Prediction and prevention of exacerbations and mortality in patients with COPD

References

• Burney PG, Patel J, Newson R, et al. Global and regional trends in COPD mortality, 1990–2010. Eur Respir J. 2015;45(5):1239–1247.
   PubMed Web of Science ®Google Scholar
• Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J Suppl. 2003;41:46s–53s.
   PubMedGoogle Scholar
• Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. Eur Respir J. 2007;29(6):1224–1238.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest. 2000;117(5 Suppl 2):398S–401S.
   PubMed Web of Science ®Google Scholar
• O’Donnell DE, Parker CM. COPD exacerbations. 3: pathophysiology. Thorax. 2006;61(4):354–361.
   PubMed Web of Science ®Google Scholar
• Bhowmik A, Seemungal TA, Sapsford RJ, et al. Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax. 2000;55(2):114–120.
   PubMed Web of Science ®Google Scholar
• Drost EM, Skwarski KM, Sauleda J, et al. Oxidative stress and airway inflammation in severe exacerbations of COPD. Thorax. 2005;60(4):293–300.
   PubMed Web of Science ®Google Scholar
• Hurst JR, Perera WR, Wilkinson TM, et al. Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(1):71–78.
   PubMed Web of Science ®Google Scholar
• Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J. 2007;29(3):527–534.
   PubMed Web of Science ®Google Scholar
• Qiu Y, Zhu J, Bandi V, et al. Biopsy neutrophilia, neutrophil chemokine and receptor gene expression in severe exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2003;168(8):968–975.
   PubMed Web of Science ®Google Scholar
• Saetta M, Di Stefano A, Maestrelli P, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med. 1994;150(6 Pt 1):1646–1652.
   PubMed Web of Science ®Google Scholar
• Lopez-Campos JL, Agusti A. Heterogeneity of chronic obstructive pulmonary disease exacerbations: a two-axes classification proposal. Lancet Respir Med. 2015;3(9):729–734.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013;1(3):199–209.
   PubMed Web of Science ®Google Scholar
• Donaldson GC, Seemungal TA, Bhowmik A, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847–852.
   PubMed Web of Science ®Google Scholar
• Kanner RE, Anthonisen NR, Connett JE; Lung Health Study Research G. 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;164(3):358–364.
   PubMed Web of Science ®Google Scholar
• Seemungal TA, Donaldson GC, Bhowmik A, et al. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608–1613.
   PubMed Web of Science ®Google Scholar
• Jahnz-Rózyk K, Targowski T, From S. [Costs of exacerbations of chronic obstructive pulmonary disease in primary and secondary care in 2007–results of multicenter Polish study]. Pol Merkur Lekarski. 2009;26(153):208–214. Polish.
   PubMedGoogle Scholar
• Nielsen R, Johannessen A, Benediktsdottir B, et al. Present and future costs of COPD in Iceland and Norway: results from the BOLD study. Eur Respir J. 2009;34(4):850–857.
   PubMed Web of Science ®Google Scholar
• Ornek T, Tor M, Altın R, et al. Clinical factors affecting the direct cost of patients hospitalized with acute exacerbation of chronic obstructive pulmonary disease. Int J Med Sci. 2012;9(4):285–290.
   PubMed Web of Science ®Google Scholar
• Wouters EF. Economic analysis of the confronting COPD survey: an overview of results. Respir Med. 2003;97(Suppl C):S3–S14.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Brill SE, Allinson JP, et al. Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease. BMC Med. 2013;11:181.
   PubMed Web of Science ®Google Scholar
• Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2016. Global strategy for the diagnosis, management, and prevention of COPD [cited 2016 Feb 29]. Available from: http://www.goldcopd.org/
   Google Scholar
• Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128–1138.
   PubMed Web of Science ®Google Scholar
• 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(13):1184–1192.
   PubMed Web of Science ®Google Scholar
• Papaioannou AI, Bartziokas K, Papiris S, et al. Duration of hospitalization and lung function deterioration as predictors of future chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2016;193(6):698–700.
   PubMed Web of Science ®Google Scholar
• Lange P, Marott JL, Vestbo J, et al. Prediction of the clinical course of chronic obstructive pulmonary disease, using the new GOLD classification: a study of the general population. Am J Respir Crit Care Med. 2012;186(10):975–981.
