key: cord-010078-8lkkez3n
authors: nan
title: Invited Speakers
date: 2010-11-24
journal: Respirology
DOI: 10.1111/j.1440-1843.2010.01863.x
sha: 
doc_id: 10078
cord_uid: 8lkkez3n

nan

The physiology of respiration reaches its extreme limits when man is exposed to the effects of high altitude, which is basically a decrease in ambient pressure and temperature. The process of acclimatization of humans to high altitude occurs within minutes of ascent, starting with increases in cardiac output, and ventilation. These result in acute changes in PaO 2 and PaCO 2 . Slower changes of acclimatization include increase in hemoglobin concentration (polycythemia), and muscle capillarity, but decrease in mitochondrial volume density and cellular aerobic capacity. Through acclimatization, animals and human inhabitants of high altitude areas have developed adaptations that allow them to function as near normal as those living at sea level. Humans who undergo acute ascent to high altitude could acclimatize, but some fail to do so. If there is failure to acclimatize, Oxygen diffusion impairment results, due to decreased partial pressure, and lower affi nity of Hb for oxygen. In addition, there is signifi cant increase in ventilation/perfusion heterogeneity. The resulting hypoxia leads to hypoxic pulmonary vasoconstiction (HPV) which results from multiple components: changes in epithelial cell wall that lead to intracellular calcium increase and/or calcium sensitization. Subsequently, pulmonary hypertension develops, with actual breaks in the capillary endothelium leading to an infl ammatory process (seen more during exercise), and decrease in alveolar fl uid clearance. These mechanisms contribute to the development of alveolar edema, High Altitude Pulnary Edema (HAPE), which is one of the two major diseases due to Acute Mountain Sickness (AMS). Both HAPE and the other AMS, High Altitude Cerebral Edema (HACE) could be potentially fatal, and must be recognized and treated early. Knowledge of the pathophysiology of the AMS would allow more rational approaches to their prevention and treatment. High altitude illnesses can develop among healthy individuals who sojourn for recreation and work: cerebral form called acute mountain sickness (AMS) and potentially fatal pulmonary form called high altitude pulmonary edema (HAPE). AMS is generally self-limited. High-altitude cerebral edema (HACE) is likely a continuum of AMS and the end-stage of AMS. AMS is not a precondition for the development of HAPE. HAPE develops in non-acclimatized mountaineers after rapid ascent to altitudes above 2500 m. HAPE may develop even in the absence of AMS. Severe AMS may be a risk factor for HAPE. The altitude, the rate of ascent to new altitude, (>300 m/day to an altitude above 4000 m), and individual susceptibility are major determinants of AMS and HAPE. On ascent to high altitudes all people have swelling of the brain. Patient with AMS often experience "hangover headache." Other symptoms occur within the fi rst 6 to 36 h. These include malaise, anorexia, nausea and vomiting, and insomnia. AMS patient must be evaluated for signs of global encephalopathy rather than focal fi ndings, although retinal hemorrhage is commonly seen. When these are present, the subject has HACE until proven otherwise. Patient may die if not treated promptly. Brain herniation is the usual cause of death. The hallmark of HAPE is an excessively elevated PAP which precedes the development of pulmonary edema. Symptoms are incapacitating fatigue, chest tightness, dyspnea with effort, orthopnea, cough, and pink frothy sputum in advanced stage of disease. Prevention of all altitude complications requires ascending at an increment rate to allow acclimatization. At >3000 m, one should not spend subsequent nights 300 m higher than the previous night. Trekker must take a rest day every 2 to 3 days. Anyone with AMS should not ascend until symptoms are resolved. Acetazolamide and Dexamethazone are effective in prevention and treatment of AMS from proceeding to HAPE or HACE. At the fi rst sign of HACE, patients should descend to a lower altitude while supplementary oxygen is given. Increasing oxygenation is the highest priority in the treatment of and prevention of HAPE. If supplemental oxygen is unavailable, then descent, use portable hyperbaric chamber, or both become lifesaving. Nifedipine is necessary only when supplemental oxygen is unavailable or descent is impossible. Because of its pulmonary vasodilatory effects, phosphodiesterase inhibitors can be used for prevention and treatment of HAPE. Rudolf Virchow in 1856 described that the 3 determinant risk factors for venous blood clot formation are stasis, endothelial injury and hypercoagulable state. Dr Simpson et al 1940, a British surgeon observed that during the London Blitz, the World War II, Britons who were forced to remain on sitting in cramped position and deck chairs for hours during the air raids developed fatal pulmonary embolism. It was suggested in 1954 by Homans that "prolonged dependency stasis" or immobilization is one factor that predisposes patients to develop thrombosis in the deep veins of the legs. Several risk factors have been identifi ed for developing venous thromboembolism (VTE). Travel is one of the transient risk factors. It is not confi ned to one mode of travel such as air travel. It is also incriminated to other modes of land travel such as car, bus and train. The term "economy class syndrome" was proposed by Symington and Stock (1966) and by the group of Cruickshank (1988) for venous thromboembolism occurring in patients during air fl ight travel. It is usually seen in patients sitting in limited or cramped circumstances in the economy coach or tourist class seats, however it is also found out that patients who were also seated in the business class also develop this syndrome. Factors implicated were the long duration of travel, immobilization or inactivity in sitting position, and the low cabin pressure, low humidity and dehydration during air fl ights. In several studies performed on large airports in Europe, the presence of genetic factors such as Factor V Leiden and environmental factors such as the use of oral contraceptives predispose patients several fold to develop venous thromboembolism. Signs and symptoms pertaining to VTE develop not only during and after the fl ight but also several weeks after the travel. Nowadays, airlines as well as bus companies have advisories and measures impose to prevent development of VTE and deaths due to VTE during the travel period.

With the steadily increasing use of air travel, more and more patients with pulmonary disease are fl ying long distances, at high altitude in partially pressurised aircraft. This is associated with long periods of reduced mobility and exposure to reduced inspired pressures of oxygen and reduced barometric pressure. Some individuals therefore may be at risk of barotrauma, hypoxia or venous thrombo-embolism (VTE). Therefore it is important to identify these individuals and adequately assess the real risk entailed by fl ying. The effect of reduced atmospheric pressure is a potential risk for patients with recent or pre-existing pneumothorax but otherwise is unlikely to be associated with risk other than that due to the associated reduced inspired oxygen fraction (FiO 2 ), typically 0.15 (15%) in a commercial aircraft at cruising altitude. The reduced (FiO 2 ) may be problematic for patients with hypoxic lung disease or in patients with other co-morbidities that may exacerbated by hypoxia. Medical history, lung function and resting oxygen saturation will help identify patients at risk although it is diffi cult to predict the clinical effects of altitude from tests (even hypoxic challenge tests) conducted at sea level. There is currently a lack of good data defi ning the clinical outcomes due to hypoxia during fl ight in patients with lung or other diseases. The risk of VTE increases with duration of fl ight above four hours, presumably related to the duration of immobility, although the role of prolonged hypoxia remains to be determined. Preventive measures are now currently invoked on most airlines and guidelines for the use of antithrombotic agents are available, stratifi ed by risk. It is anticipated that guidelines will continue to be updated as new data are made available. Cardio-pulmonary exercise testing is now well accepted as an appropriate test for the investigation of shortness of breath on exertion. In addition the test has been found to be useful for the assessment of pulmonary vascular dysfunction and the assessment of fi tness for major thoracic surgery. Even though there are well described and internationally accepted protocols to perform the test, the interpretation of a cardio-pulmonary exercise test often leaves the interpreting physician confused. Importantly with the multiple facets of the test (respiratory, cardiac, peripheral vascular) that need to be interpreted it is easy for the interpreting physician to look at a certain aspect of the test relating to their specialty and to give the other facets relatively little attention. In this presentation we review the process of interpreting cardio-pulmonary exercise tests. In addition we will interpret a number of tests based on our previous discussion on how to interpret these tests. Finally we will review the literature regarding new interpretive strategies for exercise induced pulmonary vascular disease. Bronchoscopy as an IMAGE-GUIDED INTERVENTION has benefi tted from advances in optical and non-optical imaging technologies. Some current bronchoscopy advances incorporate higher resolution CCD (Charged-couple Device) digital-"Chip" technology and magnifi cation lenses to enhance the image resolution. The hope is that improved visualization combined with analysis of concomitant tissue biopsies may realize so-called "In-vivo endoscopic diagnosis" without the need for tissue biopsies, however studies of highmagnifi cation endo-cytoscopy, co-focal micro-endoscopy and Optical Coherence Tomography (OCT) remain investigational. Further limiting these near-histologic resolution imaging modalities is the need for an initial screening of "highly suspicious" mucosa to focus attention upon. To facilitate identifi cation of abnormal airway mucosa, there are advances in the bronchoscopic detection of dysplastic and malignant mucosa. Newer generations of Autofl uorescent (AF) bronchoscopes combine video CCD technology with AF signaling to enhance the visual resolution of the images. Non-AF technologies being evaluated for the same purpose include fi ltered-light Narrow Band Imaging (NBI) and post image-capture processing by a number of other Spectral Estimation Technologies (SET). Bronchoscopic Image Guided Interventions (BIGI) also benefi tted from advances in non-traditional bronchoscopy technologies. Foremost has been Endobronchial Ultrasound (EBUS), initially designed as radial probes modeled after Intravascular US and modifi ed for the airways. While useful in advancing our understanding of endobronchial mucosal structure, predicting tumor invasion depth and responsiveness to endobronchial interventions, radial EBUS did not permit REAL-TIME guidance. Dedicated Linear-array EBUS bronchoscope has changed this dramatically as the 7.5 MHz needle-puncture EBUS bronchoscope has increased diagnostic accuracy of peri-bronchial lymph nodes/masses from a previous average of <50% to >90% for even small targets (<1 cm) in experienced hands. Simultaneously miniaturization of radial EBUS probes (thin 1.4 mm) and incorporation of guide-sheaths have increased the utility of EBUS in evaluating parenchymal lung pathology. Concomitant work in Image processing of radiology imaging data (DICOM data of chest CT images) has made available a number of "Virtual Bronchoscopic Navigation" programs to assist the bronchoscopists in navigating towards smaller peripheral focal targets, and to improve the historic diagnostic yield of smaller (<2 cm) peripheral nodules from 20-30% up to 65-80%. These systems include passive endobronchial "road-maps" view (similar to "MapQuest"/"Google Earth") and more technology enhanced Electromagnetic Navigation Bronchoscopy (ENB) (similar to GPS guidance). All these ancillary technologies have spurred improvements in the basic bronchoscope, as thinner bronchoscopes capable of reaching peripheral segments (2.8 mm and 3.5 mm with 1.2 mm working channel; 4.0 mm with 2.0 mm working channel) are coupled with new biopsy instruments. The eventual development of steerable single fi ber scanning endoscopes with multi-wavelength imaging may change our current concepts of the bronchoscopes and how we can use them.

Journal Compilation © 2010 Asian Pacifi c Society of Respirology PG 03-02

Diagnostic Tests Pleural effusions are common and often present diagnostic challenges. The new British Thoracic Society guidelines 2010 on investigation of pleural effusions detailed some of the new approaches to undiagnosed pleural effusions. Traditional teaching recommends measurement of blood and pleural fl uid protein and LDH levels as the fi rst step of investigation to categorize the effusion into a 'transudate' and 'exudate' using Light's criteria. The need to apply this to all effusions is questionable in 2010. Current efforts focus on the development of disease-specifi c diagnostic tools incorporating clinical, radiologic and biochemical parameters.

• Elevated NTpro-BNP levels in pleural fl uids are useful in confi rming cardiac failure as the etiology of a pleural effusion, especially in patients whose fl uid may be falsely elevated into the 'exudative' range by concurrent diuretic therapy.

• Pleural NTpro-BNP levels are elevated in cardiac failure effusions, but not in other transudative effusions (eg hepatic hydrothorax).

• Pleural fl uid NTpro-BNP appears a better marker than pleural fl uid BNP. Variations in accuracy may also in part depend on the commercial kits used. Adenosine Deaminase:

• ADA measurements in pleural fl uids are useful in the diagnosis of TB pleural effusions with a sensitivity and specifi city of 92 and 90% respectively. Limiting the test to lymphocytic pleural effusions will further improve the diagnostic accuracy.

• ADA is cheap and fast to perform and is now widely used in endemic countries. False positives can occur with bacterial infections, rheumatologic effusions, and occasionally malignant effusions. False negatives are uncommon, and therefore present a valuable 'rule-out' test in regions of low TB rates.

• ADA is at least as diagnostically useful as pleural fl uid total interferon-gamma levels.

• IGRAs have been tested in pleural fl uid and blood of patients with TB pleural effusions in several studies. The diagnostic sensitivity and specifi city are poor and IGRAs are not recommended for the investigation of TB pleuritis.

• Serum mesothelin is a FDA-approved test for the diagnosis and monitoring of mesothelioma. • Pleural fl uid mesothelin adds information to pleural fl uid cytology in the diagnosis of mesothelioma, providing a diagnostic sensitivity of 71% (specifi city 90%). Elevated pleural fl uid mesothelin levels suggest epithelioid or biphasic mesothelioma or occasionally metastatic carcinomas. Procalcitonin:

• Early evidence suggest that serum level of procalcitonin may aid differentiation of pleural infection from pleural effusions of non-infective etiologies. The value of pleural fl uid procalcitonin level is limited. Management Strategies Imaging guidance for pleural procedures:

• Pleural procedural complications are often under-estimated and underreported. Studies have now shown that mandatory imaging guidance (especially bedside pleural ultrasound), and restricting procedural privilege to certifi ed trained clinicians can signifi cantly reduce complication rates from pleural procedures. This practice is now incorporated into many national and professional society guidelines. Intrapleural therapy for Pleural Infection/Empyema: • Recent clinical trials on intrapleural delivery of fi brinolytics alone have failed to improve important clinical outcomes of pleural infection. However, the combination of tissue plasminogen activator and DNase has shown promising results.

