Rationale for earlier treatment in COPD: A systematic review of published literature in mild-to-moderate COPD

COPD: Journal of Chronic Obstructive Pulmonary Disease

Volumn 10, Issue 1, 2013, Pages 79-103

  Maltais, François ^a   Dennis, Natalie ^b   Chan, Charles K N ^c  

^a LAVAL UNIVERSITY   (Canada)

^b PAREXEL INTERNATIONAL   (United States)

^c UNIVERSITY HEALTH NETWORK   (Canada)

Author keywords

Bronchodilator Agents; Exacerbations; GOLD Stage I; GOLD Stage II.; Quality of Life; Respiratory Function Tests

Indexed keywords

ACETYLCYSTEINE; BUDESONIDE; CARBOCISTEINE; DOXOFYLLINE; ERDOSTEINE; FLUTICASONE PROPIONATE; FORMOTEROL; INFLIXIMAB; IPRATROPIUM BROMIDE; NELTENEXINE; PROXYPHYLLINE; RAMELTEON; SALMETEROL; THEOPHYLLINE; TIOTROPIUM BROMIDE; TULOBUTEROL;

CHRONIC OBSTRUCTIVE LUNG DISEASE; COMPRESSED AIR; DISEASE COURSE; DISEASE EXACERBATION; DISEASE SEVERITY; DRUG DOSE COMPARISON; EARLY INTERVENTION; EXERCISE TEST; FORCED EXPIRATORY VOLUME; HUMAN; INTERVENTION STUDY; LUNG FUNCTION; MORTALITY; OBSERVATIONAL STUDY; PHYSICAL DISEASE; PRIORITY JOURNAL; QUALITY OF LIFE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SMOKING CESSATION; SYSTEMATIC REVIEW; TERMINAL DISEASE; TREATMENT OUTCOME;

DISEASE PROGRESSION; EXERCISE TOLERANCE; FORCED EXPIRATORY VOLUME; HUMANS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; QUALITY OF LIFE; SEVERITY OF ILLNESS INDEX; TIME FACTORS;

EID: 84874040213     PISSN: 15412555     EISSN: 15412563     Source Type: Journal    
DOI: 10.3109/15412555.2012.719048     Document Type: Review

References (80)

