Advertisement

Biomarkers in chronic obstructive pulmonary disease

  • Sharon R. Rosenberg
    Affiliations
    Asthma and COPD Program, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
    Search for articles by this author
  • Ravi Kalhan
    Correspondence
    Reprint requests: Ravi Kalhan, MD, MS, Asthma and COPD Program, Northwestern University Feinberg School of Medicine, 676 N St Clair Street, #14-047, Chicago, IL 60611.
    Affiliations
    Asthma and COPD Program, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
    Search for articles by this author
Published:February 10, 2012DOI:https://doi.org/10.1016/j.trsl.2012.01.019
      Chronic obstructive pulmonary disease (COPD) is a complex disease with multiple phenotypes that cannot be identified through measurement of lung function alone. The importance of COPD risk assessment, phenotype identification, and diagnosis of exacerbation magnify the need for validated biomarkers in COPD. A large number of potential biomarkers have already been assessed and some appear promising, in particular fibrinogen, which is likely to be the first COPD biomarker presented to the Food and Drug Administration for qualification in the drug approval process. Blood fibrinogen and c-reactive protein (CRP) have been associated with the presence of COPD and, in some instances, future risk of developing COPD in targeted populations. Sputum neutrophil counts have been used preliminarily as biomarkers of favorable response to therapy in COPD, but use in clinical settings may be limited. Other potential blood biomarkers include pulmonary and activation-regulated chemokine (PARC/CCL-18) and the clara cell secretory protein 16 (CC-16). Integrative indices, such as the BODE index, provide a framework to determine prognosis, predict outcome, and may be responsive to therapeutic interventions. Computed tomography provides a means to assess phenotypes and identify the relative extents of small airways disease and emphysema, which themselves may inform prognosis and therapeutic decision making. Fibrinogen and other markers of systemic inflammation are elevated in the context of acute COPD exacerbations and may also identify those at risk of accelerated lung function decline and hospitalization. So far, no single biomarker in COPD warrants wide acceptance emphasizing the need for future investigation of biomarkers in large-scale longitudinal studies.

      Abbreviations:

      AECOPD (acute exacerbations of COPD), BODE (body mass index, airflow obstruction, dyspnea and exercise capacity), CARDIA (coronary artery risk development in young adults), CC-16 (clara cell secretory protein 16), COPD (chronic obstructive pulmonary disease), CRP (c-reactive protein), DLCO (diffusing capacity of the lung for carbon monoxide), ECLIPSE (evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), FEV1 (forced expiratory volume in 1 second), FVC (forced vital capacity), MRC (medical research council), PARC/CCL-18 (pulmonary and activation regulated chemokine), SAA (serum amyloid A), SPD (surfactant protein D)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Kochanek K, Xu J, S. M, Minino A, H. K. Deaths: preliminary data for 2009. National Center for Health Statistics, Hyattsville, MD, 2011.

      2. NHLBI Morbidity and Mortality Chartbook. Available at: http://www.nhlbi.nih.gov/resources/docs/cht-bookhtm Accessed August 26, 2011.

        • Mathers C.D.
        • Loncar D.
        Projections of global mortality and burden of disease from 2002 to 2030.
        PLoS Med. 2006; 3: e442
        • Celli B.R.
        • MacNee W.
        • Agusti A.
        • et al.
        Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.
        Eur Respir J. 2004; 23: 932-946
        • Rabe K.F.
        • Hurd S.
        • Anzueto A.
        • et al.
        Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
        Am J Respir Crit Care Med. 2007; 176: 532-555
        • Antonelli-Incalzi R.
        • Imperiale C.
        • Bellia V.
        • et al.
        Do GOLD stages of COPD severity really correspond to differences in health status?.
        Eur Respir J. 2003; 22: 444-449
        • Cooper C.B.
        The connection between chronic obstructive pulmonary disease symptoms and hyperinflation and its impact on exercise and function.
        Am J Med. 2006; 119: 21-31
        • Atkinson Jr, A.J.
        • Colburn W.A.
        • Victor G.
        • et al.
        Biomarkers and surrogate endpoints: preferred definitions and conceptual framework.
        Clin Pharmacol Ther. 2001; 69: 89-95
        • Vestbo J.
        • Rennard S.
        Chronic obstructive pulmonary disease biomarker(s) for disease activity needed–urgently.
        Am J Respir Crit Care Med. 2010; 182: 863-864
        • Fabbri L.M.
        • Luppi F.
        • Beghe B.
        • Rabe K.F.
        Complex chronic comorbidities of COPD.
        Eur Respir J. 2008; 31: 204-212
        • Han M.K.