• Recent studies have revealed increasing concerns of complications of talc pleurodesis, and randomized studies have shown a much lower success rate than previous non-randomized literature, even in selected patients. The concept of drainage without needing to create pleurodesis has growing appeal and the use of indwelling pleural catheters is now regarded as fi rst-line therapy in increasing number of centers. Chronic respiratory disease (CRD) is non-communicable respiratory disease including asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, idiopathic pulmonary hypertension, hypersensitivity pneumonitis, occupational respiratory disease. Among these CRD asthma and COPD are important for regional health. Facts of asthma 300 million people suffer from asthma. 255,000 people died of asthma in 2005. Prevalence of asthma has increased or is increasing. Asthma is the most common disease among children Over 80% of asthma death occurs in low and lower-middle income countries. Asthma is underdiagnosed and under-treated (WHO, 2010). Facts of COPD COPD is a life-threatening lung disease that interferes with normal breathing. It is more than a "smoker's cough". An estimated 210 million people have COPD worldwide. More than 3 million people died of COPD in 2005, which is equal to 5% of all deaths globally that year. Almost 90% of COPD deaths occur in low-and middle-income countries. The primary cause of COPD is tobacco smoke (through tobacco use or second-hand smoke). The disease now affects men and women almost equally, due in part to increased tobacco use among women in high-income countries. COPD is not curable, but treatment can slow the progress of the disease. Total deaths from COPD are projected to increase by more than 30% in the next 10 years without interventions to cut risks, particularly tobacco smoking (WHO, 2010).

Prevention and Control of CRD in Asia Pacifi c were held by Dokkyo Medical University group, later designated as WHO Collaborating Centre for Prevention and Control of CRD (DU-WCC). Seven countries and a district in Asia Pacifi c joined the meeting. Prevalence of asthma in adults was reported from 0.99 to 7.2% with a median of 4.0% based on 13 reports. Prevalence of childhood asthma (13-14 y/O) was from 0.8 to 13.2% with median of 7.7% based on 13 reports. Prevalence of COPD was 3.5 to13.1% with a median of 7.1% based on 9 nation-wide surveys. In spirometry-based survey reported, prevalence of COPD was 8.5% in adults 40 years and over in Japan, 8% in adults 45 years and over, and 8.2% in adults 40 years and over in China. Management In most of the countries GINA and GOLD were adopted for their national guidelines. Major risk factors for CRD, especially for COPD were smoking and indoor air pollution for cooking/heating. Pharmacological early interventions have been reported to improve the prognosis of asthma and COPD. Occupational respiratory diseases are disorders which are induced by occupational and industrial conditions. Providing information of the risks of industrial activities would reduce this disorder. Strategic direction for the prevention and control of CRD Most of CRD are treatable and at least partially preventable. Development of user-friendly guides for prevention and control of CRD for offi cials in health care, fi rst-line health-care givers and patients and their family and its implementation would decrease the burden of these CRD. The scientifi c foundation of asthma diagnosis and management has grown in leaps and bounds. Evidence-based strategies to control asthma and treat its exacerbation are published yearly in the GINA guidelines. The 10-year Finland study showed that these strategies work. While cases treated did increase (through better detection), the hospital days and cost per case markedly decreased. The study also showed that widespread adaption and effective implementation of these strategies is best done through a national program. CMEs for medical practitioners are important but are of limited reach. All stakeholders must be enlisted to buy-in. For asthma, the target stakeholders are the health care personnel, nurses and village health volunteers included; the patients and their families; the government and its public health offi cials; the asthma advocacy groups; the community-at-large; and the pharmaceutical Industry. The idea is to present the problem to them, include their inputs in the formulation of the plan, collegially decide on target indicators of success and engage them to work for the implementation of the program in the context of what each one can do best. Duplicating the Finnish experience is a big challenge in the Asia Pacifi c Region. While most countries have their own adaptation of the GINA guidelines, few have working national asthma programs. In developing economies, the health infrastructure is not that well developed yet to absorb all guideline recommendations. Spirometry may not be widely available nor affordable. Government spending for health is commonly below the 5% of GDP level that WHO recommends. In the Philippines, signifi cant out-of-pocket health expense is borne by the patient. Furthermore, programs like TB control, dengue treatment and malaria eradication, which are no longer concerns in developed countries, compete for the meager public health funds. For low income countries, the international recommendations may have to be rewritten to emphasize on simple algorithm for separating non-infectious from infectious respiratory illnesses; practical objective measurements for diagnosis and management such as peak fl ow; available, affordable, and low-risk medications recommended for asthma control; and a simple regimen for recognizing severe asthma (GINA). To be viable, the national asthma program will have to piggy back to the existing national health delivery infrastructure which must ensure, among others, access to free or cheap medication. Lung cancer and COPD commonly coexist in smokers, and the presence of COPD increases the risk of developing lung cancer. In addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, to develop new methods of prevention, diagnosis and treatment of lung cancer and COPD. Common mechanisms may involve infl ammation, abnormal repair, oxidative stress, epithelial-mesenchymal transition, altered nicotine receptor biology and epigenetic alterations. Strategies to study genomics and epigenomics, in addition to gene-environment interaction, will yield greater insight into the shared pathogenesis of lung cancer and COPD. COPD clinical guidelines are important to guide diagnosis and management of people with COPD. The Australian 'COPDX' guidelines are evidence-based guidelines that are prepared by the Australian Lung Foundation and Thoracic Society of Australia and New Zealand. Relevant literature is searched regularly and evaluated by a clinical committee. Updates are then produced regularly during the year. Challenges regarding critical appraisal, resources and dissemination to clinicians will be discussed. National COPD guidelines in this region are different from country to country, but basically are adapted from GOLD. COPD prevalence in 12 Asia Pacifi c countries and region estimated by regional COPD working group was 6.3%. Vietnam has the highest prevalence: 6.7%. The COPD management and guideline implementation problems in the Asia Pacifi c region are: smoking, biomass using are common; continuous medical education (CME) for health workers are not compulsory; lack of device and personnel for performing proper spirometric tests; over burden for health workers; low access to medical care and low affordability for COPD medications.

All of these problems result in that COPD diagnosis are mostly in late stage, high rate of emergency room visit, ICU admission and hospitalization. The consensus is expected to cover following resolutions: reducing the smoking and biomass smoke exposure, screening for COPD in large scale using questionnaires and confi rming by spirometry, advocacy for compulsory CME on COPD, establishing asthma and COPD outpatient care unit (ACOCU) in different levels of health care settles and introducing COPD medications into insurance medication list. Infections caused by environmental mycobacteria are more common than tuberculosis in many parts of the world. The more than 120 species of mycobacteria have similarities, but generally the diseases and hosts fi t in specifi c patterns. Disease due to environmental mycobacteria can be diffi cult to diagnose and treat and can confuse workup for tuberculosis. Mycobacteria have low virulence and even lower invasiveness. They form biofi lms that protect them and allow long term persistence. The treatment is often frustrating for the patients and physicians. Learning their metabolic mechanisms and attacking them should be the strategy for combating the disease caused by these organisms. Lung cancer and COPD commonly coexist in smokers, and the presence of COPD increases the risk of developing lung cancer. In addition to smoking cessation and preventing smoking initiation, understanding shared mechanisms in these smoking-related lung diseases is critical, to develop new methods of prevention, diagnosis and treatment of lung cancer and COPD. Common mechanisms may involve infl ammation, abnormal repair, oxidative stress, epithelial-mesenchymal transition, altered nicotine receptor biology and epigenetic alterations. Strategies to study genomics and epigenomics, in addition to gene-environment interaction, will yield greater insight into the shared pathogenesis of lung cancer and COPD. Airway epithelial cells, which are the fi rst line of cells to contact with inhaled substances such as microorganisms, play an important role in the host defense by two major mechanisms. First, they actively contribute to the innate immune system by recognition of the pathogen and production of antimicrobial substances and cytokines. Second, they provide a passive barrier function that prevents invading microorganisms, air pollutants and airborne allergens into the internal milieu. On the other hands, airway epithelial cells are involved in the production of airway infl ammation in asthma and COPD by excessively and un-regulatory expressing pro-infl ammatory and pro-allergic cytokines, executing apoptosis and losing barrier function. There is very close relationship between epithelial barrier function and innate immune response of epithelial cells. For instance, losing barrier function results in not only allowing foreign substance and pathogens to invade into the internal milieu but also enhancing innate immune responses. Asthma and COPD are different diseases, but they may have the same mechanism in the pathogenesis of exacerbation of these diseases in term of losing epithelial barrier functions. In this symposium, we will present the latest information on and the regulatory mechanism of airway barrier function and discuss in the context with asthma and COPD pathogenesis and exacerbations. Key words; airway epithelial cells, barrier function, asthma, COPD 

Patients with severe and diffi cult-to-treat asthma ("refractory asthma", approximately 5% of total asthma) have impaired health status refl ected by persistent symptoms, severe airfl ow limitation and frequent asthma exacerbations despite taking maximally recommended doses of inhaled corticosteroids and long-acting β 2 -agonists. A better understanding is thus needed regarding factors associated with such troublesome condition and, in our cross-sectional observational study, clinical and demographic characteristics of patients fulfi lling the American Thoracic Society Workshop criteria for refractory asthma (AJRCCM, 2000, Group A) were compared with those of patients with severe persistent asthma defi ned on the basis of the GINA guideline (Group B). There were no signifi cant differences between the two groups with respect to age, gender, smoking status, disease duration, pulmonary function (FEV 1 , PEF, DLCO), or markers of airway infl ammation in the induced sputum (eosinophils, neutrophils, ECP, tryptase). However, in contrast to Group B, all patients in Group A were adult-onset, and 93% of the patients already had severe symptoms at the time of disease onset. Prevalence of atopy, postbronchodilator FEV 1 /FVC ratio and FEV 1 reversibility were signifi cantly less in Group A than in Group B. Patients in Group A complained of copious amounts of phlegm associated with chronic sinusitis and/or chronic bronchitis, and showed high concentrations of mucin (MUC5AC + MUC5B) in the sputum. In addition, nasal clearance time assessed by saccharine test was signifi cantly longer in the Group A than in the Group B patients, indicating impairment of airway mucociliary clearance. These fi ndings and other pathophysiological and clinical data suggest that "refractory asthma" may be a different form of asthma (phenotype) rather than a progression of asthma severity during follow-up of natural history of the disease. Furthermore, it is likely that irreversible airway narrowing possibly due to airway remodeling and airway mucus hypersecretion are important factors contributing to the pathogenesis of severe and diffi cult-to-treat (refractory) asthma. The results prompt for further longitudinal studies and interventions to defi ne the mechanisms of this unique phenotype of asthma.

Journal Compilation © 2010 Asian Pacifi c Society of Respirology Drug development is a long and expensive process. On average it takes at least 10 years and more than a billion dollars to develop a compound from basic science discovery through clinical trials and fi nal approval by regulatory authorities of a new therapeutic. One of the main obstacles to development of new compounds is the diffi culty in obtaining good pre-clinical proof of effi cacy for a new drug. Most of this is currently obtained from experiments using animal models of disease or cell lines, neither of which refl ect well human disease nor predict whether responsiveness in these models predicts responsiveness in human disease. Recent studies have focused on developing methods that employ human cells or tissues taken from the relevant organ and from relevant patient populations. Of these models, the explant model, which uses whole tissue samples, is the closest to the in vivo situation because it maintains the complex cell-to-cell interactions. In asthma, studies have shown that this model can sometime be even better than in vivo study. Thus, for example, the explant model vivo offers several advantages over in vivo allergen challenge of asthmatic volunteers. First, repeat bronchoscopy to sample the airways after initial allergen challenge is not required. Second, tissue responses of more severe asthmatics, who for safety reasons cannot be challenged with allergen in vivo, can be studied. Third, problems of dilution of secreted mediators during BAL are avoided and released mediators are not consumed by in-coming infl ammatory cells, thus increasing the sensitivity of the model. Finally, and most importantly when seeking pre-clinical proof of concept of drug effi cacy, the model allows testing of novel compounds at an early stage before its full safety profi le is established, a process that is both expensive and time-consuming. We have previously shown that the asthmatic airways generate increased T cell chemotactic activity compared to healthy controls. Using a highly selective CCR4 antagonist we have recently shown that the CCR4-chemokine axis plays a key role at least in the traffi cking of T cells into the asthmatic airways. Having established this, we then showed that predominantly the CCR4+ T cells are recruited in response to allergen stimulation. We have further shown that the selective removal of these CCR4+ T cell from blood signifi cantly reduced allergic infl ammation as shown by a marked reduction in the production of the TH2 cytokines IL-4, IL-5 and IL-13 but with no consequences for Th1 responses. Taken together, our studies have strongly suggested that inhibiting the migration of T cell to the asthmatic airway by targeting CCR4 is likely to abrogate the allergic infl ammation in the airways without affecting immune responses that serve to protect against infection. These studies have also shown the value of using such ex vivo models of asthma to provide proof of concept for new drugs, giving the pharmaceutical industry the necessary pre-clinical proof to proceed with confi dence into further clinical development.

Sleep-disordered breathing (SDB) or obstructive sleep apnea (OSA) is a prevalent but largely undiagnosed sleep disorder. Apnea-hypopnea index (AHI: the number of apneas and hypopneas per hour of sleep) is used to classify SDB severity. In ICSD-2 (international classifi cation of sleep disorders ver. 2), "OSA syndrome" was defi ned as AHI ≥ 5 with hypersomnolence/ daytime symptoms or as AHI ≥ 15 regardless of the symptoms. Epidemiological studies clarifi ed that SDB is associated with increased likelihood of hypertension, cardiovascular disease, stroke, motor vehicle accidents, depression, diminished quality of life, and even mortality. Clinical guidelines for hypertension put weights on SDB as a cause of hypertension. International Diabetes Federation (IDF) made a consensus statement on sleep apnea and type 2 diabetes. "Overlap Syndrome" (coexist of COPD and SDB) was reported to have much higher mortality than SDB alone. Sleepiness was thought to be a major symptom for OSA syndrome. It is true that there is a signifi cant trend that the severe the SDB is the more the subjects had sleepiness. However, the majority of SDB subjects (even the majority of subjects with AHI ≥ 15) do not have sleepiness (ESS: Epworth Sleepiness Scale >10). The Berlin Sleep Questionnaire was used to screen high or low risk subjects for SDB. Four-item screening tool was also developed (gender, BMI, blood pressure, snoring frequency). These tools may be useful, when certifi ed with sleep monitoring in each population. Prevalence of AHI ≥ 15, estimated from two-stage sampling, was 9-14% in male and 2-7% in female. Two-stage sampling is oversampling the subjects with sleepiness or snoring to perform sleep monitoring, and weighting of results to the survey sample. When all the participants underwent sleep monitoring, the prevalence of AHI ≥ 15 was 22-25% in male and 10-12% in female. There is a strong need for better recognition, screening and treatment of SDB. More studies are needed, especially for long-term outcomes of asymptomatic SDB. Genome-wide association studies may be useful to elucidate causes or underlying mechanisms of SDB. Continuous positive airway pressure (CPAP) is a standard treatment for patients with obstructive sleep apnea (OSA), especially for moderate to severe OSA. The mechanism of action is to provide a pneumatic splint to preserve upper airway. The pressure level required to maintain airway patency is determined by manual pressure titration by a sleep technologist during attended laboratory polysomnography (PSG) to eliminate obstructive respiratory-related events (e.g., apneas, hypopneas, respiratory effort-related arousals [RERA], and snoring). Despite wide acceptance as a standard therapy for treatment of OSA patients, very few PAP titration protocols have been published so far, and there are inconsistency and variations in CPAP titration protocol among clinical sleep laboratories. For this reason, the PAP titration Task Force developed evidence-and consensus-based standardized PAP titration protocol and published its guideline entitled "Clinical Guidelines for the Manual Titration of Positive Airway Pressure in Patients with Obstructive Sleep Apnea" in Journal of Clinical Sleep Medicine 2008. In this lecture, I will explain about manual CPAP titration guidelines as below based on publications which are recommended by Positive Airway Pressure Titration Task Force of the American Academy of Sleep Medicine (AASM): (1) Important considerations prior to CPAP titrations. (2) Criteria for CPAP pressure to be increased. (2) Minimum and maximum starting CPAP pressure.

