for pneumonia and repeat imaging in to hours. community resources and access to imaging may also affect decision to treat without imaging. routine blood and sputum culture testing is costly and often low-yield. however, more extensive diagnostic testing should be considered in patients who are at risk for infection with unusual pathogens, who are not responding to treatment, or when additional testing is likely to change antibiotic management (table ) . , it is reasonable to consider respiratory viral polymerase chain reaction (pcr) to determine viral causes of symptoms, so that inappropriate antibiotic use can be limited. additional testing for m. tuberculosis should be considered in a patient presenting with persistent cough, particularly in the setting of weight loss, malaise, night sweats, or hemoptysis. additional risk factors for tuberculosis (tb) include immigration from an endemic country, residing in a homeless shelter, intravenous drug use, or human immunodeficiency virus (hiv) infection. persons who work with people at high risk for tb infection are also considered high risk. , treatment most cases of pneumonia can be managed in the outpatient setting. several severity assessment tools have been developed to help determine appropriate treatment settings. the pneumonia severity index (psi) considers variables to stratify patients into of risk categories (i-v) based on risk of death within days. given the number of parameters required, it is not frequently used in general practice. the curb assessment tool was introduced in by the british thoracic society. similar to the psi, it calculates risk of -day mortality, but instead only uses variables (confusion, urea, respiratory rate, blood pressure, and age > ), with one point awarded for each if present, allowing for greater ease of use. , the crb can be calculated without blood urea and thus is useful in the outpatient setting. a recent systematic review and meta-analysis found no significant difference in test performance when comparing the severity tools. it was noted that the psi negative likelihood ratio suggests it may be superior in identifying low-risk patients, and the curb and crb may be superior in identifying high-risk patients. a curb or crb score of or demonstrates low risk of mortality and suggests a patient can be managed in the outpatient setting. a score of or higher should warrant hospital admission. it is always appropriate to consider a patient's social circumstances and treatment wishes when making treatment decisions , ( fig. ; curb score ). when available, treatment of cap should be guided by local resistance patterns. in previously healthy patients who are appropriate for outpatient treatment, recommended first-line treatment is with a macrolide antibiotic such as azithromycin targeting the most common causal pathogen s. pneumoniae. doxycycline is an alternative option. patients with comorbidities such as diabetes; chronic heart, lung, renal, or liver disease; alcoholism; asplenia; impaired immune system; or recent antibiotic use within the last months have an increased risk for drug-resistant s pneumoniae. as such, a respiratory fluoroquinolone or b-lactam plus a macrolide is recommended ( table ). a cochrane review found no significant differences in efficacy between antibiotic regimens, although there were differences in adverse effects when comparing antibiotics within a single class. patients appropriate for inpatient non-icu treatment should also be treated with a respiratory fluoroquinolone or macrolide with b-lactam. patients should be treated for a minimum of days and should be clinically stable with resolving symptoms before treatment is discontinued. , patients with high severity of infection or with extrapulmonary manifestations may benefit from longer duration of therapy, such as to days or until improving. , in recent years, there has been emerging data supporting the use of adjunctive corticosteroids in the inpatient treatment of cap. as this is an area of research, multiple recent systematic reviews and meta-analyses have been published, some with conflicting findings. a cochrane review that included relevant cap studies through the year showed that corticosteroid use accelerates time to symptom resolution and clinical stability, with infrequent adverse effects. similarly, a systematic review by siemieniuk and colleagues included studies from through mid- . their analysis of randomized controlled trials found significantly decreased mortality in severe pneumonia, decreased need for mechanical ventilation, decreased occurrence of acute respiratory distress syndrome, decreased time to clinical stability, and shorter duration of hospitalization. hyperglycemia requiring treatment occurred more frequently in patients treated with corticosteroids. , the most recent idsa and bts guidelines do not make recommendations regarding the routine use of adjunctive corticosteroid for cap. , given the variations in dose and route of administration, an optimal agent and dose is unknown. further research is needed to determine steroid dosing and duration, as well as what patient populations are most likely to benefit from its use. , there are a large number of studies assessing the role of the infection biomarker procalcitonin in diagnosis and monitoring of patients with bacterial infections. a cochrane meta-analysis in the primary care setting concluded that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. procalcitonin values too low or too high usually exclude bacterial infection, but not always. per practitioner discretion and, depending on patient complexity and other comorbidities, a follow-up appointment after successful management in the primary care setting may be arranged. at this appointment, repeat x-ray imaging to confirm resolution of pneumonia is not indicated if the patient seems clinically well. in patients with persistence of symptoms or who have a high risk of lung cancer (age > , > pack year smoking history), repeat x-ray imaging or low-dose computerized tomography (ct) scan to screen for lung cancer can be considered. in the united states, the pneumococcal conjugate vaccine (pcv or prevnar- ) is recommended for all babies and children younger than years, all adults aged years or older, as well as children and adults aged years through years who are at increased risk for pneumococcal disease due to certain medical conditions. the pneumococcal conjugate vaccine has been shown to have an observed % reduction in vaccine-type pneumococcal cap, persisting for at least years after receiving the vaccine. , the pneumococcal polysaccharide vaccine (ppsv or pneumovax ) is recommended for all adults aged years or older, all cigarette smokers aged to years, as well as children and adults aged to years with certain medical conditions. a cochrane review found that the polysaccharide vaccine is effective in preventing invasive pneumococcal disease in healthy adults. vaccine efficacy was, however, poorer in adults with chronic illnesses. pneumonia is considered "nonresolving" if there is an inadequate clinical response despite antibiotic treatment. the incidence of treatment failure is % to % and is associated with a -fold increase in mortality. idsa broadly classifies nonresponse into different groups: ( ) progressive pneumonia characterized by clinical deterioration and ( ) persistent pneumonia with absence or delay of clinical stability. progressive pneumonia with deterioration is characterized by respiratory failure and/ or septic shock and typically occurs within hours. persistent pneumonia with absent or delayed response is typically considered after a time period of hours, because this is often regarded as the median time required for clinical stability. , concern for nonresponse in a patient with pneumonia should initiate a systematic evaluation of possible causes. host factors that may explain poor response should be considered, including high initial severity score, risk factors for infection with unusual organisms, underlying comorbidities, or risk factors for multi-drug-resistant pathogens ( table ) . in areas with high prevalence of hiv or tb, testing is recommended. results of initial microbiological tests such as blood or sputum cultures should be reviewed, including any sensitivity data. repeat blood cultures should be obtained in the setting of clinical deterioration. additional laboratory testing for s. pneumonia and legionella pneumophila via urine antigen testing may be performed, because they may remain positive for days after initiating antibiotic treatment. additional imaging such as chest ct may be beneficial for assessing interval progression or improvement or identifying pleural effusions, lung abscesses, or pulmonary embolism. if pleural effusions are identified in a patient with treatment failure, thoracentesis should be performed to evaluate for empyema. in select patients, bronchoscopy with protected bronchial sampling or bronchoalveolar lavage (bal) may be beneficial to provide diagnostic information for infectious causes and noninfectious mimics, such as pulmonary eosinophilia, drug-induced pneumonitis, sarcoidosis, or pulmonary fibrosis. , primary or metastatic neoplastic lesions obstructing the bronchus may cause accumulation of secretions distal to the obstruction, predisposing to infection. both hodgkin and non-hodgkin lymphoma can present with lung involvement, with typical radiographic findings of hilar or mediastinal adenopathy, but may also have a presenting pattern that suggests infection. elderly patients with pneumonia may not exhibit typical symptoms or physical examination findings seen in younger adults, such as pleuritic chest pain, cough, fever, and leukocytosis. signs and symptoms more frequently seen in older adults include falls, decreased appetite, or functional impairment. a change in mental status should prompt evaluation for an infectious cause. , as with any adult, risk factors for atypical or drug-resistant pathogens should guide treatment. elderly patients with history of stroke or known dysphagia are at an increased risk for aspiration pneumonia. residents of nursing homes or long-term care facilities are at an increased risk for methicillinresistant staphylococcus aureus (mrsa) or multidrug-resistant (mdr) pathogens. evaluation of a returned traveler should include the following: appropriate history covering the travel itinerary (location and activities), onset of illness related to travel, vaccines or prophylaxis received, diet, sexual history, and exposure to animals. , respiratory tract infections are among the most common health care complaints affecting returned travelers and are diagnosed in up to % of returned patients with fever. , although upper respiratory tract infections are more common, the severity and possible mortality associated with lower respiratory tract infections such as pneumonia make it a must-not-miss diagnosis in the returned traveler. as in the united states, s pneumoniae, h. influenzae, and s. aureus are the dominant pneumonia isolates in developing countries. it must be considered that bacterial resistance patterns from different countries may differ in these otherwise commonplace bacteria. respiratory symptoms occur in up to half of patients with malaria, and the presentation may seem similar to that of pneumonia. thus, in a patient returning from a malariaendemic area, blood smear testing for malaria should be performed. increased time spent at hotels or on cruise ships in a patient presenting with symptoms of pneumonia should increase suspicion for legionella. travelers returning from east and southeast asia, as well as australia, with a severe pneumonia may have been exposed to burkholderia pseudomallei-the causative agent of melioidosis, which can cause severe necrotizing pneumonia and has % to % mortality despite appropriate antibiotic therapy. severe pneumonia may also be because of viruses such as influenza, middle eastern respiratory syndrome, or hantavirus. a returned traveler with pneumonia with eosinophilia should raise suspicion for helminth infection. , histoplasma capsulatum is a dimorphic fungus that is relatively common in north, central, and south america and given its growth in bird and bat droppings is associated with activities such as cave exploration. coccidioides immitis is endemic in the southwest united states and northern mexico, as well as smaller areas in central america. it is spread through inhalation of spores found in the soil. fungal infection with h. capsulatum and c immitis are often asymptomatic but may also present as a flulike illness with fever, malaise, and dry cough to weeks after exposure. , ventilator-associated pneumonia ventilator-associated pneumonia (vap) is a type of pneumonia that occurs in patients who have been intubated or mechanically ventilated by means of a tracheostomy for at least hours. , mechanical ventilation modifies the oropharyngeal and tracheal environment, allowing oral and gastric secretions to enter the lower airways. it is this change in lower respiratory tract bacterial flora that precipitates the beginning of pneumonia. vap is common. approximately % of patients who receive mechanical ventilation will develop vap. vap should be suspected when signs of pulmonary infection (fever, purulent secretions, leukocytosis) and radiologic evidence (air bronchograms, infiltrates) are present; bacteriologic confirmation usually follows. sensitivity and specificity of the diagnostic criteria discussed earlier are % and %, respectively. other useful diagnostic criteria have been developed, incorporating additional symptoms and similar signs and laboratory/radiologic criteria. once vap is clinically suspected, early empirical treatment is favored. delaying treatment and/or not appropriately covering for the likely microbial culprit are both associated with higher morbidity and mortality. [ ] [ ] [ ] [ ] microbiology microbial organisms associated with vap have been identified ( table ). early versus late-onset vap organisms have also been documented. , acinetobacter, citrobacter, pseudomonas, and klebsiella are the most predominant late-onset organisms, warranting more aggressive antibacterial intervention. bacterial confirmation usually requires secretion sampling, either via bronchoscopic or via nonbronchoscopic methods. obtaining pleural fluid, when present, under ultrasound guidance, is recommended. endotracheal aspirates are easily retrieved but have a high false-positive rate in icu patients due to airway colonization. bronchoscopic retrieval of distal airway specimens via bal or protected-specimen brush techniques is the best, but requires a trained bronchoscopist. selection of antibiotics is typically done empirically and based on whether the patient has any risk factors for mdr pathogens ( table ) and whether onset of vap is early (defined as within first days of being in the icu) or late ( days or later). , , evaluation and treatment of pneumonia empirical treatment should also be determined as a result of knowledge of local distribution of pathogens and their antimicrobial susceptibility patterns. early-onset vap without mdr risk factors typically should be prescribed one of the following antibiotic options : for late-onset and/or mdr factor patients, appropriate antibiotic options would include one or more of the following : antipseudomonal cephalosporins (eg, cefepime, ceftazidime) antipseudomonal carbapenems (imipenem or meropenem) beta-lactam/beta-lactamase inhibitors (piperacillin-tazobactam) with an antipseudomonal fluoroquinolone (ciprofloxacin) or aminoglycoside plus linezolid or vancomycin (if mrsa risk factors are present) telavancin is indicated for vap for susceptible isolates of s. aureus when other therapies are not suitable. dose and frequency of administration of the antibiotic choices discussed earlier are documented extensively elsewhere. atypical antibiotic choices, such as colistin, polymyxin b, telavancin, inter alia, are rarely indicated but can be used when antimicrobial resistance warrants these agents. typically, consultation with an infectious disease physician or clinical pharmacist with expertise and familiarity when using these drugs is a sine qua non. pediatric pneumonia epidemiology pneumonia is a very common affliction of childhood. pneumonia accounts for % of infectious illnesses in infants and toddlers younger than years. worldwide, approximately million new cases of pneumonia occur annually among children younger than years. pneumonia is the leading cause of death in children younger than years in developing countries, accounting for % of all deaths of children younger than years and killing , children in . , most childhood pneumonia (cp) can be treated in the outpatient setting. the rate of hospitalization for cp through age years varies per year, but in it was . per . infants younger than year had the highest rate of hospitalization ( . per ), whereas children aged to years had the lowest rate ( . per ). signs and symptoms of cp are often nonspecific and depend on several factors including age, microbial organism, and underlying health of the patient. clinical acumen is key to successfully diagnosing cp. the universal symptom of cp is cough. other symptoms may include chest pain, headache, arthralgia, nausea, and abdominal pain. most common signs to look for include fever, tachypnea, labored breathing, rhonchi, crackles, and wheezing. other physical signs to identify include grunting, nasal flaring, and chest retractions because these increase the likelihood of cp. diagnostic testing is usually performed, when available, and would include assessment of oxygen saturation by pulse oximetry, chest radiograph, complete blood cell count, respiratory microbial panel by pcr, ultrasound of the chest (when medically indicated), and cultures. disagreement about whether blood cultures are warranted exists in the literature. as per a recent study, blood cultures have not been shown to assist with clinical management in children hospitalized with pneumonia. the infectious diseases society of america, however, recommends blood cultures for all hospitalized children with pneumonia. etiologic microbial organisms differ, depending on age of the child. in infants, toddlers, and preschoolers, viruses predominate ( table ) . less common bacterial organisms may infect newborns (see table ). in older children, bacteria are the more common culprit ( table ). atypical organisms may be involved when children are immunocompromised or have other underlying comorbidities (see table ). in order to provide optimal care to a child with pneumonia, it is important to determine the severity of the pneumonia and the child's clinical status. most children will not require inpatient admission; criteria exist to help stratify severity of pneumonia and necessity of hospitalization (box and ) . choosing an antibiotic for cp is initially always an empirical process and based on local and regional microbial susceptibility and resistance patterns, along with the child's age, immunization status, and any underlying, preexisting health conditions. , , , most children can be treated with oral antibiotics in the outpatient setting. first-line and preferred agent is still amoxicillin. , , , alternative agents are cephalosporins and macrolide antibiotics; however, increasing resistance to penicillin derivatives and macrolides should be noted ( children and infants for whom there is concern about careful observation at home or who are unable to comply with therapy or unable to be followed-up children and infants who have respiratory distress and hypoxemia (oxygen saturation < %) (see table ) children and infants with comorbidities (eg, asthma, cystic fibrosis, congenital heart disease, diabetes mellitus, neuromuscular disease) poor feeding and/or signs of dehydration have been linked to development of childhood tendonitis/tendinopathy, yet recent literature indicates these disabling side effects are rare. , inpatient treatment guidelines have also been established ( table ) . isolation of the particular microbial organism is ideal, but not required, in order to determine duration of therapy. uncomplicated pneumonia treatment in the outpatient setting usually should last to days. inpatient admission for pneumonia warrants longer duration of antibiotic therapy, typically to days of combined parenteral and oral therapy or at least week after becoming afebrile. complicated cases of pneumonia will require a minimum of weeks of therapy once lack of fever is confirmed and may be extended for up to weeks. the switch from parenteral to oral therapy may occur after to hours of documented lack of fever but is not always practical in complicated and/ or icu-admitted patients. pneumonia is a common, well-recognized respiratory infection seen in primary care settings. triage of the usual presenting symptoms will generally set into motion a typical course of action, including physical examination and possibly imaging to confirm clinical suspicion. further testing depends on treatment venue (outpatient vs inpatient) and other specific criteria (see table ). empirical antibiotic therapy is the cornerstone of treatment, and knowledge of local and regional microbial susceptibility and resistance will bolster the success rate of outpatient management of pneumonia, regardless of demographic and/or accompanying morbidities. special circumstances and scenarios that may occur, including nonresolving pneumonias, pediatric or geriatric populations, travel-related infections, among others, will necessitate a more careful attention to history, physical examination, and antibiotic selection. trends in hospital inpatient stays in the united states national hospital ambulatory medical care survey: emergency department summary tables national inpatient hospital costs: the most expensive conditions by payer community-acquired pneumonia requiring hospitalization among u.s. adults the washington manual of outpatient internal medicine. philadelphia: lippincott williams & wilkins community-acquired pneumonia in adults: diagnosis and management prediction of pneumonia in outpatients with acute cough: a statistical approach the rational clinical examination: evidence-based clinical diagnosis common questions about pneumonia in nursing home residents predicting pneumonia in adults with respiratory illness infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults bts guidelines for the management of community acquired pneumonia in adults: update guidelines for diagnosis and management of community-and hospital-acquired pneumonia in adults: joint ics/ nccp(i) recommendations severity assessment tools for predicting mortality in hospitalised patients with community-acquired pneumonia. systematic review and meta-analysis defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study antibiotics for community-acquired pneumonia in adult outpatients duration of antibiotic treatment in community-acquired pneumonia corticosteroids for pneumonia corticosteroid therapy for patients hospitalized with community-acquired pneumonia corticosteroids in the adjunctive therapy of communityacquired pneumonia: an appraisal of recent meta-analyses of clinical trials procalcitonin-guided diagnosis and antibiotic stewardship revisited procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections unresolved acute pneumonia: a "bad omen pneumococcal vaccination j what you should know j cdc polysaccharide conjugate vaccine against pneumococcal pneumonia in adults updated recommendations for prevention of invasive pneumococcal disease among adults using the -valent pneumococcal polysaccharide vaccine (ppsv ) vaccines for preventing pneumococcal infection in adults what is the best approach to the nonresponding patient with community-acquired pneumonia? pulmonary infections in the returned traveler non-infectious mimics of community-acquired pneumonia the management of community-acquired pneumonia in the elderly cdc yellow book : health information for international travel travel-related respiratory infections general approach to the returned traveler histoplasmosis and other endemic fungal infections ventilator-associated pneumonia overview of nosocomial pneumonias treatment of hospital-acquired and ventilator-associated pneumonia in adults incidence of and risk factors for ventilatorassociated pneumonia in critically ill patients clinical diagnosis of ventilator-associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies philadelphia: lippincott williams and wilkins impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associate pneumonia and blood stream infection: a meta-analysis the adequacy of timely empiric antibiotic therapy for ventilator-associate pneumonia: an important determinant of outcome systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis empirical antibiotic therapy for ventilator-associated pneumonia profile of infective microorganisms causing ventilator-associated pneumonia: a clinical study from resource limited intensive care unit microbial causes of ventilator-associated pneumonia management of adults with hospitalacquired and ventilator-associated pneumonia: clinical practice guidelines by the infectious diseases society of america and the american thoracic society using local microbiologic data to develop institution-specific guidelines for the treatment of hospital-acquired pneumonia pediatric pneumonia child health epidemiology reference group of who and unicef. global, regional, and national causes of child mortality in : a systematic analysis world health organization pneumonia national hospitalization trends for pediatric pneumonia and associated complications community-acquired pneumonia in children the rational clinical examination. does this infant have pneumonia? utility of blood culture among children hospitalized with community-acquired pneumonia the management of communityacquired pneumonia in infants and children older than months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america pneumonia in children: inpatient treatment evidence-based care guideline. community acquired pneumonia in children days through years of age factors associated with antimicrobial resistance and mortality in pneumococcal bacteremia parenteral-oral switch in the management of pediatric pneumonia key: cord- - otd heg authors: prendki, v.; huttner, b.; marti, c.; mamin, a.; fubini, p.e.; meynet, m.p.; scheffler, m.; montet, x.; janssens, j.p.; reny, j.l.; kaiser, l.; garin, n.; stirnemann, j. title: accuracy of comprehensive pcr analysis of nasopharyngeal and oropharyngeal swabs for ct-scan-confirmed pneumonia in elderly patients: a prospective cohort study date: - - journal: clin microbiol infect doi: . /j.cmi. . . sha: doc_id: cord_uid: otd heg objectives: we aimed to assess the accuracy of pcr detection of viruses and bacteria on nasopharyngeal and oropharyngeal swabs (nps) for the diagnosis of pneumonia in elderly individuals. methods: we included consecutive hospitalized elderly individuals suspected of having pneumonia. at inclusion, nps were collected from all participants and tested by pcr for the presence of viral and bacterial respiratory pathogens (index test, defined as comprehensive molecular testing). routine diagnostic tests (blood and sputum culture, urine antigen detection) were also performed. the reference standard was the presence of pneumonia on a low-dose ct scan as assessed by two independent expert radiologists. results: the diagnosis of pneumonia was confirmed in of ( %) included patients (mean age years, community-acquired pneumonia in ( %)). a pathogen was identified by comprehensive molecular testing in patients ( %) and by routine methods in ( %). comprehensive molecular testing was positive for viruses in patients ( %) and for bacteria in ( %). the sensitivity and specificity were % ( % ci %– %) and % ( % ci %– %) for comprehensive molecular testing, and % ( % ci %– %) and % ( % ci %– %) for routine testing, respectively. positive likelihood ratio was . for routine methods and . for comprehensive molecular testing. conclusion: comprehensive molecular testing of nps increases the number of pathogens detected compared with routine methods, but results are poorly predictive of the presence of pneumonia. hence, comprehensive molecular testing is unlikely to impact clinical decision-making (nct ). clinical trials registration: nct . identification of the pathogen causing pneumonia is useful to guide antibiotic therapy, to help with differential diagnosis and for epidemiological reasons. hence, most current guidelines recommend microbiological investigations in patients hospitalized for suspected community-acquired pneumonia (cap) [ e ] . nevertheless the microorganism causing cap is identified in only a minority of patients [ ] . the difficulty in obtaining high-quality respiratory samples for microbiological analysis (e.g. sputum cultures) is an important limitation in the elderly [ ] . use of molecular biology technology improves the diagnostic yield in suspected pneumonia and is often prescribed by physicians, but it is unclear how it impacts clinical management [ ] . oosterheert et al. showed in a randomized controlled trial ( individuals with lower respiratory tract infections, mean age years) that pcr for viruses and atypical bacteria in nasopharyngeal and oropharyngeal swabs (nps) allowed the identification of additional pathogens but did not reduce antibiotic use or costs [ ] . a pragmatic randomized controlled trial ( individuals with acute respiratory illness, mean age years) showed that molecular point-of-care testing for respiratory viruses did not reduce the proportion of patients treated with antibiotics [ ] . finally, in a prospective observational study ( individuals with lower respiratory tract infection, mean age years), pcr detection of respiratory viruses had no impact on antibiotic use and length of stay [ ] . we aimed to assess the diagnostic accuracy of pcr detection of viral and bacterial pathogens on nps for the diagnosis of pneumonia in elderly individuals. individuals admitted to hospital for suspected pneumonia had nps collected at inclusion for the detection of multiple bacterial and viral pathogens using multiplex pcr (comprehensive molecular testing), in addition to routine testing. a chest low-dose computed tomography scan (ldct) was performed as soon as possible. results regarding the diagnostic performance of ldct have been published elsewhere [ ] . the present study is a preplanned secondary analysis evaluating the accuracy of comprehensive molecular testing in patients with suspected pneumonia. sample size is based on the power calculation of the original study. this study took place in the geriatric and internal medicine wards of geneva university hospitals, an -bed tertiary-care institution serving approximately inhabitants. the study was approved by geneva's institutional review board (cer and registered at clinicaltrials.gov (nct ). informed consent was obtained from all patients or next of kin. consecutive hospitalized individuals years old, suspected of having community-, nursing-home-or hospital-acquired pneumonia were enrolled between may and april . individuals included had at least one respiratory symptom and at least one symptom or laboratory finding compatible with infection [ ] . individuals treated for pneumonia during the previous months or treated with antimicrobial therapy for more than h before inclusion were excluded (fig. ) . demographic data, co-morbidities, vital signs, clinical findings, severity scores, results of standard laboratory tests, blood, sputum and urine cultures, urinary antigen detection, pcr for respiratory viruses on nps, and antimicrobial therapy administered were recorded prospectively. images were interpreted as consistent or inconsistent with pneumonia by two independent radiologists experienced in thoracic radiology. discordant cases were reviewed together to reach a consensus. the radiological diagnoses were taken as the reference standard and patients with a seemingly infectious infiltrate were considered to have pneumonia. the radiologists were blinded to patients' results. the nps were performed on all individuals at inclusion. these were placed in copan ® universal transport medium (copan italia spa, brescia, italy), sent to the central virology laboratory as soon as possible and processed directly (neither frozen nor thawed). nucleic acids were extracted with qiasymphony (qiagen, hombrechtikon, switzerland) using a virus/pathogen kit ( , qiagen used to detect nine bacterial species/genera: streptococcus pneumoniae, haemophilus influenzae, moraxella catarrhalis, staphylococcus aureus, mycoplasma pneumoniae, chlamydia pneumoniae, legionella spp., klebsiella pneumoniae and pseudomonas aeruginosa. the results of the pcr for viruses were available to the treating physicians whereas the results of pcr for bacteria were performed subsequently as a batch on nucleic acid extraction, which were kept at e c and were not reported to the treating physicians. comprehensive molecular testing was defined as the results of both viral and bacterial pcr. routine microbiological tests were performed according to recommendations, including blood cultures, sputum cultures in patients able to expectorate and pneumococcal and legionella pneumophila urinary antigen detection [ ] . sputum samples with or more neutrophils and fewer than ten epithelial cells were evaluated after gram-staining, and were subsequently cultured. we used frequencies, percentage, mean with range and median with interquartile range for descriptive purposes. variables including results of comprehensive molecular testing, viral pcr alone, bacterial pcr alone and routine methods, were compared between patients with and without pneumonia in univariate analysis using the mannewhitneyewilcoxon test or the kruskalewallis method for continuous variables, and fisher's exact test or chi-square test for categorical variables, as appropriate. comprehensive molecular testing was the index test. the test characteristics (sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios (lr), and diagnostic odds ratios) of comprehensive molecular testing, viral pcr, bacterial pcr, and routine methods, were computed using two-by-two tables. a p value of < . was considered significant. analyses were performed using the r statistical software package, version . . (www.cran.r-project.org). baseline characteristics of included patients are shown in table . nps were performed in / patients ( . %) and presence of pneumonia was confirmed in / ( %). pneumonia was community-acquired in / ( %). the median delay between inclusion and ldct was . h (interquartile range . e . ). among the patients without pneumonia, the most frequent diagnoses were non-respiratory sepsis, viral upper respiratory tract infection, bronchitis or exacerbation of chronic obstructive pulmonary disease, and heart failure. mean duration of antimicrobial therapy was . days. eighty-six of patients ( . %) received a combination antimicrobial therapy for a mean of . days (most frequently a b-lactam and a macrolide, according to institutional guidelines). results are depicted in table and the supplementary material (table s ). comprehensive molecular testing was positive in / patients ( %). sixty-two patients ( %) had a positive pcr for at least one virus, patients ( %) had a positive pcr for at least one bacterium, and ( %) had a positive pcr for both virus and bacteria. antimicrobial therapy was stopped in / patients ( . %) with a positive viral pcr. results are displayed in table and the supplementary material (table s ). blood cultures were performed in / patients ( %), urinary antigens for legionella spp. and streptococcus pneumoniae in / patients ( %) and / patients ( %), respectively. sputum was obtained in / patients ( %), with only / ( %) of sufficient quality to warrant further evaluation. routine methods led to the identification of a pathogen in / patients ( %). twelve patients ( %) had bacteraemia, six ( %) of which had a non-respiratory origin (four urinary and two abdominal). details for each pathogen are available in the supplementary material (table s ). comprehensive molecular testing was positive in / patients ( %) with pneumonia and / patients ( %) without. at least one viral pcr was positive in / patients ( %) with pneumonia and / ( %) without. bacterial pcr was positive in / patients ( %) with pneumonia and / ( %) without. routine methods were positive in / patients ( %) with pneumonia and / ( %) without. results are depicted in table . sensitivity and specificity were % and % for comprehensive molecular testing, % and % for routine methods, % and % for viral pcr, and % and % for bacterial pcr, respectively. the positive lr was . for routine methods and . for comprehensive molecular testing. negative lrs of routine and molecular methods were . and . , respectively. our main findings are that results of comprehensive molecular testing of nps are poorly predictive of the presence of pneumonia. positive ( . ) and negative ( . ) lr of comprehensive molecular testing are too low to affect the probability of having pneumonia. comprehensive molecular testing increased the sensitivity to % in comparison with % with routine methods. gadsby et al. achieved pathogen detection in % of patients hospitalized for cap using comprehensive molecular testing [ ] . this higher sensitivity is probably explained by collection of sputum in % of their patients, who were much younger (median age years). in comparison, sputum of adequate quality was obtained in only / ( %) of our patients. though sputum culture is recommended in international guidelines [ , ] , it is hard to obtain in elderly patients [ ] . our results compare with those of putot et al., who were able to collect sputum from only % of elderly patients hospitalized for pneumonia [ ] . obtaining more good-quality lower respiratory tract samples would require an invasive procedure [ , ] . in our cohort, % of the patients had a positive result for a virus, mainly rhinovirus and influenza virus. forty-five ( . %) had both a positive viral pcr and pneumonia. positive and negative lrs were . and . , respectively. this is in accordance with previous results in the literature. in another study assessing the performance of pcr on nps for the prediction of ct-scan-confirmed pneumonia, prevalence of positive viral pcr was %, and positive and negative lrs were . and . , respectively [ ] . certainly, many viruses, including influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus and rhinovirus, are known causes of pneumonia [ e ]. jain et al. showed that respiratory viruses were more frequently detected than bacteria in patients hospitalized for non-severe cap (median age years) [ ] . but viruses are also detected in nps in individuals with bronchitis, exacerbation of chronic obstructive pulmonary disease, and even in asymptomatic patients [ e ]. in the present study, many patients with non-respiratory sepsis or cardiac failure had positive nps. our results confirm that viruses are frequently identified in patients with symptoms of a respiratory illness, including those without pneumonia. finally, antimicrobial therapy was stopped in only % of patients with a positive viral pcr, suggesting that comprehensive molecular testing might not be an adequate means of reducing antimicrobial therapy prescription in patients with symptoms of lower respiratory tract infection. we had hypothesized that a positive bacterial pcr in nps might be a surrogate for bacterial pneumonia, allowing us to surpass the aforementioned difficulties to obtain good-quality sputum samples. however, bacterial pcr had poor diagnostic accuracy (positive and negative lrs of . and . , respectively), probably because they are not able to differentiate between pharyngeal carriage and lower respiratory tract infection. compared with the results of the capita cohort, pharyngeal carriage rate of staphylococcus aureus and streptococcus pneumoniae were lower in our cohort ( % versus % and % versus %, respectively), whereas the carriage rate was similar for haemophilus influenzae ( % versus %) and higher for moraxella catarrhalis ( % versus %) [ ] . this differences may stem from the different population enrolled, the capita cohort including community-dwelling elderly people (mean age years), a far younger and healthier population than ours. finally, the identification of a pathogen with routine methods did not result in a high diagnostic accuracy, although better than with comprehensive molecular testing. our study has several strengths. it was conducted in a consecutive cohort of unselected elderly patients who were submitted to extensive testing. we used a robust reference standard based on ldct scan. the radiologists were blinded to participants' clinical, biological and microbiological results, so incorporation bias could be attenuated. according to recent findings, a reference standard for pneumonia based on chest x-ray may lead to frequent misclassifications, which can flaw the evaluation of microbiological test accuracy [ , ] . our comprehensive molecular testing included more respiratory bacterial pathogens than previous works [ , ] . our study also had some limitations. the lack of a control arm prevented the assessment of the impact of comprehensive molecular testing on patient management. we did not perform pcr analyses on a quantitative basis, and multiplex pcr have different analytical sensitivities according to the viruses sought. sputum was not tested with pcr because good-quality sputum could only be obtained in a small minority of patients. finally, the presence of an infiltrate on an ldct scan may be an imperfect reference standard for the diagnosis of infectious pneumonia. however, using microbiological results of the patients in the reference definition would have led to a risk of incorporation bias. the present study highlights the difficulties in identifying a causative agent in elderly patients with suspected pneumonia. viruses and bacteria are frequently isolated by pcr in the upper airway of elderly patients but their presence is not useful for predicting the presence or absence of pneumonia. hence they are unlikely to be helpful in making patient management decisions. further investigation is needed to assess the usefulness of pcr sampling in patients with proven pneumonia to direct treatment. the authors declare no conflict of interest. the study was supported by grants from the geneva university hospitals (hug) (research & development grant, medical directorate, hug) and the ligue pulmonaire genevoise, a non-profit association involved in the care of patients with respiratory diseases. infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults bts guidelines for the management of community acquired pneumonia in adults: update guidelines for the management of adult lower respiratory tract infectionsdfull version evolving understanding of the causes of pneumonia in adults, with special attention to the role of pneumococcus impact of microbiological samples in the hospital management of community-acquired, nursing home-acquired and hospital-acquired pneumonia in older patients comprehensive molecular testing for respiratory pathogens in community-acquired pneumonia impact of rapid detection of viral and atypical bacterial pathogens by real-time polymerase chain reaction for patients with lower respiratory tract infection routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (respoc): a pragmatic, open-label, randomised controlled trial a comparison of nasopharyngeal and oropharyngeal swabbing for the detection of influenza virus by real-time pcr low-dose computed tomography for the diagnosis of pneumonia in elderly patients: a prospective, interventional cohort study diagnosis and management of community and hospital acquired pneumonia in adults: summary of nice guidance pneumonia in the very old lower respiratory tract virus findings in mechanically ventilated patients with severe community-acquired pneumonia viral infection in patients with severe pneumonia requiring intensive care unit admission viruses detected by systematic multiplex polymerase chain reaction in adults with suspected community-acquired pneumonia attending emergency departments in france viral pneumonia in older adults respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness human metapneumovirus: review of an important respiratory pathogen radiographic and ct features of viral pneumonia ct findings in viral lower respiratory tract infections caused by parainfluenza virus, influenza virus and respiratory syncytial virus rhinovirusdnot just the common cold community-acquired pneumonia requiring hospitalization among us adults heterogeneous and dynamic prevalence of asymptomatic influenza virus infections respiratory syncytial virus evaluation among asymptomatic and symptomatic subjects in a university hospital in sao paulo, brazil in the period of viral shedding and transmission potential of asymptomatic and paucisymptomatic influenza virus infections in the community the impact of the -valent pneumococcal conjugate vaccine on pneumococcal carriage in the community acquired pneumonia immunization trial in adults (capita) study early chest computed tomography scan to assist diagnosis and guide treatment decision for suspected community-acquired pneumonia this work was presented at the th eccmid (madrid). we thank the patients and their families for their participation in this study. we also thank the pneumoldct study group, clinicians, radiology technicians, research nurses and case managers who helped us to enrol our participants, and our translator, mr darren hart. we acknowledge the contribution of the escmid study group for infections in the elderly (esgie, www.escmid.org/esgie). vp and js conceived the study, wrote the grant to obtain funding, obtained ethical approval, analysed the results and wrote the manuscript. vp, mpm and am participated in recruitment and followed the participants and the samples. ms and xm were the radiologist experts. bh, ng, cm, am, pef, jpj, jlr and lk helped design the study and contributed to the manuscript. js performed the statistical plan and analyses. supplementary data to this article can be found online at https://doi.org/ . /j.cmi. . . . key: cord- -k whepc authors: chan, kai man; gomersall, charles d title: pneumonia date: - - journal: oh's intensive care manual doi: . /b - - - - . - sha: doc_id: cord_uid: k whepc nan • pneumonia can be caused by over organisms. • the relationship between specific clinical features and aetiological organism is insufficiently strong to allow a clinical diagnosis of the causative organism. • early administration of appropriate antibiotics is important. the net result is that the differential diagnosis is wide and treatment should be started before the aetiological agent is known. the differential diagnosis and the likely causative organisms can be narrowed by using epidemiological clues, the most important of which are whether the pneumonia is community-acquired or healthcare-associated and whether the patient is immunocompromised. note that the flora and antibiotic resistance patterns vary from country to country, hospital to hospital and even icu to icu within a hospital and this must be taken into account. evidence-based guidelines have been issued by the british thoracic society, the infectious diseases society of america (idsa) and american thoracic society (ats) and the european respiratory society. links to these and other pneumonia-related guidelines can be found at the following 'link page': http://www. aic.cuhk.edu.hk/web /pneumonia% guidelines.htm. an acute infection of the pulmonary parenchyma that is associated with at least some symptoms of acute infection, accompanied by an acute infiltrate on a chest radiograph (cxr), or auscultatory findings consistent with pneumonia (e.g. altered breath sounds, localised crackles) in a patient not hospitalised or residing in a long-term care facility for ≥ days prior to the onset of symptoms. the overall incidence is - per inhabitants per year, with - % requiring hospital admission. overall, % of patients are admitted to icu. the overall mortality of hospitalised patient is approximately %. pneumonia produces both systemic and respiratory manifestations. common clinical findings include fever, sweats, rigors, cough, sputum production, pleuritic chest pain, dyspnoea, tachypnoea, pleural rub and inspiratory crackles. classic signs of consolidation occur in less than % of cases. multi-organ dysfunction or failure may occur depending on the type and severity of pneumonia. the diagnosis of pneumonia may be more difficult in the elderly. although the vast majority of elderly patients with pneumonia have respiratory symptoms and signs, over % may also have non-respiratory symptoms and over a third may have no systemic signs of infection. investigations should not delay administration of antibiotics as delays are associated with an increase in mortality. important investigations include: pneumonia . urinary legionella antigen. this test is specific (> %). in patients with severe legionnaires disease sensitivity is - % for l. pneumophilia serogroup (the most commonly reported cause of legionella infection). thus a positive result is virtually single or predominant organism on a gram stain of a fresh sample or a heavy growth on culture of purulent sputum is likely to be the organism responsible. the finding of many polymorphonuclear cells (pmn) with no bacteria in a patient who has not already received antibiotics can reliably exclude infection by most ordinary bacterial pathogens. specimens should be obtained by deep cough and be grossly purulent. ideally the specimen should be obtained before treatment with antimicrobials, if this does not delay administration of antibiotics, and be transported to the laboratory immediately for prompt processing to minimise the chance of missing fastidious organisms (e.g. strep. pneumoniae). acceptable specimens (in patients with normal or raised white blood cell counts) should contain > pmn per low-power field (lpf) and < - squamous epithelial cells (sec)/lpf or > pmn per sec. these criteria should not be used for mycobacteria and legionella infection. certain organisms are virtually always pathogens when recovered from respiratory secretions (box . ). patients with risk factors for tuberculosis (tb) (box . ), and particularly those with cough for more than a month, other common symptoms of tb and suggestive radiographic changes, should have sputum examined for acid-fast bacilli. sputum cannot be processed for culture for anaerobes owing to contamination by the endogenous anaerobic flora of the upper respiratory tract. in addition to the factors listed in table . , foul-smelling sputum, lung abscess and empyema should raise suspicion of anaerobic infection. . aspiration of pleural fluid for gram stain, culture, ph and leucocyte count -all patients with a pleural effusion > cm thick on a lateral decubitus chest x-ray. contamination and colonisation. pcr assays are more sensitive than culture for mycoplasma and chlamydia species and at least as sensitive for legionella. pcr assays also detect legionella strains other than serogroup . the bts guidelines recommend pcr of lower respiratory tract sample or, if unavailable, throat swab for the diagnosis of mycoplasma pneumonia. pcr for chlamydophilia should be performed when invasive respiratory samples were collected from patients with severe community-acquired pneumonia. the role of pcr in diagnosing pcp is mainly limited to non-hiv patients, in whom conventional microscopy and staining of induced sputum and bal have a lower sensitivity than in hiv patients. management general supportive measures intravenous fluids may be required to correct dehydration and provide maintenance fluid. a general approach should be made to organ support with an emphasis on correcting hypoxia. increased mortality among those who do not receive empirical antibiotics that cover the infecting pathogen(s) is well documented. each unit should have its own regimens tailored to the local flora and antibiotic resistance patterns. in the absence of such regimens the regimen outlined in figure other investigations should be considered in patients with risk factors for infection with unusual organisms. bronchoalveolar lavage may be useful in immunocompromised patients, those who fail to respond to antibiotics, or those in whom sputum samples cannot be obtained. molecular diagnosis (e.g. pcr-based methods) has the advantages of quick results (within hours), enhanced sensitivity, independence from organism viability and hence previous antibiotics, and theoretical possibility for determination of antimicrobial susceptibility. of note, it is important to test for genes specific for the organism in question and the sampling site remains important. pcr is most useful when per formed on specimens from a normally sterile site. for example, pcr for pneumococcus is positive in % of blood samples from adult patients with confirmed or probable pneumococcal pneumonia, whereas blood cultures are positive in only %. for respiratory specimens under most circumstances, interpretation remains problematic due to low specificity related to floral should be modified in the light of risk factors (see table . ). quinolones may be less appropriate in areas with a high prevalence of tb as their use may mask concurrent tb infection. appropriate antimicrobial therapy should be administered within hour of diagnosis. , there is controversy regarding the appropriate change to empirical therapy based on microbiological findings. , changing to narrower-spectrum antimicrobial cover may result in inadequate treatment of the - % of patients with polymicrobial infection. increasing evidence demonstrates improved outcome with combination antimicrobial as compared with monotherapy, particularly in severely ill patients with bacteraemic pneumococcal pneumonia. odds ratio of death was . to for monotherapy as compared with combination therapy. benefits were seen only in combination therapy with macrolide as part of the regimen, but not in combination with fluroquinolone regimen. for the treatment of drug-resistant strep. pneumoniae (drsp) the regimens in figure . are probably suitable for isolates with a penicillin mic < mg/l. if the mic is ≥ mg/l an antipneumococcal fluoroquinolone, vancomycin, teicoplanin or linezolid should be given. no clinical trial has specifically addressed this issue. courses as short as days may be sufficient. idsa/ ats guidelines recommend stopping after a minimum of days if the patient is afebrile for - hours and organ dysfunction has largely resolved. short courses may be suboptimal for patients with bacteraemic s. aureus pneumonia, meningitis or endocarditis complicating pneumonia or infection with less common organisms (e.g. burkholderia pseudomallei or fungi) or pseudomonas aeruginosa. procalcitonin may be useful to guide antibiotic therapy, but not all studies have demonstrated a benefit. this can be assessed subjectively (a response is usually seen within - days of starting therapy) or objectively on the basis of respiratory symptoms, fever, oxygenation, wbc count, bacteriology, cxr changes, c-reactive protein reduction and procalcitonin reduction of - % from peak value. the average time to defervescence varies with organism, severity and patient age ( days in elderly patients, . days in young patients with pneumococcal pneumonia, - days in bacteraemic patients with pneumococcal pneumonia, - days in patients with m. pneumoniae pneumonia and days in patients with legionella pneumonia). both blood and sputum cultures are usually negative within - hours of treatment although p. aeruginosa and m. pneumoniae may persist in the sputum despite effective therapy. cxr changes lag behind clinical changes with the speed of change depending on the organism, the age of the patient and the presence or absence of comorbid illnesses. the cxr of most young or middle-aged patients with bacteraemic pneumococcal pneumonia is clear by weeks, but resolution is slower in elderly patients and patients with underlying illness, extensive pneumonia on presentation or legionella pneumophilia pneumonia. if the patient fails to respond consider the following questions: • has the patient got pneumonia? • are there host factors that explain the failure (e.g. obstruction of bronchus by a foreign body or tumour, inadequate host response)? • has a complication developed (e.g. empyema, superinfection, bronchiolitis obliterans organising pneumonia, metastatic abscess)? • is the right drug being given in an adequate dose by the right route? • is the organism resistant to the drug being given? • are there other organisms? • is the fever a drug fever? useful investigations include computerised tomography (ct) of the chest, thoracocentesis, bronchoalveolar lavage (table . ) and transbronchial or open-lung biopsy. scoring systems have been developed to predict adverse outcome and icu admission including pneumonia severity index (psi), curb- , crb- , modified ats major and minor criteria, scap prediction rule, smart-cop, rea-icu index and cap-piro. although they may help identify the sicker patients they should not be used as a sole determinant of icu admission as local admission criteria will be affected by local facilities, both in and outside icu. it should be noted that none of the criteria has been prospectively demonstrated to avoid late transfers or lower mortality. influenza pneumonia may present with severe respiratory failure and multi-organ failure. however the pattern of organ failure appears to vary between strains with h n being associated with a much higher mortality and a higher incidence of multi-organ failure than pandemic h n , which itself presented differently to seasonal influenza. in particular, trophism for lower respiratory tract, a higher rate of icu admission and a higher rate of extrapulmonary complications were observed. early initiation of oseltamivir is recommended for critically ill patients although there is no direct evidence of outcome benefit. glucocorticoids do not appear to be useful and may prolong viral replication. bacterial superinfection should be considered, with grampositive cocci being most frequently isolated. failure and cancer) can cause infiltrates on a chest x-ray. identification of the organism responsible is even more difficult than in patients with community-acquired pneumonia owing to the high incidence of oropharyngeal colonisation by gram-negative bacteria. blood cultures are positive in only about % of cases of nosocomial pneumonia. ventilator-associated pneumonia (vap) is nosocomial pneumonia arising > - hours after intubation. reported incidence of vap is between and % for those receiving mechanical ventilation for more than hours. it is associated with a higher incidence of multi-drug-resistant organisms. nosocomial pneumonia is thought to result from microaspiration of bacteria colonising the upper respiratory tract. other routes of infection include macroaspiration although there are data demonstrating that surgical masks are as effective as n (ffp ) masks in preventing transmission of seasonal influenza in non-icu settings it is important to note that the capacity for airborne transmission (and hence the need for n masks) is dependent on the exact characteristics of the organism and the frequency of aerosol-generating procedures so these data should not be extrapolated to other influenza viruses and icu settings. nosocomial pneumonia occurs in . - % of hospital patients, with a higher incidence in certain groups (e.g. postoperative patients and patients in icu). diagnosis may be difficult: the clinical features of pneumonia are non-specific and many non-infectious conditions (e.g. atelectasis, pulmonary embolus, aspiration, heart table . procedure for obtaining microbiological samples using bronchoscopy and protected specimen brushing and/or bronchoalveolar lavage , infection control in patients suspected of having a disease that is transmitted by the airborne route (e.g. tuberculosis): • the risk of transmission should be carefully weighed against the benefits of bronchoscopy, which may generate large numbers of airborne particles • perform bronchoscopy in a negative-pressure isolation room • consider the use of a muscle relaxant in ventilated patients, to prevent coughing • staff should wear personal protective equipment, which should include a fit-tested negative-pressure respirator (n , ffp or above) as a minimum; use of a powered air-purifying respirator should be considered suction through the endotracheal tube should be performed before bronchoscopy avoid suction or injection through the working channel of the bronchoscope perform protected specimen brushing before bronchoalveolar lavage management is based on the finding that early treatment with antimicrobials that cover all likely pathogens results in a reduction in morbidity and mortality. the initial selection of antimicrobials is made on the basis of epidemiological clues ( fig. . , table . ). antimicrobials should be administered within hour of diagnosis. the results of microbiological investigations are used to narrow antimicrobial cover later. treatment should be reassessed after - days or sooner if the patient deteriorates ( fig. . ). an outline of management based on an invasive approach is given in figure . . current ats guidelines recommend days' treatment provided the aetiological agent is not p. aeruginosa or other non-lactose fermenter and the patient has a good clinical response with resolution of clinical features of infection. the outcome of patients who receive appropriate initial empirical therapy for ventilator-associated pneumonia for days is similar to those who receive treatment for days. of gastric contents, inhaled aerosols, haematogenous spread, spread from pleural space and direct inoculation from icu personnel. diagnosis is based on time of onset (> hours after admission to a healthcare facility ), cxr changes (new or progressive infiltrates) and either clinical features and simple laboratory investigations or the results of quantitative microbiology. using a clinical approach, pneumonia is diagnosed by the finding of a new infiltrate or a change in an infiltrate on chest radiograph and growth of pathogenic organisms from sputum plus one of the following: white-blood-cell (wbc) count greater than × l /l, core temperature ≥ . °c, sputum gram stain with scores of more than two on a scale of four of polymorphonuclear leucocytes and bacteria. these are broadly similar to those required in community-acquired pneumonia: • chest x-ray: although studies using a histological diagnosis as the gold standard have demonstrated that pneumonia may be present despite a normal cxr, most definitions of nosocomial pneumonia require the presence of new persistent infiltrates on a cxr. • respiratory secretions: considerable controversy surrounds the issue of whether invasive bronchoscopic sampling (table . ) of respiratory secretions is necessary. whether invasive sampling is employed or tracheal aspirates are used, empirical broad-spectrum antibiotics should be started while results are awaited. the results of microbiological analysis of respiratory secretions are used to either stop antibiotics or narrow the spectrum. although the use of an invasive strategy is associated with a higher likelihood of modification of initial antimicrobials, the effect on important clinical outcome such as mortality, antibiotic-free days, and organ dysfunction is variable. although tracheal aspirates may predominantly reflect the organisms colonising the upper airway, they may be useful in indicating which organisms are not responsible for the pneumonia, thus allowing the antimicrobial cover to be narrowed. the use of dual therapy is not well supported by evidence but it does reduce the probability that the pathogen is resistant to the drugs being given. if an extended spectrum β-lactamase-producing strain or an acinetobacter sp. is suspected a carbapenem should be given. if legionella pneumophilia is suspected use a quinolone. risk factors for mrsa infection in areas with a high incidence of mrsa include diabetes mellitus, head trauma, coma and renal failure. or with enlarged cervical nodes or other manifestations of extrapulmonary disease. clinical disease is seldom found in asymptomatic individuals, even those with strongly positive tuberculin test (heaf grade iii or iv). the outlook for patients with tuberculosis who require icu admission is poor. in one retrospective study the in-hospital mortality for all patients with tuberculosis requiring icu admission was % but in those with acute respiratory failure it rose to %. the presentation and management of tb in hiv-positive patients are different (see below). identification of mycobacteria multiple , sputum samples should be collected, preferably on different days, for microscopy for acid-fast bacilli and culture. if sputum is not available bronchial washings taken at bronchoscopy and gastric lavage or aspirate samples should be obtained. gastric aspirates need to be neutralised immediately on collection. bronchoscopy and transbronchial biopsy may be useful in patients with suspected tb but negative sputum smear. pleural biopsy is often helpful and mediastinoscopy is occasionally needed in patients with mediastinal lymphadenopathy. part of any biopsy specimen should always be sent for culture. nucleic acid amplification tests on sputum have sensitivity similar to culture in . % on the th day of icu in a recent study using a multicentre high-quality database and incorporating novel statistical methodology to control evolution of severity of illness. several guidelines for prevention of ventilatorassociated pneumonia and hospital-acquired pneumonia have been published. [ ] [ ] [ ] [ ] [ ] interventions can be divided into general infection control measures and specific measures. general measures include alcoholbased hand disinfection, hospital education programme on infection control, the use of microbiological surveillance and a programme to reduce antibiotic prescription. the major specific recommendations are summarised in table . . there is no evidence that 'bundles' of recommendations are more effective than the sum of the individual components. the main risk factors are listed in box . . typical clinical features include fever, sweating, weight loss, lassitude, anorexia, cough productive of mucoid or purulent sputum, haemoptysis, chest wall pain, dyspnoea, localised wheeze and apical crackles. patients may also present with unresolved pneumonia, pleural effusions, spontaneous pneumothorax and hoarseness , no effect on vap, mainly for staff safety . chlorhexidine oral decontamination , , . sedation vacation and weaning protocol , . judicious use of stress ulcer prophylaxis mortality reduction demonstrated when topical antimicrobials combined with short-course systemic antibiotics, bsac recommended sdd in patients expected to require mechanical ventilation for > hours, etf discourage routine use due to concern of emergence of resistant organisms not yet reviewed by guidelines . high-volume low-pressure ultrathin membrane endotracheal tube cuff with ssd . ultrathin membrane cuff with tapered shape and ssd . low-volume low-pressure endotracheal tube cuff with ssd . balloon device for biofilm removal . saline instillation before tracheal suctioning hme = heat moist exchanger; ssd = subglottic secretion drainage. smear-negative patients with pulmonary tuberculosis but have the advantage of a much more rapid result. there is, however, a significant false-negative rate. a normal cxr almost excludes tb (except in hiv-infected patients) but endobronchial lesions may not be apparent and early apical lesions can be missed. common appearances include patchy/nodular shadowing in the upper zones (often bilateral), cavitation, calcification, hilar or mediastinal lymphadenopathy (may cause segmental or lobar collapse), pleural effusion, tuberculomas (dense round or oval shadows) and diffuse fine nodular shadowing throughout the lung fields in miliary tb. inactivity of disease cannot be inferred from the cxr alone. this requires three negative sputum samples and failure of any lesion seen on cxr to progress. cxr appearances in hiv-positive fit-tested negative-pressure respirator (n , ffp or higher). use of a powered air-purifying respirator should be considered when bronchoscopy is being performed. detailed infection control advice can be obtained via the 'link page' (http://www.aic.cuhk. edu.hk/web /pneumonia% guidelines.htm.). the lungs are amongst the most frequent target organs for infectious complications in the immunocompromised. the incidence of pneumonia is highest amongst patients with haematological malignancies, bone marrow transplant (bmt) recipients and patients with aids. the speed of progression of pneumonia, the cxr changes ( table . ) and the type of immune defect provide clues to the aetiology. bacterial pneumonias progress rapidly ( - days) whereas fungal and protozoal pneumonias are less fulminant (several days to a week or more). viral pneumonias are usually not fulminant, but on occasions may develop quite rapidly. bronchoscopy is a major component of the investigation of these patients. empirical management based on cxr appearances is outlined in table . . early noninvasive ventilation may improve outcome amongst immunocompromised patients with fever and bilateral infiltrates. pneumocystis jiroveci pneumonia (pcp) the incidence of this common opportunistic infection has fallen substantially in patients with aids who are receiving prophylaxis and effective antiretroviral therapy, with most cases occurring in patients who are not receiving hiv care or among patients with advanced immunosuppression. the onset is usually insidious with dry cough, dyspnoea and fever on a background of fatigue and weight loss. crackles in the chest are rare. approximately % of patients have a concurrent cause for respiratory failure (e.g. kaposi sarcoma, tb, bacterial pneumonia). useful investigations are: . cxr: classical appearance is diffuse bilateral perihilar interstitial shadowing, but in the early stages this is very subtle and easily missed. the initial cxr is normal in %. in a further % the changes are atypical with focal consolidation or coarse patchy shadowing. none of the changes are specific for pcp and may be seen in other lung diseases associated with aids. pleural effusions, hilar or mediastinal lymphadenopathy are unusual in pcp but common in mycobacterial infection or kaposi's sarcoma or lymphoma. induced sputum: in this technique the patient inhales nebulised hypertonic saline from an ultrasonic nebuliser. this provokes bronchorrhoea and the patient patients with tb differ from those in non-hiv-infected patients. the decision to initiate anti-tb treatment should be based on level of clinical suspicion, results of afb smear and sometimes mycobacterial culture. if the initial clinical suspicion is strong and the patient is seriously ill attributable to possible tb, treatment should be initiated promptly, sometimes before the result of afb smear. subsequent positivity of afb smear or nucleic acid amplification test provides support to the continuation of treatment. combination chemotherapy consisting of four drugs is necessary for maximal efficacy. treatment is divided into initial phase and continuation phase. the most commonly used initial regimen consists of weeks of rifampicin mg daily ( mg for patients < kg), isoniazid mg daily, pyrazinamide g daily ( . g for patients < kg) and ethambutol mg/kg daily as initial phase treatment. ethambutol should be used only in patients who have reasonable visual acuity and who are able to appreciate and report visual disturbances. this mandates careful consideration in patients who require heavy sedation. visual acuity and colour perception must be assessed (if ethambutol is to be used) and liver and renal function checked before treatment is started. steroids are recommended for children with endobronchial disease and, possibly, for patients with tuberculous pleural effusions. pyridoxine mg daily should be given to prevent isoniazid-induced neuropathy to those at increased risk (e.g. patients with diabetes mellitus, chronic renal failure or malnutrition or alcoholic or hiv-positive patients). negative afb smear should not delay initial treatment if clinical suspicion remains high. supporting features included chronic cough, weight loss, characteristic chest x-ray findings, emigration from a high-incidence country, no other immediate diagnosis, and positive tuberculin test. patients admitted to an icu with infectious tb or suspected of having active pulmonary tb should be managed in an isolation room with special ventilation characteristics, including negative pressure. patients should be considered infectious if they are coughing or undergoing cough-inducing procedures or if they have positive afb smears and they are not on or have just started chemotherapy, or have a poor clinical or bacteriological response to chemotherapy. , patients with non-drug-resistant tb should be non-infectious after weeks of treatment which includes rifampicin and isoniazid. as tb spreads through aerosols it is probably appropriate to isolate patients who are intubated even if only their bronchial washings are smear-positive. staff caring for patients who are smear-positive should wear personal protective equipment including a and/or diuretics (patients often fluid-overloaded). approximately % of patients with hiv-related pcp who require mechanical ventilation survive to hospital discharge. initiation of antiretroviral therapy in patients presenting with hiv-related pcp is controversial. the centers for disease control and prevention (cdc) recommend against doing so in the acute phase, but recent data suggest that the outcome may be improved by initiation within the first days of icu admission. this is the most common cause of acute respiratory failure in hiv-positive patients. bacterial pneumonia is more common in hiv-infected patients than in the general population and tends to be more severe. strep. pneumoniae, h. influenza, pseudomonas aeruginosa and s. aureus are the commonest organisms. nocardia and gram negatives should also be considered. atypical pathogens (e.g. legionella) are rare. response to appropriate antibiotics is usually good but may require protracted courses of antibiotics because of high tendency to relapse. patients with severe immunodeficiency (cd + t lymphocyte count < /µl) and a history of pseudomonas infection or bronchiectasis or neutropenia should receive antibiotics that cover p. aeruginosa as well as other gram negatives. the possibility of concurrent pcp or tuberculosis should be excluded. tb may be the initial presentation of aids, particularly in sub-saharan africa. the pattern of tb in hiv patients coughs up material containing cysts and trophozoites. the technique is time-consuming and requires meticulous technique and is less sensitive than bronchoscopy but less invasive. the possibility of concurrent tuberculosis should be considered and steps taken to minimise the risk of spread of infection. the diagnosis in over % of cases. specimens should be sent for cytology. transbronchial biopsy is not necessary in most cases. pcr using bronchial lavage specimens may be useful in non-hiv patients with suspected pcp. antipneumocystis treatment should be started as soon as the diagnosis is suspected. treatment of choice is trimethoprim plus sulfamethoxazole (co-trimoxazole) mg/kg/day + mg/kg/day for weeks plus prednisolone mg orally twice daily for days followed by mg twice daily for days and then mg per day until the end of pcp treatment. side-effects of co-trimoxazole are common in hiv patients (nausea, vomiting, skin rash, myelotoxicity). the dose should be reduced by % if the wbc count falls. patients who are intolerant of co-trimoxazole should be treated with: • pentamidine mg/kg/day i.v. or • primaquine with clindamycin or • trimetrexate with leucovorin (±oral dapsone). response to treatment is usually excellent, with a response time of - days. if the patient deteriorates or fails to improve: consider (re-)bronchoscopy (is the diagnosis correct?), treat co-pathogens and consider a short course of high-dose i.v. methylprednisolone fungi are rare but important causes of pneumonia. they can be divided into two main groups based on the immune response required to combat infection with these organisms. histoplasma, blastomycosis, coccidioidomycosis, paracoccidioidomycosis and cryptococcus require specific cell-mediated immunity for their control and thus, in contrast to infections that are controlled by phagocytic activity, the diseases caused by these organisms can occur in otherwise healthy individuals although they cause much more severe illness in patients with impaired cell-mediated immunity (e.g. patients infected with hiv and organ transplant recipients). with the exception of cryptococcus these organisms are rarely seen outside north america. aspergillus and mucor spores are killed by non-immune phagocytes and as a result these fungi rarely result in clinical illness in patients with normal neutrophil numbers and function. this is effectively a combination of the two types of fungal infection in which impaired cell-mediated immunity predisposes to mucosal overgrowth with candida but impaired phagocytic function or numbers is usually required before deep invasion of tissues occurs. primary candida pneumonia (i.e. isolated lung infection) is uncommon , and more commonly pulmonary lesions are only one manifestation of disseminated candidiasis. even more common is benign colonisation of the airway with candida. in most reported cases of primary candida pneumonia amphotericin b has been used. in disseminated candidiasis treatment should be directed to treatment of disseminated disease rather than candida pneumonia per se. this is a highly lethal condition in the immunocompromised despite treatment and therefore investigation and treatment should be prompt and aggressive. it is associated with exposure to construction work. definitive diagnosis requires both histological evidence of acute-angle branching, septated non-pigmented hyphae measuring - µm in width, and cultures yielding aspergillus species from biopsy specimens of involved organs. recovery of aspergillus species from respiratory secretions in immunocompromised, but not immunocompetent, patients may indicate invasive disease with a positive predictive value as high as depends on the degree of immunosuppression. in patients with cd + t lymphocytes > cells/µl the clinical presentation is similar to tb in non-hiv-infected patients, although extrapulmonary disease is more common. in patients with cd + t lymphocytes < cells/µl extrapulmonary disease (pleuritis, pericarditis, meningitis) is common. severely immunocompromised patients (cd + t lymphocytes < cells/µl) may present with severe systemic disease with high fever, rapid progression and systemic sepsis. in these patients lower and middle lobe disease is more common, miliary disease is common and cavitation is less common. sputum smears and culture may be positive even with a normal cxr. response to treatment is usually rapid. management of tb in hiv is complex owing to numerous drug interactions; consultation with an expert in treatment of hiv-related tb should be strongly considered. complex interactions occur between rifamycins (e.g. rifampicin and rifabutin) and protease inhibitors and nonnucleoside reverse transcriptase inhibitors used to treat patients infected with hiv. the choice of rifampicin or rifabutin depends on a number of factors including the unique and synergistic adverse effects for each individual combination of rifampicin and anti-hiv drugs, and consultation with a physician with experience in treating both tb and hiv is advised. idsarecommended dosage adjustment for patients receiving antiretrovirals and rifabutin can be obtained via the 'link page' (http://www.aic.cuhk.edu.hk/web / pneumonia% guidelines.htm.). the optimal time for initiating antiretroviral therapy in patients with tb is controversial. early therapy may decrease hiv disease progression but may be associated with a high incidence of adverse effects and an immune reconstitution reaction. cmv pneumonitis , risk of infection is highest following allogeneic stem cell transplantation, followed by lung transplantation, pancreas transplantation and then liver, heart and renal transplantation and advanced aids. if both the recipient and the donor are seronegative then the risk of both infection and disease are negligible. if the recipient is seropositive the risk of infection is approximately % but the risk of disease is only %, regardless of the serostatus of the donor. however if the recipient is seronegative and the donor is seropositive the risk of disease is %. if steroid pulses and antilymphocyte globulin are given for treatment of acute rejection the risk of developing disease is markedly increased. infection may be the result of primary infection or reactivation of latent infection. it is clinically important, but often difficult to distinguish between cmv infection and cmv disease and a definitive diagnosis can be made only histologically. detection of cmv-pp antigen in peripheral wbc and detection of cmv dna or rna in the blood by quantitative polymerase chain needle aspiration or, if there is debris within the fluid, drainage using an intercostal drain. the diagnosis is confirmed by aspiration of pus. the mainstay of treatment is drainage either by intercostal drain or by surgical intervention. patients who present before the pus is loculated and a fibrinous peel has formed on the lung can usually be treated by simple drainage. the combination with intrapleural fibrinolysis may be beneficial. optimal surgical management, which consists of decortication (open or thoracoscopic), is indicated if the empyema is more advanced or if simple drainage fails. this is a major procedure and many patients with cardiac or chronic respiratory disease will not tolerate it. alternatives for these patients are instillation of thrombolytics into the pleural space or thoracostomy. antibiotics have only an adjunctive role. broad-spectrum antibiotic regimens with anaerobic cover should be used until the results of microbiological analysis of the aspirated pus are available. all tables and figures are reproduced from icu web (www.aic.cuhk.edu.hk/web ) with permission of the authors. - % in patients with leukaemia or bone marrow transplant recipients. bronchoalveolar lavage with smear, culture and antigen detection has excellent specificity and reasonably good positive predictive value for invasive aspergillosis in immunocompromised patients. although radiological features may give a clue to the diagnosis they are not sufficiently specific to be diagnostic. in acutely ill immunocompromised patients intravenous therapy should be initiated if there is suggestive evidence of invasive aspergillosis while further investigations to confirm or refute the diagnosis are carried out. first-line therapy is voriconazole. echinocandins and amphotericin are alternatives. this may be an uncomplicated effusion that resolves with appropriate treatment of the underlying pneumonia or a complicated effusion that develops into an empyema unless drained. complicated effusions tend to develop - days after initial fluid formation. they are characterised by increasing pleural fluid volume, continued fever and pleural fluid of low ph (< . ) that contains a large number of neutrophils and may reveal organisms on gram staining or culture. an outline of management is given in figure . . collection of pus in the pleural space. follows infection of the structures surrounding the pleural space, including subdiaphragmatic structures, and chest trauma, or may be associated with malignancy. anaerobic bacteria, usually streptococci or gram-negative rods, are responsible for % of cases. the diagnosis is usually simple. the patient is usually septic and may have a productive cough and chest pain. the chest x-ray may show features suggestive of a pleural effusion and underlying consolidation but may also show an abscess cavity with a fluid level, in which case ct scanning will be required to distinguish between an abscess and an empyema. ultrasound can be useful to confirm the presence of fluid in the pleural space and to determine whether it can be drained by guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare associated pneumonia infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults pneumonia guidelines committee of the bts standards of care committee. british thoracic society guidelines for the management of community acquired pneumonia in adults: update management of communityacquired pneumonia in adults cdc, and infectious diseases society of america. treatment of tuberculosis the standardization of bronchoscopic techniques for ventilator-associated pneumonia new issues and controversies in the prevention of ventilator-associated pneumonia guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare associated pneumonia infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults pneumonia guidelines committee of the bts standards of care committee. british thoracic society guidelines for the management of community acquired pneumonia in adults: update guidelines for the management of adult lower respiratory tract infections update in community-acquired and nosocomial pneumonia value of intensive diagnostic microbiological investigation in low-and high-risk patients with community-acquired pneumonia nucleic acid amplification tests for the diagnosis of pneumonia interpreting assays for the detection of streptococcus pneumonia severity of pneumococcal pneumonia associated with genomic bacterial load polymerase chain reaction for diagnosing pneumocystis pneumonia in non-hiv immunocompromised patients with pulmonary infiltrates early mortality in patients with community-acquired pneumonia: causes and risk factors surviving sepsis campaign guidelines for management of severe sepsis and septic shock antibiotics for bacteremic pneumonia: improved outcomes with macrolides but not fluoroquinolones high-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm an esicm systematic review and meta-analysis of procalcitonin-guided antibiotic therapy algorithms in adult critically ill patients management of communityacquired pneumonia in adults avian influenza (h n ): implications for intensive care clinical characteristics and -day outcomes for influenza a (h n ) complications and outcomes of pandemic influenza a (h n ) virus infection in hospitalized adults: how do they differ from those in seasonal influenza? corticosteroid treatment in critically ill patients with pandemic influenza a/h n infection analytic strategy using propensity scores bacterial coinfections in lung tissue specimens from fatal cases of pandemic influenza a (h n ) -united states clinical and economic consequences of ventilator-associated pneumonia: a systematic review invasive approaches to the diagnosis of ventilator-associated pneumonia: a meta-analysis ventilator-associated pneumonia and mortality: a systematic review of observational studies attributable mortality of ventilator-associated pneumonia. a reappraisal using causal analysis guidelines for preventing health-careassociated pneumonia . recommendations of cdc and the healthcare infection control practices advisory committee shea/idsa practice recommendation. strategies to prevent ventilator-associated pneumonia in acute care hospitals guidelines for the management of hospital-acquired pneumonia in the uk: report of the working party on hospital-acquired pneumonia of the british society for antimicrobial chemotherapy vap guidelines committee and the canadian critical care trials group. comprehensive evidencebased clinical practice guidelines for ventilatorassociated pneumonia: prevention defining, treating and preventing hospital acquired pneumonia: european perspective active tuberculosis in the medical intensive care unit: a -year retrospective analysis national collaborating centre for chronic conditions. tuberculosis. clinical diagnosis and management of tuberculosis and measures for its prevention and control management of tuberculosis in the united states cdc, and infectious diseases society of america. treatment of tuberculosis guidelines for preventing the transmission of mycobacterium tuberculosis in health-care settings noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure treating opportunistic infections among hiv-infected adults and adolescents: recommendations from cdc, the national institutes of health, and the hiv medicine association/infectious diseases society of america improvements in outcomes of acute respiratory failure for patients with human immunodeficiency virusrelated pneumocystis carinii pneumonia centers for disease control. updated guidelines for the use of rifabutin or rifampicin for the treatment and prevention of tuberculosis among hiv-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors the lung in the immunocompromised patient management of cytomegalovirus infection and disease after solid-organ transplantation area under the viraemia curve versus absolute viral load: utility for predicting symptomatic cytomegalovirus infections in kidney transplant patients cytomegalovirus infection in organ-transplant recipients: diagnostic value of pp antigen test, qualitative polymerase chain reaction (pcr) and quantitative taqman pcr guidelines for treatment of candidiasis practice guidelines for diseases caused by aspergillus voriconazole versus amphotericin b for primary therapy of invasive aspergillosis the pleural cavity the standardization of bronchoscopic techniques for ventilator-associated pneumonia new issues and controversies in the prevention of ventilator-associated pneumonia key: cord- -ouwwkxox authors: stevens, jennifer p.; howell, michael d. title: ventilator-associated pneumonia and other complications date: - - journal: evidence-based critical care doi: . / - - - - _ sha: doc_id: cord_uid: ouwwkxox ventilator-associated pneumonia occurs in patients who have been intubated for two to three days with significant exposure to hospital-acquired organisms. treatment should be initiated rapidly and cover p. aeruginosa, escheriochia coli, klebsiella pneumonia, and acinetobacter species as well as methicillin-resistant s. aureus. within h or with the availability of culture results, antibiotics should be narrowed. active research is on-going to identify patients at risk for ventilator-associated complications and to minimize the likelihood of infection in these patients. a -year-old woman with a history of type diabetes mellitus, chronic obstructive pulmonary disease, obesity hypoventilation syndrome, and sleep apnea, along with coronary artery disease with a -vessel bypass five years prior, developed new onset shortness of breath and fever after babysitting her -year-old grandchild. she arrived at the emergency room with worsening respiratory status. her ventilation rapidly deteriorated despite the use of noninvasive positive pressure ventilation and she became minimally responsive, prompting endotracheal intubation and admission to the medical intensive care unit. a chest x-ray at that time showed a lobar infiltrate. cultures from endotracheal aspirates were negative. after three days of management of her copd with intravenous steroids, antibiotic coverage with levofloxacin, and inhaled bronchodilator therapy, her oxygenation continued to improve. she continued to fail her spontaneous breathing trial, however, and remained intubated. on icu day , however, she developed a new fever and her oxygenation worsened. having previously been down to an fio of . , this fraction was increased to . , and her peep was increased to cm from cm of water to maintain adequate oxygenation. a chest xray now shows diffuse, bilateral infiltrates ( fig. . ). answer ventilator-associated pneumonia (vap) despite aggressive and supportive management, pneumonias that arise from hospital settings remain a challenging and enduring clinical entity. ventilatorassociated pneumonia is defined as pneumonia in those patients who have been intubated for at least two to three days, with worsening radiographic features, increasing secretions, bronchospasm, or hemoptysis, or with worsening status on the ventilator. while early treatment is essential, rapid de-escalation of antibiotics in the face of negative culture results is also important. sampling of the respiratory tract is necessary to further guide management and noninvasive sampling is preferred [ ]. samples may be obtained either through tracheobronchial aspiration, bronchoalveolar lavage, mini-bal, or protected specimen brush (psb). careful observation of individual hospitals' bacterial antibiogram is essential to provide treatment targeted to the resistance profile of each institution. the most common mdr pathogens include p. aeruginosa, escheriochia coli, klebsiella pneumonia, and acinetobacter species as well as methicillin-resistant s. aureus [ ]. a high suspicion for vap followed by rapid diagnosis and treatment is critically important. zilberberg and colleagues found that among nearly patients alive at h with hcap, inappropriate empiric antibiotic therapy was associated with a significant increase in mortality ( % versus . %, p = . ; or . % ci . - . in multivariable logistic regression). treatment escalation did not change the risk of death in this single-center study [ ] . unfortunately, treatment is often delayed. in one study among patients, . % of patients had their therapy for vap inappropriately delayed, defined as ≥ h passing between vap onset and providing the appropriate antimicrobial treatment. a delay in writing the antibiotic orders was the primary reason for delay in therapy in % of cases [ ]. patients with vap should universally initiated on therapy for ( ) mrsa (for example, with vancomycin or linezolid) and for ( ) resistant gramnegatives, such as pseudomonas aeruginosa, klebsiella pneumoniase, and acinetobacter spe-cies. treatment options could include: antipseudomonal cephalosporins (cefepime or ceftazidime), antipseudomonal carbapenems (imipenem or meropenem), β-lactam/β-lactamase inhibitor (piperacillin-tazobactam). for patients for whom combination therapy is considered (see evidence contour below), addition of an antipseudomonal flouroquinolone or an aminoglycoside should be considered. the dominant pathogens in one's local icu should also contribute to decision making for appropriate choices of therapy but should be guided by the overall principles of the ats/idsa guidelines, as demonstrated by the impact hap collaboration [ , ] . in addition to mdr risk factors, appropriate antimicrobial therapy should consider the patient's risk factors for: ( ) extended-spectrum beta-lactamase-producing enterobactereriaceae; ( ) legionella; and ( ) anaerobes. if esbl enterobactereiaceae is suspected, a carbapenem should be used. concerns about legionella should prompt use of a macrolide or fluroquinolone over an aminoglycoside. some providers would treat patients with recent aspiration events for anaerobes, using clindamycin, β-lactam/β-lactamase inhibitors, or a carbapenem. for all other patients for whom the suspicion of vap is low, appropriate therapy should be guided by the patient's risk factors for multidrug resistant organisms. in the absence of risk factors for mdr organisms, the ats/idsa guidelines recommend antibiotic therapy that targets streptococcus pneumonia, haemophilus influenza, methicillin-sensitive staphylococcus aureus, and antibiotic-sensitive enteric gram negatives: ceftriaxone or levofloxacin, moxifloxacin, or ciprofloxacin, ampicillin/sulbactam or ertapenem [ ]. while not all patients with hcap have mdr organisms, distinguishing between the two may be difficult with recent residence in a nursing home or hospitalization for more than h in the past months appearing to increase the patient's risk the most [ , ]. patients with ventilator-associated pneumonia should have the duration of antimicrobial therapy guided by type of organism. in a study of patients using a randomized controlled design, there was no difference in mortality in the arm treated for days versus days, although patients with pseudomonas spp. had higher rates of recurrence [ ] . a subsequent meta-analysis demonstrated patients with lactose nonfermenting gram-negative bacilli had nearly a -fold increased odds of recurrence with shorter therapy courses [ ] . however, more recent systematic reviews and the ats/idsa guideline [ ] has challenged this distinction. the current recommendation for all vap, including non-fermenting gram-negative bacilli, is to treat for a short course ( or days) [ ] . it is critical to de-escalate antimicrobial therapy when a specific pathogen has been identified, or when cultures are negative at around h. this helps prevent over-use of antibiotics and the development of resistance. observational data provide a strong safety signal. in a study of surgical patients, neither mortality ( % versus %) nor recurrent pneumonias ( % versus %) differed between patients with vap who underwent de-escalation versus those who did not [ ] . among patients with vap in kollef et al., deescalation of therapy occurred for % of patients. these patients had a lower mortality rate ( %) than those patients who underwent escalation ( %) or who had not change to their regimens ( %) [ ] . another possible guide to safely de-escalate antibiotic therapy may be procalcitonin levels. in subgroup analyses of the prorata trial, investigators found that patients with ventilatorassociated pneumonia assigned to the study arm (where antibiotics were discontinued after procalcitonin levels reached < . μg) had . fewer days ( % ci . days - . days) than those patients assigned to the control arm, without a difference in mortality found in the overall study [ ] . other studies that have looked at procalcitonin to guide therapy for undifferentiated septic shock or in broader settings have replicated that mortality does not appear to be affected when procalcitonin is used to guide therapy, although the findings on duration of antibiotics is more heterogeneous [ , ] . current recommendations, however, are to continue to use clinical evidence rather than biomarkers [ ]. not all fevers are pneumonia, even in icu patients with radiographic infiltrates. if patients are not improving at - h and respiratory cultures taken before antibiotics are negative, be vigilant for other causes of fever (such as central line infections, etc.) and for complications of pneumonia (such as empyema). this scenario should also prompt reconsideration of the potential presence of resistant pathogens, and it may warrant consultation with infectious disease specialists. in all patients with suspected vap, obtain an endotracheal aspirate for culture at minimum. whether to pursue bronchoscopic sampling (or other invasive techniques) is more controversial. endotracheal aspirates are very sensitive -a negative result is quite helpful because it has a high negative predictive value. positive results can be harder to interpret. in one study, in episodes of pneumonia, endotracheal aspirate was found to have a sensitivity of . % and specificity of % as compared with protected brush specimen [ ] . other studies have employed the clinical pulmonary infection score (cpis) with a cut-off of as a noninvasive method of identifying patients with vap, using autopsy findings of pneumonia as the gold standard (table . ) [ ] . fabregas et al. found a score of greater than had a sensitivity of % but a specificity of % [ ] . conversely, bronchoscopic sampling may be less sensitive but is more specific for pneumonia. randomized controlled trials are mixed. an rct of patients found no benefit to invasive sampling in unadjusted analyses, but did after adjustment for baseline factors [ ] . a more recent rct of patients found no benefit to bronchoalveolar lavage over endotracheal aspirate [ ] . our practice is to perform immediate endotracheal aspirate in all patients with suspected vap, but to reserve bronchoalveolar lavage or protected brush for selected cases. the current recommendation from the ats/idsa is for coverage with either ( ) mg/kg of vanco-mycin every h with a target serum trough between and mg/kg or ( ) mg of linezolid. one major prospective trial of patients, however suggested that linezolid may be superior to vancomycin. in this study, % of patients treated with vancomycin had cultures persistently positive for mrsa, while only % of patients treated with linezolid did. at days, however, there was no difference in mortality rates, although nephrotoxicity did occur at greater rates with vancomycin [ ] . as research in this space continues to evolve, linezolid may be a particularly good option among patients with renal failure, although current guidelines suggest either therapy for treatment. coverage with a second agent for gram-negative bacilli may be warranted based on local microbiologic patterns and was recommended by the recommendations for vap treatment by the ats/idsa [ ]. current recommendations from the update are to prescribe antipseudomonal antibiotics when patients have risk factors for antimicrobial resistance, when the prevalence of gram-negative isolates resistant to the proposed monotherapeutic agent exceds %, and when antimicrobial susceptibaility rates are unavailable [ ]. however, it is worth noting that synergy of medications has only been demonstrated in vitro and in neutropenic or bacteremic patients and one randomized controlled trial did not demonstrate differences in clinical outcomes between monotherapy and combination therapy groups [ , , ]. an observational cohort study in lancet suggested combination therapy may be harmful, as the cohort of patients with ats/ idsa-compliant antimicrobial therapy had a higher risk of death at days than the noncompliant group [ ] . this remains controversial, whether these individuals were at higher risk of death from the medications, the infections, or misidentification of them as at higher risk for mdr infection. further research will be necessary to identify who, if anyone, should be receiving such broad antibiotic coverage from the outset. the score may be calculated as a noninvasive method of determining whether a patient is a low-risk for pneumonia. a score of more than has a % sensitivity and % specificity to identify vap [ ] while clinical suspicion and identification of ventilator-associated pneumonia should remain high, significant controversy has revolved around establishing a reliable epidemiological surveillance definition. prior to january the centers for disease control's surveillance reporting definition the included several subjective components, including the change in the "character of sputum" and in radiographs [ ] [ ] [ ] [ ] [ ] . as a result, several studies identified little agreement either across infection control experts at a single institution [ ] or across multiple institutions [ ] . other definitions that sought to identify episodes of vap either through greater invasive strategies or through other scoring mechanisms fared equally poorly [ ] . in response, an effort of many professional societies and the cdc generated an alternative approach with the creation of the entity ventilator associated event (vae) [ ] . intended to cast a broader net, this newly-defined condition is intended to identify the majority of iatrogenic harm from mechanical ventilation, including but not limited to pneumonia [ , ] . further, it is designed to be reliable as it is solely based on any changes made to the ventilator that would indicate worsening oxygenation after a period of stability and at least three days into the course of mechanical ventilation. review of radiology has been removed from the definition. there are subsequent sub-categories of harm, including probably or possible pneumonia, which are based on antibiotic changes and evidence of positive qualitative or quantitative cultures. (table . ) [ ] . while several studies have shown that this definition does lead to a reliable identification of individuals at higher risk of in-hospital mortality, it remains unclear the breadth of true disease states captured by definition [ , ] . lilly and colleagues found that the new vae definition captured neither pneumonias nor hospital-acquired complications % of the time [ ] . in contrast, boudma and colleagues found ventilator-associated condition to be reasonably sensitive at identifying episodes of vap ( . ) but not specific ( . ) [ ] . further, adult respiratory distress syndrome is likely to be captured alongside vap under the larger label of vae [ , ] . the first major intervention study to date designed to attempt to reduce rates of vae demonstrated found spontaneous awakening trials and spontaneous breathing trials a patient must be intubated with stable ventilator settings for or more days before this may be applied to be effective [ ] . however, this remains a significant area of evolving science. other modifiable risk factors for patients with vap should be considered, in an effort to minimize the likelihood of developing vap at the outset. these were described in a recent update on preventing ventilator associated pneumonia by the society for healthcare epidemiology of america (shea) and the infectious disease society of america (idsa) and are summarized in table . [ ] . recommendation level of recommendation minimizing sedation and assessing readiness to extubate daily through pairing spontaneous breathing trials and spontaneous awakening trials, which have been shown in two randomized control trials and one meta-analysis to reduce length of stay and duration of mechanical ventilation [ ] [ ] [ ] [ ] high instituting early mobilization and physical therapy, which has been shown to decrease length of stay and improve earlier return to independent function [ ] moderate implementing strategies to reduce pooling of secretions above the endotracheal tube cuff, such as using endotracheal tubes with subglottic suctioning for patients requiring mechanical ventilation of h or more [ ] [ ] [ ] . a meta-analysis demonstrated reduction in vap rates and length of mechanical ventilation [ ] moderate changing ventilator circuits only when needed rather than on a schedule, which does little to decrease vaps but does reduce costs [ ] high making use of noninvasive positive pressure ventilation (nippv) whenever possible, but only in the populations which have been shown to have some benefit (e.g. in chronic obstructive pulmonary disease or cardiogenic pulmonary edema) [ ] . this recommendation, however, cautions use of nippv that may delay intubation, such as profound hypoxemia, acute respiratory distress syndrome or impaired consciousness [ ] high keeping the head of the bed elevated to at least °, which has only been shown to decrease vap rates in one of three randomized control trials, but has little downside [ ] [ ] [ ] low emergency department stratifying risk factors for multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia comparison of vs days of antibiotic therapy for ventilatorassociated pneumonia in adults: a randomized trial shortcourse versus prolonged-course antibiotic therapy for hospital-acquired pneumonia in critically ill adults short-vs long-duration antibiotic regimens for ventilator-associated pneumonia: a systematic review and meta-analysis does deescalation of antibiotic therapy for ventilatorassociated pneumonia affect the likelihood of recurrent pneumonia or mortality in critically ill surgical patients? clinical characteristics and treatment patterns among patients with ventilator-associated pneumonia use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms procalcitonin algorithm in critically ill adults with undifferentiated infection or suspected sepsis. a randomized controlled trial tracheal aspirate correlates with protected specimen brush in long-term ventilated patients who have clinical pneumonia short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. a proposed solution for indiscriminate antibiotic prescription clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies invasive and noninvasive strategies for management of suspected ventilator-associated pneumonia. a randomized trial the canadian critical care trials group. a randomized trial of diagnostic techniques for ventilator-associated pneumonia linezolid in methicillin-resistant staphylococcus aureus nosocomial pneumonia: a randomized, controlled study antibiotic therapy for pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of patients canadian critical care trials g. randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia implementation of guidelines for management of possible multidrugresistant pneumonia in intensive care: an observational, multicentre cohort study does this patient have ventilator-associated pneumonia? ventilator-associated pneumonia: is zero possible? the paradox of ventilator-associated pneumonia prevention measures eight initiatives that misleadingly lower ventilator-associated pneumonia rates ventilator-associated pneumonia (vap) event. ; pneu definitions from cdc interobserver variability in ventilatorassociated pneumonia surveillance when policy gets it right: variability in u.s. hospitals' diagnosis of ventilator-associated pneumonia* alternative case definitions of ventilator-associated pneumonia identify different patients in a surgical intensive care unit improving surveillance for ventilator-associated events in adults ventilator-associated conditions versus ventilator-associated pneumonia: different by design strategies to prevent ventilator-associated pneumonia in acute care hospitals: update automated surveillance for ventilator-associated events descriptive epidemiology and attributable morbidity of ventilatorassociated events prevalence and test characteristics of national health safety network ventilator-associated events ventilator-associated events: prevalence, outcome, and relationship with ventilator-associated pneumonia improving ventilator-associated event surveillance in the national healthcare safety network and addressing knowledge gaps: update and review the preventability of ventilator-associated events. the cdc prevention epicenters wake up and breathe collaborative daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized controlled trial efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (awakening and breathing controlled trial): a randomised controlled trial effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously a comparison of four methods of weaning patients from mechanical ventilation. spanish lung failure collaborative group early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial intermittent subglottic secretion drainage and ventilatorassociated pneumonia: a multicenter trial continuous subglottic suctioning for the prevention of ventilator-associated pneumonia : potential economic implications is continuous subglottic suctioning cost-effective for the prevention of ventilator-associated pneumonia? subglottic secretion drainage for the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis prospective study of nosocomial pneumonia and of patient and circuit colonization during mechanical ventilation with circuit changes every hours versus no change noninvasive positive-pressure ventilation and ventilator-associated pneumonia complications of non-invasive ventilation techniques: a comprehensive qualitative review of randomized trials supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study reducing the risk of ventilator-acquired pneumonia through head of bed elevation key: cord- -n vxazst authors: papazian, laurent; klompas, michael; luyt, charles-edouard title: ventilator-associated pneumonia in adults: a narrative review date: - - journal: intensive care med doi: . /s - - - sha: doc_id: cord_uid: n vxazst ventilator-associated pneumonia (vap) is one of the most frequent icu-acquired infections. reported incidences vary widely from to % depending on the setting and diagnostic criteria. vap is associated with prolonged duration of mechanical ventilation and icu stay. the estimated attributable mortality of vap is around %, with higher mortality rates in surgical icu patients and in patients with mid-range severity scores at admission. microbiological confirmation of infection is strongly encouraged. which sampling method to use is still a matter of controversy. emerging microbiological tools will likely modify our routine approach to diagnosing and treating vap in the next future. prevention of vap is based on minimizing the exposure to mechanical ventilation and encouraging early liberation. bundles that combine multiple prevention strategies may improve outcomes, but large randomized trials are needed to confirm this. treatment should be limited to days in the vast majority of the cases. patients should be reassessed daily to confirm ongoing suspicion of disease, antibiotics should be narrowed as soon as antibiotic susceptibility results are available, and clinicians should consider stopping antibiotics if cultures are negative. ventilator-associated pneumonia (vap) is defined by infection of the pulmonary parenchyma in patients exposed to invasive mechanical ventilation for at least h and is part of icu-acquired pneumonia. vap remains one of the most common infections in patients requiring invasive mechanical ventilation. despite recent advances in microbiological tools, the epidemiology and diagnostic criteria for vap are still controversial, complicating the interpretation of treatment, prevention, and outcomes studies. vap imposes a significant economic burden. a recent cost evaluation from the usa estimated that the attributable cost of vap to be $ , ( % ci $ , -$ , ) [ ] . we will focus this review on current understanding of the epidemiology, diagnosis, prevention, and treatment of ventilator-associated pneumonia. other conditions such as ventilator-associated tracheobronchitis are not detailed. incidence vap is reported to affect - % of patients receiving invasive mechanical ventilation for more than days, with large variations depending upon the country, icu type, and criteria used to identify vap [ ] [ ] [ ] . vap rates in north american hospitals have been reported to be as low as - . cases per ventilator-days [ ] . european centers, however, report much higher rates. the eu-vap/cap study, for example, reported an incidence density of . vap episodes per ventilator-days [ ] . lower-middle-income countries also report higher rates compared to us hospitals and highincome countries in particular ( . vs . per ventilator-days; p = . ) [ ] . these large discrepancies are at least in part explained by differences in definitions, differences in how definitions are applied, diagnostic limitations of all definitions, and differences in microbiological sampling methods [ ] . the daily risk of vap peaks between days - of mechanical ventilation, whereas the cumulative incidence is closely related to total duration of mechanical ventilation [ , ] . the centers for disease control and prevention's national healthcare safety network (nhsn) has reported large decreases in the incidence of vap for both medical and surgical icus over the past years [ ] . these results were not confirmed, however, by an analysis using a stable definition for vap conducted by the medicare patient safety monitoring system (mpsms) from through [ ] . the incidence of vap was roughly % throughout the study period in a selected population of patients of at least years with principal diagnoses of acute myocardial infarction, heart failure, pneumonia, and selected major surgical procedures [ ] . these discrepancies suggest the possibility of variations in how surveillance criteria are applied and support the use of more objective surveillance parameters [ ] . comprehensive research to identify novel diagnostic biomarkers could be of interest in this context. incidence rates greatly vary based on the studied population. for example, vap rates as high as . / ventilator-days have been reported in cancer patients [ ] . a high incidence is also reported in trauma patients ( . % in one series of patients) [ ] , explained at least in part by the alteration of immune function after major traumatic injury, aspiration resulting from brain injury and lung contusion [ ] . the increased incidence observed in chronic obstructive pulmonary disease (copd) patients might be explained by prolonged duration of invasive mechanical ventilation (muscular weakness), high incidence of microaspiration and bacterial colonization (defective mucociliary clearance), and altered local and general host defense mechanisms [ ] . acute respiratory distress syndrome (ards) is also associated with a high risk of vap. even with the use of lungprotective strategies, incidence as high as % has been reported [ ] among ards patients in general and % in patients receiving extra-corporeal membrane oxygenation (ecmo) [ ] . age does not appear to be particularly associated with risk of pneumonia in ventilated patients. a secondary analysis of a european cohort study [ ] reported . vaps per ventilation days in middle-aged ( - years) patients, . in old patients ( - years) , and . in very old patients (≥ years). logistic regression analysis was unable to identify a higher risk of vap among elderly patients [ ] . in contrast, male gender is generally recognized as an independent risk factor for vap [ ] . the most important risk factor for vap, however, is likely the underlying medical conditions of mechanically ventilated patients including their comorbidities and severity of illness. accounting for difference in patient populations and vap definitions is crucial for the implementation of suitable surveillance programs, analyzing differences in vap rates between different icus, and evaluating potential therapeutic approaches, and prevention strategies. the systematic use of incidence density as a parameter to evaluate vap epidemiology would also be helpful to reach these latter objectives. although all-cause mortality associated with vap has been reported to be as high as %, there is still considerable controversy regarding the extent to which vap contributes to death in icu patients. in contrast, vap has been consistently associated with prolonging duration of both mechanical ventilation and icu stay. different methods have been used to evaluate the attributable mortality of vap. observational cohort studies done in the nineties reported conflicting results [ , ] . however, these studies included heterogenous populations and were not prospective [ ] . as the risk of acquiring vap is not constant throughout the duration of mechanical ventilation (the risk is higher during the first days), there is a risk of bias due to icu mortality and discharge acting as competing endpoints (the sickest patients may have very short lengths of stay because of early death). more sophisticated statistical approaches have therefore been used, such as multistate and competing risks models, to estimate the attributable mortality of vap. a competing risk survival analysis, treating icu discharge as a competing risk of icu mortality among patients treated in french icus, reported that the icu mortality attributable to vap was very low, about % on day and . % on day [ ] . in ards patients, crude mortality rates of up to . % have been reported in patients with vap versus . % in patients without vap (p = . ) [ ] . however, after adjusting for confounding factors, vap was no longer associated with icu death [ ] . even after using a multistate approach controlling for the same risk factors, the occurrence of a bacterial vap was not associated with the risk of icu death [ ] . this is consistent with recent reports in cancer patients [ ] and in traumatic brain injury patients [ ] , in which vap was not associated with death. another approach to limit the risk of biases related to the presence of confounding factors is to use randomized-controlled trials evaluating the preventive effects on vap and mortality. based on aggregate data from randomized studies on vap prevention, the estimated attributable mortality rate of vap was % [ ] . a similar approach using individual patient data for meta-analysis, including patients from vap prevention trials, estimated an attributable mortality of %, with higher mortality rates in surgical icu patients and in patients with mid-range severity scores at admission (i.e., acute physiology and chronic health evaluation scores [apache ] - and simplified acute physiology score [saps ] scores of - [ ] in contrast, attributable mortality was close to zero in trauma patients, medical patients, and patients with low or high severity of illness scores [ ] . antimicrobial resistant pathogens may increase the mortality rates associated with vap although this is controversial [ , ] }. in summary, vap is associated with prolonged duration of mechanical ventilation and prolonged icu stay, whereas mortality is mainly driven by patients' underlying conditions and illness severity. future studies should focus on more homogeneous groups of patients in order to better elucidate the differential contributions of underlying disease, type, and number of organ failures and pathogen identity and resistance profile to the risk of death associated with vap. the organisms associated with vap vary according to many factors including duration of mechanical ventilation, length of hospital and icu stays before vaps, timing and cumulative exposure to antimicrobials, the local ecology, and the occurrence of any potential epidemic phenomena in a given icu. usual gram-negative microorganisms involved in vap are pseudomonas aeruginosa, escherichia coli, klebsiella pneumoniae, and acinetobacter species; staphylococcus aureus is the major gram-positive microorganism [ ] [ ] [ ] [ ] [ ] [ ] . it is generally recognized that early-onset vap (within the first days of hospitalization) in previously healthy patients not receiving antibiotics usually involves normal oropharyngeal flora, whereas late-onset vap (occurring after at least days of hospitalization) and vap in patients with risk factors for multidrug resistant (mdr) pathogens are more likely to be due to mdr pathogens [ ] . however, mdr pathogens may be isolated in early-onset vap, mainly in the presence of certain risk factors such as antimicrobial exposure within the preceding days [ ] [ ] [ ] . some reports have found comparable rates of mdr pathogens in patients with early-versus late-onset vap [ , , ] . other risk factors for mdr pathogens generally recognized include prior colonization or infection with mdr pathogens, ards preceding vap, acute renal replacement therapy prior to vap, and the presence of septic shock at time of vap [ ] . the recent international guidelines of the european respiratory society, european society of intensive care medicine, european society of clinical microbiology and infectious diseases and asociación latinoamericana del tórax suggested that additional risk factors should be taken into account such as high local rates of mdr pathogens, recent prolonged hospital stay (> days of hospitalization) and previous colonization with mdr pathogens [ ] . resistance to third-and fourth-generation cephalosporins in enterobacteriaceae strains due to the expression of acquired extended-spectrum β-lactamases (esbls) and/ or ampc β-lactamases is a major worry [ ] . the spread of carbapenemase-producing strains is also a growing concern. mdr isolates of pseudomonas aeruginosa are increasingly prevalent [ ] ; one-half to two-thirds of acinetobacter baumannii strains causing vap are currently carbapenem-resistant [ ] . colistin resistance has increased following rising rates of colistin consumption to treat extensively drug-resistant (xdr) organisms [ ] . vap may be caused by multiple pathogens which can complicate the therapeutic approach [ , , ] . fungi rarely cause vap [ ] . candida spp. is the most common yeast isolated in respiratory samples [ ] . colonization of the lower respiratory tract by candida spp. affects up to % of mechanically ventilated patients and could be associated with an increased risk of bacterial vap, most notably caused by pseudomonas aeruginosa [ ] . however, available data do not support a direct role of candida spp. as a vap-causative pathogen [ ] . in a recent report, the relationship between candida spp. colonization and bacterial vap was prospectively evaluated in patients presenting with multiple organ failure [ ] . whereas patients ( . %) had tracheal colonization with candida spp., no association with bacterial vap was found [ ] . aspergillus spp. (mainly aspergillus fumigatus) may be involved in some late-onset vap, particularly in patients with a recent history of influenza [ ] . a recently proposed clinical algorithm assessed the relevance of positive cultures and might be helpful for clinicians to decide whether to treat or not [ ] . finally, respiratory viruses including influenza, respiratory syncytial virus, and others may be responsible for vap [ ] [ ] [ ] [ ] . the herpesviridae herpes simplex virus (hsv) and cytomegalovirus (cmv) can cause viral reactivation pneumonia in immunocompromised and nonimmunocompromised mechanically ventilated patients. histopathological evidence of hsv bronchopneumonitis has been reported in up to % of mechanically ventilated patients with worsening respiratory status [ ] . cmv reactivation is observed in - % of critically ill patients, especially in those with multi-organ failure and prolonged icu stays [ , ] . histologically proven cmv pneumonia has been reported in ards patients with persistent clinical deterioration and negative bronchoalveolar lavage bacterial culture [ ] [ ] [ ] [ ] . other viruses have been identified in mechanically ventilated patients, but their pathogenicity needs to be confirmed [ , ] . vap diagnosis is traditionally defined by the concomitant presence of the three following criteria: clinical suspicion, new or progressive and persistent radiographic infiltrates, and positive microbiological cultures from lower respiratory tract specimens [ , , , ] . the first step to diagnose vap is clinical suspicion. many criteria for suspecting vap exist (fever, leukocytosis, decline in oxygenation…), but their usefulness, alone or in combination, is not sufficient to diagnose vap [ ] . scores have been proposed to help improve diagnostic accuracy, the most used being the clinical pulmonary infection score (cpis) developed by pugin et al. [ ] : the original description of this score is based on variables (temperature, blood leukocytes, tracheal secretions aspect, oxygenation, radiographic infiltrates, and semiquantitative cultures of tracheal aspirates with gram stain), and patients with a score above are at risk of having vap. one randomized study found that using cpis to determine when to stop antibiotics led to less antibiotic consumption compared to a clinical strategy of fixed durations of antibiotics [ ] . however, using cpis to determine when to start antibiotics may be associated with undue antibiotic use due to its low specificity, particularly as compared to obtaining lower respiratory tract specimens for culture [ ] . therefore, recent guidelines do not recommend cpis to diagnose vap [ , ] . vap should rather be suspected in patients with clinical signs of infection, such as at least two of the following criteria: new onset of fever, purulent endotracheal secretions, leukocytosis or leucopenia, increase in minute ventilation, decline in oxygenation, and/or increased need for vasopressors to maintain blood pressure. these signs are not specific for vap, however, and can often be observed in the many conditions that mimic vap (e.g., pulmonary edema, pulmonary contusion, pulmonary hemorrhage, mucous plugging, atelectasis, thromboembolic disease, etc.). although almost all definitions for suspecting (and diagnosing) vap include radiographic criteria (new or progressive and persistent infiltrates), it is well known that chest x-rays are neither sensitive nor specific for vap [ , , ] . figures and display two patients for whom radiological criteria were falsely negative ( fig. ) or not contributive (fig. ) . computed tomography (ct) scan may be a good alternative since it is more sensitive; however, a strategy based on systematic lung ct-scan has obvious drawbacks, the main issues being feasibility, maintaining patient safety during transport, and availability. lung ultrasound has recently been proposed as a diagnostic aid for vap; however, data on its sensitivity and specificity are lacking [ ] . biomarkers such as c-reactive protein, procalcitonin or soluble triggering receptor expressed on myeloid cells (strem- ) have been proposed as diagnostic markers for vap; however, they lack accuracy and their use is, to date, not recommended for vap diagnosis [ , , [ ] [ ] [ ] [ ] . more research is needed to identify sensitive and specific biomarkers that could help the clinician to diagnose vap, identify the causative pathogen, and guide antibiotic therapy. a translational approach, with application of genomic, proteomic, and metabolomic methodologies, may be helpful in improving our understanding of the pathophysiology of vap and helping identify judicious biomarkers or profiles that could help clinicians [ ] . in summary, there is no single clinical criterion, biomarker or score that is accurate enough to diagnose vap. therefore, vap should be considered whenever there are new signs of respiratory deterioration potentially attributable to infection (e.g., fever, purulent sputum, leukocytosis, worsening oxygenation, unexplained hypotension, or increasing vasopressor requirements), with or without new or progressive pulmonary infiltrates. once vap is suspected, the second step of the diagnostic workup is to perform microbiological sampling (fig. ) . recently, scientific societies from north america and europe proposed recommendations to diagnose vap [ , ] (table ). the european guidelines [ ] suggested obtaining distal quantitative samples before antibiotic treatment, since it is known that, if samples are obtained after starting antibiotic treatment, the results may be altered or emerge as negative. the use of distal quantitative cultures, which may be more specific than blind (non-directed) sampling techniques, may help to reduce overutilization of antibiotics particularly if clinicians only start antibiotics in patients with positive gram stains, positive cultures, or suspected septic shock [ ] . direct examination and gram staining use are controversial. the american guidelines [ ] suggest that a high-quality gram stain from a respiratory specimen with numerous and predominant organisms provides further support for the diagnosis of vap. the absence of microorganisms on gram stain, however, does not reliably exclude vap, and so it is important to also review culture results. the limited sensitivity and specificity of gram stain are another reason why we need to identify additional rapid diagnostic strategies including biomarkers and rapid microorganism identification and susceptibility assays. presentations of diagnostic sampling techniques for vaps are sometimes confusing. invasive techniques are those which are distal and directed by bronchoscopy, such as bronchoalveolar lavage (bal), protected specimen brush (psb) or lung biopsies (an uncommon sampling method). blind mini-bal using a plugged fig. chest x-rays and ct-scan of a -year-old man who developed ventilator-associated pneumonia. chest x-ray performed the day vap was suspected seems normal (a), whereas the ct-scan performed the same day showed consolidation of the left inferior lobe (b, d). bronchoalveolar lavage yielded enterobacter aerogenes. the next day, chest x-ray showed progression of pulmonary infiltrates (c). vap diagnosis based on chest x-ray would have been delayed telescopic catheter (or blind protected specimen brush) is a non-directed sampling technique which is not always distal (because there is no confirmation of the correct placement of the tip of the catheter) and which is considered as "non-invasive" even though bleeding and pneumothoraces are possible complications. these "invasive techniques" also present several disadvantages: the need for qualified personnel to perform these procedures (even though it is now a conditional skill to become an intensivist in many countries), potential risks for the patient (hypoxemia, barotrauma, bleeding), and the associated costs especially when using disposable bronchoscopes. however, the use of bronchoscopic bal combined with quantitative cultures may achieve more reliable identification of causative agents with a higher specificity than qualitative sampling methods and allows sufficient fluid return to perform complementary analyses (i.e., cytology, albumin levels, viruses identification, galactomannan determination, procollagen iii in ards patients). qualitative cultures obtaining using proximal sampling methods such as endotracheal aspirates may overestimate the presence of bacteria potentially lead to unnecessary antibiotics use, and promotion of antibiotic resistance. however, they can be performed more quickly and simply compared to bronchoscopy, with fewer complications and resources (fig. ) . a metaanalysis of randomized trials comparing invasive microbiological sampling techniques with quantitative cultures versus noninvasive sampling methods with either quantitative or semiquantitative cultures did not find any differences in patients' outcomes [ , ] . a common dilemma is the question of whether to start antibiotics when invasive quantitative culture results are negative or below the diagnostic threshold for patients with suspected vap. the infectious diseases society of america (idsa)/american thoracic society (ats) guidelines suggest withholding antibiotics in such cases so long as they are clinically stable [ ] . this strategy might be associated with less unnecessary antibiotic use, which should reduce antibiotic-related adverse events (such as clostridium difficile emergence and rising antibiotic resistance) and costs. however, intensivists should always use their clinical judgment to temper this decision if there is other compelling evidence of pulmonary infection, if the patient received antimicrobial therapy prior to microbiological sampling, if there is associated septic shock, if the patient is immunocompromised, and/or if the patient fails to improve despite managing potential non-infectious causes of clinical deterioration. although not recommend by the recent guidelines, some patients may receive antibiotics before microbiological sampling, results of this latter being therefore negative many times. in such cases, giving a full course ( days, see below) of antibiotics