- Email: [email protected]
ATS 2008 Conference Report: Much PROgress
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4 (2008) 120– 124
ATS 2008 Conference Report: Much PROgress The 2008 American Thoracic Society (ATS) International Conference was held in Toronto, Canada, between the 16 and 21 May 2008. This review aims to summarise some of the sessions relating to COPD, providing an overview of key developments over the previous 12 months and an opportunity to review preliminary information from new and on-going studies. The keynote lecture, the COPD ‘Clinical Year in Review’, was delivered this year by Professor Wisia Wedzicha from University College London, UK. She highlighted a number of important papers from the previous 12 months, in four key themes, which are also discussed in the sections below. Key themes: COPD Year in Review
A higher than expected prevalence of COPD globally. The increasing importance of factors other than smoking in
the development of COPD, such as biomass fuels, environmental tobacco smoke and early lung development. The increasing interest in the use of biomarkers to predict COPD outcomes. New information on interventions that reduce exacerbations, which also inform on the mechanisms underlying these events.
In the sections below we will expand on these themes and discuss some of the other key areas relating to COPD from the 2008 ATS conference.
1.
COPD epidemiology
Prominence was given in the Year in Review lecture to a special edition of the Lancet, publication of which had coincided with the 2007 European Respiratory Congress. This featured three original papers, which were all concerned with COPD epidemiology. The BOLD study reported on international differences in the prevalence of COPD,1 which are not completely explained by differences in age and smoking. One explanation for these differences may be exposure to passive smoking and air pollutants, and this was the subject of a second paper.2 This large study from China estimated that 1.9 million excess doi:10.1016/j.rmedu.2008.08.002
deaths among never smokers could be attributable to COPD acquired through passive smoking in the current Chinese population. A second Chinese study, published in Thorax,3 had highlighted the likely important role of indoor biomass pollutants in a rural population from the south of that country. The importance of this work lies in the billions of people worldwide who use such techniques for cooking and heating their homes. The role of biomass fuels was also examined in abstract presentations, including interesting epidemiological data from Mexico, suggesting a differential effect of tobacco versus biomass smoke on lung function decline, with the former having the larger effect.4 Despite biomass smoke being an important contributor to COPD, our understanding of these patients’ pathophysiology, epidemiology and responses to treatment lags behind our understanding of COPD due to tobacco smoke exposure. Other factors important in the causation of COPD were highlighted in an Austrian abstract, where never smokers, females and those exposed to agricultural dusts account for a substantial proportion of COPD.5 Another explanation for differences in COPD prevalence may be related to our definition of the disease. BOLD study data have been used to compare spirometric definitions of COPD. Using a fixed ratio alone (i.e. FEV1/FVCo0.7) may spuriously increase the prevalence of COPD in an aging population. Adjusting the ratio for age may reduce falsepositive diagnoses and also requiring a low FEV1 further minimises this change.6 Other abstracts highlighted that simple measures such as routine spirometry in a primary care setting increase the recorded prevalence of COPD by about 22%, although this is less if a symptom-based questionnaire is also used.7 In the future we may even have diagnostic COPD clinics in local pharmacies, as they are a potential untapped resource for spirometry.8 Increasing the recorded prevalence under these circumstances would enable early initiation of treatment and prevention of exacerbations. The third Lancet paper examined the effects of lung development on the risk of COPD9 and concluded that poor post-natal airway function should also be recognised as a risk factor for COPD. Certainly, the concept that prevention of COPD might need to start in fetal life would be a paradigm shift in this disease.
ARTICLE IN PRESS R E S P I R AT O RY M E D I C I N E : C O P D U P D AT E
A further epidemiological debate remains the role of chronic bronchitis in the development of COPD. New data from the TESAOD study reported associations between chronic bronchitis and airflow obstruction in 1654 participants studied since 1972. The conclusion? Chronic bronchitis was a risk factor for the development of COPD amongst smokers.10 Moreover, in individuals who have COPD the presence of chronic cough and sputum production has been associated with frequent exacerbations.11 This sub-phenotype may benefit from the development of specific treatments. Combining data from multiple studies is tightening our understanding of the genetic determinants of COPD, and in particular to a group of genes co-located on the long-arm of chromosome 2.12 Genetic polymorphisms may not only be important in the development of COPD, but may also play a role in bronchodilator responsiveness phenotypes.13 Other abstracts highlighted that genetic polymorphisms may also be associated with susceptibility to exacerbations.14,15 The next studies highlighted in the Year in Review were by Langsetmo et al.16 and Vijayasaratha and Stockley.17 Both served to reinforce the concept that not all exacerbations experienced by a patient will be reported to health-care professionals. Indeed, in the former study, less than one-third were reported and this remains a challenge for the future. Finally, Professor Wedzicha highlighted on-going work defining the important topic of the statistical treatment of exacerbations.18 This may seem esoteric but it is not widely appreciated that analysis of these events differs between trials in ways that may make comparisons between studies complex.
2.
COPD therapeutics
The past 12 months have seen the publication of a number of large, important therapeutic trials in COPD including TORCH19 and INSPIRE20 that have extended our evidence base for the use of long-acting bronchodilators alone and in combination with inhaled corticosteroids. An interesting and unexpected finding of these studies has been an increased incidence of clinician-diagnosed pneumonia in patients taking regimes containing inhaled corticosteroids. A further analysis of the INSPIRE dataset21 concluded that many of these events were unresolved exacerbations and it may be that steroid-containing regimes are altering the phenotypic presentations of exacerbations. Elsewhere, the year has seen publication of interesting results from the US Veterans Normative Aging study22: ‘statins’ are known to have anti-inflammatory properties and observational data suggest that these drugs can attenuate lung function decline, with an effect size that is modified by smoking status. b-Blockers have also recently been suggested to be effective in reducing mortality in COPD, despite potential concerns about their safety.23 Dransfield, in a retrospective analysis of patients hospitalized for exacerbation of COPD, reported an odds ratio for death of 0.39 (95% CI 0.14–0.99) for patients prescribed these drugs, in a multivariate analysis controlling for other likely confounding variables.