        • Agusti A.
        • Calverley P.M.
        • et al.
        COPD Phenotypes: the future of COPD.
        Am J Respir Crit Care Med. 2010; 182: 598-604
        • Agusti A.
        • Sobradillo P.
        • Celli B.
        Addressing the complexity of chronic obstructive pulmonary disease: from phenotypes and biomarkers to scale-free networks, systems biology, and P4 medicine.
        Am J Respir Crit Care Med. 2011; 183: 1129-1137
        • Schols A.M.
        • Slangen J.
        • Volovics L.
        • Wouters E.F.
        Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 1998; 157: 1791-1797
        • Ries A.L.
        • Kaplan R.M.
        • Limberg T.M.
        • Prewitt L.M.
        Effects of pulmonary rehabilitation on physiologic and psychosocial outcomes in patients with chronic obstructive pulmonary disease.
        Ann Intern Med. 1995; 122: 823-832
        • Hurst J.R.
        • Vestbo J.
        • Anzueto A.
        • et al.
        Susceptibility to exacerbation in chronic obstructive pulmonary disease.
        N Engl J Med. 2010; 363: 1128-1138
        • Calverley P.M.A.
        • Anderson J.A.
        • Celli B.
        • et al.
        Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease.
        N Engl J Med. 2007; 356: 775-789
        • Tashkin D.P.
        • Celli B.
        • Senn S.
        • et al.
        A 4-year trial of tiotropium in chronic obstructive pulmonary disease.
        N Engl J Med. 2008; 359: 1543-1554
        • Rennard S.I.
        • Tashkin D.P.
        • McElhattan J.
        • et al.
        Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial.
        Drugs. 2009; 69: 549-565
        • Hogg J.C.
        Pathophysiology of airflow limitation in chronic obstructive pulmonary disease.
        Lancet. 2004; 364: 709-721
        • Martinez F.J.
        • Curtis J.L.
        • Sciurba F.
        • et al.
        Sex differences in severe pulmonary emphysema.
        Am J Respir Crit Care Med. 2007; 176: 243-252
        • Gosselink J.V.
        • Hayashi S.
        • Elliott W.M.
        • et al.
        Differential expression of tissue repair genes in the pathogenesis of chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2010; 181: 1329-1335
        • Fishman A.
        • Martinez F.
        • Naunheim K.
        • et al.
        A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema.
        N Engl J Med. 2003; 348: 2059-2073
        • Coxson H.O.
        • Mayo J.
        • Lam S.
        • Santyr G.
        • Parraga G.
        • Sin D.D.
        New and current clinical imaging techniques to study chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2009; 180: 588-597
        • Anzueto A.
        Impact of exacerbations on COPD.
        Eur Respir Rev. 2010; 19: 113-118
        • Donaldson G.C.
        • Wedzicha J.A.
        COPD exacerbations. 1: Epidemiology.
        Thorax. 2006; 61: 164-168
        • Wedzicha J.A.
        • Calverley P.M.
        • Seemungal T.A.
        • Hagan G.
        • Ansari Z.
        • Stockley R.A.
        The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.
        Am J Respir Crit Care Med. 2008; 177: 19-26
        • Wilkinson T.M.A.
        • Donaldson G.C.
        • Hurst J.R.
        • Seemungal T.A.R.
        • Wedzicha J.A.
        Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2004; 169: 1298-1303
        • Kalhan R.
        • Arynchyn A.
        • Colangelo L.A.
        • Dransfield M.T.
        • Gerald L.B.
        • Smith L.J.
        Lung function in young adults predicts airflow obstruction 20 years later.
        Am J Med. 2010; 123 (468 e1-7)
        • Zeiger R.S.
        • Dawson C.
        • Weiss S.
        Relationships between duration of asthma and asthma severity among children in the Childhood Asthma Management Program (CAMP).
        J Allergy Clin Immunol. 1999; 103: 376-387
        • Hancox R.J.
        • Poulton R.
        • Greene J.M.
        • et al.
        Systemic inflammation and lung function in young adults.
        Thorax. 2007; 62: 1064-1068
        • Aronson D.
        • Roterman I.
        • Yigla M.
        • et al.
        Inverse association between pulmonary function and C-reactive protein in apparently healthy subjects.
        Am J Respir Crit Care Med. 2006; 174: 626-632
        • Mannino D.M.
        • Ford E.S.
        • Redd S.C.
        Obstructive and restrictive lung disease and markers of inflammation: data from the Third National Health and Nutrition Examination.
        Am J Med. 2003; 114: 758-762
        • van Durme Y.M.T.A.