may expose the patient to prolonged undue antibiotics and may promote antibiotic resistance. therefore, our recommendation is to reevaluate the patient at - h; if the clinical course is favorable, and the likelihood of infection is low, antibiotics could be stopped. another solution is to use procalcitonin to stop antibiotics at - h if the procalcitonin level is < . ng/ml or has decrease of more than % as compared to the peak value [ , , ] . another common situation is a patient who receives antibiotics for more than h at the time of microbiological sampling (whatever the indication, for an extrapulmonary infection for example). if microbiological results are negative, that suggests that the patient does not have vap. therefore, no new antibiotics should be started, and the decision on what to do with the current antimicrobial treatment should be based on the initial indication. one of the challenges in diagnosing vap, whatever the technique used (endotracheal aspirates or bronchoscopic-guided bal), is to decrease the time from sampling to pathogen identification. indeed, it currently takes at least - h using conventional microbiological methods to identify the pathogen(s) responsible for infection and its (their) sensitivity to antimicrobial treatment (fig. ) . during that time, empiric broad-spectrum fig. chest x-ray of a -year-old woman with h n influenzaassociated acute respiratory distress syndrome ("white lungs"). she developed fever, leukocytosis, purulent tracheal secretions and bronchoalveolar lavage (obtained during fiber optic bronchoscopy) yielded pseudomonas aeruginosa. chest x-ray was unchanged (same chest x-ray since week) and obviously not useful for suspecting/diagnosing ventilator-associated pneumonia antibiotics are often given [ , , ] . one of the key issues in antimicrobial stewardship is to decrease the consumption of broad-spectrum antibiotics [ ] both by limiting their prescription and shortening their duration. over the past few years, molecular methods have been developed to decrease the time between sampling organism identification, and determination of antibiotic susceptibilities. for example, the use of polymerase chain reaction (pcr) to detect bacterial dna can shorten the time of organism identification and susceptibilities, but it is restricted to specific pathogens and resistance mechanisms, for example meca to detect methicillin resistance in staphyloccocus aureus strains [ ] . although this technique is not available to determine resistance patterns for pathogens commonly responsible for vap such as pseudomonas aeruginosa [ ] or it requires a positive culture to detect resistance mechanisms [ ] , it is routinely used in many places to allow for very early de-escalation and narrowing of antimicrobial treatment in specific situations, for example to withdraw or withhold anti-mrsa antibiotics (fig. ) . recently, new tools using multiplex pcr directly applied to fresh (bronchoscopic) samples have been developed to identify pathogens. some tests screen just for the main pathogens responsible for vap, and some of them also screen for selected resistance mechanisms. the pneumonia application of the unyvero system (curetis ag, holzgerlingen, germany) allows testing for different bacteria and one fungus, including those most frequently responsible for vap, as well as resistance markers, directly in clinical specimens, with a turnaround time of to h [ ] . recent studies have evaluated this new technique as compared to conventional microbiological methods and found a concordance rate fig. schematic representation of vap diagnosis and treatment. clinical suspicion of vap refers to the association of some of the following criteria: fever, purulent sputum, leukocytosis, impaired oxygenation, unexplained hypotension or shock, new (or progression of ) pulmonary infiltrates on chest x-ray (not always observed). empirical treatment takes into account the underlying disease and its severity, the presence of risk factors for multiple-drug-resistant pathogens (antibiotic therapy in the previous days, hospital stay > days, septic shock at vap onset, ards prior to vap onset, acute renal replacement therapy prior to vap onset, previous colonization with mdr pathogen) and local pattern of antimicrobial susceptibility. immunocompromised patients, patients with empyema, lung abscess or necrotising pneumonia should receive prolonged antimicrobial course [ ] between the two techniques of - % for pathogen identification, and of - % for identifying resistance [ ] [ ] [ ] [ ] . however, this kind of technique is limited by the risk of over-detection, i.e., detection of dna of nonviable organisms, detection of pathogens at non-pathogenic thresholds, and the detection of non-pathogenic organisms (i.e., colonizers rather than invaders). this kind of technique will probably facilitate major advances in the management of vap in the near future, allowing clinicians to tailor antibiotics within a few hours (fig. ) . however, improvements in the breadth and sensitivity of the technique as well as studies evaluating the safety and efficacy of rapid diagnostics to improve the suitability and duration of antimicrobial treatment as well as impacts on patients' outcomes are needed before it can be routinely recommended. the clinical signs used to diagnose vap are neither sensitive nor specific either alone or in combination. even lung biopsies are not definitive because of the uneven distribution of lung lesions and variability in pathologists' interpretations. as such, it is highly unlikely that there will be a worldwide consensus on how best to define and conduct surveillance. this bespeaks the critical need for further research to develop and validate new diagnostic tools to support surveillance, prevention, and treatment studies as well as quality improvement initiatives. this need is particularly acute in the usa where regulators and legislators have considered including hospitals' vap rates in benchmarking and reimbursement policies. in this context, the us centers for disease control and prevention developed the concept of ventilator-associated events (vae), a surveillance strategy designed to broaden the focus of surveillance to encompass multiple causes of respiratory deterioration in ventilated patients, not just pneumonia, to make surveillance more objective, and to allow for the possibility of automated surveillance using electronic clinical data. the definition includes subcriteria to try to identify the subset of vaes that might be infection-related and which might be due to pneumonia in particular, but there are no data to suggest that vae definitions are any more (or less) accurate than traditional surveillance definitions [ ] . while lower respiratory tract surveillance cultures may help to predict the involvement of mdr microorganisms in patients that develop vap and thus decrease unnecessary broad-spectrum antibiotics use, there are no clear data that this strategy improves clinical outcomes or lowers costs [ , ] . consensus diagnostic criteria that can be objectively applied are needed to compare incidence rates between hospitals and countries for the purposes of public health planning and reimbursement. many of our presumptions about how best to prevent vap have recently been challenged. oral care with chlorhexidine and stress ulcer prophylaxis may be harmful, new data affirm the long-held fear that selective oral and should patients with suspected vap be treated based on the results of invasive sampling (bal, psb, blind mini-bal) with quantitative culture results, noninvasive sampling (endotracheal aspiration) with quantitative culture results, or noninvasive sampling with semiquantitative culture results? recommendation we suggest noninvasive sampling with semiquantitative cultures to diagnose vap, rather than invasive sampling with quantitative cultures and rather than noninvasive sampling with quantitative cultures (weak recommendation, low-quality evidence) if invasive quantitative cultures are performed, should patients with suspected vap whose culture results are below the diagnostic threshold for vap (psb with < cfu/ml, bal with < cfu/ml) have their antibiotics withheld rather than continued? recommendation noninvasive sampling with semiquantitative cultures is the preferred methodology to diagnose vap; however, the panel recognizes that invasive quantitative cultures will occasionally be performed by some clinicians. for patients with suspected vap whose invasive quantitative culture results are below the diagnostic threshold for vap, we suggest that antibiotics be withheld rather than continued (weak recommendation, very low-quality evidence) we suggest obtaining distal quantitative samples (prior to any antibiotic treatment) in order to reduce antibiotic exposure in stable patients with suspected vap and to improve the accuracy of the results. (weak recommendation, low quality of evidence) we recommend obtaining a lower respiratory tract sample (distal quantitative or proximal quantitative or qualitative culture) to focus and narrow the initial empiric antibiotic therapy. (strong recommendation, low quality of evidence) digestive decontamination may not be effective in icus with high baseline rates of antibiotic resistance, and subglottic secretion drainage may not shorten duration of mechanical ventilation or icu length-of-stay as was once thought [ ] [ ] [ ] [ ] [ ] . the practices most consistently associated with earlier extubation and/or lower mortality rates are those focused on limiting exposure to invasive mechanical ventilation by avoiding intubation and speeding extubation [ ] . interpreting the vap prevention literature is challenging because many initiatives have been reported to lower vap rates, but the limitations of vap diagnostic tools and criteria make it difficult to discern the true effect of prevention strategies [ ] . unless and until we develop sensitive and specific markers for the presence or absence of vap, providers are advised to consider more objective outcomes when evaluating the potential merits of proposed prevention strategies [ ] . these include duration of mechanical ventilation, icu length-of-stay, ventilator-associated events, antibiotic utilization, and mortality. comparing prevention measures' impacts on vap rates versus more objective outcomes can sometimes lead to surprising discrepancies. for example, meta-analyses of randomized trials of oral care with chlorhexidine suggest this intervention may lower vap rates but increase mortality [ , ] . we will use this lens to briefly review common vap prevention strategies. several recent trials evaluated the potential benefits of modifying endotracheal tube cuff shapes and/or materials to minimize seepage of microbe-laden fluids across the cuff and into the lungs. unfortunately, neither tapered cuffs nor ultrathin polyurethane proved to be any better than conventional cylindrical cuffs or polyvinyl fig. current and potential future workup processes for identification of pathogens responsible for vap. to date, it takes - h. to identify pathogen responsible for ventilator-associated pneumonia (vap) and its susceptibility to antibiotics (purple boxes), delaying the definitive, targeted treatment at that time (green boxes). awaiting these results, physicians prescribe empiric broad-spectrum antimicrobial treatment. the use of specific, targeted polymerase chain reaction (pcr) may allow shortening this time to - h., but for specific pathogens and specific resistance mechanisms. a potential future workup process will be to use multiplex pcr (blue box) to identify within less than h pathogens responsible for vap and their resistance to antimicrobials chloride at preventing vap or improving objective outcomes [ ] [ ] [ ] [ ] . likewise, manually monitoring cuff pressures every h to minimize inadvertent drops in endotracheal tube cuff pressure was no better at preventing vap, decreasing length-of-stay, or lowering mortality in a recent single center study compared to checking cuff pressures only at intubation, following frank tube migration, or detection of a cuff pressure leak [ ] . a meta-analysis of three randomized trials of automated cuff pressure monitoring did report significantly lower vap rates with automated cuff pressure systems, but the analysis was limited by small numbers, substantial heterogeneity, and limited evaluation of secondary outcomes [ ] . subglottic secretion drainage has repeatedly been associated with lower vap rates in both individual randomized trials and meta-analyses but does not appear to shorten the time to extubation, icu length-of-stay, prevent ventilator-associated events, or lower mortality rates [ ] . earlier meta-analyses did suggest a possible impact on time to extubation and icu discharge but were confounded by ambiguous study results and high levels of heterogeneity [ , ] . two studies have reported an association between subglottic secretion drainage and less antibiotic utilization, but a third did not [ ] [ ] [ ] . recent studies have also called into question the effectiveness and safety of oral chlorhexidine. there is no association between oral care with chlorhexidine and lower vap rates on meta-analysis of double-blind randomized trials [ ] . more concerningly, some meta-analyses and observational studies have reported that oral care with chlorhexidine may increase mortality rates, perhaps because some patients may aspirate some of the antiseptic triggering acute lung injury [ , , , , , ] . a cluster randomized de-adoption study is currently underway to better characterize the safety and effectiveness of oral chlorhexidine for ventilated patients [ ] . elevating the head of the bed to prevent reflux of gastric secretions into the lungs is the most commonly practiced intervention to prevent vap [ , ] but is supported by surprisingly few randomized trials. a cochrane review of randomized trials enrolling patients did report collectively fewer clinically suspected vaps in patients randomized to head-of-bed elevation, but no effect on microbiologically confirmed vap and no effect on objective outcomes [ ] . some investigators have hypothesized that putting patients in the lateral trendelenburg may be a better way to prevent vap by recruiting gravity to carry oral secretions away from the lungs. a recent study confirmed this hypothesis, but the trial was terminated early due to a surfeit of adverse events among patients randomized to lateral trendelenburg [ ] . selective oral and digestive decontamination is one of the very few preventative strategies in critical care that has repeatedly been associated with lower mortality rates [ , ] . this strategy is widely practiced in the netherlands, but practitioners elsewhere have been loath to adopt antibiotic decontamination for fear that it might promote antibiotic resistance, particularly in icus with high baseline rates of antibiotic-resistant bacteria and antibiotic utilization. ironically, oral and digestive decontamination may actually decrease overall antibiotic utilization presumably by decreasing the incidence of infections requiring treatment [ ] . nonetheless, a recent cluster randomized trial of oral and digestive decontamination in icus with high baseline rates of antibiotic resistance and antibiotic utilization found no significant impact on bloodstream infections or mortality [ ] . probiotics may protect patients from vap by modulating the microbiome and inhibiting colonization with invasive pathogens. some randomized trials have reported lower vap rates, but this signal is not present on meta-analysis restricted to double-blinded studies [ ] . a large multicenter study is currently underway [ ] . stress ulcer prophylaxis has been associated with higher vap rates in some observational studies and in a recent meta-analysis of randomized trials [ , , ] . a large randomized trial of pantoprazole vs placebo, however, reported no difference between arms in pneumonia rates [ ] . at the same time, stress ulcer prophylaxis had a relatively modest effect on gastrointestinal bleeding rates ( . % vs . %) and no impact on transfusion requirements or mortality rates. additional large randomized trials are underway. the prevention practices that have most consistently been associated with improving objective outcomes for ventilated patients have been those focused on avoiding intubation and minimizing exposure to invasive ventilation by using high flow oxygen or noninvasive ventilation as alternatives to intubation, lightening sedation, using spontaneous breathing trials to prompt early extubation, and early mobilization [ , ] . these interventions appear to be synergistic insofar as minimizing sedation facilitates mobilization and early extubation. observational studies of quality improvement collaboratives have reported that bundling these practices together is associated with earlier extubation and lower mortality rates [ ] [ ] [ ] [ ] . it will be important, however, to confirm these findings in randomized trials given the many potential sources of bias in observational studies [ ] . table summarizes current knowledge about vap prevention. intravenous (iv) antimicrobial therapy is the cornerstone of vap treatment. physicians face a dilemma, however, between avoiding ineffective treatment, inappropriate initial antimicrobial treatment being associated with increased mortality [ ] ; and on the other hand, reducing the consumption of broad-spectrum antibiotics, the latter being associated with increased bacterial resistance [ ] . therefore, treatment of vap should be a two-step process: the first step is empiric treatment, the choice and immediacy of treatment being driven by disease severity (i.e., mortality risk) and risk factors of mdr pathogens; and the second step is definitive treatment, for which clinicians should try to avoid overuse of antibiotics. the choice and timing of antimicrobial agents used should take into account four parameters: severity of the current illness, type and number of underlying diseases and their severity, risk factors for mdr pathogens, and the local pattern of antimicrobial susceptibility. risk factors for mdr pathogens include high (> %) local prevalence of pathogen resistance, antibiotic therapy in the previous days, hospital stay > days, septic shock at vap onset, ards prior to vap onset, acute renal replacement therapy prior to vap onset and previous colonization with mdr pathogens [ , ] . in non-immunocompromised patients with early-onset vap and no risk factors for mdr pathogens (as defined above), monotherapy with narrow-spectrum antibiotic (non-pseudomonal third generation cephalosporin) can be used (table ) [ ] (this situation is not mentioned in the idsa/ats guidelines [ ] ). in other situations, initial empiric treatment should include a broad-spectrum β-lactam targeting pseudomonas aeruginosa and/ or esbl-producing enterobacteriaceae (ceftazidime, cefepime, piperacillin-tazobactam or a carbapenem) plus a non-β-lactam antipseudomonal agent, such as aminoglycosides (amikacin or tobramycin) or fluoroquinolones (ciprofloxacin or levofloxacin) ( table ). the choice of the β-lactam agent should take into account previously used antibiotics, local pattern of susceptibilities and patient colonization with mdr pathogen. for example, a carbapenem should be preferred in patients colonized with esbl-producing enterobacteriaceae. indeed, although carbapenem are overprescribed in esbl carriers, - % of vap episodes in these patients are due to an esblproducing enterobacteriaceae, and it seems difficult not head-of-bed elevation [ ] may lower rates understudied, few and contradictory randomized trials tapered endotracheal tube cuffs and ultrathin polyurethane [ , ] no impact in vivo studies document persistently high rates of subclinical aspiration despite the theoretical advantages of these designs automated endotracheal tube cuff pressure monitoring [ ] may lower rates understudied, merits further evaluation subglottic secretion drainage [ ] may lower rates extensively studied but despite lower vap rates no impact on duration of mechanical ventilation, icu length-ofstay, ventilator-associated events, or mortality. unclear impact on antibiotic utilization [ , , ] may increase vap rates observational studies and some meta-analyses suggest higher vap rates but a recent large randomized trial found no impact vap prevention bundles [ ] likely lower vap rates extensively studied, almost exclusively in before-after and time-series analyses. may be associated with lower mortality rates. most benefit likely from minimizing sedation and encouraging early extubation to take into account this pathogen in the empirical antimicrobial treatment [ , ] . moreover, it has been shown that % of infection-related ventilator-associated complications were neither vap nor attributable to a documented icu infection [ ] , indicating that efforts should be concentrated on the diagnostic strategy, to use carbapenems only in patients with true infection, and to withhold carbapenems when the likelihood of infection is low. the use of new beta-lactam agents (ceftazidimeavibactam, ceftolozane-tazobactam, meropenemvaborbactam, imipenem-relebactam) in the empirical treatment of vap should probably be reserved in patients colonized with mdr/xdr pathogens, such as carbapenem-resistant enterobacteriaceae or xdr pseudomonas aeruginosa susceptible only to these drugs. the idsa/ats guidelines recommend empiric coverage of methicillin-resistant staphylococcus aureus (mrsa) in patients who received antibiotics in the preceding days or those hospitalized in units with high (> %) or unknown mrsa prevalence among vap patients [ ] . european guidelines state that mrsa coverage should be considered if the unit has > % of staphylococcus aureus respiratory isolates as mrsa [ ] . a recent study performed in the usa showed that among patients with hospital-acquired pneumonia (not specifically vap) in hospitals with mrsa prevalence > %, only % grew mrsa on respiratory specimen culture, indicating that potentially % would have been over treated by using the hospital-wide prevalence of mrsa instead of the vap-specific prevalence of mrsa [ , ] . moreover, mrsa vap prevalence is low in several countries [ ] . therefore, the empiric use of an anti-mrsa agent should be restricted to units with high (> %) incidence of vap secondary to mrsa, or in patients already colonized by mrsa. one of the goals for clinicians should be to avoid overuse of antibiotics. first, antibiotics should be stopped if no pathogen is retrieved. indeed, many episodes of suspected vap are not vap [ ] . second, in patients with bacteriologically proven vap, antibiotics should be narrowed once culture results and susceptibility tests are [ ] . in patients with esbl-producing enterobacteriaceae vap susceptible to piperacillin-tazobactam, the use of this drug could be discussed as an alternative to carbapenem since results of the merino trial may be disputable [ ] [ ] [ ] [ ] . moreover, the place of new betalactam agents (ceftolozane-tazobactam, ceftazidimeavibactam) as carbapenem-sparing agents remains to be determined, since their impact on emergence of antimicrobial resistance as compared to carbapenem is not known. their use should be reserved as last resort agents in mdr/xdr difficult to treat pathogens (carbapenemresistant enterobacteriaceae, xdr pseudomonas aer-uginosa…). last, antimicrobial therapy can be safely switched to monotherapy once pathogens responsible for infection are identified and susceptibility results have been obtained, even for non-fermenting gramnegative bacilli such as pseudomonas aeruginosa [ ] . indeed, the usefulness of combination therapy is mostly to increase the likelihood of appropriateness of treatment rather than improving the prognosis of patients. therefore, double antipseudomonal coverage in patients with pseudomonas aeruginosa vap with uncomplicated course should be avoided once susceptibility tests are available [ , ] . both european and us guidelines recommend that the duration of antimicrobial treatment for vap should not exceed days in most patients, including those infected with non-fermenting gram-negative bacilli (pseudomonas aeruginosa, acinetobacter spp….) [ , , , ] . longer course may be appropriate for immunocompromised patients and are likely necessary for patients with empyema, lung abscess, or necrotising pneumonia [ ] . shortening duration of antimicrobial below days is currently not recommended [ , , , ] , but some authors have demonstrated that treatment duration can be customized based on procalcitonin kinetics and have been able to treat some patients for < days using this strategy [ , , ] . nebulisation of antibiotics has grown in recent years, but the ideal candidates to receive this treatment are not well defined [ ] . to date, nebulized antibiotics cannot be recommended as an alternative to the intravenous route, partly because data are lacking on this indication, partly because - % of patients with vap have concurrent bacteraemia, and partly because multiple and repeated daily use of nebulisation may prolong duration of mechanical ventilation [ , ] . the use of nebulised antibiotics as an adjunctive treatment (i.e., in addition to effective intravenous therapy) is also not recommended; two recent randomized-controlled trials failed to demonstrate superiority of nebulised antibiotics (amikacin alone or combined with fosfomycin) over placebo in patients with vap due to "traditional pathogens" [ , ] . the use of nebulised antibiotics should therefore be restricted to patients with vap to xdr-gram-negative pathogens susceptible only to colistin or aminoglycosides [ ] . indeed, three meta-analyses found that in patients infected with such pathogens, the use of nebulised colistin combined with iv colistin led to better outcomes compared to iv colistin alone [ ] [ ] [ ] . whether or not nebulised antibiotics may decrease emergence of bacterial resistance, as suggested by two studies performed in patients with ventilator-associated tracheobronchitis, remains to be determined [ , ] . the use of pathogen-specific antibodies as an adjunctive or preventive treatment is currently under investigation. aerucin (aridis ® ) is an igg mab that binds to the pseudomonas alginate exopolysaccharide involved in cellular adhesion. a phase , placebo-controlled, double-blind study to assess its safety and efficacy as adjunctive therapy to standard antibiotics in patients with p aeruginosa hap/vap (nct ) has been performed recently, but results are not yet available. recent studies have evaluated the usefulness of antibodies to neutralize or inhibit specific s. aureus or p. aeruginosa virulence factors [ ] . the purpose of this kind of strategy is to reduce the risk for developing vap in patients colonized by these pathogens. results of these studies are promising, since a phase trial targeting pseudomonas aeruginosa virulence factors showed trend toward lower rate of infection due to this pathogen [ ] , and the recently released results of the saatelite study, that evaluated an antibody against staphylococcus aureus virulence factor, found also trend toward lower incidence of staphylococcus aureus pneumonia [ ] . although this strategy is more preventive than curative, the usefulness of these anti-virulence agents as adjuvant to antibiotics remains to be evaluated. there is no definitive answer to this question. the recent pth trial suggested that acyclovir does not change the number of ventilator-free days in patients presenting with hsv oropharyngeal reactivation disease [ ] . intriguingly, however, the same study reported a near significant decrease in mortality among patients randomized to acyclovir [ ] . antiviral prophylaxis using valganciclovir or valacyclovir was able to decrease blood reactivation in a randomized study involving patients [ ] . however, the valacyclovir arm was halted prematurely because of higher mortality by days without clear explanation [ ] . in another interventional trial, ganciclovir prophylaxis did not reduce plasma interleukin levels in critically ill cmv-seropositive adults [ ] . the ganciclovir group did, however, have more ventilator-free 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empiric antibiotics. an evaluation of veterans affairs medical centers effect of piperacillin-tazobactam vs meropenem on -day mortality for patients with e. coli or klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial antibiotics for ceftriaxone-resistant gram-negative bacterial bloodstream infections use of non-carbapenem antibiotics to treat severe extended-spectrum beta-lactamase-producing enterobacteriaceae infections in intensive care unit patients a multinational, preregistered cohort study of beta-lactam/beta-lactamase inhibitor combinations for treatment of bloodstream infections due to extended-spectrum-betalactamase-producing enterobacteriaceae effect of adequate single-drug vs combination antimicrobial therapy on mortality in pseudomonas aeruginosa bloodstream infections: a post hoc analysis of a prospective cohort influence of empiric therapy with a beta-lactam alone or combined with an aminoglycoside on prognosis of bacteremia due to gram-negative microorganisms german study group competence network s ( ) effect of empirical treatment with moxifloxacin and meropenem vs meropenem on sepsis-related organ dysfunction in patients with severe sepsis: a randomized trial comparison of vs days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the european society of clinical microbiology and infectious diseases nebulized ceftazidime and amikacin in ventilatorassociated pneumonia caused by pseudomonas aeruginosa aerosol therapy for pneumonia in the intensive care unit a randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of gram-negative ventilator-associated pneumonia: iasis trial inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with gram-negative pneumonia (inhale): a double-blind, randomised, placebo-controlled, phase , superiority trial nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of pneumonia caused by multidrug-resistant pathogens: a systematic review and meta-analysis the role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit reduction of bacterial resistance with inhaled antibiotics in the intensive care unit new strategies targeting virulence factors of staphylococcus aureus and pseudomonas aeruginosa safety and pharmacokinetics of an anti-pcrv pegylated monoclonal antibody fragment in mechanically ventilated patients colonized with pseudomonas aeruginosa: a randomized, double-blind, placebo-controlled trial suvratoxumab reduces staphylococcus aureus pneumonia in high-risk icu patients: results of the saatellite study acyclovir for mechanically ventilated patients with herpes simplex virus oropharyngeal reactivation: a randomized clinical trial safety and efficacy of antiviral therapy for prevention of cytomegalovirus reactivation in immunocompetent critically ill patients: a randomized clinical trial prevention of intensive care unit-acquired pneumonia probiotics for preventing ventilator-associated pneumonia in mechanically ventilated patients: a meta-analysis with trial sequential analysis key: cord- -vrs je x authors: powers, karen s. title: acute pulmonary infections date: - - journal: pediatric critical care study guide doi: . / - - - - _ sha: doc_id: cord_uid: vrs je x acute lower respiratory infection is a common cause of morbidity in infants and children, and at times, requires intensive care and mechanical ventilation. viral bronchiolitis and bacterial pneumonia account for the majority of lower respiratory tract infections that lead to respiratory insufficiency and pediatric intensive care admission. twenty-seven percent of children who require mechanical ventilation for at least h in pediatric intensive care units are diagnosed with bronchiolitis and % have the diagnosis of pneumonia. the median length of time intubated for an acute pulmonary infection leading to respiratory failure is approximately days. acute lower respiratory infection is a common cause of morbidity in infants and children, and at times, requires intensive care and mechanical ventilation. viral bronchiolitis and bacterial pneumonia account for the majority of lower respiratory tract infections that lead to respiratory insuffi ciency and pediatric intensive care admission. twenty-seven percent of children who require mechanical ventilation for at least h in pediatric intensive care units are diagnosed with bronchiolitis and % have the diagnosis of pneumonia. the median length of time intubated for an acute pulmonary infection leading to respiratory failure is approximately days. viral bronchiolitis remains the leading cause for hospital admission in infancy and the most frequent cause of acute respiratory failure in children admitted to pediatric intensive care units in north america. pneumonia in children younger than years of age has an annual incidence karen s. powers of - cases per , . community acquired pneumonia can also lead to severe respiratory compromise especially in children with pre-existing disease. a detailed understanding of the diverse etiologies and distinct clinical courses of acute pulmonary infections is essential for the pediatric critical care practioner. this chapter will focus on bronchiolitis and pneumonia as the two leading causes of pulmonary infections leading to picu admission. approximately one third of children develop bronchiolitis during the fi rst years of life. of these, only in ( % of all infants in the united states) will require hospitalization. although hospitalization rates have increased over the last three decades, mortality remains low. overall mortality rate is - %, but as high as % in high risk infants. most deaths occur in infants younger than months of age with co-morbidities such as prematurity, congenital heart disease, congenital or acquired lung disease or immunodefi ciency. respiratory syncytial virus (rsv) was fi rst isolated in and still represents the major cause of bronchiolitis. other causative viruses include parainfl uenza, adenovirus, enterovirus, infl uenza and most recently human metapneumovirus and human bocavirus (hbov). in the northern hemisphere, rsv outbreaks occur from october to june. human metapneumovirus (hmpv) recently has been identifi ed as the causative agent in - % of bronchiolitis cases, possibly surpassing parainfl uenza as the second most common etiology. its prevalence is slightly higher in the late winter and spring. parainfl uenza infections peak at months of age, representing approximately - % of cases of bronchiolitis. parainfl uenza (piv- ) is endemic throughout the year, but especially common in the late spring. males are . - times more likely to require hospitalization for bronchiolitis and are likely to have more severe disease. an x-linked genetic trait that results in a reduced tolerance to hypoxia has been postulated and would be consistent with the observation of increased mortality in newborn males with infant respiratory distress syndrome. virtually all children by the age of two will have been infected with rsv, all children by the age of fi ve will have been infected with hmpv, and all children by the age of nine will have been infected with hbov. the remainder of the discussion on bronchiolitis will be divided into rsv and non-rsv bronchiolitis. although etiologic agents may differ, clinical courses are often similar. respiratory syncytial virus (rsv) accounts for - % of bronchiolitis, infecting one-half of all infants within the fi rst year of life and hospitalizing approximately , infants yearly (about % of affected infants). approximately % of these infants require mechanical ventilation. co-infection with either hmpv or rhinovirus occurs in - % of young children. two types of rsv exist -types a and b. type a is more common and is believed to cause more severe disease, although data is not conclusive. both types may exist simultaneously in the community. infants less than year will typically shed the virus for about days. children with immunodefi ciencies may shed the virus for months. the immune response varies with age and contributes to both termination of the disease and its pathologic features. the virus is transmitted from respiratory secretions by close contact with infected persons or by contact with contaminated objects or surfaces. there is a % rsv transmission rate within families and about one-half of hospital workers will acquire rsv. therefore, hand washing and the wearing of gowns and gloves is of primary importance to attenuate transmission. mortality from rsv bronchiolitis continues to decline with better intensive care and the use of preventive therapies. male infants are more likely to require hospitalization and usually manifest more severe disease. about ½ of all infants will be infected with rsv bronchiolitis in their st year of life; % will be hospitalized; % of hospitalized infants will require mechanical ventilation. antibody-mediated immunity rsv introduced onto the nasal or conjunctival mucosal surface causes profuse rhinorrhea within a few days. during the fi rst months of life, passively acquired maternal antibodies are protective. however, as maternal antibody titers gradually decrease, infants become susceptible to severe disease. cell-bound iga may develop to help clear the virus. circulating igg directed against the glycoprotein (g) and fusion (f) proteins (operative in syncytia formation) on the viral surface will develop several days later. infants less than months of age appear to induce a weaker antibody response likely due to the presence of maternal antibodies. virus-specifi c ige in the respiratory tract is associated with disease severity. often, complete and effective immune responses are not induced, thus re-infections are possible even during the same season. epithelial cells and alveolar macrophages are key activators of cellular immunity. although these cells enhance viral clearing, they also contribute to airway infl ammation through the release of cytokines and chemokines. these include interleukin (il)- , tumor necrosis factor-alpha, il- , il- , macrophage-infl ammatory protein (mip)- -alpha and rantes (regulated upon activation, normal t cell expressed and secreted). release of these cytokines and chemokines are believed to be partially responsible for airway infl ammation and hyperreactivity. the effects of these mediators persist beyond the acute infection and contribute to prolonged pulmonary dysfunction. children who require mechanical ventilation have lower peripheral t cell counts compared to hospitalized infants not requiring mechanical ventilation. these infants demonstrate low t cell proliferative responses and interferon (ifn-g ) production. il- is required for the initiation of cellular immunity. the length of time requiring mechanical ventilation has been found to be inversely related to il- production. the role of th /th -like cytokine profi les, expressed as ifn-g /il- ratios, is controversial. in some studies, these ratios decreased after polyclonal stimulation in hospitalized infants with rsv. however, more recent studies have shown normal ratios following polyclonal stimulation. neutrophils are the predominant cell found in the airways of infants with rsv bronchiolitis. elevated levels of il- are found in high concentrations in the nasal secretions of infected children and act as a neutrophil chemoattractant. further evidence of cellular induced injury is seen in post-mortem examination where peribronchial lymphocyte infi ltration with bronchial epithelial necrosis is typically present. infants typically present with tachypnea, rhinorrhea, cough, low-grade fever, irritability, poor feeding and vomiting. respiratory rates greater than breaths per minute are often associated with room air saturations of less than %. infants may also have tachycardia, mild conjunctivitis, otitis media, or pharyngitis. low-grade fever usually persists for - days. in addition, infants may develop a metabolic acidosis from poor caloric and fl uid intake. apnea often is the fi rst presenting symptom of rsv bronchiolitis in small infants. the etiology of apnea remains unknown; however, is likely related to the immaturity of the respiratory control center in the brainstem. the incidence of apnea in infants with bronchiolitis is approximately - %. the heterogeneous nature of rsv induced lung disease can cause atelectasis in some areas and overdistension in others. chest roentgenograms often show hyperinfl ation with fl attening of the diaphragms and patchy or peribronchial infi ltrates. atelectasis, especially of the right upper lobe, is often seen. infants may have high lung volumes with the functional residual capacity often being twice normal. the decrease in dynamic compliance and increase up regulation of the infl ammatory cascade with release of chemokines and cytokines are contributory to the airway infl ammation and hyperreactivity. c hapter • ac ute pu lmonary i n fections in airway resistance leads to marked increase in work of breathing, often worse during expiration from lower airway obstruction. alterations in gas exchange and hypoxemia are secondary to a ventilation-perfusion mismatch. the anatomical differences between young infants and older children contribute to the severity of the disease in the young. due to the highly compliant cartilaginous chest wall and poor thoracic musculature, the infant's chest wall has diffi culty countering the lung's inherent tendency towards collapse. this leads to a greater propensity of small infants towards atelectasis compared with older children. the absence of effective collateral ventilation in infants also contributes to the development of atelectasis and impaired gas exchange. cellular debris in small airways and peribronchial edema increase airways resistance leading to wheezing as the predominant symptom in some infants. despite the potential for severe impairment in lung function, most hospitalized infants improve within - days. typically, by weeks, they have normal respiratory rates, oxygenation, and ventilation. chest radiographs usually normalize by day . however, about % of infants will have a protracted course, with some mild respiratory symptoms persisting for months. viral respiratory infections have been linked to the development of asthma later in childhood. the tucson children's respiratory study group prospectively followed for years, infants who had bronchiolitis and found an increased risk for subsequent wheezing episodes. some infants are at an increased risk for severe rsv disease such as those with chronic lung disease due to prematurity (bronchopulmonary dysplasia), cystic fi brosis, congenital heart disease, and immunodefi ciencies. in children with cystic fi brosis, rsv accounted for % of symptomatic infections, % of hospitalizations for infants less than year, and % of infants requiring mechanical ventilation. in a study of hospitalized infants with congenital heart disease infected with rsv, % required intensive care, % received mechanical ventilation, and . % died. children having undergone hematopoietic stem cell transplants who develop rsv infections have an extremely high mortality of - % despite mechanical ventilation and antiviral therapy. environmental factors such as crowding, passive exposure to tobacco smoke, and lack of breast-feeding are associated with the development of severe disease. compared to national averages, native american and alaskan children younger than year of age have higher rates of infections. there are three subtypes of human parainfl uenza viruses. hpiv- is most frequently isolated from children with bronchiolitis, while piv- and piv- most commonly cause croup. similar to rsv, both cell-mediated hyper-responsiveness to viral antigen and virus-specifi c ige responses are observed in children with parainfl uenza bronchiolitis. upper airway edema with concomitant obstructive symptoms may be present. children that are infected with parainfl uenza have a signifi cant likelihood of developing asthma later in life. the human metapneumoviruses (hmpv) are a group of rna viruses of the paramyxoviridae family identifi ed in humans in . hmpv appears to be the second most common cause of bronchiolitis in children throughout the world. the majority of children are born with maternal hmpv specifi c igg which wanes to around % by - months of age. by age fi ve, essentially % of children have been exposed to hmpv and will have neutralizing antibody to hmpv. there are two subgroups, a and b, with group a having more severe clinical symptoms. clinical presentation of children with this virus is similar to rsv. the pulmonary infl ammation generally peaks on day which includes interstitial edema and infl ammatory cell infi ltrates of the bronchioles and alveoli. these infl ammatory changes can persist for up to days. about half of infected children are - months of age, and infection is primarily in the winter months. human bocavirus (hbov) was recently discovered in . with amino acid sequencing, this new member of the parvoviridae family was found to be closely related to the bovine parvovirus and the canine minute virus, hence the name bocavirus (bo for bovine and ca for canine). detection of the hbov from the respiratory tract in symptomatic children and its absence of detection in non-symptomatic controls strongly suggest the virus to have a role in respiratory infections in children. co-infection is commonly described in up to % of samples. it remains unclear if hbov is a primary pathogen or acts to exacerbate other viral illnesses. the pathogenesis of hbov has not been well described, but with the high occurrence of wheezing and lower respiratory tract symptoms in children infected with the virus, it is speculated that this virus may be a signifi cant contributor to asthma exacerbations. the majority of infected children have rhinorrhea, cough, and wheezing, however, diarrhea has been reported in up to % of these children. in children with high viral loads, hbov has been detected in the serum suggesting the potential for disease beyond the respiratory tract. both infl uenza a, including novel infl uenza strains such as h n , and infl uenza b can cause a clinical picture consistent with bronchiolitis in the small infant. these viruses may cause severe multisystem disease and are discussed in greater detail in the viral pneumonia section. rapid diagnostic assays are available for early detection of many viruses. the older assays are antigen-based and include indirect immunofl uorescence/direct immunofl uorescence (ifa/ dfa), enzyme immunoassay (eia), optical immunoassay (oia), and neuraminidase activity assays. although still widely used because they are inexpensive and technically simple, they have a low specifi city and sensitivity. molecular assays are becoming the new "gold standard" for respiratory virus detection -replacing tissue culture that may take days. the published sensitivities and specifi cities approach % when compared to tissue culture or antigen assay. these assays generally use polymerase chain reaction (pcr) amplifi cation. signifi cant advancements in these assays are being made to simplify the performance of the assay and decrease the required time. the most important cause of false negative test results remains poor specimen handling or inadequate sample collection. other than aiding with cohorting of hospitalized patients, serologic detection of respiratory viruses is rarely clinically useful. regardless of the viral etiology of bronchiolitis, supportive care remains the mainstay of treatment. supplemental humidifi ed oxygen is frequently needed. due to many infants being obligate nasal breathers, frequent nasal suctioning may be benefi cial to maintain an unobstructed upper airway. the affected infant or child is often unable to take adequate fl uids complicated by increased insensible losses from the respiratory tract; hence, intravenous fl uids may be required. infants and children with severe respiratory distress should be kept npo in the event respiratory failure ensues and endotracheal intubation is required. antibiotics are not routinely indicated in previously healthy children infected with rsv. progressive disease, leukocytosis, persistent fever, consolidation on radiograph or systemic toxicity should prompt an evaluation of bacterial co-infection and the use of empiric antibiotics. high risk patients often require close monitoring and care in an intensive care unit. these include infants less than weeks of age or infants with a history of prematurity, congenital heart disease, bronchopulmonary dysplasia, immunodefi ciency or neurologic disease. infants with rsv bronchiolitis typically have a combination of hyperinfl ation, pulmonary infi ltrates, supportive therapy is the mainstay of treatment for bronchiolitis. ribavirin, bronchodilators, and corticosteroids have not shown to be of benefi t. secondary bacterial infections are rare. and atelectasis. therefore, no one mode of ventilation can be recommended for all infants. non-invasive positive pressure (niipp) modes (cpap or bipap) may be attempted in infants where their primary respiratory embarrassment is secondary to atelectasis. however, this may not be suitable if the disease process appears severe or protracted as prolonged use of nipp may make feeding diffi cult, cause breakdown of facial tissue, or be diffi cult to maintain without signifi cant sedation that further compromises ventilation. if an infant requires endotracheal intubation, the mode of mechanical ventilation should be tailored to the predominant lung pathology present (i.e. atelectasis versus hyperinfl ation). children with signifi cant air trapping may need mechanical ventilation similar to a child with asthma, providing low respiratory rates and longer inspiration and exhalation times. the more typical infant will lose functional residual capacity (frc) because of atelectasis and alveolar infi ltrates. therefore, despite having some air trapping, these infants often need peep to be adjusted to recruit alveoli and return frc to normal. in the setting of elevated pulmonary vascular resistance (pvr) which may occur in infants with congenital heart disease or bronchopulmonary dysplasia, lowering pvr by traditional methods such as maintaining oxygenation, deep sedation, muscle relaxation and even nitric oxide may be indicated. ribavirin is the only fda-approved antiviral drug for rsv. ribavirin inhibits viral replication and is active against rsv, infl uenza a and b, adenoviruses, and hepatitis viruses. for lower respiratory tract diseases, ribavirin is typically administered via aerosolization. in , a meta-analysis of studies involving ribavirin was discouraging and was consistent with the common clinical experience that ribavirin did not improve clinical outcomes. therapy targeted at attenuating the virus-induced infl ammatory cascade has also been disappointing. corticosteroid administration was not associated with reduction in clinical scores, the need for hospitalization, or the length of hospitalization. routine use of any corticosteroid given via any route (intravenous, enteral or aerosolized) is not indicated, except in patients with pre-existing chronic lung disease. bronchodilators have not shown a clear benefi t in patients with acute rsv bronchiolitis. in randomized control trials, involving infants, evaluating the effect of salbutamol or albuterol on bronchiolitis, ( %) showed no effect. the remaining three studies demonstrated only a small transient improvement in the acute clinical score. although the routine use of bronchodilator therapy cannot be recommended, it has become acceptable practice to attempt to see if individual infants are beta agonist responsive or not. if no clinical response is seen after a trial of a beta agonist, its use should be discontinued. in the s, fi ve randomized trials involving infants, evaluating the effect of nebulized adrenaline (epinephrine) on bronchiolitis showed clinical improvement, with reductions in oxygen requirement, respiratory rate, wheezing, and decrease in pulmonary vascular resistance. two of these studies showed lower hospital admission rates and earlier discharge. a cochrane systematic review suggested a potential benefi t with epinephrine administration. however, subsequent studies have not supported its routine use. as with albuterol, a clinical trial in selected infants seems reasonable. nebulized hypertonic saline has been used for treating hospitalized, as well as ambulatory, children with viral bronchiolitis with variable success. a recent cochrane meta-analysis of nebulized hypertonic saline has shown an improvement in clinical scores and decrease in hospital duration. several studies have evaluated the benefi t of surfactant and nitric oxide for severe respiratory distress. the results have been inconclusive and do not currently support their routine use. heliox, a mixture of oxygen ( - %) and helium ( - %) with lower viscosity than air has been used successfully in cases of airway obstruction, croup, airway surgery, and asthma to reduce respiratory effort during the period of airway compromise. several studies have shown improved respiratory distress scores in patients on heliox with continuous positive airway pressure obviating the need for intubation and mechanical ventilation. palivizumab is a neutralizing humanized mouse monoclonal antibody directed against the rsv-f glycoprotein. it was licensed by the food and drug administration (fda) in for premature infants and infants with bronchopulmonary dysplasia. the randomized, double blind, placebo controlled impact-rsv trial involving , high risk infants found a signifi cant reduction of % in hospitalizations. with the exception of very rare anaphylaxis, no signifi cant adverse effects have been observed. palivizumab has been approved for use in infants with congenital heart disease. the cardiac synagis study group included , children with congenital heart disease in a randomized, double blind, placebo controlled trial; it found a % relative reduction in rsv associated hospitalizations with no deaths attributable to the palivizumab. since cardiopulmonary bypass can decrease serum drug concentrations by about %, it is recommended that an additional dose be given following surgery, if continued protection is desired. palivizumab should be administered intramuscularly as mg/kg every days for a total of fi ve doses during rsv season, which is generally from november through march, to high risk infants. infants or children that develop an rsv infection should continue to receive prophylaxis following recovery because the naturally acquired antibodies are not fully protective. motavizumab, a new, enhanced potency, humanized rsv monoclonal antibody has demonstrated - times greater neutralizing activity against rsv. in completion of a phase iii trial, motavizumab was found equal to palivizumab for the prevention of rsv hospitalization and superior to palivizumab for reduction of rsv-specifi c outpatient medically attended lower respiratory tract infections (malris). pneumonia describes any infl ammatory condition of the lung in which the alveoli are compromised by aspirated foreign matter, infl ammatory fl uid, or cellular debris. infection is the primary cause of parenchymal injury to the lung. pathogens include viruses, bacteria and fungi. signs and symptoms of pneumonia are non-specifi c and may be occult in the young infant. children often have fever, chills, headache, malaise, restlessness, and irritability. gastrointestinal complaints such as abdominal pain, distention, or emesis may also be present in young children. the symptoms are often preceded by minor upper respiratory tract infections characterized by low-grade fever and rhinorrhea. with more signifi cant involvement of the lower respiratory tract, tachypnea, dyspnea, cough, nasal fl aring, grunting, or retractions may be seen. the older child may demonstrate productive sputum and complain of pleuritic chest pain. on auscultation of the chest, rales and/or decreased breath sounds might be heard over areas of consolidation or pleural effusions. however, due the short path for transmission of breath sounds and the small chest size in infants, breath sounds may not be decreased, even in the presence of effusions. children with pleural irritation might prefer to lie on the affected side with legs fl exed and may complain of radiating pain to the neck and shoulder or into the abdomen. community acquired pneumonia (cap) is a common, and at times, a serious infection in children. the incidence of cap is - cases per , children less than years of age and - cases per , children - years of age. the exact prevalence of the etiologic agents causing pediatric pneumonia is diffi cult to ascertain. it is often diffi cult to differentiate viral from bacterial pneumonia based solely on clinical examination. specifi c pathogens causing cap can be determined in only approximately one-third of children using commonly available cultures, antigen detection, or serologic techniques. blood cultures yield pathogens in only about - % of infants and children with bacterial cap and many children do not undergo viral testing as it is often unnecessary. with these inherent limitations, it is generally thought that viruses account for approximately % of cap in children under the age of years and approximately % of cap in preschool children ages - years. palivizumab should be used as preventive therapy in infants with chronic lung disease and congenital heart disease. cardiopulmonary bypass signifi cantly lowers the serum level of palivizumab, so it should be redosed following surgery if continued protection desired. viral causes decline in the school age and adolescent child and bacterial causes such as streptococcus pneumoniae and mycoplasma become important pathogens ( fig. - ) . overall, bacteria account for - % of community-acquired pneumonias. the likelihood of infection with different bacteria varies by age. in the newborn period, organisms from the maternal genital tract are likely causes and include group b streptococcus , escherichia coli , enteric gram-negative bacilli, listeria , and chlamydia . in older infants, streptococcus pneumoniae becomes a signifi cant cause and remains so until years of age. group a streptococcus and staphylococcus aureus are uncommon causes. moraxella catarralis is a common cause of upper respiratory tract disease, but rarely causes pneumonia. about % of infants with pertussis will have bacterial co-infection. in children older than years of age, streptococcus pneumoniae remains the most common cause. hemophilus infl uenzae type b (hib), and most recently streptococcus pneumoniae , have decreased signifi cantly as causes of cap due to the widespread use of effective vaccines. in the older child and young adolescent, the atypical pneumonias, mycoplasma and chlamydia , become more prevalent and viral causes less common. rare bacterial pneumonias can occur with animal contact and include: francisella tularensis (rabbits); chlamydia psittaci (parrots and birds); coxiella burnetii (sheep); and salmonella choleraesuis (pigs). children with congenital anatomical defects, immunodefi ciencies, and genetic disorders are at increased risk for bacterial, viral and fungal pneumonia. the airways are normally sterile below the sublaryngeal area to the lung parenchyma. there are several protective mechanisms that include anatomic and mechanical factors, local immune defenses, and the systemic immune response. microbes are fi ltered by nasal hairs or are expelled from the airways by the epiglottic refl ex, cough refl ex, and mucociliary apparatus. immunoglobulin a (iga) is the predominant immunoglobulin present in the upper respiratory tract. iga is able to bind two antigens simultaneously, forming large antigen-antibody complexes. in this manner, the microbes are neutralized and removed by ciliary clearance, thus preventing microbial binding to the epithelium. in the lower tract, immunoglobulin g (igg) provides humoral protection by opsonizing microbes for phagocytosis by neutrophils and macrophages, activating the complement cascade, and by neutralizing bacterial it is diffi cult to determine the etiologic agent causing pneumonia, but when microbial agents are identifi ed, bacteria are isolated in - %. etiology of community acquired pneumonia based on age endotoxin. alveolar macrophages produce superoxide anions, hydrogen peroxide, and hydroxyl radicals that serve an important role in the host defense; however, uncontrolled production can lead to lung injury. in addition to oxygen radicals, a number of cytokines are produced by the alveolar macrophages. these include il- , il- , tnf, transforming growth factor-β (tgf-b ), chemotactic factors, platelet derived growth factor, and m-csf. these cytokines play a central role in phagocytic recruitment and activation. infection occurs when one or more of the defense mechanisms is altered or if the inoculum is too large. pathogens typically gain entry through inhalation of aerosolized material or through aspiration of resistant organisms inhabiting the upper airways. less frequently, pneumonia can occur via hematogenous spread. in children with bacterial pneumonia, a signifi cant portion will have a concurrent or preceding viral infection. viral infection may predispose to bacterial superinfection by reducing clearance mechanisms and by weakening the host immune response. pathogens entering the lower airways evoke an exudative consolidation of pulmonary tissues. initially, there is hyperemia of lung parenchyma due to vascular engorgement and capillary leak causing exudation and intra-alveolar fl uid accumulation. fibrin is then deposited and the airways are infi ltrated with neutrophils. consolidation causes a decrease in lung compliance and vital capacity and a total reduction in the surface area available for gas exchange. a physiologic shunt (v/q mismatch) occurs as there is increased blood fl ow through poorly ventilated segments of lung, resulting in hypoxia. compensatory hypoxic vasoconstriction may occur in an attempt to reduce v/q mismatch and hypoxia, especially in localized areas of consolidation. with treatment, resolution of consolidation will occur in - days. the exudate undergoes enzymatic digestion and is either reabsorbed or removed by coughing. if the bacterial infection extends into the pleural cavity, an empyema may result. streptococcus pneumoniae is a gram-positive diplococcus that is frequently found in the upper respiratory tract. there are over capsular serotypes with % of infections caused by serotypes. it is the most common bacterial cause for pneumonia occurring at a peak age of - months. typically, it causes a lobar or segmental consolidation, but it may manifest as patchy infi ltrates in infants. pleural effusions occur in up to % of children that require hospitalization (fig. - ) . pneumatocoele formation is rare. hemolytic uremic syndrome is associated with neuraminidase-producing strains. treatment is typically with a penicillin or cephalosporin. emerging resistance may require initial therapy with vancomycin. in hospitalized patients, parenteral therapy is generally needed for - h after fever resolves, followed by completion of - days of enteral therapy. pneumococcal conjugate vaccines (pcv) have been developed that confer immunity against and serotypes. the -valent pcv (prevnar) was licensed for use in the united states in . a -valent pcv has been recently introduced and will replace the -valent pcv. the pcvs have been highly effective at reducing hospitalizations among children younger than years for pneumococcal pneumonia. pcv is now recommended universally for children younger than months of age and older children at high risk due to underlying diseases. high risk children include those with sickle cell disease and other types of functional asplenia, human immunodefi ciency syndrome, primary immunodefi ciency, children receiving immunosuppressive therapy, and children with chronic pulmonary or cardiac disease. a -valent pcv is available for pneumonia occurs when one or more of the host defense mechanisms are altered. viruses enhance the host susceptibility to bacterial pathogens by affecting clearing mechanisms and by weakening the host immune response. streptococcus pneumoniae is the most common bacterial cause for pneumonia. c hapter • ac ute pu lmonary i n fections high risk children who need expanded serotype coverage. children with sickle cell disease or functional asplenia should continue to receive antibiotic prophylaxis regardless of whether or not they have received pneumococcal vaccines. approximately - % of infants born to chlamydia trachomatis -infected mothers will become infected at one or more anatomical site, including conjunctiva, nasopharynx, rectum, and vagina. about % of infants with nasopharyngeal infections will develop pneumonia. the infants usually present at about - weeks of age with cough and congestion, but an absence of fever. the cough often interferes with the ability to feed. infants generally have tachypnea and rales on examination and chest x-ray frequently shows hyperinfl ation. a peripheral eosinophilia may be present. c . trachomatis is susceptible to macrolides, tetracyclines, quinolones, and sulfonamides. erythromycin for - weeks is the treatment of choice for neonatal pneumonia. mycoplasma pneumoniae and chlamydia pneumoniae play a greater role in causing respiratory tract disease in children then previously thought. an indolent course that develops over - days manifested by low-grade fever, scratchy sore throat, aches, and headaches characterizes both pathogens. after a few days, rales may be heard, particularly in the bases where the infi ltrates tend to occur. these organisms have been associated with the initiation, promotion, and exacerbation of asthma in children. in addition, a pertussis-like illness with acute bronchitis has been described. a recent study has shown that nearly half of the cases of community-acquired pneumonia in children aged - years were associated with m . pneumoniae or c . pneumoniae . classic atypical pneumonias caused by these organisms are usually mild and self-limited. however, a number of studies have suggested that severe pulmonary infection may occur in otherwise healthy children. pleural effusions, pneumatocoeles, lung abscesses, pneumothoraces, bronchiectasis, chronic interstitial fi brosis, and acute respiratory distress syndrome although rare complications, have all been reported. serological testing is the most common means of diagnosis, but this is often retrospective. cultures obtained from swabbing the nasopharynx may take several days to grow. pcr techniques are currently being refi ned and standardized. treatment with antibiotics reduces the rate of recurrent wheezing episodes, decreases morbidity, and shortens the duration of symptoms. the organisms are susceptible to tetracyclines, macrolides, and quinolones. the optimal doses and duration of treatment is unclear; however, some data suggest that prolonged treatment for greater than weeks may be more desirable to decrease symptoms and eradicate the organism from the nasopharynx. chlamydia pneumoniae have an increased prevalence in older children. chest radiograph of year old female with streptococcus pneumoniae pneumonia. note the combination of consolidation and effusion affecting the right lung. (image provided courtesy of fa maffei) staphylococcus aureus is a gram-positive organism that can be found on the skin, nasal mucosa, and other mucus membranes. about - % of children are carriers. it is generally spread by direct contact or by respiratory particles. s . aureus is an unusual cause of lower airway disease in otherwise healthy children. it is more typically isolated from infants and young children with debilitating conditions. primary s . aureus pneumonia presents in the winter or early spring with a short febrile prodrome and a rapid onset of pulmonary symptoms. blood cultures are positive in - % of patients. secondary staphylococcal pneumonia will have a more prolonged prodrome with no seasonal predilection, but is often seen after infl uenza infections. as this secondary pneumonia is usually a result of hematogenous spread, blood cultures are positive in about % of patients. unilateral lobar disease is more typical with primary disease, while diffuse bilateral infi ltrates are more frequent with secondary pneumonia. effusions can be diagnosed in about % of children at presentation, but ultimately will develop in about % of cases. pneumatocoeles occur in up to - % of children. treatment is with nafcillin or oxacillin, but more organisms are becoming resistant and require therapy for serious or invasive disease with vancomycin, linezolid, daptomycin, or quinupristin-dalfopristin. methicillin resistant staphylococcus aureus (mrsa) was once considered to be restricted to hospitals and long-term care facilities. however, community acquired mrsa (ca-mrsa) is now a signifi cant cause of a variety of infections (including pneumonia) in children without prior health care facility exposure. the majority of community acquired mrsa infections involve minor skin and soft tissue infections, but invasive and sometimes fatal infections can occur in otherwise healthy individuals. ca-mrsa and healthcare-associated mrsa (ha-mrsa) can be distinguished by several important features. patients with ca-mrsa by defi nition have not had recent hospitalization (acute or chronic care), prolonged antibiotic use or chronic underlying disease. toxin production also distinguishes ca-mrsa from ha-mrsa. panton valentine leukocidin (pvl) is a toxin which is present in most ca-mrsa isolates, but rarely in ha-mrsa isolates. pvl toxin lyses white blood cells leading to leukopenia and a decreased ability to kill s . aureus . its production has been implicated as a contributor to the development of ca-mrsa necrotizing pneumonia. ca-mrsa isolates, unlike ha-mrsa, lack multi-drug resistance. ca-mrsa is generally more susceptible to clindamycin, trimethoprim-sulfamethoxazole and doxycycline than ha-mrsa, probably because ha-mrsa has developed resistance to survive in the healthcare setting. group a betahemolytic streptococcus (gabhs) is a gram-positive organism responsible for about % of pharyngitis and tonsillitis in children. it is rare as a primary cause of pneumonia. when it does occur, the children generally have high fever and appear toxic. the pneumonia is typically lobar. associated empyemas are common and pneumatocoeles may develop. there are several virulent toxin-producing gabhs m-serotypes that are associated with toxic shock syndrome. pre-existing varicella disease with disruption of skin and soft tissue as the port of entry is reported approximately - % of the time. an associated pneumonia occurs in - % of children with toxic shock syndrome. gabhs are highly susceptible to penicillins and cephalosporins. in cases of toxic shock, clindamycin is often added to inhibit the production of streptococcal pyrogenic exotoxins a (spe-a) and b (spe-b). about - % of infants with perinatally acquired group b streptococcus (gbs) infections will have pneumonia. the infant usually has systemic disease and blood cultures are frequently positive. late-onset gbs is predominantly caused by the type iii serotype. in these infants, the infection is usually manifest as bacteremia without a focus or with meningitis. pneumonia is rare in late-onset disease. gbs is uniformly sensitive to penicillin. while staphylococcus aureus pneumonia is uncommon, effusions ultimately develop in about % of cases and pneumatocoeles occur in - %. pertussis, or "whooping cough" is a highly contagious respiratory tract infection caused by the gram-negative pleomorphic bacillus bordetella pertussis and less commonly bordetella parapertussis . with the development and widespread use of a vaccine in the s, a significant and sustained decrease in incidence has occurred. however, despite immunization rates greater than %, cyclical recurrences of the disease have occurred every - years since the s. this is likely secondary to the waning of immunity in adolescents and young adults. under-immunized or unimmunized infants are the most vulnerable. nearly all deaths reported from pertussis occur in infants younger than months of age. pertussis is often divided into catarrahal (fever, rhinnorhea and initiation of cough), paroxysmal (severe coughing episodes, lymphocytosis, potential for complications) and convalescent stages (slow waning of cough over weeks to months). complications include secondary bacterial or viral pneumonia, apnea, malnutrition, pulmonary hypertension and neurologic involvement including seizures and encephalopathy. infants less than months of age are at highest risk for complications and mortality. characteristic paroxysms of cough with an end inspiratory whoop occur in children. infants may present with a nonspecifi c cough with associated apnea and cyanosis, without a whoop. adolescents may be asymptomatic or have only a mild prolonged cough. an increased white blood count up to , with a lymphocytosis is characteristic early in the course of the disease. the preferred test for laboratory confi rmation is the detection of b. pertussis dna by pcr assay. bacteriologic culture provides a defi nitive diagnosis. if administered during the early stages of the disease (fi rst - days of illness), erythromycin for days may decrease symptoms and reduce the risk of spread. a day course of azithromycin or a - day course of clarithromycin has been found to be as effective with less gastrointestinal symptoms. corticosteroids, bronchodilators, or intravenous immunoglobulins have not demonstrated effi cacy. supportive care with supplemental oxygen, mechanical ventilation, intravenous fl uids, maintenance of adequate caloric intake, and treatment of secondary bacterial infections are the mainstay of therapy. the use of extracorporeal membrane oxygenation in infants with hypoxemia, pulmonary hypertension and right heart failure refractory to conventional mechanical ventilation has resulted in poorer outcomes than expected. vaccination in infancy with booster doses in adolescence is preventative. about - % of pneumonias in children are caused by viruses. there is considerable evidence that viral infections often precede bacterial pneumonias and cause weakening of the host defenses. viral pneumonias with rsv and parainfl uenza are discussed in more detail in the bronchiolitis section. infl uenza is the main viral cause of pneumonia in school-aged children requiring hospitalization. there are three serotypes, a, b, and c which are further divided into subtypes based on the hemagglutinin and neuraminidase genes. hemagglutinin , , and and neuraminidase and typically infect humans. the gene segments for the surface glycoproteins are unstable, so mutations, called antigenic shift, occur regularly. epidemics occur annually during the winter months with a short, - day incubation period. the virus causes destruction of the ciliated respiratory epithelium within day of symptoms. airway edema and infi ltration with infl ammatory cells into the airway mucosa and epithelium follows. slow repair occurs over - weeks. a severe fulminating pneumonia may result in hemorrhagic exudates that contain many polymorphonuclear and mononuclear cells. destruction of the respiratory epithelium often leads to secondary bacterial infections. during the - infl uenza season, infl uenza-related deaths occurred in children; of these, % were less than years of age. forty-fi ve percent of the older children ( - years of age) did not have an underlying medical condition. rare complications of although death from infl uenza pneumonia is uncommon, a signifi cant number of the children that died were previously healthy. infl uenza include acute myositis, rhabdomyolysis, myocarditis, pericarditis, reye syndrome, encephalitis, transverse myelitis, and guillain-barré syndrome. children may present with an abrupt clinical course manifested by high fever, myalgias, headaches, scratchy sore throats, and dry cough. peripheral white blood counts are usually less than , . pulmonary infi ltrates often involve multiple lobes. bacterial co-infection, especially with mrsa, increases morbidity and mortality signifi cantly. rimantidine and amantadine can shorten the course for infl uenza type a disease by limiting viral replication, but only if given within the fi rst h of the disease. prophylactic dosing is - % effective and does not interfere with antibody production from the vaccine. both drugs have central nervous system and gastrointestinal side effects, including an increase in the incidence of seizures. oseltamivir and zanamivir have recently been approved for the treatment of infl uenza infections in children. they inhibit neuraminidase, an enzyme produced by infl uenza a and b. the course of disease in healthy adults can be reduced by - days, if started within h of the onset of symptoms. zanamivir is a dry powder aerosol that must be delivered by a special breath-activated device. bronchospasm in patients with asthma has been reported. aspirin or aspirin-containing products should be avoided due to the risk of reye syndrome. immunoprophylaxis is the most effective strategy for the prevention of infl uenza infection. inactivated vaccines have effi cacy rates from % to %. currently, the inactivated vaccine is recommended for all children older than months of age with high risk conditions including chronic pulmonary or cardiac disease, immunosuppressive disorders, sickle cell disease and other hemoglobinopathies, diseases requiring long-term aspirin therapy, chronic metabolic and renal diseases; healthy children aged - months; and household contacts over the age of months of high risk persons. a live, attenuated infl uenza vaccine was licensed in . it is administered by the intranasal route and is approved for healthy children aged - years. avian infl uenza viruses do not normally infect species other than birds and pigs. however, in , the fi rst human death from avian infl uenza occurred in hong kong in a year old with reye syndrome. subsequently, an epidemic occurred among humans in hong kong with close contact to live, infected poultry. the subtype h n appears to be the most ominous due to its ability to rapidly mutate and infect new species. the overall mortality rate is greater than %. the avian viruses are not believed to be transmissible from person-to-person, but some recent cases are being investigated for this possibility. children uniformly present with fever and cough. symptoms range from typical infl uenza-like symptoms to conjunctivitis to respiratory disease and failure. signifi cant laboratory data include leukopenia and thrombocytopenia. all children who developed pneumonia and progressed to ards died. diagnosis remains diffi cult, as no tests are widely available. of the antiviral drugs available for infl uenza a, the most recent h n strains in southeast asia are resistant to rimantadine and amantadine. therefore, treatment is mainly supportive. a prototype h n vaccine was made available to manufacturers in april , but production is diffi cult because the standard means of producing infl uenza vaccines from specially grown chicken eggs is not feasible. h n kills the embryo before enough viruses can be harvested for vaccine production. in april, , the centers for disease control confi rmed the emergence of a novel infl uenza a (h n ) virus with genes from swine viruses of the eurasian lineage and genes from avian infl uenza viruses. by june, , the fi rst infl uenza pandemic since was declared, affecting over countries and territories. in comparison to illnesses with seasonal infl uenza, the majority of cases occurred in individuals younger than years of age, with nearly half of the cases occurring in children under years of age . the clinical symptoms can be typical for infl uenza; fever, sore throat, cough, and muscle aches with the addition of vomiting and diarrhea in children. a wide range of complications although antiviral medications may attenuate the course of infl uenza when given early, immunoprophylaxis with vaccines is the most effective strategy for the control of infl uenza infections. avian infl uenza has occurred in epidemics among persons with close contact to live, infected poultry. all children with pneumonia that progressed to ards succumbed to the disease. have been reported that include mild-to-moderate (otitis media, sinusitis, myositis, and febrile seizures) to more severe complications such as myocarditis, rhabdomyolysis or encephalitis. severe complications may frequently involve invasive bacterial co-infection (i.e. mrsa) and/or exacerbation of underlying medical conditions in particular asthma. children who present initially with uncomplicated infl uenza may have rapidly progressive hypoxemic respiratory failure and multiorgan system dysfunction that is refractory to all therapies ( fig. - ) . of reported h n deaths, approximately % were in children. the majority of these children had comorbid asthma, neuro-developmental conditions, or obesity. an american academy of pediatrics work group identifi ed children at greatest risk for life-threatening h n infl uenza disease (table - ) . the centers for disease control has recommended prompt empiric antiviral therapy for infants, children, and adolescents of any age presenting with suspected or confi rmed h n infl uenza and any of the following conditions: illness requiring hospitalization ■ progressive, severe, or complicated illness, regardless of previous health ■ presence of signifi cant risk factors (see table ■ - ) the h n strain has been found to be resistant to amantadine and rimantadine, but is usually sensitive to neuraminidase inhibitors, specifi cally oseltamivir or zanamir. in , oseltamivir was emergently approved for treatment in children less than months of age. resistance to oseltamivir has been reported and is thought due to the h y mutation. interestingly, the mutation confers resistance to oseltamivir, but not to zanamivir. peramivir, a neuraminidase inhibitor, an unapproved (investigational) antiviral available in an intravenous formulation received an emergency use authorization permit from the fda for use in children with confi rmed severe refractory h n infl uenza. its use should be restricted to children that are not responding to either oral or inhaled antiviral drugs or if the parenteral route is the only dependable method of drug delivery. a vaccine was manufactured and licensed using the same standards as seasonal infl uenza by late . a single dose was found to provide adequate protection in children older than years of age, younger children requiring two doses separated by at least days. adenoviruses have been implicated in - % of pneumonias in children. adenoviruses are classifi ed into serotypes with types , , a, , and being the most common etiologic agents of lower respiratory disease and causing a severe necrotizing pneumonitis. these serotypes are associated with serious pulmonary sequelae, such as bronchiectasis, bronchiolitis obliterans, unilateral hyperlucent lung, and persistently abnormal pulmonary function tests. adenovirus infections peak between months and years of age. mortality from severe respiratory infections can be high, because the disease often involves multiple organ systems. survivors may have permanent lung injury often in the form of bronchiolitis obliterans. in the immunocompromised host, mortality rates are as high as - %. cidofovir has in vitro activity against adenovirus, but proof of effi cacy is limited. therapy is supportive. severe acute respiratory syndrome is a newly described pulmonary infection caused by a novel sars-associated coronavirus. sars-cov is highly contagious and was coined "the fi rst plague of the twenty-fi rst century". the disease rapidly spreads among household contacts and healthcare personnel. children less than years of age account for only approximately % of those affected, with a mean age of years. no deaths were reported among children in the outbreak. children and adults present with fever, malaise, cough, coryza, chills or rigor, sputum production, headache, myalgia, leukopenia, lymphopenia, thrombocytopenia, mildly elevated activated partial thromboplastin times, and elevated levels of lactate dehydrogenase. radiographs of the chest show non-specifi c infi ltrates. apart from diarrhea, patients have minimal extrapulmonary symptoms. early diagnosis by reverse transcription-polymerase chain reaction (rt-pcr) can be made with % sensitivity on nasopharyngeal aspirates within the fi rst days of the illness. the clinical course follows a triphasic pattern. there is an incubation period of - days with a prodrome of high fever, chills, malaise, headache, and myalgias. diarrhea occurs in up to % of adults. after - days, the disease progresses to involve the lower airways with a dry non-productive cough and dyspnea. in - % of cases, acute respiratory distress syndrome (ards) follows and often patients require mechanical ventilation. deaths occur from respiratory failure. young children run a milder and shorter biphasic clinical course. cough is found in approximately half the children, and crackles are rarely heard despite radiographic evidence of infi ltrates. a regimen of antibiotics, ribavirin, and corticosteroids was proposed based on initial anecdotal success. however, ribavirin has demonstrated minimal activity against sars-cov isolates in vitro . non-randomized studies of corticosteroids have reported favorable outcomes. a pediatric series of children with confi rmed sars treated with ribavirin and corticosteroids showed no adverse effects and all survived. mortality from adenovirus infections remains high because of multiple organ system involvement. sars rarely affects children, and when it does, morbidity is less, with no reported mortalities. . neurological disorders, such as epilepsy, cerebral palsy, developmental delay and neuromuscular disorders . chronic respiratory diseases associated with impaired pulmonary function and/or diffi culty handling lung secretions, moderate and especially severe persistent asthma, technology-dependent children (e.g., those requiring oxygen, tracheostomy, or a ventilator) . primary immunodefi ciencies or conditions that require medications or treatments that result in secondary immunodefi ciencies . congenital heart disease . metabolic (e.g., mitochondrial) or endocrine disorders, especially if cardiopulmonary function is impaired adapted from http://www.aap.org/new/swinefl u.htm hantavirus cardiopulmonary syndrome is a viral zoonotic disease that affects healthy children and adolescents who are exposed to aerosols of rodent excreta. the deer mouse is the main rodent reservoir. most cases occur in the southwestern united states, but cases have been confi rmed in states. hcps presents with a prodrome of fever, chills, myalgia, headache, and gastrointestinal symptoms. respiratory compromise requiring supplemental oxygen generally occurs within h. the disease can progress to respiratory distress and ards. the majority of deaths result from hypoxemia and cardiac dysfunction with marked hypotension and ventricular arrhythmias. in adults, the case fatality rate is approximately %. a recent case series of children aged - years, revealed that % of infected children developed hcps, % died, and % were critically ill and required mechanical ventilation. treatment is supportive as ribavirin has not been proven to reduce mortality. extracorporeal membrane oxygenation was used on two patients, one of which survived. laboratory evaluation reveals thrombocytopenia, leukocytosis, and circulating immunoblasts. an elevated prothrombin time of ³ s is predictive of severe disease. no deaths were reported in children younger than years of age. diagnosis can be made by detection of hantavirus-specifi c immunoglobulin m, hantavirus-specifi c rna by polymerase chain reaction, or hantavirus antigen by immunohistochemistry. respiratory infections in children with primary or acquired immunodefi ciencies requiring intensive care are not uncommon. these infants and children are susceptible to many organisms that are rarely pathogenic in a normal host. primary immunodefciencies include abnormalities or defi ciencies in immunoglobulins and antibodies, t and b cells, phagocytes, natural killer cells, and complement. acquired immunodefi ciencies include asplenia, human immunodefi ciency virus (hiv), corticosteroid therapy, and immunosuppresion used for marrow or solid organ transplants. immunocompromised children can present with attenuated signs and symptoms of respiratory infections. in addition to physical examination and chest roentgenograms, these children often require chest computed tomography to better delineate the extent of disease. bronchoalveolar lavage, needle aspiration, or lung biopsies might be required to make a defi nitive diagnosis. pulmonary specimens should be tested for common bacteria as well as for pneumocystis carinii, acid-fast bacilli, nocardia, legionella, crytococcus, aspergillus, candida, histoplasma, coccidioides, and blastomyces. viruses such as cytomegalovirus, varicella, herpes virus, and measles should be considered. pneumocystis carinii (now known pneumocystis jiroveci ) is an opportunistic pulmonary pathogen in infants and children with human immunodefi ciency virus (hiv) and other primary immunodefi ciencies, malnutrition, hematological malignancies, solid organ and bone marrow transplant recipients, and patients on high dose corticosteroid therapy for infl ammatory and collagen-vascular diseases. it is a unicellular organism that exists as a cyst (the diagnostic form). the organism attaches to the type i alveolar cells resulting in an alveolitis characterized by ventilation-perfusion mismatch and decreased pulmonary compliance. if untreated, pcp carries a mortality rate of - %, and nearly % in the hiv-seropositive child. fortunately, the incidence has markedly decreased with the administration of chemoprophylactic agents to high risk patients. children typically present with fever, tachypnea, non-productive cough, and hypoxia with an absence of rales on auscultation of the chest. initially, they may have an elevated ph and low carbon dioxide levels. lactate dehydrogenase levels are generally elevated. bilateral diffuse alveolar infi ltrates are seen with initial hilar involvement subsequently spreading to the periphery (fig. - ) . diagnosis is made by demonstrating the organism with the methenamine silver nitrate stain on pulmonary tissue, respiratory secretions, or lung fl uid. bronchoalveolar lavage is the most widely used technique to obtain lung fl uid for diagnosis. treatment consists of supportive therapy hantavirus is rare in infants and school-aged children. no deaths have been reported in children less than years of age. with supplemental oxygen; ultimately continuous positive airway pressure or mechanical ventilation may be necessary if respiratory failure occurs. trimethoprim-sulfamethoxazole (tmp-smx) is the recommended initial treatment. in patients that cannot tolerate tmp-smx, then pentamidine isoethionate should be used. corticosteroids in anti-infl ammatory doses as an adjunct to antimicrobial therapy have improved clinical outcomes. concurrent pulmonary infections were found in % of patients, most frequently bacterial or cytomegalovirus pneumonia. determination of the etiologic agent in pneumonia is diffi cult. fortunately, in most community-acquired pneumonias, identifi cation of the specifi c causative organism is not critical. however, in children with a complicated course that fails to respond to standard therapies, defi nitive diagnosis of the etiologic agent is essential. complete blood counts, infl ammatory markers, and chest radiographs do not differentiate the causative agents for pneumonia. blood cultures are rarely positive outside of the neonatal period. rapid antigen tests are available for rsv, parainfl uenza, infl uenza, and adenovirus. nasopharyngeal swabs for viral cultures generally take - days to become positive, and in one study, % of the patients had been discharged prior to the positive results. older children and adolescents might be able to produce sputum for gram stain and culture. an adequate specimen should contain more the leukocytes and fewer than squamous epithelial cells per low-power fi eld. in the intubated patient, sputum can be more easily acquired. however, interpretation of the results of gram stains and cultures is at times diffi cult in differentiating colonizing from pathologic organisms. colonization of the endotracheal tube may occur as early as h, but most frequently between and h. the oropharynx becomes colonized within h, the stomach at - h, and the lower respiratory tract between and h. in addition, a comparison of infectious agents isolated by both tracheal aspirates and bronchoalveolar lavage found only % concordance. bronchoalveolar lavage (bal) can be safely used to obtain secretions from the lower airways for gram stain and culture. it is especially useful in the diagnosis of pneumonia in the immunocompromised child. however, bal performed directly through the bronchoscope carries a risk of contamination. the smallest bronchoscope that can accommodate a protected specimen brush is . mm and requires a . mm endotracheal tube for passage. the smallest fl exible fi beroptic bronchoscope with a suction channel has an external chest radiograph of severe pneumocystis carinii pneumonia in a month old male with combined immunodefi ciency. note the diffuse alveolar involvement and air bronchograms. (image provided courtesy of fa maffei) diameter of . mm and is too small to admit a double-sheathed brush. non-bronchoscopic double-lumen plugged catheters can be inserted blindly through the endotracheal tube to obtain a non-contaminated specimen. the sensitivity and specifi city of these samples are similar to those obtained by a bronchoscopic guided protected specimen. transthoracic needle aspirations are performed in some centers with good results. one study reported a diagnostic success rate in % of patients. the incidence of pneumothorax was approximately %, but none required subsequent placement of a pleural drainage catheter. a lung biopsy is rarely needed to make a defi nitive diagnosis. supportive treatment with oxygen and intravenous fl uids are often standard therapies. as both pneumonia and mechanical ventilation can cause an elevation in anti-diuretic hormone levels, careful fl uid monitoring is essential to avoid overhydration, excessive lung water and hyponatremia. initial antibiotic choices should be empiric and based upon the likely organisms for each age group, because of the diffi culty in identifying the causative agent. the child's respiratory status including respiratory rate, work of breathing, pulse oximetry, and central nervous system response should be closely monitored. non-invasive bi-level positive airway pressure (bipap) has been effective for use in children with mild to moderate respiratory insuffi ciency, defi ned as an a-a gradient > and < or pao /fio ratio < but > mm hg. serial evaluation of mask-face contact areas is essential to avoid skin breakdown. children with moderate or severe respiratory insuffi ciency often require intubation and mechanical ventilation. children with respiratory failure secondary to pneumonia often require increased positive end expiratory pressure (peep), increased inspiratory time, and aggressive pulmonary toilet to recruit alveoli. for patients requiring high levels of peep, adequate sedation is often required to prevent patient/ventilator asynchrony and barotrauma. spontaneous respirations should be encouraged while on mechanical ventilation. rarely, the use of neuromuscular blockade is required to allow mechanical ventilation. prone positioning may improve ventilation/perfusion (v/q) mismatching in dependent lung regions. lung protective strategies allowing permissive hypercapnea with small lung volumes to ventilate and appropriate peep to maintain alveolar recruitment is recommended for children with pneumonia. high frequency oscillatory ventilation can also be utilized to maintain mean airway pressure and alveolar recruitment. airway pressure release ventilation (aprv) provides recruitment of alveoli while allowing spontaneous respirations. in children with severe respiratory distress syndrome, treatment with bovine surfactant may improve oxygenation. extracorporeal life support continues to have a role in children with reversible severe acute hypoxemic respiratory failure refractory to mechanical ventilation. pneumonias can often be complicated by the development of pleural effusions and empyemas. these occur when the fl uid production by the interstitial lung tissue exceeds the maximum pleural lymphatic fl ow. parapneumonic effusions often occur from pneumonia as white blood cells and other debris of infection block the lymphatics resulting in elevation of protein in the pleural space, increase in colloid osmotic pressure, and consequent failure of fl uid reabsorption. on physical exam, the child will have decreased breath sounds over the effusion. in older children, auscultatory percussion changes might be appreciated. plain chest radiographs can reveal most clinically signifi cant effusions. ultrasound and chest computed tomograms are useful in determining the volume and quality of the fl uid and the presence of loculations. simple parapneumonic effusions or transudates can also be differentiated from exudates by using the criteria of light et al. (table - ). a pleural fl uid ph less than . indicates a complicated effusion that is likely exudative and requires drainage whereas a pleural fl uid ph more than . suggests that the effusion may be managed with systemic antibiotics alone. complicated parapneumonic effusions or empyemas occur when the fl uid becomes purulent. during this stage, the effusions undergo a fi brinopurulent stage with many polymorphonuclear leukocytes, bacteria, and cellular debris entering the fl uid. fibrin is deposited over the pleural surfaces and loculations begin to form. the ph and glucose levels fall as the ldh levels rise. if untreated, they often progress to a third organizing stage in which the exudate non-invasive bipap ventilation can be effective for children with moderate respiratory insuffi ciency. develops into an inelastic, fi brotic peel that restricts the lung. simple parapneumonic effusions usually resolve with thoracentesis or tube thoracostomy and antibiotic treatment of the pneumonia. more complicated parapneumonic effusions have been successfully treated with thoracotomy tubes and fi brinolytics. however, although risks for bleeding are reportedly low, this therapy requires close monitoring of chest tube drainage and instillation of expensive medications with intermittent clamping of the chest tube. no single recommendation for the choice of fi brinolytic agent or dosage has been established. also, if tried late in the organizing phase, this is often unsuccessful due to loculations and the high viscosity of the purulent fl uid. surgical debridement either by open procedure or by video-assisted thorascopic surgery (vats) is often needed for organizing, complicated parapneumonic effusions. multiple studies have reported that early vats or thoracotomy for empyema leads to a shorter hospital stay. the treatment modality is best determined by the temporal stage and nature of the effusion. acute pulmonary infections are common diagnoses that require admission to the pediatric intensive care units. understanding the pathophysiology of lower respiratory infections enables the intensivist to tailor therapy to the individual child and pathogen. early establishment of a specifi c etiology and the selection of the correct treatment plan directly impacts clinical outcome. video-assisted thorascopic surgery (vats) for the treatment of empyemas has been associated with shorter hospital stay. which of the following therapies have been proven to be a consistent benefi t for rsv bronchiolitis? a. aminophylline b. bronchodilators c. corticosteroids d. ribavirin e. supportive care . palivizumab is indicated for which of the following children? a. a month old, former week premature infant who just underwent surgical repair of a large ventricular septal defect who received palivizumab weeks ago b. a month old, former week premature infant with mild bronchopulmonary dysplasia who received palivizumab weeks ago c. a month old, former week premature infant with peripheral pulmonic stenosis who has never received palivizumab d. a month old full term infant with a urea cycle defect who has never received palivizumab e. an month old, former week premature infant with bronchopulmonary dysplasia who received his fi fth dose of palivizumab a month ago pleural fl uid may be classifi ed as exudative, if one or more of the following criteria are met: ■ pleural fl uid protein divided by serum protein > . (sensitivity %, specifi city %) ■ pleural fl uid lactate dehydrogenase (ldh) divided by serum ldh > . (sensitivity %, specifi city %) ■ pleural fl uid ldh is more than two-thirds of the upper limit of normal for serum ldh (sensitivity %, specifi city %) adapted from light ( ) human bocavirus and acute wheezing in children american academy of pediatrics subcommittee on diagnosis and management of bronchiolitis. diagnosis and management of bronchiolitis the yield of fl exible fi beroptic bronchoscopy in pediatric intensive care patients immunological mechanisms of severe respiratory syncytial virus bronchiolitis human metapneumovirus infection in young children hospitalized with acute respiratory tract disease: virologic and clinical features a multicenter, randomized, controlled trial of dexamethasone for bronchiolitis natural infection of infants with respiratory syncytial virus subgroups a and b: a study of frequency, disease severity, and viral load the use of albuterol in hospitalized infants with bronchiolitis advances in the treatment and prevention of severe viral bronchiolitis the presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically signifi cant congenital heart disease systemic corticosteroids in infant bronchiolitis: a meta-analysis drainage, fi brinolytics, or surgery: a comparison of treatment options in pediatric empyema does vats provide optimal treatment of empyema in children? a systematic review intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children clinical picture, diagnosis, treatment, and outcome of severe acute respiratory syndrome (sars) in children noninvasive therapy with helium-oxygen for severe bronchiolitis pleural effusion pleural effusions: the diagnostic separation of transudates and exudates nebulized % hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis development of wheezing disorders and asthma in preschool children heliox therapy in infants with acute bronchiolitis nasal continuous positive airway pressure with heliox versus air oxygen in infants with acute bronchiolitis: a crossover study diagnosis and management of pneumonia in children community-acquired pneumonia in children selected populations at increased risk from respiratory syncytial virus infection human metapneumovirus and human bocavirus in children mixed respiratory virus infections mycoplasma pneumoniae and chlamydia pneumoniae cause lower respiratory tract disease in paediatric patients children's hospital respiratory syncytial virus database: risk factors, treatment and hospital course in infants and young children infection with sin nombre hantavirus: clinical presentation and outcome in children and adolescents ribavirin for respiratory syncytial virus lower respiratory tract infection: a systematic overview risk of bacterial infection in previously healthy respiratory syncytial virus-infected young 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intensive care etiological diagnosis of childhood pneumonia by use of transthoracic needle aspiration and modern microbiological methods a multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis respiratory syncytial virus and other respiratory viruses effect of exogenous surfactant (calfactant) in pediatric acute lung injury. a randomized controlled trial current concepts on pulmonary host defense mechanisms in children nebulized hypertonic saline solution for acute bronchiolitis in infants bronchiolitis: recent evidence on diagnosis and management key: cord- -f dukpso authors: niederman, m.s. title: pneumonia | community acquired pneumonia, bacterial and other common pathogens date: - - journal: encyclopedia of respiratory medicine doi: . /b - - - / - sha: doc_id: cord_uid: f dukpso community-acquired pneumonia (cap) is the number one cause of death from infectious diseases in the us, and the patient population that is affected is becoming increasingly more complex due to the presence of chronic illness which is commonly managed in outpatients who are at risk for pneumonia. the number one pathogen causing cap is pneumococcus, which is commonly resistant to multiple antibiotics, thus complicating management. other common pathogens include atypical organisms (chlamydophila pneumoniae, legionella pneumophila, mycoplasma pneumoniae), hemophilus influenzae, enteric gram-negatives (especially in those with chronic illness and aspiration risk factors), and staphylococcus aureus. successful management requires careful assessment of disease severity so that a site-of-care decision can be made (outpatient, inpatient, intensive care unit), appropriate samples for diagnostic testing collected, and antibiotic therapy initiated in a timely and accurate fashion. initial antibiotic therapy is empiric, but even with extensive diagnostic testing, less than half of all patients have an etiologic pathogen identified. all patients with cap require therapy for pneumococcus, atypical pathogens, and other organisms, as dictated by the presence of specific risk factors. because pneumonia has both short-term and long-term impact on mortality, it is also important to focus on prevention of this illness, which requires smoking cessation, and giving at-risk individuals both pneumococal and influenza vaccines. pneumonia, a respiratory infection of the alveolar space, can vary from a mild outpatient illness to a severe illness necessitating hospitalization and intensive care. it is the sixth leading cause of death in the us and the number one cause of death from infectious diseases. when the infection occurs in patients who are living in the community it is termed community-acquired pneumonia (cap), while it is called nosocomial pneumonia if it arises in patients who are already in the hospital. presently, the distinction between community-acquired and nosocomial infection is less clear because the 'community' includes complex patients such as those who have recently been hospitalized, those in nursing homes, and those with chronic diseases who are commonly managed in such facilities as dialysis centers or nursing homes. when this latter group develops pneumonia, it has been termed healthcare associated pneumonia (hcap) and this illness shares clinical features with cap, but the etiologic pathogens may overlap with those seen in more traditional nosocomial pneumonia. thus, the relationship between bacteriology and the site of origin of infection is a reflection of several factors, including: the types of patients who develop the illness, their host defense related predisposition to infection with specific pathogens, and their environmental exposure to certain organisms. this discussion focuses on pneumonia arising out of the hospital in immune-competent individuals, but excludes discussion of patients with human immunodeficiency virus (hiv) infection or traditional immune suppression (cancer chemotherapy, immune suppressive medications). in , over . million people were diagnosed with cap in the us, but the majority, . million, were treated out of the hospital. although the majority of cases of cap are managed in the outpatient setting, the greater part of the cost of treatment is focused on hospitalized patients. those who are admitted to the hospital commonly tend to be older and have a high frequency of comorbid illness. in the us, the population of elderly patients is increasing, and those aged over make up about one-third of all cap patients, but this group accounts for more than half of the cost because of the frequent need for elderly cap patients to be hospitalized. the reported mortality of cap varies with the population being evaluated, ranging from less than % among outpatients, to % among all hospitalized cap patients, but rising to over % among those admitted to the intensive care unit (icu). while most studies have focused on the in-hospital mortality of cap, one recent evaluation of cap patients over the age of found that while the short-term risk (in-hospital mortality) of illness was an % death rate, the mortality rate at year was over %, emphasizing that for many patients, cap is a marker of underlying serious comorbidity, and a predictor of poor outcome, even after hospital discharge, for a variety of reasons. these findings add to the emphasis on pneumonia prevention, especially through the use of available vaccines. the complexity of cap management is also increasing because the etiologic pathogens are changing. historically, cap was regarded as a bacterial illness caused by one pathogen, streptococcus pneumoniae. today, the number of etiologic pathogens has mushroomed to include not only bacteria, but also viruses (influenza, severe acute respiratory syndrome (sars)), fungi, and a number of other recently identified organisms (such as legionella, chlamydophila pneumoniae). not only is the number of pathogens expanding, but our ability to treat is being challenged by the rising frequency of resistance among bacteria to a wide range of commonly used, and often overused, antimicrobial agents. pneumonia is an infection of the gas-exchanging units of the lung, most commonly caused by bacteria, but occasionally caused by viruses, fungi, parasites, and other infectious agents. in the immunocompetent individual, it is characterized by a brisk filling of the alveolar space with inflammatory cells and fluid. if the alveolar infection involves an entire anatomic lobe of the lung, it is termed 'lobar pneumonia', and multilobar illness can be present in some instances. when the alveolar process occurs in a distribution that is patchy, and adjacent to bronchi, without filling an entire lobe, it is termed as 'bronchopneumonia'. pneumonia occurs when a patient's host defenses are overwhelmed by an infectious pathogen. this can happen because the patient has an inadequate immune response, often as a result of underlying comorbid illness (congestive heart failure, diabetes, renal failure, chronic obstructive lung disease, malnutrition), because of anatomic abnormalities (endobronchial obstruction, bronchiectasis), as a result of acute illness-associated immune dysfunction (as can occur with sepsis or acute lung injury), or because of therapy-induced dysfunction of the immune system (corticosteroids, endotracheal intubation). pneumonia can also occur in patients who have an adequate immune system, if the host defense system is overwhelmed by a large inoculum of microorganisms, which can occur in a patient with massive aspiration of gastric contents. in patients outside the hospital, a normal immune system can be overcome by a particularly virulent organism, to which the patient has no pre-existing immunity (such as certain bacteria or viruses) or to which the patient has an inability to form an adequate acute immune response. bacteria can enter the lung via several routes, but aspiration from a previously colonized oropharynx is the most common way that organisms lead to pneumonia. although most pneumonias result from microaspiration, patients can also aspirate large volumes of bacteria if they have impaired neurologic protection of the upper airway (stroke, seizure), or if they have intestinal illnesses that predispose to vomiting. other routes of entry include inhalation, which applies primarily to viruses, legionella pneumophila and mycobacterium tuberculosis; hematogenous dissemination from extrapulmonary sites of infection (right-sided endocarditis); and direct extension from contiguous sites of infection (such as liver abscess). keeping these concepts in mind, it is easy to understand why previously healthy individuals develop infection with virulent pathogens such as viruses, l. pneumophila, mycoplasma pneumoniae, c. pneumoniae, and s. pneumoniae. on the other hand, chronically ill patients can be infected by these organisms, as well as by organisms that commonly colonize patients, but only cause infection when immune responses are inadequate. these organisms include enteric gram-negative bacteria (escherichia coli, klebsiella pneumoniae, pseudomonas aeruginosa, acinetobacter spp.) and fungi. recent studies have evaluated the normal lung immune response to infection and have shown that it is generally 'compartmentalized', and thus most patients with unilateral pneumonia have an inflammatory response that is limited to the site of infection, not spilling over to the uninvolved lung or to the systemic circulation. in patients with localized pneumonia, tumor necrosis factor (tnf) and interleukins and (il- , il- ) levels were increased in the pneumonic lung and generally not increased in the uninvolved lung or in the serum. in patients with severe pneumonia, the immune response is characterized by a spillover of the immune response into the systemic circulation, reflected by increases in serum levels of tnf and il- . it remains uncertain why localization does not occur in all individuals, and why some patients develop diffuse lung injury (acute respiratory distress sydrome, ards) or systemic sepsis as a consequence of pneumonia. recent studies have suggested that genetic polymorphisms may explain some of these differences, with patients who have certain inherited patterns of immune response being more prone than others to severe forms of pneumonia, and even mortality from this illness. for example, certain genetic polymorphisms are associated with a greater risk of death from sepsis but not cap. specifically, tnf- polymorphisms increase sepsis mortality, but not mortality from cap. in addition, cap severity is increased with genetic changes in the il- - locus, which are often present along with changes in the tnf- locus. another genetic change associated with an increased risk of septic shock from cap is a modification in heat shock protein - . currently, we are aware of the large number of genes that can affect the severity and outcome of cap, but much more must be learned to put these findings into a true clinical context. even with extensive diagnostic testing, an etiologic agent is defined in only about half of all patients with cap, pointing out the limited value of diagnostic testing, and the possibility that we do not know all the organisms that can cause cap. for example, in the past three decades, a variety of new pathogens for this illness have been identified, including l. pneumophila, c. pneumoniae, hantavirus, and the sars virus (a coronavirus). in addition, antibiotic resistant variants of common pathogens such as s. pneumoniae (pneumococcus) have become increasingly common and are referred to as drug-resistant s. pneumoniae (drsp). for all patients with cap, pneumococcus (including drsp) is the most common pathogen, and some studies have suggested that it may be responsible for many of the patients with no established etiologic diagnosis, using standard diagnostic methodology. recent studies have also suggested that atypical pathogens (m. pneumoniae, c. pneumoniae, and l. pneumocphila) are common in patients with cap, often as copathogens, along with bacterial organisms. viruses may be present in up to % of all patients, but specialized diagnostic testing, usually involving acute and convalescent titers, is needed, thus explaining the ordinary low frequency of documenting these organisms. hemophilus influenzae is a common organism in patients who smoke cigarettes, and in those with chronic obstructive lung disease. enteric gramnegatives are not common causes of cap, but can be present in up to % of hospitalized patients, particularly those with advanced age, comorbid illness, or a high likelihood of aspiration. in general, certain specific patients are at risk for infection with specific pathogens, in different frequencies. table summarizes the common pathogens causing cap in both outpatients and inpatients. the classification is based on the severity of illness and the presence of clinical risk factors for specific pathogens, referred to as modifying factors. patients with severe cap may have a slightly different spectrum of organisms than less severely affected individuals, being commonly infected with pneumococcus, atypical pathogens, enteric gram-negatives (including p. aeruginosa), staphylococcus aureus, and h. influenzae. the modifying factors that increase the risk of infection with drsp are: age over years, beta-lactam therapy within the past months, alcoholism, immune suppressive illness (including therapy with corticosteroids), multiple medical comorbidities, and exposure to a child in a day care setting. the modifying factors for enteric gram-negatives include: residence in a nursing home, underlying cardiopulmonary disease, multiple medical comorbidities, and recent antibiotic therapy. the risk factors for p. aeruginosa infection are: structural lung disease (bronchiectasis), corticosteroid therapy ( mg day À prednisone), broad-spectrum antibiotic therapy for days in the past month, and malnutrition. table shows that certain clinical conditions are associated with specific pathogens, and these associations should be considered in all patients when obtaining a history. as mentioned, s. pneumoniae is the most common pathogen for cap, in any patient population, possibly even among those without an etiology recognized by routine diagnostic testing. in one study, transthoracic needle aspirates were used to define the etiology of cap in patients with no identified organisms by conventional diagnostic testing, using a polymerase chain reaction (pcr) probe analysis of the samples, and in half of the patients in whom the needle provided a diagnosis when other methods had failed, pneumococcus was identified. the organism is a gram-positive, lancet-shaped diplococcus, of which there are different serotypes, each with a distinct antigenic polysaccharide capsule, but % of all infections are caused by one of serotypes, which are now included in a vaccine. infection is most common in the winter and early severe cap, with risks for p. aeruginosa all of the pathogens above, plus p. aeruginosa pneumococcus resistant to the class of agents to which the patient was recently exposed spring, which may relate to the finding that up to % of patients have a preceding viral illness. the organism spreads from person to person, and commonly colonizes the oropharynx before it leads to pneumonia. pneumonia develops when colonizing organisms are aspirated into a lung that is unable to contain the aspirated inoculum. infection is more common in the elderly; those with asplenia, multiple myeloma, congestive heart failure, or alcoholism; after influenza; and in patients with chronic lung disease. in patients with hiv infection, pneumococcal pneumonia with bacteremia is more common than in healthy populations of the same age. the classic radiographic pattern is a lobar consolidation, but bronchopneumonia can also occur, and in some series, this is the most common pattern. bacteremia is present in up to % of hospitalized patients with this infection, but the impact of this finding on mortality is uncertain. extrapulmonary complications include meningitis, empyema, arthritis, endocarditis, and brain abscess. since the mid- s, antibiotic resistance among pneumococci has become increasingly common, and penicillin resistance, along with resistance to other common antibiotics (macrolides, trimethoprim/sulfamethoxizole, selected cephalosporins), is present in over % of these organisms. fortunately, in the us, a large number of penicillin-resistant organisms are of the intermediate type (penicillin minimum inhibitory concentration, or mic, of . - . mg l À ) and not of the high-level type (penicillin mic of . mg l À or more). it is difficult to show a clinical impact of in vitro resistance on outcomes such as mortality in large numbers of patients, but most experts believe that organisms with a penicillin mic of x mg l À , still an uncommon finding, can lead to an increased risk of death. in an early study of the topic, there was no impact of resistance on mortality, after adjusting for severity of illness in a population with nearly a % frequency of in vitro resistance. more recently, some studies have shown that resistance can affect outcome. in a group of patients with pneumococcal bacteremia, of which more than half were hiv-positive, high-level resistance was a predictor of mortality. other investigators did not find an increased risk of death from infection with resistant organisms, but did find an enhanced likelihood of suppurative complications (empyema), and a more prolonged length of stay in hospital. these conflicting data may have been the result of studying relatively few patients, many of whom did not have high levels of in vitro resistance. one large study evaluated more than patients with pneumococcal bacteremia and cap and found an increased mortality for patients with a penicillin mic of at least mg l À or greater, or with a cefotaxime mic of . mg l À or more. however, this increased mortality was only present if patients who died in the first days of therapy were excluded from analysis. fortunately, very few organisms are currently at this level of resistance, which may explain the conflicting findings in various studies. more recently, another study using both a cohort and matched control methods found that severity of illness, and not resistance or accuracy of therapy, was the most important predictor of mortality. in some studies, severity of illness was greater in patients without resistant organisms, implying a loss of virulence among organisms that become resistant, a finding echoed in other studies that have found that the absence of invasive illness is a risk factor for pneumoccal resistance. there are also conflicting data on the impact of discordant therapy in patients infected with drsp. in one study of bacteremic infection, the only antibiotic associated with a poor outcome, in the presence of in vitro resistance, was cefuroxime. in another study, discordant therapy in general was associated with an increased risk of mortality, as was multilobar illness, underlying chronic obstructive pulmonary disease (copd), and hospitalization within the past months, but these latter factors did not have as much of a risk of death as did discordant therapy. also in this study, discordant therapy was less likely if patients were treated with ceftriaxone or cefotaxime, compared to other therapies. macrolide-resistant pneumococcus is also occurring with increasing frequency, and up to % of organisms may be resistant to these agents in vitro. however, it is important to understand that most macrolide resistance in the us is low level, and due to an efflux mechanism, and thus it is a type of resistance that may not be clinically relevant, because local concentrations of macrolides at respiratory sites of infection may be adequate for effective therapy. however, some resistance is higher level and due to an inability of the antibiotic to bind to its ribosomal site of action, and this form of resistance may be much higher level and more likely to be clinically relevant. there are however, very few reports of macrolide failures in cap, especially considering the widespread use of these agents. reports of breakthrough bacteremia have appeared, but have been due to organisms that were resistant by either the efflux or ribosomal mechanism. it is likely that higher levels of resistance will become more likely in the future, and the impact on outcome is likely to be more apparent. resistance of pneumococcus has even been reported to the quinolones, which are ordinarily a reliable class of antibiotics for these organisms. in general, one important risk factor for resistance is repeated use of these agents in the same patient. in fact, pneumococcal resistance to beta-lactams (penicillins and cephalosporins), macrolides, and quinolones is more likely if a patient has received the same agent in the recent past. it remains uncertain how long after antibiotic exposure that there is still risk of resistance, but - months has been reported for beta-lactams, up to months for macrolides, and up to months for quinolones. with these data in mind, new guidelines have suggested that cap patients should not receive the same antibiotic as in the recent past, with a relatively arbitrary cutoff of defining this time interval as 'within the past months'. originally the term 'atypical' was used to describe the unusual clinical features of infection with certain organisms, but recent studies have suggested that the term does not accurately describe a unique clinical pneumonia syndrome related to specific pathogens. however, the term has been retained to refer to a group of organisms which includes m. pneumoniae, c. pneumoniae, and legionella, and this group of organisms cannot be reliably eradicated by betalactam therapy (penicillins and cephalosporins), but must be treated with a macrolide, ketolide (telithromycin is the only one currently available), tetracycline, or a quinolone. some recent studies have shown that these infections are common in patients of all ages, not just young and healthy individuals as originally described, and these organisms have even been reported among the elderly in nursing homes. in addition, they can occur as either primary pathogens, or may be part of a mixed infection, along with traditional bacterial pathogens. when mixed infection is present, it may lead to a more complex course and a longer length of stay than if a single pathogen is present. there may be a particular synergy between c. pneumoniae and pneumococcus, with either sequential, or mixed infection with c. pneumoniae leading to a more severe course for pneumococcus. the frequency of atypical pathogens can be as high as % of all cap patients, in some series, with as many as % of patients having mixed infection identified. although these high incidence numbers have been derived with serologic testing, which is of uncertain accuracy, the importance of these organisms is suggested by studies of inpatients, which have shown a reduced mortality and length of stay when patients receive empiric therapy that accounts for these organisms, compared to regimens that do not account for these organisms. in fact, several studies of patients with pneumococcal bacteremia have even suggested a mortality benefit to combination therapy that provides coverage for atypical pathogens, as well as pneumococcus. atypical organism pneumonia may not be a constant phenomenon, and the frequency of infection may vary over the course of time and with geographical location. in one study, the benefit of providing empiric therapy directed at atypical pathogens was variable, being more important in some calendar years than in others. the incidence of legionella infection among admitted patients has varied from % to % or more, and is also a reflection of geographic and seasonal variability in infection rates, as well as a reflection of the extent of diagnostic testing. for legionella to be identified, it is necessary to collect both acute and convalescent serologic studies. in patients with severe cap, atypical pathogens can be present in almost % of all patients, but the responsible organism may vary over time. in one series, legionella was the most common atypical pathogen leading to severe cap, but in the same hospital a decade later, it had been replaced by mycoplasma and chlamydophila infection. l. pneumophila is a small, weakly staining, gramnegative bacillus first characterized after an epidemic in , and can occur either sporadically or in epidemic form. at present, although multiple serogroups of the species l. pneumophila have been described, serogroup causes the most cases of pneumonia. the other species that commonly causes human illness is legionella micdadei. legionella is a water-borne pathogen and can emanate from air-conditioning equipment, drinking water, lakes and river banks, water faucets, saunas, and shower heads. infection is more common in the summer and early fall, and is generally caused by inhalation of an infected aerosol generated by a contaminated water source. when a water system becomes infected in an institution, endemic outbreaks may occur, as has been the case in some hospitals, particularly in patients who are receiving corticosteroid therapy. in its sporadic form, legionella may account for - % of all cases of cap, being a particular concern in patients with severe forms of illness. as mentioned, it is very difficult to use clinical features to predict the microbial etiology of cap; however, the classic legionella syndrome is characterized by high fever, chills, headache, myalgias, and leukocytosis. the diagnosis is also suggested by the presence of a pneumonia with preceding diarrhea, along with early onset of mental confusion, hyponatremia, relative bradycardia, and liver function abnormalities, but this syndrome is usually not present. symptoms are rapidly progressive, and the patient may appear to be quite toxic, so this diagnosis should always be considered in patients admitted to the icu with cap. m. pneumoniae can cause cap year-round, with a slight increase in the fall and winter. all age groups are affected, and although it is common in those less than years of age, it is also a common cause of cap, even in older adults. respiratory infection occurs after the organism is inhaled and then binds via neuraminic acid receptors to the airway epithelium. an inflammatory response with neutrophils, lymphocytes, and macrophages then follows, accompanied by the formation of immunoglobulin m (igm) and then igg antibody. some of the observed pneumonitis may be mediated by the host response to the organism rather than by direct tissue injury by the mycoplasma. up to % of infected individuals will have circulating immune complexes. although mycoplasma causes pneumonia, infection is often characterized by its extrapulmonary manifestations. up to half of patients will have upper respiratory tract symptoms, including sore throat and earache (with hemorrhagic or bullous myringitis). pleural effusion is quite common, being seen in at least % of patients with pneumonia, although it may be small. other extrapulmonary manifestations include neurologic illness such as meningoencephalitis, meningitis, transverse myelitis, and cranial nerve palsies. the most common extrapulmonary finding is an igm autoantibody that is directed against the i antigen on the red blood cell and causes cold agglutination of the erythrocyte. although up to % of patients may have this antibody and a positive coombs' test, clinically significant autoimmune hemolytic anemia is uncommon. other systemic complications include myocarditis, pericarditis, hepatitis, gastroenteritis, erythema multiforme, arthralgias, pancreatitis, generalized lymphadenopathy, and glomerulonephritis. the extrapulmonary manifestations may follow the respiratory symptoms by as long as weeks. the most common gram-negative organism causing cap is h. influenzae (see below). enteric gram-negatives are generally not common in cap, unless the patient is elderly and has chronic cardiac or pulmonary disease, has healthcare associated pneumonia, or is alcoholic. in these patients, organisms such as e. coli and k. pneumoniae can be found. p. aeruginosa is an uncommon cause of cap, but can be isolated from patients with cap and bronchiectasis, and in those with severe forms of cap, particularly in the elderly patient aged over . controversy has persisted about how commonly enteric gram-negative bacteria are a cause of cap. however, in one large study of hospitalized cap patients, careful diagnostic testing identified gram-negative enterics in %, with more than half of these being p. aeruginosa. identified risk factors for gramnegative infection were: probable aspiration, previous hospital admission within days of admission, previous antibiotics within days of admission, and presence of pulmonary comorbidity. risk factors for p. aeruginosa were pulmonary comorbidity and previous hospitalization. infection with a gramnegative increased the chance of dying by more than threefold, with a mortality rate of %, and these patients also need icu admission and mechanical ventilation more often than patients with other organisms. these organisms have always been a concern in patients with poor dentition who aspirate oral contents, and those at risk have been patients with neurologic or swallowing disorders, as well as individuals who abuse alcohol and opiate drugs. several recent studies have questioned whether these organisms are really common in patients with risk factors for aspiration. in one evaluation of residents of longterm care facilities who had severe aspiration pneumonia (defined by the presence of risk factors for oropharyngeal aspiration), requiring icu admission, bacteriology was determined by protected bronchoalveolar lavage (bal) within h of admission. when a pathogen was identified, the organisms were: enteric gram-negatives in %, anaerobes in %, and s. aureus in %. many of the anaerobes were recovered with aerobic gram-negatives, and their presence did not correlate with oral hygiene, but the presence of gram-negatives did correlate with functional status, being more common in patients who were totally dependent. many patients received inadequate therapy for anaerobes, yet most recovered, raising a question about whether infection with these organisms really needs to be treated. these findings suggest that anaerobes may not always be pathogens, but may be colonizers in the institutionalized elderly, including those with aspiration risk factors. this gram-negative coccobacillary rod can occur in either a typable, encapsulated form or a nontypable, unencapsulated form. the encapsulated organism can be one of seven types, but type b accounts for % of all invasive infections. encapsulated organisms require a more elaborate host response, and thus they are more virulent than unencapsulated organisms. however several studies have shown that in adults, particularly those with copd, infection with unencapsulated bacteria is more common than infection with encapsulated organisms. the organism may cause bacteremic pneumonia in some patients, particularly in those