Bringing Stability to the Chronic Obstructive Pulmonary Disease Patient: Clinical and Pharmacological Considerations for Frequent Exacerbators

Drugs

Volumn 77, Issue 6, 2017, Pages 651-670

  Gulati, Swati ^a   Wells, J Michael ^a,b  

^a UNIVERSITY OF ALABAMA AT BIRMINGHAM   (United States)

^b BIRMINGHAM VA MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIOXIDANT; BETA ADRENERGIC RECEPTOR STIMULATING AGENT; BRONCHODILATING AGENT; CORTICOSTEROID; LONG ACTING DRUG; MACROLIDE; MUCOLYTIC AGENT; MUSCARINIC RECEPTOR BLOCKING AGENT; PHOSPHODIESTERASE IV INHIBITOR; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT;

AIRFLOW; CHRONIC OBSTRUCTIVE LUNG DISEASE; COMBINATION CHEMOTHERAPY; COMORBIDITY; CORTICOSTEROID THERAPY; DISEASE EXACERBATION; HUMAN; HYPERINFLATION; MICROFLORA; MONOTHERAPY; REVIEW; RISK FACTOR; VACCINATION; CLASSIFICATION; INFLAMMATION; PATHOLOGY; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

ADRENERGIC BETA-2 RECEPTOR AGONISTS; HUMANS; INFLAMMATION; MUSCARINIC ANTAGONISTS; PHOSPHODIESTERASE 4 INHIBITORS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE;

EID: 85014069216     PISSN: 00126667     EISSN: 11791950     Source Type: Journal    
DOI: 10.1007/s40265-017-0713-5     Document Type: Review

References (141)

1. Miniño AM, Xu J, Kochanek KD. Deaths: preliminary data for 2008. Natl Vital Stat Rep. 2010;59:1–52.
2. Yu AP, Yang H, Wu EQ, et al. Incremental third-party costs associated with COPD exacerbations: a retrospective claims analysis. J Med Econ. 2011;14:315–23. doi:10.3111/13696998.2011.576295.
3. Dransfield MT, Kunisaki KM, Strand MJ, et al. Acute exacerbations and lung function loss in smokers with and without COPD. Am J Respir Crit Care Med. 2017;195:324–30. doi:10.1164/rccm.201605-1014OC.
4. Vestbo J, Edwards LD, Scanlon PD, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med. 2011;365:1184–92. doi:10.1056/NEJMoa1105482.
5. Donaldson GC, Law M, Kowlessar B, et al. Impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192:943–50. doi:10.1164/rccm.201412-2269OC.
6. Seemungal TA, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418–22. doi:10.1164/ajrccm.157.5.9709032.
7. Müllerova H, Maselli DJ, Locantore N, et al. Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort. Chest. 2015;147:999–1007. doi:10.1378/chest.14-0655.
8. Piquet J, Chavaillon J-M, David P, et al. High-risk patients following hospitalisation for an acute exacerbation of COPD. Eur Respir J. 2013;42:946–55. doi:10.1183/09031936.00180312.
9. Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest. 2000;117:398S–401S.
10. Burge c, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J. 2003;21(Suppl. 41):46s–53s
11. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106:196–204.
12. Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163:349–55. doi:10.1164/ajrccm.163.2.2003122.
13. Seneff MG, Wagner DP, Wagner RP, et al. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA. 1995;274:1852–7.
14. Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128–38. doi:10.1056/NEJMoa0909883.
15. Beeh KM, Glaab T, Stowasser S, et al. Characterisation of exacerbation risk and exacerbator phenotypes in the POET-COPD trial. Respir Res. 2013;14:116. doi:10.1186/1465-9921-14-116.
16. Bhowmik A, Seemungal T, Sapsford R, Wedzicha J. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000;55:114–20. doi:10.1136/thorax.55.2.114.
17. Perera WR, Hurst JR, Wilkinson TMA, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J. 2007;29:527–34. doi:10.1183/09031936.00092506.
18. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet. 2008;372:1107–19. doi:10.1016/S0140-6736(08)61452-X.
19. Russell DW, Wells JM, Blalock JE. Disease phenotyping in chronic obstructive pulmonary disease: the neutrophilic endotype. Curr Opin Pulm Med. 2016;22:91–9. doi:10.1097/MCP.0000000000000238.