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Regarding exacerbation therapy, a meta-analysis24 has reported that short-course antibiotic treatment (p5 days) is not inferior to longer course (45 days) in patients with less severe exacerbations of COPD. However, it is not just drug treatment that is important, a systematic review of the use of physiotherapy during acute exacerbations highlights its importance for airway clearance for copious secretions and peripheral muscle strength training.25 Predicting outcomes at exacerbation using biomarkers, a major theme in recent years, continues to generate much interest. Stolz reported that B-type natriuretic peptide (BNP) levels may risk stratify patients admitted with exacerbation,26 predicting the need for more intensive support (but not shortor longer-term mortality), whilst Bozinovski et al.27 reported data that Serum Amyloid A protein may aid in differentiating exacerbations that can be managed in an ambulatory care setting from those requiring hospitalisation. Regarding data presented at the conference itself, the CURB-65 score, developed for community-acquired pneumonia, was assessed in 247 patients and shown to reflect mortality.28 In another abstract, Lipoxins (anti-inflammatory lipid mediators) were found to be insufficiently elevated at exacerbation in COPD and may provide an important biomarker or even therapeutic target for the future.29 Preventing exacerbations may be an even more important strategy and interesting data from Washko et al.30 have highlighted the ability of lung-volume reduction surgery to achieve this aim, through mechanisms that at present remain unclear. This may prove beneficial to severe patients as in advanced emphysema, endoscopic reduction surgery is emerging as a safe and viable option.31 Generally therapies that prevent exacerbations are thought to be anti-inflammatory but Powrie et al.32 demonstrated a significant effect of tiotropium in reducing exacerbations in the absence of an effect on either local or systemic inflammatory markers. The combination of salmeterol–fluticasone is also effective in reducing exacerbations, and data from Bourbeau et al.33 provided evidence for an anti-inflammatory effect greater than that seen with the steroid component alone. As always, data were also available on newer drugs in development including ultra-long-acting (once-daily) b2 agonists (carmoterol34 and indacterol35), longer-acting inhaled corticosteroids such as fluticasone furoate36 and variant anti-cholinergics such as aclidinium bromide.37 Non-pharmacological approaches continue to develop too; one novel approach to increase lung elastic recoil is by covering the surface in a nylon/polyurethane net38 and evidence of the durability of lung-function changes with endobronchial volume reduction out to 12 months.39 Moreover, with emerging data that gastro-oesophageal reflux may be important in exacerbations, there was provocative first data from a randomised but open-label Japanese study, suggesting that proton-pump inhibition may have dramatic effects on exacerbation frequency, even in the absence of clinical reflux disease.40 Transplantation remains an option for selected subjects, but two abstracts reported the recurrence of pulmonary disease in patients with a1-anti-trypsin deficiency.41,42 Data from a single-blind study in Hong Kong employing sham ventilation suggest that domiciliary NIV may reduce the recurrence of hypercapnic respiratory failure
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in patients who have survived to discharge following NIV treatment for a first episode.43 ‘Changing the Natural History of COPD’ was the title of a major symposium. In addition to those results already in the public domain, Professor Celli (Boston, US) looked forward to the results of the forthcoming UPLIFT study—expected to be presented at the September ERS congress. UPLIFT is a large randomised trial of tiotropium bromide enrolling around 6000 subjects and with decline in FEV1 as the primary end-point. The rationale for a pure bronchodilator affecting lung function decline is novel, but there is evidence in ARDS, for example, that lung stretch is associated with lung inflammation and therefore a drug effective at reducing dynamic hyperinflation may therefore be indirectly anti-inflammatory. Dr Sethi (Buffalo, US) presented the first results of the PULSE study. PULSE randomised participants to 5-day courses of moxifloxacin 400 mg every 8 weeks, or placebo, for 48 weeks. Over 1100 patients were randomised and it appears that there is a significant reduction in exacerbation frequency of around 25%, particularly for those patients with baseline sputum production, and without a significant risk of antibiotic resistance in either respiratory or GI flora. The formal report is awaited with interest. Also in this session, Professor Bailey (Birmingham, US) outlined those studies developed by the ‘COPD Clinical Research Network’ of the US NHLBI. Four studies are in progress: ‘AMBOX’ to assess whether the use of lightweight portable oxygen cylinders increases oxygen usage and physical activity; ‘MACRO’—a randomised controlled trial of azithromycin to impact exacerbation frequency; ‘LEUKO’ a randomised trial of zileuton to speed exacerbation recovery in patients hospitalised with COPD exacerbation and ‘PNEUMO’—a comparative trial of standard capsular polysaccharide Pneumococcal vaccine with a diphtheria-protein-conjugated version, which may have greater immunogenicity. Whilst there is emerging evidence for the use of macrolides in COPD (and data were presented on the effect of azithromycin on alveolar macrophage phagocytosis44), the use of zileuton is novel. This drug reduces leukotriene biosynthesis by affecting the 5-lipoxygenase enzyme and certain leukotrienes, such as LTB4, and are thought to be important in COPD through their action as neutrophil chemo-attractants. Professor Fabbri (Modena, Italy) ended the session with the question ‘What Next?’. His answer was the effective recognition and treatment of co-morbidities associated with COPD. Certainly there were further reports on the high prevalence of co-morbidities in patients with COPD, and the finding that the number of co-morbidities present is related to hospitalisation.45 However, this should not distract us from the need to develop new therapeutics for the COPD lung, nor to use those treatments that we do have in more appropriate ways. By way of example, there was lively discussion between Professors Peter Calverley (Liverpool, UK) and Peter Barnes (London, UK) in a Pro-Con debate on the use of corticosteroids in COPD. There is now clear evidence of COPD as a steroid-resistant disease and further in vitro work has investigated the mechanisms underlying reduced HDAC activity,46 whilst clinical trials have added to the data suggesting that theophyllines may to some degree restore corticosteroid sensitivity.47