   PubMed Web of Science ®Google Scholar
• Jones P, Higenbottam T. Quantifying of severity of exacerbations in chronic obstructive pulmonary disease: adaptations to the definition to allow quantification. Proc Am Thorac Soc. 2007;4(8):597–601.
   PubMedGoogle Scholar
• 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(5 Pt 1):1418–1422.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Mezzi K, Fogel R, et al. Baseline symptom scores and future risk of severe exacerbation: the SPARK study. Eur Respir J. 2015;46(suppl 59):PA1006.
   Google Scholar
• Schikowski T, Mills IC, Anderson HR, et al. Ambient air pollution: a cause of COPD? Eur Respir J. 2014;43(1):250–263.
   PubMed Web of Science ®Google Scholar
• 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(8):943–950.
   PubMed Web of Science ®Google Scholar
• Papaioannou AI, Bartziokas K, Loukides S, et al. Cardiovascular comorbidities in hospitalised COPD patients: a determinant of future risk? Eur Respir J. 2015;46(3):846–849.
   PubMed Web of Science ®Google Scholar
• Boyd CM, Darer J, Boult C, et al. Clinical practice guidelines and quality of care for older patients with multiple comorbid diseases: implications for pay for performance. JAMA. 2005;294(6):716–724.
   PubMed Web of Science ®Google Scholar
• Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11:122.
   PubMed Web of Science ®Google Scholar
• Mannino DM, Watt G, Hole D, et al. The natural history of chronic obstructive pulmonary disease. Eur Respir J. 2006;27(3):627–643.
   PubMed Web of Science ®Google Scholar
• Sin DD, Anthonisen NR, Soriano JB, et al. Mortality in COPD: role of comorbidities. Eur Respir J. 2006;28(6):1245–1257.
   PubMed Web of Science ®Google Scholar
• Hwang YI, Lee SH, Yoo JH, et al. History of pneumonia is a strong risk factor for chronic obstructive pulmonary disease (COPD) exacerbation in South Korea: the epidemiologic review and prospective observation of COPD and health in Korea (EPOCH) study. J Thorac Dis. 2015;7(12):2203–2213.
   PubMed Web of Science ®Google Scholar
• Baker EH, Bell D. Blood glucose: of emerging importance in COPD exacerbations. Thorax. 2009;64(10):830–832.
   PubMed Web of Science ®Google Scholar
• Mullerova H, Shukla A, Hawkins A, et al. Risk factors for acute exacerbations of COPD in a primary care population: a retrospective observational cohort study. BMJ Open. 2014;4(12):e006171.
   PubMed Web of Science ®Google Scholar
• Martinez CH, Okajima Y, Murray S, et al. Impact of self-reported gastroesophageal reflux disease in subjects from COPDGene cohort. Respir Res. 2014;15:62.
   PubMed Web of Science ®Google Scholar
• Tsai C-L, Lin Y-H, Wang M-T, et al. Gastro-oesophageal reflux disease increases the risk of intensive care unit admittance and mechanical ventilation use among patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study. Crit Care. 2015;19:110.
   PubMed Web of Science ®Google Scholar
• Baumeler L, Papakonstantinou E, Milenkovic B, et al. Therapy with proton-pump inhibitors for gastroesophageal reflux disease does not reduce the risk for severe exacerbations in COPD. Respirology. 2016 Mar 11. doi:10.1111/resp.12758. [Epub ahead of print]
   Google Scholar
• Lee S-W, Lin C-H, Lien H-C, et al. Proton pump inhibitors did not increase risk of pneumonia in patients with chronic obstructive pulmonary disease. J Clin Med Res. 2015;7(11):880–883.
   PubMedGoogle Scholar
• Anthonisen NR, Connett JE, Enright PL, et al.; Lung Health Study Research G. Hospitalizations and mortality in the lung health study. Am J Respir Crit Care Med. 2002;166(3):333–339.
   PubMed Web of Science ®Google Scholar
• Mannino DM, Thorn D, Swensen A, et al. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32(4):962–969.
   PubMed Web of Science ®Google Scholar
• Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367(10):913–921.
