COPD pp 147-168 | Cite as

Phenotypes of COPD

  • Jamie ShethEmail author
  • MeiLan Han


Significant heterogeneity exists in chronic obstructive pulmonary disease (COPD) patients with respect to clinical presentation, physiology, imaging characteristics, response to therapy, disease progression, and ultimately survival [1]. While FEV1 correlates to many outcomes of interest, no single measure adequately reflects this disease complexity. The goal of phenotyping is to identify patient subgroups with unique characteristics with the ultimate goal of altering clinically meaningful outcomes through targeted therapeutic approaches. While various definitions have been described, a consensus definition that was recently proposed defines a phenotype as, “a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression or death)” [1]. In many cases, the discovery and validation of phenotypes occurs through a multi-step process (Fig. 10.1) where for instance a unique group of patients may initially be identified through a biological or molecular signature and validated by demonstrating a similar response to therapy [2].


  1. 1.
    Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, Macnee W, Make BJ, Rabe KF, Rennard SI, Sciurba FC, Silverman EK, Vestbo J, Washko GR, Wouters EF, Martinez FJ. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010;182:598–604.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Martinez CH, Han MK. Contribution of the environment and comorbidities to chronic obstructive pulmonary disease phenotypes. Med Clin North Am. 2012;96:713–27.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R. 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.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Lokke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: a 25 year follow up study of the general population. Thorax. 2006;61:935–9.PubMedPubMedCentralGoogle Scholar
  5. 5.
    McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, Wright AC, Gefter WB, Litzky L, Coxson HO, Pare PD, Sin DD, Pierce RA, Woods JC, McWilliams AM, Mayo JR, Lam SC, Cooper JD, Hogg JC. Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med. 2011;365:1567–75.PubMedPubMedCentralGoogle Scholar
  6. 6.
    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;272:1497–505.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Shavelle RM, Paculdo DR, Kush SJ, Mannino DM, Strauss DJ. Life expectancy and years of life lost in chronic obstructive pulmonary disease: findings from the NHANES III follow-up study. Int J Chron Obstruct Pulmon Dis. 2009;4:137–48.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Tan WC, Sin DD, Bourbeau J, Hernandez P, Chapman KR, Cowie R, FitzGerald JM, Marciniuk DD, Maltais F, Buist AS, Road J, Hogg JC, Kirby M, Coxson H, Hague C, Leipsic J, O’Donnell DE, Aaron SD, Can CCRG. Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study. Thorax. 2015;70(9):822–9.PubMedGoogle Scholar
  9. 9.
    Castaldi PJ, Dy J, Ross J, Chang Y, Washko GR, Curran-Everett D, Williams A, Lynch DA, Make BJ, Crapo JD, Bowler RP, Regan EA, Hokanson JE, Kinney GL, Han MK, Soler X, Ramsdell JW, Barr RG, Foreman M, van Beek E, Casaburi R, Criner GJ, Lutz SM, Rennard SI, Santorico S, Sciurba FC, DeMeo DL, Hersh CP, Silverman EK, Cho MH. Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema. Thorax. 2014;69:415–22.PubMedGoogle Scholar
  10. 10.
    Eisner MD, Anthonisen N, Coultas D, Kuenzli N, Perez-Padilla R, Postma D, Romieu I, Silverman EK, Balmes JR, Committee on Nonsmoking Copd E, Occupational Health A. An official American Thoracic Society public policy statement: novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182:693–718.PubMedGoogle Scholar
  11. 11.
    Han MK, Postma D, Mannino DM, Giardino ND, Buist S, Curtis JL, Martinez FJ. Gender and chronic obstructive pulmonary disease: why it matters. Am J Respir Crit Care Med. 2007;176:1179–84.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Camp PG, Ramirez-Venegas A, Sansores RH, Alva LF, McDougall JE, Sin DD, Pare PD, Muller NL, Silva CI, Rojas CE, Coxson HO. COPD phenotypes in biomass smoke- versus tobacco smoke-exposed Mexican women. Eur Respir J. 2014;43:725–34.PubMedGoogle Scholar
  13. 13.
    Gonzalez-Garcia M, Maldonado Gomez D, Torres-Duque CA, Barrero M, Jaramillo Villegas C, Perez JM, Varon H. Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease. J Bras Pneumol. 2013;39:147–54.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Moreira MA, Barbosa MA, Queiroz MC, Teixeira KI, Torres PP, Santana Junior PJ, Montadon Junior ME, Jardim JR. Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure. J Bras Pneumol. 2013;39:155–63.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Lieberman J, Winter B, Sastre A. Alpha 1-antitrypsin Pi-types in 965 COPD patients. Chest. 1986;89:370–3.PubMedGoogle Scholar
  16. 16.
    Tobin MJ, Cook PJ, Hutchison DC. Alpha 1 antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. A survey by the British Thoracic Association. Br J Dis Chest. 1983;77:14–27.Google Scholar
  17. 17.
    Larsson C. Natural history and life expectancy in severe alpha1-antitrypsin deficiency, Pi Z. Acta Med Scand. 1978;204:345–51.PubMedGoogle Scholar
  18. 18.
    Janus ED, Phillips NT, Carrell RW. Smoking, lung function, and alpha 1-antitrypsin deficiency. Lancet. 1985;1:152–4.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Black LF, Kueppers F. Alpha1-antitrypsin deficiency in nonsmokers. Am Rev Respir Dis. 1978;117:421–8.PubMedGoogle Scholar
  20. 20.
    Green CE, Vayalapra S, Hampson JA, Mukherjee D, Stockley RA, Turner AM. PiSZ alpha-1 antitrypsin deficiency (AATD): pulmonary phenotype and prognosis relative to PiZZ AATD and PiMM COPD. Thorax. 2015;70(10):939–45.PubMedGoogle Scholar
  21. 21.
    Stockley RA, Turner AM. Alpha-1-antitrypsin deficiency: clinical variability, assessment, and treatment. Trends Mol Med. 2014;20:105–15.PubMedGoogle Scholar
  22. 22.
    Ferris BG. Epidemiology standardization project (American Thoracic Society). Am Rev Respir Dis. 1978;118:1–120.PubMedGoogle Scholar
  23. 23.
    Forey BA, Thornton AJ, Lee PN. Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema. BMC Pulm Med. 2011;11:36.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Dijkstra AE, Smolonska J, van den Berge M, Wijmenga C, Zanen P, Luinge MA, Platteel M, Lammers JW, Dahlback M, Tosh K, Hiemstra PS, Sterk PJ, Spira A, Vestbo J, Nordestgaard BG, Benn M, Nielsen SF, Dahl M, Verschuren WM, Picavet HS, Smit HA, Owsijewitsch M, Kauczor HU, de Koning HJ, Nizankowska-Mogilnicka E, Mejza F, Nastalek P, van Diemen CC, Cho MH, Silverman EK, Crapo JD, Beaty TH, Lomas DA, Bakke P, Gulsvik A, Bosse Y, Obeidat MA, Loth DW, Lahousse L, Rivadeneira F, Uitterlinden AG, Hofman A, Stricker BH, Brusselle GG, van Duijn CM, Brouwer U, Koppelman GH, Vonk JM, Nawijn MC, Groen HJ, Timens W, Boezen HM, Postma DS, LifeLines Cohort s. Susceptibility to chronic mucus hypersecretion, a genome wide association study. PLoS One. 2014;9:e91621.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Orlandi I, Moroni C, Camiciottoli G, Bartolucci M, Pistolesi M, Villari N, Mascalchi M. Chronic obstructive pulmonary disease: thin-section CT measurement of airway wall thickness and lung attenuation. Radiology. 2005;234:604–10.PubMedGoogle Scholar
  26. 26.