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One of the reasons we intervene in COPD is, of course, to reduce mortality, and the large TORCH dataset has shed new light on what exactly our patients die from.48 As only around 40% of patients with COPD will die from their disease, we need to be alert to prevalent co-morbidities and, indeed, statins were developed for their beneficial effects on cardiovascular outcomes, for example. In a large study investigating factors associated with death or re-hospitalisation, McGhan reported that age, male gender, prior hospitalizations and certain co-morbid conditions were the major risk factors.49 This again emphasizes the importance of effectively treating co-morbidities and, indeed, the significant mortality following hospital admission for exacerbation with 21% of this population dead at 1 year. We must not forget that COPD is not just a disease of the lungs, there are systemic manifestations and treating the ‘whole patient’ is extremely important. This theme was highlighted in a session addressing ‘psychosocial factors and health outcomes in COPD’. Pulmonary rehabilitation, which is now accepted as standard therapy, is being increasingly applied in various stages of COPD. In one abstract it was suggested that inpatient pulmonary rehabilitation in advanced COPD improves quality of life and exercise tolerance even though lung function did not improve.50 A further abstract reported that long-term weekly rehabilitation maintains exercise capacity and reduces hospitalisation.51
3.
PRO: patient reported outcomes
A major theme at this year’s congress was the concept of a ‘PRO’ or ‘patient reported outcome’. Not so long ago the major outcomes in COPD trials related to lung function parameters such as FEV1. Hard clinical end-points remain important; mortality, for example, but more recently, the COPD community has realised that what matters to our patients should also matter to us. Hence, ‘patient reported outcomes’. There are many PRO, and some such as health-status have wellvalidated tools to assess them, such as the St. George’s Respiratory Questionnaire (SGRQ). Until we have a validated biomarker, exacerbations remain an important PRO and here there is considerable variation in definitions, not just relating to the presence of exacerbation, but also their frequency and severity. Such problems cause difficulties in interpreting results across clinical trials and have resulted in initiatives involving the US FDA to develop validated exacerbation assessment tools. Two such tools have been developed thus far; both from first principles of qualitative patient assessment, and both are now at the stage of assessment in clinical trials. A number of abstract presentations described the development of the tools: the United BioSource Corporation Exact-PRO initiative52 and a tool developed by GlaxoSmithKline.53 The topic of PRO was the subject of a major symposium on ‘Measuring Outcome in COPD’.
4.
Summary
In summary, the ATS provided the usual mix of review and new developments: rest assured, as these preliminary data
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reach publication the most significant findings will be covered in Respiratory Medicine COPD Update: the only dedicated digest publication keeping you up to date with developments in COPD. R E F E R E N C E S
1. Buist SA, et al. International variation in the prevalence of COPD (The BOLD study): a population-based prevalence study. Lancet 2007;370:741–50. 2. Yin P, et al. Passive smoking exposure and risk of COPD among adults in China: the Guangzhou Biobank cohort study. Lancet 2007;370:751–7. 3. Liu, et al. Biomass fuels are the probable risk factor for chronic obstructive pulmonary disease in rural South China. Thorax 2007;62:889–97. 4. Ramirez-Venegas A, Sanchez MC, Regalado J, et al. FEV1 decline over time in COPD women domestically exposed to biomass smoke [abstract]. Am J Respir Crit Care Med 2008;177:A400. 5. Lamprecht B, Schirnhofer L, Buist AS, et al. Never smokers comprise approximately one third of COPD cases—results from the Austrian burden of obstructive lung disease (BOLD) study [abstract]. Am J Respir Crit Care Med 2008;177:A235. 6. Vollmer WM, Gislason T, Gulsvik A, et al. Comparison of spirometry criteria for diagnosing COPD [abstract]. Am J Respir Crit Care Med 2008;177:A234. 7. Hodder R, Go0ldstein R, Stanbrook M, et al. COPD case finding using symptom-based targeted vs routine Spirometry in primary care patients at high risk for COPD [abstract]. Am J Respir Crit Care Med 2008;177:A401. 8. Castillo D, Burgos F, Giner J, et al. Early detection of COPD in high-risk pharmacy cutomers. A pilot study [abstract]. Am J Respir Crit Care Med 2008;177:A401. 9. Stern DA, et al. Poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study. Lancet 2007;370:758–64. 10. Guerra S, Sherrill DL, Venker C, Martinez FD. Chronic bronchitis as an independent risk factor for developing airflow limitation among smokers [abstract]. Am J Respir Crit Care Med 2008;177:A398. 11. Burgel PR, Nesme-Meyer P, Chanez P, et al. Frequent exacerbations and chronic bronchitis concurred for a distinct phenotype in COPD [abstract]. Am J Respir Crit Care Med 2008;177:A286. 12. Hersh CP, Pillai SG, Zhu G, et al. Multi-study fine mapping of a COPD susceptibility locus on chromosome 2q [abstract]. Am J Respir Crit Care Med 2008;177:A907. 13. Kim WJ, Hersh CP, DeMeo DL, et al. Pharmacogenetics of bronchodilator responsiveness in COPD patients [abstract]. Am J Respir Crit Care Med 2008;177:A502. 14. Foreman MG, DeMeo DL, Hersh CP, et al. Polymorphisms in innate immunity genes are associated with COPD exacerbations [abstract]. Am J Respir Crit Care Med 2008;177:A303. 15. Quint JK, Baghai-Ravary R, Goldring JJP, et al. IL8 genotypes and exacerbation frequency in chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A304. 16. Langsetmo L, Platt RW, Ernst P, et al. Underreporting exacerbation of chronic obstructive pulmonary disease in a longitudinal cohort. Am J Respir Crit Care Med 2008;177:396–401. 17. Vijayasaratha K, Stockley RA. Reported and unreported exacerbations of COPD. Chest 2008;133:34–41. 18. Aaron SD, et al. Counting, analysing and reporting exacerbations of COPD in randomised controlled trials. Thorax 2008;63:122–8.