(3) An interval and minimum pressure to eliminate obstructive respiratory events. (4) Different algorithms for CPAP pressure to be increased to eliminate obstructive respiratory events observed for patients ≥12 years and <12 years. Interventional Bronchoscopy has typically been associated with obstructive tumor removal to regain central airways patency; such interventions, whether with rigid or fl exible instruments were also limited to the navigable fourth or fi fth generation airways. Tissue destructive techniques included ablative heat techniques (laser, electrocautery and Argon Plasma Coagulation), cold techniques (cryotherapy) and mechanical coring with the rigid bronchoscope. A current new crop of tissue debridement devices include modifi cations of established technologies: fl exible CO2 laser fi ber usable beyond the trachea, cryotherapy using non-contact surface cryospray, rotational microdebrider devices adopted from Otolaryngology, pulsating balloon resectors. The latter three devices do not involve heat that may cause post-treatment infl ammation and cartilage destruction and subsequent airway fi brosis or malacia. Previous direct intra-lesional injection, with Mitomycin or steroid was directed towards non-malignant fi brotic lesions, conversely on-going studies with cytotoxic agents (5FU) and compounds thought to have immune adjuvant effects (PTS) are demonstrating potential utility in endobronchial tumors. Photo-Dynamic Therapy (PDT) compounds with shorter half-lives require fewer bronchoscopies and have shortened photo-toxicity side effects. Therapeutic Bronchoscopic Image Guided Interventions (BIGI) have benefi tted from advances in "Virtual Bronchoscopic Navigation" software available to improve reaching small peripheral lesions. For radiation therapy for focal lung lesions not resectable because of patient co-morbidities or preference, the accurate placement of fi ducial markers (gold) are used to direct high-dose rate external-beam Intentiy Modulated Radiation Therapy (IMRT) including CyberKnife machine. Trials also demonstrate feasibility and effi cacy of treating peripheral lesions by High-Dose Rate (HDR) Brachytherapy through catheters placed with image guidance. One area of new focus is bronchoscopy in the management of chronic Obstructive Lung Diseases (OLD) including emphysema and severe asthma. Based on Lung Volume Reduction Surgery for severe emphysema with heterogeneous distribution and air-trapping, non-surgical Bronchoscopic Lung Volume Reduction (BLVR) has taken on a number of innovative approaches including exclusion by spigots (Watanabe), valves (Emphysys, Spiration), metallic coil retraction (PneumRx), airway bypass to relieve trapped gas (Broncus), atelectasis by bio-glue (Aeris) or by heat steaming (Uptake). Although none of the clinical devices in trials have shown unqualifi ed success, some devices are now being marketed (Europe), or are available on a compassionate basis for management of Broncho-Pleural Fistulas (BPF). Airway Radio-Frequency Ablation (RFA) of airway smooth muscle is USA-FDA approved for management of severe asthma. Future innovations in Interventional Bronchoscopy will likely incorporate advances in diagnostic bronchoscopy such as video-autofl uorescence and "in-vivo biopsy" techniques to guide local endobronchial therapies for in-situ cancers; image processing software to design custom stents for compromised airways; and drug-eluting stents to maintain airway integrity in a variety of malignant and benign airway diseases. 

Pleuroscopy describes a minimally invasive procedure that provides the physician a window into the pleural space. It refers to a procedure that is performed in an endoscopy suite or operating room with the patient under conscious sedation and local anesthesia. Increasingly these procedures are being performed by nonsurgeon pulmonologists to diagnose pleural pathology such as pleural effusions or pleural carcinomatosis; talc pleurodesis and chest tube placement under direct visual guidance. Pleuroscopy was fi rst conceived in a report dated 1866, which documented the fi rst endoscopic examination of the pleural space by Richard Cruise in a 11 year old girl with empyema. It did not gain widespread application until 1910 when Hans Christian Jacobaeus published his technique also known as the Jacobaeus operation. In this procedure he created a pneumothorax by severing adhesions using galvanocautery that collapsed the underlying lung, and allowed safe entry as well as unobstructed examination of the pleural space. Since then, pleuroscopy has been applied both as a diagnostic and therapeutic tool. For a hundred years, rigid endoscopic instruments such as stainless steel trocars and telescopes have been pivotal in the technique. Smaller telescopes and instruments have been applied with excellent views of the pleural space and comparable diagnostic yield. A signifi cant advance is the creation of fl exrigid pleuroscope that is fashioned like the fl exible bronchoscope. The fl ex-rigid pleuroscope consists of a handle, and a shaft that measures 7 mm in outer diameter, 22-cm proximal rigid portion and 5-cm fl exible distal end. The fl exible tip is movable by a lever on the handle, which allows 2-way angulation 160 degrees up and 130 degrees down. It has a 2.8 mm-working channel that accommodates biopsy forceps, needles and other accessories, and is compatible with various electrosurgical and laser procedures. The fl ex-rigid pleuroscope allows autoclaving. A notable advantage is its easy interface with existing processors and light sources made by the manufacturer for fl exible bronchoscopy or GI endoscopy at no additional costs. Although certain endoscopic characteristics such as nodules, polypoid masses and "candle wax drops" are suggestive of malignancy, early stage mesothelioma can resemble pleural infl ammation. Autofl uorescence and narrow band imaging have been incorporated to white light pleuroscopy to enhance diagnostic accuracy. Both modes of imaging discriminate early malignant lesions from non-specifi c infl ammation, aid in selecting appropriate sites for biopsy and better delineate tumor margins for more precise staging, but are of little value at present in clinical practice since most patients with malignant pleural effusions have extensive pleural involvement that is easy to diagnose with white light pleuroscopy For pleuroscopic guided pleural biopsies, specimens obtained with the rigid forceps are larger than those with the fl ex-rigid pleuroscope since they are limited by size of the fl exible forceps, which in turn depends on the diameter of the working channel. The fl exible forceps also lacks mechanical strength in obtaining pleural specimens of suffi cient depth, which can be overcome by the use of insulated tip (IT) diathermic knife. Full thickness parietal pleural biopsies are obtained with IT knife, and the electrocautery knife is particularly useful when smooth thickened lesions are encountered, of which nearly half are due to mesothelioma. To improve analgesia before talc poudrage, lidocaine can be administered to the parietal pleura via spray catheter inserted through the working channel of the pleuroscope. Similarly talc poudrage can be administered under visualization using the spray catheter. With the introduction of the fl ex-rigid pleuroscope, similar in design and handling to the fl exible bronchoscope, and compatible with standard light source and video processor available in most bronchoscopy suites, pleuroscopy will enjoy an expanded interest as more practitioners acquire the skill. The fl exrigid pleuroscope is a signifi cant invention in the history of minimally invasive pleural procedures and will revolutionize the practice of pulmonary medicine by replacing conventional biopsy methods in future. 

The common known causes of interstitial lung disease (ILD) are drug toxicities, environmental exposures and collagen vascular disease (CVD). Among these causes, drug or environmental exposures can be excluded by medical history. However, CVD-related ILD may often be confused with idiopathic interstitial pneumonia (IIP) because the radiological and histological characteristics of CVD-related ILD are often indistinguishable from those of their idiopathic counterparts and occasionally, systemic manifestations of the underlying CVD develop several months or years after the diagnosis of ILD. Early diagnosis of occult CVD is very important in patients presenting with ILD, because there are signifi cant differences in prognosis between the IIP and CVD-ILD groups. Patients with CVD-ILD survive longer than those with IIP. Additionally, different treatment regimens and evaluation for additional systemic involvement or malignancy may be needed in patients with CVD-ILD. Although, CVD-ILD and IIP is often considered indistinguishable, there are some clues that can help clinicians detect occult CVD in patients presenting with ILD. First, a thorough medical history and physical examination can detect occult CVD. Its importance cannot be overemphasized. The CVDs frequently associated with ILD are scleroderma, rheumatoid arthritis (RA), polymyositis/dermatomyositis (PM/DM), Sjögren's syndrome, mixed connective tissue disease (MCTD), undifferentiated connective tissue disease (UCTD) and systemic lupus erythematosus (SLE). Therefore, symptoms and signs that occur frequently in these CVDs should be searched for. These symptoms and signs include Raynaud's phenomenon, gastro-esophageal refl ux disease, telangiectasis, dry eyes, dry mouth, arthritis, the characteristic skin lesions of DM (heliotrope rash, Gottron's papule, mechanic's hand) and various serositis etc. Second, certain fi ndings on HRCT can help in the diagnosis of CVD. Although the parenchymal abnormalities are similar to their idiopathic counterparts, the presence of airway-related abnormalities -mosaic attenuation, bronchial wall thickening, and nodules -are more common in CVD-ILD. The presence of extrapulmonary abnormalities may also provide important clues to the underlying diagnosis. Patients with CVD more frequently have pleural and pericardial effusions, pericardial thickening, enlarged pulmonary artery and esophageal dilatation. HRCT can also show joint abnormalities or soft tissue calcifi cations. Third, there are some serologic tests that can help in the diagnosis of CVD even in patients with obscure symptoms. High titers of antinuclear antibody and rheumatoid factor are often found in patients with CVD. Other more disease specifi c tests currently available are anti-SSA/SSB antibody for primary Sjögren's syndrome, anti-Scl-70 antibody for systemic sclerosis, anti-Jo-1 antibody for PM/DM, anti-U1 ribonucleoprotein (RNP) antibody for MCTD, antibody to cyclic citrullinated peptides (CCP) for rheumatoid arthritis and so on. Fourth, the frequent pathologic patterns of ILD associated with CVD are NSIP, UIP, OP, LIP and DAD. Among them, NSIP is the most frequent pathologic pattern in CVD-ILD. Therefore, pathologic pattern consistent with NSIP should raise suspicions about the possibility of CVD. Other pathologic fi ndings that may be suggestive of an underlying CVD include follicular bronchiolitis and lymphoid follicles. However, it is still impossible to diagnosis all occult CVDs at the outset of ILD because the initial clinical presentations can be essentially indistinguishable from those of IIP. Therefore, close follow up for a developing CVD is very important especially in patients with NSIP. The role of pathological diagnosis for Non-neoplastic lung disease is important and critical. However, agreement of pathological diagnosis in IIPs may not be that high. Despite the expectations after publication of 2002 ATS/ERS classifi cation of idiopathic interstitial pneumonias (IIPs), interobserver variability in the pathological diagnosis of IIPs is still problematic. There are several major reasons for the poor agreement in pathological diagnosis of IIPs in which the biggest reason is a lack of specifi c and diagnostic fi nding to any type of IIPs. In the session, I would fi rst share the virtual steps of making diagnosis on surgical lung biopsy with audience, indicate recent data of inter-observer agreement in IIPs cases, and then, introduce factors behind the poor agreements followed by several possible solutions to this important issue. Children's interstitial lung disease (ChILD) differs from adult interstitial lung disease in that certain classic idiopathic pneumonias described in adults are not seen in children and unique forms of interstitial lung disease are found in infants and young children but not in adults. The most common form of idiopathic interstitial pneumonia in adults is idiopathic pulmonary fi brosis (IPF), also known as cryptogenic fi brosing alveolitis (CFA), a progressive and fatal disorder, defi ned pathologically as usual interstitial pneumonia (UIP). UIP is characterized by a heterogeneous mixture of normal lung, mild infl ammation, and fi brosis and the presence of fi broblastic foci, felt to be the leading edge of fi brosis. Previously, although many infants and children were given the diagnosis of IPF, CFA, or UIP, they did not have the characteristic fi broblastic foci. Thus although the UIP pattern is occasionally seen in the context of another primary disorder, such as ABCA3 mutations, true IPF/UIP does not exist in children. The tendency to use the term IPF in children merely serves to obscure the real diagnosis and creates anxiety in families whose affected children may not actually have a fatal disorder. Unique conditions have been described mainly in infants and young children that do not occur in adults. These include growth abnormalities, inborn errors of surfactant metabolism, neuroendocrine cell hyperplasia of infancy (NEHI), and pulmonary interstitial glycogenosis (PIG). Growth abnormalities occur as a consequence of an early insult to the lung that results in retarded or arrested lung development and alveolar simplifi cation. Risk factors associated with growth abnormalities include prematurity, congenital heart disease, and chromosomal defects, most commonly Down syndrome. The major advance in ChILD has been the discovery of genetic mutations that lead to surfactant dysfunction. These include mutations in the SP-B, SP-C, ABCA3, TTF-1, and GM-CSFRa genes. Clinical presentation can vary from severe respiratory failure at birth leading to death (SP-B, ABCA3 mutations) to more insidious onset with chronic lung disease (SP-C, ABCA3, TTF-1, GM-CSFRa mutations). NEHI is a chronic benign form of ChILD presenting in the fi rst year of life with tachypnea, crackles, hypoxemia, characteristic features of symmetric ground glass densities in the right middle lobe and lingula and central lung regions on HRCT, and a mixed restrictive/obstructive pattern on infant lung function testing. Lung biopsy shows increased numbers of neuroendocrine cells and neuroepithelial bodies in the distal airways with otherwise normal lung architecture. PIG is another benign form of ChILD seen in infants and characterized by interstitial widening with glycogen-rich interstitial cells. PIG is seen as a primary disorder ("pure" PIG) and as a patchy disorder seen in the background of some other primary disorder, such as a growth abnormality ("patchy" PIG).