    Kim V, Davey A, Comellas AP, Han MK, Washko G, Martinez CH, Lynch D, Lee JH, Silverman EK, Crapo JD, Make BJ, Criner GJ, Investigators CO. Clinical and computed tomographic predictors of chronic bronchitis in COPD: a cross sectional analysis of the COPDGene study. Respir Res. 2014;15:52.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ, M, groups Ms. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685–94.PubMedGoogle Scholar
  28. 28.
    Rennard SI, Calverley PM, Goehring UM, Bredenbroker D, Martinez FJ. Reduction of exacerbations by the PDE4 inhibitor roflumilast—the importance of defining different subsets of patients with COPD. Respir Res. 2011;12:18.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Grootendorst DC, Gauw SA, Verhoosel RM, Sterk PJ, Hospers JJ, Bredenbroker D, Bethke TD, Hiemstra PS, Rabe KF. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax. 2007;62:1081–7.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Spina D. PDE4 inhibitors: current status. Br J Pharmacol. 2008;155:308–15.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Bundschuh DS, Eltze M, Barsig J, Wollin L, Hatzelmann A, Beume R. In vivo efficacy in airway disease models of roflumilast, a novel orally active PDE4 inhibitor. J Pharmacol Exp Ther. 2001;297:280–90.PubMedGoogle Scholar
  32. 32.
    Hatzelmann A, Schudt C. Anti-inflammatory and immunomodulatory potential of the novel PDE4 inhibitor roflumilast in vitro. J Pharmacol Exp Ther. 2001;297:267–79.Google Scholar
  33. 33.
    Miravitlles M. Cough and sputum production as risk factors for poor outcomes in patients with COPD. Respir Med. 2011;105:1118–28.PubMedGoogle Scholar
  34. 34.
    Lange P, Groth S, Nyboe J, Appleyard M, Mortensen J, Jensen G, Schnohr P. Chronic obstructive lung disease in Copenhagen: cross-sectional epidemiological aspects. J Intern Med. 1989;226:25–32.PubMedGoogle Scholar
  35. 35.
    Sobradillo V, Miravitlles M, Jimenez CA, Gabriel R, Viejo JL, Masa JF, Fernandez-Fau L, Villasante C. Epidemiological study of chronic obstructive pulmonary disease in Spain (IBERPOC): prevalence of chronic respiratory symptoms and airflow limitation. Arch Bronconeumol. 1999;35:159–66.PubMedGoogle Scholar
  36. 36.
    Pallasaho P, Lundback B, Laspa SL, Jonsson E, Kotaniemi J, Sovijarvi AR, Laitinen LA. Increasing prevalence of asthma but not of chronic bronchitis in Finland? Report from the FinEsS-Helsinki Study. Respir Med. 1999;93:798–809.PubMedGoogle Scholar
  37. 37.
    von Hertzen L, Reunanen A, Impivaara O, Malkia E, Aromaa A. Airway obstruction in relation to symptoms in chronic respiratory disease—a nationally representative population study. Respir Med. 2000;94:356–63.Google Scholar
  38. 38.
    Cerveri I, Accordini S, Verlato G, Corsico A, Zoia MC, Casali L, Burney P, de Marco R, European Community Respiratory Health Survey Study G. Variations in the prevalence across countries of chronic bronchitis and smoking habits in young adults. Eur Respir J. 2001;18:85–92.PubMedGoogle Scholar
  39. 39.
    Janson C, Chinn S, Jarvis D, Burney P. Determinants of cough in young adults participating in the European Community Respiratory Health Survey. Eur Respir J. 2001;18:647–54.PubMedGoogle Scholar
  40. 40.
    Huchon GJ, Vergnenegre A, Neukirch F, Brami G, Roche N, Preux PM. Chronic bronchitis among French adults: high prevalence and underdiagnosis. Eur Respir J. 2002;20:806–12.PubMedGoogle Scholar
  41. 41.
    Lundback B, Lindberg A, Lindstrom M, Ronmark E, Jonsson AC, Jonsson E, Larsson LG, Andersson S, Sandstrom T, Larsson K, Obstructive lung disease in Northern Sweden S. Not 15 but 50% of smokers develop COPD?—report from the obstructive lung disease in Northern Sweden studies. Respir Med. 2003;97:115–22.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Miravitlles M, de la Roza C, Morera J, Montemayor T, Gobartt E, Martin A, Alvarez-Sala JL. Chronic respiratory symptoms, spirometry and knowledge of COPD among general population. Respir Med. 2006;100:1973–80.PubMedGoogle Scholar
  43. 43.
    Pelkonen M, Notkola IL, Nissinen A, Tukiainen H, Koskela H. Thirty-year cumulative incidence of chronic bronchitis and COPD in relation to 30-year pulmonary function and 40-year mortality: a follow-up in middle-aged rural men. Chest. 2006;130:1129–37.PubMedGoogle Scholar
  44. 44.
    de Marco R, Accordini S, Cerveri I, Corsico A, Anto JM, Kunzli N, Janson C, Sunyer J, Jarvis D, Chinn S, Vermeire P, Svanes C, Ackermann-Liebrich U, Gislason T, Heinrich J, Leynaert B, Neukirch F, Schouten JP, Wjst M, Burney P. Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm. Am J Respir Crit Care Med. 2007;175:32–9.PubMedGoogle Scholar
  45. 45.
    Miravitlles M, Soriano JB, Garcia-Rio F, Munoz L, Duran-Tauleria E, Sanchez G, Sobradillo V, Ancochea J. Prevalence of COPD in Spain: impact of undiagnosed COPD on quality of life and daily life activities. Thorax. 2009;64:863–8.PubMedGoogle Scholar
  46. 46.
    Harmsen L, Thomsen SF, Ingebrigtsen T, Steffensen IE, Skadhauge LR, Kyvik KO, Backer V. Chronic mucus hypersecretion: prevalence and risk factors in younger individuals. Int J Tuberc Lung Dis. 2010;14:1052–8.PubMedGoogle Scholar
  47. 47.
    Kim V, Han MK, Vance GB, Make BJ, Newell JD, Hokanson JE, Hersh CP, Stinson D, Silverman EK, Criner GJ, Investigators CO. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene study. Chest. 2011;140:626–33.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Martinez CH, Kim V, Chen Y, Kazerooni EA, Murray S, Criner GJ, Curtis JL, Regan EA, Wan E, Hersh CP, Silverman EK, Crapo JD, Martinez FJ, Han MK, Investigators CO. The clinical impact of non-obstructive chronic bronchitis in current and former smokers. Respir Med. 2014;108:491–9.PubMedGoogle Scholar
  49. 49.
    Miravitlles M, Calle M, Soler-Cataluna JJ. Clinical phenotypes of COPD: identification, definition and implications for guidelines. Arch Bronconeumol. 2012;48:86–98.PubMedGoogle Scholar
  50. 50.
    Soler-Cataluna JJ, Cosio B, Izquierdo JL, Lopez-Campos JL, Marin JM, Aguero R, Baloira A, Carrizo S, Esteban C, Galdiz JB, Gonzalez MC, Miravitlles M, Monso E, Montemayor T, Morera J, Ortega F, Peces-Barba G, Puente L, Rodriguez JM, Sala E, Sauleda J, Soriano JB, Viejo JL. Consensus document on the overlap phenotype COPD-asthma in COPD. Arch Bronconeumol. 2012;48:331–7.PubMedGoogle Scholar
  51. 51.