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19. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775. 20. Wedzicha JA, Calverley PMA, Seemungal TA, et al. for the INSPIRE Investigators Am J Respir Crit Care Med 2008;177: 19–26. 21. Calverley P, Stockley R, Seemungal T, et al. Assessment of Pneumonia reports in the INSPIRE study [abstract]. Am J Respir Crit Care Med 2008;177:A132. 22. Alexeeff SE, et al. Statin use reduces decline in lung function: VA normative aging study. Am J Respir Crit Care Med 2007;176:742–7. 23. Dransfield MT, et al. Use of b blockers and the risk of death in hospitalised patients with acute exacerbations of COPD. Thorax 2008;63:301–5. 24. El Moussaoui R, et al. Short-course antibiotic treatment in acute exacerbations of chronic bronchitis and COPD: a metaanalysis of double-blind studies. Thorax 2008;63:415–22. 25. Hill K, Patman S, Brooks D, et al. Systematic review of physiotherapy during acute exacerbations of chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A137. 26. Stolz DA, et al. Use of B-type natriuretic peptide in the risk stratification of acute exacerbations of COPD. Chest 2008;133:1088–94. 27. Bozinovski S, et al. Serum Amyloid A is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:269–78. 28. Chang CL, Sullivan GD, Karalus NC, et al. Predicting mortality in acute exacerbation of chronic obstructive pulmonary disease using CURB65 scores [abstract]. Am J Respir Crit Care Med 2008;177:A132. 29. Karlsson AS, Anderson GP, Thompson M, et al. Anti-inflammatory Lipoxin A4 is diminished in acute, severe exacaerbations of COPD [abstract]. Am J Respir Crit Care Med 2008;177:A303. 30. Washko GR, et al. The effect of lung volume reduction surgery on chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;177:164–9. 31. O’Callaghan DS, Remund KF, Coyle J, et al. Treatment of advanced emphysema by endoscopic volume reduction [abstract]. Am J Respir Crit Care Med 2008;177:A18. 32. Powrie DJ, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J 2007;30:472–8. 33. Bourbeau J, et al. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Thorax 2007;62:938–43. 34. Bateman ED, Make BJ, Nandeuil MA. Carmoterol—safety and tolerability of a long-acting b-2 Agonist in patients with COPD [abstract]. Am J Respir Crit Care Med 2008;177:A653. 35. Higgins M, Beier J, Yang W, et al. Cardiac safety of indacterol, a novel once-daily bronchodilator [abstract]. Am J Respir Crit Care Med 2008;177:A653. 36. To Y, Rossios C, Adcock IM, et al. Novel ultra-long acting steroid (fluticasone fuorate) shows more potent anti-inflammatory action than fluticasone propionate in PBMCs from COPD patients [abstract]. Am J Respir Crit Care Med 2008;177:A651. 37. Chanez P, Burge S, Dahl R, et al. Once-daily administration of aclidinium bromide, a novel, long-acting anticholinergic: a Phase II, dose-finding study [abstract]. Am J Respir Crit Care Med 2008;177:A650. 38. Sato T, Sakai H, Takahashi A, et al. New surgical approach for COPD: covering lung with an elastic net [abstract]. Am J Respir Crit Care Med 2008;177:A17. 39. Sciurba FC, McLennan G, Ernst A, et al. Durability of endobronchial valve (EBV) effect on lung function at 6 and
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47.
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12 months in heterogeneous emphysema [abstract]. Am J Respir Crit Care Med 2008;177:A18. Sasaki T, Nakayama K, Yasuda H, et al. A proton pump inhibitor, lansoprazole, reduces frequency of exacerbations in patients with chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A139. Galazaka M, Groves S, Moainie S, et al. Accelerated pulmonary function decline in lung transplant patients with alpha-1antitrypsin deficiency emphysema [abstract]. Am J Respir Crit Care Med 2008;177:A389. Phillips KA, Lama VN, Chang AC, et al. Development of a1-anti-trypsin deficiency related disease following lung transplantation for emphysema [abstract]. Am J Respir Crit Care Med 2008;177:A389. Chu CM, Cheung AP, Chan VL, et al. A randomized trial of home non-invasive ventilation vs. sham ventilation in survivors of acute hypercapnic respiratory failure in COPD [abstract]. Am J Respir Crit Care Med 2008;177:A767. Hodge SJ, Hodge G, Ahern J, et al. Low dose azithromycin improves efferocytosis (Apoptosis and Macrophage Function) in COPD patients [abstract]. Am J Respir Crit Care Med 2008;177:A620. Cote CG, Pinto-Plata VM, Nekach H, et al. Co-morbidities in COPD: how many and how significant [abstract]. Am J Respir Crit Care Med 2008;177:A782. Takagi D, Getting S, Adcock IM, et al. Oxidative-stress induced dissociation of HDAC2 and Mi-2 corepressor may cause steroid insensitivity seen in COPD [abstract]. Am J Respir Crit Care Med 2008;177:A264. Ford PA, Durham AL, Russell EK, et al. A clinical trial demonstrating that low dose theophylline attenuates steroid
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49.