        • Verhamme K.M.C.
        • Aarnoudse A.-J.L.H.J.
        • et al.
        C-reactive protein levels, haplotypes, and the risk of incident chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2009; 179: 375-382
        • Engstrom G.
        • Segelstorm N.
        • Ekberg-Aronsson M.
        • Nilsson P.M.
        • Lindgarde F.
        • Lofdahl C.G.
        Plasma markers of inflammation and incidence of hospitalisations for COPD: results from a population-based cohort study.
        Thorax. 2009; 64: 211-215
        • Kalhan R.
        • Tran B.T.
        • Colangelo L.A.
        • et al.
        Systemic inflammation in young adults is associated with abnormal lung function in middle age.
        PLoS ONE. 2010; 5: e11431
        • Gan W.Q.
        • Man S.F.
        • Sin D.D.
        The interactions between cigarette smoking and reduced lung function on systemic inflammation.
        Chest. 2005; 127: 558-564
        • Walter R.E.
        • Wilk J.B.
        • Larson M.G.
        • et al.
        Systemic Inflammation and COPD: The Framingham Heart Study.
        Chest. 2008; 133: 19-25
        • Sin D.D.
        • Man S.F.
        Why are patients with chronic obstructive pulmonary disease at increased risk of cardiovascular diseases? The potential role of systemic inflammation in chronic obstructive pulmonary disease.
        Circulation. 2003; 107: 1514-1519
        • Dahl M.
        • Tybjaerg-Hansen A.
        • Vestbo J.
        • Lange P.
        • Nordestgaard B.G.
        Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2001; 164: 1008-1011
        • Engstrom G.
        • Lind P.
        • Hedblad B.
        • et al.
        Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins.
        Circulation. 2002; 106: 2555-2560
        • Tran B.
        • Kalhan R.
        The emerging role of systemic inflammation in chronic obstructive pulmonary disease.
        Clin Pulm Med. 2008; 15: 55-62
        • Cowburn A.S.
        • Condliffe A.M.
        • Farahi N.
        • Summers C.
        • Chilvers E.R.
        Advances in neutrophil biology: clinical implications.
        Chest. 2008; 134: 606-612
        • O’Donnell D.E.
        • Voduc N.
        • Fitzpatrick M.
        • Webb K.A.
        Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease.
        Eur Respir J. 2004; 24: 86-94
        • Perng D.W.
        • Huang H.Y.
        • Chen H.M.
        • Lee Y.C.
        • Perng R.P.
        Characteristics of airway inflammation and bronchodilator reversibility in COPD: a potential guide to treatment.
        Chest. 2004; 126: 375-381
        • Willemse B.W.
        • ten Hacken N.H.
        • Rutgers B.
        • Lesman-Leegte I.G.
        • Postma D.S.
        • Timens W.
        Effect of 1-year smoking cessation on airway inflammation in COPD and asymptomatic smokers.
        Eur Respir J. 2005; 26: 835-845
        • Barnes N.C.
        • Qiu Y.S.
        • Pavord I.D.
        • et al.
        Anti-inflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease.
        Am J Respir Crit Care Med. 2006; 173: 736-743
        • Lapperre T.S.
        • Snoeck-Stroband J.B.
        • Gosman M.M.
        • et al.
        Effect of fluticasone with and without salmeterol on pulmonary outcomes in chronic obstructive pulmonary disease: a randomized trial.
        Ann Intern Med. 2009; 151: 517-527
        • He Z.Y.
        • Ou L.M.
        • Zhang J.Q.
        • et al.
        Effect of 6 months of erythromycin treatment on inflammatory cells in induced sputum and exacerbations in chronic obstructive pulmonary disease.
        Respiration. 2010; 80: 445-452
        • Seemungal T.A.
        • Wilkinson T.M.
        • Hurst J.R.
        • Perera W.R.
        • Sapsford R.J.
        • Wedzicha J.A.
        Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations.
        Am J Respir Crit Care Med. 2008; 178: 1139-1147
        • Ford P.A.
        • Durham A.L.
        • Russell R.E.
        • Gordon F.
        • Adcock I.M.
        • Barnes P.J.
        Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD.
        Chest. 2010; 137: 1338-1344
        • Kanehara M.
        • Yokoyama A.
        • Tomoda Y.
        • et al.
        Anti-inflammatory effects and clinical efficacy of theophylline and tulobuterol in mild-to-moderate chronic obstructive pulmonary disease.
        Pulm Pharmacol Ther. 2008; 21: 874-878
        • Grootendorst D.C.
        • Gauw S.A.
        • Verhoosel R.M.
        • et al.
        Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD.