with segmental pneumonias as opposed to those with bronchopneumonia. the encapsulated type b organism is more common in patients with segmental pneumonia than in those with bronchopneumonia. most patients with this infection have some underlying illness such as alcoholism, smoking history, or copd. cap can also be caused by s. aureus, which can lead to severe illness and to cavitary lung infection. this organism can also seed the lung hematogenously from a vegetation in patients with right-sided endocarditis or from septic venous thrombophlebitis (from central venous catheter or jugular vein infection). when a patient develops post influenza pneumonia s. aureus can lead to secondary bacterial infection, along with pneumococcus and h. influenzae. most recently, there have been reports of cap caused by methicillin-resistant s. aureus (mrsa), and if this becomes a more common occurrence, it may change the way this disease is treated empirically. to date, most patients with mrsa cap have had a severe necrotizing pneumonia, generally following influenza or another viral infection. the organism responsible has had a specific virulence factor, the panton-valentine leukocidin, and all the organisms causing pneumonia appear to be genetically related. the incidence of viral pneumonia is difficult to define, but during epidemic times, influenza should be considered, and it can lead to a primary viral pneumonia, or to secondary bacterial pneumonia. one careful study of over non-immune-compromised cap patients collected paired sera for respiratory viruses, and found that % had viral pneumonia, with about half being pure viral infection and the others being mixed with bacterial pneumonia. patients with congestive heart failure were at more risk of pure viral pneumonia than they were of pneumococcal infection. influenza (a more than b), parainfluenza, and adenovirus were the most commonly identified viral causes of cap. while influenza a and b still remain the most common causes of viral pneumonia, vigilance to new agents is essential as evidenced by the recent experience with sars, which demonstrated the potential of epidemic, person-to-person spread of virulent respiratory viral infection. continued concern about epidemic viral pneumonia remains, with the current worry being focused on avian influenza, and bioterrorism with agents such as smallpox. patients with an intact immune system who develop cap generally have respiratory symptoms such as cough, sputum production, and dyspnea, along with fever and other complaints. cough is the most common finding, and is present in up to % of all patients, but is less common in those who are elderly, those with serious comorbidity, or individuals coming from nursing homes. the elderly generally have fewer respiratory symptoms than a younger population, and the absence of clear-cut respiratory symptoms and an afebrile status have themselves been predictors of an increased risk of death. this may be the consequence of nonrespiratory presentations being an indication of an impaired immune response, as well as a factor leading to delayed presentation to medical attention and recognition of the correct diagnosis. pleuritic chest pain is also commonly seen in patients with cap, but its absence has been identified as a poor prognostic finding. in the elderly patient, pneumonia can have a nonrespiratory presentation with symptoms of confusion, falling, failure to thrive, altered functional capacity, or deterioration in a pre-existing medical illness, such as congestive heart failure. in general, overall symptoms are less prominent in those above age than in those who are younger. patients with advanced age generally also have a longer duration of symptoms such as cough, sputum production, dyspnea, fatigue, anorexia, myalgia, and abdominal pain than younger patients. studies have found no association between the type of etiologic microorganisms and the clinical presentation of cap, except for pleuritic chest pain, which is likely to be more common in pneumonia caused by bacterial pathogens such as s. pneumoniae than in nonbacterial pneumonia. delirium or acute confusion can be more frequent in the elderly patients with pneumonia than in age-matched controls who do not have pneumonia. very few elderly patients with pneumonia are considered well nourished, with kwashiorkor-like malnutrition being the predominant type of nutritional defect, and the one associated with delirium on initial presentation. physical findings of pneumonia include tachypnea, crackles, rhonchi, and signs of consolidation (egophony, bronchial breath sounds, dullness to percussion). patients should also be examined for signs of pleural effusion. in addition, extrapulmonary findings should be sought to rule out metastatic infection (arthritis, endocarditis, meningitis), or to add to the suspicion of an 'atypical' pathogen such as m. pneumoniae or c. pneumoniae. one of the most important evaluations in any patient suspected of having pneumonia is a measurement of respiratory rate. in the elderly, an elevation of respiratory rate may be the initial presenting sign of pneumonia, preceding other clinical findings by as much as - days. in prospective evaluations in a long-term care setting, most patients who were diagnosed with lower respiratory tract infection had a respiratory rate above the normal range of - min À , and in general the elevated rate preceded other clinical findings. although this finding is certainly not specific, it appears to be a very sensitive indicator of the presence of respiratory infection. in general, tachypnea is the most common finding in elderly patients with pneumonia, being present in over % of all patients, and being present more often in the elderly than in younger patients with pneumonia. measurement of respiratory rate not only has diagnostic value, but also prognostic significance. in evaluating patients with cap, the finding of a respiratory rate min À is one of several factors associated with increased mortality. in the past, the clinical and radiographic features of cap have been characterized as fitting into a pattern of either 'typical' or 'atypical' symptoms, and the pattern was used to predict a specific etiologic agent. recent studies have shown that this approach is not highly accurate, and there is only a weak relationship between clinical features and the etiologic pathogen, primarily because host as well as pathogen factors play a role in defining patient symptoms. the typical pneumonia syndrome is characterized by sudden onset of high fever, shaking chills, pleuritic chest pain, lobar consolidation, a toxic appearing patient, with the production of purulent sputum. although this pattern has been attributed to pneumococcus and other bacterial pathogens, these organisms do not always lead to such classic symptoms, especially in the elderly, as discussed above. the atypical pneumonia syndrome, which is characterized by a subacute illness, nonproductive cough, headache, diarrhea, or other systemic complaints, is usually the result of infection with m. pneumoniae, c. pneumoniae, legionella sp., or viruses. however, patients with impaired immune responses (especially the elderly with chronic illness) may present in this fashion, even with bacterial pneumonia. clinical features have been shown to be only about % accurate in differentiating pneumococcus, m. pneumoniae, and other pathogens from one another. in addition, careful comparisons of patients with s. pneumoniae, h. influenzae, l. pneumophila, and c. pneumoniae have shown no significant differences in their clinical presentations. the limitations of clinical features in defining the microbial etiology also apply to evaluations of radiographic pattern. one of the most important patient assessments is to define severity of illness, which can be used to guide decisions about whether to hospitalize a patient, and if so, whether to admit the patient to the icu. while a number of prediction models have been developed to predict severity of illness and to guide the admission decision, no rule is absolute and the decision to admit a patient should be based on social as well as medical considerations, and remains an 'art of medicine' determination. in general the hospital should be used to observe patients who have multiple risk factors for a poor outcome, those who have decompensation of a chronic illness, or those who need therapies not easily administered at home (oxygen, intravenous fluids, cardiac monitoring). risk factors for a poor outcome include: a respiratory rate x min À , age x years, systolic blood pressure o mmhg, diastolic blood pressure p mmhg, multilobar pneumonia, confusion, blood urea nitrogen . mg dl À , pao o mmhg, paco mmhg, respiratory or metabolic acidosis, or signs of systemic sepsis. the two best-studied and widely regarded prediction rules for pneumonia severity are the pneumonia severity index (psi) and the curb- rule, a modification of a prognostic model developed by the british thoracic society. the psi uses a number of demographic and historical findings, physical findings, and laboratory data to assign a score to each patient, and the score is used to categorize patients into one of five classes, each with a different risk of death. this tool has worked very well to define mortality risk, but has had variable success in predicting need for admission, is cumbersome to use, and does not discriminate very well among the most severely ill patients. the curb- rule is simpler, using only five assessments: % confusion, % urea mmol l À , % respiratory ratex min À , % blood pressureo mmhg systolic or p mm diastolic, and age x years. each of the five criteria is scored and as the score rises from to , mortality risk rises. in recent studies, both tools have worked equally well to identify patients at low risk of dying, but the curb- has been more discriminating in recognizing patients who need icu care (score of at least ) and who have the highest risk of death. a major difference between the two models is that the psi weights advanced age and chronic illness very heavily, while the curb- model includes age as only one of several risk factors, and comorbid illness is not measured, but instead most of the score is based on acute physiologic abnormalities. none of the prediction models includes social factors in the scoring system, and clearly these issues need to be included in patient assessment, paying attention to whether the patient has a stable home environment for outpatient care, an ability to take oral medications, the absence of acute alcohol or drug intoxication, and stability of other acute and chronic medical problems. there is no specific rule for who should be admitted to the icu, but in general the icu is used for approximately % of all cap patients, and this population has a mortality rate of at least %, compared to a mortality rate of % for all admitted patients, and a - % mortality rate for outpatients. there is some debate about the benefit of icu care for patients with cap, but the benefit seems most certain if patients are admitted early in the course of severe illness, making assessment of mortality risk an important clinical assessment. criteria for icu admission, in addition to need for mechanical ventilation and septic shock, are the presence of at least two of the following: pao /fio ratio o , multilobar infiltrates, systolic blood pressure o mmhg. the entry point into most treatment algorithms for cap is the presence of a new radiographic infiltrate, but not all patients with this illness will have this finding when first evaluated. even when the radiograph is negative, if the patient has appropriate symptoms and focal physical findings, pneumonia may still be present. in one study, nearly patients with clinical signs and symptoms of cap were evaluated with both a chest radiograph and a high-resolution computed tomography (ct) scan of the chest and there were almost % of patients identified by ct scan to have pneumonia who had a negative chest radiograph. in addition, more extensive abnormalities were found on ct scan in many patients than were present on the chest radiograph. the findings of this study confirm the need to repeat the chest film after - h in certain symptomatic patients with an initially negative chest film. the reason for an initially negative chest film is not clear, but some studies have suggested that febrile and dehydrated patients can have a normal radiograph when first admitted, although the idea of hydrating a pneumonia is in the realm of 'conventional wisdom' and anecdotal reports. although a variety of radiographic patterns can be seen in pneumonia, and radiographic findings cannot generally be used to predict microbial etiology in cap, there are certain patterns that have been associated with specific pathogens. focal consolidation can be seen with infections caused by pneumococcus, k. pneumoniae (with upper lobe consolidation and the classic bulging down of the upper lobe fissure), aspiration (especially if in the lower lobes or other dependent segments), s. aureus, h. influenzae, m. pneumoniae, and c. pneumoniae. interstitial infiltrates should suggest viral pneumonia as well as infection due to m. pneumoniae, c. pneumoniae, chlamydia psittaci, and pneumocystis jerovici. lymphadenopathy with an interstitial pattern should raise concerns about anthrax, francisella tularensis, and c. psittaci, while adenopathy can be seen with focal infiltrates in tuberculosis, fungal pneumonia, and bacterial pneumonia. cavitation can be the result of an aspiration lung abscess, or infection with s. aureus, aerobic gram-negatives (including p. aeruginosa), tuberculosis, fungal infection, nocardia, and actinomycosis. pleural effusion may appear on the initial chest radiograph and if present, it is necessary to distinguish empyema from a simple parapneumonic effusion by sampling the pleural fluid. pneumococcal pneumonia is the infection most commonly complicated by effusion ( - % of patients), but other pathogens causing effusion include h. influenzae, m. pneumoniae, legionella, and tuberculosis. once the clinical evaluation suggests the presence of pneumonia, the diagnosis should be confirmed by chest radiograph. although some patients may have clinical findings of pneumonia (focal crackles, bronchial breath sounds), and a negative chest radiograph, the need for antibiotic therapy of cap has been established in studies of patients with a radiographic infiltrate. in some populations, such as the elderly and chronically ill, the clinical diagnosis is difficult, and for these individuals, a chest radiograph is essential to define the presence of parenchymal lung infection. although a radiograph is recommended in all outpatients and inpatients, it may be impractical in some settings outside of the hospital. a chest radiograph not only confirms the presence of pneumonia, but can be used to identify complicated illness and to grade severity of disease, by noting such findings as pleural effusion and multilobar illness. as mentioned above, there is no specific radiographic pattern that can be used to define the etiologic pathogen of cap, but certain findings can be used to suggest specific organisms, such as anaerobes if a cavitary infiltrate is found, or tuberculosis if a posterior upper lobe infiltrate is present. even with extensive testing, most patients do not have a specific pathogen identified, and many who do, have this diagnosis made days or weeks later, as the results of cultures or serologic testing become available. in addition, recent studies have emphasized the mortality benefit of prompt administration of effective antibiotic therapy, with a goal of administering intravenous antibiotics within h of admission to the hospital, for those with moderate to severe illness. thus, therapy should never be delayed for the purpose of diagnostic testing, and the diagnostic workup should be streamlined, with all patients receiving empiric therapy based on predicting the most likely pathogens, as soon as possible. recommended testing for outpatients is limited to a chest radiograph and pulse oximetry, if available, with sputum culture being considered in patients suspected of having an unusual or drug-resistant pathogen. for admitted patients, diagnostic testing should include a chest radiograph, assessment of oxygenation (pulse oximetry or blood gas, the latter if retention of carbon dioxide is suspected), and routine admission blood work. if the patient has a pleural effusion, this should be tapped and the fluid sent for culture and biochemical analysis. although blood cultures are positive in only - % of cap patients, they can be used to define a specific diagnosis and to define the presence of drugresistant pneumococci. one concern with blood cultures is that they be limited to patients with a reasonable likelihood of being positive. if low-risk patients routinely have blood cultures, it is possible that the frequency of false positives may exceed the true positives, and lead to inaccurate and unnecessary therapy. one study of a large medicare database found that predictors of bacteremia, among admitted patients, were: absence of prior antibiotics, comorbid liver disease, systolic blood pressure o mmhg, fever o or c, pulse min À , blood urea nitrogen mg dl À , serum sodium o , white blood cell count o or . based on these findings, blood cultures will have the greatest yield of true positive results in patients who have at least one of these risk factors above, or if none, when there is also no history of receiving antibiotics prior to admission. sputum culture should be limited to patients suspected of infection with a drug-resistant or unusual pathogen. the role of gram's stain of sputum to guide initial antibiotic therapy is controversial, but this test has its greatest value in guiding the interpretation of sputum culture, and can be used to define the predominant organism present in the sample. the role of gram's stain in focusing initial antibiotic therapy is uncertain since the accuracy of the test to predict the culture recovery of an organism such as pneumococcus depends on the criteria used. investigators have shown the practical limitations of the test, because fewer than half of all patients can even produce a sputum sample, only about half of these are valid, and very few are diagnostic, and thus it is uncommon to choose an antibiotic directed to the diagnostic result. even if gram's stain findings are used to focus antibiotic therapy, this would not allow for empiric coverage of atypical pathogens which might be present with pneumococcus, as part of a mixed infection. in spite of these limitations, gram's stain can be used to broaden initial empiric therapy by enhancing the suspicion for organisms that are not covered in routine empiric therapy (such as s. aureus being suggested by the presence of clusters of gram-positive cocci, especially during a time of epidemic influenza). routine serologic testing is not recommended. however, in patients with severe illness, the diagnosis of legionella can be made by urinary antigen testing, which is the test that is most likely to be positive at the time of admission, but a test that is specific only for serogroup infection. commercially available tests for pneumococcal urinary antigen have been developed, but their role in the clinical management of cap is still being defined. bronchoscopy is not indicated as a routine diagnostic test, and should be restricted to immune-compromised patients, and to selected individuals with severe forms of cap. the initial therapy for patients with cap should be focused on the provision of antibiotics and supportive care. antibiotics are given on a empiric basis, since it is virtually impossible to rely on clinical or laboratory data to provide an exact etiologic pathogen, at the time of initial diagnosis, and thus therapy must be focused on the pathogens most likely to be present for a given type of patient. supportive care includes oxygen as needed, hydration, possibly chest physiotherapy, as well as bronchodilators and expectorants. for more severely ill patients, it may be necessary to support the blood pressure with pressors, use corticosteroids for possible relative adrenal insufficiency, and provide other therapies directed at signs of sepsis (such as drotrecogin alpha in selected patients). there may also be benefit from the routine use of corticosteroids in severe pneumonia, for unclear reasons, because some studies have shown a survival benefit to this intervention. initial empiric therapy is selected by categorizing patients on the basis of place of therapy (outpatient, inpatient, icu), severity of illness and the presence or absence of cardiopulmonary disease or specific modifying factors that make certain pathogens more likely. by using these factors, a set of likely pathogens can be predicted for each type of patient (table ) , and this information can be used to guide therapy. if a specific pathogen is subsequently identified by diagnostic testing, then therapy can be focused. in choosing empiric therapy of cap, certain principles should be followed ( table ) . empiric therapy for outpatients with no cardiopulmonary disease or modifying factors should be with a new oral macrolide (azithromycin or clarithromycin) or a tetracycline. although erythromycin has been used for these patients, its value is limited by its lack of coverage of h. influenzae, and a higher frequency of intestinal complications (nausea, vomiting) than with the newer macrolides. therapy with an antipneumococcal quinolone (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin) is not necessary in these outpatients, because they are not at risk for organisms such as drsp and enteric gram-negatives. however, outpatients with cardiopulmonary disease and/or modifying factors, should not receive macrolide monotherapy, but should be treated with either a selected oral beta-lactam (table ) with a macrolide or with monotherapy using an oral antipneumococcal quinolone (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin) alone. the ketolide telithromycin can also be used in this population as oral monotherapy for patients at risk for drsp, but with no risk factors for aspiration or for enteric gramnegatives. for the non-icu inpatient, therapy can be with an intravenous macrolide (azithromycin) alone, provided that the patient has no underlying cardiopulmonary disease, and no risk factors for infection with drsp, enteric gram-negatives, or anaerobes. although very few patients of this type are admitted to the hospital, macrolide monotherapy has been documented to be effective in this population. the majority of inpatients will have cardiopulmonary disease and/or modifying factors, and they can be treated with either a selected intravenous beta-lactam (table ) combined with a macrolide, or they can receive an intravenous antipneumococcal quinolone (gatifloxacin, levofloxacin, moxifloxacin) alone. from the available data, it appears that either regimen is therapeutically equivalent, and although not proven, it may be useful to use these two types of regimens interchangeably, striving for 'antibiotic heterogeneity', selecting an agent in a different class from what the patient received in the past - months. although oral quinolones may be as effective as intravenous quinolones for admitted patients table principles of antibiotic therapy administer initial antibiotic therapy within h of arrival to the hospital treat all patients for pneumococcus and for the possibility of atypical pathogen coinfection: use either a macrolide alone (selected patients with no cardiopulmonary disease or modifying factors) or for those outpatients with cardiopulmonary disease or modifying factors: use monotherapy with a quinolone, a ketolide (if no risk factors for enteric gram-negatives), or the combination of a selected beta-lactam with a macrolide or ketolide or tetracycline limit macrolide monotherapy to outpatients or inpatients with no risk factors for drsp, enteric gram-negatives, or aspiration limit ketolide monotherapy to outpatients with risk factors for drsp, but no risk factors for enteric gram-negatives provide initial therapy for hospitalized patients with an intravenous agent, or if oral only, use a quinolone for patients at risk for drsp, acceptable oral beta-lactams are: cefpodoxime, cefuroxime, high-dose ampicillin ( g day À ) or amoxicillin/clavulanate (up to g day À ) for inpatients at risk for drsp, the selected acceptable intravenous beta-lactams include: ceftriaxone, cefotaxime, ertapenem, ampicillin/sulbactam limit antipseudomonal therapy to patients with risk factors: antipseudomonal agents include: beta-lactams such as cefepime, imipenem, meropenem, piperacillin/tazobactam; quinolones such as ciprofloxacin or high-dose levofloxacin ( mg day À ); and aminoglycosides such as amikacin, gentamicin, or tobramycin; aztreonam is a monobactam that is also active, but cannot be used alone the new antipneumococcal quinolones, in order of decreasing antipneumococcal activity are: gemifloxacin (oral only), moxifloxacin (oral and intravenous), gatifloxacin (oral and intravenous), levofloxacin (oral and intravenous) never use monotherapy for patients with severe cap. if no pseudomonal risk factors use a selected beta-lactam (above) plus a macrolide or antipneumococcal quinolone. for those with pseudomonal risk factors, use an antipseudomonal beta-lactam (above) plus either ciprofloxacin/high-dose levofloxacin or the combination of an aminoglycoside with either a macrolide or antipneumococcal quinolone (above) vancomyin and linezolid should be used rarely and only in those with severe cap and either meningitis (vancomycin) or severe necrotizing pneumonia after influenza (either agent) with moderately severe illness, most admitted patients should receive initial therapy intravenously to be sure that the medication has been absorbed. once the patient shows a good clinical response, oral therapy can be started. selected inpatients with mild to moderate disease can initially be treated with the combination of an intravenous beta-lactam and an oral macrolide, switching to exclusively oral therapy once the patient shows a good clinical response. in the icu population, all individuals should be treated for drsp and atypical pathogens, but only those with appropriate risk factors (above) should have coverage for p. aeruginosa. since the efficacy, dosing, and safety of quinolone monotherapy has not been established for icu-admitted cap patients, the therapy for such patients, in the absence of pseudomonal risk factors, should be with a selected intravenous beta-lactam, combined with either an intravenous macrolide or an intravenous quinolone. for patients with pseudomonal risk factors, therapy can be with a two-drug regimen, using an anti-pseudomonal beta-lactam (cefepime, imipenem, meropenem, piperacillin/tazobactam) plus ciprofloxacin or highdose levofloxacin, or alternatively, with a three-drug regimen, using an anti-pseudomonal beta-lactam plus an aminoglycoside plus either an intravenous nonpseudomonal quinolone or macrolide. the antipneumococcal quinolones are being widely used in both inpatients and outpatients as monotherapy because as a single drug, given once daily, it is possible to cover pneumococcus (including drsp), gram-negatives, and atypical pathogens. quinolones penetrate well into respiratory secretions, and are highly bioavailable, achieving the same serum levels with oral or intravenous therapy, thereby allowing moderately ill outpatients to be managed effectively with oral antibiotics. there are differences among the available agents in their intrinsic activity against pneumococcus, and, based on mic data, these agents can be ranked from most to least active as: gemifloxacin (available only in oral form), moxifloxacin, gatifloxacin, and levofloxacin. some data suggest a lower likelihood of both clinical failures and the induction of pneumoccal resistance to quinolones, if the more active agents are used in place of the less active agents. in addition to the general approach to therapy outlined above, there are several other therapeutic issues in the management of cap, which are highlighted in table . these include the need for timely administration of initial antibiotic therapy, the limited use of therapy directed at methicillin-resistant s. aureus, the need for routine atypical pathogen coverage for all patients, and the emphasis on using highly active agents in all patients with risk factors for infection with drsp. the reason for this last recommendation is because if a patient is at risk for infection with drsp, use of a highly active agent is not only likely to minimize the risk of treatment failure, but may also rapidly and reliably eradicate pneumococcal organisms that have low levels of resistance, so that there is less selection pressure for emergence of organisms with high level of resistance. the majority of outpatients and inpatients will respond rapidly to the empiric therapy regimens suggested above, with clinical response usually occurring within - h. clinical response for inpatients is defined as improvement in symptoms of cough, sputum production, and dyspnea, along with ability to take medications by mouth, and an afebrile status for at least two occasions h apart. when a patient has met these criteria for clinical response, it is appropriate to switch to an oral therapy regimen and to discharge the patient, if he is otherwise medically and socially stable. radiographic improvement lags behind clinical improvement, and in a responding patient, a chest radiograph is not necessary until - weeks after starting therapy. if the patient fails to respond to therapy in the expected time interval, then it is necessary to consider infection with a drug-resistant or unusual pathogen (tuberculosis, anthrax, c. burnetii, burkholderia pseudomallei, pasteurella multocida, endemic fungi, or hantavirus); a pneumonic complication (lung abscess, endocarditis, empyema); or a noninfectious process that mimics pneumonia (bronchiolitis obliterans with organizing pneumonia, hypersensitivity pneumonitis, pulmonary vasculitis, bronchoalveolar cell carcinoma, lymphoma, pulmonary embolus). the evaluation of the nonresponding patient should be individualized but may include ct scanning of the chest, pulmonary angiography, bronchoscopy, and occasionally open lung biopsy. prevention of cap is important for all groups of patients, but especially the elderly, who are at risk for both a higher frequency of infection and a more severe course of illness. appropriate patients should be vaccinated with both pneumococcal and influenza vaccines, and cigarette smoking should be stopped in all at-risk patients. even for the patient who is recovering from cap, immunization while in the hospital is appropriate to prevent future episodes of infection, and the evaluation of all patients for vaccination need and the provision of information about smoking cessarion are now performance standards used to evaluate the hospital care of cap patients. pneumococcal vaccine pneumococcal capsular polysaccharide vaccine can prevent pneumonia in otherwise healthy populations, as was initially demonstrated in south african gold miners and american military recruits. the benefits in those of advanced age or with underlying conditions in nonepidemic environments are less clearly defined. in immunocompetent patients over the age of , effectiveness has been documented to be %. the vaccine efficacy has ranged from % to % in patients with diabetes mellitus, coronary artery disease, congestive heart failure, chronic pulmonary disease, and anatomic asplenia. its effectiveness has not been proven in immune-deficient populations such as those with sickle cell disease, chronic renal failure, immunoglobulin deficiency, hodgkin's disease, lymphoma, leukemia, and multiple myeloma. a single revaccination is indicated in a person who is aged over years who initially received the vaccine years earlier and was less than years old on first vaccination. if the initial vaccination was given at age or older, repeat is only indicated (after years), if the patient has anatomic or functional asplenia, or has one of the immune compromising conditions listed above. the available pneumococcal vaccine is widely underutilized, and the -valent pneumococcal vaccine carries the pneumococcal serotypes causing the majority of clinical infection seen in the us. a proteinconjugated pneumococcal vaccine has been licensed and it appears more immunogenic than the older vaccine, but it contains only seven serotypes, and is recommended for healthy children, and has not yet been shown to be effective in adults for preventing both pneumococcal bacteremia and hospitalization for pneumonia. hospital-based immunization for most admitted patients could be highly effective, since over % of all patients with cap have been admitted to the hospital, for some indication, in the preceding years, and hospitalization could be defined as an appropriate time for vaccination. the current vaccine includes three strains: two influenza a strains (h n and h n ) and one influenza b strain. vaccination is recommended for all patients aged over , and to those with chronic medical illness (including nursing home residents), and to those who provide healthcare to patients at risk for complicated influenza. it is given yearly, usually between september and mid november (in the northern hemisphere). when the vaccine matches the circulating strain of influenza, it can prevent illness in - % of healthy persons aged over . for older persons with chronic illness, the efficacy is less, but the vaccine can still attenuate the influenza infection and lead to fewer lower respiratory tract infections and the associated morbidity and mortality that follow influenza. endotoxins. leukocytes: neutrophils. pleural effusions: pleural fluid analysis, thoracentesis, biopsy, and chest tube community-acquired pneumonia due to gram-negative bacteria and pseudomonas aeruginosa: incidence, risk and prognosis microbiology of severe aspiration pneumonia in institutionalized elderly validation of predictive rules and indices of severity for community acquired pneumonia mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance antimicrobial therapy of community-acquired pneumonia a prediction rule to identify low-risk patients with community-acquired pneumonia associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia timing of antibiotic administration and outcomes for medicare patients hospitalized with community-acquried pneumonia empiric antibiotic therapy and mortality among medicare pneumonia inpatients in western states pneumonia: still the old man's friend? multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of consecutive patients defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study addition of a macrolide to a b-lactam-based empirical antibiotic regimen is associated with lower in-patient mortality for patients with bacteremic pneumococcal pneumonia testing strategies in the initial management of patients with community-acquired pneumonia predicting bacteremia in patients with community-acquired pneumonia guidelines for the management of adults with community-acquired lower respiratory tract infections: diagnosis, assessment of severity, antimicrobial therapy and prevention high resolution computed tomography for the diagnosis of community-acquired pneumonia fungal infection generally originates from an exogenous, environmental source acquired by inhalation, ingestion, or trauma. fungi are rarely associated with significant disease in the normal host, although many more cause serious disease in the immunocompromised host. opportunistic fungal infections have become increasingly common, especially in aids patients, and constitute a major cause of morbidity and mortality in this group. pathogenicity depends on the interplay between components of the host immune system and specific features of the fungal strain. considerable efforts are underway to conduct genetic characterization of fungal virulence and host susceptibility factors in disease. genome projects have been undertaken for a number of the key fungal pathogens. here we consider the etiology, pathology, clinical features, management, and molecular mycology of blastomycosis, coccidioidomycocis, histoplasmosis, paracoccidioidomycosis, aspergillosis, candidosis, cryptococcosis, and mucormycosis. fungi are a diverse group of eukaryotic organisms that have cell walls and no chlorophyll. they exist in nature as parasites or saprobes, dependent on living or dead organic matter for nutrition. about species of fungi have been described, but less than have been associated with human disease. fungal infection usually originates from an exogenous, environmental source acquired by inhalation, ingestion, or trauma. very few fungi cause significant disease in the normal host, but many more can cause disease in the immunocompromised host. thus, pathogenicity can be considered to depend on the interplay between aspects of the host immune system and specific features of the fungal strain. considerable efforts are underway to conduct genetic characterization of fungal virulence and host susceptibility factors in disease. genome projects have been undertaken for a number of key pathogens (see 'relevant websites').systemic mycoses often start in the lung, but may spread to other organs. they are usually acquired by inhaling spores of organisms growing as saprobes in the soil or decomposing organic material, or as plant pathogens. the organisms that cause systemic fungal infection in humans can be divided into two groups, true pathogens and opportunists. true pathogens, able to invade and grow in tissues of a normal host, include histoplasma capsulatum, coccidoides immitis, blastomyces dermatidis and paracoccidioides braziliensis ( table ). in general, infections with true pathogenic fungi are asymptomatic or mild, of short duration, occur in regions endemic for the fungus, and follow inhalation of spores from the environment. individuals either recover from infection with protective immunity to re-infection or sometimes develop chronic granulomatous disease. in the immunocompromised host, however, true pathogenic fungi may cause significant, relapsing, life-threatening disease that is difficult to treat. opportunist fungi, such as aspergillus fumigatus, are less virulent and less well-adapted organisms that are only able to invade the tissues of a debilitated or immunocompromised host. resolution of infection does not confer protection and re-infection or reactivation may occur. many of these organisms are ubiquitous saprobes found in the soil, decomposing organic key: cord- -ljqrxjvv authors: leroy, o. title: – apport des explorations microbiologiques au diagnostic des infections des voies respiratoires basses date: - - journal: med mal infect doi: . /j.medmal. . . sha: doc_id: cord_uid: ljqrxjvv the diagnosis of community-acquired pneumonia is usually based on clinical and radiological criteria. the identification of a causative organism is not required for the diagnosis. although numerous microbiological techniques are available, their sensitivity and specificity are not high enough to guide first-line antimicrobial therapy. consequently, this treatment remains most often empiric. if the causative organism is identified, the antimicrobial treatment is adapted. sputum analysis may be proposed as a diagnostic tool for patients with an acute exacerbation of chronic obstructive pulmonary disease, in specific cases (prior antibiotherapy, hospitalization, failure of the empiric antimicrobial treatment). les infections respiratoires basses de l'adulte peuvent correspondre à des tableaux cliniques très différents selon que l'infection touche le parenchyme pulmonaire ou l'arbre bronchique, selon l'état sous-jacent de ce dernier (sain, asthme, bronchite chronique, bronchiectasies, mucoviscidose…), selon communautaire, c'est-à-dire acquise en milieu extrahospitalier ou se révélant au cours des premières heures du séjour hospitalier [ ] . puis celui de l'exacerbation des bronchopneumopathies chroniques obstructives (bpco). de nombreuses explorations complémentaires sont disponibles pour isoler l'agent causal d'une pneumonie aiguë communautaire (pac). bien évidemment, ne serait ce que pour des raisons logistiques et économiques, il est illusoire de penser qu'une recherche étiologique exhaustive s'avère nécessaire pour tous les patients souffrant d'une pac. pour tenter de clarifier l'exposé, les points suivants seront successivement évoqués : • analyse critique des examens microbiologiques disponibles ; • indications selon le type de patients (ambulatoire, en médecine, en réanimation, en institution pour personnes âgées) et les situations (voyage, contexte épidémique) ; • stratégie d'utilisation et modalités de réalisation en ville, à l'hôpital ; • prospective : méthodes de diagnostic rapide. pour des raisons thérapeutiques évidentes, l'enquête microbiologique au cours d'une pac a pendant de nombreuses années été exclusivement centrée sur la recherche d'agents bactériens. en l'absence d'antiviraux efficaces sur les virus à tropisme respiratoire, la recherche de ces pathogènes est longtemps apparue sans impact thérapeutique pratique et a peutêtre été délaissée par les cliniciens. actuellement, les données se modifient avec d'une part la mise sur le marché de traitements antiviraux, et d'autre part, la reconnaissance accrue de la responsabilité de nombreux virus à l'origine d'infections du tractus respiratoire inférieur. toutefois, le caractère récent de cette recherche d'agents viraux à l'origine de pac fait que les techniques utilisées sont encore souvent du domaine de laboratoires hautement spécialisés. il nous est donc apparu plus aisé d'envisager dans les trois premiers chapitres de l'exposé uniquement le versant bactériologique du diagnostic des pac. le versant virologique sera uniquement envisagé dans le quatrième et dernier chapitre. pour les exacerbations des bpco, nos propos seront très limités dans la mesure où il existe des recommandations consensuelles très récentes à propos du rôle des explorations microbiologiques. avant toute chose, il importe de souligner le point suivant : il n'existe pas de « gold standard » pour le diagnostic microbiologique d'une pac. ce point fondamental explique que, pour la plupart des techniques microbiologiques, les valeurs de sensibilité et de spécificité qui seront rapportées pourront être difficiles à comparer d'une étude à l'autre et seront, parfois, soumises à caution. sur un échantillon de sécrétions trachéobronchiques obtenu par expectoration, de nombreuses techniques microbiologiques, plus ou moins complexes, peuvent être appliquées. dans ce chapitre, seules les techniques simples que sont l'examen direct après coloration de gram et la culture sur milieux usuels seront évoquées. cet examen cytobactériologique simple, tel qu'il a été défini, revêt en fait de nombreux écueils. tout d'abord, techniquement, il n'est pas toujours aisé d'obtenir une expectoration correcte, sans souillure par les sécrétions oropharyngées. ensuite, il n'est pas simple microbiologiquement de différencier une colonisation des voies aériennes inférieures d'une infection parenchymateuse pulmonaire. enfin, l'absence de standard diagnostique rend illusoire la comparaison d'études n'ayant pas utilisé la même référence pour chiffrer les valeurs de sensibilité et de spécificité. ces difficultés expliquent peut-être les variations considérables dans les résultats des diverses études à notre disposition et sûrement dans l'idée que chacun se fait de cet examen. ainsi, à titre d'exemple, dans une méta-analyse publiée en et prenant en compte des données publiées entre et , reed et al. [ ] notent que la sensibilité et la spécificité de l'examen direct du crachat pour le diagnostic des pac à pneumocoque varient respectivement de à et de à %… avant d'être analysé et mis en culture, l'échantillon bactériologique doit être validé. il faut, en effet, s'assurer qu'il s'agit bien d'un prélèvement issu du tractus respiratoire inférieur. bien que les critères varient parfois d'une étude à l'autre, la plupart des auteurs considèrent que lorsqu'il y a moins de dix cellules épithéliales squameuses et plus de leucocytes par champ à faible grossissement, l'échantillon est valide. cette validation ne semble pas toutefois facile comme en témoignent les résultats de l'étude de cooper et al. [ ] . cinquante échantillons consécutifs de secrétions trachéobronchiques (expectoration ou aspiration endotrachéale) ont donné lieu à une préparation sur lame en double exemplaire. trois bactériologistes ont lu la lame initiale, sa copie, puis à nouveau l'original. ainsi, lectures ont été effectuées. une concordance concernant le nombre de neutrophiles et de cellules épithéliales par champ a été complète dans respectivement et % des cas. la difficulté de préparation de l'échantillon pour l'examen direct et la culture a également été soulignée. nagendra et al. [ ] ont évalué la reproductibilité de l'examen direct de l'expectoration et de la culture lors de l'élaboration de la lame et de la mise en culture. dix échantillons d'expectoration ont été fournis pendant quatre mois par cinq centres hospitaliers. chaque échantillon a donné lieu à une préparation technique par trois techniciens différents qui chacun préparait une lame pour l'examen direct et la culture. pour être valides, les échantillons d'expectoration devaient contenir moins de cellules épithéliales. ainsi, échantillons ont été considérés comme tels. dans % des cas, il existait des variations dans l'identification, par l'examen direct, d'au moins un des morphotypes bac-tériens. de même, dans % des cas, il a été constaté des variations dans le résultat des cultures pour au moins un des germes. le rôle de la quantification bactérienne dans la prise en compte du résultat de la culture doit être également discuté. selon les recommandations usuelles françaises, un résultat positif ne doit être pris en compte que « s'il existe une culture pure d'un micro-organisme unique ou au moins cfu/ml » [ ] . bien évidemment, une telle exigence n'est requise que si le pathogène isolé peut être un germe colonisant usuel des voies aériennes. toutefois, il faut souligner que ce seuil bactérien n'est pas requis dans les recommandations usuelles nordaméricaines ou britanniques. de même, dans la plupart des publications émanant d'équipes non françaises, la mise en évidence en culture d'un pathogène est considérée comme valide, quel que soit le nombre de colonies identifiées, dès lors que l'échantillon est microscopiquement valide. enfin, malgré d'importantes recherches, je dois avouer mon incapacité à retrouver le travail princeps qui avait permis de fixer ce seuil de cfu/ml comme étant celui en deçà duquel le résultat devait être considéré comme invalide. abstraction faite de ces problèmes d'interprétation, l'intérêt de l'examen direct et la culture de l'expectoration, en termes de résultat positif, semble hautement dépendant de la gravité de la pneumonie. quatre publications récentes illustrent ce propos : • dans une série de patients traités en ambulatoire, marrie et al. [ ] notent que seuls ( ( , %) des échantillons avec examen direct négatif. dans la plupart des cas, le pathogène retrouvé par l'examen direct et/ou la culture est le pneumocoque. au vu des données de la littérature [ , [ ] [ ] [ ] [ ] , les pourcentages de résultats positifs au cours des pac à pneumocoque bactériémiques varient entre et % pour l'examen direct et entre et % pour la culture de l'expectoration (tableau ). ces résultats pourraient apparaître à première vue relativement décevants. toutefois, il s'agit le plus souvent de travaux anciens, comportant peu de patients et n'ayant pas toujours exclu les patients déjà sous antibiotiques au moment du prélèvement. un travail récent de musher et al. [ ] relativise ces pourcentages bruts et fournit des résultats plus encourageants. dans un collectif de patients ayant une pac à pneumocoque bactériémique, les auteurs ont étudié les fréquences de positivité de l'examen direct et de la culture de l'expectoration selon que cet examen était réalisé, valide et en fonction de la durée de l'éventuelle antibiothérapie instaurée avant que le prélèvement soit réalisé. les critères de validité de l'échantillon étaient plus de dix polynucléaires/cellule épithéliale au grossissement × . trentetrois examens directs et ces données montrent que l'examen direct et la culture de l'expectoration dès lors qu'ils sont correctement effectués chez un patient sans antibiothérapie sont fréquemment positifs au cours des pac à pneumocoque les plus graves, c'est-à-dire bactériémiques. si l'on fait abstraction des problèmes d'interprétation liés aux résultats faussement positifs consécutifs à des souillures, l'hémoculture est usuellement reconnue comme une méthode diagnostique fiable et spécifique en pathologie infectieuse. tableau pourcentage d'isolement du pneumocoque par l'examen direct et la culture de l'expectoration au cours des pac à pneumocoque bactériémiques [ , [ ] [ ] [ ] [ ] année nombre la relation entre la gravité de la pneumonie, non plus appréciée par le lieu d'hospitalisation, mais par un élément objectif tel que le « pneumonia severity index » (psi = score de fine) a fait l'objet d'au moins deux études qui malheureusement apportent des résultats contradictoires. une première étude, publiée en [ ] , portant sur patients, retrouve une augmentation de la fréquence de positivité de l'hémoculture avec celle du risque de décès apprécié par la classe de risque établie selon le psi initial. la seconde [ ] jusqu'à ces dernières années, la détection d'antigènes pneumococciques au niveau urinaire par les techniques telles que la contre-immunoélectrophorèse, l'agglutination sur latex, la coagglutination ou les tests enzymatiques s'était toujours avérée décevante. la sensibilité de ces techniques est usuellement inférieure à %. récemment est apparu sur le marché un test immunochromatographique (binax now ® ) capable de détecter un polysaccharide c de la paroi cellulaire, commun à tous les pneumocoques, et dont les résultats sont disponible en minutes. [ , ] , il semble que la colonisation oropharyngée par le pneumocoque soit rare chez l'adulte et ne soit donc pas à l'origine de faux résultats positifs [ ] . au vu de ces résultats, il est possible de penser que ce test permettrait un diagnostic rapide, en moins de minutes, de près de % des pac pneumococciques bactériémiques et de près de % des pac pneumococciques non bactériémiques. À l'heure où se posent des questions concernant la prise en charge des pac pneumococciques bactériémiques (mono-ou bithérapie ?) [ ] et où la résistance du pneumocoque peut poser des problèmes, avoir à disposition une méthode de diagnostic rapide de la pneumonie pneumococcique serait loin d'être négligeable. au vu des travaux de marcos et al. [ ] , il est même possible de penser que la sensibilité du test pourrait être accrue par la concentration des urines au détriment toutefois d'une réponse un peu moins rapide. le caractère apparemment hautement spécifique de ce test pourrait également permettre une interprétation d'un résultat positif chez les patients ayant une pneumonie pour laquelle un pathogène autre que streptococcus pneumoniae a été isolé et chez les patients pour lesquels la recherche étiologique est restée négative (tableau ). dans le premier cas, cela pourrait vouloir dire qu'un s. pneumoniae, non isolé par les techniques traditionnelles, est associé au(x) pathogène(s) isolé(s) chez au moins à % des patients. dans le second cas, cela pourrait signifier qu'au moins à % des pac sans étiologie apparente sont d'origine pneumococcique. il convient bien sûr d'émettre quelques réserves, liées au caractère récent de ce test qui n'a pas encore fait ses preuves en routine et de répondre aux questions suivantes : [ ] . dans la première étude [ ] , prospective, portant sur patients présentant une bactériémie à pneumocoque ( avaient une pneumonie et une bactériémie sans pneumonie), les auteurs ont répété pour patients, ayant un test initial positif, le test au cours de la première semaine d'antibiothérapie (tableau ). À j , % des examens étaient encore positifs. dans la seconde étude, murdoch et al. [ ] ont montré que % des patients ayant un test initial positif avaient encore un test positif en moyenne six semaines après le début des symptômes. le plus long délai de positivité observé a été de jours. ces données suggèrent deux commentaires, l'un positif, l'autre négatif. le commentaire positif concerne la possibilité d'affirmer l'origine pneumococcique d'une pneumonie au cours de la première semaine du traitement antibiotique. le commentaire négatif concerne les éventuels résultats faussement positifs chez les patients ayant déjà présenté une pneumonie pneumococcique au cours des quelques semaines (six semaines, voire plus) précédant l'épisode actuel. le diagnostic de rechute ou de récidive précoce d'une pneumonie pneumococcique ne peut donc être fondé sur cette technique. ainsi, en résumé, ce test semble pouvoir permettre un diagnostic rapide des pac pneumococciques, notamment celles associées avec une bactériémie. non influencé par l'antibiothérapie antérieure ou en cours, il permet également un diagnostic étiologique « rétrospectif » chez les patients ayant des prélèvements usuels, fondés sur la culture, négatifs. bien que ce test demeure longtemps positif, sa spécificité globalement élevée doit être soulignée. ces données ne doivent pas toutefois faire perdre de vue, comme le souligne pesola [ ] que dans plus de % des cas, les pac ont une étiologie plurimicrobienne et qu'il n'est peut être pas raisonnable de focaliser l'antibiothérapie uniquement sur le pneumocoque en cas de test positif. depuis la découverte de la maladie en , espèces et sérogroupes de legionella sp. ont été décrits. l. pneumophila comporte sérogroupes dont le plus fréquemment incriminé à l'origine des pac est le sérogroupe [ ] . dans la littérature récente, au moins cinq revues ont été consacrées au diagnostic microbiologique de la légionellose [ ] [ ] [ ] [ ] [ ] . au vu de ces publications, il apparaît important de souligner les points suivants à propos de la recherche d'antigènes urinaires de l. pneumophila. environ % des patients présentant une infection à l. pneumophila du sérogroupe excrètent au cours de leur maladie des antigènes au niveau urinaire. cette excrétion apparaît un à trois jours après le début de la maladie et peut durer un an. initialement, la recherche d'antigènes urinaires se faisait par technique radio-immunologique. celle-ci a été remplacée par une technique elisa au milieu des années . la concentration des urines par chauffage durant cinq minutes améliore la sensibilité de la technique et sa spécificité en éliminant les faux positifs liés à des antigènes d'autres bacilles à gram négatif. il existe également une technique immunochromatographique. les ces données intéressantes ne doivent pas cependant cacher les limites de la méthode. tout d'abord, il faut insister sur le fait que cette technique ne dépiste que les infections liées à l. pneumophila du sérogroupe . la sensibilité de la méthode dépend donc hautement de la prévalence de ce sérogroupe dans l'ensemble des cas de légionellose. moins ce sérotype sera prévalent, moins la technique sera sensible. ensuite, il faut souligner que l'excrétion à la fois retardée par rapport au début de la maladie et prolongée pendant plusieurs semaines peut être à l'origine de faux résultats, négatifs et positifs. au début de la maladie, il est fréquent que le test soit négatif. il faudra donc savoir le répéter quelques jours plus tard. À l'inverse, le test demeure longtemps positif et il faudra éviter d'évoquer trop vite le diagnostic de récidive. pour conclure, il semble important de rapporter les propos de waterer et al. [ ] qui estiment que la sensibilité de cette technique est trop faible pour qu'un clinicien puisse exclure formellement legionella spp. à l'origine d'une pneumonie et qui pensent que cette recherche est très probablement peu coût-efficace. À partir d'échantillons provenant du tractus respiratoire inférieur (expectoration, voire prélèvements endoscopiques) ou supérieur (prélèvement nasopharyngé), un certain nombre de techniques ont été mises au point pour le diagnostic des infections liées à des germes tels que chlamydia pneumoniae, mycoplasma pneumoniae ou legionella spp. nous allons passer en revue pathogène par pathogène les avantages et les inconvénients de ces diverses techniques. . . . infections à m. pneumoniae [ , ] une culture peut être réalisée à partir d'échantillons du tractus respiratoire inférieur ou nasopharyngés. elle est lente (de quelques jours à plusieurs semaines d'incubation), laborieuse et coûteuse (milieux hautement spécifiques, nombreuses manipulations). de plus, il est assez difficile d'en connaître les valeurs de sensibilité et de spécificité. en prenant pour référence la sérologie ou la pcr, la culture aurait une sensibilité de l'ordre de %. sa spécificité serait plus élevée, proche de %. toutefois, concernant cette dernière, il importe de souligner les points suivants : • seulement, un peu plus de la moitié des patients avec culture positive présentent une multiplication par du titre des anticorps en réaction de fixation du complément [ ] [ , ] c. pneumoniae est une bactérie intracellulaire obligatoire. la technique de culture est complexe. toutefois, il s'agit de la seule méthode capable de démontrer la viabilité d'un pathogène, sa sensibilité aux antibiotiques, ses caractéristiques microbiologiques et son évolution sous traitement. les prélèvements sur lesquels la culture peut être réalisée sont les écouvillons naso-ou oropharyngés, les expectorations, les lba et les biopsies pulmonaires. la sensibilité et la spécificité de la culture sont mal connues. il faut cependant savoir que des cultures positives sur des échantillons prélevés au niveau des voies aériennes supérieures ont déjà été rapportées chez des patients asymptomatiques. . . . infections à l. pneumophila [ ] [ ] [ ] la culture demeure l'examen de référence pour le diagnostic des légionelloses. celle-ci peut s'effectuer sur des échantillons issus d'expectoration, d'aspiration endotrachéale, de lavage bronchoalvéolaire (lba) ou de biopsie pulmonaire. la spécificité de la culture est élevée, voire absolue. la sensibilité est en revanche faible, notamment pour les raisons suivantes : ainsi, en prenant pour référence les données sérologiques, la sensibilité diagnostique de la culture se situerait de façon optimale aux alentours de %. elle apparaît toutefois, pour les raisons que nous venons de citer, souvent inférieure à % [ ] [ ] [ ] . en prenant pour référence l'immunofluorescence directe sur les crachats, la sensibilité de la culture atteint dans une étude % [ ] . cependant, dans des séries où le diagnostic de légionellose est fait sur des arguments sérologiques ou sur la présence d'antigène urinaire, les cultures sont négatives chez à % des patients présentant une recherche positive par immunofluorescence [ ] [ ] [ ] . en conclusion, la plupart des experts soulignent la faible utilité diagnostique de la culture pour le diagnostic de légionellose en raison de la faible sensibilité de la méthode et du délai nécessaire à l'obtention du résultat. À partir d'échantillons respiratoires, il est également possible d'effectuer une recherche de legionella spp par la technique d'immunofluorescence directe par anticorps. il s'agit d'une technique délicate à réaliser, ce qui est une source d'erreur potentiellement fréquente. les limites immédiates de la technique sont au nombre de deux. la première concerne les échantillons analysés. bien évidemment si le patient n'expectore pas, il n'y a pas de matériel analysable et il faudra alors réaliser soit une aspiration endotrachéale soit un prélèvement endoscopique. la seconde concerne les anticorps utilisés. ceux-ci sont spécifiques du sérotype de legionella. la sensibilité de la méthode dépendra donc du ou des sérotypes recherchés et de la fréquence respective des différents sérotypes incriminés en clinique humaine. la sensibilité de cette technique dépend aussi de la méthode de référence utilisée. en référence à la culture, la sensibilité est comprise entre et %. par rapport à la sérologie, elle est de l'ordre de %. en prenant en compte toutes les modalités diagnostiques (culture, antigène urinaire, sérologie), elle est également de l'ordre de %. en prenant pour référence ces trois méthodes diagnostiques, la spécificité est proche de %. il faut toutefois signaler que des faux positifs par contamination par des pathogènes tels que pseudomonas fluorescens ou haemophilus influenzae ont été rapportés. cela est plus fréquent lorsque des anticorps polyvalents sont utilisés. ainsi, il faut retenir de l'immunofluorescence directe qu'il s'agit d'une méthode spécifique dont la sensibilité est proche de % chez les patients pouvant fournir un échantillon respiratoire. de plus, bien que cette technique procure des résultats rapides, elle ne peut être réalisée que par des laboratoires très spécialisés. les méthodes sérologiques ont longtemps été les seules techniques à même d'évoquer la responsabilité étiologique d'agents tels que chlamydia spp, mycoplasma spp et legionella spp. nous envisagerons, pathogène par pathogène, les diverses techniques disponibles. . . . infections à l. pneumophila [ ] [ ] [ ] les méthodes sérologiques représentent encore actuellement la méthode de diagnostic la plus communément utilisée. différentes techniques ont été décrites : immunofluorescence indirecte, agglutination sur latex, micro-elisa, contreimmunoélectrophorèse ou microagglutination. en europe, le test rapide de microagglutination est largement utilisé. le test de référence serait toutefois plutôt représenté par l'immunofluorescence indirecte [ ] . la sensibilité diagnostique de ces méthodes varie selon le test utilisé, la méthode de référence et selon le sérogroupe de legionella incriminé. ainsi, globalement, la sensibilité varie dans les séries entre et %. elle serait plus élevée avec le test de microagglutination ( %) et lorsque qu'il s'agit d'un sérogroupe - ( - %). les points suivants permettent éventuellement de comprendre ces différences et fixent les limites de la technique sérologique : • le temps requis pour une séroconversion excède parfois plusieurs semaines. si environ % des patients développent des anticorps au cours des quatre premières semaines de la maladie, certains patients ne font leur séroconversion qu'après deux mois ou plus. il est donc nécessaire d'attendre un long délai de plusieurs semaines pour recueillir l'échantillon de convalescence nécessaire à l'affirmation de la séroconversion ; • les infections liées à des legionella spp autre que l. pneumophila ne donnent une séroconversion que dans moins d'une fois sur deux. concernant la spécificité de la sérologie, les points suivants doivent être mis en exergue : • chez près de % des patients, la présence d'anticorps est encore détectable mois après le début de la maladie ; • la prévalence d'anticorps anti-legionella dans la population générale est élevée ; ces faits soulignent la non-pertinence diagnostique d'un seul taux élevé d'anticorps. le travail de plouffe et al. est à ce titre tout à fait exemplaire [ ] . il démontre qu'un seul titre supérieur à / ne différencie pas les patients avec une légionellose de ceux ayant une pac d'autre étiologie. soixante-huit patients avec une légionellose certaine et patients avec une pac mais sans culture positive ni séroconversion ont été étudiés. un taux d'anticorps initial supérieur à / est retrouvé chez % des légionelloses prouvées versus % chez les autres (p > , ). au terme de cette revue, il apparaît clairement que le sérodiagnostic est plus un outil épidémiologique qu'une technique utile pour le diagnostic et le traitement initial d'un patient souf-frant de pac. pour terminer, il apparaît important de souligner que des experts français [ ] ont récemment suggéré que le diagnostic de légionellose probable pouvait être retenu devant un titre unique d'anticorps supérieur à / . cette suggestion va à l'encontre des données colligées plus haut et notamment de celles rapportées par plouffe et al. . . . infections à chlamydia spp. [ , , ] l'isolement de c. pneumoniae étant délicat, le diagnostic de ces infections repose usuellement sur la sérologie. différentes techniques sont disponibles : micro-immunofluorescence, réaction de fixation du complément, réaction immunoenzymatique. toutefois, la méthode de micro-immunofluorescence est la méthode sérologique de choix. outre le fait que le délai de résultat soit long (en cas de primo-infection, la réponse igm apparaît en trois semaines. la réponse igg apparaît en six à huit semaines), cette technique a de nombreuses limites : la méthodologie n'est pas standardisée, l'interprétation des résultats est subjective et, enfin, la présence chez les sujets sains d'une séropositivité résiduelle, voire celle d'un seul titre élevé d'igg chez des sujets âgés ou bpco sans signe apparent d'infection rend délicate l'interprétation d'un seul taux d'anticorps. il est donc actuellement proposé comme critères d'infection aiguë uniquement la séroconversion des igg avec une multiplication par du taux ou un taux unique d'igm supérieur ou égal à . comme pour c. pneumoniae, le diagnostic d'une infection due à c. psittaci repose sur soit sur une séroconversion avec multiplication du taux des anticorps par en réaction de fixation du complément ou en micro-immunofluorescence, soit sur un titre d'igm supérieur ou égal à en microimmunofluorescence. . . . infections à m. pneumoniae [ , ] en raison du manque de sensibilité et de la complexité de la culture, la sérologie a longtemps représenté la méthode de référence pour le diagnostic des infections à m. pneumoniae. historiquement, la réaction de fixation de complément a été la première utilisée. ont ensuite été proposées les techniques suivantes : immunofluorescence indirecte, agglutination sur microparticules et méthodes immunoenzymatiques. avant d'envisager les valeurs respectives de sensibilité et de spécificité de ces diverses techniques sérologiques, il convient de savoir qu'elles auront d'importantes limites pour les simples raisons suivantes : • les igg ne sont généralement pas détectables durant la première semaine de la maladie. elles atteignent un pic cinq semaines après le début de la maladie ; • les igm apparaissent la première semaine de la maladie et atteignent un pic au cours de la troisième semaine. toutefois, chez l'adulte, la production d' différentes techniques invasives ont été évaluées pour le diagnostic microbiologique des pac. il s'agit notamment de la ponction transtrachéale, de la ponction transpariétale et des endoscopies bronchiques avec simple fibroaspiration, brossage distal protégé et/ou lavage bronchoalvéolaire (lba). les deux premières méthodes avaient été développées pour s'affranchir de la contamination oropharyngée. en raison de son caractère trop invasif, la ponction transtrachéale est tombée en désuétude. la seconde est encore utilisée par quelques cliniciens. une revue récente de la littérature a fait le point sur cette technique [ ] . la ponction transthoracique s'effectue, sans anesthésie, dans la zone de condensation pulmonaire repérée par une radiographie thoracique face et profil. environ , ml de liquide est aspiré pour analyse. les données obtenues chez les sujets ou animaux sains suggèrent que le tissu pulmonaire sain comporte rarement assez de pathogènes pour produire une culture significative à partir d'une ponction transthoracique. la spécificité de la technique apparaît donc très élevée. les faux positifs peuvent avoir trois origines : • contamination du prélèvement lors de la ponction. celle-ci ne devrait pas dépasser ce qui est observé avec les hémocultures soit environ à % de contamination ; • détection d'une infection sanguine par piqûre vasculaire. en cas de pneumonie, le fait de savoir si le pathogène provient du sang ou du poumon ne semble pas avoir d'intérêt ; • culture d'une bactérie de surinfection. il ne s'agit pas à proprement parler de faux positifs et ces données bactériologiques doivent être prises en compte pour le traitement des patients. la sensibilité de la technique est difficile à évaluer dans la mesure où il n'y a pas de technique de référence… chez l'adulte, l'étude de publications rapportées entre et et compilant patients montre que la ponction isole un ou plusieurs pathogènes dans % des cas. d'une étude à l'autre, il existe une grande variation de résultats qui semble être expliquée par l'âge différent des patients étudiés, leur origine géographique disparate et, enfin, leur accessibilité aux soins très différente. en prenant pour référence les hémocultures, il est possible de chiffrer la sensibilité de la ponction transpariétale. À partir de études publiées entre et , les auteurs estiment la sensibilité de l'aspiration à %. les auteurs estiment que la fréquence du diagnostic étiologique passe de % avec des hémocultures isolées à % lorsque la ponction est ajoutée aux hémocultures. en dehors de problèmes techniques, les faux négatifs des cultures des liquides obtenus par ponction semblent essentiellement liés à une antibiothérapie antérieure. la réalisation de pcr sur ces prélèvements devrait faire disparaître cet écueil. les complications sont représentées par le décès (< , %), le pneumothorax ( , %) et les hémorragies pulmonaires sévères (< , %). cette technique semble donc contreindiquée en cas de troubles de l'hémostase (tp < % ou thrombopénie < /mm ). de même, une hypoxie sévère rendant impossible une apnée de deux secondes, une hypertension artérielle pulmonaire primitive (htap) ou une bpco avec bulles d'emphysème contre-indiquent généralement cette technique. au terme de leur revue, les auteurs suggèrent que la ponction transthoracique pourrait être utile en cas d'échec du traitement initial, en cas de surinfection nosocomiale et, enfin, en cas de suspicion de tuberculose avec analyse négative de l'examen direct du crachat ou des tubages gastriques. l'endoscopie bronchique permet de réaliser une fibroaspiration, un brossage distal protégé et/ou un lba. la fibroaspiration n'apparaît pas supérieure à l'examen cytobactériologique usuel des expectorations dans la mesure où la contamination par la flore oropharyngée est fréquente. elle n'est donc potentiellement utile que chez les patients incapables d'expectorer. risque moindre de contamination oropharyngée. celles-ci seront cultivées et une quantification bactérienne sera obtenue en cas de culture positive. le seuil de cfu/ml est considéré comme cliniquement pertinent pour la brosse. pour le lba, le seuil de significativité de la culture varie entre et cfu/ml selon les études [ ] . les prélèvements endoscopiques ont dans la littérature été utilisés dans deux indications majeures chez les patients non immunodéprimés : le diagnostic microbiologique initial de la pac et la gestion de l'échec du traitement initial. les principales études consacrées au diagnostic primitif bactériologique de la pac ont été les suivantes : • dès , jimenez et al. [ ] pour conclure sur l'intérêt des techniques endoscopiques avec brossage distal protégé et/ou lba pour le diagnostic microbiologique des pac, il nous paraît important de rapporter les propos de marquette et tonnel [ ] : « même si le lba peut être réalisé, en unité de réanimation, chez le patient sévèrement hypoxique, le risque de la technique n'est pas contrebalancé par un bénéfice suffisant dans les cadre des pac toutvenant. chez le patient dont la sévérité nécessite une intubation et une ventilation assistée, il est à notre sens déraisonnable de proposer un brossage, la sonde d'intubation offrant un accès direct permettant l'aspiration de sécrétions ». les techniques endoscopiques ont également été proposées pour guider la conduite thérapeutique en cas d'échec du traitement initial. les résultats retrouvés dans la littérature [ ] [ ] [ ] [ ] sont assez décevants dans la mesure où la culture obtenue par endoscopie est peu fréquemment positive (tableau ). . indications selon le type de patients (ambulatoire, en médecine, en réanimation, en institution pour personne âgée) et les situations (voyage, contexte épidémique) envisager que les indications des explorations à visée microbiologique puissent être différentes selon le type de patients et/ou les situations épidémiologiques revient à penser qu'il existe peut-être des différences étiologiques selon la gravité de la pac (ou le lieu d'hospitalisation du patient souffrant de cette infection) et des éléments anamnestiques, cliniques ou radiologiques en faveur d'une étiologie particulière. ces deux questions seront envisagées tour à tour. le cas particulier des pac du sujet âgé sera évoqué séparément avec l'étude de l'impact potentiel de l'âge puis celui du lieu de vie (institution versus domicile) sur l'étiologie. enfin, nous verrons si le contexte épidémique et le lieu géographique où a été acquise la pac peuvent orienter le clinicien vers certaines étiologies particulières. • dans le premier travail [ ] , portant sur patients hospitalisés pour une pac, ils ont montré en analyse multivariée que les pac sévères, admises en réanimation, étaient significativement associées avec des agents étiologiques tels que s. pneumoniae (or = , ) ou les bacilles à gram négatif (entérobactéries, p. aeruginosa ; or = , ) ; • dans le second travail [ ] , ils ont apparié patients admis en réanimation pour une pac avec autant de patients hospitalisés pour une pac, en dehors d'un service de réanimation. il n'existait aucune différence étiologique significative entre les deux populations (tableau ). enfin, il apparaît utile de rapporter le travail de roson et al. [ ] . dans un collectif de patients hospitalisés, les données étiologiques ont été analysées selon la sévérité de la pac appréciée par le pneumonia severity index (tableau ). bien que les auteurs n'aient pas réalisé de tests statistiques sur ces données, un calcul rapide du χ montre que l'incidence de s. pneumoniae et celle des pathogènes intracellulaires varient significativement selon les classes de psi. concernant le pneumocoque, même si la différence entre les classes est significative, elle apparaît difficile à interpréter… c'est plus simple pour les agents pathogènes intracellulaires dont la fréquence est plus élevée en cas de pac avec un pneumonia severity index bas. en résumé, l'aspect étiologique d'une pac varie selon sa sévérité et par conséquent son lieu de prise en charge. dans les formes ambulatoires, les agents intracellulaires tels que les mycoplasmes et les chlamydiae sont significativement plus fréquemment en cause que dans les pac nécessitant une hospitalisation. parmi ces dernières, il ne semble exister aucune différence entre les pac sévères admises en réanimation et celles traitées hors réanimation. comme cela a été récemment souligné par un groupe de travail [ ] , « aucun signe clinique ou radiologique n'a de valeur discriminante suffisante pour préciser, sur ces seuls arguments, le micro-organisme en cause ». ce point clairement établi ne sera donc pas revu. [ , ] . enfin, l'insuffisance cardiaque chronique sous-jacente serait plus en faveur d'une pneumonie virale que d'une pneumonie à pneumocoque [ ] . le travail le plus abouti sur ce sujet est celui de ruiz [ ] . À partir d'un collectif de patients, cet auteur a pu retrouver certaines relations entre le terrain sous-jacent et l'étiologie (tableau ). bien évidemment, ces résultats sont intéressants pour une enquête étiologique ciblée. toutefois, on peut se demander ce qui se passe lorsque les comorbidités se cumulent : qu'en est-il chez un alcoolique, fumeur, bronchopathe, de ans ? dans deux publications récentes [ , ] , les auteurs ont compilé les données de la littérature à propos des agents étiologiques de la pneumonie du sujet âgé de plus de ans et de celle acquise en institution (tableau ). les résultats sont déconcertants tant les variations de la fréquence d'isolement des divers pathogènes causals sont importantes. les nombreuses revues consacrées à la pneumonie du sujet âgé arrivent à des conclusions similaires, à savoir que l'aspect étiologique des pac du sujet âgé est mal connu [ ] [ ] [ ] [ ] . cette ignorance est particulièrement nette dans le cas des pneumonies acquises en institution. le rôle potentiellement majeur joué par les bacilles à gram négatif dans ces pneumonies a été souligné par une grande étude portant sur plus de patients [ ] . toutefois, ce résultat est soumis à caution dans la mesure où il est difficile chez de tels patients de différencier colonisation et infection. comme le souligne marrie [ ] , la colonisation oropharyngée par des bacilles à gram négatif croît avec l'âge et est particulièrement fréquente chez les patients institutionnalisés. les prélèvements usuels de crachats sont donc potentiellement à l'origine de résultats bactériologiques erronés. comme précédemment, il nous est donc apparu important de rapporter les rares études comparant, sur le même site et avec les mêmes méthodes de recherche étiologique, les patients selon leur âge et selon le lieu d'acquisition de la pneumonie. deux études, l'une portant sur des patients hospitalisés pour une pneumonie acquise en ville [ ] et l'autre sur des patients admis en réanimation pour une pneumonie acquise en ville [ ] , ont comparé les données étiologiques obtenues selon l'âge des patients (tableau ). concernant les bactéries usuelles, aucune différence majeure n'apparaît entre les patients âgés de plus de ans, voire de plus de ans et les patients plus jeunes. les bactéries dites atypiques sont en revanche, peutêtre plus fréquentes chez les sujets les plus jeunes. ce dernier point a d'ailleurs été souligné par ruiz et al. [ ] qui ont montré qu'un âge inférieur à ans était significativement corrélé la comparaison de l'aspect étiologique des pneumonies acquises en institution avec celles acquises en ville a fait l'objet de deux études (tableau ). dans la première, réalisée en angleterre [ ] , les patients ayant acquis une pneumonie en institution ont été appariés avec des patients du même âge ayant acquis leur infection en ville. aucune différence d'étiologie n'a été retrouvée entre les deux populations. dans la seconde, réalisée aux usa [ ] , les patients admis en réanimation pour une pneumonie sévère acquise en institution ont bénéficié d'une recherche étiologique exhaustive comprenant un lba protégé. staphylococcus aureus est l'agent dominant des pneumonies acquises en institution avec un pourcentage non négligeable de souches résistantes à la méthicilline. bien évidemment, ces travaux sont difficilement comparables dans la mesure où ils n'ont pas été réalisés dans le même pays, n'ont pas utilisé la même méthodologie diagnostique et n'ont pas étudié des patients de gravité comparable. toutefois, ils mettent en exergue un problème majeur qui est celui de la définition même de la pneumonie acquise en institution. il paraît en effet « audacieux » d'inclure sous le même vocable toutes les pneumonies acquises au sein d'une collectivité de personnes âgées. cette nuance indispensable à faire entre les différentes pneumonies acquises par le sujet âgé en dehors de son domicile est le préalable incontournable à une conduite diagnostique rationnelle. dans la plupart des conférences d'experts telles que celles proposées récemment par les nordaméricains et les britanniques [ , , ] , la pneumonie acquise en institution est considérée comme une pneumonie communautaire et doit donc être prise en charge en tant que telle. dans leurs recommandations de , les experts de l'infectious diseases society of america [ ] avaient toutefois rappelé que seules pouvaient être considérées comme communautaires les pneumonies acquises en ville ou survenant au cours des premiers jours d'un séjour dans une institution de long séjour. enfin, pour certains auteurs [ ] les pneumonies acquises dans les unités de long séjour devraient à l'inverse être considérées comme nosocomiales et donc être prises en charge différemment des pneumonies communautaires. comme on peut le voir, la situation demeure confuse. un travail récent d'el sohl et al. [ ] pourrait apporter un début de solution. À partir de l'étude de patients admis en réanimation pour une pneumonie sévère acquise en institution, cet auteur a pu construire un algorithme évaluant le risque qu'un germe résistant (s. aureus résistant à la méthicilline ou p. aeruginosa) soit incriminé en tant qu'agent causal de la pneumonie. ce risque est majeur ( %) chez les patients ayant eu une antibiothérapie antérieure (plus de trois jours de traitement au cours des six mois précédant la pneumonie) et une autonomie limitée (score adl > , ). À l'inverse, le risque est nul chez les patients autonomes sans antibiothérapie antérieure. dans certaines circonstances, le lieu d'acquisition de la pac ou le contexte épidémiologique doivent inciter le clinicien à évoquer certaines étiologies spécifiques ou plus fréquentes qu'à l'ordinaire [ ] [ ] [ ] . ces circonstances, en fait assez nombreuses, sont rapportées dans le tableau . selon le lieu de prise en charge de la pac, sa gravité, le terrain sous-jacent, voire le lieu d'acquisition, le spectre étiologique d'une pac peut avoir quelques particularités. toutefois, chez un patient donné, il n'existe aucun élément suffisamment pertinent pour exclure une quelconque étiologie… dans ce chapitre, il aurait pu être envisagé de passer en revue, pathogène par pathogène, les examens microbiologiques les plus à même d'affirmer leur responsabilité en tant qu'agent causal d'une pac. cet exercice apparaît toutefois plus fastidieux qu'utile. il semble préférable d'envisager la stratégie d'utilisation des diverses techniques microbiologiques sous un angle plus général pour tenter de répondre aux questions suivantes : • quel est l'impact d'une recherche étiologique sur le pronostic des patients ? , c. pneumoniae (%) a dont % de souches résistantes à la méthicilline. • quel est l'impact pronostique de l'antibiothérapie ? • quel est l'impact d'une donnée microbiologique positive sur la prise en charge des patients ? une fois les éléments de réponse obtenus, les modalités pratiques, quotidiennes, d'utilisation des explorations microbiologiques seront abordées. il n'existe que peu de travaux dans la littérature sur ce sujet. ils sont toutefois unanimes : la réalisation d'explorations microbiologiques et la connaissance de l'agent causal n'ont aucun impact pronostique significatif. deux études ont été réalisées chez des patients hospitalisés pour une pac [ , ] . dans la première, les auteurs ont rétrospectivement évalué l'impact d'un diagnostic microbiologique positif dans une cohorte de patients ayant bénéficié d'une analyse de l'expectoration, d'hémocultures et d'une analyse sérologique à la recherche de m. pneumoniae et des virus respiratoires [ ] . les patients soumis à cette enquête étiologique ont, trois mois après l'épisode pneumonique, une mortalité plus faible que ceux sans enquête étiologique réalisée ( versus % ; p = , ). toutefois, cette différence semble plutôt liée à un terrain sous-jacent moins altéré qu'à l'enquête étiologique proprement dite. concernant le pronostic immédiat, aucune différence n'a été retrouvée entre les patients avec et sans diagnostic étiologique précis. dans la seconde étude, van der eerden et al. [ ] ont comparé l'impact de deux démarches thérapeutiques : la première correspondait à une antibiothérapie probabiliste fondée sur les recommandations usuelles, la seconde à une antibiothérapie ciblée fondée sur les données des explorations microbiologiques. les taux de mortalité étaient identiques dans les deux groupes ( versus %, respectivement). rello et al. ont étudié patients admis en réanimation pour une pac sévère [ ] . un diagnostic microbiologique pré-cis a été fait pour , % des patients au prix d'explorations multiples y compris invasives. la mortalité a été de , % chez les patients avec diagnostic étiologique établi et de , % chez les patients sans diagnostic étiologique. sanyal et al. [ ] ont étudié patients avec une pac sévère. tous les patients ont bénéficié d'hémocultures et d'une analyse de l'expectoration. parmi eux, patients en échec thérapeutique à la e heure ont bénéficié d'une modification du traitement antibiotique, soit empirique (n = ), soit fondée sur les données des explorations microbiologiques (n = ). la mortalité a été la même dans les deux groupes ( / versus / ). enfin, el solh et al. [ ] ont étudié patients présentant une pac et admis en réanimation pour un échec du traitement instauré dans l'institution où ils séjournaient. tous les patients ont bénéficié d'explorations étiologiques multiples, y compris invasives. dans cas, les explorations se sont révélées positives. la mortalité globale dans ce collectif de patients a été de %. elle n'était pas différente selon que les explorations avaient ( %) ou non ( %) isolé un agent étiologique précis. les données concernant l'impact pronostique de l'antibiothérapie n'existent que pour les pac nécessitant une hospitalisation. il n'existe à notre connaissance aucune donnée à propos des pac traitées en ambulatoire. bien que les définitions utilisées ne soient pas toujours identiques et que les études soient peu nombreuses et parfois discordantes, le rôle délétère d'une antibiothérapie inadaptée aux germe(s) causal(s) apparaît très probable : • roson et al. [ ] le rôle pronostique du délai d'instauration de l'antibiothérapie par rapport à l'admission hospitalière du patient a été évalué dans deux études. dans la première, réalisée par meehan et al. dans six d'entre elles, il apparaissait qu'un traitement empirique par une quinolone ou par une association β-lactamine + macrolide, comparé avec un traitement par une β-lactamine seule, était associé avec une réduction de la mortalité. dans un souci de clarté, il nous est apparu important de rapporter seulement quelques-unes de ces huit études, auxquelles s'ajoutent quelques publications plus récentes, en différenciant le cas général des pac de celui des pac à pneumocoque. parmi les travaux sélectionnés par oosterheert et al. [ ] , l'étude la plus significative est peut-être celle de gleason et al. [ ] . dans un collectif de patients de plus de ans hospitalisés, les auteurs ont montré qu'en référence au traitement par une céphalosporine de troisième génération sans activité anti-pseudomonas utilisée en monothérapie, un traitement par une telle céphalosporine combinée avec un macrolide ou une quinolone en monothérapie était associé avec une diminution significative de la mortalité à jours. deux études non prises en compte par oosterheert et al. en raison de leur publication postérieure apportent des résultats similaires : • brown et al. [ ] avant d'envisager les modalités pratiques de réalisation des explorations microbiologiques au cours des pac, il faut d'emblée insister sur le fait que seul l'intérêt individuel immédiat du patient sera pris en compte dans ce chapitre. bien évidemment, les connaissances épidémiologiques globales sont importantes pour la prise en charge d'un patient. personne ne peut nier l'intérêt des travaux évaluant, par exemple, l'évolution de la sensibilité du pneumocoque. toutefois, aussi importantes que soient ces données, elles ne peuvent justifier une recherche étiologique exhaustive pour tous les patients souffrant de pac. de telles explorations exhaustives devraient peut être se limiter aux patients admis dans des centres pilotes dont les caractéristiques restent à définir. les points suivants seront donc successivement envisagés : • limites et intérêts individuels du diagnostic microbiologique ; • analyse critique des recommandations de sociétés savantes étrangères ; • propositions personnelles. pour définir au mieux ces points, il faut répondre aux trois questions suivantes. la première question concerne le diagnostic même de la pac : le diagnostic étiologique est-il nécessaire au diagnostic positif de pac ? même si l'isolement d'un pathogène par une technique spécifique peut conforter le diagnostic, le critère microbiologique ne fait pas partie des critères diagnostiques usuellement requis. la deuxième question est celle de savoir si une donnée étiologique pourrait guider le traitement antibiotique initial. ainsi que nous l'avons vu précédemment, le pronostic d'une pac peut être aggravé par une antibiothérapie tardive et inadéquate. comme la symptomatologie clinique, le tableau radiologique et les données anamnestiques sont incapables de prédire avec suffisamment de sensibilité et de spécificité l'étiologie de la pac, le traitement probabiliste initial ne pourra être fondé que sur des considérations épidémiologiques générales, voire sur d'éventuels examens microbiologiques dont le résultat peut être obtenu en quelques heures. dans l'état actuel des techniques, il n'y a que peu d'examens à même de fournir un résultat rapide. bien évidemment, il ne s'agit pas des hémocultures et encore moins des techniques sérologiques. certaines méthodes complexes (immunofluorescence par exemple) de recherche des pathogènes au niveau des sécrétions respiratoires fournissent théoriquement des résultats rapides. malheureusement, ces techniques n'étant disponibles que dans des laboratoires spécialisés, il est évident que le délai d'obtention du résultat est loin d'être aussi rapide qu'annoncé. ainsi, il n'existe que trois examens capables de fournir un résultat rapide. il s'agit de l'examen direct des expectorations et de la recherche d'antigènes pneumococciques ou de l. pneumophila type dans les urines. ces examens ont toutefois d'importantes limites : premièrement, ils ne peuvent souvent incriminer que deux des pathogènes causals potentiels, s. pneumoniae et l. pneumophila. deuxièmement, même en cas de positivité, il ne faut pas perdre de vue que leur spécificité est loin d'être absolue et que dans un certain nombre de cas, la pac a une étiologie plurimicrobienne. il est donc peut-être déraisonnable de focaliser l'antibiothérapie sur le seul pathogène isolé. les experts de l'ats [ ] insistent d'ailleurs sur le fait que l'examen direct de l'expectoration ne devra pas être utilisé pour diminuer la largeur du spectre antibactérien du traitement empirique mais, au contraire, pour l'élargir si un pathogène, non couvert par le traitement empirique usuel, est suspecté. enfin, en cas de négativité, leur sensibilité est trop faible pour exclure définitivement s. pneumoniae et l. pneumophila. comme on peut le voir, il ne semble donc pas exister réellement d'explorations microbiologiques capables de guider utilement l'antibiothérapie initiale. la troisième question concerne l'impact du diagnostic microbiologique sur l'adaptation éventuelle de l'antibiothérapie après à heures d'administration. À ce moment-là, le clinicien dispose d'une part de paramètres cliniques, biologiques et radiologiques permettant d'évaluer l'efficacité du traitement et, d'autre part, du résultat de certaines explorations microbiologiques telles que les cultures des expectorations ou sécrétions trachéobronchiques et telles que les hémocultures. sans entrer dans le détail des critères d'évaluation, quatre situations sont envisageables : • le traitement est un succès et les explorations microbiologiques sont négatives. il est logique de penser que le traitement ne sera pas modifié ; • le traitement est un succès et les explorations microbiologiques isolent un pathogène précis. la question est alors la suivante : faut-il modifier l'antibiothérapie sur la foi de cette donnée microbiologique avec notamment réduction du spectre antibactérien selon la sensibilité du pathogène isolé. plusieurs éléments semblent devoir être pris en compte. tout d'abord, il faut dire qu'il n'existe pas de techniques microbiologiques suffisamment rapides pour infirmer en à heures la responsabilité d'un pathogène tel que l. pneumophila, c. pneumoniae ou m. pneumoniae. comme, par ailleurs, les données de la littérature soulignent le bénéfice thérapeutique d'une antibiothérapie incluant à la fois une β-lactamine et un macrolide, il semble déraisonnable de stopper un traitement efficace sur ces pathogènes sur la seule foi de l'isolement d'une autre bactérie usuelle. ensuite, concernant le pneumocoque, certaines données récentes suggèrent qu'une bithérapie efficace est bénéfique en cas de bactériémie. ainsi, en cas d'hémocultures positives à pneumocoque, le bien-fondé d'une simplification du traitement n'est pas certain. ces données expliquent peutêtre les résultats de la littérature où l'adaptation du traitement aux données microbiologiques est loin d'être la règle [ , ] ; • le traitement est un échec et les données microbiologiques permettent d'incriminer un pathogène résistant au traitement initial empirique. bien évidemment, le traitement sera adapté. malheureusement, il est probable que ce retard à l'instauration d'un traitement adéquat ait des conséquences délétères irrémédiables [ , ] ; • le traitement est un échec et les données microbiologiques initiales sont négatives. il se pose le problème de nouvelles explorations microbiologiques, notamment invasives. malgré la logique de cette démarche, il semble malheureusement qu'un diagnostic étiologique tardif ne modifie pas le pronostic sévère observé dans ces circonstances [ ] . comme, on peut le constater, les contraintes de l'antibiothérapie au cours de la pac sont telles que la place laissée aux explorations microbiologiques dans la prise en charge globale d'un patient avec pac pourrait dans l'état actuel des techniques être minimale. depuis , diverses sociétés américaines (infectious disease society of america, american thoracic society) [ , , ] et anglaises (british thoracic society) [ , ] ont émis des recommandations concernant les explorations microbiologiques à réaliser chez un patient présentant une pac. elles sont schématisées dans le tableau . comme on peut le voir, aucun bilan étiologique n'apparaît indispensable pour les patients traités en ambulatoire. pour les patients hospitalisés, en dehors des services de réanimation, le bilan proposé varie d'une recommandation à l'autre. les experts américains proposent tous des hémocultures. ils sont plus nuancés vis-à-vis de l'analyse cytobactériologique des expectorations. les recommandations récentes font état de l'intérêt de la recherche des antigènes urinaires pneumococciques. les recommandations britanniques sont simplifiées à l'extrême puisque les experts suggèrent que les hémocultures puissent ne pas être utiles et que l'analyse de l'expectoration n'est utile que chez les patients indemnes de toute antibiothérapie antérieure. pour les patients admis en réanimation, le bilan proposé est plus complet avec hémocultures, analyse cytobactériologique des expectorations et recherche d'antigè-nes urinaires de l. pneumophila et de pneumocoque. vis-àvis des sérologies et des explorations invasives endoscopiques les avis semblent partagés. tout d'abord, il apparaît indispensable de différencier les pneumonies acquises au domicile des pneumonies acquises en milieu institutionnalisé. pour les pneumonies acquises en ville, en dehors d'une institution : • il apparaît inutile de proposer un quelconque bilan pour les patients traités en ambulatoire ; • pour les patients hospitalisés en dehors d'un service de réanimation, les propositions minimalistes britanniques sont séduisantes. il est en effet clair que les hémocultures, en raison de leur faible fréquence de positivité et de leur résultat tardif, ne sont que peu contributives à la prise en charge thérapeutique initiale. il en va de même pour l'analyse cytobactériologique des expectorations. dans un contexte épidémique évocateur, la recherche d'antigènes urinaires de l. pneumophila apparaît cependant indispensable ; • en cas de pneumonie admise en réanimation, la recherche d'antigènes urinaires de pneumocoque pourrait être utile dans la mesure où, positive, elle pourrait être le témoin initial d'une bactériémie. un tel résultat pourrait, de fait, conduire à la mise en route d'une bithérapie antipneumococcique efficace. de même, la recherche d'antigènes urinaires de l. pneumophila pourrait conduire à l'instauration d'un traitement adéquat d'une légionellose grave. les hémocultures seraient intéressantes, ne serait ce que pour stopper une bithérapie initiale en cas de négativité. enfin, l'analyse cytobactériologique des sécrétions trachéobronchiques prélevées lors de l'intubation, chez les patients nécessitant une ventilation mécanique, apparaît utile et semble pouvoir remplacer les prélèvements endoscopiques. pour les patients non ventilés, l'obtention d'une expectoration permettant une analyse correcte apparaît plus illusoire. de même, la place de [ ] [ ] [ ] [ ] . jusqu'à ces dernières années, affirmer l'origine virale d'une infection pulmonaire communautaire n'était ni aisé ni utile : [ ] [ ] [ ] [ ] [ ] [ ] . la plupart de ces travaux ont été réalisés sur des échantillons de population comportant à la fois des enfants et des adultes. les résultats (tableau ) montrent que la sensibilité de ces tests rapides est de l'ordre de - % avec une spécificité supérieure à %. les progrès récents des méthodes du diagnostic moléculaire, telles que la pcr, permettent d'imaginer que la plupart des agents viraux responsables d'infections respiratoires basses puissent être rapidement identifiés. il importe toutefois de signaler d'emblée que ces techniques, ainsi que l'interprétation des nombreuses études réalisées sur le sujet, ont d'importantes limites. tout d'abord, il s'agit de techniques complexes qui ne sont disponibles que dans des laboratoires spécialisés. ainsi, même si elles peuvent potentiellement fournir un résultat rapide en quelques heures, elles ne sont pas d'une disponibilité aisée d'une part et d'autre part, même dans les laboratoires de pointe, elles ne sont pas toujours accessibles heures sur . ensuite, bon nombre d'études ont été réalisées avec des techniques « maison » ce qui rend les résultats parfois difficilement comparables d'un travail à un autre. enfin, comme toujours, l'absence de « gold standard » diagnostique rend aléatoire les valeurs de sensibilité et de spécificité rapportées [ ] . quoi qu'il en soit, pour certains virus, comme les picornavirus, les hantavirus ou les coronavirus, il n'existe pas de technique d'immunofluorescence directe permettant leur dépistage rapide dans des échantillons cliniques. la pcr apparaît donc comme l'un des seuls moyens de diagnostic rapide. un travail réalisé par johnston et al. [ ] a ainsi montré, dans une population essentiellement pédiatrique, que la pcr permettait d'identifier un picornavirus trois fois plus souvent que la culture. pour les coronavirus, l'émergence du sras soulignait l'importance du diagnostic microbiologique rapide. la littérature revue par murdoch [ ] permet de souligner les points suivants. pendant les deux premières semaines de la maladie, la mise en évidence du virus par pcr est la méthode la plus sensible, tandis que la sérologie devient la méthode privilégiée de détection dans la phase de convalescence. différentes techniques de pcr ont été mises au point. le virus peut être détecté au niveau d'échantillons respiratoires supérieurs tableau comparaison des tests de diagnostic rapide de la grippe avec la culture virale et/ou l'immunofluorescence directe [ ] [ ] [ ] [ ] [ ] [ ] ou inférieurs ainsi qu'au niveau des urines ou des selles. pendant les cinq premiers jours de la maladie, la positivité de la pcr chez les patients qui auront un sras sérologiquement prouvé est au niveau de l'expectoration, des aspirations nasopharyngées, des écouvillons de gorge ou de nez, des selles et de l'urine respectivement de , , , et [ ] [ ] [ ] . il est assez difficile d'évoquer des chiffres de sensibilité et de spécificité dans la mesure où la pcr détecte généralement plus de virus que les autres techniques (tableau ). soit il s'agit de vrais résultats positifs et on doit alors parler de sensibilité supérieure à celle des autres techniques, soit il s'agit de faux résultats positifs et alors il faut évoquer une faible spécificité. À l'heure actuelle, il semble impossible de trancher en faveur de l'une ou l'autre des deux hypothèses. nous avons largement passé en revue dans les chapitres précédents les divers examens permettant l'isolement des bactéries causales des pac. il importe toutefois d'évoquer le rôle que peut ou que pourrait jouer la technique de pcr pour le diagnostic bactériologique de ces infections. deux revues récentes de la littérature, réalisées par murdoch [ , ] [ ] [ ] [ ] infections bactériennes au cours des pac. celui-ci semble être double : d'une part, cette technique peut identifier des pathogènes pour lesquels la culture in vitro est impossible, insensible, complexe ou longue. d'autre part, elle est indépendante, à l'opposé des cultures, de la viabilité du pathogène causal. la sensibilité ne semble donc pas influencée par une éventuelle antibiothérapie antérieure. parmi les désavantages et/ou limites actuelles, il faut citer : • l'absence d'étude possible de la sensibilité du pathogène identifié ; • la difficulté à évaluer, en l'absence de « gold standard » diagnostique, la sensibilité et de la spécificité de la pcr. il faut toutefois insister sur les points suivants : ○ la présence dans les échantillons étudiés d'inhibiteurs, dont la nature est souvent inconnue, peut diminuer la sensibilité de la méthode ; ○ à l'inverse, la spécificité de la technique est grandement influencée par son incapacité à différencier contamination, colonisation et infection ; • l'absence fréquente de pcr commerciales rend la validité des résultats hautement dépendante des techniques utilisées par le laboratoire qui les produit. cela est à l'origine d'un manque de reproductibilité des résultats, ce qui rend la comparaison interlaboratoire difficile ; • la sensibilité de la pcr dépend de la nature des échantillons étudiés. selon les données actuelles, la pcr pourrait être appliquée pour la recherche de nombreuses bactéries (tableau ). la technique de pcr a ainsi été évaluée pour le diagnostic des pac dues à l. pneumophila, m. pneumoniae, chlamydia spp et coxiella burnetii. bien que cela apparaisse d'emblée moins utile et, en contradiction avec nos propos précédents, la pcr a également été évaluée pour le diagnostic des infections à pneumocoque… . . . rôle de la pcr pour le diagnostic des infections pneumococciques un certain nombre de travaux ont été consacrés à l'étude de la technique de pcr pour le diagnostic des pac à pneumo-coque. malheureusement, il est très difficile de savoir quelle peut être la sensibilité ou la spécificité d'une telle technique en raison du manque patent de référence diagnostique. de plus, la spécificité de la pneumolysine dépistée par la pcr ne semble pas absolue. les gènes codant la pneumolysine ont été retrouvés chez d'autres streptocoques tels que le s. mitis. par conséquent, la spécificité de la technique pourrait être faible. selon murdoch [ ] [ ] [ ] [ ] [ ] [ ] [ ] . ces données montrent bien que même en se limitant aux pac avec hémoculture(s) positive (s), la fréquence de positivité de la pcr réalisée sur le sérum varie considérablement d'une étude à l'autre. quant à l'interprétation des résultats positifs de la pcr chez les patients ayant des cultures négatives, on peut tout autant évoquer une faible spécificité de la méthode qu'une meilleure sensibilité de celle-ci… . . . rôle de la pcr pour le diagnostic des infections à l. pneumophila une grande variété de techniques de pcr ont été évaluées pour la recherche des legionella spp. quand elles sont appliquées sur des échantillons respiratoires, elles apparaissent aussi sensibles voire plus sensibles que la culture. chez les patients incapables d'expectorer, ce qui est fréquent au cours de la légionellose, le recours à des prélèvements tels que le lba les nombreuses études évaluant l'intérêt de la pcr pour le diagnostic des pac à m. pneumoniae ont été récemment colligées par daxboeck et al. [ ] . selon ces auteurs, cette technique s'avérerait plus sensible que toutes les autres méthodes diagnostiques. toutefois, la pcr pourrait poser des problèmes de spécificité. en effet, plusieurs études ont retrouvé un manque de corrélation entre une pcr positive et la réponse immunitaire avec apparition d'anticorps. bien que cette discordance apparente soit également connue pour la culture et la sérologie [ ] , elle demande réflexion. plusieurs explications à cette discordance entre culture ou pcr positives et absence d'anticorps ont été avancées : • la première correspond au fait que la présence de m. pneumoniae au niveau du tractus respiratoire n'est pas obligatoirement associée avec une symptomatologie clinique [ ] ; • la deuxième correspond au fait que la réponse immunitaire est retardée et que la présence de m. pneumoniae peut au cours de la maladie précéder l'élévation des anticorps… malgré cela, les auteurs considèrent qu'une pcr positive associée avec un tableau clinicoradiologique de pac doit conduire à instaurer un traitement efficace sur m. pneumoniae. cette technique de pcr peut s'appliquer sur des échantillons issus du tractus respiratoire inférieur mais aussi sur des échantillons provenant d'un écouvillonnage pharyngé. ce dernier point est tout particulièrement intéressant car il exonère le clinicien des difficultés éventuelles de prélèvement. avant de considérer cette technique comme étant celle devant faire référence, il convient toutefois de standardiser les protocoles de prélèvements et de comparer les très nombreuses techniques actuellement employées. . . . rôle de la pcr pour le diagnostic des infections à chlamydia spp. [ ] bien que la pcr apparaisse pour certains experts au moins aussi sensible que la culture [ ] , il semble assez difficile de se faire une idée précise de l'intérêt de cette technique pour de nombreuses raisons : les résultats des différentes études sont souvent contradictoires. l'absence de standardisation de la technique rend difficile la comparaison entre les différentes publications. enfin, l'absence de « gold standard » rend difficile l'évaluation de la sensibilité et de la spécificité. le travail de verkooyen et al. [ ] illustre parfaitement ce dernier point. les auteurs ont étudié patients avec une pac nécessitant une hospitalisation. la pcr a été réalisée soit sur un prélèvement nasopharyngé, soit sur un prélèvement de gorge soit sur un lba. vingt-trois patients avaient une évaluation sérologique compatible avec le diagnostic d'infection à c. pneumoniae. neuf de ces patients avaient une pcr positive. À l'inverse, patients avaient une pcr positive avec une sérologie négative. bien évidemment, il est difficile de savoir si la pcr est plus sensible que la sérologie ou, à l'inverse, moins spécifique… enfin, actuellement, il est difficile de savoir quel est le meilleur site de prélèvement pour rechercher par pcr une infection à c. pneumoniae. signalons enfin qu'il n'existe que peu de données sur l'intérêt de la pcr pour le diagnostic des infections à chlamydia psittaci. diagnostic des pac à pneumocoque par la pcr [ ] [ ] [ ] [ ] [ ] [ ] Études milieux de réalisation pcr référence pcr+/référence+ pcr+/référence- [ ] liquide [ ] . l'immunofluorescence est la technique de référence. il semble toutefois que les techniques de pcr puissent également être appliquées pour le diagnostic de cette infection [ ] . une publication récente [ ] suggère même que deux techniques de pcr soient associées (pcr et pcr nichée) pour accroître la sensibilité et la spécificité de la méthode. comme précédemment avec les virus, avoir à disposition une technique de pcr multiple capable d'identifier à la fois m. pneumoniae et/ou c. pneumoniae et/ou l. pneumophila pourrait être très utile. quelques études [ ] [ ] [ ] portant sur un faible nombre de patients, montrent des résultats intéressants dans la mesure où la technique de pcr apparaît au moins aussi performante que la sérologie en termes de sensibilité (tableau ). dans un futur assez proche, la pcr qui est encore une technique d'exception, pourrait devenir un examen incontournable pour le diagnostic rapide des pac. deux publications récentes, l'une consacrée aussi bien aux patients ambulatoires qu'aux patients hospitalisés [ ] et l'autre consacrée aux patients admis en réanimation pour une pac sévère [ ] laissent entrevoir le rôle que pourraient jouer les techniques de biologie moléculaire dans l'amélioration des performances du diagnostic microbiologique des pac (tableau ). dans un futur plus éloigné, il faut évoquer le rôle potentiel des techniques de diagnostic par « micropuces ». ces techniques sont, dans l'absolu, capables de dépister dans le même temps de très nombreux agents pathogènes et d'évaluer l'interaction entre l'hôte et le pathogène [ ] . toutefois, à notre connaissance, il n'existe pas encore actuellement de données précises concernant l'intérêt pratique de ces méthodes en pathologie infectieuse bronchopulmonaire usuelle. les agents bactériens et viraux incriminés au cours des exacerbations aiguës de bpco sont très nombreux. dans le tableau , quelques résultats d'études récentes ont été rapportés [ ] [ ] [ ] [ ] . bien évidemment, ces données sont très loin d'être exhaustives. leur seul but était de montrer d'une part que tous les pathogènes incriminés au cours des pac l'ont aussi été au cours des exacerbations aiguës de bpco et d'autre part que la responsabilité respective des différents pathogènes dépend de la méthode diagnostique utilisée. les recommandations récentes de prise en charge émanant de la 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development of a multiplex real-time quantitative pcr assay to detect chlamydia pneumoniae, legionella pneumophila and mycoplasma pneumoniae in respiratory tract secretions cap study group. multiplex pcr for the simultaneous detection of chlamydia pneumoniae, mycoplasma pneumoniae and legionella pneumophila in community-acquired pneumonia improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction high prevalence of respiratory viral infections in patients hospitalized in an intensive care unit for acute respiratory infections as detected by nucleic acid-based assays chips with everything: dna microarrays in infectious diseases bronchial microbial patterns in severe exacerbations of chronic obstructive pulmonary disease (copd) requiring mechanical ventilation relationship between bacterial flora in sputum and functional impairment in patients with acute exacerbations of copd. study group of bacterial infection in copd microbial airway colonization is associated with noninvasive ventilation failure in exacerbation of chronic obstructive pulmonary disease infectious etiologies in acute exacerbation of copd recommandations pour la prise en charge des bronchopneumopathies chroniques obstructives standards for the diagnosis and treatment of patients with copd: a summary of the ats/ers position paper agents infectieux incriminés au cours des exacerbations de bpco [ ] [ ] [ ] [ ] key: cord- -o skj r authors: plouffe, joseph f.; martin, daniel r. title: re-evaluation of the therapy of severe pneumonia caused by streptococcus pneumoniae date: - - journal: infectious disease clinics of north america doi: . /j.idc. . . sha: doc_id: cord_uid: o skj r pneumonia caused by streptococcus pneumoniae is the most deadly form of community-acquired pneumonia. the death rate of bacteremic pneumococcal pneumonia has remained constant over the past years. several retrospective reviews of bacteremic pneumococcal pneumonia suggest that dual therapy with a beta-lactam and a macrolide antimicrobial agent is associated with a lower case fatality rate than therapy with a beta-lactam alone. these studies are reviewed, potential mechanisms are suggested, and future studies are discussed. with the advent of modern microbiology, streptococcus pneumoniae (pneumococcus) was identified as the cause of community-acquired pneumonia (cap) in the most patients [ ] . the case fatality rate (cfr) of untreated bacteremic pneumococcal pneumonia was %. early studies defined the importance of opsonizing antibodies to the infecting serotype. serum therapy was instituted in the s and resulted in the decrease of the cfr to %. with the advent of antimicrobial therapy in the s, the cfr of bacteremic pneumococcal disease was decreased further to %. the changing pattern of pneumococcal pneumonia was recognized [ ] . over the next years, even though the pneumococcus remained susceptible to penicillin, the cfr remained constant. modern icus failed to improve on the % cfr [ ] . to further complicate matters, in the s, some s pneumoniae strains developed resistance to penicillin and other antimicrobial agents used to treat pneumonia [ ] . several retrospective studies have suggested that combination therapy with a b-lactam and a macrolide antimicrobial agent results in a lower cfr than does therapy with a b-lactam alone [ ] [ ] [ ] . this article addresses the available data on the treatment of bacteremic pneumococcal pneumonia and discusses the biologically feasible explanations behind new therapy. guidelines for the treatment of the clinical syndrome of cap have been published by several pulmonary and infectious disease societies [ , [ ] [ ] [ ] [ ] . these guidelines are addressed in detail in other articles in this issue. to evaluate bacteremic pneumococcal pneumonia, series of cap cases should be examined, as physicians infrequently know whether a patient has pneumococcal pneumonia on initial presentation. over the years, many series of cap cases have been published and reflect the changing nature of cap [ , [ ] [ ] [ ] [ ] [ ] [ ] . in series of cap through the s s pneumoniae was the predominant pathogen, accounting for more than % of cases. in each subsequent decade, another pathogen or group of pathogens has been identified as causes of cap. mycoplasma pneumoniae was identified as the initial cause of atypical pneumonia in the s. the importance of anaerobic organisms in aspiration pneumonia was identified in the s. legionella pneumophila was discovered to be the cause of the epidemic of legionnaires disease in . chlamydia pneumoniae was identified as another cause of atypical pneumonia [ ] . the importance of atypical and other viral causes of cap in adults (ie, respiratory syncytial virus, parainfluenza, hantavirus, metapneumonia virus, coronavirus [severe acute respiratory syndrome]) have been identified by various investigators, including those at the centers for disease control and prevention and world health organization [ ] [ ] [ ] [ ] [ ] . more recent series have been able to identify s pneumoniae in only % to % of patients with cap, and no specific cause was found in % to % of patients [ , ] . approximately one third of patients had taken at least one dose of antibiotics before presenting to the physician. the services of many microbiology laboratories have been scaled back because of hospital budgetary constraints. the consolidation of many hospitals has led to the use of centralized or reference laboratories, which prolongs the time from specimen collection to processing. these factors have decreased the ability to culture pyogenic organisms, such as s pneumoniae. centers that use methods in addition to culture for s pneumoniae (antigen detection, serological means) have reported finding more cases of pneumococcal pneumonia than cases of pneumonia caused by unidentified pathogens, suggesting that many patients without a definable cause have pneumococcal pneumonia [ , ] . patients with increased susceptibility to pneumococcus may be susceptible to other pulmonary pathogens, leading to dual infections. some pathogens, such as influenza virus, render the host more susceptible to the pneumococcus [ ] . predisposition to pneumococcal infection may hold true for patients with antecedent m pneumoniae and c pneumoniae infections [ ] [ ] [ ] [ ] . lessons learned from the series of patients with cap include the fact that it may be difficult to identify cases of pneumococcal pneumonia, patients with pneumococcal pneumonia may have additional infections [ , ] , and patients with pneumonia reflect the demographics of the changing u.s. population. studies of pneumococcal bacteremia suggest that the incidence of disease is increasing in the u.s. population [ , [ ] [ ] [ ] . pathophysiology s pneumoniae is acquired through inhalation of large droplets from a carrier. the pneumococcus must colonize the oropharyngeal epithelial cells and then be able to multiply. microaspiration of these organisms to the lungs causes the pneumonia. the efficiency of this process is low in most instances, as patients with pneumococcal pneumonia are not placed in respiratory isolation. in certain closed populations, such as jails, long-term care facilities, and day care centers, the process' efficiency is higher, and outbreaks can occur. the defense system of the host is helpful in controlling s pneumoniae attachment (conjugate vaccine), growth, and spread to lungs. factors that inhibit ciliary function, such as smoking or viral infections, increase the likelihood of acquiring pneumococcal pneumonia. once in the pulmonary parenchyma, the pneumococcus elicits an intense inflammatory reaction. phagocytosis in enhanced if type-specific opsonizing antibodies are present. bacteremia is more likely to occur in the absence of these antibodies (hypogammaglobulinemia), diminished function of phagocytic cells (alcoholism), decreased inflammatory response (complement deficiencies), and the absence of the clearing function of the spleen (sickle cell disease, splenectomy). before the early s, most s pneumoniae isolates were susceptible to most of the antimicrobial agents that were used to treat respiratory infections. since then, higher concentrations of penicillin have been required to inhibit growth of the pneumococcus [ ] . the changing susceptibilities of antimicrobial agents are discussed in detail in another article in this issue. in general, b-lactam antibiotics effectively treat nonmeningeal (ie, pneumonia, bacteremia) pneumococcal disease in most cases. although several respiratory pathogens may have a higher cfr (rate for pseudomonas aeruginosa, %) than s pneumoniae ( %- %), the total number of cap-related deaths caused by pneumococci exceeds the number of deaths caused by all other pathogens [ ] . it seems logical that the changes in the treatment of cap that result in more favorable outcomes also would be beneficial in patients with pneumococcal pneumonia. changes that have been associated with improvements in cfr in some series of patients with cap include more rapid antibiotic delivery [ ] , combination therapy with a cephalosporin with good pneumococcal activity and macrolide (versus the cephalosporin alone), and therapy with a fluoroquinolone (ciprofloxacin; versus a cephalosporin alone) [ ] . culture of s pneumoniae from a normally sterile body fluid (blood pleural fluid) in a patient with an acute pneumonia usually is accepted as definite sign of pneumococcal pneumonia [ , ] . there is some debate as to the value of culturing s pneumoniae from expectorated sputum even with a compatible gram stain, although clinicians with experience in pneumococcal pneumonia value the information provided by high-quality pulmonary secretions [ ] . a rapid s pneumoniae urinary antigen has been evaluated [ , ] and shown to have good specificity in the adult population ([ % in most studies) and reasonable sensitivity ( %- % in most studies). the test was too sensitive in heavily colonized children and could not discriminate among infected or colonized children in underdeveloped countries [ ] . a study from spain studied patients who were hospitalized with acute cap in whom a s pneumoniae urinary antigen (spua) test was performed [ ] . pneumococci were found in cultures from only patients ( %; half from blood, half from sputum). the spua test was positive in of patients with positive cultures ( %); however, an additional patients had positive spua tests with cultures that were negative for pneumococcus. because the specificity has been reported to be greater than % in adults, most of these patients also had pneumococcal pneumonia. in this study, of patients ( %) would have pneumococcal pneumonia, a proportion of pneumococcal pneumonia cases that is similar to the proportion in other large series of hospitalized cases of cap. the sensitivity of the spua test would be of patients ( %) or at least would be four times greater than the combination of cultures of sputum and blood ( of patients [ %]). cultures still would be important in determining antimicrobial susceptibility. several retrospective studies suggest that monotherapy with an effective cephalosporin is not adequate treatment for pneumococcal pneumonia. mufson and stanek [ ] reported on patients with pneumococcal bacteremia in huntington, west virginia over years. the data were analyzed in -year periods. overall, the incidence of pneumococcall bacteremia increased, and the cfr decreased. in each -year period, a regimen including a macrolide and b-lactam resulted in lower cfr than did regimens involving a b-lactam alone or two antibiotics (excluding macrolides). no specifics were provided on the timing of the initial dose and changes in therapy. fluoroquinolones were used infrequently. although this study was retrospective and did not control for severity of illness, it may have offered the first clue that monotherapy of pneumococcal bacteremia with a cephalosporin is less efficacious than combination therapy with a cephalosporin and a macrolide. waterer et al [ ] reported data on antimicrobial therapy in patients with bacteremic pneumococcal pneumonia from hospitals in tennessee between january and july . immune-compromised patients were excluded. seven patients with s pneumoniae isolates resistant to empiric therapy also were excluded. patients received one antibiotic active against the patient's isolate (single effective therapy [set]), two effective antibiotics (dual effective therapy [det]), or more than two effective antibiotics (met). logistic regression analysis was used to calculate the odds ratio (or) for death adjusted for predicted mortality. compared with det, the or for set was . ( % confidence interval [ci], . - . ). all deaths occurred in cases with pneumonia severity index (psi) classes iv and v. even after excluding deaths that occurred in first hours of hospitalization, set was an independent predictor of death (or, . ; %ci . - . ). analysis was done to evaluate coverage for atypical pathogens. the cfr was . % ( of patients) in patients receiving atypical coverage and was . % ( of ) in patients not receiving atypical coverage; however, the predicted mortality rate was higher in the latter group of patients. multivariate analysis did not show that lack of atypical coverage was a predictor of death (p = . ). the investigators suggest that prospective studies should address set versus det in patients with pneumococcal bacteremia in psi classes iv and v. they state that the s pneumoniae urinary antigen should help in rapidly identifying the subset of patients with pneumococcal pneumonia. martinez et al [ ] performed a retrospective analysis of a -year ( - ) database of patients with bacteremic pneumococcal pneumonia. of patients analyzed, ( %) received empiric therapy with a b-lactam plus a macrolide, whereas ( %) received empiric therapy with a b-lactam alone. potential risk factors for in-hospital death were identified in stepwise logistic regression analysis. multivariate analysis revealed that absence of a macrolide in the initial empiric regimen independently was associated with death (p = . ). other independent predictors of death included shock, age greater than years, and a blood culture isolate of an s pneumoniae strain resistant to penicillin and erythromycin. a total of patients ( %) died. even when the data were reanalyzed to exclude early deaths (occurred \ hours after presentation), the absence of a macrolide in initial therapy was associated with death (or, . ; %ci, . - . ). in this study, a macrolide could be combined favorably with a cephalosporin or a b-lactamase inhibitor. a previous study of patients with cap, but not nonbacteremic pneumococcal pneumonia, found that treated with blactamase inhibitors and a macrolide were less effective than treatment with a cephalosporin alone [ ] . as with most retrospective studies, there were differences among the popuations. the group receiving cephalosporin alone had higher incidences of comorbid conditions, hiv infection, hematologic malignancies, neutropenia, nosocomial bacteremia, and penicillin-resistant isolates. in the group receiving b-lactamase inhibitors and a macrolide, more patients experienced shock and resultant admission to icu. the investigators caution that a prospective, randomized trial is necessary to definitively determine the effect of macrolides. bacteremic pneumococcal pneumonia remains a serious life-threatening infection. the incidence of pneumococcal bacteremia seems to be increasing. the cfr with bacteremic pneumococcal pneumonia has not changed much in the past years. there always have been unanswered questions with regard to severe pneumococcal disease. why does the cfr differ among different centers and countries [ , ] ? why do some countries have many cases of nosocomial s pneumoniae infections [ ] and others (eg, the united states) have a minimal number of such cases [ ] ? reports have suggested that combination antimicrobial therapy containing a macrolide is more effective than therapy with a cephalosporin or b-lactam alone [ ] [ ] [ ] . this article addresses the published literature. why would a b-lactam (cephalosporin) in combination with a macrolide be more efficacious than a b-lactam (cephalosporin) alone in the treatment of patients with bacteremic pneumococcal pneumonia? are there interactions between the two antibiotics against streptococcus pneumoniae? although some antibiotic combinations have been shown to be synergistic in vitro and in vivo (ie, ampicillin and gentamicin against enterococci), no data suggest that such a synergistic activity exists between a cephalosporin or penicillins and a macrolide against pneumococci [ ] . there is evidence that the combination of penicillin and tetracycline have antagonistic effects in patients with pneumococcal meningitis [ ] . one possible explanation for the decreased mortality rate with combination therapy could be that the macrolide is somewhat antagonistic against the rapid killing of the pneumococci by the cephalosporin. this effect could slow the rapid lysis of pneumococci and abate the resultant intense inflammatory response. would the use of two empiric antibiotics make it more likely that at least one would be active against the pneumococcus? in their study, waterer et al [ ] excluded organisms resistant to empiric therapy and still demonstrated a benefit of macrolide use. lujan et al [ ] demonstrated that discordant therapy was associated with a higher cfr. this finding was seen only among physicians who did not use third-generation cephalosporins. pneumococcal resistance to ceftriaxone or cefotaxime was minimal ( % of patients). what is the possibility that the macrolide is treating a secondary infection in a patient with pneumococcal bacteremia? influenza infection predisposes to pneumococcal pneumonia and bacteremia through several mechanisms. co-infections with atypical pathogens that would be resistant to a cephalosporin but susceptible to a macrolide, including m pneumoniae and c pneumoniae, have been described [ ] [ ] [ ] [ ] [ ] [ ] [ ] . it is not clear whether patients with dual infections fare worse if only the pneumococcal bacteremia is treated. co-infection with s pneumoniae and l pneumophila has been described [ ] . in most epidemiologic studies of cap, an etiologic agent is not identified in a large proportion of patients ( %- %) [ , ] . it is possible that other pulmonary pathogens that are susceptible to macrolides have not been identified. mcnally et al [ ] screened acute and convalescent serum samples from patients with pneumonia of unknown cause. legionella bozemanii was identified as the potential cause in % of cases using the criterion of fourfold rise in antibody titers between acute and convalescent samples. it is possible that other legionella [ ] or legionella-like organisms requiring different growth medium will be identified [ , ] . what is the possibility that the immune-modulating activity of macrolides is important in reducing the mortality rate? the intense host inflammatory response with sepsis sometimes is deleterious. multiple studies have used different agents to try to diminish this exaggerated immune response [ ] [ ] [ ] [ ] . steroids were studied in multiple doses in many studies, and success was difficult to demonstrate in patients with sepsis. if given before antibiotics, however, steroids seemed to help reduce the morbidity rate in patients with bacterial meningitis [ , ] . studies of patients with difficult sepsis in various stages of illness who were treated with antibodies to endotoxin and tumor necrosis factor (tnf) have had differing results. one murine study showed that antibodies to tnf had a deleterious effect in mice with pneumococcal pneumonia that also were treated with ceftriaxone [ ] . review of human trials with antibody to tnf did not show any effect on the mortality rate in patients with severe sepsis and bacterial pneumonia [ ] . other components of the complex inflammatory response, such as granulocyte colony-stimulating factor (g-csf), have been investigated in mice and humans. local production of g-csf seems to occur at the site of infection in patients with unilateral pneumonia [ ] . macrolides have been shown to inhibit various factors in the inflammatory response, mostly in mice. no human studies have shown that the immune-modulating activity of macrolides has a beneficial effect. further investigation into the complex immune response and its saluatory or deleterious effect on the mortality rate is important. there have been a large number of articles addressing the issue of in vivo susceptibility data with erythromycin and other macrolides [ ] [ ] [ ] and how it correlates with clinical outcome [ ] . a retrospective study ( ) ( ) ( ) ( ) from spain examined patients who were admitted with cap and treated with combination therapy [ ] . all of the patients received ceftriaxone. the type of macrolide therapy was chosen by the attending physician. the choices were mg of oral azithromycin daily for days (n = ) or mg of intravenous clarithromycin twice daily with a switch to oral treatment (total duration of treatment, days; n = ). the patients had similar ages, comorbidities, and psis. the length of stay (los) for the azithromycin group was days shorter (p \ . ). the cfr was . % in the azithromycin group and . % in the clarithromycin group (p \ . ). there was no obvious reason for the differences in the two treatment arms. the investigators suggested that compliance might have been an issue, because patients in the azithromycin arm received their -day course in the 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alpha production in the respiratory tract key: cord- - rhzhpij authors: rocha neto, ozéas galeno da; leite, ricardo ferreira; baldi, bruno guedes title: atualização em pneumonia comunitária viral() date: - - journal: rev assoc med bras ( ) doi: . /s - sha: doc_id: cord_uid: rhzhpij viral pneumonia is a prevalent cause of respiratory infection in immunocompetent adults. it has varied presentation, from mild to severe respiratory failure, requiring mechanical ventilation. however, in brazil, there have been few studies on the clinical presentation and diagnosis of this infection. thus, the authors of the present article intend to review the main viral agents that cause community-acquired pneumonia and to discuss the currently available diagnostic and therapeutic methods. a pneumonia continua a figurar entre as principais causas de morbimortalidade no mundo e, apesar dos recentes avanços no campo do diagnóstico, estima-se que em menos de % dos casos seja possível estabelecer com precisão o agente causador dessa infecção. no brasil, a maioria dos estudos sobre pneumonia da comunidade diz respeito apenas a opções de tratamento e evolução clínica, e pouco se sabe a respeito dos padrões microbiológicos locais. as bactérias permanecem como o principal grupo de patógenos identificados, mas o real papel de outros agentes, como fungos, protozoários e vírus, continua a ser alvo de especulação. este é um artigo open access sob a licença de cc by-nc-nd este é um artigo open access sob a licença de cc by-nc-nd este é um artigo open access sob a licença de cc by-nc-nd apesar dos vírus serem apontados como importante causa de pneumonia adquirida na comunidade, apenas recentemente, principalmente a partir da pandemia ocorrida em , houve um maior interesse em relação à participação desses agentes nesse tipo de infecção. entre os principais vírus causadores de pneumonia em adultos imunocompetentes destacamse o influenza, o sincicial respiratório (vsr), o adenovírus e o parainfluenza humano (hpiv). a partir da utilização de novas técnicas moleculares, recentemente têm sido isolados vírus pouco identificados até então, como o rinovírus, o coronavírus e o metapneumovírus. , o objetivo dessa revisão é apresentar as modalidades de investigação complementares e as opções terapêuticas disponíveis atualmente, além de discutir os principais vírus implicados na gênese da pneumonia adquirida na comunidade em adultos imunocompetentes. a incidência de pneumonia viral tem aumentado significativamente nos últimos anos e, dependendo da virulência do agente em questão e das comorbidades do paciente, sua apresentação pode variar desde uma forma leve e autolimitada até casos extremamente graves, com insuficiência respiratória. os resultados de exames laboratoriais, a evolução clínica e os padrões específicos identificados em exames de imagem, considerados no passado como direcionadores seguros da etiologia do processo infeccioso, são inespecíficos e não se sabe ao certo sua importância no diagnóstico. desse modo, a aplicação de novos exames laboratoriais auxiliares com maior sensibilidade e especificidade contribui para o diagnóstico definitivo, otimizando o tratamento dessa afecção. no entanto, deve-se ressaltar que o isolamento desses agentes não significa necessariamente infecção ativa. nesse contexto, é imprescindível conhecer as opções diagnósticas para a identificação dos vírus, assim como as limitações de cada método para a adequada interpretação clínica. os métodos atualmente validados para a definição etiológica da infecção viral, resumidos na tabela , são sorologia, cultura, avaliação citológica, detecção rápida de antígenos e técnicas de amplificação gênica, embora não amplamente disponíveis e muitas vezes de alto custo. virtualmente, quase todos os vírus podem ser diagnosticados através de sorologia. entretanto, há a necessidade de coleta pareada de