1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 2010. http://www.goldcopd.com.
2. Buist AS, McBurnie MA, Vollmer WM, Gillespie S, Burney P, Mannino DM, Menezes AM, Sullivan SD, Lee TA, Weiss KB, Jensen RL, Marks GB, Gulsvik A, Nizankowska-Mogilnicka E; BOLD Collaborative Research Group. International variation in the prevalence of COPD (the BOLD Study): a populationbased prevalence study. Lancet 2007 Sep 1; 370(9589):741-750.
3. Troosters T, Sciurba F, Battaglia S, Langer D, Valluri SR, Martino L, Benzo R, Andre D, Weisman I, Decramer M. Physical inactivity in patients with COPD, a controlled multicenter pilot-study. Respir Med 2010 Jul; 104(7):1005-1011.
4. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. 2011. http://www.goldcopd.com.
5. Benfield T, Lange P, Vestbo J. COPD stage and risk of hospitalization for infectious disease. Chest 2008 Jul; 134(1):46-53.
6. Bridevaux PO, Gerbase MW, Probst-Hensch NM, Schindler C, Gaspoz JM, Rochat T. Long-term decline in lung function, utilisation of care and quality of life in modified GOLD stage 1 COPD. Thorax 2008 Sep; 63(9):768-774.
7. de Marco R, Accordini S, Cerveri I, Corsico A, Sunyer J, Neukirch F, Künzli N, Leynaert B, Janson C, Gislason T, Vermeire P, Svanes C, Anto JM, Burney P; European Community Respiratory Health Survey Study Group. An international survey of chronic obstructive pulmonary disease in young adults according to GOLD stages. Thorax 2004 Feb; 59 (2):120-125.
8. de Marco R, Accordini S, Anto JM, Gislason T, Heinrich J, Janson C, Jarvis D, Künzli N, Leynaert B, Marcon A, Sunyer J, Svanes C, Wjst M, Burney P. Long-term outcomes in mild/ moderate chronic obstructive pulmonary disease in the European community respiratory health survey. Am J Respir Crit Care Med 2009 Nov 15; 180(10):956-963.
9. Ekberg-Aronsson M, Pehrsson K, Nilsson JA, Nilsson PM, Löfdahl CG. Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis. Respir Res 2005 Aug 25; 6:98.
10. Geijer RM, Sachs AP, Verheij TJ, Lammers JW, Salome PL, Hoes AW. Are patient characteristics helpful in recognizing mild COPD (GOLD I) in daily practice? Scand J Prim Health Care 2006 Dec; 24(4):237-242.
11. Kogler H, Metzdorf N, Glaab T, Welte T. Preselection of patients at risk for COPD by two simple screening questions. Respir Med 2010 Jul; 104(7):1012-1019.
12. Kornmann O, Beeh KM, Beier J, Geis UP, Ksoll M, Buhl R; Global Initiative for Obstructive Lung Disease. Newly diagnosed chronic obstructive pulmonary disease. Clinical features and distribution of the novel stages of the Global Initiative for Obstructive Lung Disease. Respiration 2003 Jan-Feb; 70(1):67-75.
13. Lange P, Mogelvang R, Marott JL, Vestbo J, Jensen JS. Cardiovascular morbidity in COPD: A study of the general population. COPD 2010 Feb; 7(1):5-10.
14. Maleki-Yazdi MR, Lewczuk CK, Haddon JM, Choudry N, Ryan N. Early detection and impaired quality of life in COPD GOLD stage 0: a pilot study. COPD 2007 Dec; 4(4):313-320.
15. Pedone C, Scarlata S, Sorino C, Forastiere F, Bellia V, Antonelli Incalzi R,. Does mild COPD affect prognosis in the elderly? BMC Pulm Med 2010 Jun 7; 10:35.
16. Stav D, Raz M. Prevalence of chronic obstructive pulmonary disease among smokers aged 45 and up in Israel. Isr Med Assoc J 2007 Nov; 9(11):800-802.
17. Stratelis G, Jakobsson P, Molstad S, Zetterstrom O. Early detection of COPD in primary care: screening by invitation of smokers aged 40 to 55 years. Br J Gen Pract 2004 Mar; 54(500):201-206.
18. Toljamo T, Kaukonen M, Nieminen P, Kinnula VL. Early detection of COPD combined with individualized counselling for smoking cessation: a two-year prospective study. Scand J Prim Health Care 2010 Mar; 28(1):41-46.
19. Vestbo J, Lange P. Can GOLD Stage 0 provide information of prognostic value in chronic obstructive pulmonary disease? Am J Respir Crit Care Med 2002 Aug 1; 166(3):329-332.
20. Zielinski J, Bednarek M; Know the Age of Your Lung Study Group. Early detection of COPD in a high-risk population using spirometric screening. Chest 2001 Mar; 119(3):731-736.
21. Zielinski J, Bednarek M, Górecka D, Viegi G, Hurd SS, Fukuchi Y, Lai CK, Ran PX, Ko FW, Liu SM, Zheng JP, Zhong NS, Ip MS, Vermeire PA. Increasing COPD awareness. Eur Respir J 2006 Apr; 27(4):833-852.
22. Ora J, Laveneziana P, Ofir D, Deesomchok A, Webb KA, O'Donnell DE. Combined effects of obesity and chronic obstructive pulmonary disease on dyspnea and exercise tolerance. Am J Respir Crit Care Med 2009 Nov 15; 180(10):964-971.
23. Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk in Communities (ARIC) study. Respir Med 2006 Jan; 100(1):115-122.
24. Decramer M, Cooper CB. Treatment of COPD: the sooner the better? Thorax 2010 Sep; 65(9):837-841.
25. Price D, Freeman D, Cleland J, Kaplan A, Cerasoli F. Earlier diagnosis and earlier treatment of COPD in primary care. Prim Care Respir J 2011 Mar; 20(1):15-22.
26. Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, Conway WA Jr, Enright PL, Kanner RE, O'Hara P, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 1994 Nov 16; 272(19):1497-1505.
27. Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med 2002 Sep 1; 166(5):675-679.
28. Burchfiel CM, Marcus EB, Curb JD, MacLean CJ, Vollmer WM, Johnson LR, Fong KO, Rodriguez BL, Masaki KH, Buist AS. Effects of smoking and smoking cessation on longitudinal decline in pulmonary function. Am J Respir Crit Care Med 1995 Jun; 151(6):1778-1785.
29. Scanlon PD, Connett JE, Waller LA, Altose MD, Bailey WC, Buist AS. Smoking cessation and lung function in mild-tomoderate chronic obstructive pulmonary disease. The Lung Health Study. Am J Respir Crit Care Med 2000 Feb; 161(2 Pt 1):381-390.
30. Decramer M, Celli B, Kesten S, Lystig T, Mehra S, Tashkin DP; UPLIFT Investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet 2009 Oct 3; 374(9696):1171-1178.
31. Jenkins CR, Jones PW, Calverley PM, Celli B, Anderson JA, Ferguson GT, Yates JC, Willits LR, Vestbo J. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res 2009 Jun 30; 10:59.
32. van Grunsven P, Schermer T, Akkermans R, Albers M, van den Boom G, van Schayck O, van Herwaarden C, van Weel C. Short-And long-term efficacy of fluticasone propionate in subjects with early signs and symptoms of chronic obstructive pulmonary disease. Results of the DIMCA study. Respir Med 2003 Dec; 97(12):1303-1312.
33. Kryger M, Roth T, Wang-Weigand S, Zhang J. The effects of ramelteon on respiration during sleep in subjects with moderate to severe chronic obstructive pulmonary disease. Sleep Breath 2009 Mar; 13(1):79-84.
34. Löfdahl CG, Postma DS, Pride NB, Boe J, Thorén A. Possible protection by inhaled budesonide against ischaemic cardiac events in mild COPD. Eur Respir J 2007 Jun; 29(6):1115-1119.
35. Dal Negro R, Visconti M, Trevisan F, Bertacco S, Micheletto C, Tognella S. Erdosteine enhances airway response to salbutamol in patients with mild-to-moderate COPD. Ther Adv Respir Dis 2008 Oct; 2(5):271-277.
36. Kryger M, Wang-Weigand S, Zhang J, Roth T. Effect of ramelteon, a selective MT(1)/MT (2)-receptor agonist, on respiration during sleep in mild to moderate COPD. Sleep Breath 2008 Aug; 12(3):243-250.
37. O'Donnell DE, Laveneziana P, Ora J, Webb KA, Lam YM, Ofir D. Evaluation of acute bronchodilator reversibility in patients with symptoms of GOLD stage I COPD. Thorax 2009 Mar; 64(3):216-223.
38. Pauwels RA, Löfdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV; European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. Longterm treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med 1999 Jun 24; 340(25):1948-1953.
39. Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, Mahler D, Saadeh C, Siler T, Snell P, Korenblat P, Smith W, Kaye M, Mandel M, Andrews C, Prabhu R, Donohue JF, Watt R, Lo KH, Schlenker-Herceg R, Barnathan ES, Murray J; COPD Investigators. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007 May 1; 175(9):926-934.
40. van Grunsven PM, van Schayck CP, van Deuveren M, van Herwaarden CL, Akkermans RP, van Weel C. Compliance during long-term treatment with fluticasone propionate in subjects with early signs of asthma or chronic obstructive pulmonary disease (COPD): results of the Detection, Intervention, and Monitoring Program of COPD and Asthma (DIMCA) Study. J Asthma 2000 May; 37(3):225-234.
41. Di Lorenzo G, Morici G, Drago A, Pellitteri ME, Mansueto P, Melluso M, Norrito F, Squassante L, Fasolo A; SLMT02 Italian Study Group. Efficacy, tolerability, and effects on quality of life of inhaled salmeterol and oral theophylline in patients with mild-to-moderate chronic obstructive pulmonary disease. Clin Ther 1998 Nov-Dec;20(6):1130-1148.
42. Rabe KF, Timmer W, Sagkriotis A, Viel K. Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD. Chest 2008 Aug; 134(2):255-262.