   PubMed Web of Science ®Google Scholar
• Laurin C, Moullec G, Bacon SL, et al. Impact of anxiety and depression on chronic obstructive pulmonary disease exacerbation risk. Am J Respir Crit Care Med. 2012;185(9):918–923.
   PubMed Web of Science ®Google Scholar
• Papaioannou AI, Bartziokas K, Tsikrika S, et al. The impact of depressive symptoms on recovery and outcome of hospitalised COPD exacerbations. Eur Respir J. 2013;41(4):815–823.
   PubMed Web of Science ®Google Scholar
• Duvoix A, Dickens J, Haq I, et al. Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax. 2013;68(7):670–676.
   PubMed Web of Science ®Google Scholar
• Thomsen M, Nordestgaard BG. Myocardial infarction and ischemic heart disease in overweight and obesity with and without metabolic syndrome. JAMA Intern Med. 2014;174(1):15–22.
   PubMed Web of Science ®Google Scholar
• Miller BE, Tal-Singer R, Rennard SI, et al. Plasma fibrinogen qualification as a drug development tool in COPD: perspective of the COPD biomarker qualification consortium. Am J Respir Crit Care Med. 2016;193:607–613.
   PubMed Web of Science ®Google Scholar
• Vedel-Krogh S, Nielsen SF, Lange P, et al. Blood eosinophils and exacerbations in COPD: the Copenhagen general population study. Am J Respir Crit Care Med. 2016;193(9):965–974.
   PubMed Web of Science ®Google Scholar
• 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(6):435–442.
   PubMed Web of Science ®Google Scholar
• Siddiqui SH, Guasconi A, Vestbo J, et al. Blood eosinophils: a biomarker of response to extrafine beclomethasone/formoterol in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(4):523–525.
   PubMed Web of Science ®Google Scholar
• Pavord ID, Lettis S, Locantore N, et al. Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD. Thorax. 2016;71(2):118–125.
   PubMed Web of Science ®Google Scholar
• Rabe KF. Treating COPD–the TORCH trial, P values, and the Dodo. N Engl J Med. 2007;356(8):851–854.
   PubMed Web of Science ®Google Scholar
• Drummond MB, Hansel NN, Connett JE, et al. Spirometric predictors of lung function decline and mortality in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(12):1301–1306.
   PubMed Web of Science ®Google Scholar
• Marin JM, Carrizo SJ, Gascon M, et al. Inspiratory capacity, dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute-walk test in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(6):1395–1399.
   PubMed Web of Science ®Google Scholar
• O’Donnell DE, Revill SM, Webb KA. Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(5):770–777.
   PubMed Web of Science ®Google Scholar
• Tantucci C, Duguet A, Similowski T, et al. Effect of salbutamol on dynamic hyperinflation in chronic obstructive pulmonary disease patients. Eur Respir J. 1998;12(4):799–804.
   PubMed Web of Science ®Google Scholar
• Casanova C, Cote C, De Torres JP, et al. Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;171(6):591–597.
   PubMed Web of Science ®Google Scholar
• Tantucci C, Donati P, Nicosia F, et al. Inspiratory capacity predicts mortality in patients with chronic obstructive pulmonary disease. Respir Med. 2008;102(4):613–619.
   PubMed Web of Science ®Google Scholar
• Nishimura K, Izumi T, Tsukino M, et al. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest. 2002;121(5):1434–1440.
   PubMed Web of Science ®Google Scholar
• Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925–931.
   PubMed Web of Science ®Google Scholar
• Müllerova H, Maselli DJ, Locantore N, et al. Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort. Chest. 2015;147(4):999–1007.
   PubMed Web of Science ®Google Scholar
• Suissa S, Dell’Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality. Thorax. 2012;67(11):957–963.
   PubMed Web of Science ®Google Scholar
• Divo M, Cote C, De Torres JP, et al. Comorbidities and risk of mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(2):155–161.
   PubMed Web of Science ®Google Scholar
• Divo MJ, Casanova C, Marin JM, et al. COPD comorbidities network. Eur Respir J. 2015;46(3):640–650.
   PubMed Web of Science ®Google Scholar
• Oga T, Nishimura K, Tsukino M, et al. Analysis of the factors related to mortality in chronic obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med. 2003;167(4):544–549.