In conclusion, it is important to recognize the differences between pediatric and adult interstitial lung disease so that the proper diagnosis and prognosis can be given and the appropriate treatment applied. Journal Compilation © 2010 Asian Pacifi c Society of Respirology not to treat acute bronchitis with initial antibiotics, with the following exceptions. Those at high risk of serious complications because of preexisting co-morbidity, patients over 65 years of age with acute cough and two or more of the following, or patients over 80 years of age with one or more of the following; (1) Admission to hospital in the previous year (2) Type 1 or type 2 diabetes (3) History of congestive heart failure (4) Current use of oral glucocorticoids. Clinicians need to address patients' concerns, perspectives, and expectations about the treatment and explain to patients that antibiotics are not necessary for a self-limiting respiratory tract infection. Physicians should tell patients that antibiotic use increases the risk of an antibiotic resistant infection. And physicians also need to spend time answering questions and offer a contingency plan if symptoms worsen, and advise patients to return for a consultation if symptoms are not starting to settle in accordance with the expected course of the illness or if symptoms worsen signifi cantly. Some physicians are certain that patients will benefi t from antibiotics and prescribe for expectation of fast relief. They are mostly comfortable with their prescribing decisions by their clinical experiences. Taiwan's study demonstrates substantial variations among physician groups in the practice of prescribing antibiotics for viral respiratory infections. Older physicians and those practicing in clinics rather than medical centers were signifi cantly more likely to prescribe antibiotics, and dispensing doctors in contrast to those without dispensing privileges or on-site pharmacists were signifi cantly highly prescribing antibiotics. Statistical data from NHIC in Korea showed that general physicians in clinics prescribe antibiotics in 68% of acute bronchitis patients, while doctors at tertiary hospitals showed less but still fairly high rate of 51%. Efforts and interventions to reduce the potentially inappropriate prescription of antibiotics should target modifi able factors. Quality improvement (QI) strategies like using active clinician education, delayed prescriptions and targeting management, may yield reductions in antibiotic use. Anti-tussives are occasionally useful and can be offered for short-term symptomatic relief of coughing. A meta-analysis and systematic review found that beta-2-agonists were not effective for the treatment of acute bronchitis or cough of <4 weeks duration in children or in adults unless airfl ow obstruction was present. Summary Acute bronchitis is one of most commonly diagnosed and treated diseases in daily clinical practice. However, since it is mostly a self limiting disease, the standardization of diagnosis and treatment has long been neglected leaving various controversies in the management, particularly the use of antibiotics. The inappropriate prescription of antibiotics for acute bronchitis will surely lead to the emergence of resistant organisms in the community let alone the increase of socio-economic burden. Further attention and research is needed for the reasonable approach to the treatment of acute bronchitis in order to prevent overuse of antibiotics and improve health-economy. Prevalence Acute bronchitis is one of the most common conditions encountered in clinical practice, accounted for approximately 10 million visits to Korean physicians in 2008, and consistently ranks among the top 10 reasons for ambulatory visits in the United States. Defi nition Acute bronchitis refers to a clinical syndrome distinguished by a relatively brief, self-limited infl ammatory process of large and midsized airways that is manifested predominantly by cough with or without phlegm production which lasts for up to 3 weeks and absence of fi ndings suggestive of pneumonia. Acute bronchitis should be distinguished from acute exacerbations of chronic bronchitis and acute infl ammation of the small airways -asthma or bronchiolitis. Those with underlying lung disease, congestive heart failure, or a compromised immune system are considered to be at high risk for complications of acute bronchitis. Etiology Acute bronchitis is one of the most common causes of antibiotic abuse. In healthy communities, there is little evidence of bacterial infection in people with bronchitis, but there are few practical studies to distinguish between bacterial and viral bronchitis. Within this context, the use of antibiotics to treat acute bronchitis is controversial but common in real practice.

Viruses are usually considered the most common cause of acute bronchitis but have been isolated in a minority of patients. Those isolated in acute bronchitis include, in order of frequency of occurrence, are Infl uenza, Parainfl uenza, Respiratory Syncitial Virus (RSV), Coronavirus, Adenovirus, and Rhinovirus. The yield of specifi c pathogens varies according to several factors, including the presence or absence of an epidemic, the season of the year, and the infl uenza vaccination status of the population. Bacterial pathogens are thought to play a very minimal role in acute bronchitis. The bacteria that have been causally linked to acute bronchitis in otherwise healthy individuals include only Mycoplasma pneumoniae, Chlamydophila pneumoniae and Bordetella pertussis. Antibiotic treatment of patients with pertussis is indicated to limit transmission, but there are no compelling data to support the prospect that cough will be less severe or less prolonged with antibiotic therapy. Clinical Manifestations Acute bronchitis cannot be distinguished from upper respiratory infections in the fi rst few days. Acute bronchitis is suggested by the persistence of cough for more than fi ve days, and most often lasts from 10 to 20 days. Approximately 50% of patients with acute bronchitis report the production of purulent sputum. It usually represents sloughing of cells from the tracheobronchial epithelium, along with infl ammatory cells, and does not signify bacterial infection. Pulmonary function test fi ndings consistent with bronchial hyperresponsiveness are common. FEV1 less than 80% at the initial visit was present in 40% of adults from the mid western United States with no history of underlying lung disease. PFT abnormalities are usually transient, typically resolving after 2 to 3 weeks, although they may last as long as 2 months. Fever is a relatively unusual sign in acute bronchitis and, when accompanying cough, suggests either infl uenza or pneumonia. Diagnosis Acute bronchitis is established in a patient who has the sudden onset of cough, with or without sputum expectoration, and without evidence of pneumonia, the common cold, acute asthma, or an acute exacerbation of chronic bronchitis. The absence of the following fi ndings reduces the likelihood of pneumonia suffi ciently to eliminate the need for a chest radiograph: (1) heart rate >100 beats/min; (2) respiratory rate >24 breaths/min; (3) oral body temperature of >38°C; and (4) chest examination fi ndings of focal consolidation, egophony, or fremitus. Chest radiography should be reserved for use in patients with any of these fi ndings or cough lasting >3 weeks. An exception, however, is a cough in elderly patients; pneumonia in elderly patients is often characterized by an absence of distinctive signs and symptoms. Rapid diagnostic tests exist for several pathogens currently linked to acute bronchitis. Patients with severe paroxysmal cough, with or without post-tussive vomiting should be evaluated for pertussis regardless of the immunization history. Rapid tests should be used primarily when the suspected organism is treatable, the infection is known to be circulating in the community, and the patient has suggestive symptoms or signs. Treatment Statistical data from Korea National Health Insurance Corporation (NHIC) shows that approximately 50-60% of patients with acute bronchitis receive antibiotics despite the evidence that, with few exceptions, they are ineffective. Meta-analyses of randomized, controlled trials all concluded that routine antibiotic treatment is not justifi ed. The decision not to use an antibiotic should be addressed individually and explanations should be offered because many patients expect to receive an antibiotic based on previous experiences and public expectations.

Main challenges for appropriate antibiotic use in acute bronchitis are the diagnosis is based on clinical fi ndings, without standardized diagnostic methods and sensitive or specifi c confi rmatory laboratory tests. How to identify accurately the few patients who are seriously ill or whose symptoms could be meaningfully ameliorated by prompt antibiotic treatment is not standardized. 

Recent studies have suggested that the annual decline in FEV1 is greater in GOLD stage II than in later stages of the disease. (1) If the decline in pulmonary function predominantly occurs early in the course of the disease, then it is logical that diagnosis and intervention aimed at reducing the progression of the disease should mainly occur in the early stages of the disease. Severity of COPD at diagnosis differs enormously on where it is done: population based studies, screening or hospital patients. Epidemiologic Studies: prevalence, underdiagnosis and severity There are increasingly more data on the prevalence and distribution of COPD from around the world. The prevalence of chronic obstructive pulmonary disease (COPD) varies from country to country, mainly due to the effects of cumulative exposure to smoking and the increased life span of the population. (2) (3) (4) (5) Systematic review of epidemiological studies concluded that the prevalence of COPD, in adults aged 40 years and more, worldwide ranges around 9-10%. (6) These differences may be related, at least in part, to differences in genetic background, smoking habits and exposure to other environmental risk factors, and are accompanied by differences in diagnostic rates and in management of the disease around the world.

There is a large underdiagnosis of COPD with about only one out of three or four of all subjects fulfi lling diagnostic criteria of COPD identifi ed by the health care system. (2) (7) (8) COPD in general population is diagnosed at earlier stages. Data from Latinamerica (PLATINO), similar from those from Spain, showed severity was distributed as follows: stage I, 59 % and stage II, 33.8%. Screening for COPD Screening, combined with smoking cessation advice, help motivated smokers to attempt quitting smoking. (10) In general practice, when individuals were preselected on the basis of smoking age and respiratory symptoms chronic cough was a better predictor of airfl ow obstruction than other symptoms, such as wheeze and dyspnoea. Age was also a good predictor of obstruction; smokers over 60 with cough had a 48% chance of having an obstruction. (11) Diagnosis at the Hospital The decrease in lung function is gradual. The disease is usually diagnosed late because patients may adapt to the condition or doctors may not notice the symptoms. By then, the patient is diagnosed at the Hospital, when lung function is often poor, sometimes less than 50% of normal.

The relationship between lung disease and increased body weight can take two forms: the effects of increased body weight on the normal respiratory system and the association of increased body weight with diseases of the respiratory system. Obesity (body mass index, BMI, greater than 30 kg/m 2 ) can reduce normal static lung volumes (principally functional residual capacity, but also total lung capacity and residual volume at very high BMI), ventilation (particularly during sleep and exercise) and gas exchange (increased gas transfer). The epidemic of overweight and obesity has been associated with the increased prevalence of asthma through proposed mechanisms such as dietary effects, reduced lung volumes and lung recoil affecting airway responses to breathing, a general infl ammatory effect and through associated sedentary lifestyle. However more recent epidemiological data suggests the association between asthma and obesity is not as close as once thought.

Overweight and obesity clearly are associated with the high prevalence of obstructive sleep apnoea with increased body weight increasing the likelihood of upper airway collapse on a background of reduced upper airway dimensions and snoring and reducing minute ventilation in patients with obstructive sleep apnoea, predisposing to hypoventilation and chronic hypercapnoeic respiratory failure. The increased load to breathing also affects breathing, especially during sleep, in patients with respiratory muscle weakness or abnormal chest wall mechanics due to kyphoscoliosis or previous chest wall surgery such as thoracoplasty. Increased body weight will also exacerbate the effects on symptoms of existing chronic respiratory diseases including asthma, chronic obstructive pulmonary disease and interstitial lung diseases. Avoidance of weight gain and continued efforts at weight loss remain an important goal in patients with respiratory disease. This presentation will be a review of recent fi ndings and implications from imaging studies in asthma. The use of 3-dimensional imaging in asthma has provided useful insights into the understanding of pathophysiology of disease, which may have implications on how asthma is treated. Small airways disease plays a major role in asthma and has traditionally been diffi cult to probe. However, the combined use of new imaging methods combined with complex lung function has provided useful insights into pathophysiology. Findings and implications from HRCT, PET, SPECT and MRI will be discussed. The assessment of pulmonary function has changed very little over the past 30 to 40 years. All techniques performed in the laboratory still view the lung as a very simple single compartment unit. Measures of volume and fl ow only assess disease in the medium to large airways whilst the small airways receive relatively little attention. However there are a number of emerging techniques on the horizon that have the potential to give great insight in to the periphery of the lung where most respiratory disease emanates. The measurement of mechanics using the Forced Oscillation Technique and gas mixing using the Multiple Breath Nitrogen Washout test are now emerging as very powerful tools for assessment of peripheral lung function. In this presentation we will be discussing the state of the art in terms of assessing pulmonary function and what may we expect to see in the future. COPD is a major public health problem in Asia. COPD prevalence was 8.2% (12.4% in males and 5.1% in females) in China (>40 yrs), 9.5% in Japan (>40 yrs).

In most of the developing countries in Asia, COPD is always underdiagnosed by physicians owning to lack of routine spirometry test and only based on symptomatic diagnosis.

Smoking is the most important risk factor contributing to development of COPD. However, COPD prevalence was 4.2% in Chinese non-smokers (>40 yrs) and 8.8% in Korea (>45 yrs), similar to those in Mexico City (6.2%) and Caracas (6.6%). In China, non-smokers accounted for 38.6% of COPD patients compared with 24.9% in USA and 22.9% in the UK. Exposure to environmental tobacco smoke (passive smoking) and indoor air pollution (particularly the coal and biomass combination) may contribute to the higher prevalence of COPD in developing countries.