sangue (fase aguda/fase de convalescença), uma vez que é necessário o aumento em quatro vezes da titulação em relação à primeira amostragem para a confirmação diagnóstica. por essa razão, a sorologia não é rotineiramente utilizada por se mostrar pouco útil na fase aguda da doença, já que nessa fase raramente os títulos se elevam nesses níveis. em nosso meio, a sorologia está disponível para boa parte dos vírus respiratórios da comunidade como o adenovírus, o vsr e o influenza sazonal. a cultura viral também pode ser empregada para a maior parte dos vírus respiratórios, tendo como desvantagem o longo tempo para obtenção do resultado e a necessidade de meio específico para cultivo. para a realização da cultura, podem ser utilizadas amostras de tecidos das vias aéreas superiores e/ou inferiores, do escarro, do lavado nasofaríngeo e do lavado broncoalveolar. na cultura de células são observados efeitos citopáticos do vírus, como a formação de coleções sinciciais de células gigantes multinucleadas, ou evidências de crescimento viral. a posterior identificação específica do vírus nas culturas celulares pode ser realizada por técnicas de imunofluorescência (direta ou indireta) ou sondas de ácidos nucleicos. outras a desvantagem do método é a sua baixa sensibilidade, de modo que a ausência desses achados não é capaz de descartar doença ativa. são testes rápidos realizados a partir de espécimes de fácil obtenção, como swab ou lavado nasal. o exame de elisa (enzyme linked immunosorbent assay) está disponível para a maioria dos vírus respiratórios patogênicos, sendo capaz de detectar antígenos virais, enquanto o método de imunofluorescência necessita de células infectadas intactas. ambos os métodos têm sensibilidade e especificidade variada conforme o agente em pesquisa. a especificidade para o vírus influenza sazonal, por exemplo, é próxima a %, e a sensibilidade é de %. entretanto, quando o agente suspeito é o vírus influenza h n , o rendimento é extremamente baixo, não sendo, portanto, recomendado para confirmação da infecção por esse agente . os antígenos permanecem positivos por semanas, contudo são menos sensíveis que a cultura viral, podendo ser empregados de forma complementar para aumentar o rendimento diagnóstico do material amostrado. a técnica de polymerase chain reaction (pcr) ou reverse transcriptase polymerase chain reaction (rt-pcr) é extremamente sensível e específica para detectar a presença de vírus. para a maioria dos vírus respiratórios é o exame de escolha e, se disponível, deveria ser empregado em conjunto aos métodos diagnósticos citados anteriormente. o desenvolvimento atual dessa técnica permitiu o conhecimento de novos agentes causadores de bronquiolite e de pneumonia tanto na população pediátrica como em adultos. esse método pode ser aplicado em amostras de swab nasofaríngeo ou de secreções brônquicas e tem a vantagem de poder ser realizado em outros fluidos corpóreos, como no sangue de pacientes imunossuprimidos com suspeita de infecção por citomegalovírus. uma nova técnica molecular chamada multiplex reverse transcriptase polymerase chain reaction (mrt-pcr) permite a detecção rápida de um conjunto de vírus respiratórios formados por influenza a e b, vsr a e b, hpiv , e , metapneumovírus e adenovírus. sua desvantagem é a baixa sensibilidade para influenza h n , descrito pelo método como não tipável. influenza é um rna vírus da família orthomyxoviridae, sendo descritos três sorotipos: a, b e c. esses vírus são responsáveis por aproximadamente a % das pneumonias em adultos saudáveis, com taxas maiores sendo encontradas durante surtos e epidemias. , o influenza a pode ser disseminado por aerossóis e se alojar em todo o trato respiratório. comumente, é o sorotipo mais virulento, compreendendo uma série de outros subtipos. o influenza b normalmente causa doença em populações que abrigam locais fechados, como creches e internatos. o influenza c é o sorotipo menos comum, sendo encontrado como agente patogênico em relatos esporádicos. os vírus influenza a e b são responsáveis por cerca de % das pneumonias virais em adultos ocorridas na comunidade. seu impacto é maior em idosos e em outras populações de risco, como gestantes, imunossuprimidos e portadores de doenças crônicas, principalmente cardíacas e pulmonares. recentemente um subtipo de influenza a, o h n , conhecido como causador da gripe suína, emergiu como uma importante e ameaçadora pandemia, acometendo de forma grave desde pacientes imunossuprimidos, como transplantados, a outras populações de risco, como gestantes, obesos, portadores de doenças cardíacas e pulmonares. os indivíduos acometidos eram, em geral, mais jovens que os atingidos por influenza sazonal. , estima-se que houve aproximadamente . óbitos entre abril de a janeiro de , segundo previsões da organização mundial de saúde. no brasil, a % dos pacientes admitidos necessitaram de internação em ambiente de terapia intensiva e, do total, a % precisaram de ventilação mecânica invasiva. a taxa de mortalidade por h n no país foi de mortes em . . , a infecção pelo vírus influenza leva à morte celular, especialmente nas vias aéreas superiores. quando ele infecta diretamente as vias aéreas inferiores, pode haver hemorragia sem acúmulo proporcional de células inflamatórias. ocorre ainda prejuízo do clearance mucociliar, podendo determinar aderência de bactérias ao epitélio respiratório. há também prejuízo na função das células t, neutrófilos e macrófagos, o que leva à diminuição das defesas do hospedeiro. todos esses acontecimentos em conjunto facilitam a concomitante infecção bacteriana frequentemente observada. o período de incubação é de um a dois dias e os sintomas duram normalmente de três a cinco dias, existindo, didaticamente, três formas de apresentação clínica: pneumonia primária por influenza; infecção por influenza com pneumonia bacteriana secundária; e coinfecção simultânea, viral e bacteriana. a pneumonia primária se manifesta com tosse persistente, dor em orofaringe, cefaleia e mialgia por mais de cinco dias, associados ao surgimento de dispneia progressiva e cianose. essa é a forma menos frequente de apresentação, sendo, contudo, a mais grave. a pneumonia por influenza com infecção bacteriana secundária é caracterizada por recrudescimento de febre alta, tosse e escarro purulento após melhora inicial, associado ao surgimento de novas opacidades na radiografia de tórax. os principais agentes envolvidos são o streptococcus pneumoniae ( %), staphylococcus aureus e haemophilus influenzae. a pneumonia por coinfecção viral e bacteriana se manifesta de modo semelhante à pneumonia com infecção bacteriana secundária, não occorrendo, porém, a melhora inicial. nesse contexto, tanto o vírus quanto o agente bacteriano são isolados em conjunto nas pesquisas microbiológicas. os marcadores inflamatórios, como a proteína c reativa e a pró-calcitonina, também se mostraram pouco úteis na diferenciação entre pneumonia bacteriana e viral, uma vez que nos casos mais graves, como observado na pandemia de h n , foram identificados níveis aumentados dessas duas substâncias em pacientes com pneumonia viral. as alterações radiológicas pulmonares são inespecíficas, podendo ser identificadas desde opacidades peri-hilares e peribrônquicas, consolidações, até opacidades intersticiais difusas e bilaterais, especialmente nas formas mais severas da doença ou em pacientes neutropênicos (fig. ) . o vírus influenza pode ser isolado em escarro, lavado nasal ou swabs nasal ou faríngeo, com menor rendimento para o último em meio de cultura. dentre as culturas positivas, % são detectadas dentro dos três dias da inoculação e o restante até o sétimo dia. os testes rápidos apresentam atuam bloqueando os canais iônicos da proteína m viral e inibem o seu desencapsulamento. seu uso deve ser indicado dentro de horas do início dos sintomas nos casos não complicados, porém sua eficácia não foi testada em pneumonias graves. além disso, muitas das cepas são atualmente resistentes a esses fármacos, que, portanto, não devem ser recomendados como único fármaco em terapia empírica. o oseltamivir e o zanamivir são substâncias que bloqueiam a proteína de superfície neuraminidase e aprisionam o vírus dentro do epitélio respiratório infectado, evitando sua disseminação. também devem ser preferencialmente administrados em horas do início do quadro. são ativos contra influenza a e b e possuem baixo potencial indutor de resistência, embora alguns casos já tenham sido descritos nos estados unidos durante a pandemia de h n . nos casos de pneumonias graves, a medicação pode ser oferecida mesmo após horas do início dos sintomas. quando houver insuficiência respiratória potencialmente fatal, como ocorreu em muitos casos da pandemia por h n , manobras de resgate para hipoxemia refratária, como recrutamento e ventilação em posição prona, podem ser instituídas em associação à terapia antiviral. o vsr faz parte da família paramyviridae, sendo a causa mais comum de infecção das vias aéreas inferiores em crianças. atualmente, vem sendo identificado como importante causa de pneumonia em adultos, principalmente em idosos, tornando-se a segunda causa mais frequente entre os vírus nessa população. o vsr é altamente contagioso, disseminando-se por meio de gotículas e fômites. a população de risco é formada principalmente por crianças abaixo de seis meses, portadores de doenças crônicas, como fibrose cística, doenças cardíacas congênitas, idosos institucionalizados e pacientes imunossuprimidos. a mortalidade geral em adultos varia, de acordo com o estado imunológico, de a % em adultos saudáveis a % em transplantados de medula óssea. o vsr é raramente diagnosticado em adultos. a infecção é caracterizada por sintomas persistentes nas vias aéreas superiores, como coriza, otalgia e faringite, associada à tosse prolongada, seca ou produtiva, dispneia e sibilância, podendo ocasionar bronquite, bronquiolite e pneumonia grave com alta especificidade para os vírus influenza a e b ( a %), porém com baixa sensibilidade ( a %). vale ressaltar que na suspeita de h n esse teste não está recomendado, sendo o rt-pcr o exame com maior utilidade diagnóstica. a avaliação histológica é outra opção diagnóstica possível, por meio de análise ultraestrutural obtida por biópsia de pulmão. o tratamento deve ser realizado com medidas de suporte, como suplementação de oxigênio, analgésicos, antipiréticos e terapia antiviral em casos selecionados. as substâncias aprovadas para o tratamento da infecção por influenza são amantadina, rimantadina, oseltamivir e zanamivir (tabela ). a amantadina e a rimantadina são aprovadas para prevenção e tratamento, não sendo efetivas contra o influenza b. elas necessidade de ventilação mecânica. comparativamente à infecção pelo vírus influenza, observa-se maior frequência de rinorreia e escarro purulento, além de menor frequência de febre e sintomas gastrointestinais. alguns marcadores inflamatórios obtidos das vias aéreas e do sangue, como moléculas solúveis de adesão intercelular tipo i (sicam- ), interleucina ( il ) e il , foram testados em crianças e parecem mostrar correlação positiva, quando em altas concentrações, com a gravidade e a duração da internação. as alterações radiológicas pulmonares associadas à infecção pelo vsr são inespecíficas, sendo descritas, na maior parte dos casos, opacidades alveolares bilaterais e alterações intersticiais semelhantes às observadas na infecção pelo vírus influenza. , o vírus pode ser isolado em cultura, onde o maior rendimento é encontrado em amostras de lavado nasofaríngeo e secreção traqueal. em imunossuprimidos, a positividade da cultura ocorre em até % dos lavados nasofaríngeos, em até % das secreções traqueais e em até % dos lavados broncoalveolares. os testes rápidos para detecção de antígenos virais têm sensibilidade de a % e alta especificidade ( a %). amplificação gênica com rt-pcr também está disponível. a ribavirina age impedindo a transcrição viral e é o único antiviral atualmente disponível para o tratamento da pneumonia pelo vsr (tabela ). a recomendação atual é que a medicação seja considerada apenas para os casos graves ou nos doentes de alto risco de complicações. a imunoglobulina intravenosa específica para vsr (palivizumab) também pode ser empregada em conjunto com a ribavirina nos pacientes críticos e de alto risco de complicações, principalmente nos transplantados de medula óssea. o adenovírus é um dna vírus extremamente contagioso, existindo sorotipos diferentes. a infecção pelo adenovírus pode ocorrer em qualquer época do ano, sendo responsável por aproximadamente % das pneumonias em crianças. historicamente, esse vírus também é identificado como um importante agente causador de surtos de infecções respiratórias em áreas de bases militares nos estados unidos. seus sorotipos são classificados em sete subgrupos ou espécies (a a g) e as infecções pulmonares são causadas predominantemente pelos sorotipos , , , , , , e . embora seja um vírus que determine baixa mortalidade, o subtipo pode provocar quadros graves de insuficiência respiratória nos pacientes susceptíveis, como transplantados de órgãos sólidos, portadores de hiv e pacientes com outros tipos de prejuízo da imunidade celular, embora existam relatos de casos fatais na evolução pós-operatória de cirurgia cardíaca em pacientes previamente imunocompetentes. a disseminação do adenovírus ocorre por inoculação direta em conjuntiva, por aerossóis, fezes e fômites, sendo o vírus capaz de sobreviver em áreas contaminadas no ambiente durante várias semanas. pode ocorrer ainda reativação do vírus em pacientes imunossuprimidos, produzindo uma variedade de síndromes clínicas, incluindo ceratoconjuntivite, gastroenterite, hepatite e cistite hemorrágica, associadas ou não à pneumonia. a mortalidade por pneumonia atinge taxas que variam de a %, principalmente em transplantados de medula óssea. o quadro clínico é caracterizado por febre, tosse, rinorreia, faringite, tonsilite e otite média, com duração média de três a cinco dias. leucocitose e provas de atividade inflamatória elevadas podem ser observadas, sendo importante a diferenciação entre infecções de origem bacteriana. na radiologia, as opacidades pulmonares são frequentemente reticulonodulares, mas consolidações também podem ser observadas. , para a confirmação do diagnóstico, pode-se realizar cultura de secreções respiratórias, na qual podem ser evidenciados efeitos citopáticos após dois a dias do início do quadro. o sorotipo pode ser diagnosticado por detecção rápida de antígenos e técnicas de pcr, principalmente em imunossuprimidos. , não existem estudos controlados a respeito da melhor forma de tratamento ou qual a substância mais indicada para cada síndrome clínica específica. dessa forma, o emprego de antivirais se baseia em recomendação de especialistas e em relatos de casos. as substâncias que podem ser utilizadas são a ribavirina, cidofovir, ganciclovir e vidarabina, havendo um maior número de relatos em favor da terapia combinada de cidofovir/ ribavirina, principalmente em pacientes com evolução grave e antecedente de transplante de medula óssea (tabela ). o hpiv é um paramyxovírus classificado em quatro subtipos diferentes ( , , e ). esse vírus é a segunda causa mais comum de infecção viral em crianças, responsável por aproximadamente a % das infecções respiratórias, sendo também identificado como agente causador de pneumonia em adultos (principalmente os sorotipos hpiv e ). a transmissão pode ocorrer por contato direto com hospedeiro infectado, por fômites ou gotículas respiratórias. uma vez instalada, a infecção promove a secreção de altos níveis de citocinas inflamatórias, como interferon alpha, il , il , e fator de necrose tumoral alpha (tnf alpha). esses mediadores são responsáveis pela produção abundante de muco do epitélio respiratório, edema submucoso e de cordas vocais, podendo determinar a obstrução parcial das vias aéreas superiores e o estridor característico dessa afecção. o período de incubação é de um a três dias e os sintomas característicos de crupe, como rouquidão e estridor laríngeo (sinal do campanário), comum em crianças, são menos prevalentes nos adultos imunocompetentes. o hpiv é a principal cepa causadora de bronquiolite e pneumonia, levando ao surgimento de sintomas inespecíficos como febre, coriza, sibilânica, tosse seca e dispneia. o quadro pode mimetizar uma série de outras infecções respiratórias, principalmente no imunossuprimido, sendo a identificação de acometimento pronunciado das vias aéreas superiores, como sinusopatia e estridor, um importante indício para a suspeita diagnóstica. relatos de bronquiolite obliterante com pneumonia em organização e pneumonia por células gigantes também foram descritos após infecção por esse agente. do ponto de vista radiológico, as alterações mais observadas são opacidades focais de padrão alveolar, embora o acometimento difuso com padrão intersticial também tenha sido descrito. estudo prévio demonstrou que a infecção pode se associar com a presença de múltiplos nódulos < mm, não cavitados, e de distribuição peribrônquica. , o isolamento por meio de cultura pode ser realizado preferencialmente em secreções nasais. o rt-pcr é o método mais sensível e rápido para o diagnóstico. , o tratamento de suporte geralmente é suficiente, devendo a terapia específica ser recomendada apenas para os pacientes de alto risco ou com sintomatologia grave. nesses casos, o agente de escolha, baseado em estudo in vitro e em série de casos, é a ribavirina oral ou aerossolizada (tabela ). com o avanço dos métodos diagnósticos e maior acesso a técnicas de pcr, outros agentes, como metapneumovírus, coronavírus e rinovírus, tem sido atualmente reconhecidos como causadores de pneumonia na comunidade. o metapneumovírus humano é um vírus relativamente novo como patógeno respiratório, tendo sido descrito incialmente na holanda, em . esse vírus pertence à mesma família do vsr e hpiv, sendo geralmente adquirido na primeira infância e responsável por bronquiolite, crupe e pneumonia. reinfecção pode ocorrer em idade adulta, com os casos mais graves atingindo idosos, portadores de doenças cardíacas e pulmonares e imunossuprimidos. o período de incubação é de aproximadamente cinco dias e o quadro clínico é semelhante às demais viroses, com congestão nasal, tosse, sibilância, febre e dispneia. rouquidão é um achado mais frequente que na infecção por vsr. as imagens do tórax revelam opacidades alveolares bilaterais em % dos casos, podendo ocorrer ainda opacidades nodulares e derrame pleural. É um vírus de difícil isolamento em culturas, com taxa de replicação muito lenta. o rt-pcr é o método de eleição para o diagnóstico. o tratamento ainda não está bem estabelecido, mas o uso de ribavirina isoladamente ou em combinação com imunoglobulina parece promissor nos casos de maior gravidade. os coronavírus foram reconhecidos como causadores de pneumonia após uma epidemia grave ocorrida na china, em . quatro subtipos humanos são reconhecidos: hcov- e, hcov-oc , hcov-nl e hcov-hku . o período de incubação da infecção associada ao coronavírus é de dois a cinco dias e os sintomas mais comuns são mialgia, calafrios e dispneia, podendo haver progressão para insuficiência respiratória. febre é pouco frequente. outros achados que podem ser obervados são plaquetopenia, elevação de transaminases e do dímero-d. o padrão radiológico é inespecífico, evidenciandose comumente opacidades pulmonares difusas em vidro despolido na tomografia de tórax. casos de pneumomediastino também foram relatados. , nos casos de evolução grave, inibidores de protease, como lopinavir e ritonavir, e interferon alfa e beta, podem ser administrados. não há evidência de eficácia com ribavirina. o rinovírus, membro da família picornaviridae, é o principal causador de resfriado na população em geral e o segundo agente mais prevalente como causa de bronquiolite na população pediátrica, sendo, em alguns estudos, o agente mais relacionado às exacerbações de crianças asmáticas. apesar de controverso, alguns trabalhos demonstram uma prevalência desse vírus em até % dos casos de pneumonia grave internados em ambiente de terapia intensiva. o diagnóstico é difícil e realizado através de técnicas de pcr, uma vez que outros métodos, como sorologias e culturas, não são factíveis e a detecção rápida dos antígenos não é padronizada. como observado nos relatos recentemente publicados, os vírus vêm sendo cada vez mais apontados como causadores de infecções ou coinfecções respiratórias graves, inclusive em pacientes imunocompetentes. nesse contexto, é fundamental considerar a presença desses patógenos como potenciais causadores de doença pulmonar e, principalmente, ampliar a capacidade dos serviços para identificá-los. a partir de uma possibilidade mais ampla de diagnóstico de infecções virais, haverá a perspectiva de não apenas aumentar o conhecimento do perfil epidemiológico das pneumonias comunitárias virais, mas também de planejar melhores estratégias terapêuticas e de prevenção para a sociedade. implementation of community-acquired pneumonia guidelines at a public hospital in brazil clinical, epidemiological, and etiological profile of inpatients with community-acquired pneumonia at a general hospital in the sumaré microregion of brazil viral pneumonia: epidemiological, clinical, pathophysiological, and therapeutic aspects incidence and characteristics of viral community-acquired pneumonia in adults que evidências temos para o diagnóstico diferencial inicial entre pneumonia bacteriana e viral? evaluation of four methods for the diagnosis of respiratory syncytial virus infection in older adults high rate of viral identification and coinfections in infants with acute bronchiolitis direct detection of respiratory syncicial virus, parainfluenza virus, and adenovirus in clinical respiratory specimens by multiplex reverse transcription-pcr assay viral infection in adults hospitalized with community-acquired pneumonia: prevalence, pathogens and presentation the role of viroses in the aetiology of community-acquired pneumonia in adults influenza a (h n ) pneumonia in an immunossupressed patient after heart transplantation caiaffa filho hh. epidemiology of human infection with the novel virus influenza a (h n ) in the hospital das clínicas follow-up after acute respiratory distress syndrome caused by influenza a (h n ) virus infection staphylococcus aureus community-acquired pneumonia during the to influenza season the behavior and diagnostic utility of procalcitonin and five other inflammatory molecules in critically ill patients with respiratory distress and suspected influenza a h n infection chest computed tomography findings in severe influenza pneumonia occurring in neutropenic cancer patients pathological and ultrastructural analysis of surgical lung biopsies in patients with swineorigin influenza type a/h n and acute respiratory failure use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza prone position ventilation, recruitment maneuver and intravenous zanamivir in severe refractory hypoxemia caused by influenza a (h n ) immune response to respiratory syncytial virus in young brazilian children prevalence and clinical aspects of respiratory syncytial virus a and b groups in children seen at hospital de clínicas of uberlândia, mg, brazil respiratory syncytial virus is an important cause of community acquired lower respiratory infection among hospitalized adults correlation between inflammatory mediators in the nasopharyngeal secretion and in the serum of children with lower respiratory tract infection caused by respiratory syncytial virus and disease severity management of respiratory syncytial virus infections in the imunocompromissed child epidemiology of adenovirus respiratory infections in military recruit populations fatal adenoviral necrotizing bronchiolitis case in a post-cardiac surgery intensive care unit adenovirus infections in patients undergoing bone-marrow transplantation treatment of adenovirus infections in patients undergoing allogenic hematopoietic stem cell transplantation respiratory disease due to parainfluenza virus in adult bone marrow transplant recipients improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction pre-emptive oral ribavirin therapy of paramyxovirus infections after haematopoiestic stem cell transplantation: a pilot study viral pneumonia a newly discovered human pneumovirus isolated from young children with respiratory tract disease immune modulatory activity of ribavirin for serious human metapneumovirus disease: early i.v. therapy may improve outcomes in immunosuppressed sct recipients epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong, people's republic of china a cluster of cases of severe acute respiratory syndrome in hong kong role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings bronquiolite aguda, uma revisão atualizada viral infection in patients with severe pneumonia requiring intensive care unit admission human rhinovirus in bronchial epithelium of infants with recurrent respiratory symptoms key: cord- -egkd o u authors: nan title: world pneumonia day — november , date: - - journal: mmwr morb mortal wkly rep doi: nan sha: doc_id: cord_uid: egkd o u nan the sixth annual world pneumonia day is being observed november , , to raise awareness about pneumonia's toll and to promote interventions to protect against, treat, and prevent the disease globally. the united states has made great strides in protecting children from the serious, and sometimes deadly, effects of pneumonia through recent vaccination efforts. tennessee, for example, is experiencing historically low rates of pneumonia hospitalizations in children aged < years since pneumococcal conjugate vaccines were introduced in ( ). data suggest that this progress also is being seen across the country ( ) . in spite of this success, however, pneumonia still kills approximately , people in the united states each year, % of whom are adults aged ≥ years. in response, this year cdc recommended pneumococcal conjugate vaccine for adults aged ≥ years. globally, pneumonia kills nearly million children aged < years each year ( ). in addition to bacterial pathogens, many viruses such as respiratory syncytial virus, influenza, and measles also are major causes of pneumonia globally. many deaths and illnesses from pneumonia can be prevented with the use of ) pneumococcal, haemophilus influenzae type b (hib), influenza, and measles vaccines; ) appropriate antimicrobial therapy; and ) supportive health care, among other strategies. communities around the world face a range of respiratory disease threats, including reemerging or newly identified pathogens. in late summer, infection with the uncommon enterovirus ev-d led to the hospitalization of hundreds of children in multiple states ( ) . in and around the arabian peninsula, a recently recognized coronavirus (middle east respiratory syndrome coronavirus) has been fatal in about one third of reported cases ( ) . vaccines are not available to provide protection against these or many of the other pathogens that commonly cause pneumonia, including respiratory syncytial virus, human metapneumovirus, and mycoplasma pneumoniae, highlighting the importance of research into vaccine development as well as effective treatment and diagnostics for viral and bacterial pneumonia. additional information regarding world pneumonia day is available at http://worldpneumoniaday.org. declines in pneumonia hospitalizations of children aged < years associated with introduction of -valent pneumococcal conjugate vaccine-tennessee effect of -valent pneumococcal conjugate vaccine on admissions to hospital years after its introduction in the usa: a time series analysis global, regional, and national causes of child mortality in - , with projections to inform post- priorities: an updated systematic analysis epub ahead of print severe respiratory illness associated with enterovirus d -missouri and illinois updated information on the epidemiology of middle east respiratory syndrome coronavirus (mers-cov) infection and guidance for the public, clinicians, and public health authorities key: cord- - dpjik authors: sandora, thomas j.; harper, marvin b. title: pneumonia in hospitalized children date: - - journal: pediatr clin north am doi: . /j.pcl. . . sha: doc_id: cord_uid: dpjik pneumonia is one of the most common infections in the pediatric age group and one of the leading diagnoses that results in overnight hospital admission for children. various micro-organisms can cause pneumonia, and etiologies differ by age. clinical manifestations vary, and diagnostic testing is frequently not standardized. hospital management should emphasize timely diagnosis and prompt initiation of antimicrobial therapy when appropriate. issues of particular relevance to inpatient management are emphasized in this article. pneumonia is one of the most common infections in the pediatric age group and one of the leading diagnoses that results in overnight hospital admission for children. in , , patients younger than years were discharged from hospitals in the united states with a primary diagnosis of pneumonia [ ] . in north america, the annual incidence of pneumonia in children younger than years is to cases per ; in children aged years and older, the annual incidence is to cases per [ , ] . in developing countries, which account for more than % of episodes of clinical pneumonia worldwide, researchers estimate that more than million new cases occur annually in children younger than years [ ] . pneumonia can be classified as either community-acquired pneumonia (cap) or nosocomial pneumonia; hospital-acquired pneumonia may be ventilatorassociated pneumonia or may be acquired in the absence of mechanical ventilation. ventilator-associated pneumonia differs in several respects from cap and is addressed separately in this article. although no precise definition is universally applied, cap is generally defined as an infection of the lungs that is marked by symptoms of acute infection (ie, fever, cough, or dyspnea) and is typically associated with abnormal auscultatory findings (eg, rales or altered breath sounds) or the presence of an acute infiltrate on chest imaging in an individual not hospitalized or residing in a long-term care facility for at least days before onset of symptoms [ ] . a large number of micro-organisms can cause pneumonia in children. table lists the most frequent etiologic agents that are identified in each age group. overall, viruses are responsible for a large percentage of cases of cap in the pediatric age group, and they are particularly common in children aged weeks to years [ ] . in a recent us study of children aged months to years who were hospitalized for pneumonia, % were found to have a viral etiology [ ] . in general, the most frequently isolated respiratory viruses are respiratory syncytial virus, parainfluenza viruses, influenza a and b, and adenovirus, although other viruses may occur in specific settings (eg, cytomegalovirus or herpes simplex infection in neonates). most cases of viral pneumonia can be managed without invasive diagnostic testing, and aside from supportive care, no specific antimicrobial therapy is generally required. for these reasons, the remainder of this article focuses on bacterial pneumonia, although important distinctions related to viral etiologies are highlighted when appropriate. the epidemiology of bacterial cap differs by age and has been impacted by vaccine strategies. from birth to weeks of age, the most common causes of pneumonia are group b streptococci and gram-negative rods (particularly enterics such as escherichia coli). although viruses predominate from weeks to months of age, bacterial pneumonia can occur in this age group. afebrile pneumonia at this age is frequently caused by chlamydia trachomatis; this agent rarely requires hospital admission unless found in combination with another respiratory tract pathogen, such as respiratory syncytial virus or pertussis. streptococcus pneumoniae is the most common bacterial cause of febrile pneumonia among children aged weeks to years. a recent study from texas found that % of children between months and years of age who were admitted with pneumonia had a bacterial pathogen isolated, and s. pneumoniae was confirmed in % of those cases [ ] . other less commonly isolated bacteria include haemophilus influenzae (historically type b before widespread vaccine use, but currently includes nontypable h. influenzae), streptococcus pyogenes, staphylococcus aureus, and other streptococcal species (including the streptococcus milleri group). in children aged years and older, the most common bacterial pathogens are mycoplasma pneumoniae and chlamydophila pneumoniae (previously known as chlamydia pneumoniae). these atypical agents account for nearly one fourth of all cases of bacterial pneumonia among school-aged children and adolescents [ ] . pneumococcus remains high on the list of agents identified table provides a list of these less frequent pathogens and the risk factors or clinical situations that should prompt consideration of more unusual infections. finally, it is important to remember that a significant proportion of cases of pediatric pneumonia represents a mixed infection [ ] . pathogen, host, and environmental factors all play a role in the development of pneumonia, which typically begins with tracheal colonization by the infecting micro-organism [ ] . the initial line of defense against the establishment of a respiratory pathogen is the barrier defenses of the airway, namely the mucosal barrier of respiratory epithelium and the mucociliary apparatus that is responsible for clearing foreign material and micro-organisms from the airway [ ] . once the lower respiratory tract is inoculated with a sufficient burden of bacteria, the normal inflammatory response that fights infection (which includes components such as antibodies, complement, phagocytes, and cytokines) also results in damage to functioning lung tissue [ ] . the bacteria that commonly cause pneumonia also possess specific virulence factors that enhance their survival and propagation while concurrently resulting in injury to the pulmonary host. for example, s. pneumoniae contains pneumolysin, a pore-forming protein that enables the bacterium to kill host cells, which results in complement activation and a vigorous inflammatory response [ ] . pneumonia also may result from direct seeding of the lung tissue after bacteremia, which may be a particularly important mechanism for bacteria such as pneumococcus and s. aureus. several studies have evaluated the use of various clinical symptoms and signs in children with pneumonia. tachypnea widely has been shown to be the most sensitive indicator [ ] [ ] [ ] [ ] . the world health organization defines tachypnea as a respiratory rate (rr) of more than breaths/min in infants younger than months of age, rr of more than breaths/min from ages to months, and rr of more than breaths/min in children older than months [ ] . several studies have found that cutoffs of more than breaths/min in children younger than months and more than breaths/min in children aged to months provide the greatest combination of sensitivity and specificity in identifying children with lower respiratory infections [ ] [ ] [ ] , although one study showed that a single value of breaths/min for all ages was equally useful [ ] . the precise predictive value depends on the underlying prevalence of disease [ ] , but a diagnosis of pneumonia in the industrialized world rarely would be made based solely on the presence of tachypnea (which is present in many other childhood illnesses, including bronchiolitis and asthma). fever and cough are also frequently present in children with pneumonia, and clinical signs may include retractions or abnormal auscultatory findings, such as rales or decreased breath sounds, which tend to be more specific as indicators of lower respiratory tract infection [ ] [ ] [ ] [ ] . other less specific indicators that may be seen in children include malaise, emesis, abdominal pain, and chest pain (which is particularly suggestive of bacterial pneumonia as opposed to viral etiologies, especially when pleuritic in nature). wheezing may be seen in children with bacterial pneumonia [ ] but is more suggestive of bronchiolitis or viral lower respiratory tract infection. the diagnosis of pneumonia is likely in patients who present with fever, cough, and tachypnea and who have infiltrates on chest radiography. various other diseases can present with a similar constellation of signs and symptoms, however. the differential diagnosis may include upper respiratory tract infection, bronchiolitis, congestive heart failure, pulmonary embolism, thoracic tumors, or inflammatory disorders (such as systemic vasculitis), among other entities [ ] . table reviews diseases that should be considered when infiltrates are present on chest radiography. several laboratory studies may be helpful in establishing a diagnosis of pneumonia in children. leukocytosis may be present; in one study, % of children who presented to the emergency department with fever and a white blood cell count of more than , /mm were found to have occult pneumonia on chest radiography [ ] . pneumonia also has been shown to be the most common diagnosis in children with white blood cell counts of , /mm or more and even in children with white blood cell counts of , /mm or more [ ] . other inflammatory markers, such as c-reactive protein and the erythrocyte sedimentation rate, are generally elevated. one study found that patients with an elevated c-reactive protein were more likely to have pneumonia of proven or probable bacterial cause as opposed to viral or mycoplasma pneumonia [ ] . cultures of the blood for bacteria traditionally have been recommended in consensus guidelines for the diagnosis and management of pneumonia, particularly when a bacterial cause is suspected [ ] [ ] [ ] . this recommendation stems from previous work, which suggested that the rate of bacteremia in adults hospitalized for pneumonia was in the range of % to %. several more recent studies have attempted to evaluate the use of blood cultures in the diagnosis of pneumonia, however. in these studies, the yield of blood cultures has been lower-generally ranging from % to %-and the management of pneumonia is rarely altered [ ] [ ] [ ] . various organisms may be detected, but s. pneumoniae has been the most frequently isolated pathogen in these studies. it is likely that the current rate of bacteremia will be lower because of the introduction of the pneumococcal conjugate vaccine in the routine childhood immunization schedule. with increasing resistance to antimicrobial agents and limited available data regarding the use of cultures of the blood among children with pneumonia since the widespread use of the conjugate pneumococcal vaccine, we feel that patients with disease severe enough to require hospital admission and parenteral antimicrobial therapy generally should have cultures of blood sent before therapy. although it is uncommon to identify a pathogen, the identification of a specific organism (such as s. pneumoniae or s. aureus) and its associated antimicrobial susceptibilities can be helpful (especially in more severe cases or when pleural effusions are present). several other microbiologic tests can be considered as diagnostic aids. culture of the sputum has had variable use in published studies, with yields ranging from % to % [ , ] . to be considered reliable (ie, bronchial in origin as opposed to oropharyngeal), a sputum sample should contain fewer than ten epithelial cells per low-powered field [ ] . it is difficult to obtain a good sputum sample from children, who often have a nonproductive cough. in general, a valuable sample of expectorated sputum is difficult to obtain from a preschoolaged child. although a sputum gram stain with a single predominant organism, leukocytes, and few epithelial cells can be helpful, a negative gram stain result never should exclude pneumonia as a possible diagnosis. pneumococcal urinary antigen testing is generally not recommended as a diagnostic modality in pediatric pneumonia; despite good sensitivity, the specificity of this test is low (because it is frequently positive in individuals with nasopharyngeal colonization, particularly young children) [ , ] . viral diagnostics (either culture or antigen detection using direct fluorescent antibodies) are not necessary in most routine pneumonia cases, but they can be useful in certain circumstances (including cases that involve immunocompromised patients or to help guide infection control precautions). mycoplasma infection can be identified using serology (a positive igm is an indicator of acute infection); polymerase chain reaction testing is also available and has higher sensitivity and specificity [ ] , but it is rarely necessary outside of the research setting. c. pneumoniae may be detected rapidly by direct fluorescent antibodies from a nasopharyngeal specimen or diagnosed by serology. legionella urinary antigen is the diagnostic modality of choice when legionella pneumophila infection is suspected, and the test can remain positive for weeks after acute infection. it is important to remember that the urinary antigen is negative in cases that involve other species of legionella. the decision to perform a skin test with purified protein derivative in patients who present with pneumonia should be based on the presence of risk factors that would increase the likelihood of tuberculosis or when specific radiographic findings suggest mycobacterial disease (such as the presence of mediastinal adenopathy). the diagnosis of pneumonia frequently is made or confirmed by the presence of consolidation or infiltrates on chest radiography. the presence of respiratory signs (eg, cough, tachypnea, and rales) increases the likelihood of a positive chest radiograph, and one meta-analysis suggested that infants younger than months of age with a temperature of . f or higher but with no clinical findings of pulmonary disease (defined as rales, ronchi, retractions, wheezes, tachypnea, coryza, grunting, stridor, nasal flaring, or cough) do not require routine chest radiography, because the probability of a normal chest radiograph in the absence of these findings is at least . % [ , ] . when chest radiographs are obtained in patients who have pneumonia, various patterns may be seen. alveolar infiltrates are seen more frequently in bacterial pneumonia, whereas viral infection is more frequently associated with an interstitial pattern [ ] . these distinctions are not universal, however, and studies have confirmed that patients with viral pneumonia can present with infiltrates that have a lobar or alveolar appearance [ ] . interobserver agreement among radiologists about the pattern of infiltrates (alveolar versus interstitial) or the presence of air bronchograms also has been demonstrated to be poor [ ] . one interesting study showed that radiologists' readings of chest radiographs in febrile children aged to months were biased by the reading of the treating physician (when compared with radiologists who did not have access to that information) [ ] . mycoplasma pneumonia appears most commonly as unilateral or bilateral areas of airspace consolidation and can include reticular or nodular opacities. on high-resolution ct, ground-glass opacities, airspace consolidation, nodules, and bronchovascu-lar thickening are common [ ] . when children exhibit persistent or progressive symptoms despite seemingly adequate therapy, contrast-enhanced chest ct can be useful in detecting suppurative complications, such as empyema or necrosis, that may require further intervention [ ] . for adults with cap, a prediction rule (the pneumonia severity index) was developed and validated to identify patients who are at low risk for death and other adverse outcomes and who might be treated successfully as outpatients [ ] . a score is created using various criteria that can be assessed at initial presentation, including demographic factors (eg, age, sex, and nursing home residence), coexisting illnesses (eg, neoplastic disease, congestive heart failure, cerebrovascular disease, renal disease, and liver disease), physical examination findings (eg, mental status, rr, heart rate, blood pressure, and temperature), and laboratory and radiographic findings (eg, arterial ph, blood urea nitrogen, sodium, glucose, hematocrit, partial pressure of arterial oxygen, and pleural effusion). patients are placed into specific risk classes to guide decisions about the need for hospitalization. a similar tool for pediatric patients would be useful, but no such validated scoring system has been established. although specific admission criteria for children may vary among institutions, several criteria for admission are widely used, including ill appearance or septic physiology, hypoxia that requires oxygen administration, moderate or severe respiratory distress, inability to tolerate oral fluids or medications, and social factors, such as the absence of a telephone or the inability to follow-up with a pediatrician or return to the emergency department if disease worsens. neonates with febrile pneumonia generally should be managed as inpatients, although one field study in india suggested that infants could be treated safely in the community after the first month of life [ ] . patients with underlying conditions that could affect their clinical course adversely and children with complicated pneumonias should be admitted for initiation of therapy. because the most likely etiologic agents depend on the age of the child, it is logical to select initial empiric antibiotic regimens according to age. in neonates from birth to weeks of age, in whom group b streptococcus and gramnegative rods predominate, the initial coverage should be intravenous (iv) ampicillin and gentamicin in most cases; if disease is severe, a third-generation cephalosporin (eg, cefotaxime) may be added (while continuing the ampicillin to cover listeria monocytogenes, another pathogen in this age group). from age weeks to months, if the infant is afebrile, erythromycin ( mg/kg/d iv divided every hours) is the drug of choice for treatment of c. trachomatis. if fever is present or if a child seems ill, ceftriaxone ( mg/kg/d every hours) should be given. for patients aged months to years, when viral pneumonia (the most common cause) is suspected, no antibiotic therapy should be administered. if bacterial pneumonia is suspected, iv ampicillin ( mg/kg/d divided every hours) can be used. if the child appears ill, ceftriaxone may be chosen instead to provide broader coverage. finally, among children aged years or older, azithromycin (one dose of mg/kg, followed by mg/kg/d) or erythromycin can be used in routine cases to provide coverage of atypical organisms (particularly mycoplasma); ampicillin may be added if there is strong evidence of a bacterial etiology, and ceftriaxone (with or without a macrolide) may be used in children who are more ill. in all ages, if features that suggest s. aureus are present, oxacillin or vancomycin should be added, depending on the prevalence of methicillin-resistant staphylococcus in the community [ ] . once a specific pathogen has been identified, coverage can be narrowed accordingly. for chlamydia and mycoplasma infections, a macrolide (at the doses described previously) is the drug of choice. in patients with suspected pneumococcal pneumonia, therapeutic choices are driven by local antimicrobial susceptibility patterns. when s. pneumoniae has been recovered from an appropriate patient specimen, the antibiotic susceptibility pattern can be used to guide therapy. for isolates that are fully susceptible to penicillin (minimal inhibitory concentration b . mg/ml), ampicillin should be administered (because of its easier dosing schedule as compared with penicillin). even for isolates with intermediate susceptibility to penicillin (minimal inhibitory concentration . - mg/ml), high-dose ampicillin ( mg/kg/d) provides excellent coverage. when fully nonsusceptible isolates are encountered (minimal inhibitory concentration mg/ml), ceftriaxone should be used. unlike the treatment of meningitis, vancomycin is rarely necessary in the treatment of pneumococcal pneumonia, even when a penicillin nonsusceptible strain is the etiologic agent. it should be added only if ceftriaxone resistance (defined for pneumonia as a minimal inhibitory concentration of mg/ml) is demonstrated. a recent study from spain suggested that the combination of a beta-lactam plus a macrolide may be superior to a beta-lactam alone for the treatment of pneumococcal pneumonia in adults, but no randomized trial addressing this hypothesis has been published to date [ ] . when h. influenzae is considered a likely pathogen (such as in children with underlying lung disease), ceftriaxone or ampicillin-sulbactam is preferred rather than ampicillin because of the presence of beta-lactamasemediated ampicillin resistance among many h. influenzae isolates. the optimal length of antimicrobial therapy for the treatment of uncomplicated or complicated pneumonia has not been well established for most pathogens. there are data to suggest that a -to -day course of therapy (or a -day course of azithromycin) is adequate for the treatment of c. pneumoniae [ , ] . for pneumococcal pneumonia, treatment probably should continue until the patient has been afebrile for hours, and the total duration of therapy probably should not be less than to days (or days if using azithromycin because of its long tissue half-life). fevers may persist for several days after initiation of appropriate therapy, which reflects the resultant inflammatory cascade and tissue damage. no good data are available to support prolonged treatment courses for patients without underlying conditions (eg, cystic fibrosis) who have uncomplicated pneumonia. some data suggest that shorter courses of therapy may be equivalent to current standards, although more controlled studies are needed before this practice can be recommended routinely [ , ] . several groups have published practice guidelines for the management of cap in adults [ , , ] . no analogous clinical practice guideline for pediatric pneumonia has been accepted universally, although several suggested guidelines have been published [ , ] . despite the differences among various recommendations, these guidelines serve as excellent compilations of the existing evidence regarding multiple aspects of the treatment of pneumonia. the differences in recommended management strategies contribute to variation in care for this diagnosis, however [ ] . published studies of adult patients with cap have shown that adherence to a treatment guideline results in improvement in several outcomes, including lower costs, decreased length of stay, more appropriate antibiotic usage, and lower mortality rates [ ] [ ] [ ] [ ] [ ] [ ] . even when guidelines are used, physicians' impressions of their adherence to clinical practice guidelines do not always match their actual adherence to the recommendations contained therein, which suggests that awareness does not guarantee familiarity [ ] . the causative organism in cases of pneumonia is frequently not identified by sputum examination or blood culture. when symptoms persist despite empiric antibiotic therapy, bronchoscopy with bronchoalveolar lavage (bal) is a diagnostic option. several studies have shown that culture of bal fluid in children with pneumonia can be useful in making a microbiologic diagnosis [ , ] . although bronchoscopy is not necessary in routine cases, it should be considered when patients fail to improve with standard therapy or when concern about antibiotic resistance or unusual organisms is high and recovery of the causative agents will change management. early bronchoscopy may be critical for immunocompromised patients, for whom the selection of empiric therapy is difficult because of the expanded list of potential causes. no single set of criteria defining clinical stability for inpatients with pneumonia has gained widespread acceptance, which introduces variability in decisions about discharge. the combination of normalization of vital signs, ability to take oral nutrition, and clear mental status has been shown to predict a low risk of subsequent clinical deterioration among hospitalized adults with pneumonia [ ] . time to clinical stability and -day post-admission mortality have been suggested to be the most reliable clinically based outcome measures for cap (along with process-of-care measures, such as admission-to-antibiotic time, proportion of patients receiving guideline-based antibiotic therapy, and percentage of patients switched from iv to oral therapy within hours of reaching clinical stability) [ ] . follow-up of children with pneumonia after discharge from the hospital should include involvement from their pediatrician or other primary care provider to ensure that clinical stability continues and that antibiotic therapy is completed as prescribed. in otherwise healthy children, follow-up radiographic studies are not necessary after a single episode of pneumonia. consolidation on chest radiographs can persist for up to weeks, regardless of clinical improvement [ ] . children with m. pneumoniae infection have been found to have detectable abnormalities on high-resolution ct scans more than year after the episode [ ] . follow-up radiographs should be reserved for children with underlying conditions, recurrent or persistent symptoms, or recurrent episodes of pneumonia. in these cases, a period of at least to weeks is recommended before obtaining a follow-up radiograph [ ] . although rates of hospitalization for pneumonia among children have been rising, mortality rates from childhood pneumonia in the united states declined by % between ( , deaths from pneumonia) and ( deaths) [ ] . case fatality rates (not adjusted for underlying comorbidities) from to have been estimated to be % in children younger than years of age and % in children aged to years [ ] . although antibiotic use probably accounted for much of the decrease in mortality rates during the early part of this time period, recent declines are likely attributable in part to improved access to care for poor children [ ] . improvements in critical care medicine also may reduce mortality, which is highest in children with underlying medical conditions. most children who develop pneumonia do not have any long-term sequelae. some data suggest that up to % of children may have symptoms of asthma years after hospitalization for pneumonia, however, which may reflect either unrecognized asthma at the time of presentation with cap or a propensity to develop asthma after cap [ ] . parapneumonic effusions are not uncommon with pneumonia and can occur in conjunction with most etiologic agents. whereas s. pneumoniae accounts for most cases with parapneumonic effusions, s. aureus and s. pyogenes are associated with particularly high rates of effusion and empyema [ ] . tuberculosis is also a common cause in geographic areas with a high prevalence of disease and should be considered in the differential diagnosis of selected patients [ ] . traditionally, the classification of such effusions as transudative versus empyema has been based on laboratory analysis of the pleural fluid. characteristics that suggest empyema include ph less than . , lactate dehydrogenase more than iu/ml, and glucose less than mg/dl [ ] . additional data that may be obtained include an elevated pleural fluid white blood cell count (ie, n , /mm ) or a positive microbiologic study (including gram stain, culture, or other diagnostic tests, such as stains or polymerase chain reaction). pleural fluid cell count has limited predictive value, however [ ] , and a positive microbiologic diagnosis is made from pleural fluid analysis in less than one third of cases [ ] . ct scan findings (such as pleural thickening or enhancement, among others) have been shown to be inaccurate in predicting which effusions meet laboratory criteria for empyema [ ] . several therapeutic options are available for the management of parapneumonic effusions. antibiotic therapy alone may result in resolution in some cases. drainage of the fluid by thoracentesis or placement of a drainage tube (large-bore chest tube or pigtail catheter) can remove the effusion. one study found that either needle aspiration alone or catheter drainage resulted in similar complication rates and lengths of stay, but children who underwent primary aspiration without catheter placement had a higher reintervention rate than children who had catheter placement at the time of initial drainage [ ] . lower ph (especially b . ) and presence of loculations also were independent predictors of reintervention in this study. the natural history of parapneumonic effusions follows several stages, beginning with an exudative phase, during which the fluid is free-flowing and of low cellularity. this stage is followed to hours later by a fibropurulent phase, during which the accumulation of fibrin and neutrophils may result in loculation. finally, an organizing phase occurs, with fibroblast activity resulting in the formation of a ''peel.'' thoracoscopy with surgical débridement may be necessary when the effusion has been longstanding enough to have allowed the development of septations, which reduce the fea-sibility of tube drainage. surgery has been shown to reduce the length of stay for hospitalized children whose effusions were considered high grade (defined as containing sonographic evidence of organization such as fronds, septation, or loculation) [ ] . in particular, video-assisted thoracoscopic surgery has been shown to have numerous advantages compared with open thoracotomy, including fewer lung resections, fewer associated blood transfusions, less postoperative analgesia, shorter length of stay, faster resolution of fever, and shorter time to removal of chest drains [ ] . an alternative option for managing loculated parapneumonic effusions is the use of intrapleural fibrinolytic agents (such as tissue plasminogen activator, streptokinase, or urokinase). these agents are used when inadequate drainage is obtained after chest tube insertion. recent reports of fibrinolytic therapy in children demonstrate that % to % of effusions in the fibropurulent phase can be drained completely and another % to % can be drained partially using the technique of daily instillation of streptokinase or urokinase through a chest tube with a dwell time of hours. this technique is ineffective in draining effusions that already have reached the organizing phase, however [ , ] . increased drainage also has been demonstrated using a -hour dwell of tissue plasminogen activator [ ] . one randomized trial in children showed that children who received intrapleural urokinase treatment had a shorter length of stay compared with a placebo group [ ] . fibrinolytic therapy has been associated with several rare complications, including allergic reactions (particularly with streptokinase), hemorrhage, and bronchopleural fistula formation. a large, prospective, randomized trial is needed to define better several aspects of this treatment option, including precise indications, optimal dosing and duration of therapy, and complication rates. failure to improve despite appropriate antimicrobial therapy should raise the suspicion of complications, such as parenchymal necrosis or abscess. these complications may be identified on contrast-enhanced ct scan when plain films do not reveal the findings [ ] . decreased parenchymal enhancement may herald the development of cavitary necrosis and a prolonged and more intense illness [ ] . most children who develop cavitary necrosis eventually demonstrate resolution of the pulmonary abnormality on follow-up radiography, however, even in the absence of surgical intervention [ ] . interventional procedures (eg, percutaneous catheter placement) should be avoided in children with necrotizing pneumonia, because such procedures may increase the likelihood of complications, such as bronchopleural fistula formation [ ] . lung abscess is an uncommon complication that more frequently occurs in older children. abscesses may be primary or secondary. experts have recommended that therapy routinely should include coverage of gram-positive organisms (s. aureus and streptococci) and anaerobes, although gram-negative coverage may be required in selected circumstances. most patients can be treated medically; needle aspiration or percutaneous catheter drainage of an abscess is safe and often provides diagnostic and therapeutic value in cases that fail to resolve on antibiotic therapy alone, without the associated complication rate seen in necrotizing pneumonia [ ] [ ] [ ] . in general, percutaneous drainage should be considered if a patient's condition worsens or when clinical status fails to improve after hours of antibiotic therapy. at least weeks of iv antibiotic therapy should be delivered before lobectomy is considered [ ] . recurrent pneumonia is generally defined as two episodes in year or more than three episodes in a lifetime. most children with recurrent pneumonia have an identifiable underlying predisposing factor. in one pediatric study, the most common of these factors was aspiration secondary to oropharyngeal muscular incoordination (eg, in cerebral palsy); other identified illnesses included immune disorders (generally related to malignancy or abnormalities of the humoral immune system, including hiv infection), congenital heart disease, asthma, congenital or acquired anatomic abnormalities (eg, tracheoesophageal fistula), gastroesophageal reflux, and sickle cell anemia [ ] . evaluation of a child with recurrent pneumonia should include a detailed history that focuses on possible indicators of these underlying illnesses combined with a targeted diagnostic evaluation that may include tests such as swallowing studies, serum immunoglobulins, hiv testing, echocardiography, pulmonary function tests, sweat testing, or radiographic studies, such as chest ct. several underlying abnormalities may result in a predisposition to the development of pneumonia. patients with endotracheal tubes or tracheostomies are at risk of lower respiratory tract infection because aspiration of contaminated secretions from the oropharynx or stomach is enhanced by several factors, including pooling of secretions above the cuff with subsequent leak and prolonged supine positioning [ ] . intubated patients in an intensive care unit may have fever or respiratory compromise unrelated to lung infection, and distinguishing bacterial colonization in tracheal aspirates from pneumonia can be difficult. ventilator-associated pneumonia is best identified using a combination of diagnostic modalities. in one study, % of ventilated children with bacterial pneumonia met one of the following three criteria: ( ) bronchoscopic protected specimen brush culture with or more colony-forming units/ml, ( ) intracellular bacteria in % or more of cells retrieved by bal, ( ) bal fluid culture with or more colony-forming units/ml [ ] . patients with gastroesophageal reflux and patients who are unable to control their secretions because of neurologic impairment (underlying or drug induced) or anatomic disruption are at risk of aspiration pneumonia. aspiration of oropharyngeal contents may produce a chemical pneumonitis, but it is frequently difficult to assess whether the introduction of oral bacteria has resulted in the establishment of a lower respiratory tract infection. antibiotic therapy is routinely prescribed for presumed aspiration pneumonia, and the administration of either penicillin or clindamycin (which provide reasonable coverage for oral anaerobes) has been shown to be equally effective therapy for this indication [ ] . in children who experience an aspiration event after hospitalization or in others in whom infection with pseudomonas or other gram-negative organisms is suspected (eg, patients with cystic fibrosis), a combination agent such as ampicillin or piperacillin and a beta-lactamase inhibitor should be considered. any abnormality in the host immune system may predispose a child to develop pneumonia. some of the more common scenarios seen in hospitalized patients include malignancy (either hematologic or solid tumors), solid organ or stem cell transplant, congenital or acquired immunodeficiencies, and autoimmune disorders or immunosuppressive medications used to treat systemic illnesses. regardless of cause, the immunocompromised host should be considered high risk for infection and merits a more aggressive diagnostic and therapeutic approach. table reviews micro-organisms that may be pathogens in immunocompromised patients with pneumonia. in particular, viral infections (especially cytomegalovirus) and fungal infections (including candida and aspergillus) must be considered [ ] along with unusual organisms such as pneumocystis jaroveci (formerly known as pneumocystis carinii) or cryptococcus neoformans. results of chest radiographs in patients with neutropenia may be negative [ ] , although findings that suggest an infectious cause (such as nodules) may be visible on plain films [ ] . chest ct scan may demonstrate abnormalities that are not detected on routine radiograph and may help localize lesions (particularly nodules) that are amenable to biopsy to aid in diagnosis [ ] . mr imaging is another alternative diagnostic modality and may be more sensitive for the detection of necrotizing pneumonia than ct scan [ ] . flexible bronchoscopy can establish a diagnosis in many cases, and several sampling methods are available. in one study of immunocompromised patients, the diagnostic yield was highest using a combination of bal and transbronchial biopsy ( %), as compared with bal alone ( %), transbronchial biopsy alone ( %), or protected specimen brush sampling ( %) [ ] . finally, lung biopsy may be considered to assist in making a diagnosis in patients with a concerning clinical status in whom noninvasive testing has failed to uncover an etiologic agent [ ] . in general, decisions regarding diagnostic testing may need to be accelerated in this population of patients to permit any interventions to be performed before clinical status deteriorates and a patient is unable to tolerate invasive procedures and to allow appropriate therapy to be initiated earlier in the course of disease. the differential diagnosis of pneumonia in patients who have been hospitalized for any prolonged period should include routine infectious etiologies and hospital-acquired organisms. failure to improve with appropriate empiric therapy should raise the concern for antimicrobial resistance. organisms of particular importance in these situations may include methicillin-resistant s. aureus, vancomycin-resistant enterococci, and gram-negative rods with resistance to third-generation cephalosporins, among others. empiric coverage for pneumonia in patients in the intensive care unit or others at risk for nosocomial infections should include broad-spectrum agents that provide coverage for these antibiotic-resistant organisms (and any organisms known to be a frequent cause of hospital-acquired infections in the institution) until a specific diagnosis can be made and antimicrobial susceptibilities are available. the infection control staff and the hospital microbiology laboratory are invaluable resources in determining which organisms should be considered in these circumstances. isolation precautions are a topic of particular interest to hospitalists who manage patients with pneumonia, particularly when a specific etiologic agent has not been identified. because pneumonia can be caused by a wide variety of agents, several different infection control precautions may be appropriate. the single most important procedure to prevent the spread of infection in the hospital is hand hygiene (performed either with soap and water or a waterless alcoholbased hand sanitizer). table reviews the correct precautions for specific organisms that may be encountered in the hospital setting. two infections that merit specific mention are pertussis and influenza. these organisms are highly infectious, and exposure among hospital staff may require chemoprophylaxis. patients with pertussis or influenza should be admitted to a single room whenever possible. staff also should wear masks when entering the room of patients with influenza (despite the fact that droplet transmission precautions usually only require masks within feet), because several reports have suggested a role for airborne transmission [ ] [ ] [ ] . when pulmonary tuberculosis is suspected, strict attention to airborne precautions must be followed. in addition to the use of respirators and negative-pressure isolation rooms, visitation should be limited when possible; at our institution, two primary visitors may undergo screening chest radiography to ensure that they do not have active pulmonary infection. special organism precautions a contact refers to gown and gloves; droplet refers to mask within feet; airborne refers to n respirator to enter room; special organism precautions refers to gown and gloves and dedicated patient equipment. as medical care for complex patients increasingly shifts from the inpatient to the outpatient arena, a greater number of infections are being treated by continuing the delivery of parenteral antibiotic therapy in the home or at stepdown facilities [ ] [ ] [ ] . outpatient parenteral antimicrobial therapy (opat) is a reasonable option for patients with pneumonia who have stabilized clinically in the hospital but are judged to require prolonged parenteral treatment. the treatment of lower respiratory tract infections using opat has resulted in excellent clinical outcomes and high levels of patient and physician satisfaction [ , ] . eligibility for opat requires a suitable home environment and the selection of an antimicrobial agent with appropriate pharmacokinetic parameters and drug stability to allow a reasonable dosing schedule at home [ ] . an infectious diseases specialist (or a physician knowledgeable about the use of antimicrobial agents in opat) and a hospital pharmacist should be involved before discharge in planning for the administration of opat. the involvement of discharge planning services in the hospital also can facilitate contact with visiting nurse associations, which can arrange to instruct families in the proper techniques for iv infusions in the home. these agencies can make home visits to observe caregivers and answer questions and obtain blood for laboratory monitoring of disease or medication toxicities. the use of these services, in conjunction with careful follow-up by primary care physicians, provides the best continuity of care from the hospital to the outpatient setting and helps to ensure that patients with pneumonia receive the highest quality of care across the health care spectrum. national hospital discharge survey the tucson children's respiratory study. ii. lower respiratory tract illness in the first year of life pneumonia: an eleven-year study in a pediatric practice global estimate of the incidence of clinical pneumonia among children under five years of age practice guidelines for the management of community-acquired pneumonia in adults: infectious diseases society of america community-acquired pneumonia in children epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children guidelines for the management of community acquired pneumonia in childhood role of different routes of tracheal colonization in the development of pneumonia in patients receiving mechanical ventilation acute respiratory infections diagnosis and interventions in lower respiratory tract infections the role of pneumolysin in pneumococcal pneumonia and meningitis assessment of clinical criteria for identification of severe acute lower respiratory tract infections in children diagnostic value of tachypnoea in pneumonia defined radiologically acute lower respiratory infection in argentinian children: a month clinical and epidemiological study clinical predictors of pneumonia as a guide to ordering chest roentgenograms standardized diagnosis of pneumonia in developing countries evaluation of simple clinical signs for the diagnosis of acute lower respiratory tract infection clinical signs of pneumonia in infants under months establishing clinically relevant standards for tachypnea in febrile children younger than years clinical signs of pneumonia in children respiratory rate greater than per minute as a clinical indicator of pneumonia in filipino children with cough characteristics of streptococcus pneumoniae and atypical bacterial infections in children - years of age with community-acquired pneumonia decision rules and clinical prediction of pneumonia: evaluation of low-yield criteria clinical characteristics and outcome of children with pneumonia attributable to penicillin-susceptible and penicillin-nonsusceptible streptococcus pneumoniae occult pneumonias: empiric chest radiographs in febrile children with leukocytosis principles and practice of pediatric infectious diseases. nd edition. philadelphia churchill-livingstone extreme leukocytosis in patients presenting to a pediatric emergency department value of the c-reactive protein test in the differentiation of bacterial and viral pneumonia update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults a practical guide for the diagnosis and treatment of pediatric pneumonia guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy the contribution of blood cultures to the clinical management of adult patients admitted to the hospital with community-acquired pneumonia: a prospective observational study initial microbiologic studies did not affect outcome in adults hospitalized with community-acquired pneumonia utility of blood cultures in pediatric patients found to have pneumonia in the emergency department nonvalue of the initial microbiological studies in the management of nonsevere community-acquired pneumonia rejection criteria for endotracheal aspirates from adults evaluation of rapid assay for detection of streptococcus pneumoniae urinary antigen among infants and young children with possible invasive pneumococcal disease usefulness of urinary antigen detection by an immunochromatographic test for diagnosis of pneumococcal pneumonia in children detection of mycoplasma pneumoniae by two polymerase chain reactions and role of m. pneumoniae in acute respiratory tract infections in pediatric patients is a chest radiograph necessary in the evaluation of every febrile infant less than weeks of age? the futility of the chest radiograph in the febrile infant without respiratory symptoms comparison of radiological findings and microbial aetiology of childhood pneumonia chest x-ray appearances in pneumonia and bronchiolitis: correlation to virological diagnosis and secretory bacterial findings interobserver reliability of the chest radiograph in community-acquired pneumonia: port investigators bias and overcall in interpreting chest radiographs in young febrile children mycoplasma pneumoniae pneumonia: radiographic and high-resolution ct features in patients the yield of ct of children who have complicated pneumonia and noncontributory chest radiography a prediction rule to identify low-risk patients with community-acquired pneumonia pneumonia in neonates: can it be managed in the community? addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children high-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm short-course treatment of community-acquired pneumonia evaluation of community acquired pneumonia guidelines decreased mortality after implementation of a treatment guideline for community-acquired pneumonia medical outcomes and antimicrobial costs with the use of the american thoracic society guidelines for outpatients with community-acquired pneumonia a controlled trial of a critical pathway for treatment of community-acquired pneumonia. capital study investigators: community-acquired pneumonia intervention trial assessing levofloxacin adherence to ats guidelines for hospitalized patients with community-acquired pneumonia influence of deviation from guidelines on the outcome of community-acquired pneumonia improvement of process-of-care and outcomes after implementing a guideline for the management of community-acquired pneumonia: a controlled before-and-after design study use of guidelines in treating community-acquired pneumonia bilateral fiberoptic bronchoalveolar lavage in acute unilateral lobar pneumonia the diagnostic utility of bronchoalveolar lavage in immunocompetent children with unexplained infiltrates on chest radiograph time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines evaluation of outcomes in community-acquired pneumonia: a guide for patients, physicians, and policy-makers the radiographic resolution of streptococcus pneumoniae pneumonia late abnormal findings on high-resolution computed tomography after mycoplasma pneumonia maximizing the usefulness of imaging in children with community-acquired pneumonia mortality from pneumonia in children in the united states mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, - asthma after childhood pneumonia: six year follow up study complicated parapneumonic effusions in children caused by penicillin-nonsusceptible streptococcus pneumoniae the etiology of pleural effusions in an area with high incidence of tuberculosis parapneumonic effusions parapneumonic effusions and empyema in hospitalized children: a retrospective review of cases value of thoracentesis in the diagnosis and management of infectious pleural effusions ct appearance of parapneumonic effusions in children: findings are not specific for empyema outcomes of primary image-guided drainage of parapneumonic effusions in children implications of early sonographic evaluation of parapneumonic effusions in children with pneumonia experience with video-assisted thoracoscopic surgery in the management of complicated pneumonia in children intrapleural fibrinolytic treatment of multiloculated postpneumonic pediatric empyemas intrapleural fibrinolytic treatment of multiloculated pediatric empyemas effectiveness and safety of tissue plasminogen activator in the management of complicated parapneumonic effusions randomised trial of intrapleural urokinase in the treatment of childhood empyema pneumonia in children: decreased parenchymal contrast enhancement. ct sign of intense illness and impending cavitary necrosis cavitary necrosis complicating pneumonia in children: sequential findings on chest radiography lung abscess versus necrotizing pneumonia: implications for interventional therapy tube drainage of lung abscesses percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess in children lung abscess in infants and children underlying causes of recurrent pneumonia in children blind protected specimen brush and bronchoalveolar lavage in ventilated children a randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children pneumonia in allogenic and autologous bone marrow recipients: a retrospective study the yield of chest radiography in febrile and neutropenic patients acute lung disease in the immunocompromised host: diagnostic accuracy of the chest radiograph acute lung disease in the immunocompromised host: ct and pathologic examination findings mr imaging of pneumonia in immunocompromised patients: comparison with helical ct role of flexible bronchoscopy in immunocompromised patients with lung infiltrates lung biopsy in immunocompromised children: when, how, and who? an outbreak of influenza aboard a commercial airliner airborne infection transmission of influenza: implications for control in health care settings outpatient parenteral antimicrobial therapy (opat) for the treatment of osteomyelitis: evaluation of efficacy, tolerance and cost outpatient parenteral antimicrobial therapy for central nervous system infections the management of skin and soft tissue infections: outpatient parenteral antibiotic therapy in the united kingdom efficacy and safety of intravenous cefotaxime for treating pneumonia in outpatients treatment of lower respiratory tract infections in italy: the role of outpatient parenteral antibiotic therapy practice guidelines for outpatient parenteral antimicrobial therapy: idsa guidelines key: cord- -do i ymq authors: banu, buyukaydin title: pneumonia date: - - journal: encyclopedia of biomedical gerontology doi: . /b - - - - . - sha: doc_id: cord_uid: do i ymq pneumonia remains the main cause of morbidity and mortality from infectious diseases in the world. the important reason for the increased global mortality is the impact of pneumonia on chronic diseases especially in the elderly population and the virulence factors of the causative microorganisms. because elderly individuals present with comorbidities, particular attention should be paid for multidrug-resistant pathogens. streptococcus pneumoniae remains the most frequently encountered pathogen. enteric gram-negative rods, as well as anaerobes, should be considered in patients with aspiration pneumonia. interventions for modifiable risk factors will reduce the risk of this infection. the adequacy of the initial antimicrobial therapy and determination of patients’ follow-up place is a key factor for prognosis. also, vaccination is one of the most important preventive measures. in this section it was focused on several aspects, including the atypical presentation of pneumonia in the elderly, the methods to evaluate the severity of illness, the appropriate take care place and the management with prevention strategies. pneumonia is defined as an acute respiratory infection that affects lung parenchyma. despite the availability of antibiotic therapy and severity of illness assessments, pneumonia continues to be a leading cause of death worldwide. in the elderly population, the impact of pneumonia is greater than in other age groups. the mechanisms that increase the incidence and mortality rates in elderly pneumonia patients are not fully understood. the immunological changes that called immunosenescence are known to be responsible for the increased sensitivity of elderly people to infection diseases. the world population reached . billion and the people years and over amounted % of the total, million according to data united nations world population prospects (kaplan et al., ) . the annual incidence of pneumonia in the elderly is fourtimes that of the younger population. older adults have also higher rates of hospitalization and mortality (chong and street, ) . therefore, a better understanding of the pathophysiology, microbiology, treatment, and prevention of this common affliction is required. for proper diagnosis and treatment advice, pneumonia is classified as community-acquired pneumonia (cap), hospital-acquired pneumonia (hap), and ventilator-associated pneumonia (vap) along with the recent guidelines. in this section, the most recent data regarding the epidemiology, microbiology, diagnosis, classification, treatment, and prevention strategies are presented. the incidence of pneumonia varies according to geographical location, healthcare setting, and population. including pneumonia, lower respiratory tract infections are the fourth most common cause of death all over the world. in a study carried out in the us, the annual incidence of pneumonia was observed as . cases/ , adults, with the highest rates among adults between and years of age; . cases/ , adults and in patients up to years old; . cases/ adults (konomura et al., ) . in terms of economic impact, two studies carried out in the netherlands and japan, sustained remarkable results. the majority of cap episodes ( %) occurred among patients years and older and these episodes incurred % of the costs. the second study included , patients with cap aged years and over and reported median treatment costs of us$ per outpatient cap and us$ per hospitalized cap (klausen et al., ; kothe et al., ) . mortality in elderly patients may be % higher than in the general population ( %). in this population group, hospitalization rates are five times more likely than other patients' groups also (chong and street, ) . because of these negative impacts, several studies have attempted to identify risk factors. a population-based cohort study with , elderly patients found that immunosuppression, copd, smoking, congestive heart failure, diabetes, malignancy, and previous hospitalizations for pneumonia are independent risk factors for developing the disease in this age group (barlow et al., ) . for mortality risk, available data is useful. comorbid illness (including cerebrovascular disease, congestive heart failure, and chronic liver disease), higher infection activity index and ineffective therapy were presented along with higher mortality risk in elderly. other factors linked to increased mortality are accepted as bedridden status, delirium, the absence of fever, tachypnea, c-reactive protein levels greater than mg/l, hypoalbuminemia, acute organ failure, suspicion of aspiration and swallowing disorders (centers for disease control and prevention (cdc), ). identifying the causative agent can be useful for guiding antimicrobial therapy. although the microbiological diagnosis is fundamental to ensure appropriate therapy, it is achieved in less than % of the cases. in order to avoid the delaying that associated with increased mortality, antimicrobial therapy should be administered empirically. pathogens associated with communityacquired pneumonia in elderly patients are presented in table . in this age group, the possibility of obtaining a diagnostic sputum sample has been very low. causative organisms are only identified in %- % of the cases. globally s. pneumoniae is accepted as being the most common pathogen. also in elderly, this microorganism remains the single most common organism identified in hospitalized patients. the diagnosis of pneumococcal pneumonia has increased in recent years, due to the introduction of the pneumococcal urine antigen test. but the incidence has probably decreased because of pneumococcal vaccines along with the decreased rate of smoking (garcia vidal et al., ) . the differences in the chemical and antigenic composition of the pneumococcal capsule result in different serotypes. serotype is the most common serotype associated with adult pneumococcal infection and with septic shock (cilloniz et al., ) . haemophilus influenzae was also frequently isolated accounting for %- % in elderly. in patients with chronic obstructive lung disease, infection with this organism may be more common. moraxella catarrhalis and staphylococcus aureus (methicillin sensitive) have also been described as pathogens, with frequencies % and %, respectively (cdc, ) . intracellular pathogens are one of the other frequent microorganisms (donowitz and cox, ) . the incidence is variable depending on the difficulties with microbiological cultures. they grow poorly in standard culture media and performing additional serologic tests on all patients is not common practice. legionella pneumophila, mycoplasma pneumoniae, chlamydophila pneumoniae, chlamydophila psittaci, and coxiella burnetii are the well-established intracellular pathogens. no clinical features exist that make it possible to distinguish intracellular pathogens from classical ones. but extra-pulmonary manifestations are often associated with intracellular pathogens. severe pneumonia caused by these pathogens accounts for %- % of the cases. the major problem with these pathogens is that most antibiotics are unable to access intracellular spaces and to reach the optimal therapeutic concentrations is difficult. in those aged over years, the atypical organisms are less frequently encountered but play a significant role in the clinical spectrum (macfarlane et al., ) . chlamydophila pneumoniae is the most common, with rates of %- %, mycoplasma pneumoniae is less frequently encountered ( %- %) and coxiella burnetii is a rare causative agent in elderly (cdc, ) . although legionella pneumophila is relatively uncommon in the elderly, it should be considered presenting with atypical symptoms for example, headache, altered mental status, gastrointestinal signs or bradycardia (ruuskanen et al., ) . it appears to be reasonable to exclude this bacteria with urinary antigen testing in all elderly patients with pneumonia before atypical coverage is discontinued. infections with gram-negative bacteria are often related to comorbid illnesses. excluding nursing-home residents and hospitalized patients, these infections are infrequent in the elderly. but in severely debilitated or chronically ill elderly patients from the community, especially in those who fail to improve on standard therapy, a high index of suspicion may be warranted for this bacteria (cdc, ) . among other pathogens, respiratory viruses are considered responsible in one-third of the cases. influenza viruses (a and b), respiratory syncytial virus (rsv), parainfluenza viruses , , , coronaviruses and rhinoviruses, are the most commonly encountered ones. it is estimated that million cases of viral pneumonia occur annually (ruuskanen et al., ) . influenza virus (a and b) is usually selflimiting, but severe complications like pneumonia can occur especially in high-risk patients like elderly with comorbidities along with increased mortality risk. routine influenza screening appears reasonable in an elderly presenting with pneumonia-like complaints, but the sensitivity of available screening tests is poor and treatment decisions should not be based only the results of rapid flu testing. aspiration pneumonia is another common cause of cap. the most frequent microorganisms are anaerobic bacteria and microaerophilic streptococci from the oral flora. aspiration pneumonia may be the second most common etiology of cap in patients years and older (teramoto et al., ) . approximately % of the cap cases, a multidrug-resistant (mdr)-resistant to more than three classes of antibiotics-pathogen is an agent that most frequently being s. aureus and p. aeruginosa. in a recent european study, mdr pathogens were presented as . % of the . % cap cases with most commonly presented with methicillin-resistant s. aureus (mrsa) . community-associated methicillin-resistant s. aureus (ca-mrsa) raises concern for infection in elderly adults. the production of the toxin panton-valentine leukocidin (pvl) is the main characteristic of ca-mrsa. this toxin causes leukocyte destruction and tissue necrosis. in elderly, ca-mrsa should be considered in presentation with influenza, such as prodromes, skin lesions, cavitary infiltrates, hemoptysis or rapidly progressing pneumonia. table pathogens associated with community-acquired pneumonia in elderly patients pseudomonas aeruginosa endemic and opportunistic infections p. aeruginosa is not a frequent pathogen in the cap but severe cap requiring intensive care unit (icu) admission it was the causative agent in . %- . % of the cases with the mortality rate of between % and % (yoshimoto et al., ) . prior antibiotic treatment is the only risk factor associated with cap caused by mdr p. aeruginosa. also, s. pneumoniae has increased its resistance to several antibiotics (cephalosporins, macrolides, and fluoroquinolones) in the last two decades. between % and % of pneumococcus disease cases worldwide have mdr pattern. nevertheless, the therapeutic failure involving b-lactams has not been reported because of pharmacodynamic properties (draghi et al., ) . hap is defined as pneumonia occurring h or more after hospital admission. vap is defined as pneumonia occurring > h after endotracheal intubation. hap is the second most frequent nosocomial infection and is considered the main cause of mortality for nosocomial infections. vap is considered the main nosocomial infection in the icu. hap is divided into two groups according to the time of onset from admission. early onset is defined when pneumonia development within the first days of hospitalization. this presentation is associated with better clinical prognosis. late onset is defined when pneumonia occurs after days of hospitalization. the recently published guidelines propose that the presence of risk factors for mdr should take precedence rather than early or late onset pneumonia distinction (kalil et al., ) . the top six pathogens causing % of the hap cases are s. aureus, p. aeruginosa, klebsiella spp., escherichia coli, acinetobacter spp., and enterobacter spp. ( table ) . gram-negative bacteria are the major agent with %- % for hap cases in icu. the most frequent pathogens include p. aeruginosa, a. baumannii, h. influenzae, and enterobacteriaceae spp. (k. pneumoniae, e. coli, enterobacter species, serratia species, proteus species, etc.). the mortality increase to % with advanced age, increased disease score and inadequate initial antimicrobial treatment. an independent factor for predicting the mortality is the using of vasopressors in the case of vap where p. aeruginosa is isolated (micek et al., ) . gram-positive pathogens account for %- % of hap cases. the most frequent microorganisms; methicillin-resistant and methicillin-sensitive s. aureus, s. pneumonia, and streptococcus spp. pneumonia caused by more than two pathogenic microorganisms is defined as a polymicrobial infection. approximately %- % of vap cases are considered to have polymicrobial etiology. polymicrobial etiology generally did not influence the outcome when empiric antibiotic treatment was appropriate. mdr pathogens are a major problem for this group of patients. the clinical practice guidelines summarize the following risk factors for mdr (weiskopf et al., elderly persons suffer from a variety of comorbidities. associated factors predisposing patients to develop pneumonia are presented in table . also, multimorbidity was associated with death, hospitalization or return to the emergency department within days of discharge. in a recent study % of the cases presented with at least one comorbidity according to the aging group: - years old, . %; - years old, . % and > years old, . %.the most frequent comorbidity was presented as chronic pulmonary disease. because of immunosenescence in elderly, the risk of misdiagnosis or delayed diagnosis is more frequent. specific symptoms of pulmonary infection such as a cough, sputum, fever, chills, and chest pains may not be available. the complaints must be taken care of are altered mental status (i.e., delirium), falls, fatigue, lethargy, delirium, anorexia, tachypnea, tachycardia, and, less commonly, pleuritic pain, cough, and fever (rockwood et al., ) . in elderly, pneumonia sometimes presents as an exacerbation or decompensation of previous comorbidities and also % of the cases the radiographic findings are inconclusive or difficult to interpret. many biomarkers of infection such as leukocyte count, c-reactive protein (crp), procalcitonin have been found to play a role in the early diagnosis, but in elderly with cap, the reliability on these biomarkers is limited (liu et al., ) . all patients should be screened by pulse oximetry, for unsuspected hypoxemia in patients with diagnosed pneumonia or to determine the presence of pneumonia without obvious signs. since the microbiological diagnosis of pneumonia is important for a better clinical outcome, to follow national and international guidelines is recommended. these recommendations regarding samples and diagnostic tests are presented in table . clinical indications for more extensive diagnostic testing should be decided on a clinical basis ( table ) . some etiologic diagnoses have important epidemiologic implications and agents that should be reported to public health officials vary according to countries. in general, legionnaires disease, sars (severe acute respiratory syndrome) psittacosis, avian influenza (h n ), and possible agents of bioterrorism (plague, tularemia, and anthrax) are accepted as microorganisms to be notified. in low to mild cases of cap, recommendations for the microbiological diagnostic test is optional. in the case of the severe cap, to take blood cultures, sputum staining, sputum culture, urinary antigen test for legionella and pneumococcus are recommended. the main problems from these methods are the low yield, long turnaround time ( - h) and the effects of previous antibiotic use on microbiological results (chastre and fagon, ) . for all cases of hap, microbiological tests should be performed on respiratory samples. samples can obtain spontaneous expectoration, sputum induction, nasotracheal suctioning, and endotracheal aspiration in a patient with requires mechanical ventilation. for vap cases noninvasive sampling with endotracheal aspiration cultures and blood culture is recommended (kalil et al., ) . blood and pleural cultures: before antimicrobial treatment, performing blood culture have a high specificity but a low positivity (less than % of the cases). blood cultures are optional but especially in patients with host defect, for example, asplenia, complement deficiencies, chronic liver disease or leukopenia is indicated along with in patients with hap, the positivity of blood cultures varies from % to %. because the spreading of the infection to the blood occurs in < % of vap cases, blood cultures availability is limited. approximately % of cap cases have a pleural effusion. patients with pleural effusions cm in height on a lateral upright chest radiograph should undergo thoracentesis because of empyema is considered a risk factor for poor outcome. in pleural fluid samples, pneumococcal antigen or molecular detection are recommended also (falguera et al., ) . sputum gram stain and culture: before antimicrobial therapy, sputum sample collection is performed. for diagnostic accuracy, an adequate collection and transport of the sample are recommended. the good quality sample is considered when the sputum sample contains less than epithelial cells and more than lymphocyte cells. the benefits of a sputum gram stain; it broadens initial empirical therapy for a less common etiologies such as s. aureus and gram-negative organisms and it validates the subsequent sputum culture results. for pneumonia caused by s. pneumoniae, the sensitivity of the gram stain is $ % and for s. aureus, it is % (anevlavis et al., ) . the endotracheal aspirate is the equivalent of sputum in vap cases. gram stain and culture of the endotracheal aspirates are recommended for intubated patients. both samples share the same criteria for quality. in vap cases, for distinguishing colonization from infection, a threshold ! colony forming units/ml is recommended (cook and mandell, ) . antigen tests: legionella serotype and pneumococcus antigens are renally excreted and can be detected. sensitivity for pneumococcus ranges from % to % with specificity from % to %. for pneumococcal pneumonia, disadvantages of this test are costing amount ($$ per specimen) and false positive results with children and with chronic respiratory diseases who are colonized with s. pneumoniae (navarro et al., ) . along with legionella serogroup , %- % sensitivity and % specificity was reported. the problem is that the recommended empirical antibiotic regimens will cover both of these microorganisms and further researches are necessary to investigate the clinical usefulness of this method. the rapid antigen detection test for influenza can help for consideration of antiviral therapy. although test performance varies according to patient age, the test used, sample type and duration of illness, %- % sensitivity and $ % specificity was observed in adults. the disadvantages include cost ($$ per specimen), high rates of false-negative results and false-positive results with adenovirus and not superiority according to physician judgment. in the last years, for microbiological diagnosis of respiratory pathogens, molecular diagnostic tests are investigated. these tests provide identification of specific pathogens and differentiate bacterial and viral infection. antibiotic susceptibility, response to antibiotic therapy, assessment for prognosis and disease surveillance is evaluated with these techniques. the methods are approved by the food drug administration (fda) (gadsby et al., ) . approximately % of the cases remain without microbiological identification. conventional methods together with molecular testing will improve the microbiological diagnosis and clinical management of cases with pneumonia. a chest radiograph is required for the routine evaluation the patients who are likely to have pneumonia. chest radiographs are sometimes useful for suggesting the etiologic agent, alternative diagnoses and associated conditions. computerized tomography scans may be more sensitive when findings of radiography are negative or unclear. for patients who are hospitalized for suspected pneumonia but who have negative chest radiographic findings, it is advanced to treat presumptively with antibiotics and repeat the imaging in - h. when managing elderly patients who present with pneumonia, evaluation of severity and site-of-care decisions are critical. in elderly patients with cap, several mortality predictors have been reported. chronic comorbidities were the main predictors of mortality and readmission. the prognostic value of glucose levels was investigated and markedly elevated blood glucose levels on admission were associated with increased short-term and long-term mortality. in another study, the neutrophil-to-lymphocyte ratio was evaluated and presented better for prediction -day mortality according to the pneumonia severity index (psi) and curb- (fine et al., ; lim et al., ) . when a comparison is made in terms of mortality, between crp, white blood cell (wbc) count and these indexes, psi and curb- are observed significantly associated with mortality and icu admission. the psi is based on parameters that are evaluated at the time of clinical presentation as three demographics, five comorbid conditions five physical examination findings, and seven laboratory/imaging variables ( table ) (fine et al., ) . the primary purpose of this score is to distinguish patients that could be safely treated in an outpatient setting versus inpatient observation and treatment. the major limitations of the psi score are its focusing by age and comorbidity and not consider psychosocial variables, infrequent comorbidities, or patient preferences regarding treatment. the curb- is a less complex scoring system only requires six variables to be evaluated at presentation (table ) . (lim et al., ) . for severity assessment and hospitalization decision, the usefulness of these scores are presented in table . in curb- , age is an extremely significant variable. these scores highlight that elderly patients with pneumonia are at risk for higher severe disease and poorer clinical outcome, but the limitations of the curb- score that not contain data such as hypoxemia, electrolyte disturbance or the inability to take oral medications. for prediction icu admission and the risk of death in patients with severe cap, several other tools have also been designed. the examples include the ps-curxo , smart-cop, and cap-piro scores. all of these guidelinesdexcept onedinclude age as one of the variables associated with poor outcomes. ps-curxo uses age above years old as one of the minor criterion for determining the severity of illness. the smart-cop scoring system evaluates the need for respiratory and vasopressor support. in this score, age is not one of the severity markers but tachypnea and poor oxygenation are used as an adjustment tool. rello and colleagues developed the cap-piro score. this score evaluates predisposition, infection, response, and organ dysfunction variables (espana et al., ; charles et al., ; rello et al., ) . detailed information for all of these scores is presented in table . icu admission is another important medical decision for these patients. direct admission to an icu is required for patients with septic shock requiring vasopressors or with acute respiratory failure requiring intubation and mechanical ventilation. also, for patients with three of the minor criteria for severe cap listed in table , direct admission to an icu or high-level monitoring unit is recommended . but it must bear in mind that early recognition of sepsis in elderly compromised patients can be challenging. the classical criteria to define the systemic inflammatory response syndrome can be absent in anergic patients. in conclusion, in addition to objective criteria such as age, the clinician experience, and clinical judgment is always recommended for proper evaluation. curb- is practical and functional in order to decide when to admit a patient to the hospital and idsa/ ats guidelines major and minor criteria are proper parameters to admit a patient to the icu . antimicrobials are the mainstay of treatment for elderly patients with cap. selection of antimicrobials for empirical therapy is based on the prediction of the most likely pathogen and knowledge of local susceptibility patterns. unless outcome data clearly do not favor one drug, recommendations generally take place for a class of antibiotics. overall efficacy remain the major factor for many classes of agents, other factors like pharmacokinetics/pharmacodynamics, compliance, safety, and cost must be into consideration. the most common pathogens of cap are presented in table according to the severity of illness as judged by the site of care. in terms of analyzing the microbial etiology in elderly, a cohort study with cap patients was shown that when patients divided by age, the microbiological diagnosis possibility decreases steadily with age; - years old, %; - years old, %; and years and older, % (cillóniz et al., ) . in this age group, to consider the substantial risk factors can help for prediction the responsible microorganisms and finally select the proper antimicrobial therapy (table ) . current international guidelines for the treatment of cap do not have specific recommendations for elderly patients. in this guidelines, evaluation, following, and treatment of the patients is taking place into three categories; outpatient treatment, inpatient-non icu treatment and inpatient icu treatment . the recommendations for outpatient treatment with the listed clinical risks: . previously healthy and no use of antimicrobials within the previous months a macrolide (azithromycin, clarithromycin, or erythromycin) (strong recommendation) doxycycline (weak recommendation) . presence of comorbidities such as chronic heart, lung, liver or renal disease; diabetes mellitus; alcoholism; malignancies; asplenia; immunosuppressing conditions or use of immunosuppressing drugs; or use of antimicrobials within the previous months a respiratory fluoroquinolone (moxifloxacin, gemifloxacin, or levofloxacin [ mg]) (strong recommendation) ( point) ats, american thoracic society; cap, community-acquired pneumonia; icu, ıntensive care unit; idst, infectious diseases society of america; piro, predisposition, infection, response and organ dysfunction score; ps curxo , ph, systolic blood pressure, confusion, urea nitrogen, respiratory rate, x-ray finding, oxygen arterial pressure and age of years or more; smart-cop, systolic blood pressure, multilobar chest radiography, albumin level, respiratory rate, tachycardia, confusion, oxygenation and ph; bun, blood urea nitrogen; wbc, white blood cell. a b-lactam plus a macrolide (high-dose amoxicillin [e.g., g three times daily] or amoxicillin-clavulanate [ g two times daily] is preferred; alternatives include ceftriaxone, cefpodoxime, and cefuroxime [ mg two times daily]; doxycycline is an alternative to the macrolide) (strong recommendation) . in regions with a high rate (> %) of infection with high-level (mic > mg/ml) macrolide-resistant s. pneumoniae, consider the use of alternative agents listed above in ( ) for patients without comorbidities (moderate recommendation). the recommendations for hospital ward treatment with the listed clinical risks: . a respiratory fluoroquinolone (strong recommendation) . a b-lactam plus a macrolide (strong recommendation) preferred b-lactam agents include cefotaxime, ceftriaxone, and ampicillin; ertapenem for selected patients (patients with risks for infection with these pathogens and for patients who have recently received antibiotic therapy) with doxycyclinedas an alternative to the macrolide a respiratory fluoroquinolone should be used for penicillin-allergic patients. for most hospitals admitted patients, initial treatment should be given intravenously, but some without risk factors for severe pneumonia could receive oral therapy, especially with highly bioavailable agents such as fluoroquinolones. when an intravenous b-lactam is combined with coverage for atypical pathogens, a macrolide or doxycycline with oral therapy is appropriate for selected patients without severe pneumonia risk factors. the recommendations for icu treatment with the listed clinical risks: minimal recommended treatment is; . a b-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam) plus either azithromycin or a fluoroquinolone (strong recommendation) for penicillin-allergic patients, a respiratory fluoroquinolone and aztreonam. the most common pathogens in the icu population were (in descending order of frequency) s. pneumoniae, legionella species, h. influenzae, enterobacteriacea species, s. aureus and pseudomonas species. the recommended standard empirical regimen should routinely cover the three most common pathogens, all of the atypical pathogens, and most of the relevant enterobacteriaceae species. but for treatment of mrsa or p. aeruginosa infection, modification the standard empirical regimen is necessary. along with suspicion of these pathogens, modification to the basic empirical treatment is; . for pseudomonas infection, use an antipneumococcal, antipseudomonal b-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem) plus either ciprofloxacin or levofloxacin ( -mg dose) or the above b-lactam plus an aminoglycoside and azithromycin or the above b-lactam plus an aminoglycoside and an antipneumococcal fluoroquinolone. for penicillin-allergic patients, substitute aztreonam for the b-lactam. structural lung diseases, such as bronchiectasis, or repeated chronic lung disease exacerbations as well as prior antibiotic therapy are other clinical risk factors for infection with pseudomonas species. requiring for icu admission is not routine with these pathogens. in patients with chronic alcoholism other serious gram-negative pathogens, such as k. pneumoniae or acinetobacter species are important. clinical risk factors for cap with s. aureus include end-stage renal disease, injection drug abuse, rapid presentation and progression, associated skin lesions, prior influenza, and prior antibiotic therapy. for mssa empirical combination therapy recommended above is adequate. actually, vancomycin has never been specifically studied for cap. linezolid is detected superior to vancomycin in the retrospective analysis for nosocomial mrsa pneumonia. as newer presently available agents, daptomycin should not be used for cap, and for tigecycline, there is no available data. pathogen-directed therapy . the etiology of cap has been identified with reliable microbiological methods, antimicrobial therapy should be oriented at that pathogen (moderate recommendation) because of the benefit of combination therapy was also most pronounced in more severely ill patients, after results of cultures, discontinuation of combination therapy is most likely safe in only non-icu patients (cillóniz et al., ). . early treatment (within h of onset of symptoms) with oseltamivir or zanamivir is recommended for influenza a (strong recommendation). . oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for > h, but these drugs may be used to reduce viral shedding in hospitalized patients or for influenza pneumonia (moderate recommendation). . parenteral acyclovir is indicated for varicella zoster or herpes simplex virus pneumonia. no antiviral treatment of proven value is available for other viral types of pneumonia. . an increasing greater than % is observed for enterobacteriaceae with esbl especially in patients with recent hospitalization or elderly. ertapenem is a good therapeutic option with good sensitivity. . patients should be switched from intravenous to oral therapy when they hemodynamically stable, are able to ingest medications, and have a normally functioning gastrointestinal tract (strong recommendation). . patients should be discharged as soon as they are clinically stable, inpatient observation while receiving oral therapy is not necessary (moderate recommendation). patients with higher psi risk score take longer to reach clinical stability than do patients at lower risk, so elderly patients with multiple comorbidities generally recover more slowly. appropriate follow-up and rehabilitation planning should be initiated early for these patients. in elderly presented with delirium, its resolution may represent a clinical marker of improvement. . patients with cap should be treated for a minimum of days, should be afebrile for - h, and should have not clinical instability sign no more than one before discontinuation of therapy (moderate recommendation) (waterer et al., ; ramirez et al., ) . . if initial therapy was not active against the identified pathogen or if it was complicated by extrapulmonary infection, a longer duration of therapy may be needed (weak recommendation). criteria for clinical stability is presented in table (arnold et al., ). . most patients with cap have been treated for - days or longer, but few well-controlled studies evaluated the optimal duration of therapy. short-duration may be suboptimal for patients with bacteremic s. aureus or pseudomonas infection. the presence of cavities or other signs of tissue necrosis may require prolonged treatment. other important treatment considerations . patients with cap along with persistent septic shock despite adequate fluid resuscitation should be evaluated for therapy with drotrecogin alfa activated within h of admission (weak recommendation)dadvice patients' groups; patients with septic shock, sepsis-induced leukopenia and organ failure criteria. . hypotensive, fluid-resuscitated patients with severe cap should be screened for adrenal insufficiency (moderate recommendation). stress-dose ( - mg of hydrocortisone per day or equivalent) steroid treatment improves outcomes of vasopressordependent patients with septic shock who have documented inadequate cortisol levels. . patients with hypoxemia or respiratory distress should receive a cautious trial of noninvasive ventilation (niv) unless they require immediate intubation (moderate recommendation). . low-tidal-volume ventilation ( cm /kg of ideal body weight) should be used for patients undergoing ventilation who have diffuse bilateral pneumonia or ards (strong recommendation). . other management protocols of severe sepsis and septic shock in patients with cap do not appear to be different from those patients with other infections. advice for management of nonresponding pneumonia . %- % of hospitalized patients with cap do not respond to the initial antibiotic therapy. mortality among nonresponding patients is increased several-fold according to responding patients. the using a systematic classification for possible causes is recommended (table ) (moderate recommendation). . two patterns of undesirable response are seen in hospitalized patients: the first is progressive pneumonia or clinical deterioration, with acute respiratory failure requiring ventilatory support and/or septic shock, within the first h of hospital admission. the second pattern is that of persistent or nonresponding pneumonia. . nonresponding to antibiotics generally result in three patterns of clinical approachment ( ) transferring of the patient to a higher level of care ( ) further diagnostic testing, and ( ) changing the treatment. firstly, patients with nonresponding or deterioration are reevaluated for initial microbiological results and further history for risk factors for infection with unusual pathogens. blood cultures should be repeated. in % of the patients with cap, the etiology determined by bronchoscopy. rapid urinary antigen test can remain positive for days after initiation of antibiotics and is considered in nonresponding patients an also concomitant or subsequent extrapulmonary infections, such as an intravascular catheter, urinary, abdominal, and skin infections must be kept in mind. . other tests for selected patients with nonresponse: chest ct, bronchoscopy with lavage and transbronchial biopsies and thoracentesis. current international guidelines for cap do not provide specific recommendations for elderly patients but convenience to guidelines was associated with shorter time for clinical stability, shorter length of hospital stay, and lower in-hospital mortality (egger et al., ). an international, multicenter observational study for elderly patients is reported that adherence to the idsa/ats guidelines for hospitalized non-icu elderly patients was cost-effective but was not the most cost-effective strategy in icu patients (faverio et al., ) . in elderly patients, another important issue is age-related changes for antibiotic therapy that modify tolerability, metabolism, excretion of drugs and the risk of drug-drug interactions. in case of qt prolongation or concomitant medication that prolongs qt, using macrolides or fluoroquinolones is not suggested. in elderly, achilles tendon rupture has been reported with fluoroquinolones. with aminoglycosides, nephro and ototoxicity must be kept in mind and presence and degree of renal and/or hepatic failure is always evaluated when choosing the antibiotic treatment (faverio et al., ) . another important risk in the elderly is the frequency of aspiration. risk factors for aspiration pneumonia are age, male gender, neurologic impairment, parkinson's disease, lung disease, diabetes mellitus, malnutrition, periodontal diseases, poor oral hygiene, vomiting, proven dysphagia, proton pump inhibitor, antipsychotic or sedative drug use. diagnosing can be challenging, as a diagnostic tool, fiberoptic endoscopic evaluation of swallowing (fees) can be performed at the bedside. the most common pathogens are oropharyngeal flora including anaerobes, gram-positive cocci, and gram-negative bacilli. antibiotics against indigenous oral flora including anaerobes should be administered and both swallowing rehabilitation and oral healthcare management should be initiated. percutaneous endoscopic gastrostomy (peg) is often performed for preventing aspiration, but there is little evidence to indicate that it prevents pneumonia. a head-up position, by $ degree and mosapride, a gastroprokinetic agent may be preventing gastroesophageal regurgitation and associated aspiration. angiotensinconverting enzyme (ace) inhibitors and cilostazol have been reported effective for prevention of pneumonia, because these medications increase substance p levels in the airways and plasma, improving both swallowing and cough reflexes. for prevention, also anticholinergic agents, tricyclic antidepressants, diuretics, and selective serotonin reuptake inhibitors that which cause dry mouth should be administered cautiously. in elderly patients with pneumonia, the development of cardiac complications was associated with a % increased mortality risk. even only advanced age is associated with higher risk of long term-mortality. other causes of death after following an episode were mainly related to comorbidities, malignancy, copd and vascular diseases. as are cardiovascular and cerebrovascular events, to increase the rehabilitation and nutritional status after a cap could ameliorate physical dysfunction in elderly. the effectiveness of pneumococcal polysaccharide vaccines for prevention of invasive infections among elderly individuals and younger adults have documented with epidemiologic studies. currently, two types of vaccine are available: polyvalent pneumococcal polysaccharide vaccine (ppv )d pneumococcal serotypes includeddand the pneumococcal conjugate vaccines (pcv ). the only difference of pcv is the capsular polysaccharides that conjugated to a carrier protein for enhancement the immunogenicity. pneumococcal vaccine naïve > years old persons should receive a single dose of pcv first, followed by a dose of ppv year later. prior vaccination with ppv at age > years should also receive a dose of pcv if they have not yet received one. a dose of pcv should be given > year after of the most recent ppv dose. in patients who need to repeat ppv , the period between administration of pcv and the new dose of ppv should be at least and years since the most recent dose of ppv . for influenza, chemoprophylaxis can be used as an adjunct treatment to vaccination. oseltamivir and zanamivir are both approved for prophylaxis and may be useful for household exposure to influenza and those who work in institutions with an influenza outbreak (hayden et al., ) . as other preventive measures, modifiable risk factors as reducing or cessation of alcohol consumption, smoking cessation, improving oral hygiene, ensuring good nutritional status, avoiding contact with lower respiratory infections were accepted. cap is the fifth leading cause of death and the most common cause of death from infectious diseases in people aged years and over. s. pneumoniae is still the most common pathogen. elderly patients have a significant number of risk factors associated with higher risk for mdr pathogens. to establish supportive measures, systematic evaluation of cognitive, nutritional (hydration included) and functional status must be an important part of the clinical examination. antimicrobial selection for elderly patients with cap does not differ from that of younger adults. in clinical practice guidelines, early antibiotic administration and strict adherence to the regimes is recommended. it is not appropriate to restrict intensive care and ventilatory support only on the basis of chronologic age. there is no difference for management the patients with hap and vap in this age group. the long-term mortality rate after cap hospitalization is really high in the elderly population. as prevention, immunization measures must be improved. vaccination for pneumococcus and influenza and smoking cessation programs may help for decrease the incidence and severity of cap, especially in this age group. choose the target specific antibiotics associated with hap/vap as narrowly as possible. without risk factors for mdr organisms, empiric therapy should include one antibiotic (against p. aeruginosa, other gram-negative organisms, and methicillin-sensitive s. aureus) suggested agents include piperacillin-tazobactam, cefepime, levofloxacin, imipenem in patients with risk factors for mrsa infection, empiric coverage should include vancomycin or linezolid hap/vap treatment should always include antipseudomonal coverage. dual antipseudomonal agents from different classes are recommended for empiric therapy in patients with a risk factor for mdr gram-negative pathogens. decisions about dual coverage should be individualized there is no difference in regard to mortality, treatment failure, recurrent pneumonia, or duration of mechanical ventilation. a longer duration may be appropriate where the patient may have a delayed clinical response the guidelines recommend that discontinuation of antibiotics be based on clinical criteria and procalcitonin testing preventive measures international guidelines recommend specific measures for preventing pneumonia pneumococcal polysaccharide vaccine is recommended for persons > years of age and for those with selected high-risk concurrent diseases (chronic cardiovascular, pulmonary, renal, or liver disease, diabetes mellitus, alcoholism, asplenia, immunocompromising conditions/medications, long-term care facility residents all persons > years of age, others at risk for influenza complications; high-risk persons with household contacts and health care workers should receive inactivated influenza vaccine (strong recommendation). influenza and pneumococcal vaccines can be given at the same time in different arms vaccination status should be evaluated at hospital admission for all patients, especially those with medical illnesses (moderate recommendation) vaccination may be performed either at hospital discharge or during outpatient status (moderate recommendation) influenza vaccine should be offered to persons at hospital discharge or during outpatient therapy during the fall and winter (strong recommendation) respiratory hygiene measures, including hand hygiene and respiratory masks, should be used in outpatient settings and in emergency departments (strong recommendation) multidrug-resistant pathogens in hospitalized patients coming from the community with pneumonia a european perspective a prospective study of the diagnostic utility of sputum gram stain in pneumonia improving outcomes in elderly patients with community-acquired pneumonia by adhering to national guidelines: community-acquired pneumonia organization international cohort. study results reducing door-to-antibiotic time in 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epidemiology of america guidelines for developing an institutional program to enhance antimicrobial stewardship incidence, direct costs and duration of hospitalization of patients hospitalized with community-acquired pneumonia: a nationwide retrospective claims database analysis key: cord- -xqphom x authors: papanikolaou, ilias c; sharma, om p title: tropical lung diseases date: - - journal: hunter's tropical medicine and emerging infectious disease doi: . /b - - - - . - sha: doc_id: cord_uid: xqphom x nan the term "tropics" refers to the region of the earth lying between the tropic of cancer and the tropic of capricorn. in the tropics, warm climate, poverty, lack of education, and poor sanitation provide an ideal environment for pathogens, vectors and intermediate hosts to flourish [ ] . in this vast landmass, respiratory infections are a major cause of morbidity and mortality in children and adults [ ] . in a typical tropical clinic, - % of outpatients have respiratory complaints, and - % of inpatients have lung disease (table - ) [ ] . many tropical patients suffer from lung diseases that are found worldwide, e.g. asthma, bronchiectasis, chronic obstructive lung disease, hiv infection-related lung disease, and lung cancer. numerous dust diseases, e.g. silicosis, asbestosis, byssinosis, hypersensitivity pneumonitis, and diseases due to microbial contamination of agricultural products, remain under-recognized. diseases associated with pulmonary symptoms and infection that are concentrated in the tropics include malaria, pulmonary schistosomiasis, melioidosis, paragonimiasis, echinococcal cysts, tropical eosinophilia, and diseases related to nutritional deficiencies [ ] . in addition, individuals who come in contact with birds or animals may develop zoonoses such as tularemia, psittacosis, q fever and leptospirosis [ ] . in the tropics, indoor air pollution caused by biomass fuels used for cooking and heating of the homes and huts is an important cause of obstructive lung disease and chronic lung infections [ ] . the following are the common tropical pulmonary conditions: l pneumonia: typical and atypical l eosinophilic pneumonias and tropical pulmonary eosinophilia l bronchiectasis, asthma and chronic obstructive pulmonary disease (copd) l pleural effusion l nontuberculous granulomatous lung disease l occupational lung diseases. a reasonable approach to the patient with lung disease in the tropic starts with age, occupational exposure, physical examination, hiv status, chest x-ray and blood tests. in children, bacterial pneumonia is the most common and life-threatening disorder. known immunodeficiency suggests tuberculosis, fungi and opportunistic pathogens. peripheral blood eosinophilia with either a pleural effusion or diffuse parenchymal consolidation may suggest a parasitic infection, or, when combined with wheezing, tropical pulmonary eosinophilia. worldwide diseases like copd may affect nonsmoking individuals due to indoor pollutants. streptococcus pneumoniae is the most common bacterial cause of pneumonia. upper respiratory involvement often precedes the onset of pneumococcal pneumonia, which is characterized by fever, chills, malaise and sweating. the patient is flushed and febrile with a rapid pulse and respiratory rate. dyspnea is associated with a nonproductive cough, and sputum, if present, may be thick, tenacious or "rusty". severe pleuritic chest pain causing tachypnea and grunting respiration is often present. such symptoms are abrupt in young, immunocompetent patients ( fig. . ) [ ] . in elderly patients, symptoms may be few and can be dominated by confusion, delirium and prostration [ ] . physical examination of the affected lung, usually the lower lobe, reveals diminished lung expansion, impaired percussion note, decreased breath sounds, crepitations (crackles/rales) and bronchial breath sounds. cyanosis is common and a herpes simplex eruption may be seen on the lips. with proper treatment, most patients with pneumococcal pneumonia improve clinically and radiographically within - weeks. when resolution occurs, fever subsides within a week as the temperature decreases following a crisis pattern ( fig. . a) . delayed resolution is seen in smokers, the elderly, and in those with poor nutrition, diabetes or other comorbid illnesses. staphylococcal pneumonia (staphylococcus aureus), accounts for - % of acute community-acquired pneumonias. it is an important cause of pneumonia in children, the elderly, patients recovering from influenza, people with diabetes mellitus, and those who are immunocompromised. methicillin-resistant staphylococcus aureus (mrsa) causes illness in % of cases of upper or lower respiratory tract infection in the community and in % of patients who are hospitalized. patients with staphylococcal pneumonia are usually ill with high fever, shaking chills, chest pain, cough and purulent sputum. chest x-ray films show patchy consolidation and cavities. sputum examination is an important aid in the diagnosis of pneumonia. color, amount, consistency and odor are helpful: mucopurulent sputum is commonly found in bacterial pneumonia or bronchitis; scanty watery sputum is often noted in atypical pneumonia; "rusty" sputum is seen in pneumococcal pneumonia; and currant-jelly or dark-red sputum suggests klebsiella pneumoniae. foul-smelling expectoration is associated with anaerobic infections due to aspiration, ilias c papanikolaou, om p sharma give an inhaled bronchodilator for days* • soothe the throat and relieve the cough with a safe remedy • if coughing for more than weeks or if having recurrent wheezing, refer for assessment for tb or asthma • advise the mother when to return immediately • follow-up in days • if wheezing (even if it disappeared after rapidly acting bronchodilator) give an inhaled bronchodilator for days* • soothe the throat and relieve the cough with a safe remedy • if coughing for more than weeks or if having recurrent wheezing, refer for assessment for tb or asthma • advise the mother when to return immediately • follow-up in days if not improving a blood count usually reveals leukocytosis in bacterial pneumonia, leukopenia in viral infection, and eosinophilia in parasitic infestation. when available, chest x-ray is extremely helpful ( table - ). tuberculosis is omnipresent in the tropics; upper lobe lesions with or without cavities strongly suggest tuberculosis. in children, the integrated management of childhood illness (imci) guidelines for treating pneumonia are recommended (see fig. . ) [ ] . nevertheless, a patient's illness has to be assessed based on geography, prevalence of potential etiologies, virulence of the organism, and the drug sensitivity pattern (box . ). in some areas, particularly papua new guinea, south africa and spain, resistance of the pneumococcus to penicillin is common. for children with non-severe pneumonia, the world health organization (who) recommends oral trimethoprim-sulfamethoxazole (tmp-smx) or oral amoxicillin for days [ ] . in severe pneumonia in hospitalized children, the policy in low-income countries is to first give benzylpenicillin injections, changing the therapy to oral amoxicillin when the child responds. in very severe pneumonia, in children in low-income settings, chloramphenicol may be given first with benzylpenicillin and gentamicin in combination as an alternative [ , ] . atypical pneumonia is caused by mycoplasma pneumoniae, chlamydia pneumoniae, legionella spp., viruses, tuberculosis, fungi and parasites. this syndrome is not extensively studied in the tropics because of the expense involved in culturing and isolating various organisms and obtaining serologic and immunologic tests. mycoplasma pneumoniae infections occur worldwide, affecting mostly school-aged children and young adults. a typical patient with mycoplasma pneumonia is an older child or young adult with an insidious onset of fever, malaise, tightness of the chest, and dry brassy cough. constitutional symptoms are out of proportion to the respiratory symptoms. hemoptysis, pleural pain and gastrointestinal symptoms are uncommon. the tropical physician should be aware of the non-respiratory manifestations of mycoplasma infection, including anemia, myringitis, stevens-johnson syndrome, hepatitis and neuritis [ ] (see table - ). leptospirosis is common in tropical areas where sanitation is poor and water supply primitive. epidemics of leptospirosis occur after high rainfall in monsoon seasons when the water supply is contaminated by sewage or animal urine. about half of the patients with leptospirosis have fever, cough, hemoptysis and pneumonitis [ ] . other features are jaundice, conjunctivitis and impaired renal function. melioidosis, caused by burkholderia pseudomallei, is endemic in southeast asia (vietnam, cambodia, myanmar), northern australia and west africa. melioidosis is hyperendemic in northern australia, and in parts of northeastern thailand it is an important cause of fatal community-acquired pneumonia [ ] . patients become infected while wading through fields, paddies, and flooded roads. clinical presentation is protean and nonspecific. the radiologic picture of upper lobe infiltration and cavity formation can be indistinguishable from tuberculosis [ ] . diagnosis requires isolation of the organism. the mortality rate ranges from % to % but is higher in hivinfected and immunocompromised hosts. respiratory symptoms of cough and chest pain in typhoid are present in up to % of cases at the onset of the disease. pulmonary infiltrates may be associated with positive sputum cultures for salmonella typhi. a fever chart showing continuous fever is highly suggestive of enteric fever. diagnosis may be difficult without blood and stool culture facilities. in brucellosis, the lungs are involved in about % to % of cases, usually following inhalation of organisms. abnormalities include