    Bujarski S, Parulekar AD, Sharafkhaneh A, Hanania NA. The asthma COPD overlap syndrome (ACOS). Curr Allergy Asthma Rep. 2015;15:509.PubMedGoogle Scholar
  52. 52.
    Hardin M, Silverman EK, Barr RG, Hansel NN, Schroeder JD, Make BJ, Crapo JD, Hersh CP, Investigators CO. The clinical features of the overlap between COPD and asthma. Respir Res. 2011;12:127.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Zeki AA, Schivo M, Chan A, Albertson TE, Louie S. The Asthma-COPD overlap syndrome: a common clinical problem in the elderly. J Allergy. 2011;2011:861926.Google Scholar
  54. 54.
    Kitaguchi Y, Komatsu Y, Fujimoto K, Hanaoka M, Kubo K. Sputum eosinophilia can predict responsiveness to inhaled corticosteroid treatment in patients with overlap syndrome of COPD and asthma. Int J Chron Obstruct Pulmon Dis. 2012;7:283–9.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Menezes AM, Montes de Oca M, Perez-Padilla R, Nadeau G, Wehrmeister FC, Lopez-Varela MV, Muino A, Jardim JR, Valdivia G, Talamo C, Team P. Increased risk of exacerbation and hospitalization in subjects with an overlap phenotype: COPD-asthma. Chest. 2014;145:297–304.PubMedGoogle Scholar
  56. 56.
    Kitaguchi Y, Fujimoto K, Kubo K, Honda T. Characteristics of COPD phenotypes classified according to the findings of HRCT. Respir Med. 2006;100:1742–52.Google Scholar
  57. 57.
    Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med. 2003;168:1308–11.PubMedGoogle Scholar
  58. 58.
    Chalmers GW, MacLeod KJ, Thomson L, Little SA, McSharry C, Thomson NC. Smoking and airway inflammation in patients with mild asthma. Chest. 2001;120:1917–22.PubMedGoogle Scholar
  59. 59.
    Boulet LP, Lemiere C, Archambault F, Carrier G, Descary MC, Deschesnes F. Smoking and asthma: clinical and radiologic features, lung function, and airway inflammation. Chest. 2006;129:661–8.PubMedGoogle Scholar
  60. 60.
    Chapman KR. Chronic obstructive pulmonary disease: are women more susceptible than men? Clin Chest Med. 2004;25:331–41.PubMedGoogle Scholar
  61. 61.
    Birring SS, Brightling CE, Bradding P, Entwisle JJ, Vara DD, Grigg J, Wardlaw AJ, Pavord ID. Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study. Am J Respir Crit Care Med. 2002;166:1078–83.PubMedGoogle Scholar
  62. 62.
    Watson L, Vestbo J, Postma DS, Decramer M, Rennard S, Kiri VA, Vermeire PA, Soriano JB. Gender differences in the management and experience of chronic obstructive pulmonary disease. Respir Med. 2004;98:1207–13.PubMedGoogle Scholar
  63. 63.
    de Torres JP, Casanova C, Hernandez C, Abreu J, Aguirre-Jaime A, Celli BR. Gender and COPD in patients attending a pulmonary clinic. Chest. 2005;128:2012–6.PubMedGoogle Scholar
  64. 64.
    Martinez FJ, Curtis JL, Sciurba F, Mumford J, Giardino ND, Weinmann G, Kazerooni E, Murray S, Criner GJ, Sin DD, Hogg J, Ries AL, Han M, Fishman AP, Make B, Hoffman EA, Mohsenifar Z, Wise R, National Emphysema Treatment Trial Research G. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med. 2007;176:243–52.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Jennings JH, Digiovine B, Obeid D, Frank C. The association between depressive symptoms and acute exacerbations of COPD. Lung. 2009;187:128–35.PubMedGoogle Scholar
  66. 66.
    Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova H, Tal-Singer R, Miller B, Lomas DA, Agusti A, Macnee W, Calverley P, Rennard S, Wouters EF, Wedzicha JA, Evaluation of CLtIPSEI. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363:1128–38.Google Scholar
  67. 67.
    Tashkin D, Celli B, Kesten S, Lystig T, Decramer M. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Respir Med. 2010;104:1495–504.PubMedGoogle Scholar
  68. 68.
    Varkey AB. Chronic obstructive pulmonary disease in women: exploring gender differences. Curr Opin Pulm Med. 2004;10:98–103.PubMedGoogle Scholar
  69. 69.
    Hansell AL, Walk JA, Soriano JB. What do chronic obstructive pulmonary disease patients die from? A multiple cause coding analysis. Eur Respir J. 2003;22:809–14.PubMedGoogle Scholar
  70. 70.
    Sin DD, Wu L, Man SF. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest. 2005;127:1952–9.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Beaty TH, Newill CA, Cohen BH, Tockman MS, Bryant SH, Spurgeon HA. Effects of pulmonary function on mortality. J Chronic Dis. 1985;38:703–10.PubMedGoogle Scholar
  72. 72.
    Speizer FE, Fay ME, Dockery DW, Ferris BG Jr. Chronic obstructive pulmonary disease mortality in six U.S. cities. Am Rev Respir Dis. 1989;140:S49–55.PubMedGoogle Scholar
  73. 73.
    Hospers JJ, Postma DS, Rijcken B, Weiss ST, Schouten JP. Histamine airway hyper-responsiveness and mortality from chronic obstructive pulmonary disease: a cohort study. Lancet. 2000;356:1313–7.PubMedGoogle Scholar
  74. 74.
    Anthonisen NR, Connett JE, Enright PL, Manfreda J, Lung Health Study Research G. Hospitalizations and mortality in the lung health study. Am J Respir Crit Care Med. 2002;166:333–9.PubMedGoogle Scholar
  75. 75.
    Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–26.PubMedGoogle Scholar
  76. 76.
    Han MK, McLaughlin VV, Criner GJ, Martinez FJ. Pulmonary diseases and the heart. Circulation. 2007;116:2992–3005.PubMedGoogle Scholar
  77. 77.
    Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ. 2011;342:d2549.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Dransfield MT, Rowe SM, Johnson JE, Bailey WC, Gerald LB. Use of beta blockers and the risk of death in hospitalised patients with acute exacerbations of COPD. Thorax. 2008;63:301–5.PubMedGoogle Scholar
  79. 79.
    Rutten FH, Zuithoff NP, Hak E, Grobbee DE, Hoes AW. Beta-blockers may reduce mortality and risk of exacerbations in patients with chronic obstructive pulmonary disease. Arch Intern Med. 2010;170:880–7.PubMedGoogle Scholar
  80. 80.
    Soyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in COPD. Eur Respir J. 2007;29:279–83.PubMedGoogle Scholar
  81. 81.
    Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol. 2006;47:2554–60.PubMedGoogle Scholar
  82. 82.
    von Haehling S, Anker SD. Cachexia as a major underestimated and unmet medical need: facts and numbers. J Cachex Sarcopenia Muscle. 2010;1:1–5.Google Scholar
  83. 83.
    Gologanu D, Ionita D, Gartonea T, Stanescu C, Bogdan MA. Body composition in patients with chronic obstructive pulmonary disease. Maedica. 2014;9:25–32.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Landbo C, Prescott E, Lange P, Vestbo J, Almdal TP. Prognostic value of nutritional status in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160:1856–61.PubMedGoogle Scholar
  85. 85.