   PubMed Web of Science ®Google Scholar
• Schols AM, Slangen J, Volovics L, et al. Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157(6 Pt 1):1791–1797.
   PubMed Web of Science ®Google Scholar
• Gerardi DA, Lovett L, Benoit-Connors ML, et al. Variables related to increased mortality following out-patient pulmonary rehabilitation. Eur Respir J. 1996;9(3):431–435.
   PubMed Web of Science ®Google Scholar
• Pinto-Plata VM, Cote C, Cabral H, et al. The 6-min walk distance: change over time and value as a predictor of survival in severe COPD. Eur Respir J. 2004;23(1):28–33.
   PubMed Web of Science ®Google Scholar
• Anthonisen NR, Wright EC, Hodgkin JE. Prognosis in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1986;133(1):14–20.
   PubMed Web of Science ®Google Scholar
• Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005–1012.
   PubMed Web of Science ®Google Scholar
• Soler-Cataluna JJ, Martinez-Garcia MA, Sanchez LS, et al. Severe exacerbations and BODE index: two independent risk factors for death in male COPD patients. Respir Med. 2009;103(5):692–699.
   PubMed Web of Science ®Google Scholar
• Puhan MA, Garcia-Aymerich J, Frey M, et al. Expansion of the prognostic assessment of patients with chronic obstructive pulmonary disease: the updated BODE index and the ADO index. Lancet. 2009;374(9691):704–711.
   PubMed Web of Science ®Google Scholar
• Jones RC, Donaldson GC, Chavannes NH, et al. Derivation and validation of a composite index of severity in chronic obstructive pulmonary disease: the DOSE Index. Am J Respir Crit Care Med. 2009;180(12):1189–1195.
   PubMed Web of Science ®Google Scholar
• Sundh J, Janson C, Lisspers K, et al. The dyspnoea, obstruction, smoking, exacerbation (DOSE) index is predictive of mortality in COPD. Prim Care Respir J. 2012;21(3):295–301.
   PubMedGoogle Scholar
• Kostikas K, Bakakos P, Papiris S, et al. Systemic biomarkers in the evaluation and management of COPD patients: are we getting closer to clinical application? Curr Drug Targets. 2013;14(2):177–191.
   PubMed Web of Science ®Google Scholar
• Dahl M, Vestbo J, Lange P, et al. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(3):250–255.
   PubMed Web of Science ®Google Scholar
• De Torres JP, Pinto-Plata V, Casanova C, et al. C-reactive protein levels and survival in patients with moderate to very severe COPD. Chest. 2008;133(6):1336–1343.
   PubMed Web of Science ®Google Scholar
• Man SF, Connett JE, Anthonisen NR, et al. C-reactive protein and mortality in mild to moderate chronic obstructive pulmonary disease. Thorax. 2006;61(10):849–853.
   PubMed Web of Science ®Google Scholar
• Dahl M, Tybjaerg-Hansen A, Vestbo J, et al. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(6):1008–1011.
   PubMed Web of Science ®Google Scholar
• Danesh J, Lewington S, Thompson SG, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA. 2005;294(14):1799–1809.
   PubMed Web of Science ®Google Scholar
• Groenewegen KH, Postma DS, Hop WC, et al. Increased systemic inflammation is a risk factor for COPD exacerbations. Chest. 2008;133(2):350–357.
   PubMed Web of Science ®Google Scholar
• Man SF, Xing L, Connett JE, et al. Circulating fibronectin to C-reactive protein ratio and mortality: a biomarker in COPD? Eur Respir J. 2008;32(6):1451–1457.
   PubMed Web of Science ®Google Scholar
• Yoon HI, Li Y, Man SF, et al. The complex relationship of serum adiponectin to COPD outcomes COPD and adiponectin. Chest. 2012;142(4):893–899.
   PubMed Web of Science ®Google Scholar
• Sin DD, Miller BE, Duvoix A, et al. Serum PARC/CCL-18 concentrations and health outcomes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;183(9):1187–1192.
   PubMed Web of Science ®Google Scholar
• Stolz D, Christ-Crain M, Morgenthaler NG, et al. Copeptin, C-reactive protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD. Chest. 2007;131(4):1058–1067.