bronchopneumonia, solitary or multiple lung nodes, miliary interstitial lung disease, lung abscess and pleural effusion. organisms can be identified on stains or sputum cultures. tularemia is a generalized infection caused by francisella tularensis and occurs after skin or mucous membrane contact with infected mammals or through the bite of an arthropod, usually a tick or biting fly. diagnosis should be considered in the presence of a skin ulcer associated with fever, generalized lymphadenopathy, cough and signs of pneumonia. pneumonia, either primary from inhalation of an infected aerosol or secondary to systemic infection, occurs in about % of cases. children with malnutrition and edema should be admitted to hospital pneumonic plague is less common than either bubonic or septicemic disease. nevertheless, fatal bronchopneumonia can occur without lymphadenopathy and is characterized by watery, bloody sputum. a sputum gram stain can show bipolar stunted rods. pneumonic plague and tularemic pneumonia should be considered when a severe, rapidly progressive bronchopneumonia is reported in an endemic area, and "typical" bacterial pneumonias have been ruled out. in slaughterhouses, meat-processing plants, and areas with sheep and goat husbandry, q fever (coxiella burnetii) can cause epidemics of atypical pneumonia. inhalation of dried infected material is the chief source, and fever, headache and dry cough are the main symptoms. occasionally, the sputum is blood-streaked. bornholm disease (caused by coxsackieviruses and occasionally other enteroviruses), also known as epidemic pleurodynia or devil's grip, causes chest discomfort and cough. widespread epidemics of bornholm disease occur in the pacific islands and south africa. in - , an unusual coronavirus was responsible for more than cases of a severe acute respiratory syndrome (sars) that spread via international travel across continents from its origin in guandong province, china. the sars coronavirus was previously unknown in humans; a possible reservoir was identified in civet cats and raccoons. after droplet inhalation of the virus, there was an incubation period of - days, then fever, cough, malaise and headache occurred. pulmonary inflammation was characterized by desquamation of pneumocytes, hyaline membrane formation and acute respiratory distress syndrome (ards). the chest x-ray showed diffuse opacities or consolidation, especially in the lower lung fields. recovery could be slow and some patients developed fibrosis. mortality was - %, with the elderly and those with cardiovascular problems being especially at risk. kawasaki disease occurs in children under years of age. this acute multisystem disease of unknown cause is characterized by fever of days duration and four of five clinical features: non-purulent conjunctivitis; injected (or fissured) lips or pharynx or strawberry tongue; cervical adenopathy; a maculopapular rash; and changes in the extremities (erythema and edema of the palms and soles, associated with desquamation). pneumonitis occurs in % of the children and coronary artery dilatation and aneurysms in - % of untreated cases. in brazil there has been a seasonal rise of the condition at the beginning and end of the monsoon season [ ] . cryptococcus neoformans and c. gatti are saprophytic fungi distributed worldwide and are particularly abundant in soil contaminated by pigeon droppings in the tropics as well as in temperate countries. pulmonary infection results from inhalation of the organisms from environmental sources [ ] . systemic helminth infection usually elicits eosinophilia and increased ige. although eosinophilia can be a clue to a pulmonary helminth infestation, the definitive diagnosis requires demonstration of ova or larvae in sputum, bronchial alveolar lavage fluid, pleural fluid or lung biopsy [ ] . loeffler's syndrome refers to "simple" pulmonary eosinophilia with no or minimal systemic and pulmonary symptoms. in many helminth infestations (ascaris, strongyloidiasis, hookworm), the larvae migrate through the lung and can cause fever, cough, dyspnea, wheezing, hemoptysis and lung infiltrate. schistosomes cause two clinical syndromes. in acute disease, immature schistosomula pass through the lung, and can lead to fever, eosinophilia and pulmonary infiltrate. in chronic schistosomiasis, especially when portal hypertension has led to venous shunts, eggs can bypass the liver and plug pulmonary capillaries and arterioles, producing granuloma and pulmonary hypertension. radiographs may show dilated pulmonary arteries ( fig. . ). in paragonimiasis, the lung is the predominantly involved organ. the diagnosis must be considered in a patient from southeast asia with cough, hemoptysis (which is recurrent in > % of cases), a pulmonary cavity and pleural effusion. tropical pulmonary eosinophilia, typically in india and other south asian countries, causes immunologic hyperresponsiveness to wuchereria bancrofti, brugia malayi or other microfilariae. clinical presentation consists of nocturnal cough, wheezing, fever and weight loss. chest radiographs show diffuse interstitial miliary infiltrates ( fig. . ) ; there is a high eosinophil count. in developed countries, serum ige and antifilarial antibodies can be used to confirm the diagnosis (table - ) . bronchiectasis is a chronic, debilitating condition. dilatation and distortion of the airways leads to impaired mucociliary clearance, which encourages bacterial colonization and bronchial inflammation. patients have fever, chronic cough, mucopurulent sputum, hemoptysis (table - ) , wheezing, dyspnea and malaise (box . ) . the primary cause of copd is smoking l copd affects men and women equally l copd is not curable but can be prevented the diagnosis of bronchiectasis in developed countries is confirmed by computed tomography of the chest (fig. . ) ; whereas, in the tropics, the diagnosis is mainly clinical and depends upon a compatible history, presence of finger clubbing, sputum that settles into three layers (mucoid or frothy, mucopurulent, and purulent) and a chest x-ray, if available. treatment includes regular chest percussion, broadspectrum antibiotics for exacerbations, and influenza and pneumococcal vaccinations. the incidence of asthma in the tropics is low for unclear reasons; however, the disease remains underdiagnosed and untreated. "all that wheezes is not asthma" is a dictum that is true in the tropics, as there are many entities that cause wheezing and difficulty in breathing, including tropical eosinophilia and mitral stenosis. asthma monitoring in the tropics can be achieved by using an inexpensive peak flow meter. treatment should fit the frequency and severity of attacks. betaagonists and cromolyn sodium (sodium cromoglycate) are usually available. oral corticosteroids in short courses can be used to control severe episodes; however, long-term use of systemic corticosteroids, without adequate monitoring, is not safe. aerosol inhalers are of great value but they are expensive, difficult to use, and require painstaking teaching. chronic obstructive lung disease is a progressive disease which is characterized by airway obstruction that is only partially reversible by bronchodilator therapy. the term copd encompasses chronic bronchitis and emphysema. once a common disease of men, copd is now as frequent in women because of increased tobacco use and the widespread use of dung and biomass for indoor cooking and heating in low-income countries (box . ) . the most common symptoms are dyspnea and chronic cough. it is mild and occurs only on heavy exertion. with progression of airway obstruction, patients become more short of breath and eventually cannot breathe at rest. physical examination in the early stage is normal, but in advanced disease, prolonged expiration and expiratory wheezes are audible. in severe cases, the thoracic cage becomes barrelshaped with increased anterior-posterior diameter; percussion note is hyperresonant. when chest x-ray and pulmonary function testing are not available, a peak-flow meter is an inexpensive device to assess severity of airway obstruction and monitor the response to treatment. cessation of smoking is essential. oral theophylline and beta-agonist drugs control symptoms. antibiotics (ampicillin, tetracycline and sulfa drugs) are available to treat copd exacerbations in the tropics. pleural effusion is a frequent condition with variable clinical signs and symptoms. small effusions can remain silent and are often detected only on chest radiography. large effusions are associated with dyspnea and diminished chest movements on the affected side. vocal fremitus is reduced; percussion note is stony dull; and auscultation reveals diminished breath sounds and decreased vocal resonance. sometimes, bronchial breathing is heard at the upper level of dullness. in addition there may be a pleural friction sound. exudative effusions typically have cell counts, protein and biochemical markers opposite to those of transudates. exudates can be further classified into neutrophilic, lymphocytic and eosinophilic. neutrophilic exudates may be due to bacterial infection, gastrointestinal diseases, pulmonary embolism, collagen-vascular diseases (cvd) and asbestos-related benign effusion. pleural effusion occurs in about % cases of pneumonia, and can progress to a complicated effusion (pleural fluid ph< . , positive gram stain) or to an empyema, both necessitating pleural fluid drainage with a chest tube thoracostomy in addition to antibiotic treatment. empyema can occur in pneumococcal, staphylococcal (most often) and klebsiella infections. a right-sided pleural effusion may be associated with amebic liver abscess. the disease presenting with the highest pleural fluid lymphocytosis is tuberculous pleuritis; however, early in the course, there can be a neutrophilic exudate. a large volume of pleural fluid should be obtained for examination for acid-fast bacilli. in about one-third of cases, the tuberculin skin test is negative initially and converts to positive after - weeks. knowledge of the hiv status of a patient with pleural effusion, if positive, significantly inclines to a tuberculosis. an eosinophilic exudate is more common in the tropics. endemic parasitic and fungal infections are major causes of such an effusion. ascariasis, echinococcosis and paragonimiasis are some of the causative parasitic infections. paragonimiasis is associated with low pleural fluid glucose and low ph. fungal diseases responsible for such an effusion are histoplasmosis, cryptococcosis and coccidioidomycosis. in the absence of chest x-ray or biopsy evidence, it is not possible to diagnose pulmonary involvement due to sarcoidosis and other granulomatous diseases. consequently, in the tropics, these disorders remain undiagnosed. the possibility of sarcoidosis should be considered in a patient with dyspnea, uveitis, hepatosplenomegaly, peripheral lymphadenopathy, chronic skin lesions, and a chest x-ray film showing bilateral hilar adenopathy [ ] . the occupational disorders result from human social activity, and as such are preventable. the dusts that provoke occupational disorders can be classified into: those that induce granulomatous reaction (e.g. beryllium, talc and organic antigens); those that cause fibrosis (e.g. silica, asbestos and coal); and those that cause neither inflammation nor fibrosis, thus remaining inert (e.g. iron, barium and tin) ( podoconiosis is an endemic nonfilarial elephantiasis occurring in individuals exposed to red clay soil derived from alkaline rock. a chronic and debilitating disease, it exerts a large economic burden. the silica particles are found in the skin, lymph nodes and lymphatics of affected and unaffected individuals. these individuals have reduced lung function as compared with adults living in areas of low silica concentration [ ] . immunological aspects of tropical lung disease pneumonia: the forgotten killer of children. geneva: unicef/ who parasitic lung infections tropical infections and the lung pulmonary disease world health organization, family and community health cluster, department of child and adolescent health and development. consultative meeting to review evidence and research priorities in the management of acute respiratory infections (ari) influence of age on symptoms and presentation in patients with community acquired pneumonia integrated management of childhood illness (imci) for high hiv settings clinical efficacy of co-trimoxazole versus amoxicillin twice daily for treatment of pneumonia: a randomised controlled clinical trial in pakistan chloramphenicol alone versus chloramphenicol plus penicillin for severe pneumonia in children chloramphenicol versus benzylpenicillin and gentamicin for the treatment of severe pneumonia in children in papua new guinea: a randomised trial approach to the patient with tropical pulmonary disease pulmonary complications of leptospirosis the epidemiology of melioidosis in australia and papua new guinea melioidosis after brief exposure: a serological survey in us marines kawasaki disease: a clinical and epidemiological study of children in brazil lung biology in health and disease: tropical lung disease lung biology in health and disease: tropical lung disease assessment of respiratory function in patients with podoconiosis key: cord- -fffjcnak authors: waterer, grant title: respiratory infections in the asia‐pacific region: problems and cautious optimism date: - - journal: respirology doi: . /resp. sha: doc_id: cord_uid: fffjcnak nan over the past months, respirology has published a series of excellent reviews outlining the challenges that respiratory infections continue to pose to the asia-pacific region and beyond. the world of respiratory infection is an ever-moving landscape as we develop new strategies to target pathogens and in return existing pathogens adapt and new pathogens arise. equally, we are becoming more and more aware that respiratory infections not only pose acute health emergencies but also contribute substantially to adverse long-term health outcomes. tuberculosis is possibly the largest killer of human beings in history. while it is generally well-controlled since the s in most western countries, as dheda et al. pointed out in their review, the explosion of drugresistant tuberculosis has undermined control efforts in large areas of africa and the asian sub-continent and is now responsible for more than % of deaths. spread of multidrug-and extensive drug-resistant tuberculosis poses a global threat to health. new drugs such as bedaquiline and delamanid have been developed, but the sustained effectiveness of these antibiotics is threatened by haphazard use and, therefore, how, when and to whom they should be given is a major area of current controversy. dheda et al. argue that the outcomes from treatment of multidrug-resistant (mdr) tuberculosis are so poor that it may be unethical to withhold bedaquiline regardless of concerns about the development of resistance. equally, they argue that more resources are desperately needed to adequately control tuberculosis, and especially drug-resistant diseases, in the developing world. in contrast to a developing world problem, rodrigo-troyano and sibila reviewed the increasing problem of mdr gram-negative bacteria (mdr-gnb). this problem is mostly seen in the tertiary settings of more advanced economies. rather than poverty, malnutrition and overcrowding driving the problem as with tuberculosis, frequent use and misuse of broadspectrum antibiotics in patients with a fundamental inability to resist infection (such as in those with severe chronic obstructive airway disease, bronchiectasis, cystic fibrosis or major organ failure requiring prolonged stays in intensive care units) are responsible for mdr-gnb. as rodrigo-troyano and sibila point out, unlike tuberculosis, there has been very little progress in antibiotic development for mdr-gnb and case reports are increasing for pan-resistant organisms immune to all known therapies. while newer antibiotics are desperately needed, important factors that rodrigo-troyano and sibila did not focus on are the key role of effective antibiotic stewardship , and appropriate end-of-life care , in reducing the selective pressure for mdr pathogens. the asia-pacific is a region with diverse people, cultures and climates, and therefore, different respiratory infection challenges were touched on by several reviews and especially that by shindo and hasegawa. they point out that the prevalence of drug-resistant pathogens in patients with pneumonia has an enormous variability within our region, ranging from % to % in published studies. with such a range, reliance on guidelines published in other countries without consideration of local aetiology is a recipe for disaster. aston also pointed out that the syndrome of pneumonia needs a very different approach in developing economies compared with developed ones. first, the possibility of tuberculosis and/or human immunodeficiency virus infection, not usually major factors in developed economies, is always a potential problem. second, many of the tools for treating pneumonia in developed economies have not been tested in developing countries. lim and siow further noted that in addition to tuberculosis, in tropical countries, the spectrum of pathogens with pneumonia includes diseases such as scrub typhus, leptospirosis, chikungunya and dengue as well as parasitic pneumonias. overall, there is a very strong message that clinicians must be aware of what causes pneumonia in their local area and not rely on guidelines from elsewhere. even in developed economies, there may be subgroups of the population at risk of a different spectrum of respiratory infections. basnayake et al. highlight this fact by pointing out the very high rate of bronchiectasis in indigenous populations. a major factor in the high rates of bronchiectasis in indigenous people is the greater burden of respiratory infection, especially pneumonia, related to relative economic and social deprivation compared with the rest of the population. good examples of new pathogens threatening the global scene were covered in two reviews. hui et al. reviewed the current data on emerging influenza viruses in the asia-pacific region, especially avian influenza. yin and wunderink covered the severe coronavirus infections, middle east respiratory syndrome and severe acute respiratory syndrome. both these reviews have important lessons of how we need to approach and manage inevitable future viral pandemics. two reviews focused on improving patient outcomes from pneumonia. hadfield and bennett argued that there is now a well-defined bundle of care associated with best patient outcomes that includes rapid, guideline-concordant antibiotics, probably the combination of a beta-lactam and a macrolide, early treatment of co-morbidities including glucose and electrolyte stabilization, adequate venous thromboprophylaxis and early mobilization. mecham et al. explored the increasing use of technology to improve patient outcomes, especially clinical decision support tools. while a number of problems and barriers for widespread adoption of technology are discussed, the authors paint an optimistic picture of computer-aided decision-making reducing clinical variation and improving patient outcomes. the long-term adverse health outcomes from pneumonia are increasingly being recognized and reported. in their review, restrepo and reyes outline the extensive literature on excessive cardiovascular disease in patients with community-acquired pneumonia (cap). this is an area in need of urgent research to define therapies to reduce the long-term morbidity and mortality in cap survivors. amongst the general concern about developing antibiotic resistance and the emergence of new threats, finch et al. also paint an optimistic picture of significant advances in our understanding of the pathobiology of infectious diseases over the past decade and the promise of what is to come over the next one. in particular, they argue that the 'omics revolution' is beginning to unlock our understanding of host-pathogen interactions to a level where new therapeutic strategies are emerging. i hope that readers have enjoyed this series as much as i have and that as well as providing new clinical insights, the many observations the authors have made about the gaps in our knowledge have provided new ideas and challenges for researchers. we all hope that the optimism of finch et al. and mecham et al. will be realized and help us meet the challenge of what nature will come up with over the coming decades. grant waterer, mbbs, phd school of medicine, university of western australia, perth, wa, australia epidemiology: a mortal foe recent controversies about mdr and xdr-tb: global implementation of the who shorter mdr-tb regimen and bedaquiline for all with mdr-tb? world health organisation. global tuberculosis report . world health organisation the respiratory threat posed by multidrug resistant gram-negative bacteria development of antibiotic treatment algorithms based on local ecology and respiratory surveillance cultures to restrict the use of broad-spectrum antimicrobial drugs in the treatment of hospital-acquired pneumonia in the intensive care unit: a retrospective analysis longterm impact of an educational antimicrobial stewardship program on hospital-acquired candidemia and multidrug-resistant bloodstream infections: a quasi-experimental study of interrupted timeseries analysis end-of-life treatment and bacterial antibiotic resistance: a potential association ethical issues relating to the use of antimicrobial therapy in older adults regional differences in antibiotic-resistant pathogens in patients with pneumonia: implications for clinicians pneumonia in the developing world: characteristic features and approach to management pneumonia in the tropics the global burden of respiratory infections in indigenous children and adults: a review a clinical approach to the threat of emerging influenza viruses in the asia-pacific region sars and other coronaviruses as causes of pneumonia determining best outcomes from community-acquired pneumonia and how to achieve them community-acquired pneumonia management and outcomes in the era of health information technology pneumonia as a cardiovascular disease the past decade in bench research into pulmonary infectious diseases: what do clinicians need to know? key: cord- -ia i svg authors: larici, anna rita; cicchetti, giuseppe; marano, riccardo; merlino, biagio; elia, lorenzo; calandriello, lucio; del ciello, annemilia; farchione, alessandra; savino, giancarlo; infante, amato; larosa, luigi; colosimo, cesare; manfredi, riccardo; natale, luigi title: multimodality imaging of covid- pneumonia: from diagnosis to follow-up. a comprehensive review date: - - journal: eur j radiol doi: . /j.ejrad. . sha: doc_id: cord_uid: ia i svg due to its pandemic diffusion, sars-cov- (severe acute respiratory syndrome coronavirus ) infection represents a global threat. despite a multiorgan involvement has been described, pneumonia is the most common manifestation of covid- (coronavirus disease ) and it is associated with a high morbidity and a considerable mortality. especially in the areas with high disease burden, chest imaging plays a crucial role to speed up the diagnostic process and to aid the patient management. the purpose of this comprehensive review is to understand the diagnostic capabilities and limitations of chest x-ray (cxr) and high-resolution computed tomography (hrct) in defining the common imaging features of covid- pneumonia and correlating them with the underlying pathogenic mechanisms. the evolution of lung abnormalities over time, the uncommon findings, the possible complications, and the main differential diagnosis occurring in the pandemic phase of sars-cov- infection are also discussed. as suggested in the recently published who (world health organization) advice guide for the diagnosis and management of covid- , chest imaging should be used for diagnostic purpose in symptomatic patients if rt-pcr is not available or its results are delayed, or in case of negative result in the presence of a high clinical suspicion of covid- [ ] . cxr and ct are the imaging procedures generally performed in the diagnosis of covid- pneumonia. in this clinical setting, cxr is of easy use and is usually performed in the anteroposterior (ap) projection and in the supine position, using mobile cxr units in a dedicated and isolated room to reduce the risk of infection spreading [ , ] . chest ct is performed with the high-resolution (hrct) technique, using thin sections (< . mm) and high-spatial resolution kernel to enhance lung parenchymal anatomical details, usually without contrast medium injection. however, evidences suggest a predisposition to thrombotic and thromboembolic disease in these patients [ ] , with pulmonary embolism (pe) being a known epiphenomenon of covid- syndrome [ ] . therefore, in the appropriate clinical setting, contrast medium injection is required to rule out pe. the reported sensitivity of cxr for covid- pneumonia is relatively low in the early phase of the disease and in mild cases and it is inferior to that of rt-pcr essay at baseline ( % versus %, respectively) [ ] . the rate of negative cxr at baseline tends to decrease when the interval time between the onset of symptoms and the cxr increases. in a retrospective study of symptomatic patients with covid- infection confirmed by rt-pcr, the rate of negative cxr was . % at - days after the onset of symptoms and . % at > days [ ] . the diagnostic performance of cxr increases in clinical settings with high prevalence of disease as described by schiaffino et al. in their experience based on real-life reporting without independent image review during covid- outbreak in northern italy [ ] . cxr at admission to the emergency department showed a sensitivity of . % ( % ci, . %- . %) and a specificity of . % ( % ci: . %- . %) [ ] . therefore, bedside cxr -performed in the isolated rooms -can be efficiently used as first-line imaging modality in areas with high levels of contagion and high pre-test probability of disease, particularly in cases of shortage of rt-chest ct and rt-pcr were % ( % ci: - %) and % ( % ci: - %), respectively, for the diagnosis of covid- pneumonia [ ] . in another meta-analysis [ ] , a pooled sensitivity of % ( % ci: - %) was reported for ct in detecting covid- among studies from different areas of china; the pooled sensitivity of ct was even higher (up to %) in the region with more severe epidemic. based on its high sensitivity, ct has been proposed as the primary diagnostic tool in epidemic areas, in order to early recognize suspicious cases and possibly limit the spread of infection. however, a more recent meta-analysis including studies with patients underlined that the sensitivity of ct significantly decreases from % to % when studies with low risk of biases are included [ ] . furthermore, the possibility that ct can be normal within the first days from the onset of symptoms (day - ) in up to % of cases should be taken into consideration when assessing patients with suspected covid- pneumonia [ ] . ct can also detect abnormalities in asymptomatic patients, with a rate of %, according to inui s. et al. [ ] . the reported specificity of ct is moderate to low; it was only % ( % ci: - %) in the meta-analysis by kim et al. [ ] . the same authors observed that in regions with a prevalence of disease < %, the ppv of rt-pcr was more than ten times higher than that of ct, meaning that applying ct as a screening tool in these areas could potentially lead to a large number of false-positive results, with an unjustified increase in medical costs [ ] . due to the abovementioned limitations, some authors suggest considering ct as a supplemental diagnostic tool, especially in symptomatic patients [ ] . apart from recognizing covid- pneumonia features, imaging -especially ct -may reveal possible alternative diagnoses (e.g. pulmonary oedema, alveolar haemorrhage, other type of lung infections) that justify patient's respiratory symptoms [ , ] . the rule-out role of ct is also highlighted by the recent fleischner society consensus statement, particularly in patients manifesting with moderate-to-severe symptoms and a negative or ongoing rt-pcr test [ ] . the who advice guide also underlined that the use of chest ct is particularly helpful in patients with known pre-existing pulmonary diseases [ ] . in order to standardize the level of suspicion of covid- pneumonia on ct scans, a categorical assessment scheme, the covid- reporting and data system (co-rads) has been proposed, with levels ranging from very low (co-rads category ) to very high suspicion (co-rads category ), with a co-rads category reserved for rt-pcr proven cases [ ] . imaging also plays a role in prognostic assessment and patient stratification in covid- pneumonia. some cxr scoring systems have been recently developed to answer these needs in the clinical practice with interesting results [ , ] . in particular, higher disease scores at baseline have been associated to hospitalization, requirement for mechanical ventilation [ ] and in-hospital mortality [ ] . similarly, categorization and quantification of hrct abnormalities in covid- pneumonia have been demonstrated to correlate with development of severe disease course [ , ] , icu admission [ , ] , and in-hospital mortality [ ] . particularly, colombi et al. [ ] demonstrated that patients requiring icu admission or deceased have higher parenchymal involvement ( or more lobes) and show less aerated lung parenchyma on baseline hrct compared to the other patients. the importance of chest imaging to assess disease evolution is also unquestioned. in patients requiring hospitalization, cxr is essential in guiding clinical management, as the serial evaluation allows an adequate assessment of the evolution of findings, avoiding unnecessary radiation exposures. this is especially true in critically ill patients [ ] (fig. ) , or during regression of symptoms in favourable cases. for a late follow-up, hrct is the modality of choice, particularly in assessing eventual persistent or fibrotic lung abnormalities. lastly, imaging is essential in the early detection of complications, such as barotrauma, superimposed bacterial lung infections and empyema. ground glass (gg) opacities, a crazy paving pattern characterized by gg opacities with superimposed septal thickening, and consolidations are common hrct findings in patients with covid- pneumonia [ ] (fig. ) . incidence of these findings varies among different studied populations. in a recently published meta-analysis comprising patients, gg opacities, a combination of gg opacities and consolidations, and crazy paving have been reported in . %, . %, and . % of cases, respectively [ ] . the distribution of the above reported findings is usually bilateral and multilobar with a predominant involvement of subpleural/peripheral and posterior regions of the lungs [ ] . similar findings of gg, interstitial opacities and areas of consolidation with a peripheral and mid-basal distribution can be observed on cxr [ ] (fig. ). these imaging findings are the expression of a condition of acute lung injury (ali), the main pathological pattern of the pulmonary damage caused by sars-cov- , that presents with a wide spectrum of histologic patterns ranging from diffuse alveolar damage (dad) with hyaline membrane formation to organizing pneumonia (op) [ ] [ ] [ ] . the predominant pathogenic mechanism of ali induced by sars-cov- infection and shared by other coronaviruses is the angiotensin-converting enzyme (ace ) downregulation [ , ] , which results in excessive inflammatory cytokine release ("cytokine storm") leading to apoptosis of epithelial and endothelial lung cells [ ] . direct infection of the endothelial cells and diffuse endotheliitis have been also described in several organs of covid- patients, included the lungs, with subsequent oedema and parenchymal ischemia due to microvascular dysfunction [ ] . furthermore, a generalized microthrombotic injury, mediated by activation of complement pathways, has been observed within the lung microvasculature in pathologic specimens from patients deceased with severe covid- pneumonia [ ] . based on these observations, microthrombosis and diffuse vascular lung injury might have a role in the pathogenesis of covid- pneumonia, at least in severe and critically ill cases [ ] . it has also been assumed that in some patients the parenchymal abnormalities seen at hrct might be associated not only to inflammation or atelectasis, but also to ischemic and/or necrotic changes caused by perfusion defects [ , ] . the evolution of dad is characterized by three sequential phases [ ] . the first phase, or exudative phase, consists of interstitial and alveolar oedema, haemorrhage, and hyaline membrane formation, with alveolar obliteration and thickening of the inter-and intralobular septa; it has a duration of approximately days. the second phase, or proliferative phase, consists of fibroblast proliferation within the interstitium and the alveoli, with appearance of op foci, parenchymal remodelling and formation of reversible traction bronchiectasis and bronchiolectasis. the last fibrotic phase is characterized by collagen deposition with progressive and variable degree of fibrotic changes and usually starts weeks after the lung injury [ ] ; it is potentially reversible in mild to moderate cases. similarly, progressive temporal stages of hrct findings can be recognized in patients with covid- pneumonia. pan et al. have described stages from initial diagnosis until patient recovery; these include an early stage, between and days from the onset of symptoms, an intermediate progressive stage ( - days) and a peak stage, between and days [ ] . starting from weeks after the onset of symptoms, a gradual progressive resolution of the hrct findings can be observed (absorption stage) [ ] . wang et al. confirmed this evolution, even though in their experience the absorption phase was delayed, probably because patients with more severe disease were included in their study [ ] . a roughly similar appearance of the lung abnormalities in the different phases of the disease is appreciable also on cxr, even though with the intrinsic limitations of this imaging modality. the early stage is generally characterized by the presence of gg opacities, with the typical bilateral and multilobar distribution [ , ] ; consolidations are possible, but have been described only in a minority of patients. enlargement (greater than mm in diameter) of subsegmental pulmonary vessels within the areas of gg has also been described in the early phase of covid- pneumonia in up to % of cases [ , , , ] . the aetiology of this sign is not well defined yet, although it could be related to hyperaemia and vessel wall damage induced by pro-inflammatory factors [ ] or small vessel thrombosis. some authors have indicated that this sign might be helpful in the differential diagnosis between covid- and other viral pneumonia, even though it has been described in % of patients with other viral non-covid- pneumonia [ ] . with progressive replacement of gg opacities by consolidation, the caliber of the subsegmental pulmonary vessel returns normal. it is worth noting that maximum intensity projection (mip) reconstructions usually enhance and facilitate the identification of this sign and its evolution over time (fig. ). the progressive stage of covid- pneumonia is characterized by a more extensive lung involvement and more varied imaging features [ , ] . gg opacities increase in density and can appear diffuse or with a crazy paving pattern on hrct. consolidations can progressively develop in the areas of gg or increase in size and number respect to previous hrct scans [ ] . usually, in this phase, consolidations show patchy subpleural and peribronchovascolar distribution, which is the common appearance of the op pattern [ ] associated with the proliferative phase of dad [ , ] . similar changes are detectable also on cxr, confirming its role in identifying the temporal evolution of covid- pneumonia till the improvement ( figures , ) . the maximum disease burden is usually observed days after the onset of symptoms (peak or severe stage). at this stage other well-known hrct findings, such as reversed halo sign, band-like opacities and perilobular opacities appear [ ] . traction bronchiectasis and bronchiolectasis might be visible in this phase as ancillary findings within the consolidations, due to parenchymal remodelling (fig. ). in patients developing acute respiratory distress syndrome (ards), covid- pneumonia has an unfavourable prognosis [ , ] . in these patients, ards shows an atypical dissociation between the relatively low impairment of the lung mechanics and the severe hypoxemia [ ] , probably due to the concomitant microvascular injury that characterizes covid- [ ] . the absorption stage is characterized by a progressive clearance of the lungs over time. this stage may have quite long temporal course, with gg opacities, linear scarring and mild residual consolidations, still evident on hrct after weeks from the onset of symptoms [ ] ( fig. ) . in this phase, a decrease in density of the opacities associated with a more extensive involvement of the lung has been described (the so called "tinted" sign), possibly due to the gradual resolution of the inflammation and progressive alveolar re-expansion [ ] (fig. ) . traction bronchiectasis and bronchiolectasis tend to disappear with complete resolution of the opacities. the time required for the complete clearance of lung abnormalities may reflect the severity and the extent of lung involvement. a prompt treatment of covid- pneumonia has been correlated with a more rapid clearance of the hrct findings [ ] . however, it must be pointed out that lung abnormalities can be seen on hrct even in presence of complete clinical recovery and negative rt-pcr swab test [ ] (fig. ) . due to the young history of this outbreak, data about the morphological characteristics and potential long-term lung abnormalities in survivors from clinically significant covid- disease are lacking [ ] . however, the evolution of dad, particularly in patients who recovered after full-blown ards [ ] , may lead to lung fibrosis [ ] , which has been demonstrated on covid- pneumonia pathological specimens [ ] . therefore, a clinical and radiological follow-up might be required in order to identify and monitor potentially progressive lung fibrotic changes with the typical hrct findings of irregular interstitial thickening, traction bronchiectasis/ bronchiolectasis, coarse reticulation, and parenchymal bands [ ] . the duration and timing of follow-up with ct scans have not been defined yet. although the majority of patients present with common findings and typical manifestations of covid- pneumonia, uncommon features and atypical presentations are possible and can potentially represent a diagnostic challenge [ ] . variable rates of possible uncommon findings in different patient populations have been reported. in this section, the results of recent systematic reviews and meta-analyses are presented [ ] [ ] [ ] . when considering the distribution of parenchymal abnormalities, unilateral lesions can be observed, especially immediately after the onset of symptoms or in pauci/asymptomatic patients [ , ] and has been described in . % of cases in a meta-analysis of studies including patients [ ] . in the same meta-analysis, involvement of a single lobe and predominant involvement of the anterior lung zone with relative sparing of the posterior ones have been reported in . % and . % of cases, respectively [ ] . a peribronchovascular distribution of lung abnormalities has been found in only . % of patients among studies [ ] . when considering the lesion shape, a multifocal nodular appearance, usually with irregular margins or surrounded by peripheral gg, has been documented in . % in a meta-analysis of studies including patients [ ] . enlargement of mediastinal lymph nodes has been reported in . - . % of cases [ ] [ ] [ ] in patients with severe disease and extensive bilateral consolidative changes. the presence of lymph node enlargement has been associated with disease severity and poor prognosis. indeed, lymphadenopathies have been observed in a significantly higher number of patients ( %) with unfavorable course of disease during hospitalization than in those discharged ( %), according to a single center study on a cohort of patients [ ] . among the uncommon findings, the occurrence of pleural effusion has been found in about % of cases [ ] [ ] [ ] , while pleural thickening adjacent to the parenchymal opacities is far more common [ ] . pericardial effusion has also been rarely reported, with a pooled prevalence between . % and . % [ , ] . it is worth of note that the presence of pleural and/or pericardial effusion has been related with severe clinical course and poor prognosis of covid- pneumonia [ ] . another uncommon hrct feature related to severe disease [ ] is the evidence of bronchial wall thickening within the lung opacities, described in . % of cases [ ] , and possibly j o u r n a l p r e -p r o o f related to inflammatory bronchial wall damage and peribronchovascular interstitial oedema. hrct findings associated with small airways disease, such as endobronchial secretions and tree-in-bud opacities, have been described in a relatively small percentage of cases ( . %) [ ] . cavitation is the least common finding of covid- pneumonia, with a reported pooled prevalence of only . % [ ] . apart from the uncommon findings associated with covid- pneumonia, it should be noted that pre-existing underlying pulmonary diseases, such as fibrosis and emphysema, may lead to atypical hrct presentations of covid- pneumonia [ ] . in case of honeycombing or paraseptal emphysema, the typical subpleural distribution may be absent (fig. ) . the occurrence of gg opacities or consolidations superimposed on extensive background emphysema may lead to a "bubble-like" appearance, which could be misinterpreted as lung cysts or cavitation and lead to erroneous ruling-out of covid- . on the other hand, in case of typical findings of covid- pneumonia, detection of cystic changes within a focal peripheral gg or consolidation area on hrct should raise the possibility of a concurrent lung adenocarcinoma, especially if other red flags (e.g. spiculated margins, pleural retraction) associated with malignancies are evident (fig. ) . severely ill patients are more prone to develop complications. pneumothorax is one of these, reported in % of cases according to chen et al. [ ] and usually occurring in case of rupture of subpleural bullae [ ] . in the clinical context of covid- , pneumothorax may be spontaneous, with prolonged cough and respiratory distress as known risk factors, or due to barotrauma in patients requiring mechanical ventilation. pneumomediastinum may also occur as a consequence of increased intrathoracic pressure with rupture of the alveoli, followed by air dissection through the bronchovascular bundles into the mediastinum (macklin's effect) [ ] . subcutaneous emphysema may also be associated. such complications must be suspected in case of sudden clinical deterioration with rapid oxygen desaturation (fig. ) . mcguinness et al. reported an incidence of barotrauma of % among covid- patients requiring invasive mechanical ventilation, an incidence that was higher than the overall rate of % noted in their retrospective cohort of ards cases [ ] . the occurrence of pe has been frequently demonstrated in patients affected by covid- , particularly in those with more severe symptoms, and it has been considered as a part of the disease rather than a true complication [ ] (fig. ) , with an incidence of - % according to different series [ , [ ] [ ] [ ] [ ] . based on the above, it might be potentially reasonable to perform ct scans with contrast administration in all confirmed cases of covid- to assess pulmonary vessels and detect eventual arterial filling defects and lung perfusion defects on iodine map, if using a dual-source ct scanner in dual-energy mode [ ] . however, in the clinical practice, the current trend is to perform ct pulmonary angiogram in cases of suspected pe due to clinical worsening, not explained by an increase of parenchymal disease burden at imaging. other possible complications are bacterial infections, which should be suspected in case of appearance of multiple centrilobular nodules with or without tree-in-bud opacities, and eventual cavitation within areas of consolidation superimposed to covid- pneumonia lung abnormalities (fig. ). although in the context of the current pandemic the imaging findings described in the previous sections of this review can be indicative of covid- pneumonia in areas with high prevalence of the disease, they lack in specificity and a number of disease processes both infectious and non-infectious should be considered in the differential diagnosis, as parekh et al. have described in their recently published comprehensive review [ ] . in our experience at a large tertiary metropolitan hospital in rome during the outbreak in italy, patients with symptoms suggestive of covid- pneumonia were admitted to the emergency department between march and april , . among them, presented imaging findings indeterminate for covid- or suggestive of an alternative diagnosis at the baseline cxr and underwent chest ct scanning; these patients also presented with two consecutive rt-pcr tests negative for sars-cov- . in a retrospective evaluation of the final diagnosis, infectious diseases were present in . % of our patients ( / ), with the majority caused by bacteria ( . %), followed by indeterminate community-acquired pneumonia (cap) ( . %), viruses ( . %) and atypical pathogens ( . %). among the remaining patients with non-infectious diseases, pulmonary oedema was observed in j o u r n a l p r e -p r o o f ( . %), followed by thoracic neoplasms ( . %) (progression and/or first diagnosis of primary lung cancer; metastases due to extrathoracic neoplasms), acute exacerbation of ild (interstitial lung disease) ( . %), aspiration ( . %), ascertained drug toxicity ( . %), alveolar proteinosis ( . %), lipoid pneumonia ( . %) and diffuse alveolar hemorrhage ( . %). the most relevant cxr and hcrt findings of possible differential diagnosis among infectious and non-infectious diseases at the time of the outbreak of covid- are summarized in the table . lower respiratory tract infections and cap represent the most likely diagnosis in patients with fever, cough and dyspnoea, which are also common symptoms of covid- pneumonia. bacteria and viruses are the usual causative agents of cap, even if a definite microorganism is identified in only % to % of cases [ ] [ ] [ ] . bacterial pneumonia shows three possible patterns at imaging: lobar pneumonia, bronchopneumonia and interstitial pneumonia [ ] . when a lobar pneumonia pattern is identified, the diagnosis is relatively simple and covid- pneumonia can be reasonably excluded on the basis of radiological findings. lobar pneumonia is characterized by a homogeneous lobar or nonsegmental opacity or consolidation, with or without air bronchogram, involving predominantly or exclusively one lobe. the abnormality is commonly confined by the fissure and the lung volume is preserved (fig. ) . streptococcus pneumoniae, legionella pneumophila and mycoplasma pneumoniae are the most common bacteria responsible of a lobar pneumonia [ ] . associated findings and/or complications include parapneumonic pleural effusion, empyema, cavitation, and lung abscess formation [ , ] . the unilobar distribution and the presence of associated findings are helpful in differentiating a bacterial pneumonia from covid- . in case of a bronchopneumonia pattern, the causative agent leads to bronchial epithelium inflammation, with ulcerations and fibrinopurulent exudate formation and spreading through the airways' walls and adjacent pulmonary lobules [ ] . cxr shows multifocal patchy nodules and confluent opacities without air bronchogram. characteristic hrct findings are patchy nodules with centrilobular distribution and tree-in-bud appearance, confluent peribronchial focal consolidation without air bronchogram and lobular gg areas, associated with bronchial wall thickening and mucoid impaction. these features, commonly associated with staphylococcus aureus and gram-negative bacteria (pseudomonas aeruginosa, klebsiella j o u r n a l p r e -p r o o f pneumoniae, haemophilus influenzae) pneumonias, are highly suggestive of aerogenous spread of infection [ , ] . this behaviour is in contrast to covid- pneumonia, which shows a prevalent subpleural distribution of findings, absence of tree-in-bud opacities and it is rarely associated with airways involvement. lastly, an interstitial pneumonia pattern can be caused by mycoplasma pneumoniae and other atypical agents, which determine direct damage of the bronchioles mucosa and subsequent inflammation and oedema of the peribronchial interstitium and interlobular septa. cxr shows peribronchial thickening and bilateral interstitial and/or interstitial-alveolar opacities [ ] that may mimic covid- pneumonia. hrct shows patchy lobular gg opacities and/or consolidation, centrilobular nodules, and thickening of the peribronchovascular interstitium. single lobe involvement, the presence of centrilobular nodules and thickening of the peribronchovascular bundles are common findings in patients with mycoplasma pneumonia and might help in the differential diagnosis with covid- pneumonia [ ] (fig. ) . a wide range of respiratory viruses is responsible for the development of pneumonia [ ] . depending on the pathogenesis of the infection and on the causative agent, viral pneumonia can show different imaging patterns [ ] . for this reason, despite a certain degree of overlap, the awareness of the underlined pathogenic mechanisms is crucial to understand imaging findings and to address differential diagnosis when possible. three main different imaging patterns have been associated with viral infections: nodular/micronodular pattern, bronchiolar pattern and interstitial pattern [ ] . the nodular/micronodular pattern is characterized by bilateral scattered multifocal nodules with well-or ill-defined margins and possible gg appearance, and it is usually determined by haematogenous viral spread to the alveoli, such as in varicella-zoster virus (vzv) pneumonia. the bronchiolar pattern shows an airway-centred distribution, with centrilobular nodules, treein-bud opacities and bronchial wall thickening, with or without peribronchovascular gg opacities and small consolidations, not dissimilar from bacterial bronchopneumonia. this pattern is due to destruction of bronchial and alveolar wall, determining small airway obstruction. it is typical of respiratory syncytial virus (rsv) and human metapneumovirus (hmpv) infections (fig. ) ; it can be also observed in adenovirus pneumonia [ ] . the interstitial pattern of viral pneumonia is characterized by multifocal gg opacities, interlobular septal thickening and consolidations, expression of the development of ali with dad [ ] . this j o u r n a l p r e -p r o o f is the common imaging presentation of covid- pneumonia, as discussed above (fig. ) ; however, the interstitial pattern has been also associated with other coronavirus infections, such as severe acute respiratory syndrome coronavirus (sars-cov- ) and middle east respiratory syndrome coronavirus (mers-cov) [ , ] . sars-cov- infection is characterized by peripheral lung involvement and gg opacities more commonly than sars-cov- and mers-cov pneumonia, in which consolidations were prevalent [ ] . also, differently from covid- , sars showed unifocal distribution in . % cases as initial presentation [ ] , remaining confined to a single lung in approximately one-quarter of patients [ , ] . on the other hand, when compared to covid- pneumonia, a progressively extension from the lower lobe periphery into upper and perihilar lung zones was shown in mers [ ] , together with a significantly higher prevalence of pleural effusion ( %) [ ] . nevertheless, due to the shared pattern of lung damage, the differential diagnosis between covid- and other interstitial viral infections is challenging [ ] . in one study, a high specificity in correctly differentiating ct features of covid- from other viral infections was reached, with peripheral distribution of the abnormalities, gg appearance and vessel enlargement as clue findings for differential [ ] . however, due to some selection biases (e.g. low number of influenza-a cases), small cohort size and different reader's level of experience on reporting covid- cases, the observed results can be somewhat misleading [ ] . influenza pneumonia can cause bilateral reticulonodular opacities, usually with lower lobes predominance on cxr, and bilateral patchy gg opacities and consolidation, with ill-defined small nodules on hrct [ ] , which can be difficult to differentiate from covid- pneumonia. this is particularly true during the organizing phase of the disease when an op pattern, commonly observed also in h n influenza pneumonia, occur [ , ] . compared to covid- , influenza demonstrates higher lower lobe predominance, with more frequent subpleural and peribronchovascular distribution of the abnormalities. furthermore the presence of clustered and ill-defined lesions, nodules and bronchial wall thickening is more common in influenza pneumonia than in covid- [ , ] . among non-infectious diseases to be considered in the differential diagnosis with covid- pneumonia, heart failure with cardiogenic pulmonary oedema is one of the most important causes of acute respiratory symptoms, especially among the elderly. on cxr, particularly in the ap projection, a differentiation between the abnormalities caused by covid- and signs j o u r n a l p r e -p r o o f of pulmonary oedema may not be as easy as expected. in general, blurring of the vessels, proximal pulmonary vessel enlargement, peribronchial cuffing, evidence of bilateral kerley lines, peribronchovascular thickening, middle-lower distribution of the opacities, and bilateral pleural effusion are typical findings that can allow a confident diagnosis of pulmonary oedema, when associated with the adequate clinical context [ ] . this is especially true in patients with history of cardiac disease or in presence of cardiac devices as pacemaker (fig. ) . on hrct the differential diagnosis from covid- is straightforward, with evidence of enlargement of the pulmonary veins, gg opacities and smooth thickening of the interlobular septa and peribronchovascular bundles, mostly with a central distribution in dependent areas, associated with pleural effusion and mediastinal lymph node enlargement [ , ] . in patients with fibrotic interstitial pneumonia, such as those affected by idiopathic pulmonary fibrosis (ipf), nonspecific interstitial pneumonia (nsip) and chronic hypersensitivity pneumonitis (chp), the onset of an acute exacerbation can mimic symptoms of covid- pneumonia. acute exacerbation is defined as clinical worsening of dyspnoea over the last days, which can occasionally manifest with fever and flu-like symptoms [ ] , and is considered expression of ali. in this context, hrct is the modality of choice. the hallmarks are the newly appearance of bilateral gg opacities and/or consolidation occurring in the nonfibrotic areas of the lungs -usually with a multifocal or diffuse distribution -and the exclusion of alternative aetiologies, such as pe and infection, especially viral pneumonia [ , ] . comparison with previous examinations is particularly helpful in interpreting such cases (fig. ) . drug toxicity is a frequent cause of lung disease [ ] . imaging features are various, reflecting different underlying histopathology aspects. the op pattern is a frequent manifestation of drug reaction on hrct [ ] and may mimic covid- pneumonia in the progressive phase. the typical presentation of op include bilateral, multiple, patchy consolidations with peripheral and peribronchovascular distribution and a lower lobe predominance, associated to perilobular opacities and/or reversed halo sign [ ] . in this context, clinical data, pharmacological history and time elapsed between the start of treatment and the occurrence of symptoms are fundamental for the differential diagnosis. the nsip pattern is another possible manifestation of drug reaction on hrct [ ] and is usually characterized by diffuse gg opacities with superimposed reticulation and mild-to-severe j o u r n a l p r e -p r o o f traction bronchiectasis/bronchiolectasis, with a predominant bilateral lower lobe distribution [ ] , less likely to resemble covid- pneumonia. aspiration with inhalation of oropharyngeal or gastric contents into the laryngeal or lower respiratory tract is probably an under-recognized cause of cap and lung injury [ ] . the risk of aspiration is increased in patients with reduced level of consciousness, abnormal cough reflex, oropharyngeal dismotility, and gastroesophageal reflux disease (gerd). the onset of symptoms can be acute or subacute, mainly depending on the aspirated content and volume [ , ] . especially in recumbent patients, the zonal distribution can mimic that of covid- pneumonia, with involvement of the posterior segments of the upper lobes and the superior and basal-posterior segments of the lower lobes. either unilateral or bilateral lung involvement is possible [ , ] . cxr can show central ill-defined alveolar opacities or segmental and lobar opacities, whereas hrct demonstrates consolidation in decumbent areas and multifocal patchy gg opacities, mainly with peribronchovascular distribution [ , ] , associated with centrilobular nodules and/or tree-in-bud pattern [ ] (fig. ). despite similarities with covid- pneumonia, the evidence of aspirated material filling the airways as well as the presence of centrilobular nodules and/or tree-in-bud pattern are relevant clues for the differential diagnosis [ ] . other possible ancillary findings that may help in ruling-out covid- pneumonia are abscess, cavitation, parapneumonic effusion and empyema, or the presence of pulmonary ossification in a dendriform or nodular pattern (expression of underlying chronic aspiration) [ ] . in case of aspiration of lipoid material, exogenous lipoid pneumonia can occur. acute aspiration of large volumes of mineral oil (fire-eater pneumonia) [ ] can have a clinical presentation similar to pneumonia, while chronic aspiration (animal fats, mineral or vegetable oils) is characterized by insidious symptoms [ ] . hrct depicts centrilobular gg opacities or multiple consolidations with a peribronchovascular distribution, mainly involving the lower lobes. also, interlobular septal thickening and patchy multifocal areas of crazy paving pattern can be seen [ , ] . moreover, the presence of consolidations or mass-like opacities with attenuation values < hu (hounsfied unit) is diagnostic of lipoid pneumonia and can be seen in both the acute and chronic setting [ ] (fig. ). despite a typical peribronchovascular distribution of the abnormalities, in the absence of fat-containing masses, a definite exclusion of covid- pneumonia is not always possible based on imaging features alone. diffuse alveolar haemorrhage (dah) is another potential clinical entity which we could face in the epidemic phase of sars-cov . dah is associated with pulmonary vasculitis or connective tissue diseases among the others; haemoptysis is usually, but not always, present. cxr shows diffuse alveolar opacities, usually in the mid-zone lungs with subpleural and apical sparing, along the bronchovascular bundles. at hrct, bilateral peribronchovascular gg opacities and smooth septal thickening are visible, with possible coexistent crazy paving, ill-defined centrilobular nodules and consolidations, in case of complete alveolar filling by blood [ ] ( fig. ) . the peribronchovascular distribution makes the diagnosis of covid- pneumonia less likely. in the clinical practice, the differential diagnosis between covid- vs non-covid- patients on hrct remains a critical task due to the overlap of imaging findings. a recently published study demonstrated that use of a simple scoring system based on seven common hrct features (posterior part/lower lobe predilection, bilateral involvement, rounded ggo, subpleural bandlike ggo, crazy paving pattern, peripheral distribution, and ggo +/− consolidation) and four uncommon ones (single lobe involvement, central distribution, tree-inbud pattern, and bronchial wall thickening) might be of help in categorizing symptomatic patients as covid- vs non-covid- . a high specificity ( . %) was achieved with a score greater than [ ] . however, it should be noted that imaging findings cannot provide a definite diagnosis alone and that the association with clinical and microbiological data, in a multidisciplinary context, is determinant for an accurate and rapid identification of covid- positive cases. due to the pandemic spread of sars-cov- infection, it is essential to be familiar with common and uncommon imaging findings of covid- pneumonia and their evolution over time on cxr and hrct. cxr might be used as first-line imaging modality in the areas with high levels of contagion as well as in the serial evaluation of hospitalized and critically ill patients. on the other hand, hrct 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interstitial pneumonia: radiologic, clinical, and pathologic considerations aspiration-related lung diseases aspiration and infection in the elderly: epidemiology, diagnosis and management aspiration diseases: findings, pitfalls, and differential diagnosis lipoid pneumonia: spectrum of clinical and radiologic manifestations computed tomography of diffuse pulmonary haemorrhage with pathological correlation the authors would like to thank dr. storto for her fundamental contribution to reviewing the structure and the english language of the manuscript. key: cord- -pgda i u authors: baba, yuri; ishiguro, takashi; gochi, mina; shimizu, yoshihiko; takayanagi, noboru title: a -year-old woman with respiratory failure and bilateral ground-glass opacities date: - - journal: chest doi: . /j.chest. . . sha: doc_id: cord_uid: pgda i u a -year-old woman with diabetes mellitus was admitted to our hospital because of dyspnea on exertion. sputum cytologic evaluation revealed intranuclear inclusion bodies in the cells; we therefore considered viral pneumonia and performed a bronchoscopy. the bronchial washing fluid was positive for immunoperoxidase staining of herpes simplex virus type (hsv ) and hsv polymerase chain reaction. the patient was diagnosed as having pneumonia due to hsv and was successfully treated with acyclovir. hsv polymerase chain reaction. the patient was diagnosed as having pneumonia due to hsv and was successfully treated with acyclovir. chest ; ( ):e -e key words: bronchoscopy; herpes simplex virus pneumonia; immunoperoxidase staining a -year-old japanese housewife was admitted to our hospital due to anorexia and dyspnea on exertion. she had been diagnosed several years earlier with type diabetes mellitus and hypertension. she had also developed lip herpes several years ago. she had no history of smoking or drinking. she had been anorexic for days before and developed dyspnea on exertion from days prior to referral and admission to our hospital. she had had no contact with any people showing infectious symptoms prior to her presentation, and she had not been started on any new medications for the past few years. on admission, the patient's body temperature was . c, and oxygen saturation measured by pulse oximetry under inhalation of oxygen at l/min by nasal cannula was %. her lips and pubic region showed no exanthema. auscultation revealed diffuse fine crackles. her peripheral limbs were not edematous. a chest radiograph showed bilateral patchy opacities distributed predominantly in the upper lung fields (fig a) . no pleural effusion or obvious lymphadenopathy was observed. chest ct images obtained during inspiration revealed multifocal patchy ground-glass opacities (fig b) , bronchial wall thickening, and interlobular septal thickening but no pleural effusion or lymphadenopathy. laboratory data on admission showed a wbc count of , /mm with infectious symptoms, or a history suggestive of drug-induced lung diseases but did have fine crackles and diffuse, bilateral patchy ground-glass opacities in her chest, we initially suspected acute interstitial pneumonia and administered prednisolone ( mg/d), which is often used in the treatment of acute interstitial pneumonia. because we could not completely rule out community-acquired pneumonia due to atypical pathogens, we administered azithromycin g on hospital day (hd) . on hd , the shadows on the patient's chest radiograph increased. we therefore changed the steroid therapy to pulse therapy (methylprednisolone g daily for days). her respiratory condition continued to worsen, however. what study should be conducted next? on hd , we began to suspect viral pneumonia because of a sputum cytology finding of intranuclear inclusion bodies in the cells (fig a) . because of the patient's worsening respiratory condition, she was intubated, and a bronchoscopy was then performed to obtain a definitive diagnosis. cytologic evaluation of the bronchial washing fluid obtained from the right upper lobe revealed intranuclear inclusion bodies ( fig b) . results of culture of the bronchial washing fluid were negative for bacteria, fungus, and mycobacteria. immunoperoxidase staining for herpes simplex virus type (hsv ) of lymphocytes using bronchial washing fluid was positive (fig c) diagnosis: viral pneumonia due to hsv the patient was diagnosed as having hsv pneumonia (hsv p) based on these results. on hd , she was started on acyclovir mg/kg/d for days. the bilateral shadows on the patient's chest radiograph then improved. serum anti-hsv igg measured by using an enzyme-linked immunoassay method and complement fixation method was > times normal and titers on admission, respectively, and her hsv igg titers had remained high. hsv igm was negative at all measurements. after discharge on hd , the patient has continued to be followed up as an outpatient and has not developed relapse of hsv p. the bacterial pathogens of pneumonia have mainly been identified on the basis of culture, paired sera, and rapid diagnostic test results. pcr testing directed at respiratory viruses has been reported to find viruses more frequently than had been previously thought. [ ] [ ] [ ] [ ] these studies investigated influenza virus, respiratory syncytial virus, figure -a, chest radiograph on admission showed bilateral patchy opacities distributed predominantly in the upper lung fields. pleural effusion and lymphadenopathy were not observed. b, chest ct image on admission showed multifocal segmental and subsegmental ground-glass opacities, bronchial wall thickening, and interlobular septal thickening but no pleural effusion or lymphadenopathy. e chest imaging and pathology for clinicians coronavirus, human metapneumovirus, and adenovirus, but hsv was not included in previous reports investigating the frequency of viral infection in community-acquired pneumonia. hsv p is rare and mostly observed in transplant recipients and those receiving immunosuppressants or steroids. as far as we know, the number of reports of hsv p is limited to cases of patients unaffected by transplantation, hiv, immunosuppressants, corticosteroids, burns, or malignancy - (table ) . unfortunately, although we did not initially suspect hsv p in the current patient, cytologic findings of sputum provided a diagnostic clue, and we subsequently investigated hsv infection. the findings obtained following bronchoscopy were very helpful in diagnosing hsv p. hsv can be cultured from the oral cavity of % to % of asymptomatic adults, and it is difficult to identify hsv as a pathogen of pneumonia when the virus is cultured from the sputum. to confirm the diagnosis of hsv p, it is important to prove that hsv is positive by using pcr and according to typical cytologic and histologic findings from the lower respiratory tract and alveoli. [ ] [ ] [ ] among the reported patients with hsv p unaffected by transplantation, hiv, immunosuppressants, corticosteroids, burns, or malignancy ( table ) , eight of the were aged < years, and seven had no underlying diseases. only the current patient had diabetes mellitus with mild elevation of her glycosylated hemoglobin value, which made it difficult for us to suspect hsv p. therefore, although hsv p is rare, physicians should consider it in the differential diagnosis of patients with no underlying diseases or a fragile immunologic state. a noteworthy fact is that no skin, oral, or genital lesions suggestive of hsv infection were found in any of the patients with hsv pneumonia. hsv has two patterns of acute infection: primary infection and reactivation. the infection pattern in the current patient was considered to be reactivation because her anti-hsv igg level was high, and she had experienced a herpes virus lip infection several years earlier. acyclovir was generally selected for the treatment of hsv p, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] except in two cases ( table ). the study patient improved spontaneously with no medications, and a postmortem diagnosis of hsv p was made in the other patient. one study reported a mean treatment duration of ae days in immunocompetent patients, whereas immunocompromised patients were treated with acyclovir for ae days. acyclovir was administered to the study patient for days, and there has been no relapse of hsv p. few comments are available regarding events following recovery from hsv p; however, one patient developed acute inflammatory demyelinating polyneuropathy (a variant of guillain-barré syndrome) following improvement with acyclovir, which should alert physicians to potentially serious outcomes. another concern is corticosteroids, which we initially administered for a suspected diagnosis of acute interstitial pneumonia. limited data suggest favorable effects of corticosteroids on varicella zoster virus (in combination with acyclovir), hantavirus, and in influenza-associated pneumonia in some clinical settings, , but other reports have found them to be harmful. the study patient's condition clearly worsened following corticosteroid therapy. patients with acute interstitial pneumonia report progressive dyspnea, cough, fever, and, occasionally, flu-like symptoms, which overlap with the symptoms of viral pneumonia. careful attention should be paid in the differentiation of viral pneumonia prior to administering corticosteroids. cytologic features characteristic of hsv infection can be found at the margins of ulcers or in the alveolar cells, and they include small eosinophilic intranuclear inclusion bodies separated from the surrounding nuclear chromatin by a clear halo (cowdry type a inclusions) and a single or multinucleated cells with ground-glass changes in the involved nuclei. , the study patient exhibited these findings, which were compatible with hsv infection. we initially did not suspect hsv p, but screening of sputum cytology samples provided a clue for correcting our strategies for diagnosis and treatment. the chest radiograph findings of hsv p have been described in a few reports. most described bilateral consolidation, but nodules with irregular margins and ground-glass opacities have also been reported. ct findings of hsv p include multifocal segmental and subsegmental ground-glass opacities and consolidation, scattered distribution, and pleural effusion, which, except for pleural effusion, were also found in the study patient. furthermore, interlobular septal thickening and bronchial thickening have been reported in viral pneumonia and were also found in the current patient. teaching points . hsv virus is a cause of community-acquired pneumonia. . although hsv p is considered to be rare, it can develop in patients with diabetes mellitus with a mild increase in glycosylated hemoglobin levels and without any complications of diabetes mellitus itself. . when hsv p is suspected, investigation of samples obtained from the lower respiratory tract is recommended. . no skin, oral, or genital lesions suggestive of hsv infection were found in any of the patients with reported hsv p unaffected by transplantation, hiv, immunosuppressants, corticosteroids, burns, or malignancy. . hasty administration of corticosteroids may be harmful to patients with viral pneumonia, and thus it is important to rule out viral pneumonia prior to the administration of corticosteroids. acute interstitial pneumonia: thin-section ct findings in patients community-acquired pneumonia requiring hospitalization among u.s. adults viral pneumonia etiology of community-acquired pneumonia: impact of age, comorbidity, and severity improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction herpes simplex virus bronchopneumonia in a non-immunocompromized individual severe herpes simplex virus pneumonia in an elderly, immunocompetent patient herpes simplex pneumonia in an immunocompetent patient with progression to organizing pneumonia use of the polymerase chain reaction in the diagnosis of unsuspected herpes simplex viral pneumonia: report of a case herpes simplex pneumonia in a young immunocompetent man case records of the massachusetts general hospital. case - . an -year-old woman with pulmonary infiltrates and respiratory failure herpes simplex virus type- pneumonitis in immunocompetent young woman extracorporeal membrane oxygenation for refractory, lifethreatening, and herpes simplex virus -induced acute respiratory distress syndrome. our experience and literature review herpes simplex pneumonia: combination therapy with oral acyclovir and aerosolized ribavirin in an immunocompetent patient herpes simplex virus infection of the adult lower respiratory tract herpetic infection of the middle and lower respiratory tract a case of herpes simplex virus pneumonia with adult respiratory distress syndrome case - : a woman with pulmonary infiltrates and respiratory failure herpes simplex virus infection: biology, treatment and prevention lower respiratory tract reactivation of herpes simplex virus. comparison of immunocompromised and immunocompetent hosts medical treatment of viral pneumonia including sars in immunocompetent adult the role of corticosteroids in severe community-acquired pneumonia: a systematic review effect of low-to-moderatedose corticosteroids on mortality of hospitalized adolescents and adults with influenza a(h n )pdm viral pneumonia. influenza other respir viruses systemic glucocorticoids in childhood expiratory wheezing: relation between age and viral etiology with efficacy herpes simplex virus pneumonia: patterns on ct scans and conventional chest radiographs imaging of pulmonary viral pneumonia financial/nonfinancial disclosures: the authors have reported to chest the following: t. other contributions: the ethical committee of saitama cardiovascular and respiratory center approved the report of the present case. chest worked with the authors to ensure that the journal policies on patient consent to report information were met. key: cord- -fw b cv authors: bajaj, satish kumar; tombach, bernd title: respiratory infections in immunocompromised patients: lung findings using chest computed tomography date: - - journal: radiol infect dis doi: . /j.jrid. . . sha: doc_id: cord_uid: fw b cv respiratory infections and subsequent complications are one of the leading causes of high mortality in immunocompromised patients. although chest radiograph and computed tomography are the commonly used diagnostic tools for the early diagnosis of lung manifestations of infections, they lack the specificity for the wide range of chest infections which can occur in immunocompromised patients. systematic analysis of the imaging findings in correlation with the clinical settings along with comparison with the old images can expedite early and accurate diagnosis for subsequent appropriate management. computer tomography findings in immunocompromised patients with respiratory infections, with regards to various clinical settings, will be discussed here. infections are very common in an immunocompromised host (ich), which includes patients on chemotherapy (cancer), on immunosuppressive therapy (post transplantation patients, rheumatologic disorders) or acquired immunodeficiency diseases (aids, post-splenectomy), and their population is expanding globally. pneumonitis implies inflammation of the lung and in an immunocompromised patient (icp) may occur due to disease progression, infections or secondary to non-infectious causes like drug induced toxicities [ e , ] . lung inflammations due to infections are known as pneumonia. infection in ich may be primary or secondary due to the underlying noninfectious inflammatory condition of the lung, which further compromises the immune system of the body. respiratory infections, along with drug toxicity, are major concerns in more than two thirds of the icps. these are leading causes of therapy failure of the primary diseases, are often life threatening and are associated with high mortality after reading this article the reader will be able to: (a) understand the classification, patterns and imaging features of the respiratory infections (b) understand the role of clinical settings while interpreting computer tomography findings (c) understand some of the mimics of chest infections and morbidity. therefore, an accurate and quick diagnosis is a major cornerstone for the management team. pneumonia can be classified, on the basis of different modes of acquirement of the infections, into community-acquired pneumonia (cap), hospital acquired pneumonia (also referred as nosocomial pneumonia, hap) or ventilator associated pneumonia (vap) ( table ) . pneumonia can be further stratified as mild, moderate or severe on the basis of clinical parameters and scoring systems like pneumonia severity index (psi) or curb- [ ] . these validated scoring systems assist healthcare professionals in determination of the clinical outcomes. another method of classification divides patients into typical or atypical groups, based on the clinical manifestations and the expected pathogens differ accordingly. patient who present with classical symptoms like fever, rigors, chills, cough with expectoration, chest pain, dyspnea and whose chest radiographic findings are suggestive of common bacterial infections is considered to have typical pneumonia. on the other hand, atypical pneumonia usually presents with persistent low grade fever without the typical pneumonia symptoms and signs. the etiologic pathogen could be either a bacterial, viral, fungal or any other opportunistic organism. the most common pathogens of cap are streptococcus pneumoniae, mycoplasma pneumoniae, chlamydia pneumoniae, haemophilus influenzae, legionella pneumoniae and respiratory viruses. vap are likely due to gram negative infections such as pseudomonas aeruginosa, escherichia coli, klebsiella pneumoniae and acinetobacter as well as gram positive pathogens like staphylococcus aureus. in the early stages of immunosuppression, such as in the induction phase of chemotherapy, infections are most likely bacterial in origin. common isolated bacterial pathogens in ich are legionella, mycoplasma and chlamydia ( table ). the predominant viral agents are rhinoviruses, coronaviruses, influenza virus, respiratory syncytial virus (rsv), adenovirus and parainfluenza virus. icps as a result of organ transplantation are vulnerable to infections with cytomegalovirus (cmv) and rarely herpes virus. coronavirus and hantavirus infections are commonly observed during seasonal and non-seasonal outbreaks. pneumonia due to multidrug-resistant organisms such as s. pneumoniae (drsp) or s. aureus (mrsa) are often seen in icps. viral infections can be also be complicated by secondary bacterial super-infections. fungal infections are very common in ich with leukemia, cancer chemotherapy or organ transplant, mainly seen in later stages of immunosuppression either as a primary infection or as a result of a super-infection. pneumocystis jiroveci pneumonia (pjp) constitutes the most frequent opportunistic fungal infection. other common fungal infections reported are aspergillus fumigatus, candida albicans, and cryptococcus neoformans. histoplasmosis, blastomycosis and mucormycosis are not so common globally but are isolated in endemic areas (table ) . non-infectious etiologies like drug toxicities, cardiac causes and organizing pneumonias should always be considered in the differential diagnosis of atypical and non-resolving pneumonias. on the basis of imaging patterns, pneumonia is classified as lobar pneumonia, bronchopneumonia and interstitial or atypical pneumonia. lobar and bronchopneumonia are usually bacterial in origin, whereas, viruses, parasites and fungi are likely pathogens in interstitial pneumonia. however, one should always keep in mind overlapping imaging features. radiographically, lobar pneumonia is manifested by homogeneous consolidation with air bronchogram involving one, or less commonly, multiple lobes. segmental pneumonia shows consolidation involving one or more segments of a lobe and may occasionally manifest as a round opacity simulating a pulmonary mass, called round pneumonia. frank consolidation and air bronchogram have been associated with a higher incidence of bacteremia. klebsiella infection may show radiographic evidence of lobar expansion with bulging of interlobular fissures due to voluminous inflammatory exudates. cavitation may also be present and there is a tendency to occur in the upper lobes. legionella has a predilection for the lower lung fields. radiologic resolution tends to lag far behind the clinical improvement by six to eight weeks (fig. ). bronchopneumonia, also known as multifocal or lobular pneumonia, is radiographically identified by its patchy appearance with peri-bronchial thickening and poorly defined air-space opacities. as the illness becomes more severe, consolidation involving respiratory bronchioles and alveoli results in the development of centrilobular nodular opacities or air-space nodules. the consolidation can progress further and coalesce to give a lobular or lobar pattern of involvement. typically, air bronchogram are absent. the pathogens known to cause this pattern of pneumonia are particularly destructive. thus, abscesses, pneumatoceles, and pulmonary gangrene may develop. pathologically, bronchopneumonia stems from inflammation of large airways (bronchitis) with patchy (lobular) involvement. in severe staphylococcus infection, lobar enlargement with bulging of interlobular fissures can be seen. abscess, cavitation (with air-fluid levels), and pneumatocele are not uncommon and e % of patients develop pleural effusions, half of which are empyema. it may be noted that cavitation and associated pleural effusions are also observed in cases of anaerobic infections, gram-negative infections and tuberculosis. in pseudomonas infection, the radiographic findings tend to be nonspecific and are difficult to differentiate from the underlying lung disease. all the lobes are involved, with a predilection for the lower lobes. necrosis and cavitation may occur. invasive aspergillosis as well as pulmonary vasculitis with infarction can resemble bronchopneumonic pattern. interstitial pneumonia is classified into focal and diffuse types. the radiological appearance results from that the edema and inflammatory cellular infiltrate into the interstitial tissue of the lung. the pathological development of interstitial pneumonia generally takes of forms: ( ) an insidious infectious course that results in lymphatic infiltration of alveolar septa without parenchymal abnormality; ( ) acute or rapidly progressive disease that results in diffuse alveolar damage affecting the interstitial and air spaces. radiographically, this disease manifest with a reticular or reticulo-nodular pattern (table ) . legionella, mycoplasma and chlamydial infections cause this pattern of pneumonia commonly. legionella species usually cause a patchy, localized infiltrate in the lower lobes. associated hilar adenopathy may be present. pleural effusion is seen in up to % of cases. in rare instances, it may be associated with cavitation and a mass-like appearance (fig. ) . the infiltrates in mycoplasma pneumoniae can be unilateral, multi-lobular, or bilateral. in about % of patients, pleural effusion or hilar adenopathy may be present. chlamydia pneumonia may be sub-segmental or more extensive in elderly patients; pleural effusions are rarely seen. chest radiograph (cxr) reveals % resolution in four weeks. in % of cases, resolution takes longer than weeks. aspergillosis is a mycotic disease caused by aspergillus species, usually aspergillus fumigatus. pulmonary aspergillosis can be subdivided into five categories: (a) saprophytic aspergillosis (aspergilloma), (b) hypersensitivity reaction (allergic broncho-pulmonary aspergillosis), (c) semi-invasive (chronic necrotizing) aspergillosis, (d) airway-invasive aspergillosis (acute trachea-bronchitis, bronchiolitis, bronchopneumonia, obstructing bronchopulmonary aspergillosis), and (e) invasive pulmonary aspergillosis (ipa). ipa usually affects . clinically, viral pneumonia in adults can be divided into two groups: atypical pneumonia in otherwise normal hosts and viral pneumonia in ich. influenza virus types a and b account for the majority of viral pneumonia in immunecompetent adults. ichs are susceptible to pneumonia caused by cmv and hsv, as well as measles and adenovirus ( table ). the radiologic findings of viral pneumonia are variable and overlapping (table ). specific etiological diagnosis of a viral pneumonia cannot be made on the basis of imaging features alone (fig. ) . clinical features such as patient age, immune status, time of year, illness in other family members, community outbreaks, different stages of the underlying disease at onset, severity and duration of symptoms, and presence of a rash remain important in diagnosing viral causes of atypical pneumonia in immune-competent as well as icps. cxr is an essential tool for rapid diagnosis of lung changes and may also be help in follow up of the treatment response. however, it lacks specificity and often fails to show early and subtle findings of lung infections. computed tomography (ct) of chest has become a mainstay tool for detecting early lung changes. there is better delineation and characterization of the patho-mechanism of the findings, enabling proper differential diagnosis including infection mimics [ ] . the accuracy of radiological diagnosis can be improved significantly if it is correlated with the clinical background of the patient. hence detailed information about the particular clinical setting including clinical presentation, past medical history such as exposure to tuberculosis et al., treatment history, and overall clinical condition is essential for better evaluation and proper diagnosis [ ] . pneumonia in a vulnerable ich is influenced by several environmental and epidemiological factors like mode of exposure, i.e., cap or hap, history of previous infections and nature of ongoing drug therapy (cytotoxic, immunosuppressive) and stage of the disease. cytotoxic drugs causes neutropenia which is further complicated by increased risk of gram negative infections whereas immunosuppressive or immune-modulating drugs lead to increased risk of infections by causing defects in cell mediated immunity and phagocytosis. infections caused by mycobacterium tuberculosis (fig. ) , pneumocystis jiroveci (pcp), toxoplasma gondii and varicella zoster virus are often on account of reactivation of past infections. therefore, inquiring about past medical history suggestive of these infections is important. similarly, hap or nosocomial infections are caused by a specific group of organisms. the risk is increased by intubation, use of broad spectrum antibiotic, use of strong immunosuppressive drugs combined with histamine receptor blockers which reduce gastric acidity which in turn leads to increased colonization by gram negative bacilli, such as pseudomonas, klebsiella (fig. ), e. coli and acinetobacter. ventilators and central air-conditioning system are associated with legionella and gram negative infections. catheter and drainages increase the risk of s. aureus, p. aeruginosa and candida in vulnerable hosts. the type of immune defect also determines the specific pathogen to a larger extent. complement system defects lead to infection by extracellular or encapsulated bacteria. phagocytosis failure is mainly associated with bacterial and fungal infections. ich with humoral immunodeficiency is at risk of getting infected with encapsulated bacteria like s. aureus, s. pneumoniae, h. influenza and pjp. whereas, cell mediated immunodeficiency or t-cell defect, due to underlying primary disease or secondarily due to viral infections like cmv or epsteinebarr virus, pose a high risk of opportunistic infections. in patients with aids, pathogenic agents are determined by the cd cell count-whether below (viral and fungal) or above (pcp and mycobacterium). immune defects due to splenectomy or hypo-splenismp redisposes to infection with encapsulated microorganisms such as s. pneumoniae, h. influenza and s. aureus [ e ]. duration of immunosuppression also determines the specific pattern of chest infection. gram-negative infections and s. aureus are often seen in the early phase of neutropenia, whereas opportunistic organisms like fungus are found in the later phases of neutropenia. organ transplanted ich are susceptible to infections with likely causative pathogen depends on the post-transplant phase. in the early phase, common bacterial infections are observed, whereas viral or fungal infections predominate in later phases (usually months posttransplant). the likelihood of a particular pathogen depends on the type of immune defect, which is governed by the type of immunosuppressive therapy. the radiological diagnosis should be corroborated by special laboratory tests like polymerase chain reactions (pcr), serology, immunoassays (elisa) and galactomannan test, whenever necessary. bronchoscopy with broncho-alveolar lavage aids in detection and confirmation of pcp, candida and other infections. correct interpretation of abnormal radiological findings is limited by several factors, such as insufficient clinical information and failure in obtaining old radiological imaging for comparison. furthermore, overlapping imaging features of different organisms, lack of experience of the radiologist, subtle findings which are difficult to correlate and co-morbidities (such as congestive heart failure, cor pulmonale, radiation induced changes etc.) pose further difficulty in correct assessment of radiological changes. hence, it is suggested to adopt a comprehensive and holistic approach to the radiological diagnosis. cxr and chest ct are the frontline diagnostic tools in early detection of respiratory infections. chest ultrasonography is useful in evaluating para-pneumonic effusions and can be used to evaluate complications like pneumothorax or as an assist tool for thoracocentesis. non-enhanced ct chest is the modality of choice when plain cxr is inconclusive or inadequate for interpretation. there are certain radiological features suggestive of pneumonia and when accompanied with presence of certain "special imaging signs" can clinch the diagnosis [ ] . these characteristic findings with probable differential diagnosis will be discussed below (table ) . consolidation is the most common and easily interpretable findings on cxr and ct. it occurs mainly due to opacification of the air spaces by exudates and is usually bacterial in origin. air tracks (bronchioles) are visualized when the walls are effaced by surrounding consolidation. this is known as air bronchogram sign and a reliable sign of lung infection. focal consolidation can also be seen in other conditions like non-obstructive atelectasis, neoplasia, aspiration and organizing pneumonia. hence, these should be closely analyzed to differentiate from each other. for instance, lung volume loss with subsequent elevation of diaphragm, vascular crowding and mediastinal shift are normally due to atelectasis, whereas bulging fissure (bulging fissure sign) along with air bronchogram suggests pneumonia. bulging fissure sign is most often seen in upper lobe pneumonia caused by klebsiella and pneumococcal infections. neoplasia, large abscesses, infected bullae and other lesions can also present with this sign and a comparison with old films is utmostly helpful. silhouette sign is another very useful sign in detecting subtle changes of chest infection. this sign is characterized by obscuring of normal air interfaces of the thorax. thoracic aperture, thoracic wall, para-mediastinal spaces and pericardiac spaces are the areas where this sign is well illustrated. it can also be seen in space occupying lesions, atelectasis and localized effusions. feeding vessel sign is a very useful sign of septic emboli in ct scan when cavitating or non-cavitating nodules are associated with a pulmonary vessel [ ] . air fluid level sign is suggestive of abscess and empyema and mainly caused by s. aureus and klebsiella. the wall of this cavitation may enhance in homogeneously on ct scan with contrast. a chest wall or fissure based focal opacity, also called split pleural sign, and is normally suggestive of empyema. it may also be illustrated in case of hemothorax, pleurodesis and post lobectomy. ground glass opacities (ggo) are defined as nonspecific high attenuation of the lung parenchyma in ct scan due to decrease in air content or partial effacement resulting from exudates in the alveolar space (fig. a) . hence normal lung markings are not obscured in contrast to frank alveolar consolidations. this is not a very specific sign for infection and can be seen in other conditions like pulmonary congestion, interstitial lung disease, vasculitis, etc. the pattern of distribution of ggo with other accompanying signs may suggest a particular type of pneumonia. for example ggo confined to central and upper lobes with sparing of the subpleural spaces is very specific for pcp [ ] . tree-in-bud sign (fig. b) is a well-appreciated sign seen in various conditions such as infectious bronchiolitis, aspiration and cystic fibrosis. terminal bronchioles are normally not perceived on ct scan because of their very thin walls and caliber (less than mm). when peripheral areas of lung are opacified or plugged by exudates, they cause the appearance of a v or y shaped branching tree pattern accompanied by bud-like nodules. normally this sign spares the subpleural and peri-fissure areas (fig. b) . halo sign is a well-appreciated ct scan sign in a clinical setting of fever with neutropenia and is always suggestive of invasive aspergillosis (fig. c) [ ] . the focal infarction with surrounding hemorrhage is perceived as a halo. halo sign is a good prognostic predictor for response to therapy. reverse halo sign is seen seldom in aspergillus or mucormycosis infection where the lesion shows consolidation around a central area of ground glass like changes with interception lines (fig. d) . air crescent and monad sign are other signs suggestive of fungal infections (fig. e) . separation of the necrotic infective mass by a crescent air space in response to therapy is known as air crescent sign. it implicates good response to treatment. this is to be differentiated from an air crescent space resulting from secondary fungal infection with mycetoma (fungal ball) in a preexisting cavity, known as monad sign. this is a bad sign and usually causes hemoptysis and needs surgical or interventional management. crazy paving sign is due to alveolar opacity resulting from exudates accompanied by septal thickening leading to a characteristic picture of pedestrian path pattern, normally seen in alveolar proteinosis (fig. f ). pcp and viral infections may seldom manifest this sign. miliary pattern consists of widespread distribution of tiny nodules of less than mm in size. random type of military pattern is centrilobular and is characteristic of hematogenous spread of either mycobacterium infection or lung metastases. on the other hand, non-random type is peri-lymphatic in distribution and is a common feature of sarcoidosis [ , ] . as mentioned above, it is not always easy to pin point a specific pathogen for the cause of the pneumonia on the basis of imaging findings alone. furthermore, old pulmonary lung changes, cardiac insufficiency, atelectasis and pleural effusions can mask the new changes resulting from the current infection. hence, we recommend an algorithm (fig. ) to be followed, for proper evaluation of the various lung changes in order to have a conclusive diagnosis and follow up. due to regular follow up regime of our icps (many western countries), pneumonia with frank lobar consolidations are hardly observed these days. patchy, segmental or nonsegmental consolidations are the usual radiological presentation of typical bacterial pneumonia in case of ich with acute onset of fever. however, in hospitalized patients with similar radiological features without any relevant clinical and laboratory findings consistent with lung infection, a possible diagnosis of atelectasis, old changes and organizing pneumonias following a course of antibiotics should be considered. other accompanying features like loss of lung volume and vascular crowding may assist in the interpretation. basal infiltrates and atelectasis are difficult to differentiate from each other. in addition, a likely pneumonic infiltrate overlying a basal lung collapse should always be considered, if clinically suspected. in our experience, tree-in-bud phenomenon is often seen either as a footprint of old infection which can be verified by comparing with old films or as a sign of a fresh infective bronchiolitis usually caused by bacterial or fungal infections (fig. ) . in our clinical setting, tuberculosis is not very common in ich. it is mainly seen in patients with aids or as reactivation of an old tuberculosis infection in the migrant subgroups from the endemic areas. in aids patients, tuberculosis may cause minimal lung changes (with or without effusion), and necrotic mediastinal lymphadenopathy is often seen. cavitating and military lung lesions are observed in the advanced disease (fig. ) . nodular opacities (with or without cavitation) are commonly a manifestation of septic emboli from infected catheter, endocarditis, etc. and patients should be screened for such sources of infection (fig. ) . rarely, wegener's granulomatosis can present in a similar fashion. in cases with nodular lung changes with mediastinal lymphadenopathy, one should always consider sarcoidosis as an alternative coincidental diagnosis, particularly in a younger age group. nodular opacities may be seen in fungal infections, occurring secondary to virus infections. typical pneumonia, due to bacterial infections, is common in early stages of immunosuppression and is easy to diagnose based on clinical and laboratory parameters and their response to therapy. atypical pneumonia is not uncommon as well and can lead to serious complications with high morbidity and mortality, if not timely diagnosed and treated. generally, viral pneumonia manifests as ground glass opacities in early stages, mainly in upper and middle lung fields and a tendency of consolidation in later stages (figs. and ). reactive small mediastinal lymph nodes can be seen on ct scan. influenza virus shows midfield changes more than upper lobe changes as well as early consolidations. pneumatoceles and pneumothorax are not observed in viral infections, although these are frequent features of pcp (fig. ) . a complicated viral infection may rapidly proceed to acute respiratory distress syndrome (ards). pjp seems more frequent compared to legionella, mycoplasma and chlamydial lung infections in our ichs. fungal infections comprise the third major group of pneumonias. ipa (with the characteristic halo sign) is likely to be more frequent than candida infections. reverse halo sign is not a commonly seen entity in our practice. it is very important and imperative that radiologists be aware of lung changes, which may mimic lung infection. these are caused by various conditions like cardiogenic conditions, cryptogenic organizing pneumonia (cop) (fig. ) , progressive cancer disease with lymphangitis and chemotherapy associated lung changes. hence recognizing the relevant findings, correlating with the clinical findings and course of management can provide a complete differential diagnosis and thus play an important role in patient care. ggo due to fluid retention in bedridden ich is common. chf in old patients may present with typical findings of central and lower lobe dominant ggo accompanying with small effusions (fig. ) . atelectasis is inadvertently found in such conditions. progressive dyspnea without fever may be a feature of fig. . ct scan of years old male with bone marrow transplantation with viral infection followed by aspergillosis. lymphangitis and normally shows ct findings of perihilar and segmental reticular or reticulo-nodular opacities. cop is not very uncommon, and should be considered when consolidation persists or increases during the course of the treatment whereby the laboratory findings are not suggestive of active infection [ ] . in case of viral infections, increasing nodular opacities or consolidation, and superinfection (such as accompanied with bacterial, pneumocystis or fungal infections) should be considered. the effect of drug toxicities on the lung can manifest as infiltrates (interstitial, alveolar or both), pulmonary edema and hypersensitivity pattern and changes secondary to cardiotoxic chf. they may be asymptomatic coincidental findings or may present with progressive dyspnea. some of the newer drugs may also be accompanied with neutropenia and fever [ ] . chemotherapy induced patchy pneumonitis is not uncommon and should be considered in differential diagnosis when approaching lung parenchymal changes [ ] . these are anticipated changes in later stages of chemotherapy regime. however, paclitaxel and anti egfr agents may show similar changes in the earlier cycles of chemotherapy. many cytotoxic agents and the new agents may show ggo and consolidation (mtor antagonist like everolimus, temsirolimus, bleomycin) or a cop like image. some drugs (gemcitabine) may cause capillary leakage syndrome and few agents may cause interstitial changes due to heart failure (doxorubicin). ct chest is, in particular, a very sensitive radiological tool for detection of the early signs of respiratory infections in sick icps. the specificity of the interpretation can be improved significantly through a comprehensive approach taking into consideration of the clinical setting, past infections and treatment history. used appropriately, ct scan is a very valuable tool for early detection and differential diagnosis of lung infections in icps and therefore for the subsequent reduction of morbidity and mortality highly vulnerable patients. none. understanding and diagnosing infectious complications in the immunocompromised host evolving risk factors for infectious complications of cancer therapy imaging infection early detection of pneumonia in febrile neutropenic patients: use of thin-section ct acute lung disease in the immunocompromised host: differential diagnosis at high-resolution ct severity assessment tools for predicting mortality in hap ct findings in immnunocompromised patients with pulmonary infections pulmonary infections in immnunocompromised hosts: the importance of correlating the conventional radiological appearance with clinical setting imaging pulmonary infection: classic signs & patterns pulmonary septic emboli: diagnosis with ct reversed halo sign on high-resolution ct of cryptogenic organizing pneumonia: diagnostic implications invasive pulmonary aspergillosis in acute leukemia: characteristic findings on ct, the ct halo sign, and the role of ct in early diagnosis pattern recognition of the pulmonary manifestations of aids on ct scans tuberculosis: a radiologic review cd counts as predictors of opportunistic pneumonias in hiv infection pneumocystis jiroveci pneumonia: high-resolution ct findings in patients with and without hiv infection spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings thoracic mycoses from opportunistic fungi: radiologicpathologic correlation pulmonary fungal infection: imaging findings in immunocompetent and immnunocompromised patients viral pneumonias in adults: radiologic and pathologic findings ct findings of chemotherapy -induced toxicity: what radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity cancer patient, with dyspnea and without fever showing ggo due to mild chf key: cord- - j c authors: jullien, sophie; pradhan, dinesh; tshering, tashi; sharma, ragunath; dema, kumbu; garcia-garcia, selene; ribó, jose luis; muñoz-almagro, carmen; bassat, quique title: pneumonia in children admitted to the national referral hospital in bhutan: a prospective cohort study date: - - journal: int j infect dis doi: . /j.ijid. . . sha: doc_id: cord_uid: j c objectives: the study aim was to describe the etiological profile and clinical characteristics of pneumonia among children hospitalized in thimphu, bhutan. methods: this prospective study enrolled children aged – months admitted to the jigme dorji wangchuck national referral hospital with world health organization (who)-defined clinical pneumonia. demographic and clinico-radiological data were collected through questionnaires, physical examination, and chest radiography. blood samples and nasopharyngeal washing were collected for microbiological analysis including culture and molecular methods. results: from july to june , children were enrolled, of which . % were infants. pneumonia-related admissions were less frequent over the winter. chest radiographies were obtained in children; endpoints included pneumonia in cases ( . %), other infiltrates in ( . %), and were normal in children ( . %). non-contaminated bacterial growth was detected in / ( . %) blood cultures, with only two cases of streptococcus pneumoniae. viral detection in upper respiratory secretions was common, with at least one virus detected in / ( . %). the three most-commonly isolated viruses were respiratory syncytial virus ( / ; . %), rhinovirus ( / ; . %), and human parainfluenza virus ( / ; . %). a third of patients with viral infections showed mixed infections. case fatality rate was . % ( / ). conclusion: respiratory viral infections predominated among this cohort of who-defined clinical pneumonia cases, whereas bacterial aetiologies were uncommon, highlighting the epidemiologic transition that bhutan seems to have reached. pneumonia is the single largest cause of mortality in children aged under five years, causing an estimated . % of all deaths in children under five years of age, and over , paediatric deaths annually (liu et al., ; un igme, ) . most of these lives could be saved through more effective and equitable health system interventions, combining prevention, early and accurate diagnosis, and treatment (walker et al., ; rambaud-althaus et al., ) . the main pneumonia burden remains disproportionately concentrated in low-and middle-income countries (lmics) in southeast asia and sub-saharan africa (walker et al., ) . pneumonia deaths are decreasing, but more slowly than for other major causes of mortality, and too slowly to achieve the sustainable development goal ambition of "ending preventable child deaths" by (united nations, ) . risk factors and causative pathogens of childhood pneumonia differ across the world. obtaining reliable local data, including the burden of the disease, epidemiological trends, and the determination of the main pathogens involved, is imperative to help develop targeted interventions. therefore, adequate surveillance systems are required to monitor the effectiveness of national strategies implemented towards the reduction of the disease burden. however, the lack of local data and weak surveillance systems in many lmics hamper an adequate knowledge of the epidemiology and aetiology of childhood pneumonia in those settings where reliable data are most needed. one country that exemplifies the dearth of data regarding childhood pneumonia is the kingdom of bhutan (jullien et al., ) , a small country locked in the himalayas, with an estimated population of , in (department of information technology, ; ministry of health, ) . in this predominantly mountainous country, elevation rises from around m in the southern foothills to over m in the northern himalayan range, with the capital, thimphu, standing at m (central intelligence agency, ). the climate varies with the altitude, from tropical in the southern plains to alpine with very cold winters in the north. in thimphu, the temperature ranges from À c in winter to c in summer on average, coinciding with the monsoon that brings precipitations of around mm in july (climate-data org, ). bhutan is classified as a lower-middle income country as of (the world bank, ) . essential health services in both modern and traditional medicines are free for bhutanese citizens, based on a primary healthcare approach (world health organization, ) . we conducted this prospective hospital-based observational study to describe the epidemiology, aetiology, and clinical and radiological presentation of world health organization (who)defined pneumonia among children aged between and months admitted to the jigme dorji wangchuck national referral hospital in thimphu. this was a prospective hospital-based study conducted for consecutive months at the jigme dorji wangchuck national referral hospital (jdwnrh) in thimphu. the hospital has paediatric beds, including five in the paediatric intensive care unit (picu). all children aged - months hospitalized with who-defined pneumonia (irrespective of severity) were eligible for recruitment (world health organization, ) (see box ). children admitted in the preceding seven days or with evidence of a foreign body in the respiratory tract were excluded. potential participants were identified during day and night by the study co-investigators with the collaboration of paediatricians, paediatric residents, and nurses from the outpatient department, the emergency room, the picu, and the paediatric ward. if an eligible participant was missed during the night, the child was assessed and recruited the following morning. all eligible children were recruited provided parent(s) or guardian(s) consented to study participation. on study admission, a study identification number was assigned and a comprehensive physical examination was performed, including anthropometric measurements, vital signs, axillary temperature, and peripheral oxygen saturation in room air. demographic and clinical data were collected from the medical records and through family interviews. sample collection upon enrolment, or as soon as possible after enrolment, included blood samples and nasopharyngeal washing (npw). all the nurses in the picu and paediatric ward were trained at the beginning of the study by the lead investigator on how to collect these samples. when a child was identified for recruitment but blood had already been collected, no further blood sampling was conducted. however, if another blood analysis was clinically indicated, additional blood was obtained for the specific purpose of the study. fluid from pleural effusion was collected when clinically indicated. all recruited patients underwent a postero-anterior chest radiography upon admission. additional information of potential diagnostic interest, such as computed tomography scans, ultrasound, or cerebrospinal fluid investigation available throughout admission, was also collected. children were clinically managed and discharged as per existing hospital protocols and discretion of the treating paediatricians, and were followed-up by one study investigator in terms of outcome determination. all data were collected using digitalized and standardized forms (see supplementary material for clinical definitions and details of variables measured). the who protocol used in clinical trials of pneumococcal conjugate vaccines (pcv) was followed to interpret chest radiographs (cherian et al., ) . in brief, readers first judged the box . who definitions of pneumonia and severe pneumonia used as inclusion criteria (world health organization, ) . history of cough or reported breathing difficulty, and increased respiratory rate (rr) or chest indrawing. severe pneumonia: history of cough or reported breathing difficulty and at least one of the following: oxygen saturation < % or central cyanosis, severe respiratory distress (e.g. grunting, very severe chest indrawing), signs of pneumonia with a general danger sign: inability to breastfeed or drink, lethargy or reduced level of consciousness, convulsions. increased rr is defined according to age as follows: rr ! breaths per minute in children aged two months or more and less than months. rr ! breaths per minute in children aged months or more and less than months. quality of the film (uninterpretable or interpretable, the latter stratified as suboptimal or adequate) and then classified findings for all interpretable radiographs. significant pathology was defined as the presence of consolidation, other infiltrates, and/or pleural effusion. endpoint radiologically confirmed pneumonia was defined as consolidation, pleural effusion, or both on any hemithorax. initially, two paediatricians independently interpreted the radiographs. discordant results were read by a third reader, trained in who criteria for interpretation of chest radiographs. an additional external quality control measure was included in the study protocol, whereby a paediatric radiologist would read a random sample of % of the chest radiographs. however, as substantial discordance was observed between the two primary readers, all chest radiographs were again independently interpreted by the paediatric radiologist using the who criteria. this last reading was accepted as final interpretation for analysis. blood was collected under aseptic conditions following the hospital's validated standardized procedures. blood for haematology, biochemistry, and culture was processed following standard procedures. blood was cultured using an automated blood culture system (bact/alert ). bacterial isolates were identified by colony morphology, growth requirements, and basic biochemical tests. antibiotic susceptibility was determined using disk diffusion in accordance with the guidelines of the clinical laboratory standard institute (clsi, ) . additionally, real-time polymerase chain reaction (rt-pcr) for lyta gene of streptococcus pneumoniae in dried-spot collected blood, and host-response biomarkers in additional blood ( ml, edta tube) were investigated (findings reported elsewhere) (brotons et al., ) . the blood samples were centrifuged at  g for three minutes, and the serum was separated and stored at À c. npw samples were homogenized and aliquots frozen at À c and subsequently shipped to barcelona, spain, where they were subjected to molecular screening (multiplex rt-pcr qiastat respiratory panel, qiagen, for viral targets and four bacterial targets). npw were also subjected to detection of pneumococcus and capsular typing (findings reported elsewhere). rapid influenza diagnostic tests (alere binaxnow ) were performed as per discretion of the treating clinicians and nurses, independently of the current study. investigations for active tuberculosis included mantoux test and gastric aspirates for microscopy and genexpert . the lead investigator entered data into a computerized password-protected database (odk ) with study identification number. errors in data entry were limited by pre-defined ranges for every value. stata . was used for data analyses (statacorp, ) . mean with standard deviation (sd) and median with interquartile range (iqr) were used to summarize normally and non-normally distributed variables respectively. between st july and th june , children were admitted to the paediatric department of jdwnrh. among them, ( . %) were children aged - months with respiratory symptoms, of which ( . %) were recruited ( figure ). the baseline characteristics of the children are presented in table . median age was . months; over half of the children were infants. most children were adequately immunized according to age. there was no known case of hiv infection. children were mainly from the district of thimphu, although the study included patients from out of the districts in bhutan. on average, families reported that it had taken around min to reach the closest healthcare facility. twenty-seven children ( . %) were referred from another health centre. summer, fall, and spring each comprised around % of the recruited cases, while winter had the lowest number of pneumonia admissions ( . %). october was the month with the highest number of cases ( ; . %) ( figure ). clinical characteristics upon admission are presented in tables and . wasting (waz À sd) was detected in children ( . %). on admission, children ( . %) presented with fever, half of the children were breathing fast according to age, and three-quarters were hypoxemic. median basal oxygen saturation was % (iqr - ) among the children with available measurement in room air without oxygen therapy. on auscultation, typical lung consolidation-related sign (crackles) was most common ( . %), followed by rhonchi ( . %) and wheezing ( . %). on admission, . % of the children were anaemic, . % had leucocytosis, and . % had neutrophilia. two common inflammatory markers were tested at jdwnrh: c-reactive protein (crp) with a mean of . mg/dl (sd . ), and erythrocyte sedimentation rate (esr) with a mean of . mm (sd . ). twenty-five (sanders et al., ; bruel et al., ) . only four children presented with both high crp and esr. chest radiography was performed in / children ( . %). images were available for interpretation by the study investigators in of them ( . %). in cases, children were discharged before investigators could interpret the radiography findings and the radiograph was missing. one film was judged uninterpretable. among the final readable chest radiographs, ( . %) were normal, ( . %) were classified as primary endpoint pneumonia, and ( . %) as other infiltrates. while hiv infection was not suspected in any child by the treating physicians, active tuberculosis was suspected in children ( . %) but was not confirmed by the laboratory tests in any of them. blood culture was performed in / children ( . %), of which ( . %) had received antibiotics prior to sample collection (table ) . thoracocentesis was performed in one child with pleural effusion. six different pathogens were isolated among the eight non-contaminated positive blood cultures: s. pneumoniae (two cases), pseudomonas sp. (two cases), escherichia coli, acinetobacter sp., salmonella typhi, and serratia rubidaea (one case each). drug sensitivity results are shown in supplementary table . s. pneumoniae was isolated in the only sample of pleural fluid that was collected, which corresponds to the same child with positive blood culture, subsequently also confirmed by rt-pcr in blood. npw was collected in / children ( . %). the npw sample was too scarce or of bad quality to run the test in children ( . %). among the remaining children, ( . %) had received antibiotics prior to sample collection. bordetella pertussis was detected in three ( . %) children, and mycoplasma pneumoniae in one ( . %) child; chlamydophila pneumoniae and legionella pneumophila were not detected among respiratory samples. at least one virus was identified in / npw samples ( . %) ( coronavirus were detected in two children ( . %). routine rapid flu test was performed under the influenza national surveillance programme in / children ( . %), being positive for influenza a in seven cases, for influenza b in one case, and for co-infection of influenza a and b in one case. analysis by rt-pcr confirmed the detection of influenza virus in / children with positive rapid flu test, and detected additional cases with influenza virus. among children with at least one virus detected, / ( . %) had a positive blood culture for bacteria and / ( . %) had radiological endpoint pneumonia. among children with no virus detected, / ( . %) had a positive blood culture and / ( . %) had radiological endpoint pneumonia (supplementary table ) . no children with influenza had a positive blood culture. however, / ( . %) children with influenza identified in their nasopharynx had radiological endpoint pneumonia. lumbar puncture was not indicated in any of the children. children were hospitalized for a median of four days (iqr - ) ( table ) . thirty children required picu admission, with a median stay of h (iqr - ). three-quarters of the children were put on oxygen therapy, of which half for at least three days. most children ( . %) received antibiotics during admission. antibiotics were stopped in the first two days of admission in children ( . %) and advised to be continued after discharge in ( . %). main diagnoses given by the treating physician at discharge are shown in supplementary table . half of the children were discharged with a diagnosis of pneumonia or bronchopneumonia. in terms of the seasonal variability of the most common clinical syndromes given by the treating physician at discharge, bronchopneumonia was mainly in fall ( . %), bronchiolitis in spring ( . %), and pneumonia did not show a clear seasonal pattern (supplementary figure ) . six children had a fatal outcome (case fatality rate . %); all had been referred from other centres in critical condition. npw was not collected in three children due to the severity of their illness upon arrival. of the other three children, one child presented a triple co-infection by b. pertussis, parainfluenza virus, and influenza virus. four fatal cases were diagnosed as suffering of pneumonia, and two of bronchiolitis. two deaths occurred within the first h of admission to our centre. a summary of the main characteristics of these six children is presented in supplementary table . abbreviations: gcs: glasgow coma scale; na: not applicable; waz: weight-for-age z-score. a two children presented with convulsions. one was diagnosed as febrile convulsion, while the other child was a severe case of pneumonia which led to a fatal outcome. b some children who presented with non-severe pneumonia developed hypoxemia during their hospitalization, which is a sign of severity as per the who definition. c twenty children ( . %) did not strictly meet the who definition of pneumonia at the time of admission but were admitted to the paediatric ward with suspected pneumonia or bronchiolitis as per the clinical discretion of the treating paediatricians. four of them developed hypoxemia during hospitalization requiring oxygen therapy and were therefore classified as severe pneumonia. none of the remaining children were admitted to picu or presented other signs of severity, and were classified as nonsevere pneumonia (supplementary table ). d increased respiratory rate (rr) according to age is defined as rr ! bpm in children aged - months and rr ! bpm in children aged ! months. this is the first published series of comprehensive epidemiological, clinical, and microbiological data describing bhutanese children under five years of age hospitalized with who-defined clinical pneumonia. mortality related to pneumonia was . %, similar to other studies from lmics (jroundi et al., ; lazzerini et al., ; bénet et al., ; chen et al., ; o'brien et al., ) . nevertheless, this remains high for bhutan in spite of the country offering free and easily accessible healthcare services. the six children who died were referred from other health centres and reached the study hospital in critical condition. the high proportion of infants in our study highlights that infants are particularly vulnerable and prone to hospitalization due to severe pneumonia (fancourt et al., ; chen et al., ; jakhar et al., ). there was no child known or suspected to be infected with hiv, which is consistent with the very low number of underfive year old children infected with hiv in bhutan (unaids, ). abbreviations: crp: c-reactive protein; esr: erythrocyte sedimentation rate; hb: haemoglobin; wbc: white blood cells. a leucocytosis was defined as white blood cells greater than  cells/l for children aged between and months and greater than  cells/l for children aged between and months. abbreviations: npw: nasopharyngeal washing; pcr: polymerase chain reaction; rsv: respiratory syncytial virus; rt-pcr: real-time polymerase chain reaction. a vials for blood culture were out of stock at the hospital for few weeks during the study period, leading to blood culture not being performed in participants, although molecular screening in bloodspots in filter paper was conducted for all of these children. b coagulase-negative staphylococci, and bacillus spp were considered contaminants, as per our protocol. c bacterial growth was detected in blood cultures, but it was attributed to contamination in cases. d seven children had positive rapid flu test for influenza a, one child for influenza b, and one child for influenza a and b. out of the seven children with rapid flu test positive for influenza a, detection of influenza a by rt-pcr in npw was also positive in four cases, but negative in one case, and "failed/inhibited" in the remaining two cases. for the child with rapid flu test positive for influenza b and for the child with rapid flu test positive for both influenza a and b, rt-pcr in npw was negative for both influenza a and b in both children. e parainfluenza viruses , , , and were detected in ( . %), ( . %), ( . %), and ( . %) children respectively. f fourteen were influenza a, and two were influenza b. winter, which is the coldest season in bhutan, surprisingly showed the lowest number of cases ( . %); this finding differs from what is commonly seen in other settings, whereby hospitalization of childhood pneumonia tends to peak during the coldest season (murdoch et al., ; ben-shimol et al., ) . however, this finding is consistent with those reported by the national sentinel surveillance programme for severe acute respiratory infections, and with the proportion of all-cause paediatric admissions, lower during winter (royal centre for disease control, ). this could be partially explained by the fact that winter coincides with the school break in bhutan, with less contact among children; and families moving from the capital to the villages with lower population density. hypoxemia is a well-established predictor of severity in children with pneumonia (duke et al., ; lozano, ) . a high proportion of children in this study ( . %) presented with hypoxemia, which is much higher than reported in other settings (subhi et al., ; o'brien et al., ) . we defined hypoxemia as spo < %, which is considered appropriate for altitudes under m, as is the case with thimphu ( m). this characteristic might therefore not be generalizable to bhutanese children who live at different altitudes than that of thimphu. while bacterial aetiology was infrequent, viruses were identified in a considerable proportion of children. these microbiological findings coincide more with the etiological profile of pneumonia in children from high-income countries, highlighting the advanced stage of the epidemiologic transition that bhutan seems to have reached (omran, ; prayle et al., ) . the findings from the perch study, conducted in seven lmics with routine use of pcv, are similar (o'brien et al., ) . even in the absence of a deployed pcv in bhutan (pcv was introduced only in january ), the burden of pneumococcal invasive disease appears to be low in children. the low proportion of confirmed bacterial cases could be explained by several reasons. first, vaccination coverage was high, which is representative of the rest of the country, although the pcv was not in routine use during the recruitment period (who, ) . second, almost one-third of the children had received antibiotics prior to collection of blood sample, which reduces the yield of blood culture by around % (berkley et al., ; rhodes et al., ; driscoll et al., ; o'brien et al., ) . small blood volume is another factor known to compromise the sensitivity of blood culture (berkley et al., ; bouza et al., ; driscoll et al., ) . blood collection is challenging in children, especially in infants. blood volumes collected for each child were not recorded in this study but, in practice, around ml was dedicated for blood culture in most cases, despite the - ml recommended in the protocol. nevertheless, these findings confirm the low yield of blood culture in hospitalized children with pneumonia and question both the need of blood culture for uncomplicated cases of pneumonia and using blood culture as the preferred screening tool for invasive bacterial disease in children with pneumonia. molecular methods have been found to be more sensitive than blood culture to detect pneumococcal invasive disease (muñozalmagro et al., ; selva et al., ; o'brien et al., ) . this was not the case in this study. b. pertussis was isolated in respiratory samples of three children. this is similar to the detection rate of around % of hospitalized pneumonia cases in similar studies (jroundi et al., ; barger-kamate et al., ) . one of these three children, aged five months, had a fatal outcome. this underlines the high fatality ratio of pertussis-infected pneumonia, especially in infants who are unvaccinated, and suggests the need of intervention such as maternal vaccination to reduce morbi-mortality associated with pertussis in vulnerable populations. viral detection was common. the use of pcr techniques has increased the ability to detect respiratory viruses (ruuskanen et al., ) . however, evidence of the detection of viruses in asymptomatic individuals has raised concern about the clinical significance of these positive findings. attribution of causality is not straightforward, as viruses can commonly be found both in symptomatic but also asymptomatic individuals (jartti et al., ; ruuskanen et al., ; rudan et al., ; o'brien et al., ) . while the causative role of rsv, influenza, adenovirus, human metapneumovirus, and bocavirus in childhood pneumonia is wellestablished, the pathogenic role of other viruses such as rhinovirus is still questioned (fry et al., ; caracciolo et al., ; ruuskanen et al., ; shi et al., ; jayaweera et al., ; o'brien et al., ) . using molecular methods, rhinovirus has been shown to be the most frequent respiratory pathogen isolated in children, and its detection in asymptomatic children is significantly higher than other respiratory viruses (kusel et al., ; jartti et al., ; ruuskanen et al., ) . nevertheless, clinical relevance of rhinovirus has been proven by the association of this virus with respiratory symptoms in children, mainly wheezing (kusel et al., ; khetsuriani et al., ) . in our series, . % of the children with rhinovirus presented with wheezing. infection with coronavirus (cor e, corhku , cornl , coroc ) was low in the present study. similarly, the new coronavirus (sars-cov- ) seems to cause a low infection rate in children (world health organization, ). the reason why coronavirus infection rate in children is low is unknown. in addition, the interpretation of positive viral findings is challenging due to the identification of multiple co-existing viral infections (jartti et al., ; ruuskanen et al., ) . co-infections were common in the present study, which is consistent with the existing literature (ruuskanen et al., ; jroundi et al., ; jiang et al., ) . considering radiological pneumonia endpoint as a proxy for bacterial pneumonia, . % of children with positive npw findings had a viral-bacterial co-infection, and . % of children with influenza detected in npw had an influenzabacterial co-infection. the contribution of viral-bacterial coinfections is well-acknowledged in the aetiology of childhood pneumonia, particularly the interaction between influenza virus and s. pneumoniae (o'brien et al., ; kwofie et al., ; brealey et al., ) . the combined effect of bacteria and viruses was shown to increase the severity of the disease, and bidirectional interactions have been described: respiratory viruses leading to bacterial superinfection, and bacteria pathogens promoting respiratory viral superinfections (brealey et al., ) . however, there is still a lack of robustness supporting these findings. this study has several limitations. most children in the present study lived in thimphu, and the microbiological findings may not be generalized to the rest of the country. bhutan is very diverse: comprised of cities, such as thimphu, and isolated households in very remote areas, leading to different lifestyles and environmental exposures; and also diverse in terms of altitude, with different climates and precipitations. the burden of pneumonia requiring hospitalization was highest among infants. respiratory viruses were detected in a considerable number of children, although a clear pathogenic role cannot be established. together with the relatively low proportion of children presenting a likely bacterial pneumoniaaround a quarter as per positive blood culture and radiological findingsthese findings emphasize the advanced stage of the epidemiologic transition that bhutan seems to have reached. this study is the first step to better understand the aetiology and clinicopathological characteristics of pneumonia in bhutanese children. henceforth, the development of targeted pneumonia interventions and hypothesis-driven research is encouraged to reduce the morbidity and mortality associated with this disease. fostering a robust pneumonia aetiology surveillance in children under five years of age appears important and would allow the assessment of the impact of the recently introduced pcv in reducing the burden of pneumonia. funding sj received a pre-doctoral fellowship from the secretariat of universities and research, ministry of enterprise and knowledge of the government of catalonia and co-funded by european social fund. this work was supported by a scholarship from the spanish society of paediatric infectology (sociedad española de infectología pediátrica, seip). none of the funding sources were involved in the study design, data collection, analysis, interpretation of the data, and writing of the manuscript. the study protocol was approved by the research ethics board of health, ministry of health, in thimphu in march (protocol number po/ / ), and by the research ethics committee from the hospital clínic in barcelona (hcb/ / ). 