To reduce the risk factors (smoking, coal or biomass fuel for cooking, indoor and outdoor air pollution) are the priority for reducing the prevalence in the Asian developing countries. Government in some countries had made some effect in tobacco control and reducing air pollution. Unlike hypertension or diabetes, the management of COPD is only based on symptomatic treatment, owing to lack of specifi c biomarkers. Annual lung function test with spirometer is the only parameter in detecting early stage of COPD. Data showed that more reversibility of FEV1 was demonstrated in stages I-II COPD patients with ICS/LABA or tiotropine administration, as compared with those in stages III-IV. An intervention study at the community level has shown that early intervention (improvement of indoor ventilation, bronchodilators) was able to reverse rapid annual FEV, decline in COPD patients. More affordable medication should be developed in the low income countries. Data showed that oral administration of carbocysteine (thio compounds) reduced exacerbation rate by 24.5%, which was consistent with inhaled administration of Fluticasone/Formoterol (seretide) or tiotropine. In addition, orally administered low dose Teophylline (100 mg, Bid) improved pre-bronchodilator FEV, and reduced exacerbation rate. There was a synergistic effi cacy in FEV1, with the combination of Teophylline and inhaled corticosteroids. Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airfl ow limitation due to loss of lung elasticity and/or airway narrowing. The pathological hallmark of loss of lung elasticity is emphysema and airway wall remodeling contributes to the airway narrowing. Using computed tomography (CT) these lesions can be assessed by measuring low attenuation areas (LAA) and airway wall thickness/luminal area, respectively. Recently, COPD has been widely recognized as a systemic infl ammatory disease, and body weight loss is one of its clinical features. Traditionally, the patients who had COPD with predominant emphysema and a low body mass index (BMI) were called "pink-puffers". However, the relationship between body weight loss and emphysema had not been assessed. Based on these back ground, we have evaluated the body composition, emphysema and airway dimensions in 201 COPD patients using CT images. BMI was signifi cantly lower in the emphysema dominant phenotype compared to the airway dominant phenotype. Furthermore, BMI correlated with LAA% (ρ = −0.557, p < 0.0001) but not with WA%. Chest subcutaneous fat mass was also correlated with LAA% (ρ = −0.307, p < 0.0001). These data indicated that the "Pink-puffer hypothesis" is correct in some aspects. Next, we postulated that reduced leptin and leptin receptor signaling could contribute the development of emphysema. Serum leptin was correlated with BMI which was correlated with DL co /V A . The expression of leptin and leptin receptor was evaluated PCR in 52 human lung tissues. Both genes were detected in the lung tissues, but the expression of leptin gene was low. The leptin receptor gene expression was signifi cantly lower in COPD patients and it was signifi cantly correlated with DL co /V A . The leptin receptor gene expression in the lung did not correlated with body weight. These data suggested that the patients' physique can be associated with the relative contribution of emphysematous lesions in COPD and leptin and leptin receptor system might affect the mechanism of developing emphysema. Nutritional support has been one of possible clinical approaches as a COPD therapy these days. However, its effect is still controversial. To clarify the relationship between low BMI and emphysema and to classify the phenotypes of COPD based on the patients' physique may help to fi ne the defi nite targets for nutritional support even in the early stage of COPD.

Journal Compilation © 2010 Asian Pacifi c Society of Respirology SY 07-03

At present COPD is often only treated in GOLD stage III or IV 1 . It is without question possible to diagnose COPD earlier. If spirometry would be more readily performed in general practice, COPD could be diagnosed in GOLD stage I and II, as is evident from the practice of "spirometry days" organized by the Belgian Thoracic Society in which the majority of the patients were diagnosed in GOLD stage II 1 . Whether GOLD stage I and II truly represent the "early" stages of the disease may be debated 2 , but this defi nition of early COPD could certainly be used as an operational defi nition. It is clear now that spirometry is required for early diagnosis of COPD 3 . Although at present there is no irrefutable evidence that early treatment of COPD is warranted, there is accumulating suggestive evidence that early treatment of COPD may result in better outcomes. This evidence is primarily related to secondary analyses of the TORCH 4 and UPLIFT 5,6 studies. First, it was demonstrated in a secondary analysis of the TORCH study, that inhaled corticosteroids, long-acting betaagonists and their fi xed combination reduced the rate of decline of FEV 1 by 13, 13 and 16 mL, respectively 7 . If treatment indeed reduces the progression of the disease, then an easy case for early treatment is made. In addition, a subgroup analysis demonstrated that except for the effect on the SGRQ (St. George's Respiratory Questionnaire) all other treatment effects were numerically larger in GOLD stage II than in GOLD stage III and IV 8 . A subgroup analysis of the UPLIFT study demonstrated numerically greater treatment effects in GOLD stage II as well. In addition, Tiotropium reduced the rate of decline of FEV 1 in these patients (albeit only by 6 mL/year), which was not the case in the later GOLD stages 9 . Finally, in patients not taking any medication at the onset of the study (maintenance naïve patients) tiotropium substantially reduced the rate of decline of FEV 1 and the rate of deterioration of the SGRQscore 10 . Taken together these data demonstrated that: 1) large treatment effects were obtained in early disease; 2) indications of disease modifi cation were present in early disease. Hence, they support early treatment of COPD.

Pulmonary Rehabilitation is now the standard of care for patients with Chronic Obstructive Pulmonary Disease (COPD) who remain symptomatic despite bronchodilator therapies. Combining the best of interprofessional, personalized and evidence-informed care, pulmonary rehabilitation allows clinicians and their patients to realize signifi cant benefi ts in a variety of important patientcentered COPD outcomes. The fundamental elements required for an effective pulmonary rehabilitation program will be discussed, and the scientifi c evidence supporting their effectiveness will be summarized. Issues relating to optimal site of delivery, components of effective rehabilitation programming, duration of rehabilitation, timing of rehabilitation and target populations will be reviewed. Recent developments in this rapidly expanding area will also be highlighted. Lastly, methods to establish or enhance an existing pulmonary rehabilitation program will be discussed, with the goal of fully realizing the many substantive benefi ts of pulmonary rehabilitation in COPD. However, only very low gene transfer seen after a second dose with either 14 day and 7 day spacing. We attribute this to rapid upregulation of neutralizing antibodies against adenovirus. Anti-tumor humoral immune responses were seen almost all patients with reactions seen against known Meso tumor antigens (SV40 large T antigen and mesothelin) and against unknown proteins in cell lysates. Given the caveats of Phase 1 trials (small numbers, different doses, heavily pretreated patients), we still saw clinical responses (defi ned as prolonged stable disease, prolonged survival, partial or complete responses by modifi ed RESIST criteria, decreased metabolic tumor activity by PET scanning, or "mixed" responses) in about 1/3 of the patients. We are currently administering two doses spaced only three days apart. This appears to be well tolerated. Based on strong preclinical data supporting the combination of gene therapy and chemotherapy, we have started a trial using Ad.INF instillation into the fi rst treatment cycle of fi rst line (Cisplatin/Pemetrexed) or second line chemotherapy (Gemcitabine). Our groups is also generating "designer chimeric T cells" in which a single chain antibody fragment is linked to the transmembrane and cytoplasmic regions of the T-cell receptor. This artifi cial T-cell receptor is then transduced into T-cells that are then reinfused. The T-cells are then activated by cells expressing mesothelin. Preclinical data show striking activity against mesothelin-expressing tumors in mice.

Mesotheliomas make large amounts of the immunoinhibitory cytokine, transforming growth factor-beta (TGF-β). Preclinical studies using TGF-β blockers have shown activity in mouse models of mesothelioma and a clinical trial using an anti-TGF-β antibody is now underway at the University of Pennsylvania. In summary, gene-based and immunotherapies are being actively studied in mesothelioma and have shown some promising results. Future trials are focusing on combining these approaches with chemotherapy and surgery. Given the relatively mild and non-overlapping toxicities, we believe these, or other gene therapy and/or immunologic approaches will soon become part of the standard therapeutic armamentarium.

The burden of asbestos-related diseases (ARDs), in particular mesothelioma, has been shouldered mostly by the developed countries of the West. This is a consequence of the heavy dependence on asbestos use up to around the 1970s by those countries. In contrast, the majority of Asian countries started to depend on asbestos since then and has not yet reached the suffi cient latency time for the related diseases to manifest. Japan is an exception, because it heavily used asbestos during the period to catch-up with the West. Japan has now become one of the global epicenters of ARDs. It is a tragic consequence of experiencing the burden of ARDs that many developed countries decided to move towards banning asbestos or a de facto non-dependence. In the Asia-Pacifi c, this group comprises Australia, New Zealand, Japan, Korea and Singapore (the "forerunner" group in terms of ARDs). In contrast, the many other countries in Asia still use asbestos at substantial levels, turning Asia into the world's center of asbestos consumption today. However, as these countries start to use up the latency time, and manage to improve medical recognition, reporting and recording, ARDs will soon emerge as a major public health issue in the region. Early indications of this forecast do exist. Not only should lessons be learnt from the experiences incurred by the "forerunner" group of countries, but more importantly, they should crystallize in international collaboration involving national administrators, academia, NGOs and international organizations, for the effective recognition and countermeasures of ARDs. I will also refer to the progress made and hurdles encountered by The Asian Asbestos Initiative and the WHO Global Plan of Action on the Elimination of Asbestos-Related Diseases. At the international level, ARDs present a domino-effect that needs to be coped with.

SY 08-03

Interstitial pneumonia (IP) can be classifi ed into two groups in terms of known causes. Pneumoconiosis, drug-induced pneumonitis, radiation-induced pneumonitis, and hypersensitivity pneunonitis (HP) are categorized as IP with known causes. On the other hand, idiopathic interstitial pneumonias (IIPs), which include idiopathic pulmonary fi brosis (IPF), nonspecifi c interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), and desquamative interstitial pneumonia (DIP), have no known causes. Most physicians tend to diagnose of IP patients as IIPs without intensive examinations. However, some environmental and occupational lung diseases, especially asbestosis and chronic HP, should carefully be differentiated from IIPs. Asbestosis is one type of pneumoconiosis, which is induced by asbestos exposure with a latent period of usually more than 10 years. Bilateral fi ne crackles can be frequently auscultated and pulmonary function test shows restrictive and diffusing impairments. Chest HRCT shows subpleural dot, subpleural curvilinear shadow, ground glass opacity, interlobular septal thickening, traction bronchiectasis, and honeycombing. In our case series of asbestosis (n = 51) in Yokosuka, a town of shipyard for more than 100 years, honeycombing was seen in 6 cases (12%). Chronic HP is an allergic disease induced by long-term exposure to antigens. Major causative antigens are avian dropping and feather, mold, and bacteria. Chest HRCT tends to show traction bronchiectasis and honeycombing in advanced stages, which are similar to IPF. In surgical lung biopsy, most cases are classifi ed as NSIP-like and UIP-like patterns. To clarify the importance of unrecognized exposure to avian antigen, we precisely reviewed 56 patients with bird-related chronic HP. In the 56 patients, 24 patients were bird-breeders with direct exposure to avian antigen by contacting their own birds, whereas 32 patients seemed to be exposed to wild birds, neighbor's birds, feather duvets, stuffed bird, and fertilizer with chicken droppings without recognition of avian contact. Number of patients is very limited both in asbestosis and chronic HP, which suggests that there is a small group of subjects who are susceptible to develop pulmonary fi brosis after exposure to asbestos or antigens. However, genetic background of susceptibility to pulmonary fi brosis has not elucidated. In our case series of chronic HP (n = 184), 22 cases (12%) had the fi rst-degree family members with IP, who might have common environmental and/or genetic factors. Further studies are needed to determine host susceptibility to pulmonary fi brosis, which might contribute to clarify the pathogenesis of IP. 

Long acting beta-2 agonists has been in the doctors' armory of asthma medications for about 20 years (available in 1990 in UK and 1994 in USA). There is little doubt that LABA when combined with inhaled corticosteroids can improve asthma symptoms for a subsection of people with asthma, and is generally superior to add-on leukotriene receptor antagonist. 1 Indeed addition of LABA to inhaled corticosteroids is in all major asthma guidelines as a step-up therapy. However, after the salmeterol multicentre asthma research trial was prematurely halted, a focus on effi cacy and safety of the wide use of LABA 

Severe pulmonary arterial hypertension (PAH) is a fatal condition associated with complex pathobiology. Vasoconstriction, thrombosis, and remodeling of the pulmonary vessel wall contribute to increased pulmonary vascular resistance in PAH. The pathology of pulmonary hypertension can be classifi ed into endothelial, smooth muscle, and/or adventitial lesions, although not all compartments of the pulmonary artery wall are involved in each case of severe PAH. The classic lesion of severe PAH is the plexiform lesion, an abnormal proliferation of predominantly endothelial cells. Smooth muscle thickening can be seen in all forms of the disease but is not a constant feature in the idiopathic pulmonary arterial hypertension. The adventitia is often markedly remodeled in patients with certain forms of collagen vascular diseases associated with severe PAH, most notably scleroderma. The obligatory lining of pulmonary arteries with a monolayer of endothelial cells is disrupted in severe PAH. The three-dimensional vascular pattern is rather suggestive of an intravascular tumor-like proliferation (tumorlet), instead of a retracted scar if this lesion would represent an abnormal healing to an injury to the vascular wall. The evidence of a tumorlike endothelial cell proliferation was provided by the demonstration that plexiform lesions in patients with idiopathic PAH were preferentially monoclonal, whereas similar lesions in lung of patients with secondary PAH due to congenital heart malformations were polyclonal. Monoclonality was also observed in plexiform lesions of patients from anorexigen-induded PAH. Vasoconstriction has been related to abnormal potassium channels and to endothelial dysfunction. Endothelial dysfunction leads to impaired production of vasodilators such as nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as endothelin (ET)-1. Many of these abnormalities not only elevate vascular tone and promote vascular remodeling but also represent logical pharmacological targets. Recent genetic and pathophysiologic studies have emphasized the relevance of several mediators in this condition, including nitric oxide, prostacyclin, ET-1, serotonin, angiopoietin-1, and members of the transforming-growth-factor-beta superfamily. Disordered proteolysis of the extracellular matrix is also evident in PAH. The unraveling of the pathobiology of severe PAH may lead us to novel therapies and approaches to better treat the disease. Unfractionated heparin (UFH) and low-molecular-weight-heparin (LMWH), acted by enhancing the ability of antithrombin (AT) to inhibit coagulation proteases, have been used as initial anticoagulant therapy for VTE. They are delivered intravenously or by subcutaneous injection. Subcutaneous fondaparinux, a synthetic pentasaccharide with specifi c anti-factor Xa activity, is also recommended as the initial treatment for VTE according to recent guideline. Oral vitamin K antagonists, acting by reducing the activity of several coagulation proteases, are used for long-term anticoagulation. The major disadvantage of vitamin K antagonists is the need for frequent coagulation monitoring to maintain a therapeutic level. New anticoagulants, including oral direct thrombin inhibitors, such as dabigatran, and oral anti-factor Xa inhibitors, such as rivaroxaban and apixaban, are emerging in recent clinical trials.11 These new drugs may replace heparins and vitamin K antagonists, which are expected to have a huge impact on the treatment of VTE in the near future. Thrombolytic therapy should immediately be used in patients with massive (high risk) PTE. The effect of thrombolysis in patients with submissive (intermediate risk) PTE remains controversial. Further stratifi cation of these patients is necessary. Patients with multiple poor prognostic indicators such as right heart dysfunction, thrombolytic therapy should be considered. Several countries have started to support activities raising public awareness of VTE, with the goal to decrease mortality and morbidity. In US, National Institutes of Health (NIH) and Centres for Disease Control (CDC) have fostered thrombosis activities to improve the prevention of VTE and its long-term complications. In the United Kingdom, a thrombosis group has been formed to promote awareness among parliamentarians about the risk and management of VTE; to increase knowledge of its causes, effects, and treatments; and to monitor the implementation of government initiatives and other researches being and this program has corrected the wrong perception that PTE is a rare disease in China Pulmonary hypertension (PH) is a common complication of chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) or interstitial lung diseases (ILD). PH associated with respiratory diseases is classifi ed as diagnostic group III according to the current clinical classifi cation of Dana Point 2008. It is suggested that the pulmonary vascular abnormalities originate at an early stage of the diseases. The functional (hypoxic vasoconstriction) and morphological factors (vascular remodeling, destruction of the pulmonary parenchyma) explain the elevation of pulmonary vascular resistance that leads to PH. The PH is mild to moderate in COPD with mean pulmonary artery pressure (mPAP) usually ranging between 20 and 25 mmHg, however, worsening during exercise and exacerbations. A small proportion of COPD patients may exhibit severe PH defi ned by a resting mPAP >35 to 40 mmHg, whose prognosis is particularly poor. PH is relatively frequent in advanced ILD, particularly in idiopathic pulmonary fi brosis, which predicts a poor prognosis. The diagnosis of PH is suggested by Doppler echocardiography, but the confi rmation still requires right heart catheterization. The potential treatments of PH associated with respiratory diseases are as follows: 1) Treat underlying lung disease; 2) Provide supplemental oxygen therapy when appropriate; 3) Rehabilitation; 4) Treat right heart failure; 5) Consider vasomodulator therapy; and 6) Consider lung transplantation when indicated.