43. Kanehara M, Yokoyama A, Tomoda Y, Shiota N, Iwamoto H, Ishikawa N, Taooka Y, Haruta Y, Hattori N, Kohno N. Antiinflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease. Pulm Pharmacol Ther 2008 Dec; 21(6):874-878.
44. D'Elia C, Sechi F. Neltenexine versus carbocysteine in the treatment of exacerbations of mild chronic obstructive pulmonary disease: a randomized, controlled, open-label study. Curr Ther Res. Clin Exp 2001; 62:851-861.
45. Santra CK. Treatment of moderate chronic obstructive pulmonary disease (stable) with doxofylline compared with slow release theophylline-A multicentre trial. J Indian Med Assoc 2008 Dec; 106(12):791-2, 794.
46. AkkocaYildiz O, Onen ZP, Demir G, Eriş Gülbay B, Saryal S, Karabiyikoǧlu G. Is there any difference between effects of ipratropium bromide and formoterol on exercise capacity in moderate COPD patients? Tuberk Toraks 2006; 54(2):105-113.
47. Spencer LM, Alison JA, McKeough ZJ. Maintaining benefits following pulmonary rehabilitation: a randomised controlled trial. Eur Respir J 2010 Mar; 35(3):571-577.
48. Solèr M, Mütterlein R, Cozma G; Swiss-German OM-85 Study Group. Double-blind study of OM-85 in patients with chronic bronchitis or mild chronic obstructive pulmonary disease. Respiration 2007; 74(1):26-32.
49. Clark CJ, Cochrane LM, Mackay E, Paton B. Skeletal muscle strength and endurance in patients with mild COPD and the effects of weight training. Eur Respir J 2000 Jan; 15(1):92-97.
50. Haider T, Casucci G, Linser T, Faulhaber M, Gatterer H, Ott G, Linser A, Ehrenbourg I, Tkatchouk E, Burtscher M, Bernardi L. Interval hypoxic training improves autonomic cardiovascular and respiratory control in patients with mild chronic obstructive pulmonary disease. J Hypertens 2009 Aug; 27(8):1648-1654.
51. Faager G, Stâhle A, Larsen FF. Influence of spontaneous pursed lips breathing on walking endurance and oxygen saturation in patients with moderate to severe chronic obstructive pulmonary disease. Clin Rehabil 2008 Aug; 22(8):675-683.
52. Fujimoto K, Matsuzawa Y, Yamaguchi S, Koizumi T, Kubo K. Benefits of oxygen on exercise performance and pulmonary hemodynamics in patients with COPD with mild hypoxemia. Chest 2002 Aug; 122(2):457-463.
53. Harber P, Tashkin DP, Simmons M, Crawford L, Hnizdo E, Connett J; Lung Health Study Group. Effect of occupational exposures on decline of lung function in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007 Nov 15; 176(10):994-1000.
54. Kanner RE, Anthonisen NR, Connett JE; Lung Health Study Research Group. Lower respiratory illnesses promote FEV(1) decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease: results from the lung health study. Am J Respir Crit Care Med 2001 Aug 1; 164(3):358-364.
55. Kanner RE, Connett JE, Altose MD, Buist AS, Lee WW, Tashkin DP, Wise RA. Gender difference in airway hyperresponsiveness in smokers with mild COPD. The Lung Health Study. Am J Respir Crit Care Med 1994 Oct; 150(4):956-961.
56. Kanner RE, Connett JE, Williams DE, Buist AS. Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study. Am J Med 1999 Apr; 106(4):410-416.
57. Tashkin DP, Altose MD, Connett JE, Kanner RE, Lee WW, Wise RA. Methacholine reactivity predicts changes in lung function over time in smokers with early chronic obstructive pulmonary disease. The Lung Health Study Research Group. Am J Respir Crit Care Med 1996 Jun; 153(6 Pt 1):1802-1811.
58. Magnussen H, Watz H, Zimmermann I, Macht S, Greguletz R, Falques M, Jarreta D, Garcia Gil E. Peak inspiratory flow through the Genuair inhaler in patients with moderate or severe COPD. Respir Med 2009 Dec; 103(12):1832-1837.
59. Watson L, Vonk JM, Löfdahl CG, Pride NB, Pauwels RA, Laitinen LA, Schouten JP, Postma DS; European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. Predictors of lung function and its decline in mild to moderate COPD in association with gender: results from the Euroscop study. Respir Med 2006 Apr; 100(4):746-753.
60. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A selfcomplete measure for chronic airflow limitation-the St George's Respiratory Questionnaire. Am Rev Respir Dis 1992 Jun; 145(6):1321-1327.
61. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS; GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive disease. Am J Respir Crit Care Med 2001 Apr; 163(5):1256-1276.