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organization. revised who classification and treatment of childhood pneumonia at health facilities. geneva: evidence summaries world health organization. the kingdom of bhutan health system review world health organization. coronavirus disease (covid- ) outbreak we thank all the children and their parents or caregivers who participated in this study, as well as the paediatric department of jdwnrh including paediatricians, residents in paediatrics, and interns who contributed to identifying eligible cases for the study. we are very grateful to all nurses who participated in the collection of biological samples and contributed to the success of this study, especially those in the paediatric ward. we thank dr. kinley tshering, paediatrician, who read and interpreted all the chest radiographies; the radiological and microbiological departments of jdwnrh for their support; and laia blanco lopez for contributing to the microbiological analysis of viruses in npw. we are very grateful to gaurav kwatra and laura puyol for their assistance in the shipment of the biological samples.we are grateful to the spanish society of paediatric infectology (sociedad española de infectología pediátrica, seip) for their financial support, which contributed to the shipment and testing of biological samples. we acknowledge support from the spanish ministry of science and innovation through the "centro de excelencia severo ochoa - " program (cex - -s), and support from the generalitat de catalunya through the cerca program. cism is supported by the government of mozambique and the spanish agency for international development (aecid). no conflict of interest to declare. supplementary material related to this article can be found, in the online version, at https://doi.org/ . /j.ijid. . . . key: cord- -knyw l authors: bénet, thomas; picot, valentina sanchez; awasthi, shally; pandey, nitin; bavdekar, ashish; kawade, anand; robinson, annick; rakoto-andrianarivelo, mala; sylla, maryam; diallo, souleymane; russomando, graciela; basualdo, wilma; komurian-pradel, florence; endtz, hubert; vanhems, philippe; paranhos-baccalà, gláucia title: severity of pneumonia in under -year-old children from developing countries: a multicenter, prospective, observational study date: - - journal: am j trop med hyg doi: . /ajtmh. - sha: doc_id: cord_uid: knyw l pneumonia is the leading cause of death in children. the objectives were to evaluate the microbiological agents linked with hypoxemia in hospitalized children with pneumonia from developing countries, to identify predictors of hypoxemia, and to characterize factors associated with in-hospital mortality. a multicenter, observational study was conducted in five hospitals, from india (lucknow, vadu), madagascar (antananarivo), mali (bamako), and paraguay (san lorenzo). children aged – months with radiologically confirmed pneumonia were enrolled prospectively. respiratory and whole blood specimens were collected, identifying viruses and bacteria by real-time multiplex polymerase chain reaction (pcr). microbiological agents linked with hypoxemia at admission (oxygen saturation < %) were analyzed by multivariate logistic regression, and factors associated with -day in-hospital mortality were assessed by bivariate cox regression. overall, pneumonia cases ( , hospitalization days) were analyzed; patients died within days of hospitalization. hypoxemia prevalence was . %. detection of human metapneumovirus (hmpv) and respiratory syncytial virus (rsv) in respiratory samples was independently associated with increased risk of hypoxemia (adjusted odds ratio [aor] = . , % confidence interval [ % ci] = . – . and aor = . , % ci = . – . , respectively). lower chest indrawing and cyanosis were predictive of hypoxemia (positive likelihood ratios = . and . , respectively). predictors of death were streptococcus pneumoniae detection by blood pcr (crude hazard ratio [chr] = . , % ci = . – . ), procalcitonin ≥ ng/ml (chr = . , % ci = . – . ) and hypoxemia (chr = . , % ci = . – . ). these findings were consistent on bivariate analysis. hmpv and rsv in respiratory samples were linked with hypoxemia, and s. pneumoniae in blood was associated with increased risk of death among hospitalized children with pneumonia in developing countries. despite reduced mortality rates in recent years, pneumonia is the foremost cause of death from infectious diseases in under -year-old children worldwide, accounting for % of total deaths, mostly in developing countries. hypoxemia, frequently associated with pneumonia and a marker of disease severity, leads to -to -fold increased risk of death in children with pneumonia. a cochrane review has reported that systematic hypoxemia screening with pulse oximetry and appropriate oxygen supply are effective in preventing death from pneumonia in children. a large simulation study estimated that systematic pulse oximetry may globally prevent almost , deaths from pneumonia annually. however, the microbiological agents linked with hypoxemic pneumonia are poorly recognized. the identification of such etiological agents would serve to better target preventive (i.e., vaccination) and curative measures (i.e., antibiotics and antiviral drugs), reducing the global burden of hypoxemia and pneumonia. because of its high incidence and related mortality, particular attention must be paid to hypoxemic pneumonia in developing coun-tries. pulse oximetry is still rarely available in health-care settings of developing countries. in the absence of oximeter, hypoxemia can be detected by several clinical signs or symptoms, including cyanosis and increased respiratory rate. however, none is sensitive and specific enough to reliably detect hypoxemia. [ ] [ ] [ ] most studies of hypoxemia in children with pneumonia were performed in one country and rarely investigated the relationship between hypoxemia and microbiological results, so it would be useful to reassess them in a more recent multicontinental investigation. the risk factors of death among children with pneumonia in developing countries have already been identified, , but rarely regarding the relationship between microbiological findings and mortality. assessment of clinical, para-clinical, and microbiological predictors of death would be useful to prioritize public health campaigns. identification of microbiological agents associated with death and/or hypoxemia would be useful to better focus therapeutic measures. indeed, hypoxemic pneumonia can be treated with oxygen in conjunction with other measures, whereas non-hypoxemic pneumonia with poor vital prognosis might need other regimens, such as antibiotics/antivirals or intensive care. the objectives of the present study are to assess the microbiological agents linked to hypoxemia in hospitalized children with pneumonia in developing countries, to identify clinical and para-clinical predictors of hypoxemia and to pinpoint factors associated with death within weeks after admission. study sites and design. findings from a prospective, hospital-based, multicenter, longitudinal study, conducted at five sites in four countries located on three continents, were analyzed: lucknow and vadu in india, antananarivo in madagascar, bamako in mali, and san lorenzo in paraguay. the participating sites are members of the gabriel (global approach to biological research, infectious diseases and epidemics in low-income countries) network established by fondation mérieux. the study protocol and sites are described elsewhere. pneumonia cases from the original case-control study were followed up during hospital stay and constituted the analyzed cohort. the study population comprised children aged between and months, complying with protocol definitions and inclusion criteria. eligible patients were identified by study clinicians at each participating site. all consecutive patients hospitalized in pediatric departments, who were eligible for study entry, were enrolled during each season (dry and rainy) for at least a -year period. the study aimed at obtaining an equal number of individuals in each season at each study site. incident cases were defined as hospitalized children aged - months, with clinical features of pneumonia, as described latter, radiological confirmation of pneumonia on chest x-ray as per world health organization (who) guidelines, and informed consent statement signed by the children's parents or legal guardian. wheezing at auscultation was initially an exclusion criterion, but was amended because it slowed the inclusion process. thus, it was finally decided to include children presenting pneumonia with or without "wheezing." the present study selectively comprised sites with better quality data on oxygen saturation (so ) at admission, mortality among pneumonia cases, and documented recording of patient follow-up during hospitalization. main characteristics were compared by site, and multivariate analysis accounted for heterogeneity of sites regarding observed or non-observed potential confounding factors. patients with missing data on follow-up, so measurement, and vital status at discharge were excluded (n = ). excluded patients did not differ from those analyzed for gender and weight-for-height z score, but were older (p = . ). definition of pneumonia. pneumonia cases were defined by the following criteria: data sources and quality control. data quality was monitored and evaluated by each site and by the emerging pathogens laboratory (lyon, france) for pooled data analysis. demographic characteristics, underlying diseases, medical history, clinical examination at enrollment, therapeutics, vaccinations, and outcomes were recorded prospectively for each patient on a standardized paper form. each potential error was discussed with local investigators, and a final ruling was applied. the principal investigator at each site was informed about quality assessments and was involved in their resolution. hypoxemia was defined as so < %, according to who recommendations. so was measured at hospital admission, before the administration of oxygen or other therapeutics. vital status was recorded until patient discharge. biological samples. samples were collected in the first hours of patient hospitalization. nasal swabs/aspirates, whole blood, and pleural effusions (in case of pleurisy) were sampled from all patients. urine was collected at patient admission to ascertain history of antibiotic use. biological samples were taken before the in-hospital administration of antibiotics. whole blood allowed complete blood count and culture, with real-time multiplex polymerase chain reaction (rt-pcr) assay for the identification of staphylococcus aureus, streptococcus pneumoniae, and haemophilus influenzae type b. c reactive protein (crp) and procalcitonin (pct) were quantified in serum. respiratory specimens permitted the identification of viruses and bacteria by rt streptococcus pneumoniae-positive specimens were serotyped by multiplex rt-pcr that detects different serotypes. a centralized, blinded pcr respiratory quality control panel was provided to all sites to ensure procedure validation on-site before specimens were processed locally. statistical methods. qualitative variables were described as numbers and percentages with comparison by χ test, if appropriate, or fischer's exact test. quantitative variables were reported as median and interquartile range (iqr) and compared by the mann-whitney u test or kruskal-wallis one-way analysis of variance. positive likelihood (lr+) and negative likelihood (lr _ ) ratios of various clinical signs and symptoms were calculated to detect hypoxemic cases with the following formulae: lr+ = sensitivity/( _ specificity) and lr _ = ( _ sensitivity)/specificity. it has been underlined that lr calculation is useful to improve diagnostic accuracy. lr could thus express the proportion of hypoxemic children who presented a particular sign or symptom divided by the proportion of non-hypoxemic children with the same result. microbiological findings from different sample sites associated with hypoxemia were assessed by logistic regression modeling. multivariate analysis was performed after univariate analysis, with forced adjustment on patient age, time per quarter, and study center. microorganisms with p < . values on univariate analysis were initially entered in the multivariate model. thus, backward stepwise deletion was applied until all p values were < . . models were compared by wald testing. factors associated with in-hospital mortality were assessed with kaplan-meier curves and compared by log-rank test. follow-up was censored at days after admission or discharge, if duration of hospitalization was less than days. the characteristics of patients deceased within weeks (n = ) were compared with non-deceased patients (n = ). univariate and bivariate proportional hazard cox regression analyses were undertaken. no multivariate cox model was fitted owing to the limited number of events. bivariate analyses expressed the effect of one major risk factor from univariate analysis adjusted on one other possible confounder (age category, human immunodeficiency virus [hiv] seropositivity, time per quarter, or weightfor-height z score). all tests were two tailed, and p < . was considered significant. statistical analysis was conducted with stata version . (statacorp., college station, tx). ethics. the study protocol, informed consent statement, clinical research form, amendments, and all other study documents were submitted to and approved by the institutional research ethics committee of each site. population description. overall, children with pneumonia, accounting for , hospitalization days, were included. among them, ( . %) were male. median age was months (iqr = - months). ninety-six ( . %) patients came from lucknow, india, ( . %) were from vadu, india, ( . %) were from antananarivo, madagascar, ( . %) from bamako, mali, and ( . %) from san lorenzo, paraguay. the study periods at each site were patients differed between sites according to median weight-for-height z score (p = . ) and age category (p = . ), but did not differ between sites according to hiv seropositivity (p = . ) and mortality (p = . ). seventy patients were hypoxemic at admission. global prevalence of hypoxemia was . % ( % confidence interval [ci] = . - . %). median so was % (iqr = - %), without differences between countries (from % [iqr = - %] in mali to % [iqr = - %] in vadu, india, p = . ). table compares the characteristics of hypoxemic and nonhypoxemic patients. hiv prevalence was . % (n = ). median weight-for-height z score was _ . (iqr = _ . ; + . ). median length of hospital stay was days (iqr = - days). median crp level at admission was mg/l (iqr = - mg/l), median white blood cell count was , × cells/l (iqr = , - , × cells/l), and median neutrophil proportion was % (iqr = - %). median pct level at admission was . ng/ml (iqr = . - . ng/ml), with mean of . ng/ml (minimum: . , maximum: . ng/ml). overall, . % tested positive for urinary antibiotics at admission. among the ( . %) patients given antibiotics during hospitalization for a median duration of days (iqr = - days), ( . %) received monotherapy, with some also getting multiple antibiotic lines. the main drugs were ceftriaxone (n = , . %), amoxicillin (n = , . %), ampicillin (n = , . %), amoxicillin/sulbactam (n = , . %), amoxicillin/clavulanic acid (n = , . %), oxacillin (n = , . %), and vancomycin (n = , . %). microbiological agents associated with hypoxemia in children with pneumonia. hypoxemic (n = ) and nonhypoxemic (n = ) pneumonia cases did not differ by median number of bacteria ( versus , respectively, p = . ) or viruses detected ( versus , respectively, p = . ) in nasal swabs/aspirates. infection types (bacterial/viral/mixed) did not differ in hypoxemic and non-hypoxemic patients (p = . ). table reports the microbiological agents linked with hypoxemia. univariate analysis disclosed that hmpv and rsv detection in nasal samples was associated with increased risk of hypoxemia (p = . and . , respectively). after adjustment on age, center, and calendar time, microorganisms independently associated with heightened risk of hypoxemia were hmpv (adjusted odds ratio [aor] = . , % ci = . - . ) and rsv (aor = . , % ci = . - . ). median so was lower in rsv-and hmpv-positive patients than in -negative patients but not different between rsv-and hmpv-positive patients ( figure ). pneumococcus serotypes ab and a from respiratory samples were more frequent in hypoxemic than in non-hypoxemic patients ( . % versus . %, respectively, p = . ; . % versus . %, respectively, p = . ). the distribution of other serotypes was not significantly different in hypoxemic and non-hypoxemic children (supplemental figure ) . clinical and para-clinical presentation in children with hypoxemic pneumonia. hypoxemic patients differed from non-hypoxemic patients according to age (p = . ), history of common cold/pharyngitis (p < . ), receipt of one dose of pentavalent vaccine (p < . ), breathing rate (p = . ), blood pressure (p < . ), chest indrawing (p = . ), cyanosis (p = . ), conjunctivitis (p = . ), rasping (p = . ), radiological presentation (p = . ), mean white blood cell count (p < . ), and pct (p < . ) at admission ( table ) . lr+ of lower chest indrawing was . ( % ci = . - . ), and lr-was . ( % ci = . - . ). lr+ of cyanosis was . ( % ci = . - . ) and lr _ was . ( % ci = . - . ). other signs and symptoms were less predictive of hypoxemia (data not shown). hypoxemic patients differed from non-hypoxemic patients in mean white blood cell count (p = . ) and pct at admission (p = . ) but not regarding crp level. factors associated with death. fourteen ( . %) patients died during hospital stay. among them, died within days after hospital admission. the mortality rate was . % in hypoxemic and . % in non-hypoxemic patients (p = . ). eight deceased patients were not hypoxemic at admission. among them, the causes of death were multiple organ dysfunction syndrome (n = ), acute respiratory distress syndrome with septic shock (n = ), severe pneumonia in hiv (n = ), and cardiac arrest (n = ). table reports the microbiological, clinical, and paraclinical findings associated with death on univariate cox analysis. streptococcus pneumoniae detection by blood pcr, hypoxemia, and pct ³ ng/ml at admission were associated with increased risk of death (log-rank test: p = . , p = . , and p < . , respectively, figure a -c). other characteristics or microorganisms, including s. pneumoniae in respiratory samples, were not significantly associated with death ( supplemental tables and ) . no figure ). in addition, s. pneumoniae detection by blood pcr was associated with increased risk of death (aor = . , % ci = . - . ), independently of hypoxemia at admission (aor = . , % ci = . - . ). one of the objectives of this study was to assess microbiological agents and other predictors of hypoxemia and death in under -year-old hospitalized children with pneumonia from developing countries. we observed that two viruses, namely rsv and hmpv, detected in respiratory samples by pcr, were independently associated with increased risk of hypoxemia, while no bacterial agent was significantly linked with it. on the other hand, s. pneumoniae detection by blood pcr was associated with a higher rate of in-hospital mortality in the study population independently of hypoxemia at admission. several predictors of hypoxemic pneumonia were identified. however, none had high likelihood ratio. elevated pct concentration and hypoxemia were straightforward predictors of death in children with pneumonia. the contribution of hypoxemia to the risk of death was independent of pneumococcus detection by blood pcr. several studies have investigated factors associated with hypoxemia, particularly clinical predictors. [ ] [ ] [ ] however, few of them have researched the links between microbiological findings and severity in different developing countries, with a standardized protocol. we observed that two viruses were associated with increased risk of hypoxemia. viral pneumonia induced diffuse, bilateral, pulmonary damage, compared with bacterial pneumonia, with more frequent, well-systematized alveolar localization. this is probably the reason why we noted that the two viral etiological agents evoking pneumonia were associated with hypoxemia. rsv is the leading cause of viral pneumonia in children, frequently in association with severe disease. we observed that it might be also a major cause of hypoxemic pneumonia. on the other hand, rsv detection was not related to increased mortality, but it is estimated that , - , children could die of rsv-associated pneumonia worldwide every year. our study's power was probably too limited to demonstrate such associations. however, with prevalence of exposure in non-hypoxemic patients ranging from % to %, with bilateral tests and α < . , study power was ³ % to detect or ³ . . similar results have been reported recently in a study from botswana, where researchers noted that rsv pneumonia in children induced more complications and longer duration of hospitalization, but mortality was lower in comparison to other agents. hmpv is recognized as a frequent etiological agent of pneumonia, causing severe disease. here, we determined that detection of this virus was associated with hypoxemic pneumonia in children. these findings might be related to the fact that these two viruses in respiratory samples might be the etiological agents of pneumonia. another hypothesis is that they might be associated with co-infections. however, we did not discern any relationship between infection type (bacterial, viral, or coinfection) and the risk of hypoxemia. the main clinical predictors of hypoxemic pneumonia were lower chest indrawing and cyanosis with lr+ ratios between and . if these signs are present, hypoxemia must be suspected in the absence of pulse oximetry, and oxygen therapy should be initiated promptly. nevertheless, we did not discern that one sign had a high lr+ ratio, confirming that pulse oximetry is important for initial evaluation of pneumonia severity and should be implemented more widely in developing countries. lower chest indrawing has been reported to be predictive of hypoxemia in children from nigeria, while breathing rate ³ cycles/minute has been encountered with hypoxemia in children from papua new guinea. other predictors are less known. the designation and validation of a simple, robust score predicting hypoxemia might be useful in resource-limited settings. streptococcus pneumoniae is recognized as the main etiological agent of severe pneumonia and death from pneumonia in children. the diagnosis of pneumococcus pneumonia is, however, difficult at the individual level, because of the low sensitivity of blood culture, particularly in case of previous exposure to antibiotics. in addition, the clinical meaning of pneumococcus detection in nasal samples by molecular testing is difficult to interpret because of the high prevalence of s. pneumoniae respiratory carriage in asymptomatic children. we did not observe associations between pneumococcus detection in nasal samples and disease severity, although pneumococcus-positive blood pcr was linked with greater mortality. molecular s. pneumoniae detection by blood pcr is thus helpful in identifying bacterial pneumonia cases with the poorest prognosis who might need intensive therapies. interpretation of molecular methods, such as pcr, to identify the etiology of pneumonia in children is, however, challenging. respiratory viruses can be identified in asymptomatic children, and secondary bacterial infections in the lungs can easily be missed by these methods. in addition, identification of s. pneumoniae in blood by highly sensitive pcr may detect children with nasopharyngeal colonization only, which could lead to potential misclassification bias, particularly when using results of nasopharyngeal specimens to determine the etiology of pneumonia in children. we must be cautious with results interpretation. moreover, pct was the major biomarker associated with in-hospital death in our cohort. several studies previously found an association between pct and the risk of death or bacterial disease. [ ] [ ] [ ] [ ] however, such linkage has rarely been seen in pneumoniainfected children living in developing countries. the main strength of the present study is the prospective data collection on a standardized form at different sites, with advanced molecular diagnosis in all cases, which reinforces internal validity. its main limitations include paucity of information on exposures before hospital admission (i.e., breastfeeding, food intake, or vitamin supplementation). in addition, microbiological diagnosis of pneumonia is difficult because sensitive and specific tests are not routinely available in practice. thus, based on respiratory samples, we were unable to differentiate colonization from infection, particularly by s. pneumoniae. however, analysis of the relationship between results from different samples and severity was contributive: we did not find associations between nasal colonization by pneumococcus and disease severity, hypoxemia, or death. finally, selection bias might have occurred because of patient recruitment in hospital with inclusion of more severe cases or patients with easier access to care. however, we did not discern significant heterogeneity regarding so of infants at admission and inhospital mortality, which suggests that the results might be generalizable to different settings. we must acknowledge that % of the study population was enrolled in two sites from india, which might limit external validity. this proportion is, however, in accordance with estimates of global pneumonia incidence and related mortality: india might have accounted for almost % of the total number of severe pneumonia cases in children and % of the number of deaths worldwide. in conclusion, rsv and hmpv could be major causes of hypoxemia in children with severe pneumonia in developing countries, while s. pneumoniae detection by blood pcr is predictive of high risk of in-hospital mortality. viral etiology might be considered in hypoxemic patients, whereas in very severe pneumonia, which can lead to death, s. pneumoniae may be implicated as the primary cause, even in the absence of hypoxemia at admission. tachypnea and lower chest indrawing could be useful indicators of possible hypoxemia requiring oxygen therapy. pulse oximetry should be included for better diagnosis in developing countries. given these findings, preventive measures, such as increased vaccination coverage of children in developing countries, oxygen therapy of hypoxemic patients, and intensive cardiovascular support, even in non-hypoxemic patients, would reduce the burden of death by pneumonia in children. this protocol was developed on behalf of gabriel network members: http://gabriel. globe-network.org. we especially thank the following gabriel pneumonia experts: ron dagan from the pediatric infectious disease unit saha from the department of microbiology, bangladesh institute of child health, dhaka shishu hospital, bangladesh; and werner albrich from kantonspital aarau ag, bereich medizin, switzerland. we also thank ovid da silva for doing financial support: this study was funded by fondation mérieux and the gabriel network disclaimer: the corresponding author had full access to the data and has the final responsibility to submit the manuscript for publication e-mails: thomas. benet@chu-lyon.fr and philippe.vanhems@chu-lyon.fr. valentina sanchez picot, florence komurian-pradel, hubert endtz, and gláucia paranhos-baccalà, laboratoire des pathogènes emergents, fondation mérieux global, regional, and national causes of child mortality in - , with projections to inform post- priorities: an updated systematic analysis the prevalence of hypoxaemia among ill children in developing countries: a systematic review oxygen therapy for lower respiratory tract infections in children between months and years of age evaluating the impact of pulse oximetry on childhood pneumonia mortality in resource-poor settings oxygen and pulse oximetry in childhood pneumonia: a 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is useful in identifying bacteraemia among children with pneumonia markers that predict serious bacterial infection in infants under months of age presenting with fever of unknown origin procalcitonin in children admitted to hospital with community acquired pneumonia the diagnostic and prognostic accuracy of five markers of serious bacterial infection in malawian children with signs of severe infection streptococcus pneumoniae colonisation: the key to pneumococcal disease this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. key: cord- -ot wi xi authors: zaki, sherif r.; paddock, christopher d. title: viral infections of the lung date: journal: dail and hammar&#x ;s pulmonary pathology doi: . / - - - - _ sha: doc_id: cord_uid: ot wi xi the lungs are among the most vulnerable to microbial assault of all organs in the body. from a contemporary vantage, lower respiratory tract infections are the greatest cause of infection-related mortality in the united states, and rank seventh among all causes of deaths in the united states. , from a global and historic perspective, the scope and scale of lower respiratory tract infection is greater than any other infectious syndrome, and viral pneumonias have proven to be some of the most lethal and dramatic of human diseases. the – influenza pandemic, perhaps the most devastating infectious disease pandemic in recorded history, resulted in an estimated million deaths worldwide, including , deaths in the u.s. the global outbreak of severe acute respiratory syndrome (sars) during , although considerably smaller in scale, resulted in cases and deaths and is a dramatic contemporary example of the ability of viral pneumonias to rapidly disseminate and cause severe disease in human populations. the lungs are among the most vulnerable to microbial assault of all organs in the body. from a contemporary vantage, lower respiratory tract infections are the greatest cause of infection-related mortality in the united states, and rank seventh among all causes of deaths in the united states. , from a global and historic perspective, the scope and scale of lower respiratory tract infection is greater than any other infectious syndrome, and viral pneumonias have proven to be some of the most lethal and dramatic of human diseases. the - influenza pandemic, perhaps the most devastating infectious disease pandemic in recorded history, resulted in an estimated million deaths worldwide, including , deaths in the us. the global outbreak of severe acute respiratory syndrome (sars) during , although considerably smaller in scale, resulted in cases and deaths s and is a dramatic contemporary example of the ability of viral pneumonias to rapidly disseminate and cause severe disease in human populations. although viruses are commonly identified causes of pneumonia of infants and young children, they are relatively infrequently recognized as agents of communityacquired pneumonia in adults. in several large series that investigated a microbiologic cause of community-acquired pneumonia, viral etiologies were identified in only % to % of cases (table . ). - however, it is likely that viral pneumonias are underrecognized and underdiagnosed for various reasons. although some agents may cause distinct cytopathology or inclusions (e.g., adenoviruses, herpesviruses, and paramyxoviruses), many important pathogens (e.g., influenza viruses) do not, and none of these agents are resolved specifically in tissue by routine histologic stains. viruses require live cells for cultivation, and are generally more difficult than bacteria to isolate from clinical samples. for some viral pneumonias, the pathogen appears to initiate a cascade of destructive host responses that continue or progress even in the absence of the specific infectious agent, and in these patients the etiologic agent may be absent from host tissues at the time of autopsy. thirty to sixty percent of community-acquired pneumonias are etiologically undetermined, and it is entirely possible that viruses directly cause more episodes of pneumonia than currently appreciated. because viral infections of the lower respiratory tract often precede bacterial pneumonias, viruses may indirectly exert considerable influence on the cumulative morbidity and mortality of infectious pneumonias. , the mechanisms by which viruses may facilitate bacterial invasion of the respiratory tract are complex and varied. certain viruses cause the death of ciliated respiratory epithelium and thereby disrupt normal ciliary activity. viruses may also inhibit the phagocytic or bactericidal activities of neutrophils, t lymphocytes, and alveolar macrophages, and predispose the host to secondary infections. certain gram-positive and gram-negative bacteria adhere to and colonize virus-infected epithelium more readily than to noninfected cells by various hypothetical mechanisms, including alteration and induction of receptors at the host-cell surface and changes in the extracellular environmenty- finally, viral infections of the lung may exacerbate noninfectious pulmonary conditions (e.g., asthma and chronic obstructive pulmonary disease) and indirectly contribute to aggregate morbidity and mortality associated with these conditions. although influenza viruses remain the most frequently identified cause of viral pneumonia in adults (table . ), the diversity of agents identified as causes of viral pneumonias has expanded considerably. several newly recognized viral pneumonias have been identified since that are among the most feared and lethal of all emerging infections, including those caused by hantaviruses, nipah virus, and sars corona virus (co v). ! , - certain causes "rubella ( ), rhinovirus ( ) , mixed viral infections ( ) . source: adapted from greenberg. of viral pneumonia, particularly those that occur in vulnerable patient cohorts, have diminished during this same interval. by example, the u.s. incidence of varicella pneumonia has dropped by two thirds since universal childhood vaccination for varicella was implemented in , , and advances in the clinical management of transplant recipients have reduced the incidence of cytomegalovirus (cmv) pneumonia? also occurring during the last decade has been the development and use of powerful molecular techniques that have unveiled the identity of historic pathogens (e.g., the hini "spanish" influenza a virus), . and have facilitated the rapid characterization of emerging agents (e.g., sars-co v). it should be noted that the disease manifestations of several of these agents (e.g., human parainfluenza virus [hpiv] , respiratory syncytial virus [rsv] , and influenza) are often confined to the upper airway and are not invari- aorb rsv hpiv adeno cmv varicella other' ( ) ( ) ( ) ( . ) ( . ) ( ) ably associated with pneumonia. with some of these pathogens (e.g., influenza viruses, rsv, hantaviruses, and hpiv viruses) respiratory disease is the primary manifestation. for other agents, such as measles, nipah virus, and herpesviruses, typically the lungs are involved as part of a multisystem syndrome. the diagnosis of viral pneumonia, suspected by patient history and clinical manifestations, also can be supported histopathologically, and the general pattern of histopathologic lesions may suggest a specific diagnosis. many viruses can be identified in lung by examining the tissue response and cytopathic changes. some of these viruses cause recognizable tissue reaction patterns including necrotizing tracheobronchitis, bronchiolitis, and interstitial pneumonia. a summary of the key diagnostic histopathologic and ultrastructural features for the most common viral pathogens that cause a majority of pulmonary infections is provided in tables . and . . yes (cytoplasmic; ill-defined) yes (nuclear and cytoplasmic) pulmonary tissue reaction necrotizing bronchiolitis; smudge cells; dad severe edema, early dad interstitial pneumonia; dad; occasional multinucleation interstitial pneumonia; dad; cytomegaly dad; necrosis and rare multinucleation dad; necrosis and rare multinucleation dad; necrotizing bronchiolitis interstitial pneumonia with multi nucleation dad dad; interstitial pneumonia with occasional multinucleation necrotizing bronchiolitis, interstitial pneumonia with occasional multinucleation recently recognized; human pathology not well described interstitial pneumonia with multinucleation; dad only certain viruses can cause cytopathic changes that are sufficiently distinct to enable the pathologist to recognize a specific diagnosis on routine histologic examination of lung specimens. with the availability of special figure . . negative stain electron microscopic images of different viruses that can cause pulmonary infections. a. adenovirus. adenoviruses are protein-shelled icosahedral-shaped nonenveloped viruses that measure approximately to nm in diameter. two of the viruses are stain penetrated revealing the dna-containing nucleoprotein. b. sin nombre virus. sin nombre virus, the causative agent of hantavirus pulmonary syndrome, belongs to the genus hantavirus in the family bunyaviridae. the envelopes of hantaviruses are checkerboard in appearance, and particles measure to nm in diameter. c. herpes simplex virus. the stain has penetrated the envelope of several of these herpesvirus particles, delineating the icosahedral-shaped nucleocapsids, which measure to nm in diameter. d. cytomegalovirus. another herpesvirus; one virus particle (left) is intact while two nearby particles are stainpenetrated and show the viral nucleocapsids. the nucleocapsid of the upper right particle shows a central core that harbors the dna of the virus. e. influenza virus. influenzaviruses belong to the family orthomyxoviridae; viral particles are pleomorphic s.r. zaki and cd. paddock diagnostic techniques, such as immunohistochemistry (ihc) and in-situ hybridization (ish), many viruses can be detected in formalin-fixed, paraffin-embedded tissue samples even if specific viral inclusions cannot be found in histologic examination of tissue sections. among the techniques, ihc utilizing specific antibodies can be routinely performed on formalin-fixed tissue and can enhance the pathologist's accuracy in identifying organisms in tissue specimens. in addition to histologic pattern recognition, ihc, and ish in tissue, several other diagnostic tests are available to aid the pathologist. cell culture techniques, serology, polymerase chain reaction (pcr), and electron microscopy (em) all play vital roles in the diagnosis of these infections. while histologic techniques can be an excellent means of demonstrating organisms, tissue culture isolation remains essential for definitive identification of the virus. when a viral pneumonia is suspected, samples of lung tissues should be evaluated by cell culture, which has the advantage of being a nonbiased method for screening purposes that does not rely on the availability of specific antibodies or probes. electron microscopy offers the same utility as a broad scope diagnostic tool and has been especially critical in outbreaks of unknown etiology. it played a critical role during the hendra and nipah virus outbreaks in and , respectively, and more recently, in the early recognition of a novel coronavirus associated with sars in and in the diagnosis of emerging transplant-associated infections. . . - the advantage of this approach is that viral particles may be demonstrated by negative stain or thin section em, either directly in clinical material or after amplification in cell culture. like culture, em is not limited by narrow specificity of reagents or by prior clinical bias ( fig. . ). and can be filamentous or spherical in shape. the evenly spaced spikes cover the entire virus surface and contain both the hemagglutinin and neuraminidase surface glycoproteins. f. human metapneumovirus. these paramyxoviruses are heterogeneous in size and shape, and range in size from nm to j.lm in diameter. g. parainfluenza virus. another paramyxovirus, the viral nucleocapsid, with its typical herringbone appearance, can be seen both within the stain-penetrated particle as well as partially extruded from the virion. an important feature that can help distinguish between paramyxovirinae (parainfluenza and measles viruses) and pneumovirinae (human metapneumovirus and respiratory syncytial virus) is the diameter of the nucleocapsids, which measure nm and nm, respectively. h. severe acute respiratory syndrome (sars) coronavirus. these -to -nm particles are named for the characteristic crown-like fringe on the surface. scale bars, nm. (a,b,d,f,h: courtesy of c. humphrey; c,g: courtesy of e. palmer; e: courtesy of ea. murphy, all at centers for disease control and prevention, atlanta, ga.) adenoviruses were first cultured and identified during the early s by investigators searching for etiologic agents of acute respiratory infections. the initial adenovirus isolate was made serendipitously from adenoid tissues obtained from children during efforts to establish a primary human adenoid cell line. a related virus was identified the following year by investigators studying respiratory disease in military recruits? these agents were subsequently named adenoviruses after the original source of tissue from which the prototype strain was identified. adenoviruses are non enveloped viruses with a single, linear, double-stranded dna genome that is contained within an icosahedral capsid that measures to nm in diameter (fig. ilia) . the capsid is comprised of seven known polypeptides, including the hexon capsomere, which contains group-specific antigenic determinants. adenoviruses are a ubiquitous and diverse group of viruses found naturally in the upper respiratory tracts and gastrointestinal systems of humans, other mammals, and birds. most adenoviruses infect mucosal epithelium, although some pathogens of animals are trophic for endothelial cells, and endothelial infection has been identified in some immunocompromised humans. adenoviruses are represented by at least serotypes on the basis of resistance to neutralization by antisera to other known adenovirus serotypes, and comprise six subgroups or subgenera (a through f) that are distinguished by differential hemagglutination with erythrocytes from various animal species. , ao more than % of the known adenovirus serotypes are associated with human diseases of the upper and lower respiratory tract, conjunctiva, urinary tract, intestine, and occasionally heart, liver, and central nervous system. the others are rarely encountered and mayor may not act as pathogens in recognizable disease. it is estimated that approximately % to % of all pneumonias in infants and young children are caused by adenoviruses. , most pediatric cases of adenovirus pneumonia occur between months and years of age, and serotypes , , and (all members of the b subgenus), are the most common causes of pneumonia in this patient cohort. - serotypes and are particularly pathogenic adenoviruses that can cause disseminated and often fatal disease in previously healthy children. in adults, pneumonia is generally associated with serotypes , , and . periodic epidemics of adenovirus pneumonia in young adults have been identified, particularly among military recruits. , in a manner similar to other pathogens, adenoviruses take advantage of impaired or destroyed immune systems to establish persistent and disseminated infections in immunocompromised hosts. in this patient cohort, the s.r. zaki and cd. paddock case fatality rate of adenoviral pneumonia approaches %, compared with an approximately % mortality in immunocompetent patients. immunocompromised patients are also susceptible to a broader range of different adenovirus serotypes. by example, the commonly recognized serotypes in normal children account for only about % of the adenovirus serotypes reported for children with congenital immune deficiencies. . because some adenoviruses establish latency in lymphoid tissues and the kidneys of their host, it is believed that many, possibly most, cases of clinical disease caused by adenoviruses in immunocompromised patients are reactivated infections. the lungs of patients with adenovirus pneumonia are typically heavy and edematous, and the bronchi are generally filled with mucoid, fibrinous, or purulent exudates. the histopathologic findings ( fig. . ) include necrotizing bronchitis and bronchiolitis with extensive denudation ofthe surface epithelium,particularly in medium-sized ( to mm in diameter) intrapulmonary bronchi ( fig. . a). affected airways may be occluded by homogeneous eosinophilic material, mixed inflammatory cells, detached epithelium, and cellular debris. the lamina propria of bronchi and bronchioles is typically congested and infiltrated by predominantly mononuclear inflammatory cell infiltrates. bronchial serous and mucous glands are also often involved and show necrosis and mixed infiltrates. o as the infection progresses, there is involvement of the pulmonary parenchyma, forming bronchocentric necrosis with hemorrhage, neutrophilic and mononuclear cell infiltrates, and karyorrhexis. these findings generally occur against a background of exudative diffuse alveolar damage, with filling of the air space by macrophages, fibrin, and detached pneumocytes, and hyaline membrane formation. patients with fatal pneumonia may develop disseminated intravascular coagulopathy and demonstrate fibrin thrombi in vessels of the lungs, kidney, heart, adrenals, and central nervous system (see fig. . in chapter ). adenoviruses form intranuclear inclusions in respiratory epithelial cells of the trachea, bronchi, and bronchioles, in the acinar cells of bronchial glands, and in alveolar pneumocytes, and are generally most abundant at the viable edges of necrotic foci. by using the hematoxylin and eosin (h&e) stain, early inclusions appear as small, dense, amphophilic structures surrounded by a cleared zone and peripherally marginated chromatin, similar to herpetic inclusions. as the cellular infection progresses, the inclusion becomes larger (as large as /-lm in some cells) and more basophilic, and the margins of the nuclear membrane become blurred to form the characteristic "smudge cell" (fig. . b,c). o, tracheal aspirates of patients with adenovirus pneumonia may show distinctive features on cytologic preparations that include cells with fine strands of chromatin that radiate from a central inclusion to the marginated chromatin at the nuclear membrane ("rosette cells"), and cells with foamy, "honeycomb" nuclei, as well as typical smudge cells (see fig. . in chapter ). various methods can be used to diagnose adenovirus infections that include antigen detection, cell culture, electron microscopy, molecular assays, and serology. direct detection techniques that identify the common group-reactive hexon antigen in tissues or body fluids include fluorescence antibody assays and enzyme immunoassays. immunohistochemistry staining methods have been used successfully to detect adenovirus-infected cells in formalin-fixed, paraffinembedded tissues using various commercially available, adenovirus group-specific antibodies ( fig. . e,f). , electron microscopy of adenovirus-infected tissues reveals a paracrystalline array of virions ( fig. . d ). , most adenoviruses can be isolated in cell culture from bronchial washings, tracheal aspirates, or lung biopsy specimens during the early stage of the illness and grow well in various cell lines, including human embryonic kidney, hela, and hep- cells. cell cultures infected with adenoviruses exhibit a relatively characteristic cytopathologic effect, described as a "cluster of grapes," within to days after inoculation. serotyping of the isolate is accomplished by using hemagglutination inhibition and neutralization tests with hyperimmune type-specific animal antisera. molecular assays, particularly gene amplification using pcr, and ish methods, have been developed to detect adenovirus nucleic acid in respiratory secretions and in formalin-fixed, paraffin-embedded tissues. , , broad-range, sensitive assays that can detect any adenovirus amplify common genomic sequences (e.g., the hexon gene region). other more specific assays detect specific adenovirus types with unique genomic sequences. serologic assays include tests for groupspecific antibodies (e,g., complement fixation and enzyme immunoassays), or type-specific antibodies (e.g., neutralization and hemagglutination-inhibition assays). pitfalls associated with serologic testing for adenoviruses include occasional rises in heterotypic antibodies when typespecific assays are used, and relatively low sensitivity demonstrated by complement fixation assays. human hantaviral diseases are caused by a group of closely related, trisegmented, negative-sense rna viruses of the genus hantavirus, of the family bunyaviridae. - members of the genus hantavirus have similar morphologic features. , virus particles are to nm in diameter and generally appear spherical to ovoid, although pleomorphic forms may be seen. a lipid envelope containing glycoprotein spikes surrounds a core consisting of the genome and its associated proteins (nucleocapsids) s.r. zaki and cd. paddock arranged in delicate tangles of filaments showing occasional granulation. the presence of characteristic inclusion bodies in thin section electron microscopy and a unique grid-like pattern on negative-stain electron microscopy differentiate these viruses from other members of the family bunyaviridae ( fig. . b) . , the severity and disease type largely depends on the viral serotype. two categories of hantavirus-associated illnesses are described: hemorrhagic fever with renal syndrome (hfrs) for disease in which the kidneys are primarily involved, and hantavirus pulmonary syndrome (hps) for disease in which the lungs are primarily involved. - the isolation of the first recognized hantavirus (hantaan virus, named for the river in south korea), and its subsequent identification as the causative agent of hfrs was reported in . in , the deaths of several previously healthy individuals due to a rapidly progressive respiratory disease in the southwestern united states were etiologically linked to a previously unrecognized hantavirus. clinically, the disease differs from hfrs in its pronounced pulmonary involvement and higher mortality rates and is known as hps. . , . hantavirus-associated diseases primarily affect blood vessels and result in different degrees of generalized capillary dilatation and edema. in contrast to severe hfrs where abundant protein-rich, gelatinous retroperitoneal edema fluid is found, all hps patients have large bilateral pleural effusions and heavy edematous lungs. in fatal far eastern hfrs, a distinctive triad of hemorrhagic necrosis can be seen in the renal medullary junctional zone, cardiac right atrium, and anterior pituitary. , however, in patients with hps, hemorrhages are rare, and ischemic necrotic lesions, except those attributed to shock, are not seen. , histologically, morphologic changes of the endothelium are uncommon but, when seen, consist of prominent and swollen endothelial cells. vascular thrombi and endothelial cell necrosis are rare. in hfrs, the most severe and characteristic microscopic lesions involve the kidney; however, an interstitial pneumonitis can also be seen in some fatal cases. in contrast, the microscopic changes of north and south american hps are principally seen in the lung and spleen. , the lungs show a mild to moderate interstitial pneumonitis characterized by variable degrees of edema and an interstitial mononuclear cell infiltrate comprised of a mixture of small and enlarged mononuclear cells with the appearance of immunoblasts ( fig. . a). focal hyaline membranes composed of condensed proteinaceous intraalveolar edema fluid, fibrin, and variable numbers of inflammatory cells are observed ( fig. . b). typically, neutrophils are scanty and the alveolar pneumocytes are intact with no evidence of cellular debris, nuclear fragmentation, or hyperplasia. in fatal cases, with a prolonged survival interval, tissues show features more characteristic of the exudative and proliferative stages of diffuse alveolar damage. lung biopsies taken from patients who survive their illness appear similar with proliferated reparative type ii pneumocytes, severe edematous and fibroblastic thickening of the alveolar septa, and severe air-space disorganization with distorted lung architecture (see chapter ) . other characteristic microscopic findings in hps cases include variable numbers of immunoblasts within the splenic red pulp and periarteriolar white pulp, lymph nodal paracortical zones, hepatic portal triads, and peripheral blood ( fig. . d,e) . similarly, in severe hfrs cases, large mononuclear cells can be present in the spleen, lymph nodes, blood, and hepatic portal triads. . electron microscopic studies of hps lung tissue demonstrate infection of endothelial cells and macrophages. . the virus or virus-like particles observed are infrequent and extremely difficult to identify in autopsy tissues because of the considerable degree of viral pleomorphism and the postmortem deterioration of tissues. however, typical hantaviral inclusions are seen more frequently and their identity can be confirmed by immunolabeling ( fig. . f,g). similar inclusions are observed in epithelial cells in hfrs and are considered to be ultrastructural markers of hantavirus-infected cells. . . o using immunohistochemistry, viral antigens are found primarily within capillary endothelium throughout various tissues in both hps and hfrs. in hps, marked accumulations of hantaviral antigens are in the pulmonary microvasculature and in splenic and lymph nodal follicular dendritic cells (fig. . c). despite the extensive endothelial cell accumulations of hantaviral antigens, there is little ultrastructural evidence of cytopathic effect. hantavirus pulmonary syndrome should be suspected in cases of adult respiratory distress syndrome (ards) without a known precipitating cause among previously healthy individuals. the level of suspicion should be particularly high when patients have a known exposure to rodents in areas where peromyscus maniculatus or other reservoirs of hantavirus are found. physicians need to differentiate hps from other common acute respiratory diseases, such as pneumococcal pneumonia, influenza virus, and unexplained ards. the diagnosis of hps, suspected by patient history and clinical manifestations, can also be supported histopathologically. although there is no single pathognomonic lesion that would permit certain histopathologic diagnosis of hps, the overall constellation of histopathologic hematologic findings suggests the diagnosis. . diseases that need to be distinguished pathologically from hps include a relatively large number of different viral, rickettsial, and bacterial infections, as well as various noninfectious disease processes. virus-specific diagnosis and confirmation can be achieved through serology, pcr for hantavirus rna, or ihc for hantaviral antigens. , serologic testing can detect hantavirus-specific immunoglobulin m or rising s.r. zaki and cd. paddock titers of immunoglobulin g in patient sera and is considered the method of choice for laboratory confirmation of hps. immunofluorescent assays and enzyme-linked immunosorbent assays (elisas), which demonstrate the presence of specific antihantaviral antibodies, are currently used as rapid diagnostic tests and provide results within a few hours. recently, synthetic hantaviral nucleocapsid proteins have been used to improve the sensitivity and specificity of serologic assays. these proteins are more available than inactivated hantaviral antigens. . polymerase chain reaction detects viral rna in blood and tissues and is extremely useful for diagnostic and epidemiologic purposes. hantaviral rna can also be detected in formalin-fixed, paraffin-embedded archival tissue by reverse-transcriptase (rt)-pcr. immunohistochemistry testing of formalin-fixed tissues can be used to detect hantavirus antigens, and is a sensitive method to confirm hantaviral infections. it has a unique role in the diagnosis of fatal hps cases when serum samples and frozen tissues are unavailable but formalinfixed autopsy tissues are obtainable. • severe acute respiratory syndrome the causative agent of sars is an enveloped, positivestranded rna virus that is a member of the genus coronavirus, of the family coronaviridae. corona viruses have the largest genomes of all rna viruses and replicate by a unique mechanism that results in a high frequency of recombination. maturation of sars coronavirus (sars-co v) is similar to features previously described for other coronaviruses. - virions form by alignment of the helical nucleocapsids along the membranes of the endoplasmic reticulum or golgi complex and acquire an envelope by budding into the cisternae. the cellular vesicles become filled with virions and progress to the cell surface for release of the virus particles; large numbers of particles remain adherent to the plasma membrane at the cell surface. severe acute respiratory syndrome was recognized during a global outbreak of severe pneumonia that began in late in guangdong province, china, and gained prominence in early as cases were identified in more than two dozen countries in asia, europe, north america, and south america. the disease causes an influenza-like illness with fever, cough, dyspnea, and headache, and in severe cases it can cause death in humans. person-toperson transmission, combined with international travel of infected persons, accelerated the worldwide spread of the illness. • . several reports have described diffuse alveolar damage with various levels of progression and severity as the main histopathologic findings in sars patients ( fig. . a,b)y· - lungs typically show changes described for the proliferative phase of diffuse alveolar damage, with hyaline-membrane formation, desquamation of epithelial cells, fibrin deposit in the alveolar space, and hyperplasia of type pneumocytes. increased mononuclear infiltrate in the interstitium can be seen in some cases. other findings identified in some patients included focal intra alveolar hemorrhage, necrotic inflammatory debris in small airways, and organizing pneumonia. in addition, multinucleated syncytial cells may be seen in the intraalveolar spaces of some patients who died days or more after onset of illness ( fig. l . c). infection with some coronaviruses, including sars-co v, is known to induce cell fusion in culture producing syncytial cells similar to those sometimes observed in lungs of patients who die from sars. these cells contain abundant vacuolated cytoplasm with cleaved and convoluted nuclei, but without obvious intranuclear or intracytoplasmic viral inclusions. the ish and ihc studies of tissues from sars patients have identified corona virus infection of upper airway bronchiolar epithelium ( fig. . d_f). , - infected ciliated columnar epithelial cells can be seen focally in lining epithelium of trachea and larger bronchi ( fig. . e). many of these infected cells slough from the epithelium and can be observed by using ish within the bronchial lumen. abundant viral antigens can also be found distributed focally in parenchyma of lungs of some patients and are seen predominantly in the cytoplasm of pneumocytes, in occasional macrophages, and in association with intra alveolar necrotic debris and fibrin (fig. ll. d). double-stain studies indicate that most sars-co v-infected cells are type pneumocytes. double-stain studies also detected viral nucleic acids with a distribution similar to that seen in ihc studies, mainly in pneumocytes and in some macrophages.looelectron microscopic examination of lung tissues selected from areas with abundant ihc staining shows numerous coronavirus particles and nucleocapsid inclusions. virions are seen in cytoplasmic vesicles and along the cell membranes of pneumocytes, in phagosomes of macrophages, and associated with fibrin in alveolar spaces (fig.ll. g-i). because corona virus particles may be confused morphologically with other non viral cellular components, definitive ultrastructural identification can be achieved by using immunogold labeling electron microscopy. the primary histopathologic lesions seen in the lungs of patients who die from sars are somewhat nonspecific and can also be seen in acute lung injury cases caused by infectious agents, trauma, drugs, or toxic chemicals. multinucleated syncytial cells similar to those seen in some sars patients can also be found in a number of virus infections, including measles, parainfluenza viruses, rsv, and nipah virus infections. - in an early study of four human sars patients, viral antigens were not detected in the lung by ihe. the most likely explanation is that all patients in the study had a clinical course aver-s.r. zaki and cd. paddock aging more than weeks. for many virus infections, viral antigens and nucleic acids are cleared within weeks of disease onset by the host immune response. it is also possible that the pulmonary damage associated with sars is not caused directly by the virus, but represents a secondary effect of cytokines or other factors induced by the virus infection. similarly, in influenza virus infections, viral antigens are seen predominantly in respiratory epithelial cells of large airways and are only rarely identified in pulmonary parenchyma despite concomitant and occasionally severe interstitial pneumonitis. !os in recent reports by shieh et al. and chong et al., the temporal relationship between the duration of illness and clearance of sars-co v in human lung tissue was examined. viral antigens and nucleic acids were detected only in pulmonary tissues of patients who died early in the disease. the development of specific ihc, ish, and immunoelectron microscopy (iem) assays to identify sars-co v in formalin-fixed, paraffin-embedded samples has facilitated the assessment of the cellular tropism of sars-co v infection in human lung tissues. localization of sars-co v in the lung occurs mainly in the cytoplasm of pneumocytes, primarily type , and occasionally in alveolar macrophages ( fig. ll. f ). type pneumocytes are known to secrete pulmonary surfactant, resulting in reduced surface tension and preservation of the integrity of the alveolar space. these cells also play an important role in tissue restitution following lung damage. moreover, there is mounting evidence to support their contribution to the development of acute inflammatory lung injury following exposure to biological or chemical agents. additional studies are needed to further define the role of type pneumocytes and alveolar macrophages in sars-co v infection. cynomolgus macaques inoculated with sars-cov develop pathologic findings of pneumonia and have been proposed as an animal model. haagmans et a . showed extensive sars-co v antigen expression in experimentally infected macaques days after infection. the antigens were mainly in alveolar lining epithelial cells with morphologic characteristics of type pneumocytes, indicating type pneumocytes are the primary target for sars-co v infection early in the disease. type pneumocytes normally represent % of the alveolar epithelial cell volume and are easily damaged during pulmonary infections or other types of injury. in a more recent study on nonhuman primates, evidence of infection of type pneumocytes in addition to some type pneumocytes and macrophages was found. small animal models, such as rodents, would be very useful for evaluating vaccines, immunotherapies, and antiviral drugs, and we have recently identified the mouse as an animal model for this purpose. in those studies, microscopic examination of trachea, bronchus, lung, thymus, and heart on day after infection revealed mild and focal peri bronchiolar mononuclear inflammatory infiltrates with no significant histopathologic change in other organs. viral antigens and nucleic acids were focally distributed in bronchiolar epithelial cells, and virions were found in these same areas by ultrastructural analysis. data suggest that sars-co v replicates in mice to a titer sufficient to evaluate vaccines and antiviral agents. the mouse and other small animal models l o might also be used to test the ability of the virus to replicate and cause disease and facilitate identification of host-immune mechanisms that contribute to the resolution of sars-co v infection. cytomegaloviruses (cmv) comprise a distinct and ancient group of herpesviruses that are widely distributed in nature, share similar growth characteristics in cell culture, and cause cellular enlargement and form distinctive inclusions in infected cells. these cytopathic changes, identified by early pathologists in the salivary glands of children dying from various unrelated diseases, - led to the early designation of cytomegalic inclusion disease many years before the causative agent was isolated in the mid- s. the name cytomegalovirus was proposed in to reflect the cytopathic changes caused by these viruses. cytomegaloviruses are highly host-specific, and various mammalian hosts, including nonhuman primates, rodents, and domesticated animals, are infected with their own distinct cmy. in this context, human cmv is stringently species-specific and, with rare exception, only infects cells of human origin. ll several cell types are permissive for cmv replication, including alveolar pneumocytes, vascular endothelium, fibroblasts, monocytes, dendritic cells, and exocrine and endocrine glandular epithelial cells.ll cytomegalovirus is a ~-herpesvirus with the largest genome ( kilobase pair [kbp]) of all the herpesviruses known to infect humans. the double-stranded linear dna genome is contained within a to nm icosahedral capsid and is surrounded by an amorphous material known as the tegument. these components are enclosed in a lipid bilayer envelope that is derived from the host cell nuclear or golgi membranes and contains several vir ally encoded glycoproteins necessary for infection of other cells. mature enveloped virions range from to nm, making cmv one of the largest viruses that infect humans (fig. i . d ).ll the structure of cmv is typical of other human herpesviruses, but demonstrates some subtle ultrastructural differences from other viruses in this group including greater pleomorphism of the lipid envelope and dense body inclusions in the cytoplasm of infected cells.ll cytomegalovirus is a ubiquitous human pathogen, and in north america infects approximately % to % of the population.ll most of these infections are inapparent, although some cases of primary infection in otherwise healthy individuals result in a self-limited mononucleosis syndrome similar to that caused by epstein-barr virus; it is estimated that % to % of cases of heterophile-negative mononucleosis, and % of all cases of mononucleosis, are caused by cmy' pulmonary involvement in cmv mononucleosis is infrequent and occurs in approximately % of these casesyo congenitally acquired cmv infection has various deleterious effects on the fetus, including mental retardation, neurologic abnormalities, sensorineural hearing loss, and retinitis, and in one series pulmonary involvement occurred in % of symptomatic infants. like all herpesviruses, cmv remains with its host for life after primary infection and establishes latency in various cell types, including vascular endothelial cells, monocytes and macrophages, neutrophils, and renal and pulmonary epithelial cells. activation of viral replication occurs in persons with severely compromised immunity. patients with advanced hiv disease and recipients of hematopoietic stem cell or lung transplants are particularly at risk of developing cmv pneumonia. before the use of cmv screening and effective antiviral prophylaxis regimens, % to % of all patients undergoing allogeneic bone marrow transplantation for leukemia, and % to % of solid organ transplants, developed cmv pneumonia with case fatality rates of greater than % in some series. , , the relatively high frequency of cmv pneumonia in lung transplant recipients may be a correlate of animal model data that indicate the lungs are a major site of latent cmv infection. before the use of ganciclovir as therapy for cmv disease in aids patients, the case fatality rate for cmv pneumonia in this patient cohort was % when cmv was the only pathogen identified. mixed infections with cmv and another pathogen had an even worse prognosis, and the case fatality rate for patients with pulmonary disease caused by cmv and pneumocystis jiroveci (formerly carinii) was %. cytomegalovirus pneumonia can show various histopathologic patterns (fig. . ). extensive intra alveolar hemorrhage with scattered cytomegalic cells and relatively few inflammatory cell infiltrates may occur ( fig. . a). in a similar manner, extensive involvement of the alveolar epithelium with minimal inflammation or overt evidence of parenchymal injury has also been described. other patterns include multifocal lesions with mixed inflammatory cell infiltrates, hemorrhage, necrosis, and cytomegalic cells, or a diffuse, predominantly mononuclear cell infiltrate, interstitial pneumonitis with intraalveolar edema and fibrin deposition, and diffusely distributed cytomegalic cells (fig. . e). - the cytomegalic changes of cmv-infected cells are evident by standard h&e staining and are virtually pathognomonic of active cmv infection. the cells are enlarged ( to !j,m) and contain amphophilic to deeply basophilic intranuclear and intracytoplasmic inclusions ( fig. . b,e). the single intranuclear inclusion is composed of viral nucleoprotein and assembled caps ids, and is a large (up to !j,m), round to ovoid body with a smoothly contoured border that is generally surrounded by a clear halo that gives the inclusion a distinctive owl'seye appearance. the host cell nucleolus is often retained in the inclusion. cytoplasmic inclusions are small ( to !j,m), granular bodies that appear after the intranuclear inclusion is well developed and are not uniformly present in all cmv-infected cells (fig. . b). these inclusions represent a mixture of virions and various cellular organelles, and increase in size and number as the infection progresses. unlike the intranuclear inclusion, the cytoplasmic inclusions stain with periodic acid-schiff stain and are deeply argyrophilic with gomori's methenamine silver stain.! cytomegalovirus pneumonia is defined by the presence of signs or symptoms of pulmonary disease combined with the detection of cmv in bronchoalveolar lavage (bal) fluid or lung tissue samples. in this context, detection methods that support this definition include virus isolation, histopathologic observation of cytomegalic cells, ish, or ihc stains (fig. . f). detection by pcr alone is considered too sensitive for the diagnosis of cmv pneumonia and is insufficient for this purpose. cytomegalovirus is most often cultured in human diploid fibroblasts such as human embryonic lung and human foreskin fibroblasts. it grows slowly in conventional cell culture, and the cytopathic effect is generally not detected until the second week or longer after inoculation. for this reason, a shell vial method using centrifugation to enhance infectivity has become the standard isolation technique and can usually yield diagnostic results within hours. for centuries, the term herpes, derived from the greek erpein (to crawl), was used in medicine to describe any spreading cutaneous lesion. by the end of the th century, investigators surmised that the herpetic lesions of the lips and genitalia were manifestations of a single infectious agent, and recognized that it was a disease distinct from herpes zoster. . as with all human herpesviruses, hsv is a large, enveloped, double-stranded dna-containing virion with an icoshedral nucleocapsid approximately to l nm in diameter, composed of cap somers. the nucleocapsid is surrounded by an amorphous, sometimes asymmetric material (the tegument) that is surrounded by a thin, trilaminar envelope that contains numerous glycoprotein spikes (fig. . c ). the assembly of hsv begins in the nucleus of its host cell and the virus acquires its envelope as the capsid buds through the inner lamella of the nuclear membrane. .l two serologic types are recognized and each is most frequently associated with particular disease syndromes; however, either serotype may cause any of the aggregate clinical syndromes. herpes simplex virus- causes gingivostomatitis, pharyngitis, esophagitis, keratoconjunctivitis, and encephalitis, and is the serotype most commonly associated with adult hsv pneumonia. herpes simplex virus- typically infects genital sites such as the penis, urethra, vulva, vagina, and cervix, and is the serotype associated with approximately % of disseminated disease and pulmonary infections in newborn infants. all herpesviruses have the ability to persist in an inactive state for varying periods of time and then recur spontaneously following undefined stimuli associated with physical or emotional stress, trauma to nerve roots or ganglia, fever, immunosuppression, or exposure to ultraviolet radiation. during the primary infection, hsv replicates at the portal of entry (typically oral or genital mucosae), and infects sensory nerve endings. the virus is transported centripetally along peripheral sensory nerves to central axons and finally to nerve cell bodies in the trigeminal, sacral, and vagal ganglia, where it replicates briefly before becoming latent. - antiviral drugs have no effect on latent infection with hsv. following cues that initiate viral reactivation, hsv replicates in sensory ganglia and is transported centrifugally along sensory nerves to epithelial cells on mucosal surfaces. reactivation of hsv from the trigeminal ganglion is associated with asymptomatic excretion of virus in saliva, and with the development of herpetic ulcers on the vermillion border of the lip, oral mucosa, or external facial skin. newborn infants, severely immunosuppressed or burned patients, and patients with severe trauma are at greatest risk of developing hsv pneumonia. - lower respiratory tract disease in neonates is most commonly associated with disseminated herpetic infections. disseminated hsv infection in the newborn was first described in as "hepatoadrenal necrosis" because of the prominent and frequent necroses that occur in the livers and adrenal glands of affected neonates. most cases of neonatal disease represent primary hsv infections and are acquired during parturition from hsvinfected mothers. the incidence of neonatal hsv infection is approximately in deliveries, and disseminated disease develops in approximately % of infected neonates. in disseminated infections, signs and symptoms appear a mean of days after birth (range, to days), and approximately % to % of these patients develop pneumonia. in the pre antiviral era, % of neonates with disseminated disease died from the infection. with early diagnosis and high-dose acyclovir therapy, mortality has been reduced to approximately %? , , the disease can be exceedingly difficult to diagnose in a timely manner as only % of mothers of affected infants have clinically apparent hsv infection at the time of delivery. o neonates that survive severe disseminated disease may develop hepatic and adrenal calcifications evident on abdominal radiographs. in adults, infection of the respiratory tract with hsv may be associated with disseminated herpetic infection, but is more commonly identified as an isolated disease manifestation resulting from reactivation of latent herpetic infections in the oropharynx. herpetic tracheobronchitis is an ulcerative process characterized by large areas of denuded mucosal epithelium and fibrinopurulent exudate containing necrotic cells with densely eosinophilic cytoplasm. despite extensive tissue damage, cells with intranuclear inclusions may be sparse, and, when identified, are found most often at the margins of the ulcerated epithelium or occasionally in the mucous glands subjacent to ulcerated surfaces. ls aspiration of viruscontaining secretions into the lower respiratory tract is believed to be the most frequent cause of pulmonary infection with hsv; however, oral lesions may be absent in patients with herpetic laryngotracheobronchitis and bronchopneumonia. disease can be also associated with airway trauma caused by tracheal intubation or from hematogenous dissemination of hsv. , s , s chest radiographs of hsv pneumonia generally show ill-defined nodular or reticular densities of various sizes scattered in both lung fields. during the early stages of disease, these nodules measure to mm and are best seen in the periphery of the lungs. as the disease progresses, these lesions coalesce and enlarge to form more extensive infiltrates. herpetic infections of the airways and lung are characteristically difficult to diagnose clinically and hsv pneumonia was not described as a distinct clinical entity until . several studies attest to the relative infrequency with which this diagnosis is considered in patients with respiratory disease. for example, none of the cases of hsv disease of the middle and lower respiratory tract identified in a review of autopsies at brooke army medical center during to were suspected prior to autopsy. in a review of culture-confirmed cases of hsv pneumonia, none of the patients had been diagnosed prior to death and all had oral herpetic lesions at the time of death. recent investigations also suggest that lower respiratory tract disease caused by hsv may be more common than currently appreciated. in a study from sweden, hsv was cultured from pro- a diagnosis of tracheobronchitis and pneumonia is best established histologically (fig. . ). because lower respiratory tract hsv infections are often focused in the tracheobronchial tree, open lung biopsy may be less sensitive than bronchoscopy. herpetic lesions show extensive necrosis and karyorrhectic debris and are associated with hemorrhage and a sparse-to-moderate neutrophilic infiltrate (fig. . a,b) . intranuclear inclusions are best appreciated in cells at the leading edge of necrotic foci ( fig. . b,c). inclusions appear either as homogeneous, amphophilic, and glassy (cowdry type b inclusions), or as eosinophilic with a halo separating the inclusion from the nuclear membrane (i.e., cow dry type a inclusions). cowdry type b inclusions contain actively replicating virus. type a inclusions, considered noninfectious and devoid of viral nucleic acid or protein, represent the nuclear "scar" of hsv infection. , other changes associated with hsv, including multi nucleation and nuclear molding, and ballooning degeneration of the cytoplasm, are more frequently associated with squamous epithelium and are seldom encountered in the lung. because of the high frequency of hepatic and adrenal involvement with disseminated hsv infection in young children ( fig. . f,g), liver biopsy has been suggested as a diagnostic technique in this patient cohort. commercially available antibodies exist for ihc detection of hsv in tissues (fig. . d ).ls virus isolation remains an important diagnostic method; however, because hsv can be isolated from oropharyngeal secretions and occasionally from the lower respiratory tract of patients who lack overt pulmonary disease, virologic cultures must be interpreted in the context of complementary clinical, radiographic, and histopathologic findings as much as possible. cell culture systems susceptible to hsv include vero cells and foreskin fibroblasts. cytopathic effects generally develop within to hours after cultures are inoculated with infectious specimens. suitable specimens include scrapings made from mucocutaneous lesions, tracheobronchial aspirates, or bal specimens. in infants with evidence of hepatitis, it may also be useful to obtain duodenal aspirates for hsv isolation. polymerase chain reaction methods that amplify hsv dna from clinical specimens, including tissue and blood, can be particularly useful by specifically distinguishing between hsv-l or hsv- infections. , varicella-zoster virus (vzv), also known as human herpesvirus (hhv- ) , is a human a-herpesvirus most closely related to hsv. it has a linear, double-stranded dna genome with approximately kbp that encodes more than proteins. the icosahedral nucleocapsid is indistinguishable in appearance from other herpes viruses. the nucleocapsid and the tegument are surrounded by a lipoprotein envelope derived from the host cytoplasmic membranes. the enveloped viral particle is pleomorphic to spherical in shape and to nm in diameter. o the primary infection is initiated by inoculation of respiratory mucosa by the virus through infectious aerosols or by direct contact of skin lesions of patients with varicella or herpes zoster. after a primary viremia in the reticuloendothelial system, and secondary viremia in circulating mononuclear cells, the virus is disseminated to the skin, where it initiates a vesicular rash, and back to mucosal sites in the lungs. the release of infectious virus into respiratory droplets is a pathogenic characteristic that distinguishes vzv from other human herpesviruses. the attack rate for previously uninfected household contacts exposed to varicella is approximately %. for less sustained exposure, it is estimated to be approximately % to %. during primary infection with vzv, viral replication in keratinocytes (fig. . a) and vascular and lymphatic endothelial cells of the superficial dermis produces the generalized, pruritic, vesicular rash of varicella commonly known as chickenpox. varicella-zoster virus also establishes latent infection within satellite cells and neurons of the trigeminal and dorsal root ganglia and can reactivate under various conditions to cause herpes zoster, a painful vesicular rash commonly referred to as shingles. the origin of the term chickenpox is speculative, but believed to derive from gican, an old english term for itching. the term shingles originates from the medieval latin cinguls, or girdle, and alludes to the partial encircling of the trunk by the rash of herpes zoster. , varicella-zoster virus is ubiquitous in human populations around the world, and humans are the only known host. during the prevaccine era in the u.s., approximately million cases, to hospitalizations, and to deaths were reported annually. . the risk of severe illness during primary or recurrent vzv infection appears to depend more on host factors rather than a particular viral strain. chickenpox is considered a relatively benign infection in children, but adult patients are approximately times more likely than children to develop pneumonia. the greatest risk of severe disease and pneumonia occurs in those patients with chronic lung disease, immunesuppressing conditions, neonates, and pregnant women. varicella-zoster virus-related deaths have declined sharply in the u.s. since universal childhood vaccination was implemented in . , s.r. zaki and cd. paddock varicella pneumonia was first described in the medical literature in and is the most frequently reported complication of chickenpox in adult patients. , pneumonia occurs in approximately % to % of adults infected with vzv. , the occurrence of pneumonia during herpes zoster is rare, and limited primarily to profoundly immunosuppressed patients, particularly bone marrow transplant recipients. m varicella-zoster virus pneumonia generally develops within to days following the onset of rash and may be characterized by fever, cough, tachypnea, chest pain, and hemoptysis. . hypoxemia is common and may be severe. radiographically, the lungs show multiple, scattered, defined, nodular densities. untreated adult varicella pneumonia is fatal in approximately % of cases, but mortality is as high as % to % in certain high-risk cohorts, including pregnant women, transplant recipients, and neonates. ,lfj - massive pulmonary hemorrhage is a frequent terminal event. gross examination reveals lungs that are generally two to three times heavier than normal, firm, and plumcolored. there are often multiple necrotic and hemorrhagic lesions on the visceral pleura that resemble the pox lesions of skin. , , pox may also be seen on the parietal pleura, although pleural effusions are uncommon and rarely prominent. , the trachea and bronchi are generally edematous and erythematous with occasional vesicles on the mucosal surfaces, and there may be lobular consolidation of the lungs. microscopically, pulmonary involvement consists primarily of interstitial pneumonitis and diffuse miliary foci of necrosis and hemorrhage in the pulmonary parenchyma that involve alveolar walls, blood vessels, and bronchioles ( fig. . b,d) . other findings may include intraalveolar collections of edema, fibrin, or hemorrhage, diffuse alveolar damage, and septal edema. m , . virally infected cells with intranuclear inclusions may be identified in respiratory epithelial cells, pneumocytes, interstitial fibroblasts, or capillary endothelium ( fig. . e,f). eosinophilic intranuclear inclusions and multinucleated syncytial cells may be difficult to locate but are best identified at the edges of necrotic foci (fig. . c ). in cases of disseminated disease, similar necrotizing hemorrhagic lesions and occasional viral cytopathic changes in epithelial cells or fibroblasts may be observed in other tissues and organs, including esophagus, pancreas, liver, renal pelves, ureters, urinary bladder, spleen, bone marrow, thymus, lymph nodes, adrenal glands, and brain. , in those patients who recover from severe vzv pneumonia, some necrotic parenchymal foci may mineralize, and can be identified by chest radiograph years later as miliary, to mm, nodular opacities. microscopically, the lesions are characterized as discrete collections of dense fibrous connective tissue that surround multiple, small, calcified bodies. the periphery may include a cellular zone of fibroblasts and occasional giant cells. a radiographic survey of , persons identified pulmonary calcifications in eight ( . %) of patients who had chickenpox during adulthood compared with only eight ( . %) of the remaining , who did not report having varicella as an adult. a positive history of varicella predicts immunity in > % of persons. because pulmonary symptoms most often occur several days following the onset of the characteristic rash of varicella, a pathologic diagnosis is seldom required for a real-time diagnosis of vzv pneumonia. however, hematopoietic cell transplant recipients may present with signs of visceral dissemination and pneumonia to days before the localized cutaneous eruption of herpes zoster appears, and lower respiratory tract disease has been described in the absence of skin lesions, particularly in neonates and bone marrow transplant recipients. , , commercially available antigen detection kits can be used for rapid diagnosis of cutaneous vzv infection. epithelial cells are scraped from the base of a newly formed vesicle, applied to a slide, and stained by using fluorescein-conjugated vzv monoclonal antibodies to detect specific viral proteins in the specimen. in a similar manner, the tzanck test uses wright-giemsa stain to demonstrate multinucleated giant cells in these specimens; however, this test does not differentiate between hsv and vzv, and false-negative results are common. commercially available antibodies are also available for ihc detection of vzv in tissue specimens ( fig. . e,f); however, relatively few laboratories are able to provide well-validated assays. some commercial laboratories offer pcr amplification to detect viral nucleic acid in clinical specimens. isolation of the virus in cell culture remains the reference standard for the diagnosis of vzv. in human melanoma cells, an excellent substrate for vzv isolation, the average time for visible cytopathic effect from the virus is to days. infectious vzv is usually recoverable from the clear fluid of cutaneous vesicles of varicella for approximately days after the appearance of these lesions and for approximately week from herpes zoster lesions. the lungs are the most common organ from which vzv is isolated at autopsy, but isolates have also been obtained from heart, liver, pancreas, gastrointestinal tract, brain, and eyes. influenza is derived from the term influentia, meaning epidemic in the italian form of latin, originally used because epidemics were thought to result from astrologic or other occult influences. influenza is a highly contagious, acute respiratory illness with a spectrum of clinical illness ranging from asymptomatic or mild disease with rhinitis or pharyngitis to primary viral pneumonia with s.r. zaki and cd. paddock fatal outcome. influenza may also be associated with a broad range of other disorders affecting the heart, brain, kidneys, and muscle. influenzaviruses belong to the orthomyxoviridae family, which consists of four genera that include the two important influenza viruses types a and b associated with significant human disease. , influenza a viruses are further classified into subtypes based on the antigenicity of their hemagglutinin (ha) and neuraminidase (na) surface glycoproteins. only one type of ha and one type of na are recognized for influenza b. influenza a occurs in both pandemic and interpandemic forms. fortunately, pandemics, defined as worldwide outbreaks of severe disease, occur infrequently. interpandemic influenza, although less extensive in its impact, occurs virtually every year. the epidemiologic pattern of influenza in humans is related to two types of antigenic variation of its envelope glycoproteins, namely antigenic drift and antigenic shift. during antigenic drift, new strains related to those circulating in previous epidemics evolve by accumulation of point mutations in the surface glycoproteins. this enables the virus to evade the immune system leading to repeated outbreaks during interpandemic years. antigenic shift occurs with the emergence of a "new" potentially pandemic, influenza a virus that possesses a novel ha alone or in combination with a novel na. there are recognized ha subtypes and nine na subtypes of influenza a virus. viruses from all ha and na subtypes have been recovered from aquatic birds, but only three ha subtypes (hi, h , and h ) and two na subtypes (nl and n ) have established stable lineages in the human population since . since , widespread avian infection with influenza a (h n ) and associated clusters of human disease have aroused concern about the threat of a pandemic, and attention has been appropriately focused on control measures to deal with such an event. all influenzaviruses have a segmented, negative-sense rna core surrounded by a lipid envelope. influenzavirus particles are pleomorphic. among isolates that have undergone a limited number of passages in cell culture or eggs, more filamentous than spherical particles are seen. spherical morphology becomes dominant when the virus is extensively passaged in the laboratory. a -to -nm layer of ha (rod-shaped) and na (mushroomshaped) spikes project radially on the surface of the influenza a and b viruses. hemagglutinin facilitates entry of virus into host cells through its attachment to sialic-acid receptors. because neutralizing antibodies are directed against this antigen, it is a critical component of current influenza vaccines. neuraminidase, the second major antigenic determinant, catalyzes the cleavage of glycosidic linkages to sialic acid and the release of progeny virions from infected cells. accordingly, it has become an important target for drug inhibitors such as oseltamivir and zanamivir. the m surface component and channel of influenza a (not present in influenza b virus) regulates the internal ph of the virus and is blocked by the antiviral drug amantadine. influenzaviruses are spread person-to-person primarily through the coughing and sneezing of infected persons. the typical incubation period for influenza is to days, with an average of days. adults can be infectious from the day before symptoms begin through approximately days after illness onset. children can be infectious for ~ o days, and young children can shed virus for several days before their illness onset. severely immunocompromised persons can shed virus for weeks or months. uncomplicated influenza illness is characterized by the abrupt onset of constitutional and respiratory signs and symptoms (e.g., fever, myalgia, headache, malaise, nonproductive cough, sore throat, and rhinitis). among children, otitis media,nausea,and vomiting are also commonly reported with influenza illness. respiratory illness caused by influenza is difficult to distinguish from illnesses caused by other respiratory pathogens on the basis of symptoms alone. influenza typically resolves after to days in most patients, although cough and malaise can persist for > weeks. among certain persons, influenza can exacerbate underlying medical conditions (e.g., pulmonary or cardiac disease), lead to secondary bacterial pneumonia or primary influenza viral pneumonia, or occur as part of a co-infection with other viral or bacterial pathogens. young children with influenza infection can have initial symptoms that mimic bacterial sepsis. more than % of children hospitalized with influenza can have febrile seizures. influenza has also been associated with encephalopathy, transverse myelitis, reye syndrome, myositis, myocarditis, and pericarditis. the risks for complications, hospitalizations, and deaths from influenza are higher among persons aged ~ years, young children, and persons of any age with certain underlying health conditions than among healthy older children and younger adults. influenza-related deaths can result from pneumonia or from exacerbations of cardiopulmonary conditions and other chronic diseases. the histopathologic features of nonfatal and fatal influenza have been well described and include necrotizing bronchitis, thrombosis, interstitial inflammation, hemorrhage, hyaline membrane formation, and intra alveolar edema (figs. . a,b, . a,c, and . a). , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the pathology is more prominent in larger bronchi, and inflammation may vary in intensity in individual patients, viral inclusions cannot be identified by light microscopy (fig, . d), secondary bacterial infections with organisms such as streptococcus pneumoniae (group a streptococcus [gas]), staphylococcus aureus, and haemophilus influenzae may occur as a complication in about % to % of fatal cases and make it difficult to recognize the pathologic changes associated with the primary viral infec- tion , , , the histopathologic features in other organs may include myocarditis, cerebral edema, rhabdomyolysis, and hemophagocytosis (figs, . h and . e,f), immunohistochemistry and ish assays demonstrate that viral antigens and nucleic acids are usually sparse and are primarily seen in the bronchioepithelial cells of larger bronchioles (figs. . c,e,f and . d) . . , antigens are more readily identified in patients who die within to days of onset of illness. recent studies suggest that unlike human influenza viruses, avian virus h n preferentially infects cells in the lower respiratory tract of humans, resulting in extensive damage of the lungs with minimal pathology in the upper respiratory tract (fig. . a,c) . this may help explain why the h n avian influenza virus is so lethal to humans but so difficult to spread from person to person. these studies show that the avian virus preferentially binds to the a- , -galactose receptors, which are found only in and around the alveoli. this is in contrast to the human influenzaviruses that preferentially bind to the a- , -receptors, which are found throughout the respiratory tract from the nose to the lungs. . in birds and other animals, viral antigens can be detected in the lung as well as a variety of extrapulmonary tissues (fig. . b) . the diagnosis of influenza, suspected by history and clinical manifestations, can also be supported histopathologically. however, because of the absence of any characteristic viral inclusions and because the overall pathologic features of influenza may resemble other viral, rickettsial, and certain bacterial infections, an unequivocal diagnosis can be made only by laboratory tests such as viral culture, direct fluorescent antibody and rapid antigen assays, serology, and ihc. , , measles measles (rubeola) is an infectious, acute febrile viral illness characterized by upper respiratory tract symptoms, fever, and a maculopapular rash. the causative agent, a member of the genus morbillivirus, of the family paramyxoviridae, , is an enveloped virus that contains a negative sense, single-stranded rna genome of , nucleotides. other human pathogens in this family include parainfluenza, mumps, and respiratory syncytial viruses. measles virions are pleomorphic, generally spherical, enveloped particles from to nm in diameter. the virus is morphologically indistinguishable from other members of the paramyxoviridae family when viewed by negative contrast electron microscopy. a lipid envelope surrounds a helical nucleocapsid composed of rna and protein. two transmembrane glycoproteins, hemagglutinin (h) and fusion (f), are present in the envelope and appear as surface projections. these proteins mediate viral attachment and figure . . influenza a. a. alveolar damage in a patient with fatal influenza a showing prominent congestion with intraalveolar macrophages and fibrin deposits. b. extensive ulceration of respiratory epithelium in a large airway of a patient with fatal influenza a. the lamina propria shows florid vascular congestion and focal hemorrhage, and predominantly mononuclear inflammatory cell infiltrates. c-e. immunohistochemical staining (c,e) of influenza virus a hemagglutinin antigens in the cytoplasm of residual respiratory epithelial cells of a large airway. this same focus of extensively infected respiratory epithelium (d) demonstrates that, unlike many other viral respiratory pathogens, influenza viruses do not elicit specific cytopathic effects in infected cells. f. in-situ hybridization assay demon-• fusion with respiratory epithelium. they are also believed to playa role in virus maturation through their interaction with the matrix (m) protein, which, in turn, is thought to interact with the nucleocapsid structure. oo measles is a highly communicable disease of worldwide distribution. before the introduction of measles vaccines, epidemics occurred about every to years when the percentage of nonimmune members of a population reached critical levels. recently, epidemics have occurred in cycles of about years. in small and isolated communities, measles circulation may cease altogether unless it is reintroduced. if introduced in non immune populations, the disease tends to be more severe and may involve more than % of the population because of the highly infectious nature of the virus. although still a significant problem in underdeveloped countries, measles infection became uncommon in the us. after the development and widespread use of an effective measles vaccine. however, a recrudescence of measles infection occurred in several large us. urban centers in recent years, associated with reduced use of the vaccine among children and young adults. during the peak of this activity (i.e., between and ), greater than , measles cases and approximately measlesassociated deaths were reported. l measles virus is highly contagious, spread by aerosols and droplets from respiratory secretions of acute cases. - less frequently, contaminated fomites are involved in transmission. a person with acute measles is infective from just before onset of symptoms to defervescence of fever. in developed countries, likely settings for exposure to measles virus are infectious disease clinics, pediatric emergency rooms, and physicians' offices. s children are usually infected by years of age, resulting in lifelong immunity, and almost all adults are immune. clinical infection in children younger than months of age is generally uncommon because of passive protection afforded the infant by the transfer of maternal antibodies. however, with the resurgence of measles in the us. came the realization that most women of childbearing age strating active replication of influenza a in respiratory epithelium in a large airway. g. electron micrograph of influenza a particles (arrows) attached to the cilia of a rodent tracheal epithelial cell. viral ribonucleoproteins are evident in the central aspect of the particles. the hemagglutinin and neuraminidase surface glycoproteins make up the peripheral spike layer. (courtesy of f.a. murphy.) h. rhabdomyolysis in a patient with fatal influenza a. bar, nm. a,b,d,h, h&e; c,e, immunoalkaline phosphatase stain, naphthol fast-red, and hematoxylin counterstain; f, digoxigenin-iabeled probe followed by immunoalkaline phosphatase staining, naphthol fast-red. and hematoxylin counterstain; g, uranyl acetate, lead citrate stain. acquired immunity to measles through vaccination and not through natural infection. lower levels of maternal antibodies were found to be transferred from an immunized mother to her infant; thus, a substantial number of measles cases occurred in children younger than year of age in the us. in recent years. after an incubation period of about to weeks, the prodromal phase of measles begins with fever, rhinorrhea, cough, and conjunctivitis. koplik's spots, which are small, irregular red spots with a bluish-white speck in the center, appear on the buccal mucosa in % to % of cases shortly before rash onset. an erythematous maculopapular rash begins on the face to days after prodromal symptoms and usually spreads to the trunk and extremities. the symptoms gradually resolve, with the rash lasting for approximately days, fading in the same order as it appeared. although recovery is rapid and complete in most cases, complications can arise as a result of continued and progressive virus replication, bacterial or viral superinfections, or abnormal host immune response. . . the most common complications are secondary bacterial pneumonia and otitis media. other complications include febrile convulsions, encephalitis, liver function abnormalities, chronic diarrhea, and sinusitis. several pulmonary and central nervous system (cns) syndromes that are often fatal have been described. death occurs in about of every measles cases; however, the risk of death and other complications is substantially increased in infants, adults, malnourished and immunocompromised individuals, persons with underlying illnesses,and nonimmunized populations in underdeveloped countries. - the first step in measles infection is attachment of the virus to cd cell surface receptors on the respiratory epithelium. adhesion and fusion of the virus to the respiratory epithelium is mediated by both the hand f viral glycoproteins. this stage is followed by local replication in respiratory mucosa and draining lymph nodes. a primary viremia follows, with dissemination two types of multinucleated giant cells have been described in patient tissues during measles infection. , the reticuloendothelial giant cell (warthin-finkeldey) appears first during the incubation period and is seen in the nucleus of a pneumocyte in the lung of a patient with fatal avian influenza. unlike other influenza viruses that cause disease in humans, h n preferentially infects alveolar epithelial cells, and causes relatively minimal pathology in the upper airway. a, h&e; b,c, immunoalkaline phosphatase stain, naphthol fast-red, and hematoxylin counterstain. different lymphoid tissues throughout the body. the second type is the epithelial giant cell, which has been observed in the epithelium of essentially every major organ. the onset of the rash temporally coincides with the appearance of detectable serum antibody to measles virus. interestingly, virus replication and giant cell formation cease with the appearance of rash. t-cell immunity is essential in the process of viral clearance from lymphoid tissue and respiratory tract. while children with congenital agammaglobulinemia respond normally to measles virus infection, patients with cell-mediated immunodeficiency develop severe disease that presents as giant-cell pneumonia or encephalopathy in the absence of an exanthem. [ ] [ ] [ ] [ ] , immunity to the f surface glycoprotein is necessary to prevent the spread of measles infection. an atypical measles syndrome characterized by pulmonary consolidation with pleural effusions and hilar adenopathy has been reported in children exposed to wild-type measles virus who had previously received the killed-measles virus vaccine. - recipients of the formalin-inactivated vaccine have a good antibody response to the h protein, but antibodies to the functional region of the f protein and to the nucleoprotein are weak or absent. it has been suggested that the lack of a functional f antibody response may playa role in virus spread. the pathologic features of measles have been well described and several references containing detailed morphologic descriptions are recommended. , . - the typical morbilliform skin lesions, koplik's spots, and measles lymphadenitis are seldom seen by the surgical pathologist since the clinical diagnosis is usually apparent. histopathologic changes in the skin include mild congestion, edema, and a predominantly mononuclear infiltrate surrounding small vessels of the dermis, as well as other nonspecific features. occasional diagnostic multinucleated epithelial giant cells with eosinophilic cytoplasmic and nuclear inclusions are observed. . pathognomonic reticuloendothelial multinucleated giant cells can be observed in appendix specimens from patients mistakenly operated on for acute appendicitis before the emergence of diagnostic koplik's spots and rash. these cells, which have been reported in various lymphoreticular tissues throughout the body, are typically large and contain from a few to occasionally up to nuclei. these cells do not usually contain viral inclusions. the lymphoid tissues are typically hyperplastic, and the architecture is partially or totally obliterated by diffuse proliferation of immunoblasts. [ ] [ ] [ ] a focal or generalized interstitial pneumonitis, similar to that seen in many other viral infections, is seen in the lungs of measles patients. histopathologic features seen include various degrees of peribronchial and interstitial mononuclear cell infiltrates, squamous metaplasia of bronchial endothelium, proliferation of type ii pneumocyte alveolar lining cells, and intraalveolar edema with or without mononuclear cell exudates and hyaline membranes. secondary changes, such as bacterial or viral superinfection, or organizational changes may alter the original pathology. the hallmark of the disease is the formation of multinucleated epithelial giant cells (fig. ll.lla,b) . these cells, which are often numerous, are formed by fusion of bronchiolar or alveolar lining epithelial cells (fig.ll.l a) . in contrast to the reticuloendothelial giant cells, these cells generally contain characteristic nuclear and cytoplasmic inclusions. the intranuclear inclusions are homogeneous, eosinophilic, and surrounded by a slight indistinct halo (fig. . c,d) . the cytoplasmic inclusions are deeply eosinophilic, vary in size, and some form large masses with a "melted tallow" appearance ( fig. . d ). these giant cells may undergo degenerative changes with progressive loss of cytoplasm, increasing basophilia, and shrinkage of nuclei. the presence of measles virus in these giant cells may be demonstrated by immunofluorescent, . ihc, o. and ish techniques (fig.ll.lle,f) . these giant cells can also be seen in extra pulmonary tissues (fig. . g,h) . the diagnosis of typical cases of measles can usually be made on the basis of clinical signs and symptoms. other causes of a similar rash, but without other features of measles, include rubella, dengue virus, enteroviruses, and drug reactions, especially to ampicillin. the typical case of measles giant-cell pneumonia generally presents little diagnostic difficulty for the surgical pathologist. the presence of giant cells with both intranuclear and intracytoplasmic inclusions in a setting of interstitial pneumonitis is highly specific for measles infection. however, multinucleated giant cells are not seen in all cases of measles pneumonia and their absence should not exclude the j diagnosis. other viral and rickettsial agents may also cause a similar interstitial pneumonitis, but without the typical giant cells, and should be differentiated. as previously noted, the histopathologic features in measles pneumonia can be somewhat variable, and secondary bacterial and viral infections may modify the histology, further complicating the pathologic diagnosis ( fig. . d ). . other viral pathogens, such as respiratory syncytial virus, parainfluenza, . vzv, and a recently discovered hendra virus, as well as granulomatous diseases of the lung, may give rise to pneumonia with giant cells and should also be considered in the differential diagnosis. however, these clinical entities can be distinguished by history, histopathologic features, and laboratory tests. immunohistochemistry . , or ish , tests demonstrate viral antigens or nucleic acids in the majority of cases. laboratory confirmation is useful to avoid possible confusion with other rash-causing illnesses. diagnostic laboratory procedures consist of direct detection of either the virus or the viral antigens, usually by indirect immunofluorescence or by serologic methods using hemagglutination inhibition, neutralization, or enzyme immunoassay. specimens for serologic testing consist of acute-and convalescent-phase serum pairs. antibody appears within to days after onset of rash, and titers peak approximately weeks later. alternatively, the presence of specific immunoglobulin m (igm) antibody can be used to diagnose recent infection. human parainfluenza viruses (hpivs) are second only to rsv as a cause of lower respiratory tract disease in young children. human parainfluenza viruses are negative-sense, nonsegmented, single-stranded, enveloped rna viruses that possess fusion and hemagglutinin-neuraminidase glycoprotein "spikes" on their surface (fig. .ig). the four serotypes of hpiv belong in the family paramyxoviridae, subfamily paramyxovirinae, and genera respirovirus (hpiv-l and - ) and rubulavirus (hpiv- and - ). the virions are variable in shape and size, ranging from to nm. human parainfluenza viruses are spread from respiratory secretions through close contact with infected persons or contact with contaminated surfaces or objects. infection can occur when infectious material contacts mucous membranes of the eyes, mouth, or nose, and possibly through the inhalation of droplets generated by a sneeze or cough. human parainfluenza viruses are unstable in the environment (surviving a few hours on environmental surfaces), and are readily inactivated with soap and water. they are ubiquitous, and infect most s,r. zaki and cd. paddock people during childhood. the highest rates of serious hpiv illnesses occur among young children. serologic surveys have shown that % to % of children aged years and older have antibodies to hpiv- , and about % have antibodies to hpiv-l and - . the different hpiv serotypes differ in their seasonality, with hpiv-l causing biennial outbreaks of croup in the fall and hpiv- causing annual or biennial fall outbreaks. human parainfluenza virus- peak activity occurs during the spring and early summer months each year, but the virus can be isolated throughout the year. similar to rsv, hpivs can cause repeated infections throughout life, usually manifested by an upper respiratory tract illness (e.g., cold and sore throat). human parainfluenza viruses can also cause serious lower respiratory tract disease with repeat infection (e.g., pneumonia, bronchitis, and bronchiolitis), especially among the elderly, and among patients with compromised immune systems. each of the four hpivs has different clinical and epidemiologic features. the most distinctive clinical feature of hpiv-l and hpiv- is croup (i.e., laryngotracheobronchit is ); hpiv-l is the leading cause of croup in children, whereas hpiv- is less frequently detected. both hpiv-l and - can cause other upper and lower respiratory tract illnesses. human parainfluenza virus- is more often associated with bronchiolitis and pneumonia. human parainfluenza virus- is infrequently detected, possibly because it is less likely to cause severe disease. the incubation period for hpivs is generally from to days. most hpiv infections cause a mild, self-limited illness; however, hpiv- infections are an important cause of bronchiolitis, croup, and pneumonia that may be lifethreatening in infants and newborns. human parainfluenza virus infections are also increasingly being recognized as an important cause of severe morbidity and mortality in immunocompromised patients. , -- the mortality of bone marrow transplant patients with hpiv- infection has been reported to be as high as %. , , in patients with severe hpiv infection, multinucleated giant cells derived from the respiratory epithelium may be seen in association with an interstitial pneumonitis and organizing changes (fig. . a,b ) . , . , - these giant cells, which may contain intracytoplasmic eosinophilic inclusions, (fig. . c) , have also been reported in extrapulmonary tissues such as kidney, bladder, and pancreas. other viral causes of giant cell pneumonia, including measks, rsv, vzv, and hsv, should be considered in the histopathologic differential and laboratory testing, including ihe, can be useful in making this differentiation possible ( fig. . d) . diagnosis of infection with hpiv scan also be made by virus isolation, direct detection of viral antigens py enzyme-linked immunoassay (eia) or immunofluorescent assay (ifa) in clinical specimens, detection of viral rna by rt-pcr, demonstration of a rise in respiratory syncytial virus (rsv) is the most common cause of bronchiolitis and pneumonia among infants and children under year of age. the causative agent is a negative-sense, nonsegmented, single-stranded, enveloped rna virus. the virion is variable in shape and size and ranges from to nm. respiratory syncytial virus is a member of the family paramyxoviridae, subfamily pneumovirinae, in the genus pneumovirus, and can be ing poorly defined cytoplasmic eosinophilic inclusions. d. parainfluenza virus antigens in giant cells localized by using immunohistochemistry. a-c, h&e; d, immunoalkaline phosphatase staining, naphthol fast-red, and hematoxylin counterstain. further distinguished genetically and antigenically into two subgroups, a and b. the subgroup a strains are usually associated with more severe infections. two surface glycoproteins, g and f, are present in the envelope and mediate attachment and fusion with respiratory epithelium. the f protein also mediates coalescence of neighboring cells to form the characteristic multinucleated syncytial giant cells for which the virus name is derived. respiratory syncytial virus is spread from respiratory secretions through close contact with infected persons or contact with contaminated surfaces or objects? infection can occur when infectious material contacts mucous membranes of the eyes, mouth, or nose, and possibly through the inhalation of droplets generated by a sneeze or cough. respiratory syncytial virus is unstable in the environment, surviving a few hours on environmental surfaces, and is readily inactivated with soap and water. in temperate climates, rsv infections usually occur during annual community outbreaks, often lasting several months, during the late fall, winter, or early spring months. the timing and severity of outbreaks in a community vary from year to year. respiratory syncytial virus spreads efficiently among children during the annual outbreaks, and most children will have serologic evidence of rsv infection by years of age. illness begins most frequently with fever, runny nose, cough, and sometimes wheezing. during their first rsv infection, between % and % of infants and young children have signs or symptoms of bronchiolitis or pneumonia, and . % to % require hospitalization. most children recover from illness in to days. the majority of children hospitalized for rsv infection are under months of age. respiratory syncytial virus also causes repeated infections throughout life, usually associated with moderate-to-severe cold-like symptoms; however, severe lower respiratory tract disease may occur at any age, especially among the elderly or among those with compromised cardiac, pulmonary, or immune systems. the major histopathologic changes described in fatal rsv infections include necrotizing bronchiolitis and interstitial pneumonia (fig. . a,b) . , - bronchiallumina and airways are usually filled with necrotic debris and inflammatory cells. these findings may be accompanied by various degrees of diffuse alveolar damage (fig. . e ), organizational changes, and secondary bacterial superinfection. giant cell pneumonia is a feature seen in some cases ( fig. . c,d) . the multinucleated giant cells contain irregular, intracytoplasmic, eosinophilic inclusions surrounded by a clear halo. these inclusions are extremely difficult to identify with any degree of certainty and are only seen in about half the cases (fig. . d) . other viral causes of giant cell pneumonia should be considered in the histopathologic differential and laboratory testing, including ihc, , , can be useful in making this differentiation possible ( fig. . b,f) . diagnosis of rsv infection can also be made by virus isolation, direct detection of viral antigens in clinical specimens by eia or ifa, detection of viral rna by rt-pcr, demonstration of a rise in rsvspecific serum antibodies, or a combination of these approaches (see also fig. . , chapter ) . , - in , van den hoogen et a . described the identification of this new viral agent from clinical specimens obtained from patients with respiratory illness, which they designated human metapneumovirus (hmpv). it is a negative-sense, nonsegmented, single-stranded, enveloped rna virus. the virion is variable in shape and size, ranging from to nm (fig. . f ). it has been categorized in the family paramyxoviridae, subfamily pneumovirinae, genus metapneumovirus, based on genomic sequence and gene constellation. human metapneumovirus can be further distinguished genetically and antigenically into two subgroups, a and b. similar to rsv, hmpv infection is ubiquitous and occurs during infancy and early childhood, with annual epidemic peaks occurring in the winter and spring months in temperate regions. seroprevalence studies reveal that % of all children aged to months have antibodies to hmpv; by age years, % of patients have evidence of past infection. like rsv, hmpv has been associated with a wide spectrum of respiratory illnesses. - the patient may be asymptomatic, or symptoms may range from mild upper respiratory tract illness to severe bronchiolitis and pneumonia. although rsv, hpiv-l, and hpiv- have been definitively linked to cases of lower respiratory tract disease in infants and young children, the relative contribution of hmpv remains undetermined. like rsv and the hpivs, studies suggest that hmpv may also contribute to respiratory disease in elderly adults and the immunocompromised. - o histopathologic descriptions of features of hmpv infections are few and have not been well described. [ ] [ ] [ ] [ ] this is partly related to interpreting the clinical significance of virus detection in context with the ubiquitous nature of the virus. virus detection in such cases is usually made by culture isolation of the virus from upper airways or by pcr assays performed on nasopharyngeal aspirates or bal washings. in nonhuman primates viral antigens are observed in ciliated epithelial cells, type pneumocytes, and alveolar macrophages. this distribution is associated with mild, multifocal, erosive, and inflammatory changes in airways, and an increased number of foamy macrophages in alveoli. the bal specimens collected from patients within a few days of a positive hmpv assay show degenerative changes and cytoplasmic inclusions within epithelial cells, multinucleated giant cells, and histiocytes. the intracytoplasmic inclusions are ill-defined, eosinophilic structures that measure to ~m. lung biopsy or autopsy tissue obtained and examined later in the disease show chronic airway inflammation, intraalveolar foamy and hemosiderin-laden macrophages, and acute and organizing lung injury including areas of diffuse alveolar damage with hyaline membrane formation and foci of a bronchiolitis obliterans/organizing pneumonia like reaction ( fig. . ). in such cases, typical multinucleated giant cells or viral inclusion cannot be identified. - in-situ hybridization studies on limited number of human cases human metapneumovirus is difficult to identify with commonly used viral diagnostic procedures. the virus replicates slowly in primary and tertiary monkey kidney cell lines, and the cytopathic effect can be difficult to discern. commercial monoclonal antibody reagents to hmpv are not widely available. most hmpv studies have been conducted using rt-pcr assays or by demonstration of a rise in hmpv-specific serum antibodies. two novel paramyxoviruses, hendra and nipah, have been recently identified in australia and malaysia; these viruses have been associated with acute febrile encephalitis and respiratory tract disease. both infections are zoonotic. hendra was first identified in when patients who came in close contact with sick horses developed an influenza-like illness. two patients died with pneumonitis and multiorgan failure. the closely related nipah virus was identified during an outbreak in malaysia and singapore during - that included more than patients. patients presented with a severe acute encephalitic syndrome, but some also had significant pulmonary manifestations. , - most of the patients had a history of contact with pigs, most of them being pig farmers. in bangladesh in and , outbreaks of nipah encephalitis occurred. , similar to the malaysian outbreak, the most prominent symptoms were fever, headache, vomiting, and an altered level of consciousness. respiratory illness was much more common in the bangladesh cases, however, with % having cough and dyspnea. the reason for increased involvement of the respiratory tract in this outbreak is not known. epidemiologic and laboratory investigations identified fruit bats of the pteropus genus as asymptomatic carriers of hendra and nipah viruses and possible animal reservoirs. [ ] [ ] [ ] [ ] [ ] hendra and nipah viruses belong to the recently designated genus henipavirus within the family paramyxoviridae, subfamily paramyxovirinae. both viruses are nonsegmented, negative-stranded rna viruses composed of helical nucleocapsids enclosed within an envelope to form roughly spherical, pleomorphic virus particles. io- the structure of their genome is consistent with the other members of the subfamily. histopathologic findings in fatal cases of hendra and nipah infections are similar with varying degrees of cns and respiratory tract involvement. , - findings include a systemic vasculitis with extensive thrombosis, endothelial cell damage, necrosis, and syncytial giant cell formation in affected vessels ( fig. . a ,b,f). plaques with various degrees of necrosis, in association with inclusion-bearing neurons, can be found in both the gray and white matter of the cns (fig. . e ). multinucleated giant cells with intranuclear inclusions can occasionally be seen in lung, spleen, lymph nodes, and kidneys ( fig. . c,g). in the lung, vasculitis and fibrinoid necrosis can be seen in majority of cases. fibrinoid necrosis often involves several adjacent alveoli and is frequently associated with small vessel vasculitis. the multinucleated giant cells with intranuclear inclusions are usually noted in alveolar spaces adjacent to necrotic areas. histopathologic changes of bronchiolar epithelium are uncommon; rarely, the large bronchi may show transmural inflammation and ulceration. widespread presence of nipah virus antigens can be seen by ihc in endothelial and smooth muscle cells of blood vessels as well as in various parenchymal cells (fig. . d ). the diagnosis of nipah virus infection, suspected by patient history and clinical manifestations, can be supported by characteristic histopathologic findings. from a diagnostic standpoint, perhaps the most unique histopathologic finding is the presence of syncytial and parenchymal multinucleated endothelial cells. this feature occurs in only approximately one fourth of the cases and cannot be used as a sensitive criterion for the diagnosis of henipah virus infections; furthermore, these cells can also be seen in measles virus, rsv, hpiv, herpesviruses, and other infections. unequivocal diagnosis can be made only by laboratory tests such as ihc, cell culture isolation, pcr, or serology.l , , - the parvoviruses are small ( to nm) naked viruses that possess a single-stranded dna genome and require actively dividing cells to complete the viral replication cycle. in , allander et a . identified a new parvovirus (genus bocavirus) associated with lower respiratory tract infections in children; however, there is no information as yet that describes specific pulmonary pathology attributed to this newly identified agent. on the other hand, human parvovirus b , a member of the genus erythrovirus, has long been known to cause human disease and has been well studied. , the most commonly recognized manifestation of b infections is erythema infectiosum, and approximately one third of the cases of maternal parvovirus infections result in intrauterine parvovirus b infections. this places the fetus at increased risk for severe anemia, hydrops, and death. hydrops fetalis is the most commonly recognized complication of intrauterine parvovirus infection, accounting for % to % of all cases of nonimmune hydrops. cases tend to be clustered during community outbreaks of erythema infectiosum. . pathophysiologic effects and histopathologic findings are a result of the tropism of b parvovirus for erythroid precursor cells. villi from placentas from patients with bl -associated nonimmune hydrops are edematous, and fetal capillaries show numerous nucleated erythroid precursors, some containing parvovirus inclusions. the infected cells with eosinophilic "ground glass" intranuclear inclusions and ring-like margination of nuclear chromatin are easily recognized and in the context of a hydropic fetus are pathognomonic of b infection. the liver is the major site of blood production in the fetus and the principal organ affected by intrauterine b infection. inclusion-bearing nucleated erythrocytes can also be frequently identified in the lung, making histopathologic examination of this organ a worthwhile endeavor for confirming the diagnosis of intrauterine bi infection ( fig. il.i a,b) . - however, these cells may be infrequent and irregularly distributed, requiring examination of multiple sections and use of ihc to confirm the diagnosis (fig.l . c,d) . the combination of fever and hemorrhage can be caused by different viruses, rickettsiae, bacteria, protozoa, and fungi. however, the term viral hemorrhagic fever (vhf) is usually reserved for systemic infections characterized by fever and hemorrhage caused by a special group of viruses transmitted to humans by arthropods and rodents. the vhfs are febrile illnesses characterized by abnormal vascular regulation and vascular damage and are caused by small, lipid-enveloped rna viruses. this syndrome can be caused by viruses belonging to four different families that differ in their genomic structure, replication strategy, and morphologic features (table . ). arenaviruses, bunyaviruses, and filoviruses are negative-stranded, in the nucleus and cytoplasm of erythroid precursors by using immunohistochemistry (ihe) (same patient as in a,b). a,b, h&e; c,d, immunoalkaline phosphatase staining, naphthol fast-red, and hematoxylin counterstain. whereas fiaviviruses are positive-stranded rna viruses. hemorrhagic fever viruses are distributed worldwide, and the diseases they cause are traditionally named according to the location where they were first described. the oldest and best known is yellow fever virus; others include lassa fever, lymphocytic choriomeningitis, ebola, and dengue viruses. viral hemorrhagic fevers share many common pathologic features, although the overall changes vary among the different diseases. the similar pathologic and immunopathologic findings in cases of vhf suggest that microvascular involvement and instability is an important common pathogenic pathway leading to shock and bleeding in many instances. infection of the mononuclear phagocytic system and endothelium are thought to play c s.r. zaki and cd. paddock . . ebola virus hemorrhagic fever. a. pulmonary congestion and lack of inflammation. b. numerous filamentous ebola virus inclusions are seen within hepatocytes in association with hepatocellular necrosis. c. ebola virus-infected intra alveolar macrophages as seen by colorimetric in-situ hybridization using digoxigenin-labeled probes. d. viral anti-gens are seen in endothelial cells and other interstitial cells in this lung section. a,b, h&e; c, digoxigenin-labeled probes followed by immunoalkaline phosphatase staining, naphthol fast-red, and hematoxylin counterstain; d, immunoalkaline phosphatase staining, naphthol fast-red, and hematoxylin counterstain. figure . . yellow fever. a. pulmonary congestion in fatal case of yellow fever associated with vaccination. b. yellow fever antigens in the pulmonary interstitium of the same patient. in natural infections, yellow fever antigens are usually not seen outside the liver in fatal cases. in contrast, in vaccine-associated cases viral antigens can be found in a variety of extrapulmonary a critical role in the pathogenesis of vhfs through the secretion of physiologically active substances, including cytokines and other inflammatory mediators (figs. . c,d, . b, . b,c, and . b). at autopsy common findings include widespread petechial hemorrhages and ecchymoses involving skin, mucous membranes, and internal organs. however, in many hf patients manifestations of bleeding may be minimal or absent. effusions, occasionally hemorrhagic, are also frequently seen. widespread, focal, and sometimes massive necrosis can be commonly observed in all organ systems and is often ischemic in nature. necrosis is usually most prominent in the liver and lymphoid tissues. the most con- organs, including heart, lung, and spleen. c. extensive midzonal hepatic necrosis characteristic of yellow fever. d. abundant antigens of yellow fever virus are observed in midzonal area of hepatic lobule in this immunohistochemical preparation. a,c, h&e; b,d, immunoalkaline phosphatase staining, naphthol fast-red, and hematoxylin counterstain. sistent microscopic feature is found in the liver and consists of multifocal hepatocellular necrosis with cytoplasmic eosinophilia, councilman bodies, nuclear pyknosis, and cytolysis (figs. . b and . c). inflammatory cell infiltrates and necrotic areas are usually mild and, when present, consist of neutrophils and mononuclear cells. commonly observed histopathologic changes in the lung include various degrees of hemorrhage, intra alveolar edema, interstitial pneumonitis, and diffuse alveolar damage (figs. . a, . a, . a, . a, and . a). several references containing detailed pathologic descriptions in human cases are recommended. . . - o .' a. pulmonary hemorrhage and diffuse alveolar damage in a patient who was infected through organ transplantation. note that, unlike this case, which occurred due to immunosuppression, lcmv infections are rarely fatal and usually resolve with no specific treatment. b. abundant lcmv antigens in areas of the diagnosis of vhf should be suspected in patients with appropriate clinical manifestations returning from an endemic area, particularly if there is travel to rural areas during seasonal or epidemic disease activity. the diagnosis suspected by history and clinical manifestations can also be supported histopathologically, and the overall pattern of histopathologic lesions may suggest a specific diagnosis. however, because of similar pathologic features seen in vhf and a variety of other viral, rickettsial, and bacterial infections, unequivocal diagnosis can only be made by s.r. zaki and cd. paddock lung showing diffuse 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key: cord- -aek mvdw authors: ishiguro, takashi; kobayashi, yasuhito; takano, kenji; ozawa, ryota; shimizu, yoshihiko; takayanagi, noboru title: two cases of primary human parainfluenza virus pneumonia in which bronchoalveolar lavage fluid yielded human parainfluenza virus date: - - journal: intern med doi: . /internalmedicine. - sha: doc_id: cord_uid: aek mvdw two patients, a -year-old woman and -year-old woman, presented to our hospital with symptoms of lower respiratory tract infection. both patients showed chest imaging findings of bilateral ground-glass opacities and consolidations. we initially suspected these patients of having influenza-associated pneumonia and cryptogenic organizing pneumonia, respectively, and performed bronchoalveolar lavage, but only human parainfluenza virus- infection was detected by multiplex polymerase chain reaction testing. these findings suggest that pneumonia due to human parainfluenza virus- should be included in the differential diagnosis of such cases. human parainfluenza viruses (hpivs) are single-stranded, enveloped rna viruses belonging to the paramyxoviridae family. compared with findings in studies of hpiv infection in children, less is known about these infections in adults. in previous studies, . to . % of hospitalized patients with pneumonia were found to have hpiv infection ( , ) ; however, the characteristics of primary viral pneumonia due to hpiv are not well known. we recently experienced two cases of pneumonia in which hpiv- was isolated from bronchoalveolar lavage (bal) fluid and confirmed by a multiplex polymerase chain reaction (pcr) test (fast track diagnostics resp kit, silema, malta), which detects the following respiratory pathogens: influenza a and b viruses; coronaviruses nl , e, oc , and hku ; human parainfluenza viruses , , , and ; human metapneumovirus a/b; rhinovirus; respiratory syncytial virus a/b; adenovirus; enterovirus; human parechovirus; bocavirus; and mycoplasma pneumoniae. we herein report these cases and review the clinical and radiological features. a -year-old woman presented to our hospital with appetite loss and fever in march. on the first day of illness, she initially developed appetite loss, and on the second day, she developed a fever of . . on the fourth day, she developed dyspnea, sore throat, and cough, and on the ffth day, she presented to a local physician who found abnormal shadows on chest x-ray and referred her to our hospital. she had no noteworthy past history. she