20. Woodruff PG, Agusti A, Roche N, et al. Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management. Lancet. 2015;385:1789–98. doi:10.1016/S0140-6736(15)60693-6.
21. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173:1114–21. doi:10.1164/rccm.200506-859OC.
22. Kang HS, Rhee CK, Kim SK, et al. Comparison of the clinical characteristics and treatment outcomes of patients requiring hospital admission to treat eosinophilic and neutrophilic exacerbations of COPD. Int J Chron Obstr Pulm Dis. 2016;11:2467–73. doi:10.2147/COPD.S116072.
23. Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med. 1994;150:1646–52. doi:10.1164/ajrccm.150.6.7952628.
24. Pizzichini E, Pizzichini MM, Gibson P, et al. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med. 1998;158:1511–7. doi:10.1164/ajrccm.158.5.9804028.
25. Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. Int J Chron Obstr Pulm Dis. 2006;1:39–47.
26. Pavord ID, Lettis S, Locantore N, et al. Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD. Thorax. 2016;71:118–25. doi:10.1136/thoraxjnl-2015-207021.
27. Wedzicha JA. Role of viruses in exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2004;1:115–20. doi:10.1513/pats.2306030.
28. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164:1618–23. doi:10.1164/ajrccm.164.9.2105011.
29. Cabello H, Torres A, Celis R, et al. Bacterial colonization of distal airways in healthy subjects and chronic lung disease: a bronchoscopic study. Eur Respir J. 1997;10:1137–44.
30. Sethi S, Murphy TF. Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art review. Clin Microbiol Rev. 2001;14:336–63. doi:10.1128/CMR.14.2.336-363.2001.
31. Patel IS, Seemungal TA, Wilks M, et al. Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations. Thorax. 2002;57:759–64.
32. Huang YJ, Sethi S, Murphy T, et al. Airway microbiome dynamics in exacerbations of chronic obstructive pulmonary disease. J Clin Microbiol. 2014;52:2813–23. doi:10.1128/JCM.00035-14.
33. O’Donnell DE, Laveneziana P. The clinical importance of dynamic lung hyperinflation in COPD. COPD. 2006;3:219–32.
34. O’Donnell DE, Parker CM. COPD exacerbations. 3: pathophysiology. Thorax. 2006;61:354–61. doi:10.1136/thx.2005.041830.
35. Bhatt SP, Dransfield MT. Chronic obstructive pulmonary disease and cardiovascular disease. Transl Res J Lab Clin Med. 2013;162:237–51. doi:10.1016/j.trsl.2013.05.001.
36. Mills NL, Miller JJ, Anand A, et al. Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk. Thorax. 2008;63:306–11. doi:10.1136/thx.2007.083493.
37. Patel ARC, Kowlessar BS, Donaldson GC, et al. Cardiovascular risk, myocardial injury, and exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188:1091–9. doi:10.1164/rccm.201306-1170OC.
38. Andreas S, Herrmann-Lingen C, Raupach T, et al. Angiotensin II blockers in obstructive pulmonary disease: a randomised controlled trial. Eur Respir J. 2006;27:972–9. doi:10.1183/09031936.06.00098105.
39. Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014;370:2201–10. doi:10.1056/NEJMoa1403086.
40. Bhatt SP, Wells JM, Kinney GL, et al. β-Blockers are associated with a reduction in COPD exacerbations. Thorax. 2016;71:8–14. doi:10.1136/thoraxjnl-2015-207251.
41. McGraw DW, Forbes SL, Mak JCW, et al. Transgenic overexpression of β2-adrenergic receptors in airway epithelial cells decreases bronchoconstriction. Am J Physiol Lung Cell Mol Physiol. 2000;279:L379–89.
42. Nguyen LP, Omoluabi O, Parra S, et al. Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model. Am J Respir Cell Mol Biol. 2008;38:256–62. doi:10.1165/rcmb.2007-0279RC.
43. Bhatt SP, Connett JE, Voelker H, et al. β-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (βLOCK COPD): a randomised controlled study protocol. BMJ Open. 2016;6:e012292. doi:10.1136/bmjopen-2016-012292.
44. Parker CM, Voduc N, Aaron SD, et al. Physiological changes during symptom recovery from moderate exacerbations of COPD. Eur Respir J. 2005;26:420–8. doi:10.1183/09031936.05.00136304.
45. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143:317–26.
46. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543–54. doi:10.1056/NEJMoa0805800.