50.
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53.
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insensitivity in COPD [abstract]. Am J Respir Crit Care Med 2008;177:A651. McGarvey LP, et al. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007;62:411–5. McGhan R, et al. Predictors of rehospitalization and death after a severe exacerbation of COPD. Chest 2007;132: 1748–55. Teschler S, kenn K, Teschler H, et al. Effectiveness of a comprehensive inpatient pulmonary rehabilitation program for advanced chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A146. Ho SC, Lin HC, chen LF, et al. Weekly hospital based pulmonary rehabilitation maintains exercise capacity and reduces hospitalisation in patients with chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A149. Leidy NK, Burke LB, Powers JH, et al. The EXACT-PRO initiative: development of a standardized outcome measure for evaluating exacerbations of chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A139. Berkowitz EM, Van Parijs BA, Fernandes A, et al. Development of a patient-reported outcome (PRO) measure in AECOPD [abstract]. Am J Respir Crit Care Med 2008;177:A305.
J.K. Quint, J.R. Hurst Academic Unit of Respiratory Medicine, Royal Free and University College Medical School, London, UK E-mail address: [email protected] (J.R. Hurst)
4 (2008) 120– 124
ATS 2008 Conference Report: Much PROgress The 2008 American Thoracic Society (ATS) International Conference was held in Toronto, Canada, between the 16 and 21 May 2008. This review aims to summarise some of the sessions relating to COPD, providing an overview of key developments over the previous 12 months and an opportunity to review preliminary information from new and on-going studies. The keynote lecture, the COPD ‘Clinical Year in Review’, was delivered this year by Professor Wisia Wedzicha from University College London, UK. She highlighted a number of important papers from the previous 12 months, in four key themes, which are also discussed in the sections below. Key themes: COPD Year in Review
A higher than expected prevalence of COPD globally. The increasing importance of factors other than smoking in
the development of COPD, such as biomass fuels, environmental tobacco smoke and early lung development. The increasing interest in the use of biomarkers to predict COPD outcomes. New information on interventions that reduce exacerbations, which also inform on the mechanisms underlying these events.
In the sections below we will expand on these themes and discuss some of the other key areas relating to COPD from the 2008 ATS conference.
1.
COPD epidemiology
Prominence was given in the Year in Review lecture to a special edition of the Lancet, publication of which had coincided with the 2007 European Respiratory Congress. This featured three original papers, which were all concerned with COPD epidemiology. The BOLD study reported on international differences in the prevalence of COPD,1 which are not completely explained by differences in age and smoking. One explanation for these differences may be exposure to passive smoking and air pollutants, and this was the subject of a second paper.2 This large study from China estimated that 1.9 million excess doi:10.1016/j.rmedu.2008.08.002
deaths among never smokers could be attributable to COPD acquired through passive smoking in the current Chinese population. A second Chinese study, published in Thorax,3 had highlighted the likely important role of indoor biomass pollutants in a rural population from the south of that country. The importance of this work lies in the billions of people worldwide who use such techniques for cooking and heating their homes. The role of biomass fuels was also examined in abstract presentations, including interesting epidemiological data from Mexico, suggesting a differential effect of tobacco versus biomass smoke on lung function decline, with the former having the larger effect.4 Despite biomass smoke being an important contributor to COPD, our understanding of these patients’ pathophysiology, epidemiology and responses to treatment lags behind our understanding of COPD due to tobacco smoke exposure. Other factors important in the causation of COPD were highlighted in an Austrian abstract, where never smokers, females and those exposed to agricultural dusts account for a substantial proportion of COPD.5 Another explanation for differences in COPD prevalence may be related to our definition of the disease. BOLD study data have been used to compare spirometric definitions of COPD. Using a fixed ratio alone (i.e. FEV1/FVCo0.7) may spuriously increase the prevalence of COPD in an aging population. Adjusting the ratio for age may reduce falsepositive diagnoses and also requiring a low FEV1 further minimises this change.6 Other abstracts highlighted that simple measures such as routine spirometry in a primary care setting increase the recorded prevalence of COPD by about 22%, although this is less if a symptom-based questionnaire is also used.7 In the future we may even have diagnostic COPD clinics in local pharmacies, as they are a potential untapped resource for spirometry.8 Increasing the recorded prevalence under these circumstances would enable early initiation of treatment and prevention of exacerbations. The third Lancet paper examined the effects of lung development on the risk of COPD9 and concluded that poor post-natal airway function should also be recognised as a risk factor for COPD. Certainly, the concept that prevention of COPD might need to start in fetal life would be a paradigm shift in this disease.