was a never-smoker and was never exposed to dust. on admission, her vital signs included a body temperature of . , respiratory rate of /min, systolic blood pressure of mmhg, and heart rate of beats per min. chest auscultation showed bilateral coarse crackles. an arterial blood gas analysis under o of l/min by nasal canula showed a ph of . , partial pressure of carbon dioxide in arterial blood (paco ) (fig. a) . chest computed tomography showed ggos and consolidations in both lung fields ( fig. b and c) . pleural effusion or lymphadenopathy were not found. we performed bronchoscopy and the bal procedure from the internal segment of the right middle lobe. bal fluid ( of ml recovered) showed . × cells/ ml (neutrophils, . %; lymphocytes, . %; macrophages, . %; and eosinophils, . %) but did not show any microorganisms by gram staining or yield significant pathogens including m. pneumoniae or legionella spp. cytology of the bal fluid showed no significant findings. a transbronchial lung biopsy specimen showed alveolitis, fibrin exudation, and intraluminal organization (fig. ). blood culture was negative. we suspected her of having influenza-associated pneumonia and started ampicillin/sulbactam and peramivir. her chest shadows gradually improved, and her fever abated on hospital day (hd) . oxygen by nasal canula was stopped on hd , and she was discharged on hd . specific antibody titers against m. pneumoniae, c. pneumoniae, c. psittaci, legionella spp., influenza virus, adenovirus, and respiratory syncytial virus in paired sera did not increase, but antibodies against hpiv were not measured. we analyzed the bal fluid with multiplex pcr, which showed positive results only for hpiv- . two years after discharge, she has not relapsed. a -year-old woman presented to our hospital with cough, sputum, and sore throat of weeks duration in may. she initially visited a local physician who detected abnormal shadows on her chest x-ray and then referred her to our hospital. she had not received any antibiotics before presenting to our hospital. she had a history of gastric carcinoma when she was years old and had undergone gastrectomy. her cancer had not recurred. she was an ex-smoker with brinkman index of , but she had never been exposed to dust. on admission, her vital signs included a body temperature of . , respiratory rate of /min, systolic blood pressure of mmhg, and heart rate of beats per min. chest auscultation showed bilateral coarse crackles. an arterial blood gas analysis under ambient air showed a ph of . , paco of . torr, pao of . torr, and hco − of . mmol/l. laboratory data showed a white blood cell count of , /mm (neutrophils, . %; lymphocytes, . %; eosinophils, . %; basophils, . %; and monocytes, . %), hemoglobin of . g/dl, platelets of . × /mm , ast of iu/l, ldh of iu/l, creatinine of . mg/ dl, crp of . mg/dl, and kl- of u/ml. autoantibodies were negative, as was an anti-hiv antibody test. rapid nasopharyngeal or oropharyngeal diagnostic tests for influenza virus and mycoplasma pneumoniae and urinary antigen tests for s. pneumoniae and legionella spp. were all negative. chest x-ray showed bilateral consolidation (fig. a) , and chest computed tomography showed nonsegmental and subpleural consolidation bilaterally in the lower lobes (fig. b) . no centrilobular pulmonary nodules, pleural effusion, or lymphadenopathy was detected. we performed bronchoscopy and bal from the lateral segment of the right lower lobe. bal fluid ( of ml recovered) showed . × cells/ml (neutrophils, . %; lymphocytes, . %; macrophages, . %; and eosinophils, . %) but did not show any microorganisms by gram staining or yield significant pathogens including m. pneumoniae. cytology of the bal fluid also showed no significant findings. we could not obtain adequate specimens for evaluation via transbronchial lung biopsy. we initially suspected her of having cryptogenic organizing pneumonia (cop) and administered prednisolone mg daily. her chest shadows gradually improved, and she was discharged on hd . we analyzed the bal fluid with multiplex pcr, which showed positive results only for hpiv- . specific antibody titers against m. pneumoniae, c. pneumoniae, c. psittaci, legionella spp., influenza virus, adenovirus, and respiratory syncytial virus in paired sera did not increase, but antibodies against hpiv were not measured. we then gradually tapered the prednisolone and stopped it two months after hospital discharge. at four years since her treatment, she has not developed a relapse. we herein report two immunocompetent patients with primary hpiv- pneumonia. one patient required oxygen supplementation on admission, and both patients recovered without the administration of antiviral agents. most hpiv infections in adults cause mild upper respiratory tract symptoms, but the elderly or those with a compromised immune system are associated with progressive disease ( ) ( ) ( ) . hpiv is responsible for to % of acute respiratory illnesses in adults. in other studies, . to . % of hospitalized patients with pneumonia were found to have hpiv infection ( , ) . furthermore, hpiv is present in . % of severe pneumonias, which indicates that hpiv is a frequent pathogen of both non-severe and severe pneumonia ( ) . however, previous reports that investigated virus infections in patients with pneumonia used nasopharyngeal or oropharyngeal swabs to detect viruses, which raises the possibility of upper respiratory tract infection by hpiv. furthermore, these studies include mixed viral and bacterial infections, and the clinical characteristics of the immunocompetent patients with primary hpiv pneumonia are not fully known. in our two cases, hpiv was detected in bal fluid, which indicated the hpiv in our cases to be a pathogen of not the upper airways but the lower respiratory tract and of pneumonia. in addition, bal fluid did not yield other significant pathogens, nor did specific antibody titers against other pathogens of pneumonia in paired sera increase, which support the diagnosis of primary hpiv infection in our patients. four subtypes of hpiv (hpiv- , , , and ) have been identified, and hpiv- is the most prevalent serotype of infections. among adults hospitalized with pneumonia, hpiv- was found in . % of patients ( , ) . the causative virus in our patients was hpiv- , a subtype found in . % of adult pneumonias ( , ) . although our patients recovered successfully, tamaki et al. reported a fatal case of viremia due to hpiv- in a patient with adult t-cell leukemialymphoma treated with mogamulizumab ( ), which indicates that hpiv- can also be a fatal pathogen in immunocompromised patients. diseases mainly suspected in our patients before identification of hpiv- via multiplex pcr testing were primary influenza virus pneumonia and cop, respectively. a previous study reported that viral pneumonia is frequently misdiagnosed as cop ( ) . in the differentiation of these diseases, sore throat is a more frequent symptom of viral pneumonia than of acute interstitial lung diseases including cop ( ) , and our patients both had sore throats. however, typical symptoms in adult patients with hpiv infection include fever, rhinorrhea, cough, and a sore throat, which do not clinically distinguish it from other respiratory viruses ( ). cunha et al. reported that the clinical presentation of hpiv pneumonia closely mimics h n pneumonia ( ) . chest ct findings in our patients included bronchial wall thickening, bilateral consolidations, and ggos, which were compatible with typical ct findings of hpiv pneumonia, e. g., multifocal patchy consolidation with ggos, and centrilobular nodules with bronchial wall thickening ( ); however, these findings seem nonspecific for hpiv pneumonia. pokharel et al. reported multinucleated giant cells with organizing pneumonia as findings suggestive of hpiv infection ( ) , but the sensitivity and specificity of the pathologic findings were not known and these findings were not present in our patients. thus, it is important to include viral infections in the differential diagnosis and investigate respiratory specimens with viral pcr tests. hpiv causes epidemics during the spring season or a small secondary period of in- creased activity in the fall, and thus seasonality and local epidemiology may be clues suggestive of hpiv pneumonia. currently, no treatments with proven efficacy are approved for the treatment of hpiv infections. corticosteroids, generally dexamethasone and budesonide, are associated with fewer clinic visits and admissions for croup and the reduced use of nebulized epinephrine ( ) . we initially misdiagnosed our patient in case as having cop and administered corticosteroids. the efficacy of corticosteroid administration in immunocompetent adult patients with hpiv pneumonia is not known. some data suggest favorable effects on varicella-zoster virus (in combination with acyclovir) and hantavirus ( ) and in influenza-associated pneumonia in some clinical settings ( , ) . among previously reported patients with influenza-associated pneumonia, corticosteroids were administered without neuraminidase inhibitors in and were effective ( ) . among the patients with viral pneumonia due to non-influenza viruses, corticosteroids were administered to , of whom did not survive, but were effective in the other patients ( . %) ( ) . however, the mainstay of therapy in patients with hpiv infection is considered to be the reduction of immune suppression, which includes corticosteroids use ( ) . further studies are needed to clarify the significance of corticosteroids as a treatment option for primary hpiv pneumonia in immunocompetent patients. however, much of the available data for the use of antiviral agents in the treatment of hpiv comes from immunocompromised patients. the efficacy of antiviral drugs in immunocompetent adults with hpiv pneumonia has not been fully evaluated, and thus further studies are needed. one limitation of this report is that the possibility of detecting viruses from the upper respiratory tracts when using the bal technique cannot be denied. to avoid this concern and ensure that samples are obtained only from the lower respiratory tract, intubation or use of a protected specimen brush is required. in conclusion, we experienced two immunocompetent pa-tients with primary hpiv- pneumonia. primary hpiv pneumonia can resemble influenza-associated pneumonia and cop, and hpiv pneumonia should be 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eslamy, hedieh k.; newman, beverley title: pneumonia in normal and immunocompromised children: an overview and update date: - - journal: radiologic clinics of north america doi: . /j.rcl. . . sha: doc_id: cord_uid: h dx d pneumonia is an infection of the lung parenchyma caused by a wide variety of organisms in pediatric patients. the role of imaging is to detect the presence of pneumonia, and determine its location and extent, exclude other thoracic causes of respiratory symptoms, and show complications such as effusion/empyema and suppurative lung changes. the overarching goal of this article is to review cause, role of imaging, imaging techniques, and the spectrum of acute and chronic pneumonias in children. pneumonia in the neonate and immunocompromised host is also discussed. normal and immunocompromised children: an overview and update hedieh k. eslamy, md, beverley newman, md* pneumonia is an infection of the lower respiratory tract, involving the lung parenchyma. the world health organization estimates that there are . million cases of pulmonary infection each year in children younger than years, with as many as million cases severe enough to require hospital admission. in north america and europe, the annual incidence of pneumonia in children younger than years is estimated to be to cases per , and decreases to cases per in adolescents to years of age. , the mortality in pediatric patients caused by pneumonia in developed countries is currently low (< per per year). however, pneumonia is still the number one cause of childhood mortality in developing countries. , the overarching goal of this article is to review cause, current role of imaging, imaging techniques, and the spectrum of acute and chronic pneumonias in children. pneumonia in the neonate and immunocompromised host is also discussed. infectious agents causing pneumonia in children include viruses, bacteria, mycobacteria, mycoplasmas, fungi, protozoa, and helminths. etiologic diagnoses of pneumonia are not so easy to determine or so accurate as is sometimes implied. in addition, proof of the cause of pneumonia is not obtained in most cases. there is a great deal of overlap in the radiographic appearance of pneumonias caused by different organisms. imaging is usually poor at predicting the broad category (eg, bacterial vs viral) of infectious agent, let alone the specific agent. preexisting lung disease may not only predispose to pulmonary infection but also modify the appearance of pulmonary consolidation. furthermore, because the lungs can respond to a diverse disease processes in only a limited number of ways, it is common for the radiographic features of both acute and chronic infectious pneumonia to overlap considerably with many noninfectious lung diseases. such noninfectious lung diseases are identified as pneumonia mimics in this article. viral pneumonia is rare in the neonatal period, because of conferred maternal antibody protection, whereas bacterial pneumonia is most frequently caused by pathogens acquired during labor and delivery, and is more prevalent in premature babies. with decreasing maternal antibody levels, viral pneumonia occurs at a peak between months to years of age. bacterial infections become relatively more common in older children from years to years of age. the lung response to an infective antigen seems to be more agespecific than antigen-dependent (ie, bacteria vs viral). therefore, lobar and alveolar lung opacities are more common in older children and are more frequently caused by bacterial infections, whereas interstitial opacities are seen in all age groups, and are relatively nonspecific as to the type of causative organism. , the role of imaging, including chest radiographs, ultrasound (us) and computed tomography (ct), is to detect the presence of pneumonia, determine its location and extent, exclude other thoracic causes of respiratory symptoms, and show complications such as parapneumonic effusion/ empyema and suppurative lung complications. although magnetic resonance (mr) imaging is not routinely used for evaluating pneumonia in children, it is a promising imaging modality particularly for children with chronic lung conditions who require repeat imaging studies. frontal and lateral chest radiographs are the mainstay, and often the only, imaging needed in pediatric pulmonary infection. this imaging can be supplemented with other views such as lateral decubitus or other imaging modalities as the circumstances warrant. decubitus views are not useful when an entire hemithorax is opacified because layering fluid cannot be identified without any adjacent air. the main use of us is to identify, quantify, and characterize a parapneumonic effusion/empyema, as well as provide image guidance for drainage and identify residual collections after treatment. , operator availability and expertise are important factors in making us a useful tool for evaluating pulmonary infection. although intrapulmonary fluid-filled cavities and even lung abscesses within consolidated lung can be identified on us, ct provides a more global view of the disease process. ct is often used to further evaluate: ( ) suppurative lung complications and to differentiate these from parapneumonic effusion/empyema; ( ) patients with recurrent or chronic pneumonia and concern for an underlying lesion; and ( ) immunocompromised children with noncontributory or confusing chest radiographs and clinical findings that could be secondary to lung infection. close attention to ct technique is crucial for imaging evaluation of pneumonia in pediatric patients. ct with low radiation dose technique should be carefully performed in all cases. eighty to kvp with weight-based low milliampereseconds coupled with radiation dose modulation techniques is appropriate in most children for evaluation of pneumonia. multiple ct image acquisitions are usually not needed and the scan field of view should be tailored to the area of interest (especially if following a specific lesion serially over time) to further decrease the overall radiation dose. occasionally, it may be useful to acquire additional expiratory scans to assess air trapping, which is an early imaging finding associated with small airway disease. in this situation, often at least or both ct acquisitions can be obtained using a high-resolution ct (hrct) gap technique. to obtain optimal ct imaging at peak inspiration and close to expiratory residual volume, controlled ventilation (cvict) in infants and young children ( years old) or spirometer-controlled ct in older children may be needed. young children have little intrinsic tissue contrast. therefore, intravenous contrast is almost always needed for ct imaging of infection especially if mediastinal delineation is required. the exception is when hrct is used only for evaluating lung parenchymal and airway disease. breath-holding is usually desirable but can be adapted on a case-by-case basis depending on the needs of the study and the ability of the child to cooperate. however, for the study to be interpretable, gross patient motion should be absent. sedation or anesthesia may be required in infants, young children, or children with intellectual disability. delays between induction of anesthesia and scanning need to be minimized to prevent the potential for lung atelectasis with anesthesia. the anesthesiologist needs to pay close attention to techniques for preventing atelectasis or recruiting lung before the ct imaging. peltola and colleagues recently published their experience with mr imaging of lung infections in children using free-breathing t -weighted, short tau inversion recovery, and t -weighted with fat saturation precontrast and postcontrast sequences. their study showed that lung parenchymal, pleural, and lymph node inflammatory abnormalities can be characterized by mr imaging in children with lung infection. therefore, mr imaging might potentially be used to further evaluate suspected, acute complications of pneumonia. children with chronic lung conditions and recurrent infection, such as cystic fibrosis, who are often subjected to substantial radiation exposure from repeated ct studies, would benefit the most from mr imaging evaluation of the lungs instead of ct. although mr imaging may not provide as much detail compared with ct especially with early, small or subtle changes ( fig. ) , there are promising indications of a role for mr imaging in pulmonary infection. [ ] [ ] [ ] there are several different descriptions of basic patterns of lung diseases on chest radiographs. in this review article, we adopt the one described by hansell and colleagues. almost all of these are seen as part of the spectrum of infectious lung disease ( table ) . pneumonia and bronchiolitis are both common in infants and have overlapping clinical and imaging features. many studies, particularly those in the developing world, use the term acute lower respiratory tract illness and make no attempt to differentiate pneumonia from bronchiolitis. bronchiolitis occurs in children less than years of age, who typically present with cough, coryza, and wheezing. bronchiolitis is a major cause of morbidity and mortality in infants. respiratory syncytial virus (rsv) is the most common cause ) . such imaging findings are related to diffuse airway inflammation and partial (air trapping) or complete (atelectasis) airway obstruction. similar changes are seen in older children (> years of age) with bronchitis although the features of diffuse small airway obstruction are less common in these older children with larger airways. pneumonia can be divided into several syndromes based on clinical presentation, imaging appearance, underlying predisposition, and cause. pneumonia syndromes that are discussed in this article include acute focal pneumonia, atypical pneumonia, miliary or nodular pneumonia, progressive or fulminant pneumonia, aspiration pneumonias, pulmonary infiltrates with eosinophilia (pie), and chronic or recurrent pneumonia. neonatal pneumonia is briefly highlighted separately. pneumonia in immunosuppressed individuals is included in the general discussion of pneumonia syndromes and then specifically reviewed with regard to the different infections associated with various types of immunodeficiency. acute and chronic complications of pneumonia are also reviewed. characteristics that are typical for acute focal pneumonia include fever more than . c ( f), a toxic appearance, and a focal opacity on chest radiographs. pleuritic chest pain in lower-lobe pneumonia is sometimes referred to the abdomen and may be mistaken clinically for an acute abdominal condition. acute focal pneumonia is most often caused by bacterial infection with streptococcus pneumonia. other causes of acute focal pneumonia are summarized in box . the chest radiograph of acute focal pneumonia usually shows a dense, typically more peripheral airspace opacity, which may appear segmental, lobar, or spherical ( figs. and ) . [ ] [ ] [ ] in a febrile child with a spherical density on a chest radiograph, the most likely diagnosis is a round pneumonia but the possibility of an underlying neoplasm may be considered. round pneumonias tend to be solitary, have well-defined borders, and are often located in the perihilar region or posteriorly in the lungs. the radiograph should be carefully scrutinized for features of consolidation such as air bronchograms as opposed to those of a mass such as vascular/airway displacement or bony erosion. a second view such as a lateral radiograph may be helpful because a round pneumonia is often less masslike in appearance on an orthogonal view. this is one of the few scenarios in which radiologic follow-up after about weeks may be useful to document interval resolution of acute pneumonia. acute respiratory distress may be secondary to an intrathoracic mass causing airway or lung compression, especially when there is complete opacification of a hemithorax on radiographs (fig. ) . intrapulmonary masses including both benign and malignant entities may present clinically with acute superinfection. in addition, other conditions or anatomic variants may be mistaken for pneumonia when a chest radiograph is obtained in a child with a fever and respiratory symptoms. atypical features in pneumonia include prominent extrapulmonary features (eg, headache, sore throat, and pharyngeal exudates), minimal or disparate chest signs on physical examination, subacute onset, nonfocal lung opacity on chest radiographs, lack of clinical response to antibiotics, lack of substantial leukocytosis, and a slow disease course. common infectious causes of atypical pneumonia are summarized in box . on chest radiographs, the pulmonary opacity is seen as either airspace, reticular (linear), or bandlike opacities in a nonfocal, patchy, or mottled distribution, with various degrees of density, usually without a single dense area of consolidation (fig. ). most patients with atypical pneumonia can be classified into one of the following subgroups or a combination of two of them based on findings on chest radiographs: acute interstitial pneumonia chest radiographs show a patchy, nonfocal reticular pattern. causes of acute interstitial pneumonia include self-limited viral infections and other pathogens. subacute minimal patchy pneumonia chest radiographs show or more patches of minimal foci of airspace opacity. the most common causes of subacute minimal patchy pneumonia are mycoplasma pneumoniae, chlamydia pneumoniae, and adenoviruses. chest radiographs show a dense focal airspace opacity that is segmental or subsegmental. most of the other features of acute focal pneumonia are absent. tuberculosis needs to be excluded in these patients. most children exposed to mycobacterium tuberculosis do not develop active disease but can have latent foci that may reactivate at a later date particularly if they become immunosuppressed or debilitated. primary infection of mycobacterium tuberculosis is more likely in infants with local spread from the initial parenchymal/lymph node complex to form larger single or multifocal parenchymal lesions, typically with prominent hilar and mediastinal lymph node involvement ( fig. ) and occasional pleural or pericardial disease. the primary focus as well as involved nodes may cavitate with liquefaction of the caseous material and ultimately calcification (see fig. ). enlarged lymph nodes may encroach on adjacent bronchi and cause bronchial narrowing with resultant air trapping or collapse in the distal lung (fig. ) . distant spread to other organs may occur either via lymphatics or hematogenously (including military lung involvement). , infections with more than organism may cause the atypical pneumonia pattern, resulting in confusing persistence of the illness or prominent findings in another organ system. an example of this situation is influenza infection with superimposed typical or atypical pneumonia (see fig. b ). the more common mimics that simulate the appearance of atypical pneumonia syndromes are summarized in box . miliary or nodular pneumonia is characterized by chest radiographic findings of multiple miliary or larger nodular opacities. miliary pneumonia in pediatric patients is seen most commonly in tuberculous and fungal infections (fig. ). nodular pneumonia (including reticular and reticulonodular patterns) in pediatric patients is seen in septic emboli, viral pneumonia, lymphocytic interstitial pneumonia associated with epstein-barr virus (ebv) infection with underlying human immunodeficiency virus (hiv) infection, and some fungal and bacterial infections (box ; figs. and ). , septic pulmonary emboli usually occur secondary to a focal staphylococcus aureus infection (eg, right-sided bacterial endocarditis, septic thrombophlebitis, osteomyelitis, soft tissue infection, or urinary tract infection). the pulmonary nodules in septic emboli may cavitate (see fig. ). mimics of the pattern of miliary or nodular pneumonia are summarized in box . pneumonia is deemed progressive when it becomes radiologically and clinically worse despite antibiotic therapy that should be effective against the presumed cause. in this situation, the cause is often nonbacterial pathogens and mimics should also be carefully considered. fulminant pneumonia is defined as a severe bilateral pneumonia with an unusually rapid progression clinically or radiologically, over to hours after initial presentation. a common cause of progressive or fulminant pneumonia is the influenza virus during an epidemic. uncommon infectious causes of this pattern and mimics are summarized in boxes and , respectively ( fig. ). aspiration pneumonia refers to the pulmonary consequences of abnormal entry of fluid, particulate matter, or endogenous secretions into the lower airways. aspirated material can be relatively inert, toxic, or oropharyngeal secretions. the most commonly aspirated materials in children include oropharyngeal secretions, gastric contents, water, hydrocarbon, lipid, and foreign bodies. radiographic pulmonary opacities related to aspiration may have an upper rather than lower lobe distribution when the child aspirates in the supine position. bacterial aspiration pneumonia is an infectious process caused by the inhalation of oropharyngeal secretions that are colonized by pathogenic bacteria. the basic defect leading to bacterial aspiration pneumonia is failure of the normal oropharyngeal defense mechanisms. the patient typically has a depressed state of consciousness, abnormal swallowing, a neuromuscular defect that prevents adequate coughing, or an abnormal connection between the airway and esophagus (such as an h-type tracheoesophageal fistula). acute lung aspiration (mendelson syndrome) is an acute chemical injury caused by inhalation of gastric contents. in neurologically normal children, gastric aspiration usually occurs as a complication of anesthesia. the diagnosis of acute aspiration is mainly clinical and usually involves witnessed inhalation of vomitus or tracheal suctioning of gastric contents. , chronic lung aspiration (cla) is repeated passage of food, gastric reflux, or saliva into the subglottic airways that causes chronic or recurrent respiratory symptoms. cla may present with chronic cough, wheeze, noisy breathing, choking during feeding, recurrent episodes of pneumonia or bronchitis, and failure to thrive. chronic aspiration often results in progressive lung disease, recurrent pneumonia, chronic airway inflammation, bronchiectasis, and respiratory failure. it is a major cause of death in children with severe neurologic disorders (fig. ) . pulmonary aspiration may occur as a result of swallowing dysfunction, gastroesophageal reflux, and inability to adequately protect the airway from oral secretions or a combination of these. anatomic conditions that predispose to aspiration lung disease include esophageal stricture or obstruction (eg, vascular ring, foreign body, achalasia), cleft palate, tracheoesophageal fistula (fig. ) , laryngeal cleft, and bronchobiliary fistula. , aspiration related to near-drowning occurs when fluid enters the lungs without being prevented by laryngospasm. it typically manifests as pulmonary edema radiographically. in a recent series of children, secondary infections from aspiration related to near-drowning were rare. hydrocarbon pneumonia is an acute, intense chemical pneumonitis after unintentional aspiration of volatile hydrocarbon compounds. most cases of hydrocarbon pneumonia occur in children. chest radiographs typically show bilateral, scattered pulmonary densities with middle and lower zone predominance. such densities may become confluent and progress to acute respiratory distress syndrome (ards) and respiratory failure. they typically worsen over the first hours and then clear over the next few days. however, occasionally radiographic changes may take weeks to months to be cleared. obstructive emphysema, pneumatoceles, subsegmental, or segmental atelectasis may also be seen. lipoid pneumonia is a rare form of pneumonia caused by inhalation or aspiration of a fatty substance. oral administration of various oils is a common cultural practice, including mineral oil, olive oil, shark liver oil, cod liver oil, coconut oil, and ghee. such oily materials can readily slide into the airway even in normal infants and young children without eliciting a cough reflex and are poorly removed by cilia. lipoid pneumonias are typified by mild, subacute, or chronic clinical findings with accompanying marked radiographic changes. chest radiographs of children with lipoid pneumonia typically show bilateral parahilar illdefined, airspace opacities. in a series of pediatric patients, ct showed dense consolidation surrounded by ground-glass opacity with a geographic lobular distribution. within the dense consolidations, areas with relatively low attenuation were identified in only patient. therefore, low-density consolidation in the posterior lungs is an infrequent ct finding in the diagnosis of lipoid pneumonia in children (fig. ). interlobular septal thickening in areas of ground-glass opacity (ie, crazy paving pattern) has also been described in children with lipoid pneumonia. lipoid pneumonias may be complicated by superimposed infection especially with atypical mycobacteria. slow recovery usually takes place with cessation of the oil administration. there may be residual scarring/fibrosis especially with animal rather than vegetable oils. , foreign body aspiration can also result in pneumonia. accidental aspiration of both organic and nonorganic foreign bodies is a cause of childhood morbidity and mortality, requiring prompt recognition and early treatment to minimize the potentially serious and sometimes fatal consequence. eating is the most common circumstance during which it occurs, with small food items being the most common foreign bodies aspirated. coughing, choking, acute dyspnea, and sudden onset of wheezing are the most common symptoms. clinical signs of foreign body aspiration have low positive predictive values. chest radiographs are the initial imaging modality for patients with clinically suspected tracheobronchial aspiration of a foreign body. chest radiographs may show air trapping, atelectasis, a radiopaque foreign body (rare), or be normal (fig. ) . when the routine inspiratory chest radiograph is unhelpful or confusing, inspiratory and expiratory radiographs (in a cooperative child) or bilateral decubitus views (in a younger child unable to follow breathing instruction) are useful in confirming focal or unilateral air trapping. in selected cases, ct (possibly integrated with virtual bronchoscopy) may be considered to exclude a foreign body. ct evaluation may avoid bronchoscopy or provide the exact location and postobstructive complications of the foreign body before bronchoscopy. an underlying chronic unrecognized airway foreign body should be considered among other causes of recurrent or chronic pneumonia, particularly in the pediatric population (see fig. ). pie syndrome comprises a group of heterogeneous disorders having the common findings of lung disease and eosinophilia in the peripheral blood, bronchoalveolar lavage fluid, or pulmonary interstitium. pie syndrome is rare in children. a subclassification for the pie syndromes in children is summarized in box . , infectious causes of pie syndrome are uncommon and include chlamydia trachomatis (especially in infants less than months of age), allergic bronchopulmonary aspergillosis (in asthmatics and cystic fibrosis), parasitic larvae in lungs (toxocara, ascaris, and others), and fungi (eg, cryptococcus, candida species). the radiographic findings in pie syndromes tend to be nonspecific. chest radiographs may show interstitial, alveolar, or mixed (interstitial and alveolar) infiltrates, which tend to be bilateral and diffuse. certain pie syndromes may be associated with more specific findings. the classic radiographic appearance of chronic eosinophilic pneumonia is characterized by peripheral infiltrates with sparing of the central lung zones. this radiographic appearance has been described as the "photographic negative of pulmonary edema." bronchiectasis with mucoid impaction is generally present on chest radiographs or ct in patients with allergic bronchopulmonary aspergillosis (fig. ) . acute eosinophilic pneumonia is frequently associated with small bilateral pleural effusions. imaging is often helpful in determining the extent of disease, localizing the potential sites for lung biopsy, and in assessing response to therapy once treatment has begun. chronic pneumonia is defined as a pulmonary opacity that does not improve within month. it is best classified from the anatomic pattern, as focal, interstitial, with hilar lymphadenopathy, or with cysts, cavities, or spherical masses. spherical masses, with or without cavitations, are often features of an infectious cause. infectious causes and mimics of this pattern are summarized in boxes and (see fig. ; figs. [ ] [ ] [ ] . obstructive atelectasis may both mimic and predispose to chronic pneumonia. it may have many underlying causes, including foreign body, mucoid impaction, narrowed bronchus, and extrinsic bronchial compression by cardiovascular anomalies, lymphadenopathy, tumor, or postpneumonic inflammatory changes. anomalies of the lung, mediastinum, and diaphragm that may mimic an acute or chronic pneumonia pattern include atypical thymus, diaphragmatic eventration and hernia, tracheal bronchus, lung hypoplasia, and congenital bronchopulmonary malformations (bpms). several of these lesions, such as the bpms, predispose to recurrent or chronic infection but differentiating an infected from uninfected lesion may be difficult or impossible on imaging. sometimes having previous imaging for comparison is helpful in terms of features such as the new presence of fluid in a previously air-filled cavity or perilesional consolidation. recurrent pneumonia is defined as more than episode within a -year period or more than episodes in a lifetime. many children with a chronic pulmonary lesion (especially a congenital anomaly) are believed to have recurrent pneumonias if chest radiographs are taken only during a febrile illness. recurrent pneumonias may be either focal or interstitial (linear). underlying abnormalities that may predispose to recurrent focal pneumonia include chronic aspiration (see section on aspiration pneumonia), congenital heart disease, bronchopulmonary foregut malformations (including bpms with enteric-respiratory tract fistula), airway abnormalities (foreign body, stenosis, bronchiectasis, cystic fibrosis, immotile cilia disease), paralysis or eventration of the diaphragm, and congenital, acquired, and iatrogenic immune deficiencies. , recurrent interstitial pneumonia may be secondary to asthma, hypersensitivity pneumonitis, or pneumonias in children with aids (including pneumocystis jiroveci pneumonia, lymphoid interstitial pneumonitis, and recurrent streptococcus pneumoniae infection) (see fig. ). neonatal lung infections can be generally classified into types depending on the initial source of neonatal infection: transplacental, perinatal, and postnatal (including nosocomial) infections. transplacental infections enter the fetus hematogenously via the umbilical cord. most infants affected with transplacental infections typically recurrent aspiration caused by tracheoesophageal fistula without esophageal atresia in a day-old girl who presented with recurrent episodes of apnea, cyanosis, and choking desaturations. barium esophagram shows an oblique connection (red arrow) coursing anterosuperiorly from the esophagus to the trachea at the level of the thoracic inlet. contrast has opacified the central tracheobronchial airways. inferior to the fistula, there is a focal mild narrowing of the esophagus (blue arrow), raising concern for a congenital esophageal stricture. manifest systemic and multiorgan disease rather than a primary lung infection. the most common transplacental infection is caused by cmv, which manifests as a diffuse reticulonodular pattern. other less common, transplacentally acquired pneumonias include rubella, syphilis, listeria monocytogenes, and tuberculosis. perinatal infections can be acquired via ascending infection from the vaginal tract (most commonly group b streptococcus or escherichia coli), transvaginally during the birth process, or nosocomially in the neonatal period. radiographic findings in neonatal pneumonia are nonspecific in differentiating between various etiologic pathogens, as well as differentiating pneumonia from other causes of respiratory distress (eg, transient tachypnea of the newborn, surfactant deficiency disease, and meconium aspiration). the most common radiographic manifestation of neonatal pneumonia is bilateral coarse perihilar reticular densities with possible scattered airspace opacities (fig. ) . solitary lobar consolidations are uncommon. there is an association between group b streptococcal pneumonia and an ipsilateral diaphragmatic hernia. chest radiographs in group b streptococcal sepsis can mimic the diffuse ground-glass opacity seen in surfactant deficiency disease. however, the presence of this finding in a full-term infant or the presence of cardiomegaly or pleural effusions may help to differentiate group b streptococcal infection from surfactant deficiency disease. pneumonia caused by chlamydia trachomatis occurs in about % of infants born to women who carry this organism in their genital tract and becomes symptomatic more than to weeks after birth. chlamydia pneumonia is characterized by hyperinflation and bilateral diffuse reticular perihilar densities that are disparate with relatively mild clinical symptoms. concomitant conjunctivitis, which used to be a useful clue to the cause, is prevented by the routine instillation of antibacterial eye drops at birth. neonates with chlamydia pneumonia frequently have accompanying eosinophilia. bordetella pertussis has recently resurfaced to produce epidemics of infection, probably related to waning community immunity. the clinical presentation of pertussis in the newborn may lack some features (characteristic whooping cough and fever) typical of the disease in older children. the clinical presentation of the most severely affected newborns may be dominated by marked respiratory distress, cyanosis, and apnea. mortality caused by pertussis usually results from secondary pneumonia, encephalopathy, cardiac failure, or pulmonary hypertension. a suggested mechanism for pulmonary hypertension that may develop in newborns with bordetella pertussis infection is formation of leukocyte thrombi in pulmonary venules secondary to hyperleukocytosis. , the classic radiographic appearance in pertussis is the shaggy heart with diffuse peribronchial cuffing related to airway inflammation. however, chest radiographic findings such as hyperaeration, atelectasis, segmental consolidation, and lymphadenopathy are usually nonspecific. recurrent pulmonary infection, with bacterial, viral, or occasionally fungal pathogens, are frequent problems in neonates undergoing prolonged hospitalization and complex treatments, especially in premature infants with chronic lung disease. radiographic alterations caused by infection may be subtle when superimposed on chronic lung changes. pneumonia is a common disease in the immunocompromised host. immunocompromise may be congenital (congenital immunodeficiencies), acquired (hiv/aids, malnutrition) or iatrogenic (during chemotherapy for cancer or after tissue transplantation). immunodeficient states can result in: ( ) humoral immunodeficiency (hypogammaglobulinemia, functional b-lymphocyte deficiency accompanying hiv infection); ( ) cellular immunodeficiency (severe malnutrition, late stages of aids, some congenital immunodeficiencies such as digeorge syndrome); and ( ) neutrophil dysfunction and neutropenia (chronic granulomatous disease, pure neutropenia). iatrogenic immunodeficiencies may be a combination of neutropenia or neutrophil dysfunction, innate or drug-induced defective lymphocyte function, and drug-induced breaks in the oral and intestinal mucosal barriers. the causes of pneumonia in the immunocompromised host consist not only of the same agents that cause pneumonia in the normal host but also of several opportunistic agents depending on the type and severity of immunodeficiency as well as temporal pattern after chemotherapy or transplant. in an immunocompromised child with a noncontributory chest radiograph and clinical findings that could be attributed to a lung infection, chest ct is often required for evaluation of a possible lung infection. in this situation, there are major advantages of chest ct over chest radiographs. first, the presence, pattern, and extent of the disease process are better visualized. second, more than pattern of abnormality may be detected, suggesting dual pathologic entities. third, invasive diagnostic procedures (eg, bronchoscopy or needle aspiration) can be more precisely planned. fourth, ct also allows for increased sensitivity in assessment of the response to treatment. , although the radiographic or ct appearance might not be specific for a pathogen, knowledge of the clinical setting in combination with the type and severity of immunodeficiency and imaging pattern may narrow the differential diagnosis. a commonly encountered clinical issue is the possibility of fungal infection in immunocompromised children. the hallmark ct finding of fungal infections is the presence of pulmonary nodules. such pulmonary nodules are often clustered peripherally and can show poorly defined margins, cavitation, or a surrounding halo of ground-glass opacity (ct halo sign) (fig. ) . the ct halo sign is a nonspecific finding and represents either hemorrhage around a nodule or neoplastic or inflammatory infiltration of the lung parenchyma. in the immunocompromised host, the ct halo sign can be seen most commonly with fungal infections (eg, aspergillosis, mucormycosis, or candida) but also in viral infections (eg, cmv infection, herpes infection), organizing pneumonia, and pulmonary hemorrhage. , [ ] [ ] [ ] [ ] [ ] [ ] microorganisms associated with severe pneumonia in immunodeficiency states are summarized in box . lip is a form of subacute pneumonia seen in several states of immunologic dysregulation, particularly in children with hiv infection. lip is characterized by micronodules of proliferating lymphoid tissue associated with infection by ebv. chest radiographs in lip show a characteristic diffuse, bilateral nodular, or reticulonodular pattern . wegener granulomatosis mimicking chronic cavitary pneumonia in a -year-old male who presented with hemoptysis and respiratory distress. initial chest radiograph showed bilateral confluent airspace opacities secondary to diffuse pulmonary hemorrhage (not shown). contrast-enhanced ct obtained days after initial presentation shows multifocal consolidation with cavitation (arrow), ground-glass opacities, and a right pneumothorax. (see fig. ). other recognized associated imaging findings of lip include consolidation, mediastinal adenopathy, and bronchiectasis. , , radiologic features in common hiv-associated infections in pediatric patients are summarized in table . in pediatric patients with iatrogenic deficiencies of the immune system, pneumonia is commonly caused by opportunistic bacteria and fungi, acquired nosocomially or from resident mucosal flora (fig. ) . in addition, after solid-organ transplantation although total immunoglobulin levels are normal, children and adolescents may be susceptible to encapsulated bacteria (eg, streptococcus pneumoniae, haemophilus influenzae). viruses that commonly cause pneumonia in healthy hosts (eg, rsv, influenza, parainfluenza viruses, human axial contrast-enhanced ct shows multiple bilateral pulmonary nodules, some have rims of groundglass opacity (arrow), which is also known as the ct halo sign. microorganisms associated with severe pneumonia in immunodeficiency states in pediatric patients metapneumovirus, and adenovirus) display greater virulence in both children and adults after solid-organ or human stem cell transplantation, particularly when cellular immunity is profoundly suppressed. in the posttransplant setting, ebv can cause progressive pulmonary disease in the form of posttransplantation lymphoproliferative disease. in studies of hrct in bone marrow transplant recipients, the most useful distinguishing feature was the presence of large nodules and visualization of the halo sign, suggestive of fungal infection. , after solid-organ transplantation, nosocomially acquired bacteria predominate as a cause of pneumonia in the first month. later, viruses, especially cmv and adenovirus, as well as listeria, nocardia, and aspergillus, may be the cause. after more than months after solid-organ transplantation, community-associated bacterial pneumonia becomes more common. a variety of noninfectious pulmonary processes can present with acute or subacute clinical findings mimicking pulmonary infection. these findings include alveolar hemorrhage, pulmonary edema, drug reaction, idiopathic interstitial pneumonia, benign and malignant lymphoproliferative disorders, constrictive bronchiolitis, bronchiolitis obliterans with organizing pneumonia, and chronic graft-versus-host disease. the ct findings of many of these entities are nonspecific. , [ ] [ ] [ ] [ ] [ ] abbreviations: alveolar, focal of diffuse alveolar pattern; interstitial, focal or diffuse interstitial pattern; ln, lymphadenopathy; and , refer to relative frequency of radiographic finding with each organism/disease. acute complications of pneumonia can be categorized as suppurative lung parenchymal complications and pleural complications. suppurative lung parenchymal complications span a spectrum of abnormalities and include cavitary necrosis, lung abscess, pneumatocele, bronchopleural fistula (bpf), and pulmonary gangrene. the name given to the suppurative process depends on several factors including the severity and distribution of the process, condition of the adjacent lung parenchyma, and temporal relationship with disease resolution. , cavitary necrosis cavitary necrosis represents a dominant area of lung necrosis associated with a variable number of thin-walled cysts. characteristic findings on ct for cavitary necrosis include loss of normal lung architecture, poor parenchymal enhancement, loss of the lung-pleural margin, and multiple thin-walled fluid-filled or air-filled cavities (fig. ) . cavitary necrosis is seen earlier in chest us or ct compared with chest radiography because these cavities need to be filled with air to be visible on chest radiographs. such cavities filled with air are accomplished only after communication with bronchial airways. most pediatric patients can be managed successfully with conservative treatment. follow-up chest radiographs typically show complete or near-complete resolution of the cavitary necrosis (see fig. ). , lung abscess lung abscess is a severe complication of pneumonia in children, mostly occurring in the presence of predisposing factors, such as congenital or acquired lung abnormalities, or immunodeficiency. lung abscess represents a dominant focus of suppuration surrounded by a well-formed fibrous wall. the predominant pathogens isolated from primary lung abscesses in children include streptococcal species, staphylococcus aureus and klebsiella pneumoniae. children with a lung abscess have a significantly better prognosis than adults with the same condition. lung abscesses are uncommon in immunocompetent children. on contrast-enhanced ct, a lung abscess appears as a fluid-filled or airfilled cavity with a thick definable, enhancing wall (fig. ) . , , although lung abscess in children has been managed successfully for many years with prolonged courses of intravenous antibiotics, the evolution of interventional radiology has seen the accelerated use of percutaneously placed pigtail drainage catheters using us and ct guidance. pneumatocele pneumatocele is a term given to thin, smoothwalled air-filled cysts seen at imaging and may represent a later or less severe stage of resolving or healing lung necrosis (see fig. ). pneumatoceles are most often caused by severe lung infection from staphylococcal pneumonia. however, they may be seen with other bacterial infections including streptococcus pneumonia and after hydrocarbon aspiration. on ct, thin-walled small or large cysts containing air with or without fluid are identified. the wall of a pneumatocele does not enhance. the surrounding lung may be opacified but does not typically show findings of lung necrosis. , pneumatoceles usually resolve spontaneously over time although pneumatoceles may be atypically persistent in children with hyper-ige syndrome. large pneumatoceles containing fluid can be a source of ongoing infection and may occasionally require drainage. bronchopleural fistula bpf is defined as a communication between the lung parenchyma or airways and the pleural space. central bpfs (ie, main or lobar bronchi communicating with the pleural cavity) most often develop after traumatic injury to large airways or leak from the bronchial stump after pneumonectomy or lobectomy. the main causes for peripheral bpfs (ie, segmental or more distal airways or lung parenchyma communicating with the pleural cavity) are necrotizing pulmonary infection (ie, cavitary necrosis), trauma, lung surgery, and malignancy. , presence of air in the pleural space before aspiration or drainage attempts is suggestive of either a peripheral bpf or infection with a gas-producing organism. multidetector ct with thin-section axial and multiplanar reformation images may show a fistulous tract between the pleural space and peripheral airway or lung parenchyma in peripherally located bpfs (fig. ) . pulmonary gangrene pulmonary gangrene is a rare complication of severe lung infection with devitalization of lung parenchyma and secondary infection. the primary feature that distinguishes pulmonary gangrene from necrotizing pneumonia and lung abscess is the extent of necrosis and the fact that thrombosis of large vessels plays a prominent role in the pathogenesis. chest imaging shows lobar consolidation with bulging fissures and is followed by tissue breakdown to form many small cavities, which subsequently coalesce into a single large cavity occupying the entire lobe. such a large cavity is filled with fluid and irregular pieces of sloughed lung parenchyma. however, these findings are not invariably present. surgical resection of necrotic tissue is often necessary for proper management of children with pulmonary gangrene. [ ] [ ] [ ] [ ] the differential diagnosis of suppurative lung complications includes an underlying cystic axial contrast-enhanced t -weighted mr image of the brain shows a rim-enhancing brain abscess in the right occipital lobe. the patient underwent right lower lobectomy and craniotomy for resection of these lesions. congenital bpm that has become secondarily infected. prior and follow-up imaging may aid in the distinction. the presence of large, welldefined cysts early in the course of the illness or a systemic arterial supply to the lung may be helpful in suggesting an underlying bpm, although a chronic inflammatory process in the lower lobe can acquire some systemic vascular supply from diaphragmatic vessels. pleural complications from acute pneumonia include parapneumonic effusion and empyema. parapneumonic effusion is defined as a pleural effusion in the setting of a known pneumonia. it may be simple or complicated based on the absence or presence of the infecting organism within the pleural space, respectively. empyema is defined as thick purulent pleural effusion. it may be free-flowing or loculated. progression of a pleural effusion to empyema occurs through stages: exudative, fibrinopurulent, and organization. parapneumonic effusions complicate pneumonia in % to % of cases in pediatric patients. empyema complicates an estimated . % of all childhood pneumonias. chest radiographs can often detect a parapneumonic collection, although some fluid, especially in a subpulmonic location, may not be visible and is often seen better on a decubitus film. in cases with complete or almost complete opacification of a hemithorax with or without contralateral mediastinal shift, additional erect or decubitus views are unhelpful in defining the quantity or nature of the pleural fluid. us is most helpful in this situation because it can readily distinguish a parapneumonic collection from extensive consolidation or an underlying mass. the us determination of the echogenicity of the pleural collection (anechoic or echogenic) and showing fibrin strands, septations, loculations, or fibrinous pleural rind is helpful in determining appropriate therapy (see fig. ). treatment options for parapneumonic effusions/ empyemas include antibiotics alone, simple tube drainage, chest drain insertion with fibrinolytics, or surgery (eg, video-assisted thoracoscopic surgery or open thoracotomy with decortication). although imaging techniques are used as a guideline, they do not always accurately stage empyema, predict outcome, or guide decisions regarding surgical versus medical management. ct provides a more global overview of pleural and pulmonary abnormality from acute pneumonia, but is poor at differentiating parapneumonic effusion from empyema in pediatric patients. findings on ct, in patients with parapneumonic effusion/ empyema, include: ( ) enhancement and thickening of visceral and parietal pleura; ( ) thickening and increased density of extrapleural subcostal tissues; and ( ) increased attenuation of extrapleural subcostal fat. loculation can be inferred by the presence of a lenticular fluid collection or nondependent air. septations are usually not appreciated on ct (see fig. ). pleuropulmonary infection may occasionally spread to involve the chest wall, including soft tissues and adjacent bones. mycobacterium tuberculosis, aspergillus, and actinomyces are the most common organisms in this scenario. chronic complications or consequences of pneumonia include parenchymal scarring, bronchial wall thickening, bronchiectasis, a predisposition to asthma, constrictive bronchiolitis, fibrothorax and a trapped lung, fibrosing mediastinitis, constrictive pericarditis, and pleural thickening. for practical purposes, bronchiectasis, constrictive bronchiolitis, fibrothorax and trapped lung, and fibrosing mediastinitis are discussed in the following sections. bronchiectasis is defined by the presence of permanent and abnormal dilation of the bronchi. this condition usually occurs in the context of chronic airway infection causing inflammation. bronchiectasis is nearly always diagnosed using hrct. the main diagnostic features of bronchiectasis on hrct are: ( ) internal diameter of a bronchus that is wider than its adjacent pulmonary artery; ( ) failure of the bronchus to taper peripherally; and ( ) visualization of bronchi in the outer to cm of the lung zones (see fig. ; figs. and ). a wide variety of factors predisposing to the development of bronchiectasis have been identified, including hereditary (cystic fibrosis, ciliary dyskinesia), infective, immunodeficiency (antibody deficiency), obstructive (intrabronchial foreign body), and systemic causes. causes most commonly associated with bronchiectasis are childhood infections, including pneumonia, pertussis, complicated measles, and tuberculosis (eg, mycobacterium tuberculosis and mycobacterium avium complex). [ ] [ ] [ ] constrictive bronchiolitis (bronchiolitis obliterans) constrictive bronchiolitis (bronchiolitis obliterans) is characterized by the presence of concentric narrowing or obliteration of the bronchioles caused by submucosal and peribronchiolar fibrosis. a common cause of constrictive bronchiolitis is previous childhood infection, resulting in the so-called swyer-james syndrome, identifiable as asymmetric hyperlucent lung on chest radiographs. whereas the process may appear unilateral on chest radiographs, there is usually bilateral but asymmetric abnormality on ct (see fig. ). central bronchiectasis and a characteristic mosaic appearance with patchy expiratory air trapping are seen on hrct. causes and associations of constrictive bronchiolitis include previous infections (viral including adenovirus, rsv, influenza, parainfluenza; mycoplasma and pertussis), collagen vascular diseases, previous transplant, toxic fume exposure, ingested toxins, drugs, and cryptogenic constrictive bronchiolitis. pleural fibrosis can result from a variety of inflammatory processes (box ). the development of pleural fibrosis follows severe pleural inflammation, which is usually associated with an exudative pleural effusion. fibrothorax and trapped lung are uncommon consequences of pleural fibrosis (see fig. ). fibrothorax represents the most severe form of pleural fibrosis. with a fibrothorax, there is dense fibrosis of the visceral and parietal pleural surfaces, leading to fusion of these membranes, contracture of the involved hemithorax (and ipsilateral mediastinal shift), and reduced mobility of the lung and thoracic cage (see fig. ). decortication is the only potentially effective treatment of fibrothorax in patients with severe respiratory compromise. , a trapped lung is characterized by the inability of the lung to expand and fill the thoracic cavity because of a restrictive, fibrous, visceral pleural peel (see fig. ). restriction of lung parenchymal expansion and subsequent negative pressure in the pleural space result in filling of the pleural space with pleural fluid (usually a transudate). the diagnosis of a trapped lung implies chronicity, stability over time, and a purely mechanical cause for the persistence of a fluid-filled pleural space. patients with a trapped lung usually do not experience improvement in dyspnea after thoracentesis. in symptomatic patients, decortication should be considered. the underlying lung parenchyma should be assessed before decortication. if the trapped lung is severely diseased and fibrotic, decortication is unlikely to result in lung reexpansion and the procedure does not provide symptomatic benefit. in contrast, lung entrapment is the result of an active inflammatory process or malignancy in the pleural space, leading to a restricted pleural space. pleural fluid from lung entrapment is an exudate, and symptoms in patients with lung entrapment typically improve after thoracentesis. , fibrosing mediastinitis fibrosing mediastinitis is a rare condition characterized by proliferation of fibrous tissue within the mediastinum. symptoms are related to compression of the central airways, superior vena cava, pulmonary veins, pulmonary arteries, and esophagus. the most common cause of this disorder is fungal infection, especially histoplasma capsulatum in the united states. pneumonia is an infection of the lung parenchyma caused by a wide variety of organisms in pediatric patients. imaging evaluation plays an important role in children with pneumonia by detecting the presence of pneumonia and determining its location and extent, excluding other thoracic causes of respiratory symptoms, and showing complications such as effusion/empyema and suppurative lung changes. clear understanding of the underlying potential cause, current role of imaging, proper imaging techniques, and characteristic imaging appearances of acute and chronic pneumonias can guide optimal management of pediatric patients with pneumonia. 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anterior mediastinal tumor key: cord- -aic x authors: kim, se jin; kim, kang; park, sung bum; hong, duck jin; jhun, byung woo title: outcomes of early administration of cidofovir in non-immunocompromised patients with severe adenovirus pneumonia date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: aic x the benefits of treatment with antiviral therapy for severe adenovirus (adv) pneumonia are not well established. we described the clinical characteristics and treatment outcomes of early cidofovir treatment of severe adv pneumonia in non-immunocompromised patients. we retrospectively reviewed the medical records of all patients diagnosed with severe adv pneumonia between and . a total of seven non-immunocompromised patients with severe adv pneumonia were identified, and all isolates typed (n = ) were human adv-b . all patients had progressive respiratory failure with lobar consolidation with or without patchy ground glass opacity. three patients required vasopressors and mechanical ventilation. all patients had abnormal laboratory findings including: leukopenia, thrombocytopenia, or elevated liver enzymes. after admission, all patients received antiviral therapy with cidofovir, and the median time from admission to cidofovir administration was h and median the time from onset of symptoms to cidofovir administration was . days. after cidofovir administration, complete symptomatic improvement occurred after a median of days and radiographic resolution occurred after a median of days. consequently, all patients completely improved without complications. our data suggest that early administration of cidofovir in the course of treatment for respiratory failure as a result of adv pneumonia in non-immunocompromised patients could be a treatment strategy worth considering, especially in cases of hadv- infection. adenoviruses (adv) are non-enveloped, double-stranded dna viruses that can cause diseases of the upper and lower respiratory, gastrointestinal, and ocular systems [ ] . respiratory infection caused by adv in non-immunocompromised patients is usually mild and self-limited. in contrast, in immunocompromised patients, adv infection can be disseminated and result in a considerable mortality rate [ ] [ ] [ ] . despite the low incidence of serious illness in non-immunocompromised patients, levin et al. reported fatal adv pneumonia in a previously healthy adult in [ ] , and sporadic cases of severe respiratory disease in non-immunocompromised adults have been reported [ ] [ ] [ ] [ ] [ ] [ ] since. these reports include several outbreaks of adv respiratory infections in previously healthy adults in vulnerable populations, such as residents of mental health care centers and military recruits [ ] [ ] [ ] [ ] [ ] [ ] . previous investigations described the clinical characteristics of severe adv pneumonia as being distinct from those of other causative agents [ , , ] , and revealed that several adv serotypes were associated with severe disease states [ , [ ] [ ] [ ] . however, these efforts have not influenced the overall clinical outcomes in cases of severe adv pneumonia. currently, there are no approved antiviral agents for the treatment of severe adv pneumonia, and limited data on the clinical response to antiviral therapy in immunocompromised patients are available [ , ] . our institution, a military hospital with the highest referral rate in south korea, encounters several cases of adv pneumonia annually, some of which are severe cases [ , ] , thus we have aimed to produce favorable outcomes by applying antiviral therapy upon confirmation of the diagnosis of severe adv pneumonia. the present study describes in detail the clinical characteristics and favorable treatment outcomes of non-immunocompromised adults who had experienced severe adv pneumonia and received early cidofovir administration. we retrospectively reviewed the medical records of all consecutive patients diagnosed with adv pneumonia between december , and june , at the armed forces capital hospital ( bed referral military hospital) in gyeonggi province, south korea. the diagnosis of adv pneumonia was considered certain when it was associated with the following: ) lower respiratory and/or systemic symptoms, ) lung infiltration on chest radiography or computed tomography (ct) scan, and ) evidence of adv infection identified by positive multiplex polymerase chain reaction (pcr) for adv from lower respiratory tract samples, such as sputum, or bronchoalveolar lavage (bal) fluid. only non-immunocompromised adult patients who fulfilled the criteria for severe community-acquired pneumonia, set out in the infectious diseases society of america/american thoracic society consensus guidelines [ ] , and admitted to the intensive care unit with progressive respiratory failure, defined as a partial pressure of arterial oxygen (pao )/fraction of inspired oxygen (fio ) ratio of < mmhg and/or tachypnea (respiration rate > breaths/min) [ ] , were included in the analysis. criteria for severe community-acquired pneumonia requiring admission to the intensive care unit are one or more major criteria or three or more minor criteria [ ] . major criteria include: ) invasive mechanical ventilation and ) requiring vasopressors due to septic shock. minor criteria include: ) respiratory rate /min, ) pao /fio ratio mmhg, ) multilobar pneumonia in chest radiographs, ) decreased level of consciousness, ) blood urea nitrogen mg/dl, ) white blood cells < , /mm , ) platelets < , /mm , ) core temperature < °c, and ) hypotension requiring aggressive fluid therapy. the institutional review board of the armed forces capital hospital approved this study and permitted review and publication of patient records. all data on the study patients were analyzed anonymously. the requirement for informed consent by individual patients was waived given the retrospective nature of the study. findings including leukopenia or extrapulmonary symptoms were suspected of having atypical pneumonia [ ] , and underwent thorough examinations. infectious etiologies were investigated using peripheral blood, sputum, and bal fluid utilizing techniques such as staining and microbiological culture for bacteria and mycobacterium tuberculosis; multiplex real time pcr testing for respiratory bacterial agents including streptococcus pneumoniae, haemophilus influenza, mycoplasma pneumoniae, chlamydia pneumoniae, legionella, and bordetella; and multiplex real time pcr testing for respiratory viruses. nucleic acid extraction was performed on the magna pure lc . (roche diagnostics, mannheim, germany) using a magna pure lc nucleic acid isolation kit i (roche diagnostics) according to the manufacturer's instructions. more than fifty microliters of clinical samples were used for nucleic acid extraction and eluted in μl of elution buffer. multiplex real-time pcr was performed to screen for commonly isolated respiratory viral pathogens, including adenovirus, rhinovirus, influenza virus a/b, respiratory syncytial virus a/b, bocavirus, coronavirus e/oc /nl /hku , parainfluenza virus / / , and metapneumovirus, using a real-q rv detection kit (biosewoom, seoul, korea) on a roche light cycler ii instrument (roche diagnostics, mannheim, germany) according to the manufacturer's instructions. the presence of specific viral sequences in the reaction was detected by an increase in the fam, vic and cy fluorescence from the relevant dual-labeled probe. five primer/probe sets were used to detect respiratory viruses. the serotype of human-adv-positive samples was evaluated by sequence analysis using the partial hexon genomic region. cidofovir (mylan institutional) was initiated upon confirmation of adv infection. cidofovir, at a dosage of mg/kg weekly, was administrated in combination with oral probenecid. hydration consisted of - l of normal saline before cidofovir infusion and - l immediately thereafter to prevent renal toxicity. a total dose of -g probenecid was given orally h before infusion, and g at and h after the cidofovir infusion. the number of cidofovir courses administered was determined by the attending physician. eleven patients were newly diagnosed with adv pneumonia and admitted during the study period; all were non-immunocompromised adults. of these, four patients did not fulfill the criteria for severe community-acquired pneumonia [ ] , improved clinically with no antiviral therapy, and were excluded from the analysis. consequently, seven patients with severe adv pneumonia were analyzed in this study; their baseline characteristics are shown in table . all patients were previously healthy young males without underlying conditions. three ( %) patients were non-smokers. body mass index (kg/m ) of patients varied from . - . . the illnesses of most of the patients (n = ) occurred in early spring, while that of one occurred in the winter. three ( %) patients were from a military training facility and all patients were from different operational areas. all patients presented with acute respiratory or systemic symptoms, such as fever (n = ), cough (n = ), purulent sputum (n = ), blood-tinged sputum (n = ), and dyspnea (n = ). one patient had concurrent upper respiratory tract symptoms, and three patients had extrapulmonary symptoms such as diarrhea. all patients had respiratory distress, with hypoxemia (pao /fio ratio < mmhg). six ( %) patients had tachycardia (> beats/min) or tachypnea (> breaths/min). three ( %) patients needed vasopressors and mechanical ventilation. the median duration from onset of symptoms to admission was days. five ( %) patients received empirical antibiotics including quinolone (n = ) and third-generation cephalosporins (n = ) before admission. the two remaining patients received quinolone (n = ; identified as patient ) and piperacillin (n = ; identified as patient ) on admission. initial chest ct findings in patients with severe adv pneumonia are shown in table . most patients (n = , %) had bilateral lobar consolidation with ground glass opacity in the upper and lower lobes (fig ) ; only two patients ( %) had unilateral lobar consolidation with or without ground glass opacity. the most commonly involved lobe was the left lower lobe (n = ), followed by the right lower lobe (n = ), left lower lobe (n = ), and both lower lobes (n = ). pleural effusion was observed in all patients. the results of initial laboratory tests are shown in table . all patients had thrombocytopenia (< , /μl), most (n = , %) patients had leukopenia (< , /μl), and none had leukocytosis (> , /μl). c-reactive protein levels were elevated in all patients, with a median of . mg/dl. procalcitonin levels were elevated in five ( %) patients, with a maximum of . ng/ml. hyponatremia was observed in two ( %) patients, and all patients had elevated liver enzymes. pleural fluid analysis was performed in four ( %) patients; all results were lymphocyte-dominant exudates without evidence of empyema. adv was identified in all patients by pcr in sputum (n = ) and bal fluid (n = ). serotyping by sequence analysis was available for six patients; all isolates typed (n = ) were human adv-b (s fig). bacterial co-infection was identified in the sputum of two ( %) patients by pcr; s. pneumoniae (patient ) and s. pneumoniae + h. influenzae (patient ) were identified. no other causative agent was identified. clinical responses to antiviral therapy in each study patient the clinical responses to treatment in each patient are shown in figs and . fig shows the clinical responses of patients - , who needed vasopressors and mechanical ventilation due to septic shock and severe respiratory failure. in patient , after cidofovir administration, blood pressure stabilized after approximately days, and tachypnea, tachycardia, and fever improved within days. oxygenation completely improved within days (fig a) . in patient , blood pressure stabilized after approximately days, and tachypnea, tachycardia, and fever improved within days. oxygenation completely improved within days of cidofovir administration (fig b) . in patient , blood pressure stabilized after approximately days, and tachypnea, tachycardia, and fever within days. oxygenation completely improved within days of cidofovir administration (fig c) . in patient , tachypnea, tachycardia, and fever improved within days, and oxygenation completely improved within days, of cidofovir administration (fig a) . in patient , tachypnea, tachycardia, and fever improved in days, and oxygenation completely improved within days, of cidofovir administration (fig b) . in doi: . /journal.pone. .g patient , tachypnea, tachycardia, and fever improved in days, and oxygenation completely improved within days, of cidofovir administration (fig c) . in patient , tachypnea, tachycardia, and fever improved in days, and oxygenation completely improved within days, of cidofovir administration (fig d) . overall treatment outcomes of study patients are summarized in table . median time from admission to identification of adv infection was (range, - ) days. all patients received cidofovir, and most patients (n = , %) received cidofovir within h (minimum, h and median, h); only one patient ( %) received cidofovir h after admission. the median time from onset of symptoms to cidofovir administration was . days. three patients (patients , , and ) who needed vasopressors and mechanical ventilation received two doses of cidofovir. the other four patients (patients , , , and ) received single doses of cidofovir. six ( %) patients received adjuvant intravenous immunoglobulin for days. after cidofovir administration, clinical, radiological, and laboratory improvement occurred in all patients. complete symptomatic improvement occurred after a median of (range, - ) days, and complete radiographic resolution occurred after a median of (range, - ) days (fig ) . normalization of white blood cell count and c-reactive protein level after a median of (range, - ) days and (range, - ) days, respectively. adverse reactions (skin rash) to cidofovir occurred in one patient, and resolved completely with only conservative management. all patients recovered completely without complications. in the present study, we described favorable outcomes to antiviral therapy with cidofovir in non-immunocompromised adult patients with severe adv pneumonia. our data suggest that early administration of cidofovir in the course of respiratory failure could be a treatment strategy worth considering in severe adv pneumonia. in the seven cases discussed, cidofovir was administered more promptly than in previous fatal cases. in previous studies, most patients did not receive antiviral therapy with cidofovir; indeed, even in the few patients who did receive cidofovir, the administration time was not early in the course of respiratory failure [ , , ] and they had poor outcomes. for example, in a recent study that evaluated outcomes in five patients with severe adv pneumonia caused by adv- infection in non-immunocompromised adults [ ] , similar to our study group, four ( %) of the five patients died despite receiving appropriate respiratory support and antiviral therapy, including acyclovir, ganciclovir, and ribavirin, without using cidofovir. in a study of the etiology and epidemiology of acute viral lower respiratory tract infections of south korean soldiers in our institution, six cases of severe adv pneumonia were identified. all six patients required mechanical ventilation, most ( / ) did not receive cidofovir, and half ( / ), including one patient who was treated with cidofovir days after admission, died [ ] . moreover, in a case report of fatal adv pneumonia in immunocompetent adult identical twins, one patient did not recover despite administration of cidofovir antiviral therapy no sooner than days after the onset of symptoms [ ] . in the present study, in contrast, time from admission to identification of adv was short (median, days), and all patients received antiviral therapy on the day of diagnosis of adv infection. given this background, our findings may indicate that administration of cidofovir early in the course of respiratory failure may be a beneficial treatment strategy in severe cases of adv respiratory infection, and this may assist physicians in making decisions regarding diagnosis and treatment. in our study, all isolates typed (n = ) were human adv-b [ , ] . to date, more than human adv types have been identified [ ] [ ] [ ] [ ] , and serotypes - , , , , , and are most commonly associated with human disease. among these, human adv-b has been identified as an emergent acute respiratory disease pathogen, fully characterized by wholegenome sequencing, and has caused two recent outbreaks; one in china in [ ] and one in singapore in [ ] . in one study that evaluated cases of adv pneumonia [ ] , patients infected with human adv- had higher pneumonia severity index scores compared with those infected with other serotypes. thus, human adv- could be a major pneumonia pathogen in the general population, and further surveillance and monitoring of this agent as a cause of pneumonia are warranted. however, to date, limited data on the correlation between human adv- and clinical severity or clinical courses are available; and no data are available on the treatment responses to cidofovir in cases of human adv- infection. in these contexts, our data may have clinical significance and further studies on the associations of adv serotypes with severe respiratory infection are necessary. the pathophysiology of adv pneumonia remains unclear; few studies have been performed. for example, prince et al. [ ] and gregory et al. [ ] indicated that much of the acute damage in adenovirus infection appears to be due to dysregulation of the immune system. these features may, in part, explain the self-limiting nature of cases of even severe adv infection without antiviral therapy, and suggest that the host's immunological reaction to the infection is a major factor in the pathogenesis of the lung injury. moreover, this implies that antiviral therapy administered late in the course of respiratory failure may not be effective. however, because there are no accurate data on the pathophysiology of adv, further studies are needed. this study had several limitations. firstly, the study was not controlled with respect to the treatment administered because of its retrospective design. although we obtained favorable outcomes, other factors may have influenced the outcomes in the study patients, such as the supportive treatment strategies, including ventilator settings and the prone position, or host factors, including young age and previous good health status, and moreover, self-limiting cases of severe adv infection have been reported previously [ ] [ ] [ ] ] . to date, no controlled study has been reported on the benefits of antiviral therapy in severe adv pneumonia. this may be mainly because of the rarity of severe adv pneumonia in non-immunocompromised adults and ethical problems in using antiviral agents that have not obviously been demonstrated to have clinical effect. in this context, our data, despite the limitations, may suggest possible benefits of administering cidofovir as early as possible in severe adv pneumonia caused mainly by human adv- . based on our clinical data, further controlled studies are warranted to confirm the benefits of cidofovir. second, despite extensive microbiological testing, the possible influences of bacterial or other co-infection on treatment outcomes cannot be excluded. furthermore, this study included only a small number of patients. additionally, the study 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daltro, pedro; santos, eloá n.; gasparetto, taísa d.; ucar, maria e.; marchiori, edson title: pulmonary infections date: - - journal: pediatr radiol doi: . /s - - - sha: doc_id: cord_uid: j eyw this paper reviews the most common imaging findings of pulmonary infection in children. pneumonia is a leading cause of mortality in children in developing and industrialized countries. while the imaging findings usually are nonspecific, correlation with the patient’s age, immune status and pertinent history can limit the differential diagnoses. the paper will review the common and unique features of pneumonia caused by specific organisms and in specific patient populations. pneumonia is defined as an acute or chronic disease that causes inflammation of the lungs. it is one of the most common infections in the pediatric population and a leading cause of mortality in children in developing countries. it is usually acquired through inhalation of infected upper airway secretions, although hematogenous routes or contiguity can occur [ ] [ ] [ ] [ ] . viruses, bacteria, fungi and other microorganisms are the main etiological agents. though pneumonia from any organism can occur at any age, certain age groups are at higher risk for particular types of pneumonia. the vast majority of pneumonia in infancy and early childhood is of viral origin and accounts for % of pneumonia in children younger than years [ ] . the most common bacterial organism in children older than years is s. pneumoniae. mycoplasma is the most frequent cause of pneumonia in those older than years of age group [ , , ] . the immunological status of the child and the infectious agent also have an important role in the clinical and radiological aspects of the disease [ , ] . this paper reviews the most common causes of pulmonary infection in children, emphasizing the imaging findings. viral infections occur after the inhalation of infected aerosols. usually the infection begins in the nasopharynx and upper respiratory tract and migrates to the small airways and alveoli. the clinical presentation of viral pneumonia varies greatly depending on the infecting agent, the age and the immune status of the host [ , ] . influenza virus, respiratory syncytial virus (rsv), adenovirus and parainfluenza are common causes of viral pneumonia in children. in premature-born infants with lung disease, rsv can be devastating. recently, human metapneumovirus has been recognized as a pathogen. its ubiquity suggests that it is as important as rsv, and studies suggest its incidence is as high as that of rsv. nearly % of children ages - years are seropositive [ ] . herpes simplex virus is rare, affecting mostly newborns. patients with immunodeficiency syndromes are also at risk of pneumonia caused by other pathogens such as cytomegalovirus [ ] . influenza virus and rsv infect the pneumocytes, causing diffuse alveolar damage. the alveoli are infiltrated with neutrophils, and mononuclear cells with fibrin and edematous fluid [ , ] . in addition, the submucosa presents with hyperemia with focal hemorrhage and edema. the small bronchial diameters and poorly developed airways of the smallest children combined with their abundant mucus production cause the characteristic abnormalities revealed by chest radiograph [ , ] . ct is sometimes indicated in complicated cases of diffuse disease [ ] . the most common chest radiographic findings are bilateral symmetrical parahilar and bronchial opacities with or without atelectasis and air trapping (figs. and ). focal and asymmetrical disease are not uncommon. lymph node enlargement can occur, but pleural effusion is rare. recently viral infection has been recognized as a cause of severe pneumonias leading to respiratory failure and death. higher mortality rates are associated with coronavirus a (sars, severe acute respiratory syndrome), and influenza virus type a h n (bird flu) and type a h n . as with other viral infections, focal or diffuse interstitial opacities are the initial chest radiograph presentation, but they can progress rapidly to bilateral areas of consolidation (fig. ). in children with type a h n initial radiographs were often normal, and a trend to more severe disease was seen in children with diffuse ground-glass opacities [ ] . early recognition of the epidemic and an increased index of suspicion in patients with asthma and chronic lung diseases will help in identifying these pneumonias. the most common complication of viral pneumonia is a secondary bacterial pneumonia. damage to the respiratory tract mucosa harms local defense mechanisms and leaves the lung vulnerable to bacterial superinfection [ , , ] . postinfectious bronchiolitis obliterans (bo) is a chronic obstructive disease of the lower airways that affects mainly male infants after an episode of acute viral bronchiolitis. adenovirus is the most common agent. the virus infects the epithelial cell surface and initiates intracellular replication, resulting in squamous metaplasia of the bronchial mucosa and necrosis of the bronchiolar wall with destruction of the ciliated epithelium. peribronchiolar inflammatory opacities, edema of the submucosa and connective tissue, and increased mucus secretion cause obstruction of the bronchioles, resulting in air trapping and atelectasis. ct performed in children because of progressive disease shows mosaic perfusion, peribronchial thickening, atelectasis, bronchiectasis, air trapping and sometimes lung volume reduction (fig. ) [ , ] . swyer-james-macleod syndrome is a postinfectious bo with characteristic radiological features that are virtually pathognomonic. typically involvement is unilateral, affecting the entire lung, lobe or segment. the changes observed on chest radiography are hyperlucency, mainly because of pulmonary hypoperfusion; reduction of vascular and hilar markings; volume reduction of the affected lung or lobe, and air trapping on radiographs made at expiration. ct demonstrates these features with more detail and might demonstrate bronchiectasis (fig. ) . bronchiolitis obliterans organizing pneumonia (boop) is now called cryptogenic organizing pneumonia and should not be confused with postinfectious bronchiolitis obliterans. it shares many of the clinical features of pneumonia but is not of infectious etiology [ , ] . bacterial pneumonia is generally characterized by consolidation and filling of alveolar air spaces with exudate, inflammatory cells and fibrin. the first phase is characterized by active hyperemia and engorgement of the arterial blood vessels. edematous fluid, which might be seen in the alveoli, contains few exudative cells. in the next stage, neutrophils and fibrin material fill the alveoli, and massive extravasation occurs through interalveolar pores (pores of kohn), producing a homogeneous opacity. fibrin and exudative cells accumulate, appearing on radiographs as a clear zone adjoining the alveolar and acinar cells [ , , ] . if the process extends to the pleural space, associated pleural effusion is present. bronchopneumonia is a form of bacterial pneumonia that begins as a peribronchiolar inflammation involving many lobes and spreads to the adjacent parenchyma, causing patchy nodules and consolidation. streptococcus pneumoniae is a common infectious agent but pathogens like haemophilus influenzae, staphylococcus aureus and gram-negative enteric bacteria can cause similar clinical syndromes. the typical chest radiograph reveals homogeneous or fluffy lobar consolidation, but diffuse bilateral inhomogeneous opacities extending peripherally also can be seen, both with and without associated pleural fluid (fig. ) . as opposed to the other bacterial pneumonias, round pneumonia has an atypical radiographic appearance of pulmonary bacterial infections. it is caused most often by s. pneumoniae. it is rare in adults and occurs in less than % of children (usually younger than years of age) but is seen more frequently in the young because of the underdeveloped pores of kohn and the absence of canals of lambert characteristic of this age group. the radiographic finding usually occurs early in the disease course, and for this reason cough and respiratory symptoms can be absent in the initial presentation. the usual presentation is an area of focal nodular consolidation, often solitary, with well-defined borders and mass effect. it frequently occurs in the lower lobes, posteriorly (> %) and inferiorly (> %) [ ] (fig. ) . pneumonias have been classified as atypical based largely on the observation of clinical (low white count, little or no fever, etc.) and imaging findings disproportionate to the clinical condition. legionella species, mycoplasma pneumoniae and chlamydia pneumoniae are the most common etiologies of atypical pneumonias. reticulonodular infiltrate in one lobe is a usual presentation of mycoplasmal pneumonia. other radiographic features are lobar consolidation or pseudoconsolidation (fig. ) , atelectasis, bilateral parahilar peribronchial opacities that resemble butterfly wings, bilobar reticular pattern, pleural and pericardial effusion and hilar lymphadenopathy [ , ] . many of these features can be seen in viral pneumonia as well. to distinguish these pneumonias one needs to recognize the clinical features that don't appear to match the radiograph, such as the degree of respiratory distress or the unusual laboratory findings. for example, chlamydia trachomatis (or chlamydophila) affects young infants in the first months, and frequently a history of conjunctivitis and a staccato cough are observed. the history will reveal a vaginal delivery and a mother with vulvovaginitis. chest radiograph shows bilateral reticular interstitial involvement, hyperinflation and bronchial wall thickening. the three most common complications of bacterial pneumonia are pulmonary necrosis, pulmonary abscess and empyema. children who have complicated pneumonias might require an imaging evaluation by us or chest ct [ , ] . necrotizing lobar lesions result from thrombotic occlusion of alveolar capillaries associated with adjacent inflammation, resulting in ischemia and eventually necrosis. the typical ct findings of necrotizing pneumonia are cystic heterogeneous areas of necrosis within solid consolidation and non-enhancing lung parenchyma ( fig. ) [ ] . pulmonary abscess is a necrotic parenchymal cavity filled with pus. ct imaging shows a cystic area within consolidated lung parenchyma but with contrast rim enhancement (fig. ). chest ct with intravenous contrast administration can be very useful in atypical, complicated pneumonia presentations, although it should not be performed routinely. ct is better than chest radiograph for detecting lobar lesions such cavitary necrosis, early abscess formation, chest tube placement, fluid loculation, empyema, bronchopleural fistulas and pericardial effusions. ct also helps define lesions that might require early surgical intervention [ , ] . chest sonography, however, is mainly used to demonstrate the internal echogenicity of pleural pneumatoceles and bronchiectasis are the most common postinfectious sequelae of bacterial pneumonia. pneumatoceles are thin-walled cystic lucencies with or without septations that develop within the lung parenchyma, occurring after an acute pneumonia most often caused by s. aureus (fig. ). bronchiectasis is an abnormal irreversible dilation of the proximal and medium-size bronchi caused by weakening or destruction of the muscular and elastic components of the bronchial walls. the more commonly acquired forms occur in older children after destructive pulmonary infections that cause impaired clearance of bronchial secretions, or in cases of superimposed bacterial infections in children with previous conditions such as cystic fibrosis. bronchiectasis can be observed as thickening of the bronchial walls and marked dilatation of the bronchial channel on both radiographs and chest ct. mycobacterium tuberculosis causes tuberculosis, and its incidence is increasing worldwide. sixty percent of new childhood infections occur in children younger than years old [ ] . pulmonary tuberculosis in infancy and childhood is classically related to an inhaled innoculum. there is a small, peripheral primary focus that leads to lymphadenopathy asymmetrically distributed in paratracheal, hilar and/or subcarinal areas. the right side is more commonly affected than the left because of the usual pattern of lymphatic circulation within the lungs [ , [ ] [ ] [ ] . enlarged lymph nodes with lobulated, sharp or ill-defined borders can be partially or completely calcified. ct is reserved for complicated cases, not those with a positive skin test. lymph nodes on ct are dense soft-tissue masses with homogeneous or ring-like enhancement and lowattenuation centers. inflamed nodes sometimes erode the bronchial wall and discharge caseous material into the bronchus (fig. ) . this results in bronchogenic spread, characterized as centrilobular or branching centrilobular opacities. coalescence of the centrilobular opacities results in focal areas of bronchopneumonia [ , ] . sporadically, the primary parenchymal lesion continues to enlarge, resulting in focal pneumonitis or lobar pneumonia with thickening of the overlying pleura without distinct hilar lymphadenopathy. it is helpful to divide the disease into subtypes. primary tuberculosis, which sometimes progresses to a symptomatic infection, is often indistinguishable from other forms of bronchial pneumonia. enlarged in cases of tuberculosis, progressively destructive liquefaction of lung parenchyma leads to formation of a primary cavity or more extensive pulmonary necrosis (fig. ) . hematogenous spread can also develop with a miliary pattern of small, well-defined nodules of up to several millimeters in diameter uniformly distributed through the lungs [ , ] . it is important as well to recognize healed tb as latent infection can reactivate. the immune response to the initial infection leads to calcification of the healing lung as well as infected lymph nodes. this observation is important, as the child's immune function can change. in children who have newly diagnosed hiv infection or are undergoing chemotherapy for malignancy or transplantation, it might be important to treat latent tb before it reactivates [ ] [ ] [ ] . histoplasmosis and aspergillosis are the most common fungal pneumonias in children, most often in the immunesuppressed group (see below) [ , ] . histoplasmosis is a systemic mycosis caused by a small fungus, histoplasma capsulatum, whose natural habitat is soil contaminated by bat or bird excrement. it is endemic in some geographical regions, such as the ohio river valley. human infection occurs when airborne spores of h. capsulatum are inhaled. the most common imaging features are diffuse reticulonodular opacities with small and diffuse pulmonary nodules (fig. ) . usually it affects both lungs as well as hilar and mediastinal lymph nodes. this miliary pattern can be identical to miliary tuberculosis and blastomycosis [ ] . pulmonary nodules heal, leaving residual granulomata that undergo central calcification. mediastinal lymph nodes can also exhibit central caseation, peripheral enhancement and, frequently, calcification as in tuberculosis. another uncommon but severe complication of histoplasmosis is mediastinal fibrosis, which not only causes mass effect in the mediastinum, it can compress major blood vessels or occlude bronchi (fig. ) [ , ] . aspergillosis refers to any infection caused by several species of aspergillus: a. fumigatus, a. flavus, a. niger and a. terreus. the fungus is ubiquitous, and asymptomatic colonization is common. three factors are important to the development of active infection: the virulence of the fungus, the type and amount of exposure, and the immune status of the child. the spectrum of lung diseases ranges from allergic reactions, colonization of a preexisting lung cavity, or invasion and destruction of lung tissue, to progressive vascular invasion with involvement of the brain, skin and other organs [ ] [ ] [ ] . allergic bronchopulmonary aspergillosis (abpa) affects children with asthma or cystic fibrosis. the disease is a hypersensitivity reaction to the fungus; the findings are secondary to the reaction to the allergen. this form of the infection occurs most frequently in children with cystic fibrosis. it is important to recognize that prompt therapy can prevent progression of the child's bronchiectasis. abpa should be considered in cf patients with new asthma symptoms and when any new chest radiograph airspace changes are found and when ige titers increase [ ] . the most common ct findings are proximal and segmental bronchiectasis with or without mucous plugs and fleeting consolidations. aspergilloma, in which the fungus colonizes a preexisting lung cavity, occurs in individuals with chronic lung disease and pulmonary sequelae such as tuberculosis, bronchiectasis and pulmonary fibrosis. invasion to lung parenchyma, pleura and fibrosis is minimal, and a fungus ball might be present. neither fungal vascular invasion nor spread to other organs is observed. the disease can persist for months or years. chest ct usually reveals a consolidation with an interposed cavitation and an ovoid intracavitary mass (fungus ball, or mycetoma) consisting of fungal hyphae, mucus and cellular debris [ ] [ ] [ ] . this infection is often associated with underlying pathologies and other infections. it is not uncommonly found in cavities from tb infection or in congenital bronchopulmonary malformations, such as sequestrations. angioinvasive aspergillosis is one of the most common forms of fungal infection among immunocompromised and neutropenic children. the lesions seen on conventional chest radiograph include single or multiple nodules, cavities, and subsegmental or segmental consol- idation. in the initial phase, the most characteristic image seen on ct is the halo sign, an area of low attenuation around the centrilobular nodules that represents edema or hemorrhage (fig. ) . in later stages, ct might show areas of necrotic tissue and pulmonary sequestration within the surrounding parenchyma, resulting in the air crescent sign [ ] . ascaris lumbricoides can lead to an acute inflammatory lung process caused by the host immunological response to parasite migration. this is called loeffler syndrome, or acute allergic eosinophilic pneumonia. chest radiograph and ct often show transient nonsegmental airspace opacification, which can be unilateral or bilateral, usually with predominantly peripheral distribution. the features are not specific for this etiology of allergic eosinophilic pulmonary infiltration. echinococcosis is a parasitic disease usually caused by echinococcus granulosus, which affects humans through accidental ingestion of parasite eggs released in the feces of definitive, carnivorous hosts, such as sheep, dogs and cats. especially in children, infection can also occur through direct contact with infected domestic animals. echinococcus eggs hatch into larvae in the duodenum, then migrate through the portal system to the liver and to pulmonary alveolar lung capillaries, where they develop into spherical or oval cysts. the liver is the primary site of infection in % of patients. the ct scan might show single or multiple cysts, which can present as daughter cysts or floating cysts with internal membranes (water lily sign) (fig. ) [ ] . in addition amebiasis, malaria and protozoa infections along with toxoplasmosis are well recognized to cause pulmonary disease. the increase in hiv/aids as a cause of immunosuppression has increased the incidence of parasitic infection and pulmonary complications worldwide. the radiographic diagnosis is not specific for any of these diseases and their recognition relies upon an astute clinician and serological evaluation with polymerase chain reaction (pcr) testing. pulmonary infections are one of the most significant causes of morbidity and mortality in immunocompromised children. regardless of the immunodeficiency cause, the most common complications are infections caused by bacterial, viral or opportunistic pathogens [ , [ ] [ ] [ ] . immunodeficiency can be divided into major groups of primary and secondary. a simple model of the immune system is that it is mediated by two major mechanisms: humoral and cellular. defective development of b cells results in humoral immunity abnormalities, while defective development of t cells causes cellular immunity problems. children with impairment of cellular or humoral immune mechanisms or both experience a higher propensity for specific infections. humoral immune impairments usually result in bacterial infections, while cellmediated immune impairments make children more prone to opportunistic, viral and mycobacterial infections [ ] . this applies to children with primary immunodeficiency syndromes and secondary immunodeficiency diseases, including aids. most primary immunodeficiencies are humoral deficiencies, with iga deficiency, x-linked agammaglobulinemia and common-variable immunodeficiency the best known examples. these children are prone to repeated bacterial infections with associated pneumonia leading to postinfectious bronchiectasis (fig. ) . a much smaller group of primary immunodeficiencies is caused by changes in cellular immunity (digeorge syndrome and severe combined immunodeficiency) or in phagocyte activity like chronic granulomatous disease. digeorge syndrome, which is also called thymic aplasia or hypoplasia, is a typical example of a primary t cell deficiency with abnormal development of the thymus, parathyroid glands and heart. children with this syndrome are susceptible to opportunistic organisms and to graft-versus-host disease from blood transfusions [ ] . chronic granulomatous disease is a genetic syndrome characterized by an abnormality in an oxidative metabolic response during phagocytosis and resulting in bacterial and fungal infections. children with chronic granulomatous disease develop recurrent infections resulting in granuloma formation. these granulomatous lesions are seen in the skin, lungs, liver and lymph nodes. the onset of symptoms usually occurs early in life. chest radiograph and ct findings show fig. axial ct shows the typical halo sign in an immunocompromised child with invasive aspergillosis chronic or recurrent pneumonia, usually by aspergillus or candida organisms. hilar and mediastinal adenopathy, pleural reaction and chest wall invasion can be also present [ , ] . hyper-ige syndrome (hies, job syndrome) is a complex primary immunodeficiency disorder characterized by a spectrum of abnormalities related to the immune system, bones, connective tissue and teeth. hies was initially defined as a triad of clinical problems involving skin boils, severe episodes of pneumonia and very high serum ige levels. recurrent staphylococcal cutaneous lesions and pneumonia beginning in infancy and resulting in lung cyst formation with variable persistence and expansion are the typical findings [ ] [ ] [ ] (fig. ) . secondary immunodeficiency affects a mixed group of neutropenic children with previous chemotherapy or radiotherapy, immunosuppressed hosts after an organ or bone marrow transplant, and children with hiv/aids [ , , , ] . in the second group, the deficiency occurs to a greater extent than in cellular immunity. however, humoral immunity can also be compromised in neutropenic and severely malnourished children. children who are predominately neutropenic as a result of chemotherapy or who are in the early phase after a bone marrow transplant with or without incipient graft-versus-host disease are at risk for infection by gram-negative bacteria such as pseudomonas aeruginosa or by gram-positive bacteria such as s. aureus. fungal pneumonias caused by aspergillus or candida species can also occur. pulmonary nodules are the most frequent finding of candidiasis lung infection on chest ct. these nodules might present the halo sign or excavation. centrilobular lesions or a mixed pattern can also occur [ , ] . aids is caused by a retrovirus whose main characteristic is the development of immunosuppression and subsequent opportunistic infections and malignancies. vertical transmission is the usual form of infection in the pediatric population. lung infection is the leading cause of morbidity and mortality, causing percent of deaths. viral and bacterial pneumonia are the most frequent infections at diagnosis [ , ] . the most frequent agents are streptococcus pneumoniae, haemophilus influenzae, respiratory syncytial virus and adenovirus. children are prone to having severe presentations, and bacterial pneumonias are usually associated with cavitations, abscesses and empyema [ ] . children with aids are also susceptible to fungal and mycobacterial infections. pneumocystis jirovecii is the most common opportunistic infection in infected babies without prophylaxis. p. jirovecii has a high mortality rate during the initial episode. the most common chest radiograph and ct findings are diffuse reticular interstitial opacities that can progress to massive alveolar consolidations resulting in acute respiratory distress syndrome in infants (fig. ) . postinfection cavitations and bronchiectasis are typical after recurrent infections. cryptococcus neoformans infection is rare and has unusual presentations in hiv-infected children. the spectrum of disease ranges from asymptomatic pulmonary lesions to disseminated infection with necrotizing pneumonia, pleural effusion and meningoencephalitis [ ] (fig. ) . mycobacterium tuberculosis infection can mimic infections seen in immunocompetent children, but more severe c an older child with a right hyperlucent lung with small cavitations and incipient bronchiectasis and a left lung with ground-glass pattern after previous recurrent infections disseminated and miliary presentations of tuberculosis are becoming more frequent among children and even adolescents affected by aids (fig. ) . the main reason is that m. tuberculosis, like hiv infection, also decreases cellular immunity. mycobacterium avium-intracellulare complex is also encountered in children with aids. imaging findings are nonspecific and similar to those of other forms of mycobacterial infections [ , ] . pulmonary infection is also the most common cause of death after bone marrow transplantation. after engraftment (during the first days) profound neutropenia and mucosal injury lead to severe immune suppression. children at this time are very susceptible to all organisms fungal, bacterial and viral. as the child's neutropenia recovers the immune suppression related to antirejection medication leads to impairment of humoral and cellular immunity (days to ). these children have a high incidence of cytomegalovirus and rsv. after days the children have near normal immune function and pneumonia is less common. fungal organisms are associated with very high mortality, with aspergillus and candida the most common. it should be noted that children might not demonstrate fever or an elevated white blood cell count. ct is frequently used to monitor these children when there is a high index of suspicion for disease. fungal infections in particular demonstrate small, ill-defined nodules with or without surrounding ground-glass opacity. bacterial infections have features similar to those found in the immunecompetent child [ ] . the role of the radiologist is to help recognize the presence of pneumonia and help guide therapy. the identification of a specific organism is almost never possible from imaging alone. however, by combining imaging and clinical information, the differential diagnoses can be generated. chest radiographs remain the mainstay of pneumonia imaging, supplemented with sonography and ct for specific indications. investigation of specific organisms using image-guided sampling and serological determinations is important in designing therapy. during treatment the radiologist can recognize complications such as cavitation, abscess and empyema. the role of image-guided intervention is beyond the scope of this paper, but in many centers the radiologist might be asked to address each of these complications. pediatric chest imaging: chest imaging in infants and children in: slovis tl (ed) caffey's pediatric diagnostic imaging, th edn thoracic disease in children with aids viral vs. bacterial pulmonary infections in children (is roentgenographic differentiation possible?) thoracic disorders in the immunocompromised child differentiating bacterial from viral pneumonias in children human metapneumovirus: a ubiquitous and long-standing respiratory pathogen post infectious bronchiolitis obliterans in children radiographic follow-up of pneumonia in children high-resolution ct of peripheral airway diseases bronchiolitis obliterans in children: clinical presentation, therapy and longterm follow-up spectrum of clinical and radiographic findings in pediatric mycoplasma pneumonia mycoplasma pneumoniae pneumonia: ct features in patients round pneumonia: imaging findings in a large series of children cavitary necrosis complicating pneumonia in children: sequential findings on chest radiography the yield of ct of children who have complicated pneumonia and noncontributory chest radiography imaging of parapneumonic pleural effusions and empyema in children tuberculosis in children: where do we go now? modern imaging of tuberculosis in children: thoracic, central nervous system and abdominal tuberculosis cavitating pulmonary tuberculosis in children: correlating radiology with pathogenesis high resolution ct of the lung an update on primary care management for tuberculosis in children hiv in children: take a moment to make a difference pulmonary infections in hiv-positive children chapter histoplasmosis imaging of pediatric mediastinal histoplasmosis imaging of chronic granulomatous disease in children spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings the radiological spectrum of invasive aspergillosis in children: a -year review diagnosing allergic bronchopulmonary aspergillosis in children with cystic fibrosis angioinvasive pulmonary aspergillosis after allogeneic bone marrow transplantation: clinical and high-resolution computed tomography findings in cases radiological characteristics of pulmonary hydatid disease in children: less common radiological appearances primary immunodeficiency disorders in pediatric patients: clinical features and imaging findings the primary immunodeficiencies non-infective pulmonary disease in hiv-positive children chronic granulomatous disease hyperimmunoglobulinemia e syndrome: radiographic observations hyperimmunoglobulinemia e syndrome: pulmonary imaging considerations primary immunodeficiencies: a pictorial immunology primer for radiologists chest imaging in the immunocompromised child pulmonary disease in patients with aids: high-resolution ct and pathologic findings cryptococcosis in children risk factors for the development of bronchiectasis in hiv-infected children pulmonary infections after bone marrow transplantation: high-resolution ct findings in patients key: cord- -e zpa c authors: waterer, grant; wunderink, richard title: respiratory infections: a current and future threat date: - - journal: respirology doi: . /j. - . . .x sha: doc_id: cord_uid: e zpa c despite all the medical progress in the last years pulmonary infections continue to exact and extremely high human and economic cost. this review will focus on the human, pathogen and environmental factors that contribute to the continued global burden or respiratory diseases with a particular focus on areas where we might hope to see some progress in the coming decades. despite all the advances in medical science in the past four decades, lower respiratory tract infections remain the fourth most common cause of death in middle to high income countries and the leading cause of death in low income countries. mortality aside, respiratory tract infections have an enormous economic cost. the annual global cost is unknown, but in the usa the direct cost of community and nosocomial lower respiratory tract infections was estimated at us$ billion in . by the economic burden of non-influenza viral respiratory tract infection alone had increased to us$ billion in the usa. including direct and indirect costs (such as loss of work time), the cost of influenza alone in the usa is currently estimated at us$ billion per year, although total indirect costs have been estimated by others at over us$ billion annually. clearly, the global cost of respiratory infection must be in the trillions (us$) per year. in this final article in the pulmonary infectious diseases series we will discuss why pulmonary infections remain a major health problem and are likely to continue to be so well into the foreseeable future. the first and most obvious reason why pulmonary infections remain a problem is that potential pathogens abound in our everyday environment. while some pathogens are dependant on human-to-human spread, there are numerous examples of pathogens that normally invade their host directly from an environment source. typical examples include legionella spp., non-tuberculous mycobacteria and a plethora of fungi and molds, including cryptococcus, histoplasma, aspergillus and coccidiomycosis, just to name a few. while our immune systems have adapted in response to environmental threats, these pathogens will always remain a threat, particularly in subjects whose immune response becomes compromised by age or disease. human disease may also result from pulmonary pathogens crossing directly from animals to humans. among the well-recognized respiratory zoonoses are chlamydia psittaci (psittacosis), coxiella burnetti (q-fever), fracisella tularensis (tularaemia) and of course viral infections such as influenza and hanta. while many of these infections can be avoided by strict hygiene protocols, wherever there is close proximity between humans and animals, such as in large parts of the developing world, some inter species transmission inevitable. the largest risk in the environment, however, comes from other humans, as the vast majority of pulmonary infections are acquired from other infected individuals. this is particularly true of viral infections. the more crowded the human environment, the faster the spread of respiratory pathogens through the population. during the severe acute respiratory syndrome (sars) outbreak, extensive public health campaigns aimed at reducing spread of respiratory droplets by good cough hygiene, the avoidance of work, school or day care during acute infections, and a massive uptake in mask wearing in the general populace had a dramatic effect on the rates of all viral respiratory infections in hong kong. as relaxing these efforts led to a return to normal rates of viral transmission, much more can clearly be done to reduce community spread of pulmonary pathogens, especially during pan/epidemics. nosocomial transmission of pulmonary pathogens is also a major environmental problem. hospital outpatient clinics are a well-documented source of transmission of multi-resistant bacteria between patients with cystic fibrosis and bronchiectasis. intensive care units, particularly those with long-term ventilated patients, are also a frequent source of recurrent cross infection with multi-resistant bacteria. environmental pools of organisms within hospitals themselves have also been commonly associated with outbreaks of nosocomial pneumonia with pathogens, such as legionella, , aspergillus , and mucormycosis. while it is clear that strict infection control can reduce nosocomial infection rates, the practical necessity of pooling vulnerable hosts together combined with the inevitable ageing of health-care facilities will ensure that nosocomial outbreaks continue to be a problem. not only is the average age increasing, but the number of very elderly people in whom senescencerelated immune compromise is common has dramatically increased over the past few decades in most western countries. a very large number of age-related immune deficits have been described. key changes increasing the risk of pulmonary infections include the production of lower affinity antibodies, reduced phagocytic ability and reduced responsiveness of naïve cd -positive t cells. what is also important is that the pro-inflammatory response becomes progressively less regulated in the elderly, often termed 'inflamm-ageing'. the excess pro-inflammatory cytokine response is almost certainly a significant factor in the increased the risk of septic shock, ards and multi-organ failure in elderly patients with pulmonary sepsis. further complicating the fact that we have more vulnerable aged people in our communities is that we cluster them together. the close contact between elderly individuals in nursing homes and other agedcare residences frequently leads to rapid spread of new pathogens throughout the facility, as many case series have documented. [ ] [ ] [ ] [ ] [ ] [ ] while this close clustering is to some extent an economic necessity, much more study is required into how to limit the spread of respiratory pathogens in aged-care facilities, particularly in epidemic circumstances. age aside, advances in medical care have also meant a vastly expanded pool of people with chronic organ failure living in the community. cardiac failure, chronic renal failure and diabetes in particular are all associated with a significantly greater risk of death from pneumonia. unfortunately, it also appears that immunization, at least against influenza, has substantially reduced efficacy in these vulnerable groups. [ ] [ ] [ ] adding to increasing age and increasing numbers of people with chronic organ failure in our communities is the additional factor of deliberate immunosuppression. in recent years the marked increase in tumour necrosis factor antagonists and monoclonal antibodies targeting specific lymphoid populations in patients with inflammatory arthritis (and especially rheumatoid disease) has significantly over taken patients on immunosuppressant therapy after solid organ transplantation as the major cause of iatrogenic immunosuppression. an increased risk of tuberculosis in particular has been a major problem with tnf antagonist therapy. at the milder end of iatrogenic immunosuppression is recent evidence that inhaled corticosteroids, commonly used in asthma and copd, probably increase the incidence of pneumonia. however, whether this statistical increase in pneumonia is clinically important remains unclear as total mortality is not increased and total hospitalizations are lower, suggesting that the small increase in risk of pneumonia is more than compensated for by other beneficial effects. austrian and gold demonstrated that it takes time, possibly days, for antibiotics to alter the natural course of pneumonia. more recent papers demonstrating potential benefits of combination antibiotic therapy in pneumococcal pneumonia show a similar delay between the onset of antibiotic therapy and an identifiable benefit, , and a review of all deaths from community-acquired pneumonia in young adults in the uk also found that many presented too late to benefit from any available therapy. patients delay presentation to medical care when they have pneumonia for many different reasons. in some cases it is possible that the onset of disease is so swift that they are unable to seek help, especially if they live alone. however, many complex psychological and practical factors, including financial ability to access health-care, factor into the decision to delay medical treatment. the lack of potential for new antibiotics to alter early mortality requires new approaches to be developed. drotecogen alpha does appear to reduce some of the organ damage in patients with pneumonia and sepsis but the survival benefit is modest. as discussed in the review on streptococcus pneumoniae, reducing the virulence of invading pathogens is one promising line of research. in nosocomial pneumonia, and especially ventilator-associated pneumonia, delayed recognition and hence delayed initiation of therapy is also associated with increased mortality. , due to the frequent lack of significant inflammatory response and often the very non-specific nature of patient symptoms (if any), diagnosis of nosocomial pneumonia remains a clinical challenge. all recent guidelines have called for significant research in new diagnostic methods; [ ] [ ] [ ] however, this remains a significant unmet need. human pulmonary pathogens are so well adapted to their human hosts that many cause little or no disease in animals. some pathogens have also developed substantial adaptations to evade our immune responses to them. structural change to the cell wall of mycobacterium tuberculosis enabling it to resist digestion after phagocytosis is one well-characterized adaptation. an example of the extent to which human pathogens can adapt is the production by some viruses of an il- like protein that can directly downregulate immune response. as well as adapting to our innate immune response, pathogens also modify their genome in direct response to our attempts to reduce their virulence. the multitude of mechanisms by which bacteria have become antibiotic resistant is well documented, and due to these adaptations we now have problems with a wide range of pulmonary pathogens such as panresistant pseudomonas aeruginosa and extensively drug-resistant m. tuberculosis. even in the community setting drug-resistant pathogens, such as methicillin-resistant staphylococcus aureus, are beginning to become a significant concern as a cause of pneumonia in some regions. viruses can also adapt to anti-viral agents, for example neuraminidase inhibitor-resistant influenza. while not responding to any external pressure, the constant modification of viral genomes also ensures a steady supply of pathogens. antigenic drift and antigenic shift continue to keep influenza near the top of the list of pulmonary pathogens. new pathogens, like the coronavirus responsible for sars, are also certain to continue to emerge, much as hiv did in the s. finally, if new threats do not arise naturally, there is always the unfortunate possibility that humans will deliberately introduce them. given the capacity for pathogens to adapt, it seems likely that regardless of what antimicrobials we develop, the development of resistance is inevitable. however, even if antibiotic resistance does not develop, clearing out one pathogen simply creates space for another to move in. bronchiectasis and cystic fibrosis are classic examples of a procession of bacteria occupying vacated niches. non-tuberculous mycobacteria, which have increased significantly in the past few decades as problematic pulmonary pathogens, are another example of bacteria finding new niches. the emerging data on serogroup replacement in pneumococci in response to pneumococcal vaccination are further evidence that the efficacy of any strategy we develop to reduce bacterial infections is likely to reduce over time as bacteria adapt to the niche available. human pathogens have evolved with us and are well adapted to overcome our innate immune responses. when pressure has been applied, either through antibiotics, antivirals or vaccination, pathogens have either shown the capacity to adapt to them or new pathogens have occupied the vacated niche. as we continue to increase the population of vulnerable hosts, pulmonary infections will remain a major health problem for the foreseeable future. new antibiotics and antivirals may help with specific threats, but will not address most of the fundamental problems. new therapeutic and diagnostic approaches coupled with clinical vigilance, strict infection control and solid public health measures are the hopes for reducing the burden of pulmonary infectious disease over the coming decades. world health organization. top ten causes of death economic costs of respiratory tract infections in the united states the economic burden of non-influenza-related viral respiratory tract infection in the united states the annual impact of seasonal influenza in the us: measuring disease burden and costs economic burden of respiratory infections in an employed population respiratory infections during sars outbreak environmental contamination with an epidemic strain of pseudomonas aeruginosa in a liverpool cystic fibrosis centre, and study of its survival on dry surfaces pseudomonas cross-infection from cystic fibrosis patients to non-cystic fibrosis patients: implications for inpatient care 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nursing home residing elderly: relation to clinical factors the comparison of antibody response to influenza vaccination in continuous ambulatory peritoneal dialysis, hemodialysis and renal transplantation patients. scand role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics long-term use of inhaled corticosteroids and the risk of pneumonia in chronic obstructive pulmonary disease: a meta-analysis pneumococcal bacteremia with special reference to bacteremic pneumococcal pneumonia monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia a national confidential enquiry into community acquired pneumonia deaths in young adults in england and wales. british thoracic society research committee and public health laboratory service i really should've gone to the doctor': older adults and family caregivers describe their experiences with community-acquired pneumonia severe community-acquired pneumonia as a cause of severe sepsis: data from the prowess study new insights into pneumococcal disease appropriateness and delay to initiate therapy in ventilator-associated pneumonia clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia guidelines for the management of hospital-acquired pneumonia in the uk: report of the working party on hospital-acquired pneumonia of the british society for antimicrobial chemotherapy clinical practice guidelines for hospitalacquired pneumonia and ventilator-associated pneumonia in adults. can guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia viral interleukin (il- ), the human herpes virus cellular il- homologue, induces local anergy to allogeneic and syngeneic tumors pan-drug-resistant pseudomonas aeruginosa causing nosocomial infection at a university hospital in taiwan management of multidrug-resistant tuberculosis: update staphylococcus aureus community-acquired pneumonia during the to influenza season emergence of resistance to oseltamivir among influenza a(h n ) viruses in europe identification of a novel coronavirus in patients with severe acute respiratory syndrome bioterrorism for the respiratory physician when and how to treat pulmonary nontuberculous mycobacterial diseases serotype replacement and multiple resistance in streptococcus pneumoniae after the introduction of the conjugate pneumococcal vaccine key: cord- - ivqlsgt authors: murdoch, david r. title: how recent advances in molecular tests could impact the diagnosis of pneumonia date: - - journal: expert rev mol diagn doi: . / . . sha: doc_id: cord_uid: ivqlsgt molecular diagnostic tests have been the single major development in pneumonia diagnostics over recent years. nucleic acid detection tests (nats) have greatly improved the ability to detect respiratory viruses and bacterial pathogens that do not normally colonize the respiratory tract. in contrast, nats do not yet have an established role for diagnosing pneumonia caused by bacteria that commonly colonize the nasopharynx due to difficulties discriminating between pathogens and coincidental carriage strains. new approaches are needed to distinguish infection from colonization, such as through use of quantitative methods and identification of discriminating cut-off levels. the recent realization that the lung microbiome exists has provided new insights into the pathogenesis of pneumonia involving the interaction between multiple microorganisms. new developments in molecular diagnostics must account for this new paradigm. pneumonia continues to provide a huge global burden of disease [ ] . although the incidence of pneumonia increases with increasing age, it is not widely appreciated that pneumonia is also the world's biggest killer of young children [ ] . a wide variety of microorganisms are listed as pneumonia pathogens [ ] , and identification of pneumonia etiology is useful for both patient management and surveillance purposes. however, despite increased recognition of the burden of disease and advances in effective vaccines against major pneumonia pathogens, we continue to struggle in our efforts to identify the pathogens that cause pneumonia in individual patients [ ] . indeed, historically, we have been unable to define a causative pathogen in a significant proportion of pneumonia episodes, even with the best methods. determining the microbial etiology of pneumonia in children has been a particular challenge [ ] . the implications of poor pneumonia diagnostics extend to the population level as well; assessment of interventions, such as vaccines, is hindered by suboptimal measures of disease impact that often rely on accurate surveillance data [ ] . why is it so difficult to determine the microbial etiology of pneumonia? the inability to obtain good quality specimens from the lower respiratory tract is one fundamental problem with pneumonia diagnostics. whereas, it is relatively easy to get specimens from the site of infection with diseases such as meningitis, gastroenteritis, and endocarditis, obtaining representative and uncontaminated specimens from the lungs in pneumonia is a challenge. sputum and bronchoscopic specimens may be contaminated by normal respiratory flora, and transthoracic lung aspirates are rarely performed despite a good safety profile [ ] . instead, we are currently reliant on testing more distant clinical specimens, particularly from the upper respiratory tract, blood, or urine. in general, testing these specimens has suboptimal sensitivity and/or specificity for determining the microbial etiology of pneumonia with confidence. a second important issue hindering our ability to determine pneumonia etiology is the fact that some major pneumonia pathogens, such as streptococcus pneumoniae, haemophilus influenzae, and staphylococcus aureus, may also asymptomatically colonize the upper respiratory tract as part of normal oropharyngeal flora. consequently, the detection of these microorganisms is insufficient by itself in order to attribute pneumonia causation. this perspective reviews the current use of molecular diagnostics for determining the microbial etiology of pneumonia and future prospects for this purpose. the focus is on recent advances and their clinical applications rather than detailed description of specific technologies. presently, we are still reliant on traditional diagnostic tools that have been used for decades to determine the microbial etiology of pneumonia. current guidelines for the management of community-acquired pneumonia in adults typically recommend that microbiologic testing should be largely restricted to patients with more severe disease, and give guidance about the judicious use of blood cultures, sputum microscopy and culture, urinary antigen tests, and serology [ ] [ ] [ ] . guidelines for the management of community-acquired pneumonia in children are even more restrictive, again recommending that tests should mainly be used on patients with severe disease, with a focus on blood cultures and detection of respiratory viruses [ , ] . common to these guidelines is a cautious approach to the use of molecular diagnostics, although this may change with ongoing reviews. this caution is driven partly by the perceived and real lack of commercial and standardized assays and partly by lack of good data on diagnostic accuracy. there is also a lingering perception that molecular diagnostics are expensive tests and that use should be restricted on this basis. cost is not the barrier it used to be, and the relative price of molecular diagnostics has actually fallen over recent years. indeed, many molecular assays are now comparable in cost to conventional culture-based methods. molecular methods have been a particularly welcome addition to the pneumonia diagnostic toolbox. collectively, they represent the single biggest recent advance in the field. while not exactly new (polymerase chain reaction (pcr) assays for respiratory pathogens have been around for over years), the widespread adoption of nucleic acid detection tests (nats) by diagnostic laboratories has been relatively slow. this contrasts to nats for other infectious diseases, which have been more quickly embraced by laboratories and clinicians [ ] . a major reason for the slow uptake and acceptance of respiratory nats has been the lack of commercial assays. this situation is changing rapidly, undoubtedly spurred on by recent outbreaks of global concern, such as pandemic influenza, middle east respiratory syndrome (mers), and ebola [ ] [ ] [ ] . indeed, the increased availability of commercial assays is the major change in the area since i first started reviewing the role of molecular diagnostics in pneumonia over years ago [ , ] . to date, molecular tests for pneumonia have mainly focused on detection of specific known pathogens by nats. nats have several advantages over other existing diagnostic tools. they potentially detect low levels of all-known pneumonia pathogens in clinical specimens, do not depend on the viability of the target microbe, and can provide results within a clinically relevant time frame. they are also probably less affected by previous antimicrobial