   PubMed Web of Science ®Google Scholar
• Stolz D, Christ-Crain M, Morgenthaler NG, et al. Plasma pro-adrenomedullin but not plasma pro-endothelin predicts survival in exacerbations of COPD. Chest. 2008;134(2):263–272.
   PubMed Web of Science ®Google Scholar
• Stolz D, Breidthardt T, Christ-Crain M, et al. Use of B-type natriuretic peptide in the risk stratification of acute exacerbations of COPD. Chest. 2008;133(5):1088–1094.
   PubMed Web of Science ®Google Scholar
• Bernasconi M, Tamm M, Bingisser R, et al. Midregional proatrial natriuretic peptide predicts survival in exacerbations of COPD. Chest. 2011;140(1):91–99.
   PubMed Web of Science ®Google Scholar
• Chang CL, Robinson SC, Mills GD, et al. Biochemical markers of cardiac dysfunction predict mortality in acute exacerbations of COPD. Thorax. 2011;66(9):764–768.
   PubMed Web of Science ®Google Scholar
• Høiseth AD, Neukamm A, Karlsson BD, et al. Elevated high-sensitivity cardiac troponin T is associated with increased mortality after acute exacerbation of chronic obstructive pulmonary disease. Thorax. 2011;66(9):775–781.
   PubMed Web of Science ®Google Scholar
• Marcun R, Sustic A, Brguljan PM, et al. Cardiac biomarkers predict outcome after hospitalisation for an acute exacerbation of chronic obstructive pulmonary disease. Int J Cardiol. 2012;161(3):156–159.
   PubMed Web of Science ®Google Scholar
• Høiseth AD, Omland T, Karlsson BD, et al. Standardized evaluation of lung congestion during COPD exacerbation better identifies patients at risk of dying. Int J Chron Obstruct Pulmon Dis. 2013;8:621–629.
   PubMed Web of Science ®Google Scholar
• Celli BR, Locantore N, Yates J, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065–1072.
   PubMed Web of Science ®Google Scholar
• Fu -J-J, McDonald VM, Baines KJ, et al. Airway IL-1beta and systemic inflammation as predictors of future exacerbation risk in asthma and COPD. Chest. 2015;148(3):618–629.
   PubMed Web of Science ®Google Scholar
• Labonté LE, Bourbeau J, Daskalopoulou SS, . Club cell-16 and RelB as novel determinants of arterial stiffness in exacerbating COPD patients. PLoS One. 2016;11(2):e0149974.
   PubMed Web of Science ®Google Scholar
• Cheng DT, Kim DK, Cockayne DA, et al. Systemic soluble receptor for advanced glycation endproducts is a biomarker of emphysema and associated with AGER genetic variants in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188(8):948–957.
   PubMed Web of Science ®Google Scholar
• Smith DJ, Yerkovich ST, Towers MA, et al. Reduced soluble receptor for advanced glycation end-products in COPD. Eur Respir J. 2011;37(3):516–522.
   PubMed Web of Science ®Google Scholar
• Rabinovich RA, Miller BE, Wrobel K, et al. Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD. Eur Respir J. 2016;47:1365–1373.
   PubMed Web of Science ®Google Scholar
• Stolz D, Kostikas K, Blasi F, et al. Adrenomedullin refines mortality prediction by the BODE index in COPD: the “BODE-A” index. Eur Respir J. 2014;43(2):397–408.
   PubMed Web of Science ®Google Scholar
• Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977;1(6077):1645–1648.
   PubMed Web of Science ®Google Scholar
• 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(4):233–239.
   PubMed Web of Science ®Google Scholar
• 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(4):457–463.
   PubMed Web of Science ®Google Scholar
• Wongsurakiat P, Maranetra KN, Wasi C, et al. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest. 2004;125(6):2011–2020.
   PubMed Web of Science ®Google Scholar
• Nichol KL, Baken L, Nelson A. Relation between influenza vaccination and outpatient visits, hospitalization, and mortality in elderly persons with chronic lung disease. Ann Intern Med. 1999;130(5):397–403.