Journal Compilation © 2010 Asian Pacifi c Society of Respirology SY 11-01

Tobacco use is the most common preventable cause of death. About half of the people who don't quit smoking will die of smoking-related problems. The epidemic varies among countries and is increasingly affecting developing countries, where most of the world's smokers (82%) live. Close to half of all men in low income countries smoke daily and this has been increasing. Legislation The Framework Convention on Tobacco Control (FCTC) was adopted by WHO member countries in May 2003 to commit all countries to protect nonsmokers from tobacco smoke in public places, to eliminate all tobacco advertising, promotion and sponsorship, to require warning labels of cigarette packs and to prohibit misleading tobacco product descriptors such as "light" and "mild". Even though many countries have passed legislation mandating smoke-free environments and the total global population covered by comprehensive smoke-free laws increased from 3.1% to 5.4% in one year, the overwhelming majority of countries still have no smoke-free laws, very limited laws, or ineffective enforcement. Compliance with smoke-free laws is low. Treatment to aid smoking cessation Support for smoking cessation or "treatment of tobacco dependence" refers to a range of techniques including motivation, advice and guidance, counselling and appropriate pharmaceutical aids, all of which aim to encourage and help tobacco users to stop using tobacco and to avoid subsequent relapse. The success of these interventions depends on their synergistic use in the context of a comprehensive country tobacco-control strategy. In many countries, provision for treatment, training of health-care providers, education and information on the wide use of cessation is scarce. Therapies, as well as fi nancial resources are limited and rarely incorporated into standard health care. Also, smoking cessation is not seen as a public health priority and is not necessarily approached as a key tobacco-control strategy.

Smoking cessation services are most effective when they are part of a coordinated tobacco control programme. Brief cessation counselling is relatively inexpensive when integrated into existing primary health-care services, is usually well received by patients, and is most effective when it includes clear, strong and personalized advice to quit. Communication technologies -such as telephone quitlines, text messaging, interactive telephony, and online counselling -as well as psychological and behavioural modifi cation therapies, offer important support. Cessation prescription medicines, available in many countries like nicotine replacement therapies, Bupropion and Varenicline can double the likelihood that someone will successfully quit.

Bronchiectasis is an old disease that we all treat, but surprisingly little about this disease has been well studied. The defi nition, diagnosis, natural history, pathogenesis and treatment are all uncertain. This talk examines these points in the light of new information about biofi lms and "normal" bacteria. It asks more questions than it answers, but the questions raise thoughts on whether our usual approaches are the best. The mediastinum is generally split into three compartments strictly for the purpose of classifi cation of the most likely abnormality in the individual compartment. There are no anatomical boundaries or fascial planes that divide one compartment from the other. Classically, the compartments have been classifi ed as anterior, middle, and posterior. A recent change in classifi cation has used the categories of anterior, middle-posterior, and paravertebral compartments. Approximately 50% of mediastinal tumors are located in the anterior compartment, 25% in the middle compartment, and 25% in the posterior compartment. Asymptomatic masses are more likely to be benign than malignant, and symptomatic masses are more likely to be malignant than benign; however, there is a large variation The most common tumors in the anterior mediastinum consist of thymoma, lymphoma, germ cell tumors, and thyroid tumors. Thymoma is by far the most common anterior mediastinal tumor and approximately 2/3 are encapsulated and non-invasive while 1/3 are invasive. The most common paraneoplastic syndromes associated with thymoma include myasthenia gravis, hypogammaglobulinemia, and pure red blood cell aplasia. Benign teratomas occur in both male and females, while malignant germ cell tumors of the mediastinum are almost exclusively in males. Lymphoma can occur most commonly in the anterior or middle mediastinum and may be associated with systemic symptoms and occasionally superior vena cava syndrome. The most common abnormalities in the middle mediastinum include lymphoma, granulomatous disease, and developmental cysts. Bronchogenic cysts are almost always benign, although they can cause symptoms such as obstructive pneumonia and are generally treated with surgical resection. Recent mediastinal compartment classifi cation has switched from posterior mediastinum to naming this the paravertebral compartment. It is located posterior to an imaginary line drawn to connect the anterior aspects of the vertebral bodies on the lateral chest radiograph. The most common tumors in this location are neurogenic tumors, meningoceles, or thoracic spine lesions. The most common neurogenic tumors in adults are neurilemomas, and they are almost always benign. Neurofi bromas also occur in this compartment. They are frequently benign, but may be malignant, especially in patients with neurofi bromatosis. In these individuals, malignant tumors of the nerve sheath origin are more common. Ganglioneuroma, ganglioneuroblastoma, and neuroblastoma are more common neurogenic tumors in children or adolescents.. Cough is an important lung defense. In a refl ex manner, noxious agents are expelled from the airways as these are sensed by the receptors in the airway epithelium. In addition to appreciating its cleansing function, understanding cough refl ex is important in the diagnosis and treatment of common clinical conditions. Most diseases associated with cough are transient. A problem arises when cough persists and becomes chronic. An in-depth search for the underlying pathology is warranted since treatment directed to the cause of the cough is curative in over 90% of cases. An anatomic-diagnostic protocol ensures a systematic search for cough etiology but unfortunately, this approach can be lengthy and in many settings, impractical. Thus an empiric syndromic approach is now recommended. This paradigm shift is borne by the following premises:

(1) the current awareness of the relative frequency of the disorders (alone or in combination) that can cause cough; (2) the sensitivity and specifi city of many (but not all) diagnostic tests in predicting the cause of cough has been established; (3) a sequential evaluation and treatment for the common causes of cough using a combination of selected diagnostic tests and empiric therapy has been proven effective; and (4) a sequential and additive therapy is often crucial because more than one cause of cough is frequently present. A recent study by Dr. Aileen Wang on "The Management of Chronic Cough in a Tertiary Center: An Asian Perspective" showed that even in a Filipino immunocompetent population, the most common causes of chronic cough is Asthma, Post-nasal drip Syndrome (PNDS) and Gastroesophageal Refl ux Disease (GERD). The study concluded that: (1) The ACCP recommendations are generally applicable to an Asian setting. Research of viruses, their structure, pathogenicity and host-interactions has burgeoned. We now understand how viruses infect cells, how they replicate, how they interfere with host defences and how they interact with other tissue events and pathologies. Rhinovirus infection causing the common cold is the most frequent and 'common' infection in humans. It is also implicated in most exacerbations of asthma and COPD. The patho-biology of rhinovirus will be used to illustrate virus pathogenicity, virus-host-interactions and to highlight potential future therapeutic options.

SY 12-02

Much hope has been placed in the discovery of biomarkers to help understand the mechanisms of diseases such as COPD, help stratify the disease better and guide treatment. It is also hoped that some of these could speed up drug discovery by serving as surrogate markers that respond to novel drugs within a shorter timescale than is the case with current drug trials in which the main outcome is the spirometric measurement of forced expiratory volume in one second (FEV1). Although studies in patients with COPD have identifi ed several biomarkers, most of these need to be validated and their prognostic value is unclear. Many of the markers have been identifi ed in blood and although it is recognised that there are non-pulmonary consequences of COPD, some of which can be viewed as systemic biomarkers measured and/or generated in the lungs are likely to be most informative. There are several methods to identify and quantify biomarkers of COPD and different biological samples (blood, BAL, sputum and lung tissue) can be used to provide material for such analyses. Whilst most studies to date used commercial immunoassays (ELISA), there has been a keen interest in applying unbiased approaches such as proteomics. We have recently completed a large programme of work which applied 2-dimenshional electrophoresis and mass spectrometric analysis to identify biomarkers of COPD. Induced sputum was obtained from COPD patients with a spectrum of disease severity and control subjects. Two-dimensional gel electrophoresis and mass spectrometric identifi cation of differentially expressed proteins was fi rst applied to induced sputum from GOLD Stage 2 COPD patients and healthy smoker control subjects. Initial results thus obtained were validated by a combination of immunoassays (Western blotting and ELISA) applied to a large subject cohort. The biomarkers were localised to bronchial mucosa by immunohistochemistry. Of 1325 individual protein spots identifi ed, 37 were quantitatively and 3 qualitatively different between the two groups. 40 protein spots were subjected to tandem mass spectrometry, which identifi ed 15 separate protein species. Seven of these were further quantifi ed in induced sputum from 98 individuals. Using this sequential approach, two of these potential biomarkers (apolipoprotein A1 and lipocalin-1) were found to be signifi cantly reduced in COPD patients when compared to healthy smokers. Their levels correlated with FEV1/FVC, indicating their relationship to disease severity. In summary, a potential role for apolipoprotein A1 and lipocalin-1 in innate defence has been postulated previously; our discovery of their reduction in COPD indicates a defi cient innate defence system in airways disease that could explain increased susceptibility to infectious exacerbations.

Persistent chronic infl ammation, repetitive tissue injury, and dysregulated epithelial repair leading to tissue remodeling and fi brosis are the hallmarks of chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), chronic asthma, pneumoconiosis, pulmonary fi brosis and sarcoidosis. The innate immunity system with its pattern recognition receptors are recently identifi ed to involve in the pathogenesis of these chronic lung diseases. The neutrophilic infi ltration of the airway mediated through T H 17 and IL-17 family may play an important role in steroid-resistant asthma and status asthmaticus. In addition, the epigenetic modifi cation of gene expressions and cellular senescence may modulate the progression of chronic asthma and COPD. Histone deacetylase 2 (HDAC2), which can be inactivated by oxidative stress or PI3K-AKT pathway, may regulate corticosteroid-related anti-infl ammatory response. Manipulation of HDAC2 activity is a new treatment direction in steroid-resistant asthma and COPD. SIRT1, a NAD + -dependent deacetylase, is an important signaling pathway related to cell survival, DNA repair, and apoptosis. The SIRT1 is decreased in alveolar macrophages of smokers and COPD patients, and associated with pro-infl ammatory response through the activation of NF-κB. Understanding the complexity of infl ammatory and epigenetic regulations in chronic lung diseases may potentiate the development of novel therapies. Fibrosis is a common fi nding in chronic lung diseases, with TGF-β-related pathways play important roles. Myofi broblasts are the principal effective cells in the fi brogenic process. They can be evolved from the activation of resident pulmonary fi broblasts, marrow-derived fi brocytes, or the trans-differentiation of pulmonary epithelial cells through epithelial mesenchymal transition (EMT). Further understandings on the EMT process in lung tissue repair may help to elucidate the mechanism of lung remodeling and fi brosis. In addition, lung stem/progenitor cell study appears to be a new and potential fi eld in lung injury and repair. It is anticipated that more clear mechanisms behind lung remodeling and fi brosis can be identifi ed and new treatment modalities be developed accordingly.

SY 12-04

Cancers are genetic diseases with constitutional genomic variations that are present in normal cells contributing to an individual's risk of developing cancer such as lung cancer. Furthermore, cancer cells acquire genetic mutations and genome wide changes in their DNA as well as their epigenome compared to their normal cellular counterparts. Some of these mutations have turned out to be important driver mutations and are associated with exquisite sensitivity to targetted cancer therapies. Some of these genetic changes include EGFR and EML4-ALK fusion gene mutations. Epigenetic changes include methylation abnormalities as well as histone modifi cations, and possess the characteristic of potential reversibility which is attractive for the development of new therapies. The Human Genome Project and rapid technological advances including deep DNA sequencing have contributed signifi cantly to the ability to detect cancer specifi c genetic, genomic and epigenomic aberrations. These genetic and genomic abnormalities have promise across the translational spectrum from identifying individual susceptibility to cancers, early diagnosis markers, molecular pathology and tailoring of treatment (predictive biomarkers) as well as informing on outcome (prognostic biomarkers). Much work remains to be done to validate clinical utility and translate these potential useful biomarkers into useful clinical tools. This session will review some of the developments in the genomics and epigenomics of lung cancer and mesothelioma. Asthma is a disease that is diagnosed largely on a history of variable symptoms and the demonstration of variable airway narrowing. It is associated with airway infl ammation (CD4 T-lymphocytes, B-cell lymphoid aggregates, macrophages, eosinophils and, in adults, neutrophils) and airway wall remodelling (airway wall thickening, principally increased airway smooth muscle and deposition of collagen below the basement membrane, with minor encroachment on the airway lumen). It is not associated with a prominent effect on the lung parenchyma. The cause(s) of asthma remains unknown and the severity of disease remains largely constant. COPD is diagnosed with a spirometer and is defi ned as a fi xed reduction in FEV1, relative to FVC. When caused by cigarette smoke it is associated with airway infl ammation (CD8 T-lymphocytes, B-cell lymphoid aggregates, macrophages and neutrophils) and airway remodelling (mild increase in airway wall thickness including airway smooth muscle with encroachment on the airway lumen) and tissue destruction (emphysema and loss of small conducting airways). The severity of COPD increases with age and continued exposure to irritants. COPD has many causes including smoking cigarettes, burning of biomass fuels, asthma and early life respiratory illness and exposures (viral infections, bronchopulmonary dysplasia). As a group, patients with asthma have reduced lung function, in relation to disease severity, and may have a slightly increased rate of decline in lung function. Patients with asthma who smoke have reduced lung function and an accelerated decline in lung function. Apart from stopping smoking there is no current treatment that can improve the rate of decline in lung function in patients with asthma or COPD. Therefore prevention, early intervention and uncovering the unknown environmental and genetic contributions to airway diseases remain critical.