therapy than are culturebased diagnostic methods. there are now a wide variety of user-friendly platforms that have enabled nats to be deployed in laboratories outside of specialist tertiary referral centers. although nats have mainly focused on detecting the presence of a particular microorganism, they may also provide additional information, such as data on antimicrobial resistance and strain typing. the nats that are most widely used in diagnostic laboratories are those that detect potential pneumonia pathogens that are not part of the normal flora, namely respiratory viruses and selected non-colonizing bacteria. for these microbes, simply detecting their presence in a respiratory sample has been regarded as sufficient evidence to assign causation. in contrast, nats for other bacteria, including some of the most important pneumonia pathogens, have struggled for a defined role outside research laboratories. nats for detection of the following respiratory pathogens now have established roles. nats have revolutionized the diagnosis of viral respiratory tract infections [ , ] . with high sensitivity and specificity, rapid turnaround time, and availability as commercial assays, nats are now the testing method of choice for respiratory viruses. respiratory viruses commonly detected by nats, often in large multiplex panels, include influenza a and b viruses, respiratory syncytial virus, parainfluenza viruses, human metapneumovirus, human rhinoviruses, enteroviruses, adenoviruses, human bocavirus, and several coronaviruses (oc , e, nl , and hku ). nats are also established diagnostic tools for detection of severe acute respiratory syndromecoronavirus and mers-coronavirus [ , ] . in the context of pneumonia, the detection of a respiratory virus in an upper respiratory specimen by a nat has been regarded as sufficient to assign causation in both children and adults [ ] . however, this assumption is not always reliable. there is still debate about the exact role (if any) of some viruses in the pathogenesis of pneumonia, including human rhinoviruses and human bocavirus [ ] . this has led some to question the wisdom of using large multiplex nat panels as first-line tests for respiratory pathogens given potential problems with interpretation of positive results [ ] . in addition, when control groups are used in pneumonia etiology studies, respiratory viruses are often detected in a similar proportion of both subjects with and without pneumonia, especially in children [ , ] . these findings vary by specific virus, with influenza a and b viruses, respiratory syncytial virus, and human metapneumovirus being typically detected in a significantly higher proportion of cases with pneumonia than controls. environmental bacteria of the genus legionella are the cause of legionnaires' disease, a pneumonia that requires specific antimicrobial treatment and is often associated with outbreaks [ ] . of the many legionella species that can cause human infection, legionella pneumophila is the most common cause globally, with infection usually acquired from water sources. other species predominate in some geographic locations, particularly legionella longbeachae which is an inhabitant of soil and compost. there is no human-to-human spread of legionnaires' disease, and human infection follows environmental exposure to the causative microorganism. legionella spp. are fastidious organisms and the traditional reliance on culture, serology, and urinary antigen tests has led to underdiagnosis of legionnaires' disease globally [ ] . indeed, the almost sole reliance on the urinary antigen test, which can only detect l. pneumophila serogroup , in some parts of the world has created a 'blind spot' for legionnaires' disease caused by other species and serogroups [ ] . nats have long been used to detect legionella infection [ ] and are well-suited for this purpose. legionella are not regarded as human colonizers [ ] , and the detection of any amount of legionellae in a clinical specimen is regarded as diagnostic for infection, assuming contamination has not occurred during the testing process. furthermore, all species and serogroups can be detected. legionella dna has been detected in both upper and lower respiratory samples, urine, and blood from patients with legionnaires' disease [ ] [ ] [ ] [ ] [ ] [ ] , although sputum and other lower respiratory samples are regarded as the specimens of choice [ ] . recently, the systematic use of pcr [ ] and collection of induced sputum from patients unable to expectorate [ ] have uncovered a hidden burden of legionnaires' disease and have demonstrated the diagnostic utility of nats for this disease. arguably, nats are now the test of choice for legionnaires' disease. being an environmental organism, there has been concern about legionella contamination during testing, highlighted by the occasional documented contamination of nucleic acid extraction kits [ ] . this problem can be overcome by strict adherence to good laboratory practice. mycoplasma pneumoniae is associated with a variety of both upper and lower respiratory tract infections and is an important cause of pneumonia, frequently occurring in outbreaks. nats are now widely regarded as the methods of choice for detection of m. pneumoniae infections [ , ] , and a m. pneumoniae target has been incorporated alongside viral targets in many large respiratory multiplex panels. in practice, nats have also been useful for m. pneumoniae outbreak identification and management [ ] . both upper and lower respiratory tract specimens are suitable for testing by nats, and a positive result in the context of pneumonia is regarded as being diagnostic, as asymptomatic carriage of m. pneumoniae is uncommon [ ] . chlamydophila pneumoniae is a relatively common cause of community-acquired pneumonia in some geographic regions, but is not typically associated with severe disease [ , ] . nats have long been used for diagnostic purposes and, indeed, c. pneumoniae nats were the focus of some of the earliest efforts to standardize nats for respiratory pathogens [ ] . perhaps because of the association with milder disease, c. pneumoniae targets have not been a priority for incorporation into multiplex respiratory panels. colonization with pneumocystis jirovecii is common among the general population and is associated with pneumonia in immunocompromised individuals. nats have advantages over traditional microscopy-based diagnostic tools, detecting p. jirovecii in induced sputum, bronchoscopic, or oropharyngeal specimens with high sensitivity [ ] . indeed, it was pcrbased methods that provided some of the early evidence of the existence of p. jirovecii colonization [ ] . the use of quantitative methods has been necessary in order to discriminate between colonization and disease; thus, at least partially overcoming the problem of false-positive results. although promising, the cut-off values remain to be standardized for quantitative nats and may vary with patient population [ ] . microscopy and culture of lower respiratory samples remain the standard diagnostic tools for tuberculosis. despite improvements in culture-based methods, the slow turnaround time for laboratory diagnosis and global concern about disease burden and multidrug resistance has provided the impetus for the development of rapid testing methods [ ] . considerable effort has been put into the development of nats for mycobacterium tuberculosis, and several commercial assays are now widely available [ ] . interestingly, tuberculosis is unusual among infectious diseases in that nats are less sensitive than culture, a possible consequence of difficulty with dna extraction. sensitivities are typically - % for smear-positive specimens and - % for smear-negative specimens [ ] . importantly, small, user-friendly platforms (such as the xpert mtb/rif assay) have been developed to an extent that they have been successfully deployed in many resource-poor locations where rapid diagnostics for tuberculosis are most needed [ , ] . this is a real success story and highlights what can be achieved with molecular diagnostics outside major laboratories. nats are now established tests for the detection of the causative agents of pertussis [ ] [ ] [ ] . while bordetella pertussis is the major cause of pertussis in humans and can be complicated by pneumonia [ , ] , bordetella bronchiseptica, bordetella holmesii, and bordetella parapertussis have all been occasionally associated with (often milder) pertussis-like illnesses [ ] . nats are the most sensitive methods for the detection of b. pertussis and, with rapid turnaround times, have been invaluable tools in outbreak management [ , ] . the main limitation of b. pertussis nats is specificity, particularly the ability of the most widely used (is -based) assays to also detect b. holmesii, which is generally considered a false positive result [ ] . the use of dual target assays has been advocated to overcome this potential problem [ ] . what are the limitations of molecular diagnostic tests for pneumonia and what needs to be addressed in order to progress with development? common to all pneumonia diagnostic testing, the inability to obtain good quality specimens from the lower respiratory tract is a major problem that will only be overcome through new innovative and safe methods of specimen collection and a greater understanding of the relationships between changes in the lung and in more distant specimens in pneumonia. a second-major limitation of nats is their inability to distinguish pathogens from innocent bystanders. in essence, we need two pieces of information. first, is a particular microorganism present in the clinical specimen? second, if the microorganism is present, is it causing this episode of pneumonia? to date, diagnostic efforts have focused almost exclusively on the first question and have ignored the second, which is usually much more difficult to answer unless the microorganism is never present as a colonizer (e.g. legionella spp.). the efforts to use nats as a diagnostic for pneumococcal pneumonia illustrate some of the key issues. s. pneumoniae is regarded as the most common cause of pneumonia in all age groups and yet, molecular tests do not have an established diagnostic role [ ] . s. pneumoniae is also a common nasopharyngeal colonizer, with carriage prevalence exceeding % among children in some regions of the world [ ] . earlier pneumococcal pcr assays, such as those targeting the pneumolysin gene, had problems of poor specificity due to detection of other, closely related streptococci [ ] , although false-positive results are less likely with some of the currently more widely used targets (e.g. autolysin gene) [ ] . s. pneumoniae is frequently detected by nats in both upper and lower respiratory specimens from patients with pneumonia [ ] , but the clinical implications of a positive result are uncertain given the relative high prevalence of pneumococcal carriage. testing of blood for s. pneumoniae by pcr has been promoted as an alternative approach that can potentially avoid issues of contamination. among italian children, blood pcr showed promise as a diagnostic for invasive pneumococcal disease [ ] [ ] [ ] [ ] with high specificity [ ] . however, in other populations, positive results have been reported in control participants who do not have suspected pneumococcal disease [ ] , raising concerns about the broader utility of this approach. in particular, false-positive results are relatively common in children from developing countries where pneumococcal carriage is common [ ] . consequently, a positive pneumococcal nat result alone is usually not enough to diagnose pneumococcal pneumonia. the possible exception is the use of nats to detect s. pneumoniae in pleural fluid [ , ] . another important limitation with current nats is their focus, by nature, on specific known or suspected pneumonia pathogens. implicit with this focus is the assumption that we know the full range of key potential pathogens that cause pneumonia. this may well be correct, but there is increasing interest in the use of modern techniques, such as next generation sequencing, which provide the opportunity for discovering new or unexpected pathogens [ , ] . the broader approach of these technologies may provide novel insights into pneumonia etiology, but have yet to show added advantage as a routine diagnostic tool [ ] . no major new pneumonia pathogens have been uncovered over recent years. a key reason for the slow adoption of respiratory nats by diagnostic laboratories is the lack of commercial assays that have been approved by regulatory bodies. the impact has probably been felt more in the usa given the strict requirements of the us fda. the level and importance of regulation have been debated [ , ] , and it is clear that a balance is needed between appropriate regulation of new diagnostics, while avoiding unnecessary barriers to the deployment of useful tests. the use of molecular tests for legionnaires' disease is a good example of how assay regulation has had an impact on diagnostic strategies. despite nats being the diagnostic test of choice for legionnaires' disease, the shortage of fda-approved assays has severely limited the use of these tests in the usa, resulting in the continued use of suboptimal diagnostics and underdiagnosis of this disease [ ] . moreover, the absence of a prominent role in diagnostic algorithms has possibly led to an incorrect perception that the performance of nats is inadequate. hopefully, increased experience with these tests will reverse this perception. a major recent revelation in respiratory medicine has been recognition of the lung microbiome [ ] . until recently, the lungs in health were regarded as sterile. the use of modern culture-independent techniques has not supported this concept, consistently finding evidence of bacteria in the lower airways [ ] . this important realization has challenged our traditional paradigm of pneumonia pathogenesis. the tradition view that pneumonia is caused by a single invasive pathogen in a normally sterile site is likely wrong. increasing recognition that bacteria and viruses frequently interact in the causative pathway to pneumonia [ , ] adds additional complexity, as does the frequent finding of polymicrobial infections [ ] . under the new paradigm, dominant species emerge from the lung ecosystem in pneumonia through uncertain mechanisms, and the bacterial versus viral pneumonia concept is too simplistic. consequently, we probably need to use more sophisticated approaches to pneumonia diagnosis than assays that simply target single specific putative pathogens. we have a lot to learn and are only just beginning to understand changes in the microbiome during acute infections [ , , ] . analysis of the lung microbiome may provide insights into pneumonia etiology and reveal novel markers for pneumonia prognosis and for treatment guidance [ ] . molecular diagnostic techniques clearly have a central role in these metagenomic analyses [ , ] , providing another opportunity for next generation sequencing technology. any future developments in pneumonia diagnostics must be cognizant of new knowledge about the lung microbiome and about changes in the lungs during the pathway to pneumonia. there is likely to be less focus on just the detection of specific known pathogens, with more interest in the search for markers of change in the lung microbial ecology in the diseased state. the potential application of metagenomics in the diagnostic laboratory is still uncertain and will dependent on the emergence of improved sequencing technology and bioinformatics software. whole genome sequencing of bacterial isolates is already being increasingly used for strain characterization and epidemiological analyses [ ] . for detection of specific pathogens, existing molecular tests can detect very low microbial loads with high analytical specificity. it is unlikely that further test developments will lead to significantly improved performance than we have now. indeed, the interpretation of low-level positive results from nats already provides a dilemma for diagnostic laboratories. instead, the focus of developers should be on making test platforms that are more user-friendly and that allow shorter turnaround times. we also need to place greater attention on the meaningful interpretation of positive results in order to determine which microorganisms are actually causing individual episodes of pneumonia. one approach to help distinguish infection from contamination or colonization is to quantify microbial load by molecular methods. the situation is analogous to culturebased methods, whereby organisms isolated in greater quantities from certain cultures are regarded as more likely to be clinically significant. this approach depends on the determination of cut-off microbial load levels that will provide sufficient diagnostic accuracy to distinguish infection from colonization/ contamination. however, given the lack of suitable comparator 'gold' standards, these cut-off values are very difficult to identify in a scientific manner. they may also vary for different microorganisms. quantitative multiplex pcr has been used to determine the etiology of community-acquired pneumonia in adults using cutoffs developed for interpretation of culture results from lower respiratory tract specimens [ , ] . not surprisingly, the addition of pcr targets for common bacterial pneumonia pathogens, such as s. pneumoniae, resulted in an etiological diagnosis being made in a high proportion of cases. however, these cutoffs have been determined by expert opinion and, although generally intuitive, might be quite misleading. despite the challenges in doing so, we need more objective assessment of cut-off values using good scientific and epidemiologic principles. quantitative approaches have also been applied to nasopharyngeal specimens. among hiv-infected adults in south africa, quantitative pcr testing of nasopharyngeal samples distinguished between pneumococcal pneumonia and asymptomatic pneumococcal colonization with reasonable diagnostic accuracy [ , ] . data from other populations are needed in order to assess whether this method can be used in clinical practice. microbial load in pneumonia can also be a prognostic marker. for example, pneumococcal density in the nasopharynx [ ] and blood [ , ] are associated with disease severity in adults. we can probably also be more innovative with statistical methods to help interpret molecular test results. statistical modeling techniques can be used to help overcome the limitations of diagnostic testing for pneumonia, particularly the lack of good comparator standards. latent class analysis has been used to determine the prevalence of pneumonia caused by specific pathogens in epidemiologic studies [ , ] and for the assessment of diagnostic tests in tuberculosis [ , ] . possibly the most sophisticated use of statistical modeling techniques in the context of pneumonia etiology is currently being undertaken as part of the pneumonia etiology research for child health (perch) study [ ] . perch is a large -country case-control study focused on the causes of severe pneumonia in young children from developing countries, the findings of which will be published in . in this study, partially latent class models have been designed for estimating the population etiology distribution and the individual etiology probabilities for specific pneumonia pathogens, with a major focus on molecular diagnostic test results [ ] . the findings of perch are awaited with great anticipation, as this approach has never before been so extensively applied to the etiology of an infectious disease. we have entered a new age in pneumonia diagnostics that needs to look beyond the targeting of a limited number of potential pathogens. new knowledge about the lung microbiome and pneumonia pathogenesis, together with emerging developments in sequencing technology, provide opportunities for novel diagnostic tools to help better guide the management of pneumonia. molecular tests are now mainstream diagnostics for many respiratory infections, although we still have much to learn about using them more effectively to assist with the management of pneumonia. those involved in molecular diagnostic test development for pneumonia need to look beyond the simple detection of specific known pathogens and also provide means to accurately interpret the clinical significance of a positive result. it is not good enough to simply assess a new test by measuring analytical sensitivity and making comparisons to the performance of other similar assays. diagnostic tests must be evaluated properly following good epidemiological principles. new developments in molecular diagnostics must also be cognizant of emerging information about the lung microbiome, which will likely provide opportunities for the discovery of novel markers to help guide pneumonia management. the recent expansion in the number and variety of commercial nats is likely to continue, leading to greater uptake by diagnostic laboratories and greater incorporation into diagnostic test algorithms and guidelines for the management of pneumonia. the provision of even more user-friendly platforms will enable deployment of these tests in laboratories that have not traditionally used molecular diagnostics. further efforts are needed to evaluate the clinical application of microbial load measurement for the purpose of distinguishing pathogens from colonizing microorganisms and as a prognostic marker. it is still unclear about how new knowledge about the lung microbiome will affect the development of pneumonia diagnostics, but the impact may be profound. while it will be some time before next generation sequencing becomes a standard tool in diagnostic laboratories, this technology may provide valuable insights into the lung microbial ecology in health and disease and a greater understanding of the pathogenesis of pneumonia. with this comes a shift away from the targeting of a limited number of putative pneumonia pathogens toward the identification of signal patterns characteristic of different etiologies and stages of pneumonia. the hope is that these signals will have sufficient diagnostic accuracy to help guide pneumonia management. the author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. this includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. • identifying the microbial etiology of pneumonia is challenging, largely due to difficulty in obtaining uncontaminated specimens from the site of infection and in discriminating between colonizing microorganisms and true pathogens. • molecular tests, particularly nats, have been the major advance in pneumonia diagnostics over recent years. • although uptake has been relatively slow, nats now have established roles (often as the diagnostic of choice) for the detection of respiratory viruses and several non-colonizing bacteria (e.g. legionella species). in contrast, nats have yet to have an established role for several important bacterial pneumonia pathogens (e.g. s. pneumoniae) that also are asymptomatic colonizers of the upper respiratory tract. • further developments in molecular tests need to focus on methods to help interpret the significance of positive results. the use of quantitative nats and microbial load cutoffs has shown promise as one means to discriminate between colonizing and pathogenic microorganisms. • the recent revelation that the lung microbiome exists and new knowledge about the interaction between bacteria and viruses has changed the traditional view of pneumonia pathogenesis. new diagnostics need to account for this new paradigm and be less focused on just detecting specific known pathogens. global, regional, and national incidence, prevalence, and years lived with disability for acute and chronic diseases and injuries in countries, - : a systematic analysis for the global burden of disease study global burden of childhood pneumonia and diarrhoea community-acquired pneumonia breathing new life into pneumonia diagnostics this commentary summarizes some of the key challenges in 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european radiology doi: . /s - - - sha: doc_id: cord_uid: fn p j pneumonia is one of the leading causes of morbidity, hospitalization, and mortality in both industrialized and developing countries. in particular, pulmonary infections acquired in the community, and pneumonias arising in the hospital setting, represent a major medical and economic problem and thus a continuous challenge to health care. for the radiologist, it is important to understand that community-acquired pneumonia (cap) and nosocomial pneumonia (np) share a number of characteristics, but should, in many respects be regarded as separate entities. cap and np arise in different populations, host different spectra of causative pathogens, and pose different challenges to both the clinician and the radiologist. cap is generally seen in outpatients, is most frequently caused by streptococcus pneumoniae, mycoplasma pneumoniae, haemophilus influenzae, and chlamydia, and its radiologic diagnosis is relatively straightforward. np, in contrast, develops in the hospital setting, is commonly caused by gram-negative bacteria, and may generate substantial problems for the radiologist. overall, both for cap and np, imaging is an integral component of the diagnosis, important for classification and differential diagnosis, and helpful for follow-up. pulmonary infections are among the most frequent causes of morbidity and mortality throughout the world. in the non-immunocompromised population, pneumonia is one of the two major infectious diseases. it is the most prevalent community-acquired infection (cap) and the second most common nosocomial infectious disorder. nosocomial pneumonia (np) is associated with the highest mortality rate of nosocomial infections that contribute causally to death [ ] . many infections occur in individuals with concomitant intrapulmonary or extrathoracic disease, but may also affect otherwise healthy persons. despite advances in diagnosis and treatment, pneumonia remains one of the leading causes of death, and mortality is particularly high in immunocompromised patients, in children, and in the elderly population [ ] . radiography plays an important role in the detection and management of patients with pneumonia. among all diagnostic tests, chest radiography has a pivotal position in confirming or excluding the diagnosis of pneumonia. furthermore, it allows narrowing of the differential diagnosis, helps to direct additional diagnostic measures, and serves as an ideal tool for follow-up examinations. nevertheless, its diagnostic yield can be substantially enriched by the integration of radiologic findings with epidemiologic facts, histopathologic fundamentals, and clinical features of the individual patient. in this article we review the most important theoretical, clinical, and radiological principles regarding cap and np. specific attention is paid to the role of imaging e in diagnosis and management of disease, and on how radiologic methods can be used optimally in dealing with cap and np. community-acquired pneumonia cap is defined as pneumonia acquired in the community setting, i.e., in the environment outside hospitals [ ] . some controversy exists regarding this definition, specifically for pneumonia in nursing home residents, which is classified as cap in most countries, whereas it is not in the uk. also, the categorization of cap in mildly immuno-compromized outpatients with disorders, such as diabetes, alcoholism, or renal insufficiency, is debated. nevertheless, most guidelines define these pneumonias as caps. cap is a major health care problem. this is documented by the fact that there are - million cases per year in the us, and between , and million patients are hospitalized [ ] . cap affects mainly the young ( - of children per year) and the elderly ( - of persons over years of age) [ , ] . mortality in cap is considerable, averaging % in a meta-analysis of , patients, and ranging from % in an unselected outpatient population to % in those patients who need intensive care treatment [ ] . in cap, the infection is usually transmitted from person-to-person via small droplets of nasal or oral secretions laden with microorganisms such as bacteria or viruses. the spectrum of causative pathogens includes gram-positive bacteria such as streptococcus pneumoniae (pneumococcus) and staphylococcus aureus, gramnegative bacteria like haemophilus influenzae, atypical bacterial organisms including mycoplasma pneumoniae, chlamydia pneumoniae, and legionella pneumophilia, and viral agents, mainly the influenza viruses and adenoviruses (table ) [ , , ] . recently, a string of corona viruses has been identified as the most likely cause of the severe acute respiratory syndrome (sars) epidemic [ , ] . nevertheless, a recent study suggests that nearly half the cases of ambulatory cap are due to atypical bacteria [ ] . the term "atypical pneumonia" was origi-nally applied to pneumonias with atypical clinical, laboratory, and/or radiographic features, and was primarily used to describe atypical bacterial, viral, protozoal, and fungal infections. currently, this term is reserved for pneumonias of bacterial origin, in which the organism is difficult to isolate. in cap and np, as already mentioned, atypical pneumonias are predominantly caused by mycoplasma pneumoniae, chlamydia, and legionella pneumophila. for practical purposes it is important to emphasize that cap is almost never caused by protozoa and fungi. these groups of organisms are exclusively seen in immuno-compromized individuals, who are either neutropenic (fungi) or have impaired cellular or humoral immune function (protozoa). it appears from the literature that the list of etiologic agents implicated in cap varies according to patientrelated, seasonal, geographic, and diagnostic factors (table ). for example, the health and socio-economic status of a given patient has a certain impact on the selection of organisms potentially causing cap. otherwise healthy people are most likely to contract mycoplasma pneumonia or a mild form of pneumococcus pneumonia. in contrast, debilitated patients, alcoholics, and chronically ill persons more often present with severe pneumococcal pneumonia, or infections caused by haemophilus influenzae, staphylococcus aureus, gram-negative bacilli, or tuberculosis [ ] . legionella species and chlamydia infections seem to be more common in patients with some forms of mild immunologic compromization. patients with poor oral hygiene and individuals suffering from occasional loss of consciousness (epilepsy, alcoholism) may acquire anaerobic pulmonary infections. also, in these patients, mycobacterium tuberculosis infections are more prevalent in comparison with healthy persons without risk factors. although not commonly listed among the causative organisms of cap, tuberculosis should be considered as a relatively common cause of infection in outpatients and inpatients, especially when individuals are immuno-compromized. (tuberculosis is not covered in detail in this article, since it is covered elsewhere in this series.) the recent outbreak of sars demonstrates that seasonal and geographic factors play an important role in the diagnosis and management of cap, whereas asian states, such as china, hong kong, and singapore, as well as north american cities, were substantially affected by the epidemic, virtually no cases were registered in europe [ ] . the seasonal outbreak of viral epidemics has not only been observed in southern china (where sars is suspected to have started) but is a well-known phenomenon in the rest of the world. in cap, patients usually present with fever, cough, dyspnea, sputum production, and pleuritic chest pain [ ] . because these symptoms are non-specific (most people who have fever and cough do not have pneumonia), radiographic methods and specifically the chest x-ray are play an exquisite role in diagnosing cap. the radiographic identification of a pulmonary infiltrate is, in the appropriate clinical setting, indicative of pneumonia [ ] . a patient who has fever and cough, and does not have radiologic proof of pneumonia, cannot be considered to have pneumonia. it is important to emphasize that in cap proof of disease is not based on the identification or cultivation of a specific organism. this is because non-invasive tests, such as sputum cultures, are ineffective and correctly identify the offending organism in only - % of cases [ ] . on the other hand, invasive procedures (bronchoscopy, lavage, biopsy) are rarely used in patients with cap. as a consequence, the radiologic diagnosis constitutes an important basis for the diagnosis and (often empiric) treatment of cap. nosocomial pneumonia np is defined as lower respiratory tract infection that is neither present nor incubating at the time of admission to the hospital [ ] . it is diagnosed when a patient develops fever and leukocytosis, when pathogenic organisms are isolated from tracheobronchial secretions, and when a new infiltrate appears on the chest radiograph at least h after a patient has been hospitalized [ ] . np is the most common hospital-acquired infection with an incidence ranging from . to cases per admissions [ ] . in the subgroup of ventilated patients in an intensive care setting, however, as many as - % may develop np. reported mortality rates range from % in multihospital studies to % or higher in single referral centers and university hospitals. apparently, prognosis associated with gram-negative pneumonias is considerably worse than with gram-positive or viral agents. there are several factors contributing to the development of np [ ] . firstly, host factors, including immune status, underlying disorders, and age. secondly, a high number of hospitalized patients receive antacids and histamine -blockers, resulting in a rise of the gastric ph and an increase in gastric gram-negative bacterial counts. this gastric reservoir for gram-negative organisms frequently serves as a seed point for pharyngeal colonization, and nasogastric tubes, which are present in many severely ill patients, may provide a pathway for the bacteria to migrate. gram-negative bacterial overgrowth of the oropharyngeal epithelium may then occur particularly when the normally adherent gram-positive flora is lost [ ] . thirdly, tracheal intubation and mechanical ventilation may allow the pharyngeal germs direct access to the lungs. fourthly, in supine patients and patients with decreased sensorium, direct aspiration of gastrointestinal contents into the lungs triggers the development of np. fifthly, microbial contamination of inserted drainage tubes, lines, and catheters is an important pathogenetic factor for the development of np. also, np may result from bacteremia originating from right-sided endocarditis or septic pelvic thrombophlebitis. finally, hospital personnel and patients with active infections may serve as sources of infections with direct person-to-person transmission of the microorganisms. whatever the source of infection, the inappropriate use of broad-spectrum and prophylactic antibiotics is an additional and important factor leading to an increased susceptibility to hospital-acquired pneumonias. in np, the spectrum of causative organisms differs from that in cap and is dominated by gram-negative bacilli such as pseudomonas aeruginosa, klebsiella species, enterobactericeae species, escherichia coli, serratia marrescens and proteus species. gram-positive cocci (streptococcus pneumoniae, staphylococcus aureus), atypical bacteria (legionella species), and viruses, including the respiratory syncytial virus, complement the list of pathogens (table ) [ ] . for the clinician, it can be difficult to diagnose np. this is mainly because hospitalized patients with pneumonia do not always present with the characteristic symptoms of new fever, cough, sputum production, and elevated leukocyte count. if present, these symptoms may not necessarily be caused by pneumonia, but by a variety of other disorders [ ] . furthermore, the causative pathogen is frequently not readily identified: cultures from sputum and unprotected lavage fluid are of limited value because of the problems in distinguishing contamination from true infection. in addition, pulmonary disease in a hospital environment is frequently produced by more than one agent. these are just a few reasons why the identification of pulmonary infection, the use of various methods to identify the causative microorganism, the methodology to obtain a specimen, and the value of isolation of potential pathogens are matters of constant discussion in the clinical diagnosis of np. at present, it seems that protected catheter brushing is the best possible method to identify an organism potentially responsible for pneumonia in inpatients. radiology has a pivotal position in the diagnosis and management of cap and np. the role of imaging is not limited to the detection or exclusion of pneumonia but involves the radiologist in the etiologic work-up, in the establishment of a differential diagnosis, in the follow-up procedure and, if necessary, in planning additional diagnostic measures. chest radiography is the initial imaging method to evaluate patients with suspected pneumonia because of its reasonable accuracy, its wide availability, and its low cost and low radiation burden. it is used to confirm or exclude pneumonia, narrow the differential diagnosis, evaluate complications, and monitor disease at follow-up. computed tomograpy is reserved for unclear cases, particularly when chest radiograms are normal in patients with a high level of clinical suspicion of pneumonia, and in immuno-compromized patients, in whom early diagnosis of pneumonia may influence a patient's fate. also, ct is mandatory in cases of persistent or recurrent infiltrates. magnetic resonance currently plays a very limited role in the diagnosis and management of pneumonia. community-acquired pneumonia is most often seen in the offices of general practitioners, private radiologists, and in the outpatient department or the emergency room of hospitals. in patients with cap, the primary role of the radiologist is to detect or to exclude pneumonia, and the chest radiogram is both sensitive and specific in this task [ ] . the diagnosis of pneumonia is based on several diagnostic criteria; however, in all existing definitions of pneumonia, the presence of a pulmonary abnormality, compatible with pneumonia, is an indispensable prerequisite [ ] . the american thoracic society guidelines recommend that a chest radiograph should be obtained whenever pneumonia is suspected [ ] . although some variation exists regarding the time frame between the onset of clinical symptoms and the development of a radiographically visible abnormality, the vast majority of infiltrates appears within the time period of h ( fig. ) [ ] . this time frame allows detection or exclusion in most cases of cap, where patients are generally seen by the radiologist within a few days following initial clinical presentation. moreover, the majority of patients suspected to have cap are otherwise healthy individuals without abnormalities of the lungs that would render the identification of an infiltrate difficult; thus, one should think that the detection or exclusion of outpatient pneumonia is, in most cases, relatively straightforward. however, several studies have demonstrated that the interobserver agreement in the diagnosis of cap is only fair to good for experienced radiologists, and poor to fair for inexperienced radiologists and residents, respectively [ , ] . likewise, caution must be exercised in patients with nosocomial infections, i.e., in patients who develop pulmonary infections in a hospital setting. these patients may be seen in the radiology department within a matter of hours after the onset of clinical symptoms, a time period in which a visible radiographic abnormality may not have developed. moreover, in immuno-compromized patients, the appearance of a detectable radiographic abnormality may be delayed, particularly when an individual is neutropenic [ , ] . zornoza et al. [ ] investigated a series of consecutive patients with gram-negative pneumonia who were neutropenic following anti-neo-plastic chemotherapy. in these patients, episodes of pneumonia were initially diagnosed clinically, in the absence of radiographically detectable disease. in of episodes, an infiltrate was subsequently found on followup chest radiography. in of patients with no radiographically detectable infiltrates, the diagnosis of pneumonia was established at autopsy [ ] . the radiographic appearance of a visible pneumonic infiltrate may be delayed not only in neutropenic patients but also in patients with functional defects of granulocytes due to diabetes, alcoholism, and uremia (fig. ) . some controversy exists in the literature regarding the influence of a patient's state of hydration on the development of pneumonia [ , ] . from a practical point of view, the radiologist must be aware that in the abovementioned group of patients, pneumonia may exist without the typical appearance of a pulmonary infiltrate on the chest radiograph. computed tomography and especially thin-section ct can be helpful in these patients since it is more sensitive in the detection of subtle abnormalities and may show findings suggestive of pneumonia up to days earlier than chest radiographs (fig. ) [ ] . consequently, ct can aid in the early institution of therapy and thus help to lower mortality rates. particularly in multimorbid hospitalized patients, the identification of a pulmonary infiltrate and the diagnosis of pneumonia may be hampered by pre-existing or concomitant pulmonary disorders (fig. ) , or limited by processes that have a radiological appearance similar to that of pneumonia; these include atelectasis, edema, aspiration, hemorrhage, infarct, idiopathic interstitial pneumonias, pulmonary involvement in collagen-vascular disorders adult respiratory distress syndrome (ards), and pleural effusion. all of the above-mentioned abnormalities may mimic pneumonia or obscure or alter the otherwise characteristic radiographic appearance of an infiltrate [ ] . np may be particularly difficult to diagnose in intensive care unit (icu) patients requiring mechanical ventilation, and the identification of pneumonia in patients with ards remains an unsolved problem (fig. ). wunderink et al. compared the pre-mortem chest x-ray findings with pulmonary autopsy studies in ventilated patients with np. no radiographic sign had a diagnostic efficiency greater than %. the only abnormality that correctly predicted % of pneumonias was the presence of an air bronchogram [ ] . the most specific sign, although uncommon, was an air-space process abutting a fissure. overall, the specificity of chest radiography in establishing the diagnosis of pneumonia ranges from to % in comparison with autopsy or protected specimen brush culture [ , , ] . winer-muram et al. [ ] analyzed intensive care patients with clinical signs and symptoms of pulmonary infection and new pulmonary abnormalities that were detected on chest radiography. in these patients, fiberoptic bronchoscopy with protected specimen brushing and bronchoalveolar lavage was performed and the findings were correlated with those of chest radiography. for the diagnosis of pneumonia, chest radiography provided an overall accuracy of %, and, when ards coexisted with pneumonia, of %. interestingly, the use of clinical information does not ameliorate the diagnostic accuracy of chest radiography in the icu setting. in winer-muram's study, a further drop in accuracy resulted when the radiologist was given clinical information [ ] . these unfavorable results reflect false-negative and false-positive results, the latter originating from misinterpretation of non-pneumonic opacities and from clinical bias. the same workgroup also determined the diagnostic accuracy of ct of patients with ards receiving mechanical ventilation [ ] . the ct scans obtained in patients were interpreted as having no pneumonia present, and results of bronchoscopy revealed that of fig. a , b a -year-old patient with relapsing hodgkin's disease. in the neutropenic phase following chemotherapy the patient developed fever. a the chest radiograph demonstrates paramediastinal fibrosis as a consequence of the initial radiotherapy but reveals no signs of infection. b in contrast, the ct scan in the same patient days later shows three small focal lesions with a halo phenomenon (arrows). based on the ct findings, the patient was diagnosed to suffer from invasive aspergillosis and was treated successfully fig. a -year-old inpatient with previous smoking history and proven idiopathic pulmonary fibrosis. clinical symptoms included cough, fever, dyspnea, and malaise: crp was mg/dl and white cell count was . g/l. chest radiography does not allow identification of a pneumonic infiltrate, although the patient was diagnosed as suffering from pseudomonas aeruginosa infection (using protected catheter brushing) -year-old patient with adult respiratory distress syndrome (ards) and sepsis. supine portable chest radiogram displays extensive consolidation in both lungs, characteristic of ards, but does not allow either identification of pneumonic abnormalities or differentiation between ards and pneumonia. protected catheter brushing revealed pseudomonas aeruginosa infection these patients had no pulmonary infection. findings in this study have demonstrated that ct features are less useful in accurate identification of patients who have pneumonia but showed a fair diagnostic accuracy for ventilator-associated pneumonia in patients with ards owing primarily to identification of patients without pneumonia [ ] . finally, it is important to emphasize that the quality of radiology reports plays a critical role in the management of patients with suspected pneumonia. webber-chapman et al. demonstrated that report clarity, i.e., the lack of ambiguity in a report, reflects several factors or a combination of these [ ] . in their study, three independent variables were associated with unambiguous reports including an interpretation of whether findings supported the diagnosis of pneumonia (in reports with pneumoniarelated observations), short sentences, and the redundancy of pneumonia-related observations. in contrast, uncertainty modifiers and use of only descriptive terms introduced ambiguity in the reports. narrowing of the differential diagnosis a second and very important task for the radiologist is to aid the clinician in the narrowing of the etiologic differential diagnosis. this relates to the notion that it is frequently impossible for the clinician to identify the causative organism of a pneumonic infiltrate. reviewing the clinical literature on this topic, it becomes clear that with the full battery of microbiologic tests, the causative organisms can be identified in only - % of cases. moreover, sputum tests, which are commonly used to diagnose outpatient pneumonia, are frequently contaminated by upper respiratory tract colonization. this often results in the incorrect identification of organisms by sputum cultures in a high percentage of patients with cap [ , ] . finally, the use of invasive procedures to identify the potential causative agent is frequently limited in nosocomial infections, especially in patients who are immuno-compromized and suffer from coagulation disorders. in this situation, radiology may help. narrowing of the etiologic differential diagnosis is indeed possible using pattern recognition, and with the integration of epidemiologic, clinical, laboratory, and radiographic information. pattern recognition is based on the categorization of the radiographic features of pneumonia (such as form, shape, and density) into different morphologic "patterns" and the correlation of these patterns with the histopathologic changes caused by microbial agents. practically, radiological pattern recognition allows the identification of different groups of potentially underlying organisms. this may be of value particularly in the etiologic diagnosis of cap, where bacteria and viruses account for more than % of all microbial agents. levy e et al. analyzed the value of initial noninvasive bacteriologic and radiologic investigations in patients with cap [ ] . they demonstrated that (focal segmental or lobar) alveolar infiltrates were caused by bacterial agents in over % of cases, whereas the majority of diffuse interstitial or mixed abnormalities could be attributed to viral, atypical bacterial, or tuberculous infections (figs. , ) . notably, pattern recognition can hardly ever be carried further into the specific diagnosis of a single causative agent. for example, differentiation of the radiographic patterns of typical bacterial pneumonia (caused, for example, by haemophilus influenzae, streptoccocus pneumoniae, staphylococcus aureus, and aerobic gramnegative bacilli) and atypical bacterial pneumonia (caused by mycoplasma pneumoniae and chlamydia fig. acute air-space pneumonia in a male outpatient with symptoms suggestive of pneumonia. a chest radiogram shows a large area of consolidation with relatively well-defined borders and a central discrete air bronchogram in the left lung. this acute airspace pneumonia was caused by streptococcus pneumoniae fig. a -year-old woman with high-grade fever, dyspnea, and maculo-papular rash. varicella zoster pneumonia in this patient is characterized by diffuse bilateral patchy and confluent nodular densities, a common pattern in pulmonary vzv infection species) is generally not possible. in a prospective study of adults with cap, fang et al. compared the radiographic, clinical, and laboratory features of "typical" bacterial pneumonia with the findings of patients with atypical bacteria pneumonia and found no parameters that could reliably differentiate these groups [ ] . granados et al. prospectively compared the clinical and radiologic features of cap caused by legionella pneumophila to patients with pneumococcal infections. the authors concluded that legionella, clinically as well as radiologically, may look like a typical bacterial pneumonia [ ] . from a practical point of view, pattern recognition can aid in the differentiation of bacterial and viral pneumonias (which account for almost all community-acquired and nosocomial pneumonias). this may have implications on the therapeutic management of individual patients. once the suspicion is raised that a patient suffers from a bacterial pneumonia, pattern recognition is of limited importance, since most recent therapeutic guidelines now recommend combining antibiotic regimens covering both typical and atypical bacteria. in acute air space pneumonia (synonymously termed "lobar pneumonia"), the microorganism causes damage to the terminal air spaces (alveoli). as a result, edema pours into the alveoli, spreads rapidly through the terminal airways and pores of kohn, and may involve large portions of the lung parenchyma, or an entire segment or lobe. erythrocytes (which may already be present in early phases of the insult), leukocytes, and macrophages subsequently invade the involved parenchyma. finally, fluid, cellular infiltration, and subsequent fibrin accumulation lead to consolidation of the lung parenchyma ( fig. ) [ , ] . in patients with cap and np, acute air-space disease is most commonly caused by gram-positive bacteria such as streptococcus pneumoniae, gram-negative bacilli, and atypical bacteria such as mycoplasma pneumoniae and legionella pneumophila [ , , , , , ] . occasionally, however, it may also be seen in viral infections [ ] . here, consolidation is not uncommon in adeno-, hanta-, and coronavirus (sars) pneumonia [ , , ] . localized air-space disease is also a well-known feature of fungal and protozoal pneumonias, but these pneumonias almost never occur in cap and np, unless patients are immuno-compromized. acute air-space pneumonia (lobar pneumonia) is characterized by a mostly homogeneous consolidation of lung parenchyma, is relatively sharply demarcated, and does not typically respect segmental boundaries (fig. ) . initially, lobar pneumonia may appear in the periphery of e the lungs, and may then spread toward the medulla and/or the hilar region, resulting in a segmental, lobar, or non-segmental infiltrate (fig. ) [ , , ] . in the latter case, occasionally, a "cloud-like" appearance or a rounded lesion is seen, particularly in streptococcal and legionella pneumonia (fig. ) [ , ] . in acute air-space pneumonia, an air bronchogram is very common (fig. ). the loss of the silhouette of an adjacent mediastinal structure or a hemidiaphragm is another important diagnostic sign (fig. ) . infiltrates are either unilateral or bilateral. cavitation is rare in infections with atypical bacteria but typical in staphylococcus aureus and gramnegative pneumonias, as well as in infections with mycobacteria and anaerobes (fig. ) [ ] . the lung volume note that acute air-space disease may involve predominantly the periphery of the lungs while the perihilar area is relatively spared. the aerobronchogram is indicative of an air-space process e is usually normal in gram-positive pneumonias and often increased in gram-negative pneumonias (kiebsiella species) [ ] . at ct, acute lobar pneumonias in patients with cap most commonly show air-space consolidation with segmental and non-segmental lesions, the latter with a round or cloud-like shape (fig. ) , and involvement of the middle and outer zones of the lung [ , ] . occasionally, areas of ground-glass attenuation may abut air-space disease (fig. ) [ ] . staphylococcus aureus and pseudomonas aeruginosa are the two organisms most commonly causing the radiographic pattern defined as lobular or bronchopneumonia. this form of pneumonia differs from lobar pneumonia in that the causative organism directs its attack against the peripheral airways and damages particularly the walls of terminal and respiratory bronchioles, resulting in a necrotizing bronchiolitis and bronchitis. subsequently, inflammatory aggregates involve the adjacent lung parenchyma, triggering in the typically patchy appearance of disease (fig. ) . over time, and with progression, dense consolidation of the involved parenchyma may develop [ , , ] . lobular pneumonia can also be caused by haemophilus influenzae, mycoplasma pneumoniae, mycobacterium tuberculosis, and viruses [ ] . these organisms also tend to affect small airways and the surrounding lung parenchyma, leading to patchy centrilobular infiltrates. the radiographic appearance of early bronchopneumonia is patchy with air-space nodules (centrilobular lesions with poorly defined margins measuring - mm in diameter), lobular consolidation, and confluent focal areas of consolidation (fig. ) [ , ] . in the later phase of disease frank lobar consolidation may be seen [ ] . the disease is typically segmental (involving one or more segments) or lobar in distribution. in more than half of the cases of staphylococcus aureus infection, the infiltrates are bilateral. cavitation is rare in early bronchopneumonia but common in late-phase consolidation. at ct, centrilobular lesions and focal areas of circumscribed air-space disease (air-space nodules) are the most common findings in early bronchopneumonia (fig. ) [ , , ] . in mycoplasma pneumoniae, centrilobular lesions, focal and patchy acinar lesions, areas of ground-glass attenuation and segmental infiltrates may be isolated findings, or may coexist in a complex pattern (fig. ) [ , ] . in these cases pneumonia has the tendency to affect both medulla and cortex of the lung [ ] . as reittner et al. pointed out, areas of groundglass attenuation in a lobular distribution are a distinct feature of mycoplasma infection, and are not seen in any other form of pneumonia (fig. ) [ ] . throughout many years, the term "interstitial pneumonia" (diffuse interstitial or mixed alveolar-interstitial) was a widely accepted classification for diffuse and mostly bilateral pneumonic abnormalities. this terminology, however, is somewhat misleading, since in most cases of "interstitial" pneumonias, we find interstitial changes and alveolar disease side by side. initially, the inhaled microbial agent (mostly viruses and protozoa) damages the ciliated epithelial cells and bronchial mucous gland cells. subsequently, fig. typical radiographic characteristics of acute lobar pneumonia in a -year-old inpatient. the chest radiogram displays an extensive, dense alveolar infiltrate in the right mid-and lower lung fields with loss of the silhouettes of the lower right heart border and right hemidiaphragm. these features suggest involvement of the right lower lobe and middle lobe by the pneumonic infiltrate. in addition, an air-fluid level indicates cavitation. note that the infection has spread transbronchially to the left lung. the patient was diagnosed to have e. coli pneumonia fig. computed tomography signs of acute lobar pneumonia due to streptococcus pneumoniae. at ct, the air-space consolidation in the left lower lobe displays a round shape and an air bronchogram, and is surrounded by a halo of ground-glass attenuation (which is occasionally seen in acute air-space pneumonia) infiltrates (b, c) . areas of ground-glass attenuation in a lobular distribution are a distinct feature of mycoplasma pneumonia e edema and mononuclear (lymphocytic) cellular infiltration lead to widening of alveolar septa, and later, to the involvement of interlobular septa (fig. ). this stage represents the "simple" viral pneumonia [ , ] . it may be complicated by foci of inflammation characterized by leukocytic infiltration and focal necrosis, occasionally of bacterial origin, particularly in the later stages. in both instances, a cascade of pathophysiologic events may lead to capillary leakage with accumulation of hemorrhagic interstitial and/or alveolar edema [ , ] . polymorphonuclear cellular infiltration and hyaline membrane formation are other distinct morphologic features of this process which, in cases of severe damage, can resemble diffuse alveolar damage and/or ards, histopathologically as well as radiographically [ , ] . diffuse interstitial pneumonias are most commonly caused by viruses and protozoa, and are rarely seen in bacterial pneumonias. therefore, this form of pneumonia is rare in patients with cap; however, if identified in normally healthy outpatients, it is most commonly caused by a viral agent such as the respiratory syncytial virus (rsv). radiographically, interstitial diffuse lung disease may encompass a wide variety of findings. these include reticular, reticulonodular, nodular, patchy, and alveolar densities, and areas of increased background (groundglass) density (figs. , , ) [ , , , , , , ] . frequently, interstitial diffuse lung disease presents as a mixed interstitial-alveolar disease, sometimes even in a pure alveolar abnormality. two or more of these findings may co-exist. in the vast majority of cases, the disease is bilateral and diffusely distributed. in herpes simplex virus pneumonia, chest radiograms demonstrate mostly bilateral patchy subsegmental, segmental and lobar ground-glass densities and consolidation [ , ] . in rsv pneumonia, the radiographic abnormalities are characterized by discrete interstitial perihilar linear abnormalities. in herpes varicellae (varicella zoster) fig. histopathologic correlate of interstitial pneumonia. this histopathologic specimen (hematoxylin-eosin stain) demonstrates moderate lymphocytic infiltrates surrounding a blood vessel and extending into the neighboring alveolar walls. the presence of macrophages and pneumocytes suggest the beginning of acute alveolar damage fig. interstitial pneumonia. in a -year-old hiv-positive patient with pneumocystis carinii pneumonia the disease is characteristized by reticular, reticulo-nodular, and alveolar patchy densities predominately located in the central and basal portions of the lungs. the pattern may occasionally be confused with hydrostatic lung edema fig. a, b acute viral broncholitis and pneumonia in a -year-old recruit. a at chest radiography, the viral infection is characterized by a myriad of tiny nodules scattered throughout the lung parenchyma bilaterally. b thin-section ct reveals unimorphous centrilobular densities demarcating the peripheral terminal and respiratory bronchioles e pneumonia, diffusely distributed, well-defined patchy or nodular densities are the characteristic feature (fig. ) [ ] . in organ transplant recipients a symmetric, diffuse bilateral linear, or discrete to marked nodular pattern, potentially combined with patchy alveolar densities, is most commonly caused by cmv infection [ , ] . pleural effusions are uncommon. the ct findings include bilateral and diffusely distributed areas of groundglass densities, centrilobular patchy lesions, reticular or nodular abnormalities, and mixed reticular-alveolar infiltrates (fig. ) [ ] . macronodular lesions are the result of infection with bacteria, such as nocardia asteroides, by mycobacteria, fungi, and septic emboli (fig. ) [ , , , , , , , ] . in outpatients, mycobacterial infections are the most common cause of macronodular lesions (fig. ). in the nosocomial setting, nodular abnormalities are more frequently seen in immuno-compromized hosts, and due to infection with bacteria and fungi. nocardia asteroides causes single or multiple nodular infiltrates with or without cavitation [ ] . aspergillus fumigatus (in invasive pulmonary aspergillosis), mucor mycosis, and cryptococcus neoformans can present with single or multiple nodular infiltrates, which often quickly progress to wedge-shaped areas of consolidation [ , , ] . cavitation is common and occurs both in bacterial and fungal lesion; in the latter, the so-called air-crescent sign points towards invasive pulmonary aspergillosis. a halo phenomenon, i.e., a rim of ground-glass attenuation around a focal nodular opacity, may be seen on ct scans of different inflammatory lesions. in the appropriate clinical setting, however, it is suggestive of invasive pulmonary aspergillosis [ , ] . diffusely and randomly distributed well-defined micronodules (miliary disease) are most commonly associated with the hematogenous spread of tuberculous disease (fig. ) [ ] . in contrast, bronchogenic spread of fig. a, b patterns of micronodular disease caused by tuberculous infection. a miliary pattern with small, well-defined interstitial nodules scattered randomly throughout the lung parenchyma. b micronodular disease originating from tuberculous infection of the small airways. note that the tree-in-bud phenomena, seen in the lung periphery, are characteristic of infectious small airways disease e tb results in larger ill-defined nodules (fig. ) . these "air-space" nodules may also be seen in infectious broncholitis from viruses and mycoplasma pneumoniae [ ] . viral pneumonia in herpes or varicella zoster infection tends to present with larger nodules ranging from to mm in diameter and displaying hazy borders (fig. ) [ , ] . in patients with granulocytopenia, small and well-defined nodules are frequently caused by candida infection (fig. ) . chest radiograms commonly do not show the full extent and morphologic details of pulmonary micronodules, and ct is frequently required to more precisely characterize the disease [ ] . in lobar, lobular, and diffuse interstitial pneumonias, the patterns at ct patterns generally correspond to those seen at chest radiography. these patterns have been described in the foregoing sections. in addition, distinct findings, signs, and patterns of pneumonia and lower respiratory tract infection are revealed with the use of ct. one of the most important ct features of infection of the small airways is the tree-in-bud sign (fig. b) [ , ] . this sign is suggestive of infectious bronchiolitis and is not uncommonly seen in patients suspected of having community-acquired infection. in this patient group, it is etiologically most frequently due to infections with viruses and mycoplasma pneumoniae. in addition, bronchogenic spread of post-primary tuberculosis is a prominent cause of this specific sign [ , ] . the tree-in-bud phenomenon reflects inflammatory changes in the small peripheral bronchioli with secretions in the lumen of the airways, wall thickening, and peribronchiolar inflammation [ , ] ; thus, with respect to the pathophysiologic and histologic changes, some overlap exists with the initial phase of lobular pneumonia. indeed, it may be difficult to distinguish between advanced infectious bronchiolitis caused by mycoplasma pneumoniae, and early lobular pneumonia triggered by the same microorganism. as pointed out by reittner et al. [ ] , the thin-section ct findings in mycoplasma pneumoniae include centrilobular nodules, often in a lobular distribution, and thickening of the peribrochovasular and interlobar septal interstitium. these findings are often difficult to identify on chest radiographs but can usually be recognized on ct scans [ ] . overall, the recognition of radiographic patterns provides the opportunity to aid the clinician in the etiologic diagnosis of pulmonary infections. in principle, pattern recognition may help classify the large groups of organisms (i.e., bacilli, viruses, fungi); however, there are limitations to this approach. firstly, patterns overlap. secondly, a single organism may produce different patterns in different patients. the prototype for such chameleonlike behavior is mycoplasma pneumoniae. this atypical organism has the potential to cause acute air-space disease, bronchopneumonia, bilateral and diffuse disease, centrilobular lesions, ground-glass densities, and tree-inbud phenomena. the same holds true for the corona virus which was identified as causing sars. the same organism, in this case a virus, triggered radiologic changes with a variety of patterns including acute air-space disease, ground-glass lesions, and bilateral diffuse abnormalities (fig. ) . thirdly, radiographic patterns change with the immunologic status of the patient. this has been demonstrated for mycobacteria or aspergillus fumigatus, which may cause three different patterns depending upon the immunologic situation of an individual [ , ] . finally, patterns may be altered by pre-or co-existing lung disease. pattern recognition should only be attempted on an extensive knowledge of the radiographic features of pulmonary infections, and with the integration of clinical information. not surprisingly, several disorders may mimic pneumonia, clinically as well as radiologically. focal alveolar densities (as seen in lobar pneumonia) are a common feature in pulmonary infarction, atypical focal edema, hemorrhage, atelectasis, bronchiolitis obliterans with organizing pneumonitis (boop), and malignancies including bronchogenic carcinoma (with postobstructive pneumonitis) and lymphoma (figs. , ) [ , , ] . in diffuse bilateral disease, eosinophilic pneumonia, edema, diffuse alveolar damage, ards, acute damage to the alveolo-capillary unit in systemic lupus (fig. ) , and idiopathic interstitial pneumonias are only a few entities among many that can look like viral or protozoal pneumonia. from a practical point of view, the list of potential differential diagnoses is mostly short in suspected cap in otherwise healthy outpatients, but potentially long in hospitalized multimorbid individuals. in such patients, edema especially, ards, drug toxicity, atelectasis, and infarcts may render diagnosis of pneumonia difficult if not impossible [ ] . for example, basilar atelectasis is common in icu patients, individuals following cardiac surgery, and patients with pleural effusions [ , ] . it can easily be misinterpreted as pneumonia. radiology has many roles in the diagnosis and management of community-acquired and nosocomial pulmonary infections. in a meta-analysis and review of the medical literature on prognosis and outcome in patients with cap, fine et al. found that imaging may also contribute to an estimate of mortality in a certain case [ ] . multilobar involvement by pneumonia on chest radiographs was found to be an independent predictor of mortality (in addition to several other factors such as co-morbid illnesses, symptoms and signs, and laboratory features) [ , , ] . in patients with cap, diagnosis and management most frequently rely on chest radiography and do not require further diagnostic tests. in these patients, ct and invasive diagnostic procedures are reserved only for cases in which treatment failure or complications, such as abscess, influence the course of disease. conversely, in nosocomial or opportunistic infections, cross-sectional imaging techniques and procedures, such as needle or bronchoscopically guided biopsy, are more often required. this is because nosocomial pneumonias are associated with a high mortality rate, and because - % of these patients remain without etiologic diagnosis even when extensive noninvasive diagnostic testing is performed; thus, identification of the causative organism is more intensively pursued, with the use of fiberoptic bronchoscopic lavage, brushing, and/or biopsy. in many institutions, imaging methods, such as ct, are used for the guidance of invasive methods into areas of maximum disease. the use of transthoracic ct aspiration needle biopsy in the diagnosis of pulmonary infection is controversial. nevertheless, when noninvasive techniques, such as sputum examination and cultures, are non-diagnostic, a choice must be made between empiric therapy and an invasive test. while the majority of patients are treated empirically, the nature and course of pneumonias in nosocomial infections and in immunosuppressed individuals frequently dictates a more aggressive approach. in such cases, transthoracic needle biopsy may help to identify the causative organism [ , ] . sanchez-nieto et al. reviewed a series of transthoracic needle aspirations to evaluate the use of the procedure in diagnosis of pulmonary infections [ ] . in patients in whom pulmonary infection was suspected, a specific diagnosis was made with needle biopsy in cases. in cases in which infection was ultimately found to be present, aspiration biopsy identified the organism in cases. overall, clinically useful information was obtained in % of aspiration biopsies for pulmonary infection. since other authors report similar results, needle biopsy should enrich the radiologist's armamentarium in diagnosing and managing pulmonary infections. fig. lupus pneumonitis mimicking pneumonia. a young woman with known systemic lupus erythematosus, presenting with an episode of fever and cough. the chest radiogram demonstrates bilateral diffuse interstitial abnormalities and an increased background density of the lung parenchyma. no causative organism could be identified. the enlargement of the cardiac silhouette, due to a pericardial effusion and the amount of circulating anti-dsdna antibodies, pointed towards acute damage to the alveolar capillary unit (acute lupus pneumonitis) as an alternative imaging method, the interest in mr imaging of the lung parenchyma has been growing. although imaging quality is limited by low proton density of normal lung and susceptibility artifacts caused by the extensive air-tissue interfaces of the parenchyma, several recent studies report promising results regarding improved lesion conspicuity [ ] . leutner et al. compared t -weighted turbo spin-echo mr imaging with ct in patients with opportunistic pneumonia. features such as consolidation, ground-glass hyperintense lesions, nodules, reticular infiltrations, cavities, and cystic disease could be identified on high-quality mr images and showed fair correlation with ct scans [ ] . especially the depiction of necrotizing pulmonary lesions using the "reverse target sign" underlines the potential diagnostic possibilities of mri. the role of radiography in the follow-up of pulmonary infections is currently under debate. because of increasing economic restrictions, imaging tests are used less routinely to monitor the resolution of pulmonary infiltrates. many institutions now do not follow patients radiographically when the clinical course indicates successful treatment. in other institutions, in different health care systems, radiographic documentation of the healing process is required for medico-legal reasons. if follow-up exams are performed, it is important to consider the time period in which a pneumonic infiltrate may resolve. as a general rule, most pneumonias regress within - days. after months, two-thirds of patients with caps have cleared their lungs [ ] ; in the rest, however, complete resolution may take up to months, especially in patients with underlying lung disease, such as chronic obstructive pulmonary disease, in immuno-compromized individuals, and in the elderly [ , ] . for the radiologist it is important to separate patients with a continuous (slow) improvement of disease from those who do not adequately respond to treatment; for the latter, a list of differential diagnoses needs to be established. firstly, it is not uncommon that patients are not treated effectively and either typical or atypical bacteria are not covered by a single drug strategy; thus, in a recent article by halm and teirstein, it is suggested that patients with cap always receive combination therapy covering typical and atypical bacteria [ ] . secondly, one should consider that the disease, although mimicking infection clinically, is not related to pneumonia but represents noninfectious inflammation such as boop (fig. ) , eosinophilic pneumonia or lupus pneumonitis, acute alveolar sarcoid, or a malignant disorder including bronchoalveolar cell carcinoma, bronchogenic carcinoma with post-obstructive pneumonitis, and lymphoma. it fig. a -c bronchiolitis obliterans with organizing pneumonia (boop) mimicking pneumonia. a -year-old woman with a month history of subfebrile temperatures, cough, and failure of response to several antibiotic regimens. a the plain chest radiogram demonstrates "ground-glass" opacities in the right middle and lower lung fields as well as in the left upper lobe and left lower lobe. b, c at ct, alveolar consolidation is seen in the periphery of both upper lobes and both lower lobes. the distinct peripheral location of the abnormalities and the discretely ectatic airways raised the suspicion of boop. the diagnosis was confirmed through video-assisted fluoroscopic biopsy e is a well-established fact that all of these disorders may look like pneumonia and that misdiagnosis is not uncommon; therefore, an important role of the radiologist in these patients is to critically judge the course of the disease and to plan further diagnostic procedures, including ct scanning, if needed. computed tomography scanning is also the method of choice to evaluate patients with recurrent pulmonary infiltrates. such recurrent infections usually indicate some sort of underlying problem such as congenital or acquired immunologic disorders, cardiac abnormalities (congestive heart failure), or systemic diseases such as diabetes, chronic alcoholism, and intravenous drug abuse. if occurring in the same anatomical location, they may be the result of underlying structural defects including airway abnormalities such as chronic bronchitis, bronchiectasis, large cavities, and bronchogenic carcinoma (fig. ) . here, ct scanning is indicated to search for or exclude an underlying disorder and to plan further therapeutic measures. in patients with suspected pneumonia, the radiologist has an important role in the detection and exclusion of pulmonary infiltrate, in the 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communityacquired pneumonia delayed resolution of pneumonias key: cord- -rt g ufe authors: carter, michael j.; gurung, pallavi; jones, claire; rajkarnikar, shristy; kandasamy, rama; gurung, meeru; thorson, stephen; gautam, madhav c.; prajapati, krishna g.; khadka, bibek; maharjan, anju; knight, julian c.; murdoch, david r.; darton, thomas c.; voysey, merryn; wahl, brian; o'brien, katherine l.; kelly, sarah; ansari, imran; shah, ganesh; ekström, nina; melin, merit; pollard, andrew j.; kelly, dominic f.; shrestha, shrijana title: assessment of an antibody-in-lymphocyte supernatant assay for the etiological diagnosis of pneumococcal pneumonia in children date: - - journal: front cell infect microbiol doi: . /fcimb. . sha: doc_id: cord_uid: rt g ufe new diagnostic tests for the etiology of childhood pneumonia are needed. we evaluated the antibody-in-lymphocyte supernatant (als) assay to detect immunoglobulin (ig) g secretion from ex vivo peripheral blood mononuclear cell (pbmc) culture, as a potential diagnostic test for pneumococcal pneumonia. we enrolled children with pneumonia admitted to patan hospital, kathmandu, nepal between december and september . pbmcs sampled from participants were incubated for h before harvesting of cell culture supernatant (als). we used a fluorescence-based multiplexed immunoassay to measure the concentration of igg in als against five conserved pneumococcal protein antigens. of children with pneumonia, had a confirmed etiological diagnosis: children had pneumococcal pneumonia (defined as blood or pleural fluid culture-confirmed; or plasma crp concentration ≥ mg/l and nasopharyngeal carriage of serotype pneumococci), and children had non-pneumococcal pneumonia. children with non-pneumococcal pneumonia had either a bacterial pathogen isolated from blood (six children); or c-reactive protein < mg/l, absence of radiographic consolidation and detection of a pathogenic virus by multiplex pcr (respiratory syncytial virus, influenza viruses, or parainfluenza viruses; children). concentrations of als igg to all five pneumococcal proteins were significantly higher in children with pneumococcal pneumonia than in children with non-pneumococcal pneumonia. the concentration of igg in als to the best-performing antigen discriminated between children with pneumococcal and non-pneumococcal pneumonia with a sensitivity of . ( % ci . – . ), specificity of . ( % ci . – . ) and area under the receiver-operating characteristic curve (aurocc) . ( % ci . – . ). children with pneumococcal pneumonia were older than children with non-pneumococcal pneumonia (median . and . years, respectively, p < . ). when the analysis was limited to children ≥ years of age, assay of igg als to pneumococcal proteins was unable to discriminate between children with pneumococcal pneumonia and non-pneumococcal pneumonia (aurocc . , % ci . – . ). this method detected spontaneous secretion of igg to pneumococcal protein antigens from cultured pbmcs. however, when stratified by age group, assay of igg in als to pneumococcal proteins showed limited utility as a test to discriminate between pneumococcal and non-pneumococcal pneumonia in children. pneumonia is the leading cause of childhood mortality after the neonatal period, yet the pathogen-specific etiology of childhood pneumonia remains poorly defined (liu et al., ; feikin et al., b) . using data from randomized controlled vaccine trials, vaccine-probe studies help reveal the pathogen-specific burden of disease by estimating the difference in disease between vaccinated and unvaccinated individuals (feikin et al., ) . results from these studies estimate that approximately one third of children with pneumonia and radiographic consolidation have pneumococcal pneumonia in settings prior to the introduction of vaccines that prevent etiology-specific pneumonia, regardless of geography (o'brien et al., ; wahl et al., ) . however, microbiological data to support this prevalence estimate are lacking. accurate diagnostic tests for the etiology of pneumonia are needed to assess the etiology of pneumonia in changing epidemiological contexts, notably following vaccine implementation (feikin et al., b) . direct aspiration of infected (lung) tissue is rarely used due to perceived safety concerns (ideh et al., ; howie et al., ) , while culture of broncho-alveolar lavage samples is only possible on samples from children requiring mechanical ventilation. culture of bacteria from blood is therefore the most widely used test for bacterial pneumonia in children admitted to hospital. however, estimates of yield from "true positive" bacterial pneumonia cases are < % (cutts et al., ) , depending on prior antibiotic exposure, sample volume and culture technique (driscoll et al., ) . in the recent pneumonia etiology research for child health (perch) casecontrol study, quantitative (q)pcr of lyta to determine whole blood pneumococcal load (deloria , and density of nasopharyngeal (np) colonization with s. pneumonia , demonstrated only moderate ability to discriminate between pneumococcal pneumonia and agematched community children. an alternative approach to the diagnosis of pneumococcal pneumonia is to assess the immune response to the pathogen. unfortunately, serological assays have limited specificity in the acute phase, or require convalescent samples to discriminate from past infections (tuerlinckx et al., ; andrade et al., ) . we hypothesized that we could combine the etiological specificity of serological assays to a time-specific population of b cells (plasmablasts), that circulate during active infection (carter et al., ) , using the antibody-in-lymphocyte supernatant (als) assay. the als assay was originally developed to assess vaccineinduced serological responses, and has since been developed for the diagnosis of enteric fever and tuberculosis (chang and sack, ; sheikh et al., ; darton et al., b; sariko et al., ) . this assay is based upon testing the secretions of lymphocytes that are incubated in vitro following sampling from an unwell patient (without ex vivo stimulation). following incubation, harvested supernatant can be tested for pathogenspecific antibodies using standard serological techniques. we assessed the diagnostic performance of the als assay for the diagnosis of pneumococcal infection in a prospective study of childhood pneumonia in nepal, a low income country in south asia with a high burden of childhood pneumonia (ministry of health population (mohp) et al., ) . we used five pneumococcal proteins as target antigens (choline binding protein a, cbpa; protein for cell wall separation of group b streptococci, pcsb; pneumococcal histidine triad d, phtd; pneumolysin, ply; serine threonine kinase protein c, stkpc). these antigens are thought to be expressed by all pathogenic pneumococci, are specific to pneumococci or closely related species, and have been used to assess the serological response to pneumococcal pneumonia (andrade et al., borges et al., ) . this prospective study was carried out in accordance with the protocol and the international conference on harmonization good clinical practice standard. literate parents/legal guardians all gave informed written consent prior to enrolment. nonliterate parents/legal guardians gave verbal and thumbprint consent in the presence of a literate (non-hospital/research staff) witness who could attest to the explanation of the patient information leaflet and the agreement of the signatory. the study protocol was approved by the nepal health research council ( / ) and the oxford tropical research ethics committee ( / ). patan hospital is in the lalitpur sub-metropolitan district of nepal, contiguous with the city of kathmandu. it is one of the largest hospitals in the country, and one of few with inpatient pediatric and pediatric critical care facilities. during the study period, the primary infant vaccination schedule included diphtheria-tetanus-pertussis, bacille-calmette-guérin, hepatitis b, haemophilus influenzae type b (from ), oral and inactivated poliovirus and measles, rubella and japanese encephalitis antigens, with % coverage for all antigens in in the central development region of nepal (including lalitpur) [ministry of health population (mohp) et al., ] . tenvalent pneumococcal conjugate vaccination ( -valent pcv) was introduced to the infant immunization schedule in lalitpur in august at and weeks, and months of age. there was a limited pcv catch-up campaign among infants. children were enrolled for this study between nd december and th september . children were eligible for enrolment if ≥ days of age and < years of age and being admitted to patan hospital with a clinical diagnosis of pneumonia. a small number of patients were diagnosed with pneumonia, enrolled, and then discharged directly before admission; their data are included here (figure ) . the diagnosis of pneumonia was made by admitting pediatricians, reviewed by a consultant (attending) pediatrician, and was typically prior to results from radiographs or blood tests becoming available. children who did not have a clinical diagnosis of pneumonia were excluded from the study. a digitalized radiograph was obtained on all children on study enrolment. all radiographs were independently interpreted using standardized who criteria (liu et al., ) as endpoint consolidation, other infiltrate, or no consolidation/effusion/infiltrate by two specific readers (a pediatrician, and a radiologist). a second specific radiologist arbitrated upon all discordant results, and % of other radiographs. radiographic findings were not used to exclude children from the study. child healthy controls were enrolled from a vaccine clinic at months of age, and all controls had been vaccinated with three doses of -valent pcv (most recent dose received ≥ days prior to sampling). enrolled cases and controls all had ml of blood sampled into heparinized and sterile centrifuge tubes for this study by peripheral venepuncture within h of admission. in addition all enrolled children had full blood count, plasma (for storage) and inoculation of blood into bactec peds plus culture bottles (becton dickinson, bd; usa) for automated incubation (bactec, bd), subculture and identification of isolated organisms. heparinized blood was immediately taken to the microbiology laboratory and processed within h of sampling as described below. c-reactive protein (crp) concentrations were measured following shipment of plasma to oxford at oxford university hospitals nhs foundation trust. a single flocked swab (thermo fisher scientific, uk) was used to sample the nasopharynx, and a digital chest radiograph was taken, at admission. the np swab was immediately and aseptically placed into skim-milk-tryptone-glucose-glycerin media and transported to the on-site microbiology laboratory, cultured for pneumococci, and subjected to quellung serotyping. np swabs in stgg media were subsequently stored at − • c before transport to the uk on dry ice and further storage at − • c. all chest radiographs underwent blinded review for radiographic endpoint consolidation by two clinicians (a pediatrician and a radiologist) according to world health organization criteria (cherian et al., ) , with quality control and discordant readings arbitrated upon by a second radiologist. np swabs were defrosted and dna was extracted from µl stgg media using the qiagen dneasy kit (qiagen, uk) using a modified protocol. extracted dna was subsequently transported to micropathology ltd (warwick, uk) where samples ( µl extracted dna) were analyzed using the nxtag luminex respiratory pathogen panel (luminex corp, usa) (tang et al., ) according to manufacturer's instructions for: influenza a, influenza a h , influenza a h , influenza b, rsv a, rsv b, parainfluenza - , coronaviruses e/nl /oc /hku , human metapneumovirus, rhinovirus/enterovirus, adenovirus, human bocavirus, chlamydophila pneumoniae, legionella pneumophila, and mycoplasma pneumoniae. results were reported as positive or negative for each pathogen. we considered rsv (any group), influenza virus (any serotype) or any of the parainfluenza viruses - as pathogenic, since these were highly associated with case status in the perch study, and were prevalent (≥ cases for each virus) in our cohort. samples of fresh, heparinized, whole blood were separated by centrifugation over ficoll media with a density of . g/ml (histopaque , sigma-aldrich, usa) at g for min with minimal acceleration and deceleration. this yielded plasma, peripheral blood mononuclear cells (pbmcs) and a sediment of red cells and polymorphonuclear cells. the pbmc layer was manually aspirated and washed by resuspension and centrifugation twice into rpmi culture media plus penicillin ( u/l), streptomycin ( . mg/l), and l-glutamine ( mmol/l; all sigma-aldrich; "r medium"). following manual counting and calculation of the total number of pbmcs, the cells were resuspended into r medium plus % fetal bovine serum (heatinactivated and sterile-filtered, sigma-aldrich; "r medium"), and incubated in a sterile cell culture plate (greiner, germany) at • c and % co for h. following incubation the cell suspension was separated by centrifugation with the resulting supernatant (als) preserved with x protease inhibitors ( µl per ml of als) and stored immediately at − • c before shipping to oxford and helsinki on dry ice for further analyses. figure | classification of children by likely etiology of pneumonia into comparator groups (definite pneumococcal, probable pneumococcal, probable bacterial, unknown, influenza/parainfluenza virus, rsv, and definite other bacterial) and by diagnosis of "pneumococcal pneumonia" and "non-pneumococcal pneumonia". a fluorescent multiplexed bead-based immunoassay (fmia) to detect igg als to five pneumococcal proteins (cbpa, pcsb, phtd, ply, and stkpc) was used for this study as previously described (andrade et al., . in brief, samples of als were diluted to / in phosphate buffered saline containing % fetal bovine serum, with the fmia performed as a plex assay with , beads per region per well. igg in als were detected using rpe-conjugated goat anti-human igg (jackson immunoresearch, usa). pneumococcal reference standard serum sp (nibsc, uk) was used as the reference with an arbitrary assigned concentration of units/ml for each anti-pneumococcal antibody. we classified children by comparator groups based on likely etiology of pneumonia (where these comparator groups are used in the text, they are italicized for clarity.) this classification scheme is described in figure . specifically, we classified children into comparator groups as definite pneumococcal pneumonia (s. pneumoniae cultured from blood or pleural fluid), probable pneumococcal pneumonia (crp concentration ≥ mg/l and np carriage of serotype pneumococci), probable bacterial pneumonia (crp concentration ≥ mg/l only), unknown pneumonia (crp concentration < mg/l only), influenza/parainfluenza viral pneumonia (crp < mg/l and influenza/parainfluenza viruses detected by qpcr from np specimen), rsv pneumonia (crp < mg/l and rsv detected by qpcr from np specimen), and definite other bacterial pneumonia (other bacterial pathogen cultured from blood or pleural fluid). these were ordered by hypothesized probability of pneumococcal infection from definite pneumococcal pneumonia to definite other bacterial pneumonia (left to right, figure ). to assess the utility of acute igg als to pneumococcal proteins to identify pneumococcal pneumonia we compounded definite pneumococcal pneumonia and probable pneumococcal pneumonia into a single category (pneumococcal pneumonia); and we combined influenza/parainfluenza virus pneumonia, rsv pneumonia and definite other bacterial pneumonia into a single category (non-pneumococcal pneumonia). the classification scheme was modified from similar schemes for the development of novel diagnostic tests to discriminate between bacterial and viral infection (herberg et al., ; kaforou et al., ) . recent data have estimated a threshold to discriminate between bacterial and viral pneumonia at a crp concentration of ∼ - mg/l in children in south asia and in low and middle-income countries in the perch study (lubell et al., ; higdon et al., b) . we chose np carriage of pneumococcal serotype (by culture) as a predictor of pneumococcal infection. the association of np carriage of serotype pneumococci in cases compared with controls, has been previously established in unvaccinated populations (scott et al., ) . np carriage of serotype was also associated with cases in comparison with controls in children with pneumonia at patan hospital between and (prior to -valent pcv introduction) and , age-stratified control (non-pneumonia) children (odds ratio for case status of . , % confidence interval, ci, . - . ; figure s ). this was supported by unpublished data from childhood invasive pneumococcal disease at patan hospital from to , where / ( %) isolated pneumococci were of serotype . similar findings have been reported from other epidemiological settings (scott et al., ; johnson et al., ) . we chose np carriage (as detected by pcr) of influenza or parainfluenza virus, and rsv to represent viral pneumonia since carriage of these viruses was associated with radiographically-confirmed pneumonia in the perch study (feikin et al., a) . while we used np carriage of serotype pneumococci as a predictor of pneumococcal pneumonia, we also subsequently investigated for an association of np carriage of pneumococci with increased igg als to pneumococcal proteins. to avoid confounding with undetected pneumococcal infection, we limited this analysis to children with non-pneumococcal pneumonia (i.e., definite other bacterial pneumonia, influenza/parainfluenza pneumonia or rsv pneumonia). continuous variables were compared using student's t-test, following appropriate transformation (log transformation of age distribution; and taking the reciprocal of als concentrations to pneumococcal protein for the comparison of als concentrations to pneumococcal proteins between probable bacterial pneumonia and unknown pneumonia). assay signals that were undetectable were assigned a value below the threshold of detection. fisher exact tests, wilcoxon rank sum tests, and χ test were used as indicated. kruskal-wallis tests were used to assess for confounding of acute igg als to pneumococcal proteins with age, and length of illness. formal statistical testing for an interaction between age (grouped, due to a non-normal distribution) and acute igg als to pneumococcal proteins stratified by comparator group was not possible due to small numbers and tied als values. analyses were prespecified, with the exception of a post-hoc analysis of the effects of age on igg als to pneumococcal proteins. we used best subsets regression analysis to investigate optimal combinations of pneumococcal protein antigens for igg als to discriminate between children with pneumococcal pneumonia and non-pneumococcal pneumonia and assessed for multiple co-linearity. one thousand nine hundred four children were admitted to patan hospital during the study period. of admitted children, ( %) children had a clinician diagnosis of pneumonia, as had an additional children who were diagnosed with pneumonia, but not admitted, totaling children. children were enrolled to the study, with data on als to pneumococcal proteins available on of these children (figure ) . of children, ( %) had endpoint consolidation/effusions on chest radiograph, ( %) had infiltrates, had neither consolidation/effusions or infiltrates, (< %) were uninterpretable and ( %) children did not have a chest radiograph. of children < years of age, ( %) met the who criteria for pneumonia (fast breathing or chest indrawing) and ( %) did not. in addition, healthy infants (controls) aged months of age were enrolled, on whom als was analyzed on a random subset of infants. all healthy infant controls had received three doses of -valent pcv, with the most recent dose ≥ days prior to enrolment to this study. the clinical characteristics of children with pneumonia are described in table by comparator group (and table s by other classifications). we classified eight children as definite pneumococcal, four children as probable pneumococcal (totaling as pneumococcal pneumonia), children as probable bacterial, children as unknown, children as parainfluenza/influenza virus, children as rsv, and six children as definite other bacterial pneumonia. this totaled children as non-pneumococcal pneumonia. on comparison of children with pneumococcal pneumonia vs. children with non-pneumococcal pneumonia, there were significant differences in age (median . years, interquartile range . - . and . years, iqr . - . , t-test following log transformation of age distribution, p < . ), sex (females and %, fisher exact test, p = . ), length of illness ( days, iqr - . and . days, iqr - , wilcoxon rank sum test, p < . ), and proportion with radiographic endpoint consolidation ( and %, χ test, p < . ). the youngest child with pneumococcal pneumonia was . years of age. igg als to pneumococcal proteins was detected and quantifiable in acute samples from children with pneumonia. acute igg als was higher in children with pneumococcal pneumonia than children with all other pneumonia (including possible cases of undiagnosed pneumococcal pneumonia within the comparator groups probable bacterial pneumonia, unknown, influenza/parainfluenza pneumonia, rsv pneumonia, definite other bacterial pneumonia) for / pneumococcal proteins (figure ) . assay of acute igg als to pneumococcal proteins discriminated between pneumococcal pneumonia and all other pneumonia with good accuracy for cbpa, pcsb and phtd, but not ply or stkpc: auroc curve was . ( % ci . - . ) for cbpa, . ( % ci . , . ) for pcsb, . ( % ci . - . ) for phtd, . ( % ci . - . ) for ply, and . ( % ci . - . ) for stkpc. acute igg als was higher in children with pneumococcal pneumonia than with non-pneumococcal pneumonia for all five pneumococcal proteins (figure ) . acute igg als to pneumococcal proteins discriminated between pneumococcal pneumonia and non-pneumococcal pneumonia in children enrolled to the study with good sensitivity and specificity, with auroc curve ranging from . ( % ci . - . ) for ply, to . ( % ci . - . ) for cbpa, using thresholds derived from the youden index (table ) . there was a high degree of colinearity between acute igg als to all five pneumococcal proteins measured with pneumococcal pneumonia (and non-pneumococcal pneumonia) in best subsets logistic regression analysis. discriminating between pneumococcal pneumonia patients and healthy controls, acute igg als had an auroc curve ranging from . for ply ( % ci . - . ) to . for cbpa ( % ci . - . ; figure s , table s ). among children with pneumococcal pneumonia, there was no significant increase in acute igg als to any of the pneumococcal proteins measured with increasing length of illness (simple linear regression, p > . for all five proteins; figure s ). there were too few female cases with pneumococcal pneumonia to investigate sex differences. among children with non-pneumococcal pneumonia, there was no significant difference in acute igg als to pneumococcal proteins between children with viral pneumonia (influenza/parainfluenza, rsv) or definite other bacterial pneumonia (cbpa, p = . ; pcsb, p = . ; phtd, p = . ; ply, p = . ; stkpc, . ). children with probable bacterial pneumonia had higher concentrations of acute igg als to cbpa, pcsb, phtd, ply, and stkpc than children with unknown pneumonia (wilcoxon rank sum test, p < . for all). the proportion of children with acute igg als concentrations greater than the threshold derived from roc curve analysis differed significantly for cbpa ( % of probable bacterial pneumonia and % of unknown pneumonia, χ test, p < . ), pcsb ( and %, p = . ), phtd ( and %, p = . ), but did not differ for ply and stkpc (threshold lines not applicable to figure ). pneumococcal pneumonia was only diagnosed in children ≥ years of age. we therefore undertook a post-hoc analysis of acute igg to pneumococcal proteins in children ≥ years of age for the etiological diagnosis of pneumonia. children ≥ years of age known to have a qualitatively different humoral immune response to pneumococcal polysaccharide antigens, although not pneumococcal protein antigens, in comparison with young infants (clutterbuck et al., ; borges et al., ; ramos-sevillano et al., ) . the clinical characteristics of children ≥ . p-values were not calculated for variables that were entered into the classification scheme in figure . values are expressed as the percentage of n for each column (excepting continuous variables). years of age with pneumococcal pneumonia or non-pneumococcal pneumonia from the cohort are described in table . restricting the analysis to children ≥ years of age reduced the ability to discriminate between pneumococcal pneumonia ( children) and non-pneumococcal pneumonia ( children) for all pneumococcal proteins to non-significance in this smaller number of samples (wilcoxon rank sum tests; cbpa, p = . ; pcsb, p = . ; phtd, p = . ; ply, p = . ; stkpc, p = . ; figure and table ). a visual examination of data points did not suggest that children with definite other bacterial pneumonia had different acute igg als to pneumococcal proteins than other children with non-pneumococcal pneumonia (red crosses and black crosses, figure ). among all children enrolled, those with np carriage of pneumococci had higher acute igg als than those without np carriage of pneumococci (wilcoxon rank sum tests, p < . for all five pneumococcal proteins). among children with non-pneumococcal pneumonia (i.e., not "confounded" by definite pneumococcal or probable pneumococcal or probable bacterial or unknown pneumonia), those with np carriage of pneumococci had higher acute igg als to all five pneumococcal proteins than those without np carriage (wilcoxon rank sum tests; cbpa, p < . ; pcsb, p < . ; phtd, p < . ; ply, p < . ; stkpc, p < . ; figure ) . among children ≥ years of age with non-pneumococcal pneumonia, there were no significant differences in acute igg als to any pneumococcal protein detected between those with (n = ) and without (n = ) np carriage of pneumococci (wilcoxon rank sum tests, p > . for all comparisons, figure s ). stratification of this age group to those who had not received antibiotics prior to np sampling did not significantly affect these results. we used acute igg als to pcsb as the most parsimonious approach to investigate acute igg to pneumococcal proteins in children ≥ years of age across the cohort. the number of children (proportion) that had acute igg als greater than, or equal to, the optimum threshold to discriminate between pneumococcal pneumonia and non-pneumococcal pneumonia was: definite pneumococcal pneumonia / ( . ), probable pneumococcal pneumonia / ( . ), probable bacterial pneumonia / ( . ), unknown pneumonia / ( . ), influenza/parainfluenza pneumonia / ( . ), rsv pneumonia / ( . ), definite other bacterial pneumonia / ( . ; figure ). the development of novel diagnostic tests for the etiology of pneumonia is partly driven by the need to assess the impact of vaccination strategies on the total, and pathogen-specific burden of pneumonia in diverse settings. we have chosen to focus our work on pneumococcal pneumonia, during the introduction of -valent pcv to the infant immunization schedule in nepal. currently available diagnostic tests for pneumonia etiology lack sensitivity or specificity in children. culture of pneumococci from blood or pleural fluid from children with pneumonia is presumed to be highly specific for pneumococcal pneumonia but lacks sensitivity (o'brien et al., ; wu et al., ) . theoretically, sampling infected tissue (the lung) might improve sensitivity. a review of studies using lung biopsy followed by culture for the diagnosis of pneumonia etiology identified an increase in yield of bacterial pathogens from to % of children tested (ideh et al., ) . however, lung biopsy requires peripheral radiographic consolidation, and was therefore not possible in approximately three quarters of patients with clinically severe pneumonia in a recent prospective cohort (howie et al., ) . this, in addition to safety concerns, has prevented lung biopsy for diagnostic sampling from becoming a widespread technique (ideh et al., ) . interpretation of samples from the nasopharynx of children is limited by poor specificity, with many pathogens detected at similar prevalence in children with pneumonia and in community controls . culture or molecular detection of pathogens from of broncho-alveolar lavage samples is only possible on samples from children receiving mechanical ventilation. we hypothesized that analysis of the immune response to pneumococci may be useful as a diagnostic approach to pneumonia etiology in children. we evaluated a new diagnostic strategy, assay of als, based on quantification of antibodies against pneumococcal proteins that are spontaneously secreted by transiently circulating lymphocytes from children with pneumonia. we were able to detect, and quantify, igg als to five specific pneumococcal proteins (cbpa, pcsb, phtd, ply, and stkpc) from children with pneumonia using a multiplexed immunoassay (fmia). concentrations of als igg to these antigens were significantly higher in supernatants from pbmcs obtained from children with pneumococcal pneumonia than table | diagnostic accuracy, using thresholds derived from the youden index, for acute igg als to pneumococcal proteins to discriminate between pneumococcal pneumonia and non-pneumococcal pneumonia in children with pneumonia in nepal (all age groups). from children with non-pneumococcal pneumonia. for children of all ages, acute igg als to the best-performing antigen (cbpa) appeared highly sensitive, and moderately specific, with an auroc curve of . , for the discrimination of pneumococcal pneumonia from non-pneumococcal pneumonia. this is considerably higher than previously reported approaches, including quantification of pneumococcal dna in blood, or in np specimens by qpcr deloria knoll et al., ) , to discriminate between children with microbiologically confirmed pneumococcal pneumonia and non-pneumococcal pneumonia, or between pneumococcal pneumonia and healthy controls. despite this reasonable performance, we observed a statistically significant association between acute igg als and age, independent of diagnostic comparator group. the limited overlap in ages between children with pneumococcal pneumonia and non-pneumococcal pneumonia made adjustment for this important confounding variable infeasible. the age distribution of children with pneumococcal pneumonia in this study was consistent with unpublished data from long-term surveillance of childhood invasive pneumococcal disease at patan hospital, but is in contrast to other sites in south asia where % or more of confirmed pneumococcal pneumonia is detected in infants (baqui et al., ; arifeen et al., ; saha et al., ; manoharan et al., ) . we therefore undertook post-hoc analysis in children ≥ years of age. in this age group, als assay to the best-performing antigen (pcsb) was unable to discriminate between children with pneumococcal pneumonia and non-pneumococcal pneumonia with an auroc curve of . (with wide confidence intervals in these data). our experience suggests that this is insufficiently sensitive or specific for clinical use. assay of acute igg als may be informative for the etiological diagnosis of childhood pneumonia in epidemiological studies, but future studies will need careful accounting for age between comparator groups. we also described the effect of np carriage of pneumococci on acute igg als in children with non-pneumococcal pneumonia. previous work has shown specific igg and iga responses can be induced through stimulation of ex vivo child adenoidal mononuclear cells with pneumococcal protein antigens. these als responses were found to be positively associated with age and serum antibody concentrations, and were higher from cells from adenoids colonized by pneumococci (zhang et al., (zhang et al., , . our data suggest that np carriage of pneumococci in pneumonia-without apparent pneumococcal disease (palkola et al., (palkola et al., , )-also induces igg secretion from antibodysecreting cells, thus confounding the utility of an als-based diagnostic approach. strengths of this study include the unselected cohort, and the breadth of clinical and microbiological data used to classify the likely etiology of pneumonia by comparator group. in april and may central nepal (including the kathmandu valley) experienced earthquakes that led to the deaths of ∼ , people in the central region of nepal, and large population movements (hall et al., ) . in addition, a severe fuel shortage and increased construction from september to february may have contributed to severe pollution in the kathmandu valley through the increased burning of biofuels (budhathoki and gelband, ) . both earthquakes and increased pollution may have affected pneumococcal pneumonia incidence at patan hospital during the study period. despite the lack of additional selection, our cohort was enriched for invasive pneumococcal disease (ipd) in comparison to similar cohorts within south asia. our cohort included children bacteremic for the pneumococcus from children ( . %). in comparison, separate studies of pneumonia in rural bangladesh [ cases of ipd from children, . % (baqui et al., ) ], severe febrile illness [ cases of ipd from , children, . % (arifeen et al., )] , and cases of ipd from a meta-analysis of , blood cultures from children ( . %) across south-east asia between and (deen et al., ) , were identified. the recently published perch study isolated the pneumococcus in cases from , children ( . %) with pneumonia (o'brien et al., ) . our cohort had a similar prevalence of ipd as among rural gambian or rural kenyan children with pneumonia [ . % (cutts et al., ) and . %, respectively (berkley et al., ) ] prior to introduction of pcv. any test for pneumonia etiology should identify children in whom there is pneumococcal infection, but no bacteremia. for this reason, and to increase the number of children available for comparator standards, we defined four children with pneumonia, high crp and np carriage of serotype as pneumococcal pneumonia (figure ) . all of these children also had consolidation on chest radiograph. we chose np carriage of serotype due to its high odds ratio for carriage in pneumonia vs. community controls ( figure s ) in our unpublished data from kathmandu, and in published data from israel (greenberg et al., ) , the uk, and south america (scott et al., ) . of children with ipd admitted to patan hospital between and , ( %) had serotype pneumococci identified. we therefore believe that class of children with np carriage of serotype and high crp as pneumococcal pneumonia has biological relevance, and internal and external validity. we focused our analysis on comparisons between children with pneumococcal pneumonia and non-pneumococcal pneumonia, rather than on discriminating between children with pneumococcal pneumonia and age-matched community controls. this substantially reduced the measured diagnostic accuracy of acute igg als to pneumococcal proteins that we present in the main text (in this study: optimum antigen auroc curve . for pneumococcal pneumonia and healthy controls; . for pneumococcal pneumonia and non-pneumococcal pneumonia in all ages; . for pneumococcal pneumonia and non-pneumococcal pneumonia in children ≥ years of age). however, testing acute igg als to pneumococcal proteins for the diagnosis of pneumococcal pneumonia, in the context of an unselected cohort of pneumonia patients (as presented here), rather than in healthy controls gives a meaningful representation of accuracy in the context in which the test would be potentially implemented. assay of als for the etiological diagnosis of pneumonia might be optimized to yield more accurate diagnostic information. reviews of b cell responses to vaccination (mitchell et al., ) and to infection (carter et al., ) suggest that the optimum time for sampling transiently circulating plasmablasts from peripheral blood is - days following the onset of illness. there are difficulties defining length of illness in children with pneumonia. nevertheless, the median length of illness prior to blood sampling in our study was days. a delay in sampling until days of illness may improve test specificity. an additional method to improve specificity of the als assay would be to sort recently activated plasmablasts for incubation using flow cytometry. however, separation, washing, and incubation of pbmcs to generate and store als requires reagents (ficoll-paque) and equipment (centrifuges, incubators with co , and − • c freezers) that are not readily available in routine microbiology laboratories. the use of flow cytometry would limit the potential availability of this test further. finally, although we described a high degree of co-linearity in acute igg als to the pneumococcal proteins measured, a larger array of pneumococcal antigens might be considered to optimize als cognate antigens using variable selection methods (zou and hastie, ; darton et al., a) . quantification of als to pneumococcal capsular polysaccharides may also enable serotype-specific measure of pneumococcal pneumonia burden to inform vaccination strategies (tuerlinckx et al., ) . a major limitation of any study of pneumonia etiology is the lack of a "gold standard." blood culture is presumed to be specific, but insensitive, for bacterial pneumoniaa "silver standard" (wu et al., ) . we used a series of comparator groups ("standards") against which to test the als assay. in this cohort, the low prevalence and different age distribution of confirmed pneumococcal pneumonia cases, in comparison to other pneumonia cases, limited our measures of the diagnostic accuracy of als between comparator groups. assay of als was also confounded by the association of acute igg als with np carriage of pneumococci. diagnostic accuracy of als assay may be better in studies of pneumonia of other etiology (notably rsv pneumonia), where reasonably accurate diagnostic tests already exist with a high positive and negative predictive value for disease, as a point of comparison. despite the high prevalence of pneumococcal pneumonia in the cohort relative to other studies (baqui et al., ; arifeen et al., ; deen et al., ; o'brien et al., ) , the majority of children in the study ( %) were designated as probable bacterial pneumonia or unknown pneumonia. in a cohort that were largely unvaccinated with pcv, only children had invasive pneumococcal disease, with a further children with probable pneumococcal pneumonia. many comparisons were therefore underpowered. although this limits the ability to fully assess assay of igg als for the diagnosis of pneumococcal pneumonia, at a minimum, a clinically useful test should be "positive" in cases of ipd (the silver standard). our data show that this was not the case, with low igg als assay in of children with pneumococcal bacteremia (figure ) . in summary, we detected spontaneously secreted antibodies to pneumococcal proteins from pbmcs isolated from a figure | acute igg als to pcsb by comparator group in children ≥ years of age. the dotted horizontal line represents a threshold of . units/ml, the threshold derived from the youden index. the proportion of children with acute igg als to pcsb concentration greater than, or equal to, the threshold derived from roc curve analysis to discriminate pneumococcal pneumonia from non-pneumococcal pneumonia is annotated. proportion of children with pneumonia in nepal using the als assay. concentrations of igg als to the pneumococcal proteins cbpa, pcsb and phtd were higher in children with pneumococcal pneumonia than non-pneumococcal pneumonia, with good ability to discriminate between groups. however, these results were confounded by different age distributions of children with pneumococcal pneumonia and non-pneumococcal pneumonia. assay of als to pneumococcal proteins did not discriminate between these groups when stratified by ≥ years of age. our data suggest that assay of igg als to pneumococcal proteins is not sufficiently accurate as a diagnostic test for clinical utility. alternative new diagnostic tests for the cause of childhood pneumonia should be sought. the datasets generated for this study are available on request to the corresponding author. the studies involving human participants were reviewed and approved by nepal health research council and the oxford tropical research ethics committee. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. consortium (https://www.perform .org/) supported pcr identification of np viruses. we also thank reviewers for helpful comments. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fcimb. . /full#supplementary-material figure s | odds ratios for nasopharyngeal carriage of pneumococcal serotypes contained within -valent pcv and non-typeable (nt) pneumococci in pneumonia and community control children, adjusted for age and sex, prior to introduction of the vaccine into the kathmandu valley. error bars show % confidence intervals. figure s | acute igg als to pneumococcal proteins by children with pneumococcal pneumonia and healthy infant controls. dashed horizontal lines represent represent thresholds derived from the youden index, p-values were derived from the wilcoxon rank sum test. for all box and whisker plots: the solid line represents the median value, lower hinge th centile, upper hinge th centile, and whiskers represent . times the interquartile range. all data points have also been plotted. figure s | linear regression analysis of length of illness with acute igg als to pneumococcal proteins (grey colouring represents % confidence intervals about the regression line; p-value > . for all proteins). figure s | acute igg als to pneumococcal proteins in children with non-pneumococcal pneumonia by nasopharyngeal carriage of 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carriage status immune responses to novel pneumococcal proteins pneumolysin, pspa, psaa, and cbpa in adenoidal b cells from children regularization and variable selection via the elastic net we thank all of the children, and their parents, who participated in this study; and the clinical teams at patan hospital who gave unstinting help. phtd was kindly supplied by sanofi pasteur key: cord- -e pgjynr authors: cevey-macherel, manon; galetto-lacour, annick; gervaix, alain; siegrist, claire-anne; bille, jacques; bescher-ninet, béatrice; kaiser, laurent; krahenbuhl, jean-daniel; gehri, mario title: etiology of community-acquired pneumonia in hospitalized children based on who clinical guidelines date: - - journal: eur j pediatr doi: . /s - - -y sha: doc_id: cord_uid: e pgjynr community-acquired pneumonia (cap) is a major cause of death in developing countries and of morbidity in developed countries. the objective of the study was to define the causative agents among children hospitalized for cap defined by who guidelines and to correlate etiology with clinical severity and surrogate markers. investigations included an extensive etiological workup. a potential causative agent was detected in % of the enrolled patients, with evidence of bacterial ( %), viral ( %), and mixed ( %) infections. streptococcus pneumoniae was accounted for in % of cap. dehydration was the only clinical sign associated with bacterial pneumonia. crp and pct were significantly higher in bacterial infections. increasing the number of diagnostic tests identifies potential causes of cap in up to % of children, indicating a high prevalence of viruses and frequent co-infections. the high proportion of pneumococcal infections re-emphasizes the importance of pneumococcal immunization. which both pneumonia and viral lower respiratory tract infections are common conditions. the world health organization (who) has defined pneumonia and subsequent treatment on strict clinical signs (table ) [ , , ] . a prospective study showed that the who guidelines can also be applied in developed countries, as recommended by the guidelines of the british thoracic society (bts) [ , ] . the second difficulty is to identify the causative agent of pneumonia in children. this remains challenging for a number of reasons: endo-tracheal aspirates cannot be obtained routinely, nasopharyngeal swabs (ns) only show colonization by normal flora including the bacteria most commonly causing pneumonia, and bacteremia is demonstrated in less than % of bacterial cap. therefore, the etiology of cap remains often unknown, with the consequence that many children get an antibiotic treatment for non-bacterial infections, contributing to the increase of bacterial resistance to antibiotics [ , ] . the aims of this study, performed before the routine implementation of the heptavalent pneumococcal vaccine in switzerland, were to define, as strictly as possible, the causative agents of pneumonia among children aged from months to years hospitalized for cap on the basis of who clinical criteria, and to determine which factors could help clinicians to discriminate bacterial from viral pneumonia. participation to this prospective and descriptive study was offered to all consecutive children aged months to years old presenting with cap according to the who criteria (table ) consecutively admitted to the children's unit of the university hospitals of lausanne and geneva between march and december . they were classified according to initial severity. children with actively treated asthma, an underlying chronic disease, immunosuppression, or wheezing were excluded. children with wheezing were specifically excluded because wheezing is considered to be a symptom of asthma and/or viral bronchiolitis and not of pneumonia, and therefore these children are not treated with antibiotics. cough and fever, associated signs and symptoms, the use of antibiotics in the month before admission, and the main features of the clinical course were recorded. the ethical committees of both institutions approved the study protocol. signed consent was obtained from informed parents. on admission, a blood sample was taken for total white blood cell count (wbc) with manually verified differential count. serum crp and pct (lumitest®, brahms, berlin, germany) were measured. a senior radiologist, blinded to clinical and laboratory findings, reviewed all chest radiographs and assigned a standardized description of the x-ray as proposed by the who working group [ ] : the presence of consolidation or pleural effusion with parenchymal infiltrate defined pneumonia. on admission, before starting an antibiotic treatment, peripheral blood cultures, and during the winter epidemic, a rapid antigen detection test for rsv (coris or becton dickinson), were performed. within h after admission, nasopharyngeal aspirates (npa) were obtained after respiratory physiotherapy for viral and bacterial culture, pcr analysis, and viral antigen detection. pcr analysis was performed for mycoplasma pneumoniae and chlamydia pneumoniae. rt-pcr assays were performed for viruses including influenza a and b, rsv a and b, rhinovirus, parainfluenza - , enterovirus, human metapneumovirus, coronavirus oc , e , and nl as previously described [ , , ] . in the present study, all the assays were used as qualitative tools. pcr for m. pneumoniae and c. pneumoniae were done by a multiplex real-time pcr according to welti et al. [ ] . viral antigen detection was performed for adenovirus, para-influenza - , rsv, and influenza a and b by indirect immunofluorescence (argene antibodies) or elisa. serum samples were taken at admission and approximately weeks after hospitalization, then stored at − °c and subsequently transported on dry ice to the laboratories. the laboratory was unaware of clinical data. antibodies for influenza a and b; parainfluenza , , and ; rsv; adenovirus; and m. pneumoniae were detected by the complement fixation method. paired samples were tested in the same run. acute infection was defined by a fourfold rise or a titer higher than / . serologic tests for c. pneumoniae were done by using a micro-immunofluorescence test (mrl diagnostics). a fourfold rise between the acute and convalescent sera or an initial titer higher than fourfold the positive cut off value ( : ) were considered as indicative of a recent infection, as previously described [ ] . serum igg antibodies to pneumolysin were measured by indirect elisa on antigen-coated immulon plates (thermo labsystem), following min incubation at °c. results were compared to a pool of purified human immunoglobulins (endobulin, baxter) used as standard and expressed in elisa units/ml. samples with a rise greater than twofold between acute or convalescent sera and/or acute serum antibody titers greater than eu/ml were scored positive. these limits have been previously demonstrated to be a reliable method for the serological diagnosis of pneumococcal exposure [ , ] . the blood samples were taken at the time of admission and sera were frozen at − °c in order to be analyzed in a second phase. the detection of s. pneumoniae was performed by real-time pcr with the taqman method. the specific target was the pneumolysin gene. briefly, µl of blood specimen were pre-lysed with μl of lysis buffer (bacterial lysis buffer, roche diagnostics) and with μl of a cocktail of enzymes (lyt enzymmix, roche diagnostic). after an incubation period of min at °c, the sample was automatically extracted with a magna pure compact instrument using the magna pure compact isolation kit i. five microliters of the eluted dna were then amplified in triplicate with a taqman abi prism sequence detector (applied biosystems). any significant curve before the cycle , was considered as a positive signal, the positive cut off was defined as , copy/ml [ , , ] . the criteria for viral infection were a positive viral culture, viral antigen, positive viral serology, or viral pcr. a bacterial infection was considered if a blood culture, a pleural fluid culture, a pneumococcal pcr, or a serologic assay was positive. atypical and typical bacteria were grouped together. subjects with criteria of both viral and bacterial infections were considered to have infections of mixed etiology. patients were treated with a course of parenteral antiobiotics first (cefuroxime (n = ), ceftriaxone (n = ), amoxiclavulanic acid (n= ), floxapen (n= )), followed by oral antibiotics (amoxiclavulanic acid or cefuroxime) for a total duration of to days. parenteral cefuroxime was initially associated with clarithromycin in four patients or switched for vancomycin and amoxyclavulanic acid or for amoxycillin and clindamycin in two patients with pleural effusion. data were analyzed using epi info . d (center for disease control and prevention, atlanta, ga, usa). standard parametric and non-parametric statistical tests were done according to distribution and variance of studied variables. the level of statistical significance was defined as p≤ . . kappa statistics were computed using pairs module, version . , of pepi for windows software. a total of children were eligible during the study period. ninety-nine children were finally enrolled (six patients were excluded because of the impossibility to obtain samples and, after initial consent, five parents decided to interrupt the study). among these patients, were females ( % although there was a large variation in the number of monthly hospitalizations, no clear seasonal pattern was observed. the average duration of hospitalization was days ranging from a few hours to days. twenty-six children ( %) required supplemental oxygen therapy, nine patients ( %) needed a gastric feeding tube, and nine ( %) a thoracic drainage. three patients were transferred to the pediatric intensive care unit, two of them requiring noninvasive assisted ventilation (table ) . overall results table shows the number of samples obtained for each test. viral and atypical bacterial serology, were the most difficult to obtain (follow-up blood sample), as well as nasopharyngeal aspirates (npa), notably in children without upper respiratory tract involvement. a potential causative agent was detected in ( %) of the patients. evidence of bacterial infection alone was demonstrated in patients ( %) and viral infection alone in ( %) cases. mixed bacterial-viral infection was found in ( %) patients (fig. ) . only one patient had a positive blood culture (s. pneumoniae), while three other blood cultures were contaminated by a coagulase-negative staphylococci. one patient had a group a β-hemolytic streptococcus in pleural fluid culture. overall, bacteria with or without co-infecting pathogens were identified in % of the cases ( patients). pneumococcal pneumonia was diagnosed in patients (table ). overall, among the children ( %) had evidence of an acute viral infection ( fig. ; table ). pcr was very sensitive to detect several viruses. in no patient with a negative viral pcr, could a viral infection be detected using another method. there was a significant relationship between age and etiological category ( table ) . excluding patients with undetermined etiology, univariate analyses showed that dehydration was the only clinical sign significantly more represented in the bacterial group of pneumonia. indeed, % of children with bacterial pneumonia, while only % in the mixed group and % in the viral pneumonia group (p= . ), showed signs of dehydration, ( table ). other symptoms were not significantly associated with etiology. in particular, urs were not significantly more frequent in the viral group. the proportion of patients in each clinical severity category (who stages) did not differ significantly according to etiology (p= . ). analysis of laboratory data showed that children with bacterial pneumonia overall had higher inflammatory parameters: crp and pct values were significantly higher in the bacterial pneumonia group when mixed and bacterial pneumonia were analyzed together (table ). however, inflammatory indices were not statistically associated with clinical severity. for a cut off level of mg/l the sensitivity of crp was % but the specificity was low ( %). for a cut off level of ng/ ml the sensitivity of pct was % and the specificity %. total white blood cell count and band forms were not significantly associated with etiology. the proportion of children treated with antibiotics before hospitalization, did not differ according to the etiological category (chi square, p=. ). the average duration of hospitalization was related to clinical severity. on admission, breath sounds were described as completely normal in ( %) patients. in patients with abnormal auscultation, the most constant sign was diminished breath sounds ( patients). chest x-ray was abnormal in of patients ( %). radiological consolidation was present in ( %) patients. overall percent agreement between the presence of diminished breath sounds and radiological consolidation was . % with a kappa coefficient of . ( % ci- . to . ), confirming very poor agreement. there was no association between radiological description and severity or etiology of pneumonia. one hundred and eleven immunocompetent children, aged between months and years old, hospitalized for pneumonia, were studied prospectively to elucidate the [ , , , ] . evidence of bacterial infection was demonstrated in % of patients. s. pneumoniae was documented in % of the cases, corroborating previous reports such as the one by michelow et al. [ ] . a virus was found in % of the children. in % of the cases, a concurrent bacterial and viral infection was found. antibiotic treatment before hospitalization doesn't seem to be a factor of misdiagnosis. our study showed that in children fulfilling the who clinical definition of pneumonia and severity criteria, diagnosis was confirmed by radiological consolidation in % of cases. the poor agreement between auscultation and radiological consolidation confirms the poor sensitivity and specificity of auscultation to diagnose pneumonia in young children [ ] . as previously described [ , ] chest x-ray and blood cultures were not helpful in discriminating etiological categories of pneumonia. duration of hospitalization was correlated with clinical severity essentially because who criteria define children with stage iii pneumonia as requiring oxygen supplementation. pain was the only clinical sign significantly associated with bacterial pneumonia. acute-phase surrogate markers such as crp and pct, were significantly higher in bacterial infection regardless of the presence or absence of co-infecting viruses, corroborating several previous analyses [ , , ] even if these findings are controversial in recent literature [ ] . further analysis is needed to determine the exact utility of these tests, as the sensibility and specificity with a bacterial cut off level were quite low. finally, our data could not show a significant correlation between clinical severity and etiology of pneumonia [ ] . as reported previously [ , , , ] , our data confirm the high prevalence of viruses and showed the frequent occurrence of co-infection in childhood cap. the viruses most commonly found were rhinovirus ( %) and hmpv ( %), confirming the recent findings that these viruses frequently involved in pediatric cap [ , , , ] . rsv was less represented than in other reports [ ] , probably because all patients with typical bronchiolitis were strictly excluded. several points still have to be elucidated: whether viruses are the direct cause of pneumonia, whether they the main limitation to our study is the lack of validation and standardization of all microbiological cut off values, especially those concerning s. pneumoniae [ ] . one of the major obstacles to improve the understanding of cap is probably that we are still underdiagnosing pneumococcal and possibly other bacterial pneumonia. the use of a single antigen (pneumolysin) for the serological diagnosis of pneumococcal pneumonia may be a limitation, as well as the difficulty, in our study, to obtain convalescent serum samples (available for only % of the children). therefore, it remains difficult to distinguish a real acquired infection from a recent colonization. as recently described by nakayama et al. [ ] , the use of pcr to detect bacterial pneumonia could be a useful additional diagnostic method. however, the fact that % of young children with cap requiring hospitalization demonstrated evidence of an acute pneumococcal infection, is in accordance with the demonstrated impact of pneumococcal immunization [ , , , ] . finally, our results do not support the hypothesis that clinical severity depends on the causal agent. however, for ethical and practical reasons we chose to study only hospitalized children. therefore, we have a limited number of patients with stage i pneumonia whom we usually treat in the ambulatory setting. a further study should include this group in order to confirm, with a greater number of patients, the non-association between clinical severity at admission and etiology. in conclusion, this study used strict who clinical criteria to select suitable subjects to undergo an extensive microbiological etiological workup using a complete set of modern diagnostic tools. 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organization that partly sponsored the research and no conflicts of interest.