    Nishimura K, Izumi T, Tsukino M, Oga T. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest. 2002;121:1434–40.PubMedGoogle Scholar
  86. 86.
    Marquez-Martin E, Ramos PC, Lopez-Campos JL, Serrano Gotarredona Mdel P, Herrero SN, Aguilar RT, Cortes EB, Ruiz FO. Components of physical capacity in patients with chronic obstructive pulmonary disease: relationship with phenotypic expression. Int J Chron Obstruct Pulmon Dis. 2011;6:105–12.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Schols AM, Slangen J, Volovics L, Wouters EF. Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1791–7.PubMedGoogle Scholar
  88. 88.
    Vestbo J, Prescott E, Almdal T, Dahl M, Nordestgaard BG, Andersen T, Sorensen TI, Lange P. Body mass, fat-free body mass, and prognosis in patients with chronic obstructive pulmonary disease from a random population sample: findings from the Copenhagen City heart study. Am J Respir Crit Care Med. 2006;173:79–83.PubMedGoogle Scholar
  89. 89.
    Schols AM. Pulmonary cachexia. Int J Cardiol. 2002;85:101–10.PubMedGoogle Scholar
  90. 90.
    Engelen MP, Schols AM, Does JD, Wouters EF. Skeletal muscle weakness is associated with wasting of extremity fat-free mass but not with airflow obstruction in patients with chronic obstructive pulmonary disease. Am J Clin Nutr. 2000;71:733–8.PubMedGoogle Scholar
  91. 91.
    Mostert R, Goris A, Weling-Scheepers C, Wouters EF, Schols AM. Tissue depletion and health related quality of life in patients with chronic obstructive pulmonary disease. Respir Med. 2000;94:859–67.PubMedGoogle Scholar
  92. 92.
    Baarends EM, Schols AM, Mostert R, Wouters EF. Peak exercise response in relation to tissue depletion in patients with chronic obstructive pulmonary disease. Eur Respir J. 1997;10:2807–13.PubMedGoogle Scholar
  93. 93.
    Schols AM, Mostert R, Soeters PB, Wouters EF. Body composition and exercise performance in patients with chronic obstructive pulmonary disease. Thorax. 1991;46:695–9.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Sabino PG, Silva BM, Brunetto AF. Nutritional status is related to fat-free mass, exercise capacity and inspiratory strength in severe chronic obstructive pulmonary disease patients. Clinics (Sao Paulo). 2010;65:599–605.Google Scholar
  95. 95.
    Budweiser S, Meyer K, Jorres RA, Heinemann F, Wild PJ, Pfeifer M. Nutritional depletion and its relationship to respiratory impairment in patients with chronic respiratory failure due to COPD or restrictive thoracic diseases. Eur J Clin Nutr. 2008;62:436–43.PubMedGoogle Scholar
  96. 96.
    Ischaki E, Papatheodorou G, Gaki E, Papa I, Koulouris N, Loukides S. Body mass and fat-free mass indices in COPD: relation with variables expressing disease severity. Chest. 2007;132:164–9.PubMedGoogle Scholar
  97. 97.
    Franssen FM, Broekhuizen R, Janssen PP, Wouters EF, Schols AM. Effects of whole-body exercise training on body composition and functional capacity in normal-weight patients with COPD. Chest. 2004;125:2021–8.PubMedGoogle Scholar
  98. 98.
    Bon J, Fuhrman CR, Weissfeld JL, Duncan SR, Branch RA, Chang CC, Zhang Y, Leader JK, Gur D, Greenspan SL, Sciurba FC. Radiographic emphysema predicts low bone mineral density in a tobacco-exposed cohort. Am J Respir Crit Care Med. 2011;183:885–90.Google Scholar
  99. 99.
    Bolton CE, Ionescu AA, Shiels KM, Pettit RJ, Edwards PH, Stone MD, Nixon LS, Evans WD, Griffiths TL, Shale DJ. Associated loss of fat-free mass and bone mineral density in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2004;170:1286–93.PubMedGoogle Scholar
  100. 100.
    Nuti R, Siviero P, Maggi S, Guglielmi G, Caffarelli C, Crepaldi G, Gonnelli S. Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO study. Osteoporos Int. 2009;20:989–98.Google Scholar
  101. 101.
    Dam TT, Harrison S, Fink HA, Ramsdell J, Barrett-Connor E. Osteoporotic fractures in men research G. Bone mineral density and fractures in older men with chronic obstructive pulmonary disease or asthma. Osteoporos Int. 2010;21:1341–9.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Beauchamp MK, O’Hoski S, Goldstein RS, Brooks D. Effect of pulmonary rehabilitation on balance in persons with chronic obstructive pulmonary disease. Arch Phys Med Rehabil. 2010;91:1460–5.PubMedGoogle Scholar
  103. 103.
    Leone N, Courbon D, Thomas F, Bean K, Jego B, Leynaert B, Guize L, Zureik M. Lung function impairment and metabolic syndrome: the critical role of abdominal obesity. Am J Respir Crit Care Med. 2009;179:509–16.PubMedGoogle Scholar
  104. 104.
    Song Y, Klevak A, Manson JE, Buring JE, Liu S. Asthma, chronic obstructive pulmonary disease, and type 2 diabetes in the Women’s health study. Diabetes Res Clin Pract. 2010;90:365–71.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Lazarus R, Sparrow D, Weiss ST. Baseline ventilatory function predicts the development of higher levels of fasting insulin and fasting insulin resistance index: the normative aging study. Eur Respir J. 1998;12:641–5.PubMedGoogle Scholar
  106. 106.
    Suissa S, Kezouh A, Ernst P. Inhaled corticosteroids and the risks of diabetes onset and progression. Am J Med. 2010;123:1001–6.PubMedGoogle Scholar
  107. 107.
    O’Byrne PM, Rennard S, Gerstein H, Radner F, Peterson S, Lindberg B, Carlsson LG, Sin DD. Risk of new onset diabetes mellitus in patients with asthma or COPD taking inhaled corticosteroids. Respir Med. 2012;106:1487–93.PubMedGoogle Scholar
  108. 108.
    Han MK, Kazerooni EA, Lynch DA, Liu LX, Murray S, Curtis JL, Criner GJ, Kim V, Bowler RP, Hanania NA, Anzueto AR, Make BJ, Hokanson JE, Crapo JD, Silverman EK, Martinez FJ, Washko GR, Investigators CO. Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology. 2011;261:274–82.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Mokhlesi B, Morris AL, Huang CF, Curcio AJ, Barrett TA, Kamp DW. Increased prevalence of gastroesophageal reflux symptoms in patients with COPD. Chest. 2001;119:1043–8.PubMedGoogle Scholar
  110. 110.
    Terada K, Muro S, Sato S, Ohara T, Haruna A, Marumo S, Kinose D, Ogawa E, Hoshino Y, Niimi A, Terada T, Mishima M. Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation. Thorax. 2008;63:951–5.PubMedGoogle Scholar
  111. 111.
    Rascon-Aguilar IE, Pamer M, Wludyka P, Cury J, Vega KJ. Poorly treated or unrecognized GERD reduces quality of life in patients with COPD. Dig Dis Sci. 2011;56:1976–80.PubMedGoogle Scholar
  112. 112.