        Thorax. 2007; 62: 1081-1087
        • Sin D.D.
        • Miller B.E.
        • 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: 1187-1192
        • Broeckaert F.
        • Bernard A.
        Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker.
        Clin Exp Allergy. 2000; 30: 469-475
        • Lakind J.S.
        • Holgate S.T.
        • Ownby D.R.
        • et al.
        A critical review of the use of Clara cell secretory protein (CC16) as a biomarker of acute or chronic pulmonary effects.
        Biomarkers. 2007; 12: 445-467
        • Alexis N.E.
        • Lay J.C.
        • Haczku A.
        • et al.
        Fluticasone propionate protects against ozone-induced airway inflammation and modified immune cell activation markers in healthy volunteers.
        Environ Health Perspect. 2008; 116: 799-805
        • Vestbo J.
        • Edwards L.D.
        • Scanlon P.D.
        • et al.
        Changes in forced expiratory volume in 1 second over time in COPD.
        N Engl J Med. 2011; 365: 1184-1192
        • Ma S.
        • Lin Y.Y.
        • Tartell L.
        • Turino G.M.
        The effect of tiotropium therapy on markers of elastin degradation in COPD.
        Respir Res. 2009; 10: 12
        • Lindberg C.A.
        • Engstrom G.
        • Gerhardsson de Verdier M.
        • et al.
        Total desmosines in plasma and urine correlate with lung function.
        Eur Respir J. 2011; ([In press])
        • Stoller J.K.
        • Rouhani F.
        • Brantly M.
        • et al.
        Biochemical efficacy and safety of a new pooled human plasma α(1)-antitrypsin.
        Respitin. Chest. 2002; 122: 66-74
        • Pinto-Plata V.
        • Toso J.
        • Lee K.
        • et al.
        Profiling serum biomarkers in patients with COPD: associations with clinical parameters.
        Thorax. 2007; 62: 595-601
        • Wedzicha J.A.
        • Seemungal T.A.
        • MacCallum P.K.
        • et al.
        Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels.
        Thromb Haemost. 2000; 84: 210-215
        • Hurst J.R.
        • Perera W.R.
        • Wilkinson T.M.A.
        • Donaldson G.C.
        • Wedzicha J.A.
        Systemic and upper and lower airway inflammation at exacerbation of chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2006; 173: 71-78
        • Hurst J.R.
        • Donaldson G.C.
        • Perera W.R.
        • et al.
        Use of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2006; 174: 867-874
        • Perera W.R.
        • Hurst J.R.
        • Wilkinson T.M.
        • et al.
        Inflammatory changes, recovery and recurrence at COPD exacerbation.
        Eur Respir J. 2007; 29: 527-534
        • Seemungal T.
        • Harper-Owen R.
        • Bhowmik A.
        • et al.
        Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2001; 164: 1618-1623
        • Groenewegen K.H.
        • Postma D.S.
        • Hop W.C.
        • Wielders P.L.
        • Schlosser N.J.
        • Wouters E.F.
        Increased systemic inflammation is a risk factor for COPD exacerbations.
        Chest. 2008; 133: 350-357
        • Dev D.
        • Wallace E.
        • Sankaran R.
        • et al.
        Value of C-reactive protein measurements in exacerbations of chronic obstructive pulmonary disease.
        Respir Med. 1998; 92: 664-667
        • Dentener M.A.
        • Creutzberg E.C.
        • Schols A.M.
        • et al.
        Systemic anti-inflammatory mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of exacerbations.
        Thorax. 2001; 56: 721-726
        • Donaldson G.C.
        • Seemungal T.
        • Bhowmik A.
        • Wedzicha J.A.
        Relationship between exacerbation frequencly and lung function decline in chronic obstructive pulmonary disease.
        Thorax. 2002; 57: 847-852
        • Seemungal T.A.
        • Donaldson G.C.
        • Paul E.A.
        • Bestall J.C.
        • Jeffries D.J.
        • Wedzicha J.A.
        Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 1998; 157: 1418-1422
        • Soler-Cataluna J.J.
        • Martinez-Garcia M.A.
        • Roman Sanchez P.
        • Salcedo E.
        • Navarro M.
        • Ochando R.
        Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.
        Thorax. 2005; 60: 925-931
        • Donaldson G.C.
        • Seemungal T.A.R.
        • Patel I.S.
        • et al.
        Airway and systemic inflammation and decline in lung function in patients with COPD.
        Chest. 2005; 128: 1995-2004
        • Bozinovski S.
        • Hutchinson A.
        • Thompson M.
        • et al.
        Serum amyloid a is a biomarker of acute exacerbations of chronic obstructive pulmonary disease.