62. Antonelli-Incalzi R, Imperiale C, Bellia V, Catalano F, Scichilone N, Pistelli R, Rengo F; SaRA Investigators. Do GOLD stages of COPD severity really correspond to differences in health status? Eur Respir J 2003 Sep; 22(3):444-449.
63. Ofir D, Laveneziana P, Webb KA, Lam YM, O'Donnell DE. Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008 Mar 15; 177(6):622-629.
64. Bernardi L, Casucci G, Haider T, Brandstätter E, Pocecco E, Ehrenbourg I, Burtscher M. Autonomic and cerebrovascular abnormalities in mild COPD are worsened by chronic smoking. Eur Respir J 2008 Dec; 32(6):1458-1465.
65. de Torres JP, Pinto-Plata V, Casanova C, Mullerova H, Córdoba-Lanús E, Muros de Fuentes M, Aguirre-Jaime A, Celli BR. C-reactive protein levels and survival in patients with moderate to very severe COPD. Chest 2008 Jun; 133(6):1336-1343.
66. Nomori H, Watanabe K, Ohtsuka T, Naruke T, Suemasu K. Sixminute walking and pulmonary function test outcomes during the early period after lung cancer surgery with special reference to patients with chronic obstructive pulmonary disease. Jpn J Thorac Cardiovasc Surg 2004 Mar; 52(3):113-119.
67. Ohno Y, Iwasawa T, Seo JB, Koyama H, Takahashi H, Oh YM, Nishimura Y, Sugimura K. Oxygen-enhanced magnetic resonance imaging versus computed tomography: multicenter study for clinical stage classification of smoking-related chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2008 May; 177(10):1095-1102.
68. Swallow EB, Reyes D, Hopkinson NS, Man WD, Porcher R, Cetti EJ, Moore AJ, Moxham J, Polkey MI. Quadriceps strength predicts mortality in patients with moderate to severe chronic obstructive pulmonary disease. Thorax 2007 Feb; 62(2):115-120.
69. Torchio R, Gulotta C, Parvis M, Pozzi R, Giardino R, Borasio P, Greco Lucchina P. Gas exchange threshold as a predictor of severe postoperative complications after lung resection in mild-to-moderate chronic obstructive pulmonary disease. Monaldi Arch Chest Dis 1998 Apr; 53(2):127-133.
70. Morice AH, Celli B, Kesten S, Lystig T, Tashkin D, Decramer M, COPD in young patients: a pre-specified analysis of the four-year trial of tiotropium (UPLIFT). Respir Med 2010 Nov; 104(11):1659-1667.
71. Kohansal R, Martinez-Camblor P, Agustí A, Buist AS, Mannino DM, Soriano JB. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 2009 Jul 1; 180(1):3-10.
72. Jones PW, Brusselle G, Dal Negro RW, Ferrer M, Kardos P, Levy ML, Perez T, Soler Cataluña JJ, van der Molen T, Adamek L, Banik N. Properties of the COPD Assessment Test (CAT) in a cross-sectional European study. Eur Respir J 2011 Jul; 38(1):29-35.
73. Pinto-Plata VM, Celli-Cruz RA, Vassaux C, Torre-Bouscoulet L, Mendes A, Rassulo J, Celli BR. Differences in cardiopulmonary exercise test results by American Thoracic Society/European Respiratory Society-Global Initiative for Chronic Obstructive Lung Disease stage categories and gender. Chest 2007 Oct; 132(4):1204-1211.
74. Mannino DM, Doherty DE, Sonia Buist A. Global Initiative on Obstructive Lung Disease (GOLD) classification of lung disease and mortality: findings from the Atherosclerosis Risk inCommunities (ARIC) study. Respir Med 2006 Jan; 100(1):115-122.
75. van den Boom G, Rutten-van Mölken MP, Molema J, Tirimanna PR, van Weel C, van Schayck CP, The cost effectiveness of early treatment with fluticasone propionate 250 microg twice a day in subjects with obstructive airway disease. Results of the DIMCA program. Am J Respir Crit Care Med 2001 Dec 1; 164(11):2057-2066.
76. Vestbo J, Sørensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999 May 29; 353(9167):1819-1823.
77. Decramer M, Rennard S, Troosters T, Mapel DW, Giardino N, Mannino D, Wouters E, Sethi S, Cooper CB. COPD as a lung disease with systemic consequences-clinical impact, mechanisms, and potential for early intervention. COPD 2008 Aug; 5(4):235-256.
78. Pelkonen M, Notkola IL, Lakka T, Tukiainen HO, Kivinen P, Nissinen A. Delaying decline in pulmonary function with physical activity: a 25-year follow-up. Am J Respir Crit Care Med 2003 Aug 15; 168(4):494-499.
79. Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, Tal-Singer R, Wouters E, Yates JC, Vestbo J. Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators, Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010 Sep 10; 11:122.
80. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA. Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators, Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010 Sep 16; 363(12):1128-1138.