    Rascon-Aguilar IE, Pamer M, Wludyka P, Cury J, Coultas D, Lambiase LR, Nahman NS, Vega KJ. Role of gastroesophageal reflux symptoms in exacerbations of COPD. Chest. 2006;130:1096–101.PubMedGoogle Scholar
  113. 113.
    Martinez CH, Okajima Y, Murray S, Washko GR, Martinez FJ, Silverman EK, Lee JH, Regan EA, Crapo JD, Curtis JL, Hatabu H, Han MK, Investigators CO. Impact of self-reported gastroesophageal reflux disease in subjects from COPDGene cohort. Respir Res. 2014;15:62.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Sasaki T, Nakayama K, Yasuda H, Yoshida M, Asamura T, Ohrui T, Arai H, Araya J, Kuwano K, Yamaya M. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009;57:1453–7.PubMedGoogle Scholar
  115. 115.
    Simon-Tuval T, Scharf SM, Maimon N, Bernhard-Scharf BJ, Reuveni H, Tarasiuk A. Determinants of elevated healthcare utilization in patients with COPD. Respir Res. 2011;12:7.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328:1230–5.PubMedGoogle Scholar
  117. 117.
    Kinsman RA, Yaroush RA, Fernandez E, Dirks JF, Schocket M, Fukuhara J. Symptoms and experiences in chronic bronchitis and emphysema. Chest. 1983;83:755–61.PubMedGoogle Scholar
  118. 118.
    Weitzenblum E, Chaouat A, Kessler R, Canuet M. Overlap syndrome: obstructive sleep apnea in patients with chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5:237–41.PubMedGoogle Scholar
  119. 119.
    Marin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med. 2010;182:325–31.PubMedGoogle Scholar
  120. 120.
    Mermigkis C, Kopanakis A, Foldvary-Schaefer N, Golish J, Polychronopoulos V, Schiza S, Amfilochiou A, Siafakas N, Bouros D. Health-related quality of life in patients with obstructive sleep apnoea and chronic obstructive pulmonary disease (overlap syndrome). Int J Clin Pract. 2007;61:207–11.PubMedGoogle Scholar
  121. 121.
    Kunik ME, Roundy K, Veazey C, Souchek J, Richardson P, Wray NP, Stanley MA. Surprisingly high prevalence of anxiety and depression in chronic breathing disorders. Chest. 2005;127:1205–11.PubMedGoogle Scholar
  122. 122.
    Yohannes AM, Willgoss TG, Baldwin RC, Connolly MJ. Depression and anxiety in chronic heart failure and chronic obstructive pulmonary disease: prevalence, relevance, clinical implications and management principles. Int J Geriatr Psychiatry. 2010;25:1209–21.PubMedGoogle Scholar
  123. 123.
    Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manag. 2006;31:58–69.Google Scholar
  124. 124.
    Laurin C, Lavoie KL, Bacon SL, Dupuis G, Lacoste G, Cartier A, Labrecque M. Sex differences in the prevalence of psychiatric disorders and psychological distress in patients with COPD. Chest. 2007;132:148–55.PubMedGoogle Scholar
  125. 125.
    Hanania NA, Mullerova H, Locantore NW, Vestbo J, Watkins ML, Wouters EF, Rennard SI, Sharafkhaneh A, Evaluation of CLtIPSEsi. Determinants of depression in the ECLIPSE chronic obstructive pulmonary disease cohort. Am J Respir Crit Care Med. 2011;183:604–11.PubMedGoogle Scholar
  126. 126.
    Eisner MD, Blanc PD, Yelin EH, Katz PP, Sanchez G, Iribarren C, Omachi TA. Influence of anxiety on health outcomes in COPD. Thorax. 2010;65:229–34.PubMedPubMedCentralGoogle Scholar
  127. 127.
    Fan VS, Ramsey SD, Giardino ND, Make BJ, Emery CF, Diaz PT, Benditt JO, Mosenifar Z, McKenna R Jr, Curtis JL, Fishman AP, Martinez FJ, National Emphysema Treatment Trial Research G. Sex, depression, and risk of hospitalization and mortality in chronic obstructive pulmonary disease. Arch Intern Med. 2007;167:2345–53.PubMedGoogle Scholar
  128. 128.
    de Voogd JN, Wempe JB, Koeter GH, Postema K, van Sonderen E, Ranchor AV, Coyne JC, Sanderman R. Depressive symptoms as predictors of mortality in patients with COPD. Chest. 2009;135:619–25.PubMedGoogle Scholar
  129. 129.
    von Leupoldt A, Taube K, Lehmann K, Fritzsche A, Magnussen H. The impact of anxiety and depression on outcomes of pulmonary rehabilitation in patients with COPD. Chest. 2011;140:730–6.Google Scholar
  130. 130.
    Mahler DA, Ward J, Fierro-Carrion G, Waterman LA, Lentine TF, Mejia-Alfaro R, Baird JC. Development of self-administered versions of modified baseline and transition dyspnea indexes in COPD. COPD. 2004;1:165–72.PubMedGoogle Scholar
  131. 131.
    Jones PW. Health status measurement in chronic obstructive pulmonary disease. Thorax. 2001;56:880–7.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Brown CD, Benditt JO, Sciurba FC, Lee SM, Criner GJ, Mosenifar Z, Shade DM, Slivka WA, Wise RA, National emphysema Treatment Trial Research G. Exercise testing in severe emphysema: association with quality of life and lung function. COPD. 2008;5:117–24.PubMedGoogle Scholar
  133. 133.
    Wise RA. The value of forced expiratory volume in 1 second decline in the assessment of chronic obstructive pulmonary disease progression. Am J Med. 2006;119:4–11.PubMedGoogle Scholar
  134. 134.
    Devanarayan V, Scholand MB, Hoidal J, Leppert MF, Crackower MA, O’Neill GP, Gervais FG. Identification of distinct plasma biomarker signatures in patients with rapid and slow declining forms of COPD. COPD. 2010;7:51–8.PubMedGoogle Scholar
  135. 135.
    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;153:1802–11.PubMedGoogle Scholar
  136. 136.
    Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57:847–52.PubMedPubMedCentralGoogle Scholar
  137. 137.
    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;164:358–64.PubMedGoogle Scholar
  138. 138.
    Kanazawa H, Hirata K, Yoshikawa J. Accelerated decline of lung function in COPD patients with chronic hepatitis C virus infection: a preliminary study based on small numbers of patients. Chest. 2003;123:596–9.PubMedGoogle Scholar
  139. 139.
    Vergnenegre A, Pugnere N, Antonini MT, Arnaud M, Melloni B, Treves R, Bonnaud F. Airway obstruction and rheumatoid arthritis. Eur Respir J. 1997;10:1072–8.PubMedGoogle Scholar
  140. 140.
    Highland KB, Strange C, Heffner JE. Long-term effects of inhaled corticosteroids on FEV1 in patients with chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med. 2003;138:969–73.PubMedGoogle Scholar
  141. 141.
    Sutherland ER, Allmers H, Ayas NT, Venn AJ, Martin RJ. Inhaled corticosteroids reduce the progression of airflow limitation in chronic obstructive pulmonary disease: a meta-analysis. Thorax. 2003;58:937–41.PubMedPubMedCentralGoogle Scholar
  142. 142.
    Sandford AJ, Silverman EK. Chronic obstructive pulmonary disease. 1: susceptibility factors for COPD the genotype-environment interaction. Thorax. 2002;57:736–41.PubMedPubMedCentralGoogle Scholar
  143. 143.
    van Diemen CC, Postma DS, Vonk JM, Bruinenberg M, Schouten JP, Boezen HM. A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population. Am J Respir Crit Care Med. 2005;172:329–33.PubMedGoogle Scholar
  144. 144.
    Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M, Investigators US. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543–54.Google Scholar
  145. 145.
    Celli BR, Thomas NE, Anderson JA, Ferguson GT, Jenkins CR, Jones PW, Vestbo J, Knobil K, Yates JC, Calverley PM. Effect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study. Am J Respir Crit Care Med. 2008;178:332–8.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, Fukuchi Y, Jenkins C, Rodriguez-Roisin R, van Weel C, Zielinski J, Global Initiative for Chronic Obstructive Lung D. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176:532–55.PubMedGoogle Scholar
  147. 147.
    Han MK, Wise R, Mumford J, Sciurba F, Criner GJ, Curtis JL, Murray S, Sternberg A, Weinman G, Kazerooni E, Fishman AP, Make B, Hoffman EA, Mosenifar Z, Martinez FJ, Group NR. Prevalence and clinical correlates of bronchoreversibility in severe emphysema. Eur Respir J. 2010;35:1048–56.PubMedGoogle Scholar
  148. 148.
    Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60:925–31.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Donaldson GC, Wilkinson TM, Hurst JR, Perera WR, Wedzicha JA. Exacerbations and time spent outdoors in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;171:446–52.PubMedGoogle Scholar
  150. 150.
    Seemungal TA, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedzicha JA. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:1418–22.PubMedGoogle Scholar
  151. 151.
    Sullivan SD, Ramsey SD, Lee TA. The economic burden of COPD. Chest. 2000;117:5S–9S.PubMedGoogle Scholar
  152. 152.
    Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J, investigators T. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775–89.PubMedGoogle Scholar
  153. 153.
    Celli BR, MacNee W, Force AET. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932–46.PubMedGoogle Scholar
  154. 154.
    Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW. Bronchodilator reversibility testing in chronic obstructive pulmonary disease. Thorax. 2003;58:659–64.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Tashkin DP, Celli B, Decramer M, Liu D, Burkhart D, Cassino C, Kesten S. Bronchodilator responsiveness in patients with COPD. Eur Respir J. 2008;31:742–50.PubMedGoogle Scholar
  156. 156.
    Anthonisen NR, Wright EC. Bronchodilator response in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1986;133:814–9.PubMedGoogle Scholar
  157. 157.
    Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller MR, Navajas D, Pedersen OF, Wanger J. Interpretative strategies for lung function tests. Eur Respir J. 2005;26:948–68.Google Scholar
  158. 158.
    Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE, National Emphysema Treatment Trial Research G. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003;348:2059–73.Google Scholar
  159. 159.
    Anthonisen NR, Lindgren PG, Tashkin DP, Kanner RE, Scanlon PD, Connett JE, Lung Health Study Research G. Bronchodilator response in the lung health study over 11 yrs. Eur Respir J. 2005;26:45–51.PubMedGoogle Scholar
  160. 160.
    Dowson LJ, Guest PJ, Stockley RA. Longitudinal changes in physiological, radiological, and health status measurements in alpha(1)-antitrypsin deficiency and factors associated with decline. Am J Respir Crit Care Med. 2001;164:1805–9.PubMedGoogle Scholar
  161. 161.
    Kueppers F, Miller RD, Gordon H, Hepper NG, Offord K. Familial prevalence of chronic obstructive pulmonary disease in a matched pair study. Am J Med. 1977;63:336–42.PubMedGoogle Scholar
  162. 162.
    Beaty TH, Liang KY, Seerey S, Cohen BH. Robust inference for variance components models in families ascertained through probands: II. Analysis of spirometric measures. Genet Epidemiol. 1987;4:211–21.PubMedGoogle Scholar
  163. 163.
    Cohen BH, Ball WC Jr, Brashears S, Diamond EL, Kreiss P, Levy DA, Menkes HA, Permutt S, Tockman MS. Risk factors in chronic obstructive pulmonary disease (COPD). Am J Epidemiol. 1977;105:223–32.PubMedGoogle Scholar
  164. 164.
    Cohen BH. Chronic obstructive pulmonary disease: a challenge in genetic epidemiology. Am J Epidemiol. 1980;112:274–88.PubMedGoogle Scholar
  165. 165.
    Celedon JC, Speizer FE, Drazen JM, Weiss ST, Campbell EJ, Carey VJ, Reilly JJ, Ginns L, Silverman EK. Bronchodilator responsiveness and serum total IgE levels in families of probands with severe early-onset COPD. Eur Respir J. 1999;14:1009–14.PubMedGoogle Scholar
  166. 166.
    Silverman EK, Chapman HA, Drazen JM, Weiss ST, Rosner B, Campbell EJ, O’Donnell WJ, Reilly JJ, Ginns L, Mentzer S, Wain J, Speizer FE. Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease. Risk to relatives for airflow obstruction and chronic bronchitis. Am J Respir Crit Care Med. 1998;157:1770–8.PubMedPubMedCentralGoogle Scholar
  167. 167.
    Palmer LJ, Celedon JC, Chapman HA, Speizer FE, Weiss ST, Silverman EK. Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease. Hum Mol Genet. 2003;12:1199–210.PubMedGoogle Scholar
  168. 168.
    Casanova C, Cote C, de Torres JP, Aguirre-Jaime A, Marin JM, Pinto-Plata V, Celli BR. Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2005;171:591–7.PubMedGoogle Scholar
  169. 169.
    O’Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160:542–9.PubMedGoogle Scholar
  170. 170.
    Gelb AF, Hogg JC, Muller NL, Schein MJ, Kuei J, Tashkin DP, Epstein JD, Kollin J, Green RH, Zamel N, Elliott WM, Hadjiaghai L. Contribution of emphysema and small airways in COPD. Chest. 1996;109:353–9.PubMedGoogle Scholar
  171. 171.
    Owens GR, Rogers RM, Pennock BE, Levin D. The diffusing capacity as a predictor of arterial oxygen desaturation during exercise in patients with chronic obstructive pulmonary disease. N Engl J Med. 1984;310:1218–21.PubMedGoogle Scholar
  172. 172.
    Dillard TA, Piantadosi S, Rajagopal KR. Determinants of maximum exercise capacity in patients with chronic airflow obstruction. Chest. 1989;96:267–71.PubMedGoogle Scholar
  173. 173.
    Pinto-Plata V, Toso J, Lee K, Park D, Bilello J, Mullerova H, De Souza MM, Vessey R, Celli B. Profiling serum biomarkers in patients with COPD: associations with clinical parameters. Thorax. 2007;62:595–601.PubMedPubMedCentralGoogle Scholar
  174. 174.
    Hersh CP, Demeo DL, Lazarus R, Celedon JC, Raby BA, Benditt JO, Criner G, Make B, Martinez FJ, Scanlon PD, Sciurba FC, Utz JP, Reilly JJ, Silverman EK. Genetic association analysis of functional impairment in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173:977–84.PubMedPubMedCentralGoogle Scholar
  175. 175.
    Criner GJ, Cordova F, Sternberg AL, Martinez FJ. The National Emphysema Treatment Trial (NETT): part I: lessons learned about emphysema. Am J Respir Crit Care Med. 2011;184:763–70.PubMedGoogle Scholar
  176. 176.
    Cooper JD, Trulock EP, Triantafillou AN, Patterson GA, Pohl MS, Deloney PA, Sundaresan RS, Roper CL. Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg. 1995;109:106–16. discussion 116-109PubMedGoogle Scholar
  177. 177.