ARTICLE IN PRESS R E S P I R AT O RY M E D I C I N E : C O P D U P D AT E
A further epidemiological debate remains the role of chronic bronchitis in the development of COPD. New data from the TESAOD study reported associations between chronic bronchitis and airflow obstruction in 1654 participants studied since 1972. The conclusion? Chronic bronchitis was a risk factor for the development of COPD amongst smokers.10 Moreover, in individuals who have COPD the presence of chronic cough and sputum production has been associated with frequent exacerbations.11 This sub-phenotype may benefit from the development of specific treatments. Combining data from multiple studies is tightening our understanding of the genetic determinants of COPD, and in particular to a group of genes co-located on the long-arm of chromosome 2.12 Genetic polymorphisms may not only be important in the development of COPD, but may also play a role in bronchodilator responsiveness phenotypes.13 Other abstracts highlighted that genetic polymorphisms may also be associated with susceptibility to exacerbations.14,15 The next studies highlighted in the Year in Review were by Langsetmo et al.16 and Vijayasaratha and Stockley.17 Both served to reinforce the concept that not all exacerbations experienced by a patient will be reported to health-care professionals. Indeed, in the former study, less than one-third were reported and this remains a challenge for the future. Finally, Professor Wedzicha highlighted on-going work defining the important topic of the statistical treatment of exacerbations.18 This may seem esoteric but it is not widely appreciated that analysis of these events differs between trials in ways that may make comparisons between studies complex.
2.
COPD therapeutics
The past 12 months have seen the publication of a number of large, important therapeutic trials in COPD including TORCH19 and INSPIRE20 that have extended our evidence base for the use of long-acting bronchodilators alone and in combination with inhaled corticosteroids. An interesting and unexpected finding of these studies has been an increased incidence of clinician-diagnosed pneumonia in patients taking regimes containing inhaled corticosteroids. A further analysis of the INSPIRE dataset21 concluded that many of these events were unresolved exacerbations and it may be that steroid-containing regimes are altering the phenotypic presentations of exacerbations. Elsewhere, the year has seen publication of interesting results from the US Veterans Normative Aging study22: ‘statins’ are known to have anti-inflammatory properties and observational data suggest that these drugs can attenuate lung function decline, with an effect size that is modified by smoking status. b-Blockers have also recently been suggested to be effective in reducing mortality in COPD, despite potential concerns about their safety.23 Dransfield, in a retrospective analysis of patients hospitalized for exacerbation of COPD, reported an odds ratio for death of 0.39 (95% CI 0.14–0.99) for patients prescribed these drugs, in a multivariate analysis controlling for other likely confounding variables.
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Regarding exacerbation therapy, a meta-analysis24 has reported that short-course antibiotic treatment (p5 days) is not inferior to longer course (45 days) in patients with less severe exacerbations of COPD. However, it is not just drug treatment that is important, a systematic review of the use of physiotherapy during acute exacerbations highlights its importance for airway clearance for copious secretions and peripheral muscle strength training.25 Predicting outcomes at exacerbation using biomarkers, a major theme in recent years, continues to generate much interest. Stolz reported that B-type natriuretic peptide (BNP) levels may risk stratify patients admitted with exacerbation,26 predicting the need for more intensive support (but not shortor longer-term mortality), whilst Bozinovski et al.27 reported data that Serum Amyloid A protein may aid in differentiating exacerbations that can be managed in an ambulatory care setting from those requiring hospitalisation. Regarding data presented at the conference itself, the CURB-65 score, developed for community-acquired pneumonia, was assessed in 247 patients and shown to reflect mortality.28 In another abstract, Lipoxins (anti-inflammatory lipid mediators) were found to be insufficiently elevated at exacerbation in COPD and may provide an important biomarker or even therapeutic target for the future.29 Preventing exacerbations may be an even more important strategy and interesting data from Washko et al.30 have highlighted the ability of lung-volume reduction surgery to achieve this aim, through mechanisms that at present remain unclear. This may prove beneficial to severe patients as in advanced emphysema, endoscopic reduction surgery is emerging as a safe and viable option.31 Generally therapies that prevent exacerbations are thought to be anti-inflammatory but Powrie et al.32 demonstrated a significant effect of tiotropium in reducing exacerbations in the absence of an effect on either local or systemic inflammatory markers. The combination of salmeterol–fluticasone is also effective in reducing exacerbations, and data from Bourbeau et al.33 provided evidence for an anti-inflammatory effect greater than that seen with the steroid component alone. As always, data were also available on newer drugs in development including ultra-long-acting (once-daily) b2 agonists (carmoterol34 and indacterol35), longer-acting inhaled corticosteroids such as fluticasone furoate36 and variant anti-cholinergics such as aclidinium bromide.37 Non-pharmacological approaches continue to develop too; one novel approach to increase lung elastic recoil is by covering the surface in a nylon/polyurethane net38 and evidence of the durability of lung-function changes with endobronchial volume reduction out to 12 months.39 Moreover, with emerging data that gastro-oesophageal reflux may be important in exacerbations, there was provocative first data from a randomised but open-label Japanese study, suggesting that proton-pump inhibition may have dramatic effects on exacerbation frequency, even in the absence of clinical reflux disease.40 Transplantation remains an option for selected subjects, but two abstracts reported the recurrence of pulmonary disease in patients with a1-anti-trypsin deficiency.41,42 Data from a single-blind study in Hong Kong employing sham ventilation suggest that domiciliary NIV may reduce the recurrence of hypercapnic respiratory failure