   PubMed Web of Science ®Google Scholar
• Walters JA, Smith S, Poole P, et al. Injectable vaccines for preventing pneumococcal infection in patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2010;11:CD001390.
   Google Scholar
• Alfageme I, Vazquez R, Reyes N, et al. Clinical efficacy of anti-pneumococcal vaccination in patients with COPD. Thorax. 2006;61(3):189–195.
   PubMed Web of Science ®Google Scholar
• Bonten MJ, Huijts SM, Bolkenbaas M, et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N Engl J Med. 2015;372(12):1114–1125.
   PubMed Web of Science ®Google Scholar
• McCarthy B, Casey D, Devane D, et al. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;2:CD003793.
   PubMed Web of Science ®Google Scholar
• Puhan MA, Gimeno-Santos E, Scharplatz M, et al. Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011;10:CD005305.
   PubMed Web of Science ®Google Scholar
• Greening NJ, Williams JE, Hussain SF, et al. An early rehabilitation intervention to enhance recovery during hospital admission for an exacerbation of chronic respiratory disease: randomised controlled trial. Bmj. 2014;349:g4315.
   PubMed Web of Science ®Google Scholar
• Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;7:CD009285.
   Google Scholar
• Cheyne L, Irvin-Sellers MJ, White J. Tiotropium versus ipratropium bromide for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;9:CD009552.
   Google Scholar
• 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(15):1543–1554.
   PubMed Web of Science ®Google Scholar
• 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(5):1106–1114.
   PubMed Web of Science ®Google Scholar
• Ni H, Soe Z, Moe S. Aclidinium bromide for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;9:CD010509.
   Google Scholar
• Pleasants RA, Wang T, Gao J, et al. Inhaled umeclidinium in COPD patients: a review and meta-analysis. Drugs. 2016;76(3):343–361.
   PubMed Web of Science ®Google Scholar
• Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093–1103.
   PubMed Web of Science ®Google Scholar
• 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(7):524–533.
   PubMed Web of Science ®Google Scholar
• Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;9:CD009157.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Calverley PM, Seemungal TA, et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med. 2008;177(1):19–26.
   PubMed Web of Science ®Google Scholar
• Kew KM, Mavergames C, Walters JA. Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;10:CD010177.
   PubMed Web of Science ®Google Scholar
• Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010;65(6):473–479.
   PubMed Web of Science ®Google Scholar
• Zhong N, Wang C, Zhou X, et al. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:1015–1026.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Decramer M, Vestbo J, et al. A novel study design for the comparison between once-daily QVA149 and twice-daily salmeterol/fluticasone on the reduction of COPD exacerbations: the FLAME study. Eur Respir J 2013;42(Suppl. 57):696.
   Google Scholar
• FLAME study shows superiority of Novartis’ Ultibro® Breezhaler® over Seretide® in reducing COPD exacerbations. Novartis Press Release; 2015 [cited 2016 Feb 29]. Available from: https://www.novartis.com/news/media-releases/flame-study-shows-superiority-novartis-ultibro%C2%AE-breezhaler%C2%AE-over-seretide%C2%AE
   Google Scholar
• Singh D, Jones PW, Bateman ED, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study. BMC Pulm Med. 2014;14:178.
   PubMed Web of Science ®Google Scholar
• D’Urzo AD, Rennard SI, Kerwin EM, et al. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;15:123.
   PubMed Web of Science ®Google Scholar
• Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT). Respir Res. 2015;16:92.
   PubMed Web of Science ®Google Scholar
• Decramer M, Anzueto A, Kerwin E, et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 2014;2(6):472–486.
   PubMed Web of Science ®Google Scholar
• Donohue JF, Niewoehner D, Brooks J, et al. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respir Res. 2014;15:78.
   PubMed Web of Science ®Google Scholar
• 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(4):969–979.
   PubMed Web of Science ®Google Scholar
• Loke YK, Cavallazzi R, Singh S. Risk of fractures with inhaled corticosteroids in COPD: systematic review and meta-analysis of randomised controlled trials and observational studies. Thorax. 2011;66(8):699–708.
   PubMed Web of Science ®Google Scholar
• Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus long-acting beta(2)-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;9:CD006829.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Singh D, Vestbo J, et al. Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. Respir Med. 2014;108(8):1153–1162.