        Am J Respir Crit Care Med. 2008; 177: 269-278
        • Stolz D.
        • Christ-Crain M.
        • Morgenthaler N.G.
        • et al.
        Copeptin, C-reactive protein, and procalcitonin as prognostic biomarkers in acute exacerbation of COPD.
        Chest. 2007; 131: 1058-1067
        • Lomas D.A.
        • Silverman E.K.
        • Edwards L.D.
        • Miller B.E.
        • Coxson H.O.
        • Tal-Singer R.
        Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort.
        Thorax. 2008; 63: 1058-1063
        • Lomas D.A.
        • Silverman E.K.
        • Edwards L.D.
        • et al.
        Serum surfactant protein D is steroid sensitive and associated with exacerbations of COPD.
        Eur Respir J. 2009; 34: 95-102
        • Celli B.R.
        • Cote C.G.
        • Marin J.M.
        • et al.
        The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease.
        N Engl J Med. 2004; 350: 1005-1012
        • Ong K.-C.
        • Earnest A.
        • Lu S.-J.
        A Multidimensional grading system (BODE index) as predictor of hospitalization for COPD.
        Chest. 2005; 128: 3810-3816
        • Imfeld S.
        • Bloch K.E.
        • Weder W.
        • Russi E.W.
        The BODE index after lung volume reduction surgery correlates with survival.
        Chest. 2006; 129: 873-878
        • Cote C.G.
        • Celli B.R.
        Pulmonary rehabilitation and the BODE index in COPD.
        Eur Respir J. 2005; 26: 630-636
        • Pompeo E.
        • Mineo T.C.
        Two-year improvement in multidimensional body mass index, airflow obstruction, dyspnea, and exercise capacity index after nonresectional lung volume reduction surgery in awake patients.
        Ann Thorac Surg. 2007; 84 (discussion 9): 1862-1869
        • Puhan M.A.
        • 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: 704-711
        • Jones R.C.
        • Donaldson G.C.
        • Chavannes N.H.
        • 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: 1189-1195
        • Liu S.F.
        • Chin C.H.
        • Wang C.C.
        • Lin M.C.
        Correlation between serum biomarkers and BODE index in patients with stable COPD.
        Respirology (Carlton, Vic). 2009; 14: 999-1004
        • Han M.K.
        • Bartholmai B.
        • Liu L.X.
        • et al.
        Clinical significance of radiologic characterizations in COPD.
        COPD. 2009; 6: 459-467
        • Grydeland T.B.
        • Dirksen A.
        • Coxson H.O.
        • et al.
        Quantitative computed tomography measures of emphysema and airway wall thickness are related to respiratory symptoms.
        Am J Respir Crit Care Med. 2010; 181: 353-359
        • Diaz A.A.
        • Valim C.
        • Yamashiro T.
        • et al.
        Airway count and emphysema assessed by chest CT imaging predicts clinical outcome in smokers.
        Chest. 2010; 138: 880-887
        • Diaz A.A.
        • Come C.E.
        • Ross J.C.
        • et al.
        Association between airway caliber changes with lung inflation and emphysema assessed by volumetric CT in subjects with COPD.
        Chest. 2011; ([In press])
        • Han M.K.
        • Wise R.
        • Mumford J.
        • et al.
        Prevalence and clinical correlates of bronchoreversibility in severe emphysema.
        Eur Respir J. 2010; 35: 1048-1056
        • Bignon J.
        • Khoury F.
        • Even P.
        • Andre J.
        • Brouet G.
        Morphometric study in chronic obstructive bronchopulmonary disease. Pathologic, clinical, and physiologic correlations.
        The American review of respiratory disease. 1969; 99: 669-695
        • Matsuba K.
        • Thurlbeck W.M.
        The number and dimensions of small airways in emphysematous lungs.
        Am J Pathol. 1972; 67: 265-275
        • McDonough J.E.
        • Yuan R.
        • Suzuki M.
        • et al.
        Small-airway obstruction and emphysema in chronic obstructive pulmonary disease.
        N Engl J Med. 2011; 365: 1567-1575
        • Nakano Y.
        • Muro S.
        • Sakai H.
        • et al.
        Computed tomographic measurements of airway dimensions and emphysema in smokers. Correlation with lung function.
        Am J Respir Crit Care Med. 2000; 162: 1102-1108
        • Ohara T.
        • Hirai T.
        • Muro S.
        • et al.
        Relationship between pulmonary emphysema and osteoporosis assessed by CT in patients with COPD.
        Chest. 2008; 134: 1244-1249
        • Bon J.
        • