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Respirology (2014) 19 (Suppl. 1), 1–12

AIRWAY VISTA 2014 SPEAKER ABSTRACTS

FEV1, mMRC, CAT, SGRQ – HOW CAN WE ORGANIZE THESE PARAMETERS IN COPD MANAGEMENT? PW JONES Division of Clinical Science, St George’s, University of London, London, UK COPD is a complex disease with many facets, which means that no single measurement tells us everything we need to know. A complete understanding would require knowledge of: 1. Type and degree of inflammation 2. Type, distribution and amount of structural damage to alveoli and airways 3. Effects of these processes on lung function 4. Level of respiratory symptoms 5. Degree of comorbidity 6. Impact on health status Although this is not possible in routine practice, progress is being made in symptom assessment. FEV1: The FEV1 is required in diagnosing chronic airflow limitation and has been a cornerstone of COPD assessment. FEV1 may be relegated to the role of a categorising prognostic variable, used for grouping patients by their degree of airflow limitation. This shift in emphasis is reflected by GOLD, which changed the name of its original assessment scheme from Staging (of COPD), to Grading (of airflow limitation)1. However, even here it is known that composite measures such as the BODE that incorporates mMRC, BMI and 6-minute walking distance along with FEV1 are better predictors of death than FEV1 alone2. mMRC: The MRC Dyspnoea Scale is a very simple scale that was created as part of an epidemiological assessment tool over 50 years ago. It has been used widely and is a valuable tool in COPD assessment. It is an even better predictor of mortality than the FEV1, but it has significant limitations. It assesses disability due to breathlessness, not breathlessness directly, and combines different activities leading to breathlessness into the same response category. The categories are also quite coarse with only 5 points separating the minimum and maximum level of breathlessness. These limitations may not be serious when the mMRC is used as a grading/ prognostic measure, but it is known to have weak evaluative properties and only measures breathlessness, whereas COPD has a much wider range of symptomatic impacts. Impaired overall health status cannot be predicted reliably from mMRC scores. SGRQ: The St George’s Respiratory Questionnaire (SGRQ) and its COPDspecific derivative the SGRQ-C3, were developed to measure overall diseasespecific health impairment in COPD. The SGRQ is a long instrument that is complex to score and difficult to use in routine practice; however it has found wide acceptance in COPD-research and has a key role in clinical trials to assess the overall benefit of treatment. CAT: The COPD Assessment Test (CAT) was developed to provide a simple valid and reliable measure of overall health status impairment for use in routine clinical practice4. The CAT has only 8 items, yet performs very much like the SGRQ. There has been a very rapid uptake of the CAT with numerous validation papers over the last 4 years. The priorities in COPD-treatment are to reduce exacerbations and improve symptoms. The FEV1 is essential to make the diagnosis, but it does not give a reliable measure of the risk of exacerbations – the patient’s history is better5. Similarly, it does not provide a reliable measure of symptoms – that has to be obtained by asking the patient. Yet a patient’s overall estimate of their COPD severity does not reliably correlate with mMRC grade, suggesting that patients cannot reliably self-assess their COPD severity6. Standardised assessment with a well-validated instrument can supplement the history obtained by a specialist by quantifying the patient’s symptoms in a systematic way that can be monitored for changes over time. Alternatively, a general physician or GP can provide patients with a reliable and simple way of assessing symptom severity. GOLD 2011 recommended the mMRC or the CAT as a standardised method of assessing symptoms, however it has become clear that these two methods identify different groups of patients. COPD-assessment must reflect the complexity of the disease. Modern developments in questionnaire methodology allow reliable assessment of the overall impact of the disease in routine practice. Standardised assessment need not take time and introduces reliable patient-centred measurement of COPD-management.

doi: 10.1111/resp.12246

3. Meguro M, Barley EA, Spencer S, Jones PW. Development and Validation of an Improved, COPD-Specific Version of the St. George Respiratory Questionnaire. Chest. 2007;132(2):456–63. 4. Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first validation of the COPD Assessment Test. European Respiratory Journal. 2009;34(3):648–54. 5. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, et al. Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease. New England Journal of Medicine. 2010;363(12):1128–38. 6. Rennard S, DeCramer M, Calverley PMA, Pride NB, Soriano JB, Vermeire PA, et al. Impact of COPD in North America and Europe in 2000: subjects’ perspective of Confronting COPD International Survey. Eur Respir J. 2002;20:799–805.

References 1. Global Strategy for Diagnosis, Management, and Prevention of COPD. Available from: http://www.goldcopd.org. 2. Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, et al. The body-mass index, airflow obstruction, dyspnea and exercise capacity index in chronic obstructive pulmonary disease. NEJM. 2004;350:1005–12.

© 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology

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INFECTIONS AND COPD EXACERBATIONS A PAPI Respiratory Medicine, University of Ferrara, Italy Acute exacerbations are a common occurrence in chronic obstructive pulmonary disease (COPD) patients and the frequency of exacerbations increases with the severity of the disease. In addition to being the major cause of COPD-associated morbidity and mortality, exacerbations contribute to impaired health status, loss of lung function, and thus to disease progression. Many exacerbations are associated with symptoms of infection of the tracheobronchial tree and bacteria have been considered the main infective cause of exacerbations. However, determining the contribution of bacteria to exacerbations is difficult as COPD patients are often colonised with bacteria even when clinically stable and the relative contribution of bacteria to exacerbations may vary with disease severity. Classical models proposed that increases in the concentration of bacteria (the bacterial load) that chronically colonize the airways in stable COPD account for exacerbations. However, a comprehensive analysis of the relationship between bacterial concentrations in sputum and new pathogen acquisition showed that a change in the bacterial load is probably not the most common independent mechanism of exacerbation. The potential role of respiratory viruses in COPD exacerbations has been overlooked until recently. The use of PCR to evaluate the association between respiratory virus infections and COPD exacerbations has shown that viruses are associated to a much higher proportion of exacerbations than was previously realised. As the contribution of viruses to COPD exacerbations has only recently been appreciated little research has been carried out into the mechanisms of virus-induced inflammation. Increased eosinophilia has been reported in sputum samples of virus associated COPD exacerbations1,2. Results suggest that COPD subjects with frequent exacerbations represent a subgroup particularly susceptible to viral infections. Recent evidence documented impaired innate (Interferons) and (possibly) acquired immune responses to viral infection in COPD patients, with increased susceptibility to viral infections3. In addition, using a mouse model of cigarette smoke exposure, it has been demonstrated that cigarette smoke increases susceptibility to viral infections, possibly via alteration and/or inhibition of immune responses4–9 Another mechanism that might lead to increased susceptibility to viral infections is the upregulation of Inter-Cellular Adhesion Molecule-1 (ICAM-1), the receptor for the major group of human rhinoviruses10. It has been suggested that bacterial colonisation contributes to increased susceptibility to viral infection in COPD patients, by increasing ICAM-1 expression in bronchial epithelial cells, either directly or through induced inflammation. Further studies are required to investigate the interaction between chronic bacterial colonisation and respiratory viral infection and, in particular, whether chronic bacterial colonisation can increase susceptibility to viral infection or vice versa. The development of the first human model of virus induced COPD exacerbation, has recently clarified several aspects of virus associated COPD exacerbations3,11. In controlled conditions, human experimental models have identified specific immunological deficiencies in COPD subjects that can contribute in turning harmless rhinovirus infections into severe exacerbation episodes, especially in frequent exacerbators. This model has been demonstrated to be feasible and safe, and will facilitate identification of novel pharmacological targets that will provide opportunities to develop new treatments for exacerbations of COPD.

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pathologies in a mouse model of chronic obstructive pulmonary disease. J. Immunol. 2012;188:4468–75. Bauer C, Zavitz CC, Botelho FM, Lambert KN, Brown EG, Mossman KL, Taylor JD, Stämpfli MR. Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection. P.l.o.S. One 2010;5:e13251. Gaschler G, Zavitz CC, Bauer CM, Skrtic M, Lindahl M, Robbins CS, Chen B, Stämpfli MR. Cigarette smoke exposure attenuates cytokine production by mouse alveolar macrophages. Am. J. Respir. Cell. Mol. Biol. 2008;38:218–26. Motz G, Eppert BL, Wortham BW, Amos-Kroohs RM, Flury JL, Wesselkamper SC, Borchers MT. Chronic cigarette smoke exposure primes NK cell activation in a mouse model of chronic obstructive pulmonary disease. J. Immunol. 2010;184:4460–9. Papi A, Johnston SL. Rhinovirus infection induces expression of its own receptor intercellular adhesion molecule 1 (ICAM-1) via increased NF-kappaB-mediated transcription. J. Biol. Chem. 1999;274:9707–20. Mallia P, Message SD, Kebadze T, Parker HL, Kon OM, Johnston SL. An experimental model of rhinovirus induced chronic obstructive pulmonary disease exacerbations: a pilot study. Respir. Res. 2006;7:116.

References 1. Papi A, Bellettato CM, Braccioni F, Romagnoli M, Casolari P, Caramori G, Fabbri M, Johnston SL. Viral and bacterial etiology of severe COPD exacerbations: relationship with airway inflammation. Eur. Resp. J. 2005;26:251s. 2. Papi A, Contoli M, Caramori G, Mallia P, Johnston SL. Models of infection and exacerbations in COPD. Curr. Opin. Pharmacol. 2007;7:259–65. 3. Mallia P, Message SD, Gielen V, Contoli M, Gray K, Kebadze T, Aniscenko J, Laza-Stanca V, Edwards MR, Slater L, Papi A, Stanciu LA, Kon OM, Johnson M, Johnston SL. Experimental rhinovirus infection as a human model of chronic obstructive pulmonary disease exacerbation. Am. J. Respir. Crit. Care Med. 2011;183:734–42. 4. Gualano R, Hansen MJ, Vlahos R, Jones JE, Park-Jones RA, Deliyannis G, Turner SJ, Duca KA, Anderson GP. Cigarette smoke worsens lung inflammation and impairs resolution of influenza infection in mice. Respir. Res. 2008;9:53. 5. Feng Y, Kong Y, Barnes PF, Huang FF, Klucar P, Wang X, Samten B, Sengupta M, Machona B, Donis R, Tvinnereim AR, Shams H. Exposure to cigarette smoke inhibits the pulmonary T-cell response to influenza virus and Mycobacterium tuberculosis. Infect. Immun. 2011;79:229–37. 6. Wortham B, Eppert BL, Motz GT, Flury JL, Orozco-Levi M, Hoebe K, Panos RJ, Maxfield M, Glasser SW, Senft AP, Raulet DH, Borchers MT. NKG2D mediates NK cell hyperresponsiveness and influenza-induced

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PERSONALIZED MEDICINE IN COPD EXACERBATION S SETHI Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University at Buffalo, SUNY and Department of Veterans Affairs Western New York Healthcare System, Buffalo, NY, USA Exacerbations of COPD are episodes of airway mucosal infection that leads to exaggerated inflammation, predominantly locally but even systemically1. Given this pathogenesis, it seems appropriate that exacerbations be treated with antimicrobial and anti-inflammatory medications. This has led to the current practice where an antibiotic and a systemic corticosteroid are prescribed in the majority of exacerbations. COPD exacerbations are heterogeneous. Bacteria appear to cause only about half the exacerbations and antibiotic use seems unnecessary is many cases if universal prescription is practiced1. Similarly, universal prescription of corticosteroids for COPD exacerbation is likely overused. The time has come to question the current practice and move to a more personalized approach to the treatment of exacerbations2. Antibiotics can be life saving in severely ill patients with COPD exacerbation and can prevent subsequent clinical deterioration in less severe patients3–4. On the other hand, selection of antibiotic resistant pathogens and adverse effects are well recognized downsides of antibiotic use. Therefore, in patients with non-bacterial exacerbations, inappropriate antibiotic use is not without risk. Reliable and rapid discrimination of bacterial exacerbations from non-bacterial episodes is necessary to facilitate appropriate antibiotic therapy. Such discrimination could be done by clinical parameters, sputum microbiology or with the use of lung derived or systemic biomarkers. Among the clinical manifestations of exacerbation, sputum purulence has been advocated as a biomarker of bacterial exacerbation, and a guide for the use of antibiotics. Sputum purulence has the advantage that it does not cost anything to assess, is available at the point of care, and in some studies has been microbiologically validated5–6. However, it can be difficult to assess and has limited reliability in the third of COPD-patients who have purulent sputum production even when they are not experiencing an exacerbation7. Other factors that complicate assessment of sputum purulence is the inattention of patients to sputum color, inability to bring up sputum though experiencing chest congestion and the dynamic changes in sputum color during an exacerbation8. Another potential clinical parameter to guide antibiotic prescription is the Anthonisen type of exacerbation, based on increased dyspnea, sputum volume and sputum purulence4. If all 3 cardinal symptoms are present (type 1 exacerbation), almost all such patients have airway bacterial infection, the rate of spontaneous resolution is only 43% and antibiotics increase resolution rates and prevent clinical deterioration4,6. In contrast, with only one of the 3 cardinal symptoms (type 3 exacerbation), bacteria are isolated in the distal airway in less than 10% of episodes, the rate of spontaneous resolution is 70% and is not improved with antibiotic use4,6. Type 2 exacerbations with only 2 of the 3 cardinal symptoms lie in between the type 1 and 3 in all these parameters and antibiotic treatment needs to be individualized in these patients. Sputum microbiology lacks the sensitivity, specificity and speed needed to discriminate between bacterial and non-bacterial exacerbations. Systemic (serum) biomarkers such as procalcitonin and c-reactive protein (CRP) have been advocated for deciding antibiotic treatment of exacerbations. Advantages include speed and simplicity, but assessment of their utility and validity has shown inconsistent results8–9. Sputum biomarkers such as neutrophil elastase activity and cytokine levels deserve further study10–11. Systemic corticosteroids are usually regarded as a risk-free treatment. However, they can cause adverse effects like hyperglycemia and secondary infections in some patients. In a study in outpatient Type 1 exacerbations of COPD comparing moxifloxacin to amoxicillin/clavulanate, about a third of patients received systemic corticosteroids at the investigators discretion12. The rate of clinical failure over the next 8 weeks was significantly worse in these patients compared to those who did not receive systemic corticosteroids. Though the medical and economic consequences of exacerbations of COPD are highly significant, our current practice patterns in their treatment are crude. Refined clinical assessment, based on validated symptom scores, and/or development of reliable and convenient biomarkers should lead to a more personalized approach to the treatment of exacerbations of COPD in the near future.

4. Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES, Harding GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. AnnInternMed. 1987;106:196–204. 5. Stockley RA, O’Brien C, Pye A, Hill SL. Relationship of sputum color to nature and outpatient managment of acute exacerbations of COPD. Chest. 2000;117:1638–45. 6. Soler N, Agusti C, Angrill J, Puig De la Bellacasa J, Torres A. Bronchoscopic validation of the significance of sputum purulence in severe exacerbations of chronic obstructive pulmonary disease. Thorax. 2007 Jan;62(1):29–35. 7. Sethi S, Jones PW, Theron MS, Miravitlles M, Rubinstein E, Wedzicha JA, et al. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Respir Res. 2010;11:10. 8. Soler N, Esperatti M, Ewig S, Huerta A, Agusti C, Torres A. Sputum purulence-guided antibiotic use in hospitalised patients with exacerbations of COPD. Eur Respir J. 2012 Dec;40(6):1344–53. 9. Stolz D, Christ-Crain M, Bingisser R, Leuppi J, Miedinger D, Muller C, et al. Antibiotic treatment of exacerbations of COPD: a randomized, controlled trial comparing procalcitonin-guidance with standard therapy. Chest. 2007 Jan;131(1):9–19. 10. Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. Chest. 2000;117:380S–5S. 11. Sethi S, Wrona C, Eschberger K, Lobbins P, Cai X, Murphy TF. Inflammatory profile of new bacterial strain exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008 Mar 1;177(5):491–7. 12. Wilson R, Anzueto A, Miravitlles M, Arvis P, Alder J, Haverstock D, et al. Moxifloxacin vs amoxicillin/clavulanic acid in outpatient AECOPD: maestral results. Eur Respir J. 2012 Feb 15.

References 1. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008 Nov 27;359(22): 2355–65. 2. Sethi S. Personalised medicine in exacerbations of COPD: the beginnings. Eur Respir J. 2012 Dec;40(6):1318–9. 3. Nouira S, Marghli S, Belghith M, Besbes L, Elatrous S, Abroug F. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet. 2001;358(9298):2020–5.

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RESCUE ICS FOR ADULT ASTHMA A PAPI Respiratory Medicine, University of Ferrara, Italy International guidelines on asthma management currently recommend rapidonset inhaled β2-agonists, such as albuterol and terbutaline, alone for symptom relief in all asthmatic patients. However, asthma symptoms are associated not only with bronchoconstriction but also with increased airway inflammation and recent evidence indicates that inhaled corticosteroids have rapid clinical effects and can suppress airway inflammation within hours1,2. Recent clinical trials have shown that “as required”, or p.r.n., use of inhaled combinations of a corticosteroid and a rapid-onset β2-agonist provides clinical advantages over the traditional p.r.n. inhaled rapid-onset β2-agonists alone in patients with different degrees of asthma severity. The clinical advantages of an as needed combination of an inhaled corticosteroid added to a rapid-acting bronchodilator over as needed bronchodilator alone has been seen in all types of persistent asthma from mild to severe3,4. Several recent clinical trials of six or more months of duration, conducted in patients with mild to severe persistent asthma, have shown that rescue therapy of a single combination inhaler containing a rapid-onset β2-agonist (albuterol or formoterol) and a corticosteroid prolongs the time to the first severe asthma exacerbation, reduces the rate of exacerbations, and maintains day-to-day asthma control at a reduced load of corticosteroids (inhaled plus systemic)3,5–9. This is achieved without causing an increase in sputum eosinophilia when compared with higher fixed maintenance doses of combination inhalers plus rapid-onset inhaled β2-agonist alone as rescue therapy. A growing body of evidence suggests that patients with persistent asthma need not be managed with daily ICS, but rather can use them on an intermittent basis, triggered by the occurrence of symptoms sufficient to warrant treatment with a rescue inhaler. Large, randomized, controlled studies, over a range of asthma severity, and in a range of ages from pediatrics to adults, suggest that, in well-selected patients, a symptom-based approach to administering controller therapy may produce equivalent outcomes, while reducing exposure to ICS. These studies clearly indicate the efficacy of as-needed inhaled corticosteroids when used as rescue medication. Thus, the timing of administration and the fact that inhaled corticosteroids have a rapid-onset of anti-inflammatory action in the lower airways are crucial factors. It is likely that the as needed combination treatment optimises the efficacy of inhaled rescue intervention because, not only does it provide an effective bronchodilator to relief symptoms, but also delivers an increased dose of corticosteroid at the time when it is more needed. Currently there is no clear clinical evidence that suggests that one drug combination is better than the other. However, from a theoretical point of view, any combination of an inhaled corticosteroid with a rapid-onset inhaled β2-agonist should show equivalent efficacy, because in vitro all these drugs have shown similar effects. From a pathophysiological viewpoint, asthma symptoms are associated not only with bronchoconstriction, but also with enhanced lower airway inflammation and both β2-agonists and inhaled corticosteroids rapidly exert their bronchodilator or anti-inflammatory effects on the lower airways. The fast bronchodilator effect of rapid-onset inhaled β2-agonists bronchodilators is mediated mainly by a relaxing effect on contracted lower airway smooth muscle. A rapid anti-inflammatory effect of a single high dose of inhaled corticosteroids has been demonstrated in asthmatics with a significant reduction in sputum eosinophils, exhaled nitric oxide, increased protection against many airway hyperresponsiveness stimuli and reduced bronchial blood flow2,3,10. For these reasons the p.r.n. use of an inhaled corticosteroid added to a rapid-acting bronchodilator could represent a more effective option over as needed bronchodilator alone.

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7. Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martínez-Jimenez NE, Buhl R. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int. J. Clin. Pract. 2007;61: 725–36. 8. O’Byrne P, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y, Ekström T, Bateman ED. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am. J. Respir. Crit. Care Med. 2005;171:129–36. 9. Sears M, Boulet LP, Laviolette M, Fitzgerald JM, Bai TR, Kaplan A, Smiljanic-Georgijev N, Lee JS. Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma. Eur. Respir. J. 2008;31:982–9. 10. Mendes E, Horvath G, Campos M,Wanner A. Rapid corticosteroid effect on beta(2)-adrenergic airway and airway vascular reactivity in patients with mild asthma. J. Allergy Clin. Immunol. 2008;121:700–4.

References 1. Gibson P, Saltos N, Fakes K. Acute anti-inflammatory effects of inhaled budesonide in asthma: a randomized controlled trial. Am. J. Respir Crit. Care Med. 2001;163:32–6. 2. Erin E, Zacharasiewicz AS, Nicholson GC, Tan AJ, Neighbour H, Engelstätter R, Hellwig M, Kon OM, Barnes PJ, Hansel TT. Rapid effect of inhaled ciclesonide in asthma: a randomized, placebo-controlled study. Chest 2008;134:740–5. 3. Barnes P. Scientific rationale for using a single inhaler for asthma control. Eur. Respir. J. 2007;29:587–95. 4. Barnes P. Using a combination inhaler (budesonide plus formoterol) as rescue therapy improves asthma control. B.M.J. 2007;335:513. 5. Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, Crimi N, Vignola AM, Morelli P, Nicolini G, Fabbri LM; BEST Study Group. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N. Engl. J. Med. 2007;356:2040–52. 6. Rabe K, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet 2006;368:744–53.

© 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology

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MICROBIOME IN COPD EXACERBATION S SETHI Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University at Buffalo, SUNY and Department of Veterans Affairs Western New York Healthcare System, Buffalo, NY, USA It was widely believed that airway infection in COPD was a static process, with patients colonized by the same bacteria pathogen for long periods of time. This was thought of as an epiphenomenon with little relevance to COPD pathogenesis and the occurrence of exacerbations1. Recent findings have changed this paradigm dramatically, demonstrating that infection in COPD is dynamic, and acquisition of new strains of bacteria is the predominant mechanism of exacerbations2. Though conventional microbiology is important in understanding microbial causation of exacerbations, it is old technology with clear limitations. Only 10–30% of bacteria associated with the human body are recovered with standard culture techniques. Instead, the yield of potentially pathogenic bacteria was doubled with PCR detection3. Microbiome studies of respiratory secretions could provide exciting new observations regarding the bacterial causation of exacerbations of COPD. It could lead to discovery of new pathogens that have been difficult to obtain with standard culture techniques. Furthermore, it appears that bacterial species often associate with each other, and such association could have important implications in exacerbation causation and treatment. Microbiome analysis of a respiratory sample is most commonly done by PCR amplification of the 16S ribosomal RNA gene, a highly conserved locus of the bacterial genome4. Technological advancements have made obtaining microbiome data straightforward, rapid and relatively inexpensive. However, extensive computational analysis of the raw data is required. Though technologically superior to conventional cultures, microbiome data interpretation in COPD has been a challenge. While studies with conventional microbiology found potential pathogenic bacteria to be virtually absent in bronchoscopic samples in healthy controls, smoking and development of COPD was associated with 35–50% incidence of isolation of pathogenic bacteria5–6. In contrast, recent studies that have applied microbiome techniques to determine if smoking and COPD alter the microbiota of the lower airways have found no or minor differences from controls7–8. These contradictory findings could be explained by the extreme sensitivity of the microbiome technique to upper airway contamination9. Another possibility is that the trees are being lost when we look at the forest, i.e. important differences in a few potential pathogens are difficult to discern when the whole microbiome is explored. There has been very limited exploration of the airway microbiome at the time of COPD exacerbation. The Vicious Circle Hypothesis embodies the likely contribution of an altered microbiome to COPD progression, with an unhealthy microbiome driving the inflammatory process2. Bacterial exacerbations likely represent abrupt major changes in the microbiome with resultant large increases in airway and systemic inflammation. Several challenges need to be tackled to fully utilize the benefits of microbiome research in COPD. Paramount is the issue of upper airway and environmental contamination of lower airway samples. It is unlikely that very low concentrations of bacterial pathogens are pathological. However, significant concentration thresholds in microbiome data are currently undefined. Studies have demonstrated that the microbiome differs in sputum, bronchoalveolar lavage and lung parenchyma samples obtained from patients with COPD10. The research question and feasibility should dictate which compartment is sampled. In COPD exacerbation studies, often repeated sampling in patients with underlying severe COPD is required, which would limit sampling to non-invasive methods such as sputum collection. How the determination as to which of the various new microbes that will be identified in microbiome studies are pathogenic is still unclear, especially for unculturable pathogens. Though various obstacles need to be surmounted, ultimately lung microbiome studies will provide new insights in to how infection contributes to COPD.

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chronic obstructive pulmonary disease. EurRespirJ 1999;14:1015– 1022. Sethi S, Maloney J, Grove L, Wrona C, Berenson CS. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2006;173:991–998. Morris A, Beck JM, Schloss PD, Campbell TB, Crothers K, Curtis JL, Flores SC, Fontenot AP, Ghedin E, Huang L, Jablonski K, Kleerup E, Lynch SV, Sodergren E, Twigg H, Young VB, Bassis CM, Venkataraman A, Schmidt TM, Weinstock GM. Comparison of the respiratory microbiome in healthy nonsmokers and smokers. Am J Respir Crit Care Med 2013;187:1067–1075. Erb-Downward JR, Thompson DL, Han MK, Freeman CM, McCloskey L, Schmidt LA, Young VB, Toews GB, Curtis JL, Sundaram B, Martinez FJ, Huffnagle GB. Analysis of the lung microbiome in the “Healthy” Smoker and in copd. PLoS One 2011;6:e16384. Charlson ES, Bittinger K, Haas AR, Fitzgerald AS, Frank I, Yadav A, Bushman FD, Collman RG. Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 2011;184:957–963. Cabrera-Rubio R, Garcia-Nunez M, Seto L, Anto JM, Moya A, Monso E, Mira A. Microbiome diversity in the bronchial tracts of patients with chronic obstructive pulmonary disease. J Clin Microbiol 2012;50:3562– 3568.

References 1. Tager I, Speizer FE. Role of infection in chronic bronchitis. NEnglJMed 1975;292:563–571. 2. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med 2008;359:2355–2365. 3. Garcha DS, Thurston SJ, Patel AR, Mackay AJ, Goldring JJ, Donaldson GC, McHugh TD, Wedzicha JA. Changes in prevalence and load of airway bacteria using quantitative pcr in stable and exacerbated copd. Thorax 2012;67:1075–1080. 4. Han MK, Huang YJ, Lipuma JJ, Boushey HA, Boucher RC, Cookson WO, Curtis JL, Erb-Downward J, Lynch SV, Sethi S, Toews GB, Young VB, Wolfgang MC, Huffnagle GB, Martinez FJ. Significance of the microbiome in obstructive lung disease. Thorax 2012;67:456–463. 5. Soler N, Ewig S, Torres A, Filella X, Gonzalez J, Zaubet A. Airway inflammation and bronchial microbial patterns in patients with stable

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THE GENETIC DETERMINANTS OF PULMONARY FIBROSIS DA SCHWARTZ Department of Medicine, University of Colorado, Denver, CO, USA The overall goal of this review is to discuss how dysregulated MUC5B could result in the development of fibroproliferative lung disease. This approach is based on several recent advances. First, we have discovered that MUC5B is the strongest genetic risk factor for familial and sporadic forms of idiopathic pulmonary fibrosis (IPF). The MUC5B promoter SNP rs35705950 has been validated as a risk variant for IPF in six independent studies1–6, is the strongest known risk factor for the development of both familial and sporadic forms of IPF (odds ratio ≈ 6–8 per allele), and represents a risk variant observed in at least half of the cases of either familial or sporadic IPF. Second, MUC5B appears to be involved in the pathogenesis of IPF. The MUC5B promoter SNP is associated with enhanced MUC5B expression in both unaffected subjects1 and patients with IPF7, IPF patients have significantly more MUC5B gene expression than unaffected subjects1, MUC5B message and protein are expressed in the pathologic lesions of IPF1,8, and we have recently found that Muc5b deficient mice are resistant to both bleomycin and asbestos models of fibroproliferation (preliminary data). Third, our results suggest that excess mucus appears to be pathogenic in the preclinical/mild stages of IPF. While the MUC5B promoter SNP is the strongest known risk factor for IPF1–6, we have shown that the MUC5B promoter SNP identifies preclinical/mild stages of interstitial lung disease9, providing further evidence that excess mucus appears to be relevant in the preclinical/mild stages of disease. Based on these observations, we speculate that the MUC5B promoter SNP places individuals at risk of developing IPF via chronic mucus hypersecretion and accumulation in the peripheral airspace that impairs mucocilliary transport, results in mucus adhesion in the bronchoalveolar region, and consequently induces and potentiates chronic inflammation and injury1,10. In this review, we will discuss the role of this glycoprotein in fibroproliferative lung disease, the potential mechanisms that link MUC5B and pulmonary fibrosis, and the translational implications.

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8. Seibold MA, Smith RW, Urbanek C, Groshong SD, Cosgrove GP, Brown KK, Schwarz MI, Schwartz DA, Reynolds SD. The idiopathic pulmonary fibrosis honeycomb cyst contains a mucocilary pseudostratified epithelium. PLoS One 2013;8:e58658. 9. Hunninghake GM, Hatabu H, Okajima Y, Gao W, Dupuis J, Latourelle JC, Nishino M, Araki T, Zazueta OE, Kurugol S, Ross JC, San Jose Estepar R, Murphy E, Steele MP, Loyd JE, Schwarz MI, Fingerlin TE, Rosas IO, Washko GR, O’Connor GT, Schwartz DA. Muc5b promoter polymorphism and interstitial lung abnormalities. N Engl J Med 2013;368:2192–200. 10. Boucher RC. Idiopathic pulmonary fibrosis – a sticky business. N Engl J Med 2011;364:1560–61.

References 1. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, Fingerlin TE, Zhang W, Gudmundsson G, Groshong SD, Evans CM, Garantziotis S, Adler KB, Dickey BF, du Bois RM, Yang IV, Herron A, Kervitsky D, Talbert JL, Markin C, Park J, Crews AL, Slifer SH, Auerbach S, Roy MG, Lin J, Hennessy CE, Schwarz MI, Schwartz DA. A common muc5b promoter polymorphism and pulmonary fibrosis. N Engl J Med 2011;364:1503–12. 2. Zhang Y, Noth I, Garcia GN, Kaminski N. A variant in the promoter of muc5b and idiopathic pulmonary fibrosis. New England Journal of Medicine 2011;364:1576–7. 3. Stock CJ, Sato H, Fonseca C, Banya WA, Molyneaux PL, Adamali H, Russell AM, Denton CP, Abraham DJ, Hansell DM, Nicholson AG, Maher TM, Wells AU, Lindahl GE, Renzoni EA. Mucin 5b promoter polymorphism is associated with idiopathic pulmonary fibrosis but not with development of lung fibrosis in systemic sclerosis or sarcoidosis. Thorax 2013. 4. Noth I, Zhang Y, Ma SF, Flores C, Barber M, Huang Y, Broderick SM, Wade MS, Hysi PG, Scuirba J, Richards T, Juan-Guardela B, Vij R, Han MK, Martinez FJ, Kossen K, Seiwert SD, Christie JD, Nicolae DL, Kaminski N, Garcia JG. Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: A genome-wide association study. The Lancet Respiratory Medicine 2013;1:309–17. 5. Fingerlin TE, Murphy E, Zhang W, Peljto AL, Brown KK, Steele MP, Loyd JE, Cosgrove GP, Lynch D, Groshong S, Collard HR, Wolters PJ, Bradford WZ, Kossen K, Seiwert SD, du Bois RM, Garcia CK, Devine MS, Gudmundsson G, Isaksson HJ, Kaminski N, Zhang Y, Gibson KF, Lancaster LH, Cogan JD, Mason WR, Maher TM, Molyneaux PL, Wells AU, Moffatt MF, Selman M, Pardo A, Kim DS, Crapo JD, Make BJ, Regan EA, Walek DS, Daniel JJ, Kamatani Y, Zelenika D, Smith K, McKean D, Pedersen BS, Talbert J, Kidd RN, Markin CR, Beckman KB, Lathrop M, Schwarz MI, Schwartz DA. Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis. Nat Genet 2013;[Epub ahead of print]:613–20. 6. Borie R, Crestani B, Dieude P, Nunes H, Allanore Y, Kannengiesser C, Airo P, Matucci-Cerinic M, Wallaert B, Israel-Biet D, Cadranel J, Cottin V, Gazal S, Peljto AL, Varga J, Schwartz DA, Valeyre D, Grandchamp B. The muc5b variant is associated with idiopathic pulmonary fibrosis but not with systemic sclerosis interstitial lung disease in the european caucasian population. PLoS One 2013;8:e70621. 7. Helling BA, Yang IV, Steele MP, Brown KA, Loyd JE, Cosgrove GP, Fingerlin TE, Peljto AL, Cool C, Lynch D, Groshong S, Markin C, Talbert JL, Hennessy CE, Davidson E, Murphy E, Schwarz MI. Muc5b is a common link between idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. paper in process 2013.

© 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology

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THE IMPORTANCE OF COGNITIVE ASSESSMENT IN COPD PW JONES Division of Clinical Science, St George’s, University of London, London, UK In COPD, a range of organs show evidence of significant comorbidity, but relatively little attention has been paid to the brain and the factors that enable people to live and function independently in society. The presence of cognitive dysfunction has been recognised in hypoxic COPD for a long time1, but normoxic patients can also show evidence of an acquired loss of cognitive function2. The fact that COPD-patients exhibit a range of different cognitive defects suggests that the effect of COPD on the brain is generalised and wide-spread rather than focal. Many demographic, life style and health-related factors known to be related to cognitive dysfunction all occur in COPD and the level of association between physiological measures of COPD severity, such as FEV1 and arterial blood gas tensions, is weak3. Earlier suggestions about mechanisms causing the cognitive loss centred on possible effects low PaO2, high PaCO2 or oxidative stress on neurones3, but until recently there had been no attempt to identify any structural disturbances in the brain that might account for these changes. A recent study in stable COPD using magnetic resonance imaging showed that no loss of grey matter, suggesting that cognitive loss was not due to cerebral atrophy4. However, measuring micro-structural white matter lesions, showed damage to 46% of the white matter tracts4. This pattern is compatible with the wide range of cognitive defects seen in COPD, and absence of any specific loss of function. Others have shown evidence of deep brain micro-haemorrhages5, but it is yet to be established whether these are co-located with the areas of white matter microstructure damage. Whilst recent imaging studies suggest a pattern compatible with small vessel disease, the mechanistic link with COPD is not known. One possibility may be increased platelet aggregation that is known to occur following a COPD exacerbation6. Exacerbations that result in hospital admission are associated with a greater degree of cognitive impairment than that seen in stable COPD patients7. On the day of discharge, 20% of patients admitted for a COPD exacerbation had pathological levels of impaired processing speed with no evidence of any recovery after 3 months. Impaired cognitive function affects self-management of COPD. A correlation has been shown between metered dose inhaler technique and executive function8, and impaired delayed recall was reported in over 80% of COPD patients with poor adherence to treatment9. Knowledge of a patient’s cognitive impairment may be useful in their management and capacity to self-manage their disease. Neuro-psychological tests seem too complex to use in a routine care setting. Furthermore, simple well-known measures like the Mini Mental State Examination (MMSE) may be too insensitive to pick up more subtle yet important areas of loss. There is evidence that the much simpler Montreal Cognitive Assessment (MoCA) may be sufficiently sensitive and superior to the MMSE in this context2. Ideally all COPD-patients should probably be assessed for cognitive impairment, but it may be most efficient to focus on patients with severe hypoxia, one or more hospital admission, or poor skills to manage their COPD as outpatients.

References 1. Grant I, Prigatano GP, Heaton RK, McSweeny AJ, Wright EC, Adama KM. Progressive neuropsychologic impairment and hypoxemia. Relationship in chronic obstructive pulmonary disease. Arvives of General Psychiatry. 1987;44(1):999–1006. 2. Villeneuve S, Pépin V, Rahayel S, Bertrand J-A, Delorimier M, Rizk A, et al. Mild cognitive impairment in moderate to severe chronic obstructive pulmonary disease: A preliminary study. Chest. 2012 June 6;142:1516– 23. 3. Dodd JW, Getov SV, Jones PW. Cognitive function in COPD. European Respiratory Journal. [Review]. 2010 Apr;35(4):913–22. 4. Dodd JW, Chung AW, van den Broek MD, Barrick TR, Charlton RA, Jones PW. Brain structure and function in chronic obstructive pulmonary disease: a multimodal cranial magnetic resonance imaging study. Am J Respir Crit Care Med. 2012 August 8;186(3):240–5. 5. Lahousse L, Vernooij MW, Darweesh SK, Akoudad S, Loth DW, Joos GF, et al. Chronic Obstructive Pulmonary Disease and Cerebral Microbleeds: The Rotterdam Study. Am J Respir Crit Care Med. 2013 July 7;188:783–8. 6. Maclay JD, McAllister DA, Johnston S, Raftis J, McGuinnes C, Deans A, et al. Increased platelet activation in patients with stable and acute exacerbation of COPD. Thorax. 2011 September;66(9):769–74. 7. Dodd JW, Charlton RA, van den Broek MD, Jones PW. Cognitive Dysfunction in Patients Hospitalized with Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD). Chest. 2013 January 1;144:119–27. 8. Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-term retention of inhaler techniques require intact executive function in elderly subjects. Age Ageing. 2003 May;32(3):299–302. 9. Incalzi RA, GemmaA, Marra C, Capparella O, Fuso L, Carbonin P. Verbal memory impairment in COPD: its mechanisms and clinical relevance. Chest. 1997 December;112(6):1506–13.

© 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology

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A TRANSLATIONAL AND PRECLINICAL RESEARCH MODEL FOR ASTHMA; SEGMENTAL BRONCHOPROVOCATION GY PARK Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, IL, USA The heterogeneity of clinical phenotypes of asthma highlights the possibility of different pathogenic mechanisms being involved in each individual patient with asthma. Unfortunately, the currently available animal models of asthma do not sufficiently support the diverse pathways of asthma. Asthma is exclusively a human disease. Since the genetic susceptibility of the human genome plays an important role in the pathogenesis of asthma, it is practically impossible to regenerate a completely identical condition of human asthma in experimental animals. Considerable insight into the mechanisms and regulation of airway hyperresponsiveness (AHR) and inflammation has been gained from animal models, however, knowledge about the uniqueness of these processes in human airway diseases can only be studied and obtained in patients. A NIH workshop on bronchoprovocation and investigative bronchoscopy endorsed the continued use of this technique. We have adapted the protocol for segmental bronchoprovocation with allergen (SBP-AG) as a tool for translation research in our institution since 2009 in collaboration with Dr. Jarjour’s team at the University of Wisconsin at Madison. This procedure produces a localized exuberant allergic reaction with ∼40% of eosinophil in the BAL fluid from the challenged segment, but there was a minimal spillover reaction into the adjacent segment, and no inflammation reaction observed in the contralateral lung. The safety of this procedure has been proven in a recent study by Dr. Jarjour’s group, where 87 segmental challenges were performed in 77 allergic asthma patients. The NIH workshop summarized the contribution of this procedure to the understanding of asthma and chronic obstructive lung disease into 9 areas; (1) Identification of inflammatory cells and mediators associated with asthma, (2) Characterization of Th1 versus Th2 lymphocyte-directed inflammatory response in asthma, (3) Differential inflammatory features in different clinical phenotypes of asthma, (4) Insight into patterns of airway remodeling, (5) Characteristics of the cellular, cytokine, and chemokine responses to allergen challenge, (6) Effects of asthma therapy on features and characteristics of airway inflammation, (7) Characteristics of airway inflammation in childhood asthma, (8) Evidence for parenchymal involvement of inflammation in asthma, and (9) Description of inflammatory cellular and cytokine profiles in chronic obstructive pulmonary disease. In summary, research bronchoprovocation appears to carry a low risk of untoward effects.

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PULMONARY HYPERTENSION IN COPD W-K CHO Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA The presence of pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is associated with higher mortality, more frequent hospitalizations and decreased exercise capacity1–2. Therefore, early detection of PH is important in COPD patients. Although the diagnosis of PH in COPD requires confirmation by right heart catheterization, echocardiogram can screen PH. PH can be suggested when the right ventricular systolic pressure is greater than or equal to 36 mmHg3. Hypoxia seems to be the main mechanism of PH in COPD. Acute hypoxia causes hypoxic pulmonary vasoconstriction and chronic hypoxia results in pulmonary vascular remodeling. These together can contribute to increasing pulmonary vascular resistance. However, the correlation between the severity of PH and the degree of hypoxia is not strong, and long-term oxygen therapy does not reverse PH. Furthermore, pulmonary vascular remodeling has been quite often observed in non-hypoxic COPD patients. These imply that there might be other contributors to the development of PH in COPD. Thus far, hypercapnia, respiratory acidosis, hyperinflation, airway obstruction, loss of pulmonary capillary bed, inflammation, endothelial dysfunction or polycythemia has been suggested as other contributors4. The most important treatment of PH in COPD is oxygen therapy with a therapeutic goal of maintaining an oxygen saturation of greater than 90% during rest, sleep and exertion. However, given that long-term oxygen therapy does not reverse PH, pulmonary arterial hypertension-specific treatment has been tried but without much success. The phosphodiesterase-5 inhibitor sildenafil was found to improve hemodynamics at the expense of decreasing arterial oxygenation. The endothelin receptor antagonist, such as bosentan, has failed to show significant improvement in PH in COPD as well. These pulmonary vasodilators can non-selectively dilate the pulmonary vessels, leading to mitigating the hypoxic pulmonary vasoconstriction that improve ventilation-perfusion mismatch. Consequently, these vasodilators worsen gas exchange and hypoxemia in COPD. Therefore, the use of inhaled vasodilators, such as inhaled iloprost and nitric oxide, has been implicated as alternative options. Theoretically, by administering pulmonary vasodilators via an inhalational route, only the pulmonary vessels of better-ventilated area in the lung will dilate, resulting in preserving or improving ventilation–perfusion matching. However, clinical application of these needs further verification. Current recommendations suggest that pulmonary vasodilators could be considered for PH disproportionate to the degree of airflow obstruction after optimization of COPD treatment5. In general, PH out of proportion to the degree of airflow can be defined as when patients with mild to moderate COPD (i.e. GOLD Stages I and II) have PH or patients with COPD of GOLD Stages II and III have greater than 35 mmHg of mean pulmonary arterial pressure. However, further study will be imperative to support this6. References 1. Oswald-Mammosser M, Weitzenblum E, Quoix E, Moser G, Chaouat A, Charpentier C, Kessler R. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest. 1995 May;107(5):1193–8. 2. Kessler R, Faller M, Fourgaut G, Mennecier B,Weitzenblum E. Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999 Jan;159(1):158–64. 3. Badesch DB, Champion HC, Sanchez, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54:S55–66 4. Wrobel Jeremy P, Thompson Bruce R, Williams Trevor J. Mechanisms of pulmonary hypertension in chronic obstructive pulmonary disease: A pathophysiologic review. J Heart Lung Transplant 2012;31:557–64. 5. Minai OA, Chaouat A, Adnot S. Pulmonary hypertension in COPD: epidemiology, significance, and management: pulmonary vascular disease: the global perspective. Chest. 2010 Jun;137(6 Suppl):39S–51S. doi: 10.1378/chest.10-0087. 6. Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT), Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009 Dec;34(6):1219–63. doi: 10.1183/09031936 .00139009. Epub 2009 Sep 12.

© 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology

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OF MICE AND MEN: THE QUEST TO UNDERSTAND THE DEVELOPMENT AND PATHOLOGY OF ALLERGIC PULMONARY INFLAMMATION J KIM Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA As one of the most common chronic inflammatory disease, asthma affects 300 million people globally and additional 100 million is expected to add within 15–20 years1. However, numerous gaps in our understanding of this multifaceted disease with different risk factors, different prognosis, and different response to treatment are remained to be elucidated yet2,3. The animal model is the irreplaceable way to fill these gaps for recapitulating in vivo processes of human asthma3,4. However, the validity of animal models of human asthma as a tool to investigate the pathophysiology and to identify new targets for pharmacological intervention has been questioned by remarkable discrepancy between successful animal studies and disappointing clinical trials in patients3,4. So while the utility of animal study has been debated for last decade3,5–7, the demand for more predictive in vivo models as well as new tools based on latest and emerging technologies has been escalated. We have developed a novel mouse model of asthma induced by house dust collected from the house that has an asthmatic child and contains high levels of cockroach allergens (Bla g1 and g2) and moderate level of lipopolysaccharide8,9. Currently asthma-like pulmonary inflammation and airway hyperresponsiveness are induced by three intratracheal instillations (without using adjuvant) of commercially available cockroach extract that is used for skin test in clinic10–12. We will discuss the development, value and limitation of this model. Further, we also will discuss the strengths and limitations of other animal models as well as recent progress and innovation in developing new in vivo, in vitro, and ex vivo models in asthma study. It is suggested new animal models to better understand human asthma and accelerate the development of new drug that can do more than relief from the symptoms and reverse the diseases3. This models need to demonstrate the chronic asthmatic response, multifactorial interaction with environmental factors, airway remodeling, and the intricate role of airway epithelium during inflammation3,4. My presentation will be finalized by catching a glimpse of my journey to be a successful scientist in medical school setting in US, once again focused on strengths and limitations.

PREDICTION OF COPD PROGNOSIS: HOW CAN WE EXPLAIN THE PROGNOSIS TO PATIENTS WITH COPD? C-H LEE Department of Internal Medicine, Seoul National University Medical Center, Korea Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disease characterized by persistent airflow limitation and respiratory symptom. COPD usually progress and can lead to death and cormobidities associated with COPD also contribute on morbidity and mortality. However, the progression of COPD can vary between individuals. Accordingly, a lot of studies have been conducted to identify predictors of COPD prognosis. This review focused on predictors of COPD prognosis including mortality and lung function decline rate. Age, FEV1, hyperinflation, cachexia, low exercise capacity, more symptom, poor quality of life and experience of exacerbation have been reported as poor prognostic factors for mortality. During the decade, several indexes using multifaceted predictors showed more accurate prediction power. For example, BODE index using body mass index, FEV1, mMRC dyspnea scale and 6-minute walk distance can classify patients with COPD according to death risk more accurately than GOLD stage using only FEV1. Some investigators have proposed new indexes such as e-BODE, BODEx, updated BODE and ADO index, which were developed by modification of BODE index. Recently GOLD guideline introduced new classification for COPD patients (subgroup A-D) based on current symptom and future risk. Large cohort studies showed patients classified into subgroup C died earlier than subgroup B patients. Rapid lung function decline is the important indicator of disease progression. Interestingly ECLIPSE cohort revealed that some COPD patients showed lung function improvement over time although majorities lost their lung function progressively. In this cohort study, current smoking, exacerbation during follow-up, positive bronchodilator reversibility, presence of emphysema and higher level of CC-16 were predictors of more rapid lung function decline. In Hokkaido cohort, more severe emphysema and higher blood neutrophil count were associated with rapid decline of lung function. Many factors among these suggested as predictors for COPD prognosis could be evaluated and used easily in real clinical practice and help physicians understand COPD and manage patients.

References 1. Masoli M, Fabian D, Holt S, Beasley R, Global Initiative for Asthma P. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy. 2004;59:469–78. 2. Asthma: still more questions than answers. Lancet. 2008;372:1009. 3. Holmes AM, Solari R, Holgate ST. Animal models of asthma: value, limitations and opportunities for alternative approaches. Drug Discovery Today. 2011;16:659–70. 4. Krug N, Rabe KF. Animal models for human asthma: The perspective of a clinician. Current Drug Targets. 2008;9:438–42. 5. Wenzel S, Holgate ST. The mouse trap: It still yields few answers in asthma. Am J Respir Crit Care Med. 2006;174:1173–6. 6. Finkelman FD, Wills-Karp M. Usefulness and optimization of mouse models of allergic airway disease. J Allergy Clin Immunol. 2008;121:603–6. 7. Zosky GR, Sly PD. Animal models of asthma. Clinical & Experimental Allergy. 2007;37:973–88. 8. Kim J, Merry AC, Nemzek JA, Bolgos GL, Siddiqui J, et al. Eotaxin Represents the Principal Eosinophil Chemoattractant in a Novel Murine Asthma Model Induced by House Dust Containing Cockroach Allergens. J Immunol. 2001;167:2808–15. 9. Kim J, McKinley L, Natarajan S, Bolgos GL, Siddiqui J, et al. Anti-tumor necrosis factor-alpha antibody treatment reduces pulmonary inflammation and methacholine hyper-responsiveness in a murine asthma model induced by house dust. Clinical & Experimental Allergy. 2006;36:122– 32. 10. Kim J, Natarajan S, Bae H, Jung S-K, Cruikshank W, et al. Herbal medicine treatment reduces inflammation in a murine model of cockroach allergen-induced asthma. Annals of Allergy, Asthma & Immunology. 2011;107:154–62. 11. Kim J, Natarajan S, Vaickus LJ, Bouchard JC, Beal D, et al. Diesel Exhaust Particulates Exacerbate Asthma-Like Inflammation by Increasing CXC Chemokines. The American Journal of Pathology. 2011;179:2730–9. 12. Bouchard JC, Kim J, Beal DR, Vaickus LJ, Craciun FL, et al. Acute oral ethanol exposure triggers asthma in cockroach allergen-sensitized mice. The American Journal of Pathology. 2012;181:845–57.

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THE ROLE OF BRONCHODILATOR THERAPY IN COPD. WHICH IS THE OPTIMAL BRONCHODILATOR?

NEW DRUGS FOR COPD IN NEAR FUTURE: CAN THEY BE HOPE FOR PATIENTS WITH COPD?

SY LEE Division of Respiratory and Critical Care Medicine, College of Medicine, Korea University, Seoul, Korea

DK KIM Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul, South Korea

Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways. Anti-inflammatory therapy with inhaled corticosteroids does not seem to modify the progressive decline of lung function. Bronchodilators (BDs) improve emptying of the lungs, reduce airway resistance, and improve airflow limitation and exercise performance. All guidelines currently recommend BDs for treatment of stable COPD, which are the mainstay of pharmacologic treatment of COPD. There are the two major types of BD, β2-agonists and anticholinergics. Salbutamol and terbutaline are the short-acting β2-agonists, whose effects usually wear off within 4 to 6 hours. Salmeterol and formoterol are long-acting β2-agonists administered twice daily, while indacaterol is ultralong-acting agent, whose effect lasts over 24h. Ipratropium bromide is the shortacting anticholinergics, whose effect lasts somewhat less than 6h, and aclidinium bromide is administred twice daily. Tiotropium bromide and glycopirronium are ultralong-acting anticholinergics, which are administered once daily. A number of trials have evaluated the various combination of two BDs, salmeterol-tiotropium combination, formoterol-tiotropium combination, and indacaterol-tiotropium combination. Most of the studies have shown that combination therapy is superior to individual drugs. Comparative studies have shown that tiotropium is functionally and clinically superior to ipratropium, and indacaterol is significantly superior to both formoterol and salmeterol. Ultralong-acting BDs improve adherence to treatment as well as more effective than either short- or long-acting BDs. Tiotropium apperars to be superior to salmeterol with respect to exacerbation outcumes. The two ultra long-acting BDs, indacaterol and tiotropium have similar outcomes, although indacaterol seems to be somewhat more effective with regard to health-related quality of life (HRQoL).