47. Celli BR, Decramer M, Asijee GM, Kupas K, Tashkin DP. Effects of tiotropium on exacerbations in patients with COPD with low or high risk of exacerbations: A post-hoc analysis from the 4-year UPLIFT® trial. J COPD Found. 2015;2(2): 122–130. doi:10.15326/jcopdf.2.2.2014.0155
48. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369:1491–501. doi:10.1056/NEJMoa1303342.
49. ®) trial: spirometry outcomes. Respir Res. 2015;16:107. doi:10.1186/s12931-015-0269-4.
50. Beier J, Kirsten A-M, Mróz R, et al. Efficacy and safety of aclidinium bromide compared with placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease: results from a 6-week, randomized, controlled phase IIIb study. COPD. 2013;10:511–22. doi:10.3109/15412555.2013.814626.
51. D’Urzo A, Kerwin E, Rennard S, et al. One-year extension study of ACCORD COPD I: safety and efficacy of two doses of twice-daily aclidinium bromide in patients with COPD. COPD. 2013;10:500–10. doi:10.3109/15412555.2013.791809.
52. Fuhr R, Magnussen H, Sarem K, et al. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest. 2012;141:745–52. doi:10.1378/chest.11-0406.
53. Feldman G, Maltais F, Khindri S, et al. A randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 μg compared with tiotropium 18 μg in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:719–30. doi:10.2147/COPD.S102494.
54. Rheault T, Khindri S, Vahdati-Bolouri M, et al. A randomised, open-label study of umeclidinium versus glycopyrronium in patients with COPD. ERJ Open Res. 2016;2. doi: 10.1183/23120541.00101-2015.
55. Rennard SI, Scanlon PD, Ferguson GT, et al. ACCORD COPD II: a randomized clinical trial to evaluate the 12-week efficacy and safety of twice-daily aclidinium bromide in chronic obstructive pulmonary disease patients. Clin Drug Investig. 2013;33:893–904. doi:10.1007/s40261-013-0138-1.
56. D’Urzo A, Ferguson GT, van Noord JA, et al. Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial. Respir Res. 2011;12:156. doi:10.1186/1465-9921-12-156.
57. Kerwin E, Hébert J, Gallagher N, et al. Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study. Eur Respir J. 2012;40:1106–14. doi:10.1183/09031936.00040712.
58. Sin DD, McAlister FA, Man SFP, Anthonisen NR. Contemporary management of chronic obstructive pulmonary disease: scientific review. JAMA. 2003;290:2301–12. doi:10.1001/jama.290.17.2301.
59. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364:1093–103. doi:10.1056/NEJMoa1008378.
60. Decramer ML, Chapman KR, Dahl R, et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med. 2013;1:524–33. doi:10.1016/S2213-2600(13)70158-9.
61. Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Inhaled corticosteroids vs placebo for preventing COPD exacerbations: a systematic review and metaregression of randomized controlled trials. Chest. 2010;137:318–25. doi:10.1378/chest.09-1305.
62. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. Am J Med. 2002;113:59–65.
63. Wilt TJ, Niewoehner D, MacDonald R, Kane RL. Management of stable chronic obstructive pulmonary disease: a systematic review for a clinical practice guideline. Ann Intern Med. 2007;147:639–53.
64. Puhan MA, Bachmann LM, Kleijnen J, et al. Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis. BMC Med. 2009;7:2. doi:10.1186/1741-7015-7-2.
65. Wilt TJ, Niewoehner D, Kim C, et al. Use of spirometry for case finding, diagnosis, and management of chronic obstructive pulmonary disease (COPD). Evid Rep Technol Assess (Summ). 2005;121:1–7.
66. Burge PS, Calverley PMA, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320:1297–303.
67. Suissa S, Patenaude V, Lapi F, Ernst P. Inhaled corticosteroids in COPD and the risk of serious pneumonia. Thorax. 2013;68:1029–36. doi:10.1136/thoraxjnl-2012-202872.
68. Crim C, Calverley PMA, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34:641–7. doi:10.1183/09031936.00193908.
69. Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371:1285–94. doi:10.1056/NEJMoa1407154.
70. Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, Chen R, Decramer M, Fabbri LM, Frith P, Halpin DM, López Varela MV, Nishimura M, Roche N, Rodriguez-Roisin R, Sin DD, Singh D, Stockley R, Vestbo J, Wedzicha JA, Agusti A. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Am J Respir Crit Care Med. doi:10.1164/rccm.201701-0218PP.
71. Barnes NC, Qiu Y-S, Pavord ID, et al. Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease. Am J Respir Crit Care Med. 2006;173:736–43. doi:10.1164/rccm.200508-1321OC.
72. Calverley P, Pauwels R, Vestbo J, et al. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003;361:449–56. doi:10.1016/S0140-6736(03)12459-2.
73. Calverley PMA, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775–89. doi:10.1056/NEJMoa063070.
74. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J. 2003;21:74–81.
75. Calverley PM, Boonsawat W, Cseke Z, et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22:912–9.
76. Vestbo J, Leather D, Diar Bakerly N, et al. Effectiveness of fluticasone furoate-vilanterol for COPD in clinical practice. N Engl J Med. 2016;375:1253–60. doi:10.1056/NEJMoa1608033.
77. Cazzola M, Santus P, Di Marco F, et al. Bronchodilator effect of an inhaled combination therapy with salmeterol + fluticasone and formoterol + budesonide in patients with COPD. Respir Med. 2003;97:453–7.
78. Pascoe S, Locantore N, Dransfield MT, et al. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med. 2015;3:435–42. doi:10.1016/S2213-2600(15)00106-X.
79. Cazzola M, Molimard M. The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23:257–67. doi:10.1016/j.pupt.2010.03.003.
80. Maltais F, Singh S, Donald AC, et al. Effects of a combination of umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: two randomized, double-blind clinical trials. Ther Adv Respir Dis. 2014;8:169–81. doi:10.1177/1753465814559209.
81. Celli B, Crater G, Kilbride S, et al. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a randomized, controlled study. Chest. 2014;145:981–91. doi:10.1378/chest.13-1579.
82. Donohue JF, Worsley S, Zhu C-Q, et al. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations. Respir Med. 2015;109:870–81. doi:10.1016/j.rmed.2015.04.018.
83. Siler TM, Kerwin E, Sousa AR, et al. Efficacy and safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: results of two randomized studies. Respir Med. 2015;109:1155–63. doi:10.1016/j.rmed.2015.06.006.
84. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016;374:2222–34. doi:10.1056/NEJMoa1516385.
85. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4). Eur Respir J. 2015;45:969–79. doi:10.1183/09031936.00136014.
86. Radovanovic D, Mantero M, Sferrazza Papa GF, et al. Formoterol fumarate + glycopyrrolate for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med. 2016;10:1045–55. doi:10.1080/17476348.2016.1227247.
87. Lode H, Eller J, Linnhoff A, et al. Levofloxacin versus clarithromycin in COPD exacerbation: focus on exacerbation-free interval. Eur Respir J. 2004;24:947–53. doi:10.1183/09031936.04.00009604.
88. Dimopoulos G, Siempos II, Korbila IP, et al. Comparison of first-line with second-line antibiotics for acute exacerbations of chronic bronchitis: a metaanalysis of randomized controlled trials. Chest. 2007;132:447–55. doi:10.1378/chest.07-0149.
89. Segal LN, Clemente JC, Wu BG, et al. Randomised, double-blind, placebo-controlled trial with azithromycin selects for anti-inflammatory microbial metabolites in the emphysematous lung. Thorax. 2017;72:13–22. doi:10.1136/thoraxjnl-2016-208599.
90. Martinez FJ, Curtis JL, Albert R. Role of macrolide therapy in chronic obstructive pulmonary disease. Int J Chron Obstr Pulm Dis. 2008;3:331–50.
91. Seemungal TAR, Wilkinson TMA, Hurst JR, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178:1139–47. doi:10.1164/rccm.200801-145OC.
92. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689–98. doi:10.1056/NEJMoa1104623.
93. O’Reilly PJ, Jackson PL, Wells JM, et al. Sputum PGP is reduced by azithromycin treatment in patients with COPD and correlates with exacerbations. BMJ Open. 2013;3:e004140. doi:10.1136/bmjopen-2013-004140.
94. Simpson JL, Powell H, Baines KJ, et al. The effect of azithromycin in adults with stable neutrophilic COPD: a double blind randomised, placebo controlled trial. PLoS One. 2014;9:e105609. doi:10.1371/journal.pone.0105609.
95. Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189:1503–8. doi:10.1164/rccm.201402-0207OC.