    Keenan RJ, Landreneau RJ, Sciurba FC, Ferson PF, Holbert JM, Brown ML, Fetterman LS, Bowers CM. Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg. 1996;111:308–15. discussion 315-306PubMedGoogle Scholar
  178. 178.
    McKenna RJ Jr, Brenner M, Gelb AF, Mullin M, Singh N, Peters H, Panzera J, Calmese J, Schein MJ. A randomized, prospective trial of stapled lung reduction versus laser bullectomy for diffuse emphysema. J Thorac Cardiovasc Surg. 1996;111:317–21. discussion 322PubMedGoogle Scholar
  179. 179.
    Sciurba FC, Rogers RM, Keenan RJ, Slivka WA, Gorcsan J 3rd, Ferson PF, Holbert JM, Brown ML, Landreneau RJ. Improvement in pulmonary function and elastic recoil after lung-reduction surgery for diffuse emphysema. N Engl J Med. 1996;334:1095–9.PubMedGoogle Scholar
  180. 180.
    Gelb AF, Zamel N, McKenna RJ Jr, Brenner M. Mechanism of short-term improvement in lung function after emphysema resection. Am J Respir Crit Care Med. 1996;154:945–51.PubMedGoogle Scholar
  181. 181.
    Dantzker DR, Scharf SM. Surgery to reduce lung volume. N Engl J Med. 1996;334:1128–9.PubMedGoogle Scholar
  182. 182.
    Weinmann GG, Chiang YP, Sheingold S. The National Emphysema Treatment Trial (NETT): a study in agency collaboration. Proc Am Thorac Soc. 2008;5:381–4.PubMedPubMedCentralGoogle Scholar
  183. 183.
    Naunheim KS, Wood DE, Mohsenifar Z, Sternberg AL, Criner GJ, DeCamp MM, Deschamps CC, Martinez FJ, Sciurba FC, Tonascia J, Fishman AP, National Emphysema Treatment Trial Research G. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg. 2006;82:431–43.PubMedGoogle Scholar
  184. 184.
    Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, Lomas DA, MacNee W, Miller BE, Silverman EK, Tal-Singer R, Wouters E, Rennard SI, Investigators E. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med. 2011;365:1184–92.PubMedGoogle Scholar
  185. 185.
    Nishimura M, Makita H, Nagai K, Konno S, Nasuhara Y, Hasegawa M, Shimizu K, Betsuyaku T, Ito YM, Fuke S, Igarashi T, Akiyama Y, Ogura S, Hokkaido CCSI. Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:44–52.Google Scholar
  186. 186.
    Zulueta JJ, Wisnivesky JP, Henschke CI, Yip R, Farooqi AO, McCauley DI, Chen M, Libby DM, Smith JP, Pasmantier MW, Yankelevitz DF. Emphysema scores predict death from COPD and lung cancer. Chest. 2012;141:1216–23.PubMedPubMedCentralGoogle Scholar
  187. 187.
    Haruna A, Muro S, Nakano Y, Ohara T, Hoshino Y, Ogawa E, Hirai T, Niimi A, Nishimura K, Chin K, Mishima M. CT scan findings of emphysema predict mortality in COPD. Chest. 2010;138:635–40.PubMedGoogle Scholar
  188. 188.
    Grydeland TB, Dirksen A, Coxson HO, Eagan TM, Thorsen E, Pillai SG, Sharma S, Eide GE, Gulsvik A, Bakke PS. Quantitative computed tomography measures of emphysema and airway wall thickness are related to respiratory symptoms. Am J Respir Crit Care Med. 2010;181:353–9.PubMedGoogle Scholar
  189. 189.
    Martinez-Garcia MA, de la Rosa CD, Soler-Cataluna JJ, Donat-Sanz Y, Serra PC, Lerma MA, Ballestin J, Sanchez IV, Selma Ferrer MJ, Dalfo AR, Valdecillos MB. Prognostic value of bronchiectasis in patients with moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;187:823–31.PubMedGoogle Scholar
  190. 190.
    Johannessen A, Skorge TD, Bottai M, Grydeland TB, Nilsen RM, Coxson H, Dirksen A, Omenaas E, Gulsvik A, Bakke P. Mortality by level of emphysema and airway wall thickness. Am J Respir Crit Care Med. 2013;187:602–8.Google Scholar
  191. 191.
    Han MK. Clinical correlations of computed tomography imaging in chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2013;10(Suppl):S131–7.PubMedGoogle Scholar
  192. 192.
    Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;364:709–21.PubMedGoogle Scholar
  193. 193.
    Jain N, Covar RA, Gleason MC, Newell JD Jr, Gelfand EW, Spahn JD. Quantitative computed tomography detects peripheral airway disease in asthmatic children. Pediatr Pulmonol. 2005;40:211–8.PubMedGoogle Scholar
  194. 194.
    Matsuoka S, Kurihara Y, Yagihashi K, Hoshino M, Watanabe N, Nakajima Y. Quantitative assessment of air trapping in chronic obstructive pulmonary disease using inspiratory and expiratory volumetric MDCT. AJR Am J Roentgenol. 2008;190:762–9.PubMedPubMedCentralGoogle Scholar
  195. 195.
    O’Donnell RA, Peebles C, Ward JA, Daraker A, Angco G, Broberg P, Pierrou S, Lund J, Holgate ST, Davies DE, Delany DJ, Wilson SJ, Djukanovic R. Relationship between peripheral airway dysfunction, airway obstruction, and neutrophilic inflammation in COPD. Thorax. 2004;59:837–42.PubMedPubMedCentralGoogle Scholar
  196. 196.
    Mets OM, Zanen P, Lammers JW, Isgum I, Gietema HA, van Ginneken B, Prokop M, de Jong PA. Early identification of small airways disease on lung cancer screening CT: comparison of current air trapping measures. Lung. 2012;190:629–33.PubMedGoogle Scholar
  197. 197.
    Lee YK, Oh YM, Lee JH, Kim EK, Lee JH, Kim N, Seo JB, Lee SD, Group KS. Quantitative assessment of emphysema, air trapping, and airway thickening on computed tomography. Lung. 2008;186:157–65.PubMedPubMedCentralGoogle Scholar
  198. 198.
    Matsuoka S, Washko GR, Yamashiro T, Estepar RS, Diaz A, Silverman EK, Hoffman E, Fessler HE, Criner GJ, Marchetti N, Scharf SM, Martinez FJ, Reilly JJ, Hatabu H, National Emphysema Treatment Trial Research G. Pulmonary hypertension and computed tomography measurement of small pulmonary vessels in severe emphysema. Am J Respir Crit Care Med. 2010;181:218–25.Google Scholar
  199. 199.
    Wells JM, Washko GR, Han MK, Abbas N, Nath H, Mamary AJ, Regan E, Bailey WC, Martinez FJ, Westfall E, Beaty TH, Curran-Everett D, Curtis JL, Hokanson JE, Lynch DA, Make BJ, Crapo JD, Silverman EK, Bowler RP, Dransfield MT, Investigators CO, Investigators ES. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367:913–21.PubMedPubMedCentralGoogle Scholar
  200. 200.
    Woodruff PG, Agusti A, Roche N, Singh D, Martinez FJ. Current concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management. Lancet. 2015;385:1789–98.PubMedPubMedCentralGoogle Scholar
  201. 201.
    Lotvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127:355–60.PubMedGoogle Scholar
  202. 202.