Abstract: Despite huge global health burden of COPD, inefficient biomarkers, inadequate in-vitro and in-vivo model, heterogeneity of COPD, physiological and clinical endpoints in clinical trials, and complex pathogenetic networks were obstacles to pharmacotherapeutic advances in COPD. Although some bronchodilators and inhaled corticosteroids (ICS) have been available for decades, there are unmet needs for new drugs in managing COPD. Recently, ultra-long acting beta-2 agonist (LABA) and a selective phosphodiesterase (PDE) 4 inhibitor were introduced in clinical field. Additionally, more potent long acting muscarinic antagonists (LAMA), once daily LABA, and once daily ICS showed favorable efficacy in clinical trials. For example, new LABA/LAMA combination showed significant improvement in lung function and symptoms in moderate to severe COPD. Therefore, within a few years, new fixed various combination of long acting highly selective bronchodilators and/or new inhaled corticosteroids will be available. Single dose closed triple inhalers (ICS/LABA/LAMA) are also in advanced phase of clinical trials. New PDE4 inhibitor(s) are also waiting for their application, while the selection of efficient subgroups and long term outcomes for PDE4 inhibitor(s) should be explored. Additionally, availability of generic inhaled medication may affect the management of COPD in near future. Considering clinical efficacy of long acting agents, novel combinations, and advanced technology in inhalers devices, in part, awaiting new drugs are expecting to contribute to effective management of COPD. Nevertheless, further efforts in developing new therapeutic strategies and new pharmacotherapeutic agents beyond current spectrum are mandatory to change the natural course of COPD and satisfy the unmet needs in treatment of COPD.

© 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology

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MAXIMAL CONVENTIONAL PHARMACOTHERAPY FOR SEVERE ASTHMA

THERMOPLASTY AS A NEW THERAPY FOR SEVERE ASTHMA

B-J LEE Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea The goal of asthma management is to achieve disease control. However, a significant portion of patients remains uncontrolled despite maximal standard treatment. The management of asthmatic patients who remain uncontrolled with high-dose inhaled corticosteroids (ICS) plus long-acting beta2 agonist (LABA) is challenging. These patients experience persistent symptoms and frequent severe exacerbations, which results in high health costs. Recently, it was shown that addition of tiotropium improves lung function in patients with severe uncontrolled asthma. However, few other adjuvant treatment options are currently available. Therefore, before starting costly or potentially toxic therapies, several factors should be considered. For the example, poor adherence to prescribed medication is one of the most common causes of difficultto-control asthma. Incorrect inhalation technique is also associated with uncontrolled asthma. Several modifiable factors, such as smoking and comorbidities need to be corrected. Noninvasive evaluation of airway inflammation via sputum induction or exhaled NO may provide useful information for the intensification of anti-inflammatory treatment.

SW LEE Department of Pulmonary and Critical Care Medicine, and Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine Asthma exacerbation has a significant impact on a patient’s life, limiting participation in many activities. Most medical cost for asthmatics incurred from hospitalization or emergency room visits, associated with asthma exacerbation. Therefore, the effort to reduce exacerbation is quite important in patients with asthma and public health. The current treatment for asthma is based on inhaler therapy. Among them, inhaled corticosteroid (ICS) has many clinical benefits including increase of pulmonary function and reduction exacerbation and symptom. If asthma is not well controlled with ICS, bronchodilator or leukotriene antagonist can be added. Sometimes, anti-IgE or systemic steroid can be recommended. However, the patients with asthma are not rare who have symptom and experience recurrent experience despite of these medications. Thermoplasty is an innovative technique for severe asthma. The thermal energy was delivered to airway via the small catheter through bronchoscopy and the main purpose is to reduce the volume of airway smooth muscle. It showed significant reduction in acute exacerbation, and improvement of quality of life in asthma. Long-term follow-up also reassured the safety of this procedure. Korean Food and Drug Administration (FDA) approved this procedure, but the approval by health technology assessment (HTA) is still pending. Thermoplasty has role in the treatment of some patients with severe asthma who do not respond to current available medication. Proper case selection for this procedure will help the tailored therapy of asthma.

© 2014 The Authors. Respirology © 2014 Asian Pacific Society of Respirology

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PULMONARY REHABILITATION UPDATE IN 2013–2014 SY LIM Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea Pulmonary rehabilitation (PR) refers to a multidisciplinary program of care for patients with COPD that is designed to reduce symptoms, optimize functional status, increase participation, and reduce health care costs.1 The American Thoracic Society (ATS) and the European Respiratory Society (ERS) have adopted the new definition of PR in 2013.2 The impact of PR in mild COPD remains unestablished. A systematic review suggests that mild COPD may benefit from PR in terms of exercise capacity and health-related quality of life (HRQL), however, effects on healthcare utilization or lung function are not sufficiently significant.3 The effects of the type (continuous versus interval) and intensity (higher versus lower) of training in COPD also require investigation. Cochrane analysis reported that there were no significant differences in endurance time and six-minute walk distance improvement following higher or lowerintensity training.4 In addition, there were no significant differences between continuous and interval training. There has been increasing supportive evidence for providing PR in the acute exacerbation of COPD (AECOPD). Seymour and colleagues investigated the beneficial role of early outpatient PR following hospitalization for an AECOPD.5 A recent Cochrane review also concluded that PR immediately following an AECOPD or initiated during the AECOPD significantly reduced the likelihood of readmission.6 One subsequent randomized study have showed a trend that did not reach statistical significance in reducing the odds ratio for rehospitalization for AECOPD.7 Further studies are required to clarify the role of PR in AECOPD. Although a formal PR was not involved, the beneficial effect of combined COPD management program was reported.8 Trappenburg and colleagues also showed that an individualized action plan decreases the impact of AECOPD on health status and tends to accelerate recovery.9 Although a systematic review suggested that the longer duration of PR favored better quality of life, the optimal duration of PR program is still controversial.10 We will review the updated evidences of PR in patients with COPD.

Respirology (2014) 19 (Suppl. 1), 1–12

UNDERSTANDING THE PATHOPHYSIOLOGY IN COPD: WHAT WE HAVE LEARNED FROM IMAGING STUDIES JB SEO University of Ulsan College of Medicine In recent studies on COPD, CT has been accepted as one of important research tools in evaluating disease severity and characteristics. The extent of low attenuation area and bronchial wall thickening at segmental and distal level on volumetric CT scan acquired at suspended inspiration state are commonly used as useful markers for evaluating the severity of emphysema and airway wall inflammation, respectively. Many recently studies have proved that these imaging biomarkers are significantly related with the degree of airflow limitation, subgrouping/phenotyping of patients, prediction of treatment response, frequency of exacerbation, prediction of disease progression and so on. In addition, CT and MR imaging studies along with the computer-based analysis provide new insights of understanding pathophysiologic changes in COPD. Studies on regional air trapping using image registration between inspiration and expiration status CT scans proved the concept of small airway dysfunction as an early step of emphysema development. Analysis of complexity of distal airspace with thin section CT and fractal analysis provide the new concept of progression of emphysema. Analysis on the peripheral vascular changes with CT suggested the early change of vascular number and size in COPD progression. Combined analysis of perfusion and ventilation using CT or MR techniques has been proposed to assess regional V/Q changes with promising preliminary results. This talk will introduce the method and results these preliminary studies.

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