96. Uzun S, Djamin RS, Kluytmans JAJW, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2:361–8. doi:10.1016/S2213-2600(14)70019-0.
97. Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2013;(11):CD009764. doi:10.1002/14651858.CD009764.pub2.
98. Ray WA, Murray KT, Hall K, et al. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366:1881–90. doi:10.1056/NEJMoa1003833.
99. Spina D. PDE4 inhibitors: current status. Br J Pharmacol. 2008;155:308–15. doi:10.1038/bjp.2008.307.
100. Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007;62:1081–7. doi:10.1136/thx.2006.075937.
101. Rabe KF, Bateman ED, O’Donnell D, et al. Roflumilast: an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366:563–71. doi:10.1016/S0140-6736(05)67100-0.
102. Calverley PMA, Rabe KF, Goehring U-M, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685–94. doi:10.1016/S0140-6736(09)61255-1.
103. Fabbri LM, Calverley PMA, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374:695–703. doi:10.1016/S0140-6736(09)61252-6.
104. Rennard SI, Calverley PM, Goehring UM, et al. Reduction of exacerbations by the PDE4 inhibitor roflumilast: the importance of defining different subsets of patients with COPD. Respir Res. 2011;12:18. doi:10.1186/1465-9921-12-18.
105. Martinez FJ, Calverley PMA, Goehring U-M, et al. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015;385:857–66. doi:10.1016/S0140-6736(14)62410-7.
106. Martinez FJ, Rabe KF, Sethi S, et al. Effect of roflumilast and inhaled corticosteroid/long-acting β2-agonist on chronic obstructive pulmonary disease exacerbations (RE2SPOND): a randomized clinical trial. Am J Respir Crit Care Med. 2016;194:559–67. doi:10.1164/rccm.201607-1349OC.
107. Worndl E, Hunt EB, Kennedy MP, et al. Roflumilast in COPD. Chest. 2015;148:e31. doi:10.1378/chest.15-0664.
108. Muñoz-Esquerre M, Diez-Ferrer M, Montón C, et al. Roflumilast added to triple therapy in patients with severe COPD: a real life study. Pulm Pharmacol Ther. 2015;30:16–21. doi:10.1016/j.pupt.2014.10.002.
109. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. Br J Pharmacol. 2011;163:53–67. doi:10.1111/j.1476-5381.2011.01218.x.
110. Decramer M, Rutten-van Mölken M, Dekhuijzen PNR, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial. Lancet. 2005;365:1552–60. doi:10.1016/S0140-6736(05)66456-2.
111. Zheng J-P, Wen F-Q, Bai C-X, et al. Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease (PANTHEON): a randomised, double-blind placebo-controlled trial. Lancet Respir Med. 2014;2:187–94. doi:10.1016/S2213-2600(13)70286-8.
112. Tse HN, Raiteri L, Wong KY, et al. Benefits of high-dose N-acetylcysteine to exacerbation-prone patients with COPD. Chest. 2014;146:611–23. doi:10.1378/chest.13-2784.
113. Cazzola M, Calzetta L, Page C, et al. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev. 2015;24:451–61. doi:10.1183/16000617.00002215.
114. Zheng J-P, Kang J, Huang S-G, et al. Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study. Lancet. 2008;371:2013–8. doi:10.1016/S0140-6736(08)60869-7.
115. Camargo CA, Ginde AA, Clark S, et al. Viral pathogens in acute exacerbations of chronic obstructive pulmonary disease. Intern Emerg Med. 2008;3:355. doi:10.1007/s11739-008-0197-0.
116. Furumoto A, Ohkusa Y, Chen M, et al. Additive effect of pneumococcal vaccine and influenza vaccine on acute exacerbation in patients with chronic lung disease. Vaccine. 2008;26:4284–9. doi:10.1016/j.vaccine.2008.05.037.
117. Poole PJ, Chacko E, Wood-Baker RW, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006;(1):CD002733. doi:10.1002/14651858.CD002733.pub2.
118. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187:347–65. doi:10.1164/rccm.201204-0596PP.
119. Anthonisen NR, Skeans MA, Wise RA, et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med. 2005;142:233–9.
120. Anthonisen NR. Long-term oxygen therapy. Ann Intern Med. 1983;99:519–27.
121. Au DH, Bryson CL, Chien JW, et al. The effects of smoking cessation on the risk of chronic obstructive pulmonary disease exacerbations. J Gen Intern Med. 2009;24:457–63. doi:10.1007/s11606-009-0907-y.