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in patients who have survived to discharge following NIV treatment for a first episode.43 ‘Changing the Natural History of COPD’ was the title of a major symposium. In addition to those results already in the public domain, Professor Celli (Boston, US) looked forward to the results of the forthcoming UPLIFT study—expected to be presented at the September ERS congress. UPLIFT is a large randomised trial of tiotropium bromide enrolling around 6000 subjects and with decline in FEV1 as the primary end-point. The rationale for a pure bronchodilator affecting lung function decline is novel, but there is evidence in ARDS, for example, that lung stretch is associated with lung inflammation and therefore a drug effective at reducing dynamic hyperinflation may therefore be indirectly anti-inflammatory. Dr Sethi (Buffalo, US) presented the first results of the PULSE study. PULSE randomised participants to 5-day courses of moxifloxacin 400 mg every 8 weeks, or placebo, for 48 weeks. Over 1100 patients were randomised and it appears that there is a significant reduction in exacerbation frequency of around 25%, particularly for those patients with baseline sputum production, and without a significant risk of antibiotic resistance in either respiratory or GI flora. The formal report is awaited with interest. Also in this session, Professor Bailey (Birmingham, US) outlined those studies developed by the ‘COPD Clinical Research Network’ of the US NHLBI. Four studies are in progress: ‘AMBOX’ to assess whether the use of lightweight portable oxygen cylinders increases oxygen usage and physical activity; ‘MACRO’—a randomised controlled trial of azithromycin to impact exacerbation frequency; ‘LEUKO’ a randomised trial of zileuton to speed exacerbation recovery in patients hospitalised with COPD exacerbation and ‘PNEUMO’—a comparative trial of standard capsular polysaccharide Pneumococcal vaccine with a diphtheria-protein-conjugated version, which may have greater immunogenicity. Whilst there is emerging evidence for the use of macrolides in COPD (and data were presented on the effect of azithromycin on alveolar macrophage phagocytosis44), the use of zileuton is novel. This drug reduces leukotriene biosynthesis by affecting the 5-lipoxygenase enzyme and certain leukotrienes, such as LTB4, and are thought to be important in COPD through their action as neutrophil chemo-attractants. Professor Fabbri (Modena, Italy) ended the session with the question ‘What Next?’. His answer was the effective recognition and treatment of co-morbidities associated with COPD. Certainly there were further reports on the high prevalence of co-morbidities in patients with COPD, and the finding that the number of co-morbidities present is related to hospitalisation.45 However, this should not distract us from the need to develop new therapeutics for the COPD lung, nor to use those treatments that we do have in more appropriate ways. By way of example, there was lively discussion between Professors Peter Calverley (Liverpool, UK) and Peter Barnes (London, UK) in a Pro-Con debate on the use of corticosteroids in COPD. There is now clear evidence of COPD as a steroid-resistant disease and further in vitro work has investigated the mechanisms underlying reduced HDAC activity,46 whilst clinical trials have added to the data suggesting that theophyllines may to some degree restore corticosteroid sensitivity.47
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One of the reasons we intervene in COPD is, of course, to reduce mortality, and the large TORCH dataset has shed new light on what exactly our patients die from.48 As only around 40% of patients with COPD will die from their disease, we need to be alert to prevalent co-morbidities and, indeed, statins were developed for their beneficial effects on cardiovascular outcomes, for example. In a large study investigating factors associated with death or re-hospitalisation, McGhan reported that age, male gender, prior hospitalizations and certain co-morbid conditions were the major risk factors.49 This again emphasizes the importance of effectively treating co-morbidities and, indeed, the significant mortality following hospital admission for exacerbation with 21% of this population dead at 1 year. We must not forget that COPD is not just a disease of the lungs, there are systemic manifestations and treating the ‘whole patient’ is extremely important. This theme was highlighted in a session addressing ‘psychosocial factors and health outcomes in COPD’. Pulmonary rehabilitation, which is now accepted as standard therapy, is being increasingly applied in various stages of COPD. In one abstract it was suggested that inpatient pulmonary rehabilitation in advanced COPD improves quality of life and exercise tolerance even though lung function did not improve.50 A further abstract reported that long-term weekly rehabilitation maintains exercise capacity and reduces hospitalisation.51
3.
PRO: patient reported outcomes
A major theme at this year’s congress was the concept of a ‘PRO’ or ‘patient reported outcome’. Not so long ago the major outcomes in COPD trials related to lung function parameters such as FEV1. Hard clinical end-points remain important; mortality, for example, but more recently, the COPD community has realised that what matters to our patients should also matter to us. Hence, ‘patient reported outcomes’. There are many PRO, and some such as health-status have wellvalidated tools to assess them, such as the St. George’s Respiratory Questionnaire (SGRQ). Until we have a validated biomarker, exacerbations remain an important PRO and here there is considerable variation in definitions, not just relating to the presence of exacerbation, but also their frequency and severity. Such problems cause difficulties in interpreting results across clinical trials and have resulted in initiatives involving the US FDA to develop validated exacerbation assessment tools. Two such tools have been developed thus far; both from first principles of qualitative patient assessment, and both are now at the stage of assessment in clinical trials. A number of abstract presentations described the development of the tools: the United BioSource Corporation Exact-PRO initiative52 and a tool developed by GlaxoSmithKline.53 The topic of PRO was the subject of a major symposium on ‘Measuring Outcome in COPD’.
4.