   PubMed Web of Science ®Google Scholar
• Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med. 2013;1(3):210–223.
   PubMed Web of Science ®Google Scholar
• Aaron SD, Vandemheen KL, Fergusson D, et al. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545–555.
   PubMed Web of Science ®Google Scholar
• Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285–1294.
   PubMed Web of Science ®Google Scholar
• Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685–694.
   PubMed Web of Science ®Google Scholar
• Martinez FJ, Calverley PM, 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(9971):857–866.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Wang X, Zeng X, et al. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology. 2006;11(5):603–610.
   PubMed Web of Science ®Google Scholar
• Seemungal TA, Wilkinson TM, 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(11):1139–1147.
   PubMed Web of Science ®Google Scholar
• Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689–698.
   PubMed Web of Science ®Google Scholar
• Poole P, Black PN, Cates CJ. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;8:CD001287.
   Google Scholar
• 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(9629):2013–2018.
   PubMed Web of Science ®Google Scholar
• Decramer M, Rutten-van MM, Dekhuijzen PN, 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(9470):1552–1560.
   PubMed Web of Science ®Google Scholar
• Tse HN, Raiteri L, Wong KY, et al. High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study. Chest. 2013;144(1):106–118.
   PubMed Web of Science ®Google Scholar
• 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(3):187–194.
   PubMed Web of Science ®Google Scholar
• Wedzicha JA, Donaldson GC. Exacerbations of chronic obstructive pulmonary disease. Respir Care. 2003;48(12):1204–1213; discussion 1213–1205.
   PubMedGoogle Scholar
• Wang C-S, Wang S-T, Lai C-T, et al. Impact of influenza vaccination on major cause-specific mortality. Vaccine. 2007;25(7):1196–1203.
   PubMed Web of Science ®Google Scholar
• Waschki B, Kirsten AM, Holz O, et al. Disease progression and changes in physical activity in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(3):295–306.
   PubMed Web of Science ®Google Scholar
• Garcia-Aymerich J, Lange P, Benet M, et al. Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study. Thorax. 2006;61(9):772–778.
   PubMed Web of Science ®Google Scholar
• Agarwal R, Aggarwal AN, Gupta D, et al. Inhaled corticosteroids vs placebo for preventing COPD exacerbations: a systematic review and metaregression of randomized controlled trials. Chest. 2010;137(2):318–325.
   PubMed Web of Science ®Google Scholar
• Value of chemoprophylaxis and chemotherapy in early chronic bronchitis. A report to the medical research council by their working party on trials of chemotherapy in early chronic bronchitis. Br Med J. 1966;1(5499):1317–1322.
   PubMedGoogle Scholar
• Francis RS, May JR, Spicer CC. Chemotherapy of bronchitis. Influence of penicillin and tetracycline administered daily, or intermittently for exacerbations. A report to the Research Committee of the British Tuberculosis Association by its Bronchitis Subcommittee. Br Med J. 1961;2(5258):979–985.
   PubMed Web of Science ®Google Scholar
• Francis RS, Spicer CC. Chemotherapy in chronic bronchitis. Influence of daily penicillin and tetracycline on exacerbations and their cost. Br Med J. 1960;1(5169):297–303.
   PubMed Web of Science ®Google Scholar
• National Clinical Guideline Centre. Ronic obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary care. London: National Clinical Guideline Centre; 2010 [cited 2016 Feb 29]. Available from: http://guidance.nice.org.uk/CG101/Guidance/pdf/English
   Google Scholar
• Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775–789.
   PubMed Web of Science ®Google Scholar
• GSK and Theravance announce results from the SUMMIT COPD CV Survival Study; Press release. GlaxoSmithKline; 2015 [cited 2016 Feb 29]. Available from: http://uk.reuters.com/article/idUSnMKWS3S8Ba+1ea+MKW20150908
   Google Scholar
• Barnes PJ, Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J. 2009;33(5):1165–1185.
   PubMed Web of Science ®Google Scholar
• Almagro P, Cabrera FJ, Diez J, et al. Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de medicina interna (ESMI) study. Chest. 2012;142(5):1126–1133.
   PubMed Web of Science ®Google Scholar