122. Lacasse Y, Cates CJ, McCarthy B, Welsh EJ. This Cochrane review is closed: deciding what constitutes enough research and where next for pulmonary rehabilitation in COPD. Cochrane Database Syst Rev. 2015;(11):ED000107. doi:10.1002/14651858.ED000107.
123. Puhan M, Scharplatz M, Troosters T, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2009;(1):CD005305. doi:10.1002/14651858.CD005305.pub2.
124. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184:662–71. doi:10.1164/rccm.201104-0597OC.
125. Barker BL, Brightling CE. Phenotyping the heterogeneity of chronic obstructive pulmonary disease. Clin Sci Lond Engl. 2013;124:371–87. doi:10.1042/CS20120340.
126. Kolsum U, Brightling CE, Agusti A, et al. The prevalence and clinical characteristics associated with eosinophilic inflammation in COPD patients from the ECLIPSE (Evaluation Of COPD Longitudinally To Identify Predictive Surrogate Endpoints) cohort. In: B33 Granulocyte Act. Lung Dis. American Thoracic Society; 2014. p. A2745.
127. Takatsu K, Takaki S, Hitoshi Y. Interleukin-5 and its receptor system: implications in the immune system and inflammation. Adv Immunol. 1994;57:145–90.
128. Brightling CE, Bleecker ER, Panettieri RA, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2:891–901. doi:10.1016/S2213-2600(14)70187-0.
129. Walsh GM. Tralokinumab, an anti-IL-13 mAb for the potential treatment of asthma and COPD. Curr Opin Investig. 2010;11:1305–12.
130. Study to evaluate efficacy and safety of mepolizumab for frequently exacerbating chronic obstructive pulmonary disease (COPD) patients. Available from: http://www.ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02105948. Accessed 15 Nov 2016.
131. Barnes PJ. Mediators of chronic obstructive pulmonary disease. Pharmacol Rev. 2004;56:515–48. doi:10.1124/pr.56.4.2.
132. Rennard SI, Dale DC, Donohue JF, et al. CXCR2 antagonist MK-7123: a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:1001–11. doi:10.1164/rccm.201405-0992OC.
133. Kirsten AM, Förster K, Radeczky E, et al. The safety and tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-to-severe COPD. Pulm Pharmacol Ther. 2015;31:36–41. doi:10.1016/j.pupt.2015.02.001.
134. MacNee W, Allan RJ, Jones I, et al. Efficacy and safety of the oral p38 inhibitor PH-797804 in chronic obstructive pulmonary disease: a randomised clinical trial. Thorax. 2013;68:738–45. doi:10.1136/thoraxjnl-2012-202744.
135. Watz H, Barnacle H, Hartley BF, Chan R. Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2:63–72. doi:10.1016/S2213-2600(13)70200-5.
136. Marks-Konczalik J, Costa M, Robertson J, et al. A post-hoc subgroup analysis of data from a six month clinical trial comparing the efficacy and safety of losmapimod in moderate-severe COPD patients with ≤2% and >2% blood eosinophils. Respir Med. 2015;109:860–9. doi:10.1016/j.rmed.2015.05.003.
137. Braido F, Tarantini F, Ghiglione V, et al. Bacterial lysate in the prevention of acute exacerbation of COPD and in respiratory recurrent infections. Int J Chron Obstr Pulm Dis. 2007;2:335–45.
138. Huber M, Mossmann H, Bessler WG. Th1-orientated immunological properties of the bacterial extract OM-85-BV. Eur J Med Res. 2005;10:209–17.
139. Rozy A, Chorostowska-Wynimko J. Bacterial immunostimulants–mechanism of action and clinical application in respiratory diseases. Pneumonol Alergol Pol. 2008;76:353–9.
140. Steurer-Stey C, Bachmann LM, Steurer J, Tramèr MR. Oral purified bacterial extracts in chronic bronchitis and COPD: systematic review. Chest. 2004;126:1645–55. doi:10.1378/chest.126.5.1645.
141. Koatz AM, Coe NA, Cicerán A, Alter AJ. Clinical and immunological benefits of OM-85 bacterial lysate in patients with allergic rhinitis, asthma, and COPD and recurrent respiratory infections. Lung. 2016;194:687–97. doi:10.1007/s00408-016-9880-5.