Summary
In summary, the ATS provided the usual mix of review and new developments: rest assured, as these preliminary data
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reach publication the most significant findings will be covered in Respiratory Medicine COPD Update: the only dedicated digest publication keeping you up to date with developments in COPD. R E F E R E N C E S
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19. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007;356:775. 20. Wedzicha JA, Calverley PMA, Seemungal TA, et al. for the INSPIRE Investigators Am J Respir Crit Care Med 2008;177: 19–26. 21. Calverley P, Stockley R, Seemungal T, et al. Assessment of Pneumonia reports in the INSPIRE study [abstract]. Am J Respir Crit Care Med 2008;177:A132. 22. Alexeeff SE, et al. Statin use reduces decline in lung function: VA normative aging study. Am J Respir Crit Care Med 2007;176:742–7. 23. Dransfield MT, et al. Use of b blockers and the risk of death in hospitalised patients with acute exacerbations of COPD. Thorax 2008;63:301–5. 24. El Moussaoui R, et al. Short-course antibiotic treatment in acute exacerbations of chronic bronchitis and COPD: a metaanalysis of double-blind studies. Thorax 2008;63:415–22. 25. Hill K, Patman S, Brooks D, et al. Systematic review of physiotherapy during acute exacerbations of chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A137. 26. Stolz DA, et al. Use of B-type natriuretic peptide in the risk stratification of acute exacerbations of COPD. Chest 2008;133:1088–94. 27. Bozinovski S, et al. Serum Amyloid A is a biomarker of acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008;177:269–78. 28. Chang CL, Sullivan GD, Karalus NC, et al. Predicting mortality in acute exacerbation of chronic obstructive pulmonary disease using CURB65 scores [abstract]. Am J Respir Crit Care Med 2008;177:A132. 29. Karlsson AS, Anderson GP, Thompson M, et al. Anti-inflammatory Lipoxin A4 is diminished in acute, severe exacaerbations of COPD [abstract]. Am J Respir Crit Care Med 2008;177:A303. 30. Washko GR, et al. The effect of lung volume reduction surgery on chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med 2008;177:164–9. 31. O’Callaghan DS, Remund KF, Coyle J, et al. Treatment of advanced emphysema by endoscopic volume reduction [abstract]. Am J Respir Crit Care Med 2008;177:A18. 32. Powrie DJ, et al. Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD. Eur Respir J 2007;30:472–8. 33. Bourbeau J, et al. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Thorax 2007;62:938–43. 34. Bateman ED, Make BJ, Nandeuil MA. Carmoterol—safety and tolerability of a long-acting b-2 Agonist in patients with COPD [abstract]. Am J Respir Crit Care Med 2008;177:A653. 35. Higgins M, Beier J, Yang W, et al. Cardiac safety of indacterol, a novel once-daily bronchodilator [abstract]. Am J Respir Crit Care Med 2008;177:A653. 36. To Y, Rossios C, Adcock IM, et al. Novel ultra-long acting steroid (fluticasone fuorate) shows more potent anti-inflammatory action than fluticasone propionate in PBMCs from COPD patients [abstract]. Am J Respir Crit Care Med 2008;177:A651. 37. Chanez P, Burge S, Dahl R, et al. Once-daily administration of aclidinium bromide, a novel, long-acting anticholinergic: a Phase II, dose-finding study [abstract]. Am J Respir Crit Care Med 2008;177:A650. 38. Sato T, Sakai H, Takahashi A, et al. New surgical approach for COPD: covering lung with an elastic net [abstract]. Am J Respir Crit Care Med 2008;177:A17. 39. Sciurba FC, McLennan G, Ernst A, et al. Durability of endobronchial valve (EBV) effect on lung function at 6 and
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12 months in heterogeneous emphysema [abstract]. Am J Respir Crit Care Med 2008;177:A18. Sasaki T, Nakayama K, Yasuda H, et al. A proton pump inhibitor, lansoprazole, reduces frequency of exacerbations in patients with chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A139. Galazaka M, Groves S, Moainie S, et al. Accelerated pulmonary function decline in lung transplant patients with alpha-1antitrypsin deficiency emphysema [abstract]. Am J Respir Crit Care Med 2008;177:A389. Phillips KA, Lama VN, Chang AC, et al. Development of a1-anti-trypsin deficiency related disease following lung transplantation for emphysema [abstract]. Am J Respir Crit Care Med 2008;177:A389. Chu CM, Cheung AP, Chan VL, et al. A randomized trial of home non-invasive ventilation vs. sham ventilation in survivors of acute hypercapnic respiratory failure in COPD [abstract]. Am J Respir Crit Care Med 2008;177:A767. Hodge SJ, Hodge G, Ahern J, et al. Low dose azithromycin improves efferocytosis (Apoptosis and Macrophage Function) in COPD patients [abstract]. Am J Respir Crit Care Med 2008;177:A620. Cote CG, Pinto-Plata VM, Nekach H, et al. Co-morbidities in COPD: how many and how significant [abstract]. Am J Respir Crit Care Med 2008;177:A782. Takagi D, Getting S, Adcock IM, et al. Oxidative-stress induced dissociation of HDAC2 and Mi-2 corepressor may cause steroid insensitivity seen in COPD [abstract]. Am J Respir Crit Care Med 2008;177:A264. Ford PA, Durham AL, Russell EK, et al. A clinical trial demonstrating that low dose theophylline attenuates steroid
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insensitivity in COPD [abstract]. Am J Respir Crit Care Med 2008;177:A651. McGarvey LP, et al. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax 2007;62:411–5. McGhan R, et al. Predictors of rehospitalization and death after a severe exacerbation of COPD. Chest 2007;132: 1748–55. Teschler S, kenn K, Teschler H, et al. Effectiveness of a comprehensive inpatient pulmonary rehabilitation program for advanced chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A146. Ho SC, Lin HC, chen LF, et al. Weekly hospital based pulmonary rehabilitation maintains exercise capacity and reduces hospitalisation in patients with chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A149. Leidy NK, Burke LB, Powers JH, et al. The EXACT-PRO initiative: development of a standardized outcome measure for evaluating exacerbations of chronic obstructive pulmonary disease [abstract]. Am J Respir Crit Care Med 2008;177:A139. Berkowitz EM, Van Parijs BA, Fernandes A, et al. Development of a patient-reported outcome (PRO) measure in AECOPD [abstract]. Am J Respir Crit Care Med 2008;177:A305.
J.K. Quint, J.R. Hurst Academic Unit of Respiratory Medicine, Royal Free and University College Medical School, London, UK E-mail address: [email protected] (J.R. Hurst)