SY 13-02

Situation The ISAAC and ARIAP studies have showed the different prevalence but heavy burden caused by asthma in Asia Pacifi c countries is common. Goals With inhaled corticosteroids and other medications, the goals in managing asthma in developing countries should attain those stated in GINA: control of symptoms, maintaining normal activity levels, normal pulmonary functions, preventing asthma exacerbations, avoiding adverse affects and preventing asthma mortality. In developing countries, avoiding the abuse of short-acting beta 2 agonists, systemic corticosteroids and antibiotics is also a major problem. Accessing medical care and medications is crucial.

Steps A core group, preferably at an university medical center, is the basic step. The asthma and COPD outpatient care unit (ACOCU) run by this core group will help in getting experience and capacity building. The following steps are GINA dissemination and implementation, patient club formation, increasing awareness, training doctors and nurses, advocacy, researches, efforts for the availability of affordable asthma drugs, and multiplying ACOCU in the whole country.

The sustainability of ACOCU is assured by successful implementation of GINA. A network of ACOCU will encourage and improve the activities of ACOCUs. Successful provincial ACOCU will encourage the building of district and even commune ACOCUs. Diffi culties The continuous medical education for all doctors on GINA, the medication affordability, spirometers and mechanism to maintain an ACOCU. Despite the advances in asthma diagnosis and treatment, SLTA cases continue to present in the ER, sometimes leading to unnecessary mortalities. These are highly preventable situations with inhaled steroid based chronic therapy. With expert care, most patients get through ER/ICU urgent phase with good outcomes. These strategies are published and updated regularly in the international asthma guidelines. The Finnish experience confi rms that a national program that pushes for implementation of guideline recommendations is able to reduce asthma hospitalizations and cost of care. Not all countries have such a program but in most developed economies, the cost of asthma care including medications is covered provided the guidelines are followed. Unfortunately, even in these affl uent countries, a subset on patients still lands in the ER with SLTAs. While there may have been a failure of health care delivery, the cross-country existence of this problem raises the prospect that some patients are prone to life-threatening exacerbation. SLTAs may have its own specifi c risk factors that are distinct from the risk factors for simple hospital admission for acute severe asthma. By defi ning risk factors for SLTA within the population of those admitted to hospital with acute asthma, we may be able to develop specifi c interventional strategies to reduce its occurrence. Reported SLTA risk factors include advancing age, chronic severe asthma, increased infl ammation markers, asthma exacerbated by pneumonia and low nutritional status. Other risk factors include recent hospital admission, prior intubation, steroid dependence, non-adherence to inhaled corticosteroids, psychological or psychosocial problems, lack of access to medical care, lower FEV1, and current cigarette-smoking. A specifi c phenotype of severe brittle asthma has been reported. The backbone of ER management for SLTA includes quick assessment of severity, oxygen therapy, early use of systemic steroids and repetitive SABA bronchodilator administrations. Enhancements include the use of SABA with high intrinsic effi cacy, the addition of ipratropium in refractory cases and the concurrent administration of inhaled corticosteroid for its non-genomic, airway edema-reducing effect. MgSO4 can also be considered for refractory cases. When ventilator support is needed, NIV may be attempted in some patient. For intubated cases, the ventilatory strategy includes low TV and RR, high I : E ratio, and monitoring for the development of dynamic hyperinfl ation. The burden of the SLTA problem can be mitigated by identifying its phenotype a priori, providing preventive therapy before actual exacerbation occurs and putting in the ER/ICU the appropriate treatment protocols.

Journal Compilation © 2010 Asian Pacifi c Society of Respirology 

Available treatment of asthma using inhaled corticosteroids and long-acting inhaled β2-agonists (LABAs) is highly effective and safe. Importantly, it is also relatively inexpensive. However, many patients remain poorly controlled despite the use of optimal treatment. Most advances in asthma therapy have been achieved by improving these drugs and more recently several promising once-a-day LABAs have been developed. New corticosteroids are also being developed with differential effect on trans-activation and trans-repression of pro-infl ammatory transcription factors, thus giving them a better therapeutic index. The big challenge in asthma is posed by corticosteroid unresponsiveness which is relative and therefore requires high doses to achieve symptom control which inevitably leads to side-effects. One option being pursued is to develop activators of the nuclear enzyme histone-deactylase (HDAC)2 which is recruited to the gene initiation site of pro-infl ammatory mediators.

There is an increasing appreciation that asthma is not a single disease and is increasingly seen as a syndrome consisting of several phenotypes. So far, two relatively clear subsets have been identifi ed: eosinophilic and neutrophilic forms of asthma. With this notion in mind, attempts are being made to develop more-specifi c inhibitors for a range of mediators with the hope that sub-phenotypes of asthma will be identifi ed that respond well to either single mediator inhibitors or a combination of these. A number of cytokine modulators have been tested in clinical trials, the most notable example being anti-TNF inhibitors which is felt to be more relevant to neutrophilic asthma. Unfortunately, large clinical trials with TNF inhibitors have not found them to be very effective. Treatment with blocking antibody for the eosinophils growth factor, IL-5, has been slightly more effective, with early clinical trials showing that the treatment reduces the frequency of exacerbations in patients who have eosinophilia. Whilst the exact mechanisms leading to the development of these two subphenotypes is not fully understood, it is thought that eosinophilia represents a risk factor for exacerbations which has led to eosinophils counts in sputum being used as a guide to treatment; this has been benefi cial in reducing exacerbations. Neutrophilic forms of asthma represent a special challenge because patients with neutrophilia tend not to respond well to corticosteroids, making them reliant on bronchodilators. Such patients' asthma may be driven by mechanisms that involve IL-17 which induces the production of neutrophil chemoattractants by the epithelium, which makes IL-17 and its chemo-attractant axis a target for novel therapies. The major unmet need in asthma is the treatment of infections. There are early indicators of antibiotic treatment (macrolides) being effective in the treatment of severe asthma. But the real hope comes from novel strategies aimed at the effects of viruses which are the cause of most acute exacerbations, both in milder and more severe forms of disease. Recent studies have identifi ed a defi ciency in type I interferons (IFN), the production of which by the bronchial epithelium -the prime target of virus infection -has been shown to be reduced when epithelial cells from asthmatic are grown in culture and infected ex vivo. In the acute care setting, NIV must usually start without delay to avoid further deterioration and an increased likelihood of failure. Thus, the decision to start must be made quickly based on a bedside assessment. I recommend a simple two step process, the fi rst of which is to assess the patient's need for ventilatory assistance. If the patient has increased dyspnea (moderate to severe) and evidence of increased work of breathing including tachypnea (>24/min in obstructive diseases and >30/min in hypoxemic respiratory failure), increased accessory muscle use or abdominal paradox, the patient needs ventilatory assistance. Arterial blood gases are helpful in making this assessment, but I discourage awaiting blood gas results before starting if the need is obvious, because the window of opportunity may close if initiation is too delayed. I do recommend obtaining baseline blood gases, however, and using them for comparison with later measurements to make certain that the patient is responding.

The second simple step is to make sure patients have no contraindications to NIV. These include patients with a need for immediate intubation by virtue of a respiratory arrest, hypotensive shock, or uncontrolled arrhythmias or upper gastrointestinal bleeding. The inability to fi t a mask because of a facial deformity, recent facial surgery or burns is also a contraindication. Relative contraindications include agitation that prevents the patient from tolerating the mask, increased secretions or diminished ability to protect the airway. Patients with these contraindications are at increased risk of failure if placed on NIV and should be promptly intubated. Patients with multiple risk factors for NIV failure should be started only by experienced personnel under very close monitoring. In patients with hypercapneic respiratory failure, these include higher acute physiology scores, marked tachypnea, greater acidemia at baseline and a worse neurological score. In hypoxemic respiratory failure, risk factors for NIV failure include the diagnosis of ARDS or pneumonia, greater age, hypotension and the failure to improve oxygenation substantially within the fi rst hour. Although patients at high risk of NIV failure can still be given a trial if the clinicians judge it to be indicated, but they must be watched very closely in an ICU, with plans to intubate if there is no improvement within the fi rst hour or two. Just as the decision to endotracheally intubate a patient in respiratory failure is a clinical judgment that requires the consideration of multiple factors, so is the decision to implement noninvasive ventilation. In the largest RCT to date, CPAP and NPPV performed similarly, both improving dyspnea scores and pH more rapidly than with oxygen alone, but neither lowered intubation nor mortality rate (the major outcome variable) compared to oxygen-treated controls. However, this study enrolled patients whose intubation rate was slightly below 3% in all of groups, including controls, suggesting that they were too mildly ill to manifest a signifi cant mortality benefi t. Meta-analyses of the RCTs on CPAP or NPPV compared with O 2 therapy alone have confi rmed the benefi ts described above, even showing a signifi cant mortality benefi t with CPAP. Meta-analyses comparing the 2 modalities show equivalency of NPPV and CPAP with regard to reduction of intubation, lengths of stay and mortality, and with similar myocardial infarction rates. Therefore, by virtue of its greater simplicity and potentially lower cost, CPAP alone is generally regarded as the initial noninvasive modality of choice for cardiogenic edema patients. But because some studies have found that NPPV reduces dyspnea and improves gas exchange more rapidly than CPAP alone, NPPV is preferred by some initially and can be substituted for CPAP if patients treated initially with CPAP remain dyspneic or hypercapnic. The success of noninvasive positive pressure to treat cardiogenic pulmonary edema has encouraged its extension into the pre-hospital setting. An emerging trend is to provide CPAP devices on ambulances for initial therapy of cardiogenic pulmonary edema, a practice that has been associated with decreased need for intubations in the fi eld. Patients with advanced Chronic Obstructive Pulmonary Disease (COPD) experience poor quality of life and very high levels of symptom burden, including intractable shortness of breath, activity limitation, fatigue, social isolation, anxiety and depression. Many of the these burdens are shared with caregivers, and resources in the community to support individuals and their families with chronic illness in the community are often lacking. With the recognition that patients with advanced COPD and their caregivers have so many unmet needs, there is a growing acceptance for the need to improve the care and quality of life for patients with advanced COPD. While signifi cant gaps in our knowledge and understanding of this area remain, factors contributing to these adverse experiences will be discussed. The importance of prevention, relief, reduction, and soothing of symptoms, without affecting a cure, will be emphasized as an integral component of the care provided for these patients. Techniques and tools to optimize the care of patients with advanced COPD, including optimizing pharmacologic therapies, inter-professional team care, anticipating and appropriately initiating end-of-life planning, patient and caregiver advocacy, as well as timely and effective communication will be reviewed. Withdrawal or withholding life support in medically futile cases has been recognized as an ethical and a legal procedure. It is based on the inherent right of a person to autonomy in making health care decisions. The western model however may not apply to the Asian setting being widely varied in terms of cultures, religions and economic progress. More than an individual decision, it may actually be a communal decision with a heavy reliance on input of relations, especially the elders. Life support withdrawal often entails complete discontinuation of all measures. Efforts to avoid feelings of guilt or abandonment may make families opt for partial withdrawals even when they are not shown to be any more benefi cial. Studies have shown that distrust with the medical system does play a major role. Active discussions may be diffi cult with reticent cultures or when there are gender differences between patients or their families and the physicians.

In this era of globalization and migrations, an understanding of these differences may minimize potential confl icts that arise out of these discussions.

Awareness that the Western approach may not fi t the Asian medical model allows the health care providers to be sensitive to the needs and wants of their patients and their families. It is hoped that the data reviewed spurs the development of Asia Pacifi c guidelines that try to fi nd some uniformity in the diversity of the region. Screening for lung cancer is not currently recommended by any major medical organization. Multiple Phase II non-randomized trials of computed tomography (CT) screening have yielded enticing results. They have demonstrated that CT screening detects smaller size lung cancer of 12-15 mm in diameter. It has been documented that the chest radiographs miss 70-80% of the cancers detected by screening CT. In prevalence studies, 60-80% of detected cancers are stage I. When CT screening results were compared to a validated control group, CT has been shown to detect 3 times more lung cancer than would be expected and results in ten times more thoracic operation than would be expected. Additionally, no decrease in advanced stage cancers or decrease in lung cancer deaths were observed. To date, multiple small randomized controlled screening trials (RCT) have been reported, but they have been too small to assess if CT screening reduces mortality. A meta-analysis of baseline fi ndings from six small randomized controlled trials observed more stage I and more total lung cancers in the CT screened group. For every 1000 individuals screened with low dose CT, 9 stage I NSCLC and 235 false positive nodules were detected and 4 thoracic operations were performed for benign nodules.

The two large RCT of CT screening that may defi natively answer the question of CT screening and its ability to decrease lung cancer mortality are the National Cancer Screening Trial (NLST) and the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial. Mortality results from those two trials are anticipated in 2011 and 2015 respectively. A recent report from the NELSON trial validated the use of CT volumetric assessment of nodules to assess malignancy and determine which nodules should be treated surgically.

Currently, there is considerable effort to identify susceptibility genes for lung cancer with particular interest in 15q 24-25 which is strongly associated. This region contains several genes of interest, including three genes that encode nicotinic acetylcholine receptor subunits. However, these genes may just be associated with nicotine dependence. A recent report utilizing GWAS (genome wide association scan) methodology identifi ed 2 SNPs at 13q31.3 associated with lung cancer susceptibility in never smokers. An enormous research effort is underway related to biomarkers in airway epithelial cells, blood, sputum, breath, and urine for early diagnosis or prediction of high risk. Intense efforts are devoted to develop models of risk for determining which individuals should be offered screening.