    Vrijheid M. The exposome: a new paradigm to study the impact of environment on health. Thorax. 2014;69:876–8.PubMedGoogle Scholar
  203. 203.
    Christenson SA, Steiling K, van den Berge M, Hijazi K, Hiemstra PS, Postma DS, Lenburg ME, Spira A, Woodruff PG. Asthma-COPD overlap. Clinical relevance of genomic signatures of type 2 inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;191:758–66.PubMedPubMedCentralGoogle Scholar
  204. 204.
    Bafadhel M, McKenna S, Terry S, Mistry V, Reid C, Haldar P, McCormick M, Haldar K, Kebadze T, Duvoix A, Lindblad K, Patel H, Rugman P, Dodson P, Jenkins M, Saunders M, Newbold P, Green RH, Venge P, Lomas DA, Barer MR, Johnston SL, Pavord ID, Brightling CE. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184:662–71.PubMedPubMedCentralGoogle Scholar
  205. 205.
    Siva R, Green RH, Brightling CE, Shelley M, Hargadon B, McKenna S, Monteiro W, Berry M, Parker D, Wardlaw AJ, Pavord ID. Eosinophilic airway inflammation and exacerbations of COPD: a randomised controlled trial. Eur Respir J. 2007;29:906–13.PubMedGoogle Scholar
  206. 206.
    Brightling CE, McKenna S, Hargadon B, Birring S, Green R, Siva R, Berry M, Parker D, Monteiro W, Pavord ID, Bradding P. Sputum eosinophilia and the short term response to inhaled mometasone in chronic obstructive pulmonary disease. Thorax. 2005;60:193–8.PubMedPubMedCentralGoogle Scholar
  207. 207.
    Brightling CE, Monteiro W, Ward R, Parker D, Morgan MD, Wardlaw AJ, Pavord ID. Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2000;356:1480–5.PubMedGoogle Scholar
  208. 208.
    Leigh R, Pizzichini MM, Morris MM, Maltais F, Hargreave FE, Pizzichini E. Stable COPD: predicting benefit from high-dose inhaled corticosteroid treatment. Eur Respir J. 2006;27:964–71.PubMedGoogle Scholar
  209. 209.
    Pizzichini E, Pizzichini MM, Gibson P, Parameswaran K, Gleich GJ, Berman L, Dolovich J, Hargreave FE. Sputum eosinophilia predicts benefit from prednisone in smokers with chronic obstructive bronchitis. Am J Respir Crit Care Med. 1998;158:1511–7.PubMedGoogle Scholar
  210. 210.
    Barker BL, Brightling CE. Phenotyping the heterogeneity of chronic obstructive pulmonary disease. Clin Sci (Lond). 2013;124:371–87.Google Scholar
  211. 211.
    Singh D, Kolsum U, Brightling CE, Locantore N, Agusti A, Tal-Singer R, investigators E. Eosinophilic inflammation in COPD: prevalence and clinical characteristics. Eur Respir J. 2014;44:1697–700.PubMedGoogle Scholar
  212. 212.
    Busse WW, Katial R, Gossage D, Sari S, Wang B, Kolbeck R, Coyle AJ, Koike M, Spitalny GL, Kiener PA, Geba GP, Molfino NA. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol. 2010;125:1237–44. e1232PubMedGoogle Scholar
  213. 213.
    Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, Busse WW, Wenzel S, Wu Y, Datta V, Kolbeck R, Molfino NA. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132:1086–96. e1085PubMedPubMedCentralGoogle Scholar
  214. 214.
    Brightling CE, Bleecker ER, Panettieri RA Jr, Bafadhel M, She D, Ward CK, Xu X, Birrell C, van der Merwe R. 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.PubMedPubMedCentralGoogle Scholar
  215. 215.
    Barbu C, Iordache M, Man MG. Inflammation in COPD: pathogenesis, local and systemic effects. Rom J Morphol Embryol. 2011;52:21–7.PubMedGoogle Scholar
  216. 216.
    Nussbaumer-Ochsner Y, Rabe KF. Systemic manifestations of COPD. Chest. 2011;139:165–73.PubMedGoogle Scholar
  217. 217.
    Andelid K, Tengvall S, Andersson A, Levanen B, Christenson K, Jirholt P, Ahren C, Qvarfordt I, Ekberg-Jansson A, Linden A. Systemic cytokine signaling via IL-17 in smokers with obstructive pulmonary disease: a link to bacterial colonization? Int J Chron Obstruct Pulmon Dis. 2015;10:689–702.Google Scholar
  218. 218.
    Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59:574–80.PubMedPubMedCentralGoogle Scholar
  219. 219.
    Agusti A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PM, Wouters E, Crim C, Yates JC, Silverman EK, Coxson HO, Bakke P, Mayer RJ, Celli B, Evaluation of CLtIPSEI. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7:e37483.PubMedPubMedCentralGoogle Scholar
  220. 220.
    Agusti A, Anto JM, Auffray C, Barbe F, Barreiro E, Dorca J, Escarrabill J, Faner R, Furlong LI, Garcia-Aymerich J, Gea J, Lindmark B, Monso E, Plaza V, Puhan MA, Roca J, Ruiz-Manzano J, Sampietro-Colom L, Sanz F, Serrano L, Sharpe J, Sibila O, Silverman EK, Sterk PJ, Sznajder JI. Personalized respiratory medicine: exploring the horizon, addressing the issues. Summary of a BRN-AJRCCM workshop held in Barcelona on June 12, 2014. Am J Respir Crit Care Med. 2015;191:391–401.PubMedPubMedCentralGoogle Scholar
  221. 221.
    Vanfleteren LE, Kocks JW, Stone IS, Breyer-Kohansal R, Greulich T, Lacedonia D, Buhl R, Fabbri LM, Pavord ID, Barnes N, Wouters EF, Agusti A. Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms? Thorax. 2014;69:72–9.PubMedGoogle Scholar
  222. 222.
    Loscalzo J, Kohane I, Barabasi AL. Human disease classification in the postgenomic era: a complex systems approach to human pathobiology. Mol Syst Biol. 2007;3:124.PubMedPubMedCentralGoogle Scholar
  223. 223.
    Burgel PR, Paillasseur JL, Caillaud D, Tillie-Leblond I, Chanez P, Escamilla R, Court-Fortune I, Perez T, Carre P, Roche N, Initiatives BSC. Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur Respir J. 2010;36:531–9.PubMedGoogle Scholar
  224. 224.
    Weatherall M, Travers J, Shirtcliffe PM, Marsh SE, Williams MV, Nowitz MR, Aldington S, Beasley R. Distinct clinical phenotypes of airways disease defined by cluster analysis. Eur Respir J. 2009;34:812–8.PubMedGoogle Scholar
  225. 225.
    Paoletti M, Camiciottoli G, Meoni E, Bigazzi F, Cestelli L, Pistolesi M, Marchesi C. Explorative data analysis techniques and unsupervised clustering methods to support clinical assessment of Chronic Obstructive Pulmonary Disease (COPD) phenotypes. J Biomed Inform. 2009;42:1013–21.PubMedGoogle Scholar
  226. 226.
    Cho MH, Washko GR, Hoffmann TJ, Criner GJ, Hoffman EA, Martinez FJ, Laird N, Reilly JJ, Silverman EK. Cluster analysis in severe emphysema subjects using phenotype and genotype data: an exploratory investigation. Respir Res. 2010;11:30.PubMedPubMedCentralGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  1. 1.Division of Pulmonary and Critical CareUniversity of MichiganAnn ArborUSA

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