Journal Compilation © 2010 Asian Pacifi c Society of Respirology SY 16-02

Lung cancer is the leading death-related cancer worldwide. Molecular targeted therapy appears to be an alternative approach for patients with non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) is one of these targets, responsible for the cell growth, proliferation, apoptosis and metastasis of the tumors. EGFR-tyrocine kinase inhibitor (TKI) has been applied to target EGFR and suppress the development of tumors. Some EGFR-TKIs, including gefi tinib and erlotinib, have been approved, while the others are still under development or in clinical trials. Several studies demonstrated that EGFR somatic mutations might predict the high response rate and greater survival benefi t of EGFR-TKI. In addition, EGFR amplication, K-ras mutation, MET amplication or the EGFR T790M mutation might predict the clinical effect of these drugs. Both erlotinib and gefi tinib have been undergoing several clinical trials for NSCLC treatment as a single drug or in combination with chemotherapy. Br.21 trial showed that erlotinib improved survival with 731 previously treated NSCLC patients in a randomized multicenter during phase III study. Thus, erlotinib was approved to be the second or third-line treatment of advanced NSCLC patients. However, ISEL failed to demonstrate a statistically important benefi t of gefi tinib in overall survival as compared with placebo. Different study population, dosing and drugs of Br.21 and ISEL might explain the different results. In IPASS trial, 1217 clinical selected NSCLC patients with Asian origin and characterised by adenocarcinoma histotype were treated with gefi tinib or paclitaxel/carboplatin doublets as the fi rst line therapy. The results showed that gefi tinib had the superiority in terms of progression free survival (PFS) in patients with EGFR mutation. In EORTC 08021 and Perol trials, gefi tinib and erlotinib maintenance therapy showed the trend of improved PFS, but not overall survival in advanced NSCLC patients. The toxicity of gefi tinib and erlotinib includes diarrhea, rash, etc., which can be well-tolerated. Novel EGFR-TKIs include vandetanib, sorafenib, sunitinib, and cediranib, of which some are under evaluation in phase III trials as monotherapy or in combination with standard chemotherapy. Vandetanib targets both EGFR and VEGFR and was tested in the second phase trial, suggesting the addition of vandetanib to the single chemotherapy might improve response rates and survival. Sorafenib has been applied to different carcinoma histology and in combination with different chemotherapy. When combined with paclitaxel and carboplatin to treat patients with squamous cell cancer, no survival benefi t was seen. However, another clinical trial was launched to investigate the effect of Sorafenib, in which squamous cell cancer were not eligible. Novel EGFR-TKIs are under development with hope of overcoming resistance to EGFR-TKI gefi tinib and erlotinib. There is a great need of further clinical trials. EGFR-TKI is one of the important alternatives in treatment of NSCLC and has shown promising potential in the future. More promising results may come out if the combination and sequence of EGFR-TKI with traditional therapies, like chemotherapy, radiotherapy and surgery, can be optimized. There is also a need of disease-specifi c biomarkers to predict the effect of the drugs and identify the patients most likely to benefi t from the drugs.

Lung cancer is the number one cause of cancer death. Most cases are found after distant metastasis, and outcome of drug therapy for these patients used to be disappointing. However, we have faced a new paradigm shift, i.e., the molecular targeted therapy and the individualized therapy. Many promising data has reported from not only western countries but also Asian countries such as the effi cacy of EGFR TKI to tumors with mutated EGFR, that of ALK inhibitor to tumor with EML4-ALK fusion protein, and that of pemetrexed to non-small non-squamous cell lung cancers. New questions have emerged from these new evidences derived from some important clinical trials. Among them, questions regarding with ethnic difference would be one of the most important issues. Is survival data same between Asian and Caucasian? (Data from Japan Lung Cancer Registry Study as well as some global trials have shown survival of Asian patients with lung cancer appears to be obviously better than that of Caucasian.) Why EGFR mutation is frequent in Asian patients? Is only EGFR gene status related with prognosis of lung cancer? What would be the cause of ALK abnormality? Is the criteria of pathological diagnosis for lung cancer same between Asian countries and western countries? Here, newest evidences for treatment of lung cancer will be presented, and importance of ethnic difference and Asian trials will be discussed. The burden of Chronic Obstructive Pulmonary Disease (COPD) is growing. Despite these growing numbers, many patients with patients with COPD remain undiagnosed, the greatest number being those with milder disease. Delays in the diagnosis of COPD are common. Evidence suggests that patients with mild COPD experience increased symptoms, reduced activity levels and exercise capacity, and impaired health-related quality of life. This growing body of evidence has made it clear that mild COPD is not 'normal'. With recognition of this reality and efforts to appropriately recognize COPD at an earlier stage, clinicians must be aware of the various therapeutic options for their patients. The defi nition of mild COPD will be discussed, as well as effective strategies for the targeted early diagnosis of COPD. The numerous and varied disease manifestations and consequences for patients with milder COPD will be reviewed. In addition, practical and effective management options available to clinicians caring for patients with mild COPD will also be examined.

Clinicians have been long aware that neither the traditional distinctions of "emphysema" versus "chronic bronchitis" nor the traditional clinical phenotypes of "blue bloater" and "pink puffer" are suffi cient to categorize patents that suffer from chronic obstructive pulmonary disease (COPD). Recently, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop has used quantitative measures (FEV1 and FEV1/FVC ratio) to defi ne COPD, but this defi nition fails to take into account the full heterogeneity of COPD. With an increased understanding of pathophysiologic variation, COPD now clearly represents a spectrum of overlapping diseases with important extrapulmonary consequences. A "phenotype" describes the outward physical manifestations of a particular disease, and comprises anything that is part of the observable structure, function or behavior of an individual. Such phenotypic distinctions in COPD include: frequent exacerbator, pulmonary cachectic, rapid decliner, airways hyperresponsiveness, impaired exercise tolerance, and emphysema versus airways disease. These variable manifestations, each with unique prognostic, clinical and physiologic implications, represent distinct phenotypes within COPD. While all of these phenotypes have smoking as a common risk factor, the other risk factors that determine these phenotypes remain poorly understood. An individual smoker has variable expression of each phenotype and there is mounting evidence that COPD phenotypes have different clinical outcomes. These phenotypes can be broadly classifi ed into one of three groups: clinical, physiologic and radiographic. Thus, the paradigm that COPD is one disease may be incorrect, and suggests that COPD should be considered as a spectrum of smoking-related diseases. Failure to consider COPD phenotypes is likely to limit the power of therapeutic trials since not all COPD patients are likely to benefi t from each therapy. The challenge to future COPD researchers is to better characterize these phenotypes and identify their risk factors. Measurement of fractional exhaled nitric oxide (FeNO) is an attractive biomarker of diseases where airway eosinophilia dominates. Indeed even before any randomized controlled trials were published some were advocating treatment tailored in accordance to FeNO data. Commercially available bench-top and portable FeNO analyzers are now readily available and in some countries, FeNO measurements attract a payment. However, despite the ease of measuring FeNO, it has its drawbacks in biological and measurement issues. Biologically FeNO is signifi cantly infl uenced by atopy, intake of caffeine, exercise, ethnicity, etc On the measurement front, variabilites include: FeNO measured by different analyzers may provide different values and on-line vs off-line measurements. The cut-off for determining 'abnormally high results' is yet unknown. Not surprisingly, there is discordance on the effi cacy of tailoring asthma medications in accordance to sputum eosinophils [1] and FeNO [2] in people with asthma, although both are eosinophilia infl ammatory markers. Tailoring of medications in accordance to sputum eosinophilia (compared to standard practice) significantly reduced exacerbations in adults with asthma (Odds ratio 0.47, 95%CI 0.28, 0.87). In contrast, the benefi t of tailoring of medications in accordance to FeNO was, at best, modest. The utility and limitations of using FeNO levels in the clinical setting will be discussed in this talk. Shortness of breath and activity limitation are cardinal symptoms experienced by patients suffering from respiratory illness or disease. Cardiopulmonary exercise testing (CPET) allows for the objective evaluation of these symptoms, recognizing that exercise involves the effective integration of respiratory, cardiovascular, neuromuscular and metabolic functions. The organs involved in these varied and important roles have a sizeable reserve, with the consequence that clinical manifestations of a disease state or abnormality may not become readily apparent until the functional capacity of the organ(s) is markedly impaired. Objective assessment of various parameters during exercise, which places an increased physiologic demand on the functional reserve capacity of these organs, can provide a sensitive method for the early detection of abnormal function and responses(s). The results from exercise testing also parallel functional capacity and quality of life more closely than measurements obtained only at rest, and have been shown to accurately predict important outcomes, such as mortality, in a variety of patients and clinical circumstances.

A brief overview of normal exercise physiology and characteristic responses demonstrated by patients with various disorders frequently assessed by the Pulmonologist will be offered. In addition, a summary of the indications, conduct, and practical interpretation of CPET will be presented in this session.

Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecifi ed subgroup analysis of a randomised controlled trial

Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey

International variation in the prevalence of COPD (the BOLD Study): a population-based prevalence study

Chronic obstructive pulmonary disease in fi ve Latin American cities (the PLATINO study): a prevalence study

Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities

Global burden of COPD: systematic review and metaanalysis

Prevalence of chronic obstructive pulmonary disease in China. A large, population-based survey

Diagnostic labeling of chronic obstructive pulmonary disease in fi ve Latin American cities

COPD prevalence in a random population survey: a matter of defi nition

Treatment of COPD: the sooner the better

Clinical COPD phenotypes: a novel approach using principal component and cluster analyses

Offi ce spirometry signifi cantly improves early detection of COPD in general practice: the DIDASCO Study

Salmeterol and fl uticasone propionate and survival in chronic obstructive pulmonary disease

Clinical trial design considerations in assessing long-term functional impacts of tiotropium in COPD: the UPLIFT trial

A 4-year trial of tiotropium in chronic obstructive pulmonary disease

Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease

Effi cacy of salmeterol/fl uticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study

Effects of Tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecifi ed subgroup analysis of a randomised controlled trial

Tiotropium as a First Maintenance Drug in COPD: Secondary Analysis of the UPLIFT trial

Treating tobacco use and dependence: 2008 update. Clinical practice guideline

Tobacco Atlas

The MPOWER package. Geneva, World Health Organization

Implementing smoke-free environments. Geneva, World Health Organization

Curbing the Epidemic: Governments and the Economics of Tobacco Control

Clinical and public health signifi cance of treatments to aid smoking cessation

We report that pulmonary emphysematous lesions appear to be a dynamic phenomenon that involves not only the gradual loss of alveolar structure, but apoptosis, cellular proliferation, and cellular senescence as well. Cellular proliferation compensates for increased alveolar cell apoptosis in chronic obstructive pulmonary disease (COPD) patients. However, smoking, age, and the increased cell cycle turnover that compensates for apoptosis accelerate alveolar cell senescence, thereby halting cellular proliferation and tipping the balance toward apoptosis, which, in turn, promotes the formation of emphysematous lesions. As a result, alveolar cells disappear and the emphysematous lesions progress. At the same time, cellular senescence is thought to induce infl ammation. More specifi cally, senescent alveolar cells induce infl ammation by producing various infl ammatory cytokines in tissue. Lymphocytes and Clara cells may also age more rapidly in the lungs of COPD patients. Lymphocyte senescence may induce an autoimmune reaction and increase susceptibility to infection, and Clara cell senescence may impair airway regeneration as well as sustain airway infl ammation. Thus, cellular senescence may be involved in arrested tissue repair, chronic infl ammation, and increased susceptibility to infection, which are the typical features of COPD. There is increasing recognition that COPD is an increasing global burden. New drug treatments continue to emerge suggesting that COPD is more responsive to treatments than previously thought. However, there is still much that is unknown about COPD that will contribute to further advances in treatment and management. Pulmonary imaging can contribute by providing information on how structure and function relate to relevant clinical parameters, such as disease progression, treatment responses and exacerbations. In other words, imaging can help characterise COPD in terms of clinical outcomes or phenotypes. There have been many advances in imaging methodology, including CT, MRI, SPECT and PET. Recent fi ndings from research studies using innovative methods of studying structure and particularly function, in COPD will be reviewed. Their clinical implications will be discussed. The spectrum of children's interstitial lung disease (ChILD) encompasses a large, heterogeneous group of pediatric diffuse lung disorders that are diffi cult to diagnose and treat. As the differential diagnosis is large, a systematic approach is needed for accurate diagnosis. The classic fi rst step of obtaining a detailed history and performing a careful physical examination remains essential for providing diagnostic clues as well as assessing severity of illness. As examples, a history of hemoptysis and fatigue would suggest an alveolar hemorrhage syndrome; exposure to avian antigens, hypersensitivity pneumonitis; and a history of adenovirus pneumonia, bronchiolitis obliterans. The presence of growth failure, crackles, loud P2, and clubbing on physical examination would point to a severe and progressive lung process with cor pulmonale. Recent advances in diagnostic modalities have greatly improved the ability of clinicians to identify these disorders. In infants and children with diffuse lung disease, genetic testing can be diagnostic for surfactant dysfunction mutations (SP-B, SP-C, ABCA3, TTF-1, GM-CSFRa receptor). Infant lung function testing has proven useful for assisting in the diagnosis of certain disorders, such as neuroendocrine cell hyperplasia of infancy (NEHI) and distinguishing NEHI from surfactant mutations. HRCT may detect extent and severity of disease, but can also be useful in diagnosing specifi c disorders, such as NEHI (symmetric ground glass densities in the right middle lobe and lingula and the central lung regions), bronchiolitis obliterans (mosaic perfusion, vascular attenuation, and central bronchiectasis), hypersensitivity pneumonitis (ill-defi ned centrolobular micronodules), and pulmonary alveolar proteinosis (crazy-paving). Bronchoalveolar lavage can aid in the diagnosis of specifi c conditions, such as alveolar hemorrhage syndromes (hemosiderin-laden macrophages), aspiration (lipid-laden macrophages), hypersensitivity pneumonitis and sarcoidosis (lymphocytosis), eosinophilic pneumonias (eosinophilia), and histiocytosis (CD 1a + cells). Lung biopsy performed by video-assisted thoracoscopic surgery (VATS) has largely supplanted conventional open lung biopsy as the procedure of choice as it is equally accurate, but associated with less morbidity. Although lung biopsy remains the gold standard for diagnosis of ChILD, it must be interpreted in the context of the clinical and radiologic fi ndings. It should be emphasized that although lung biopsy can be diagnostic in some disorders, such as bronchiolitis obliterans, it may not be necessary because less invasive studies such as HRCT may be suffi cient for diagnosis. Finally, some pulmonary vascular disorders, such as pulmonary vein stenosis or atresia, may mimic ChILD. For these disorders, echocardiography, MRA, or cardiac catheterization may be required for diagnosis. With a systematic approach and improved diagnostic capabilities, it is reasonable to expect that a specifi c diagnosis can now be made in the vast majority of ChILD cases.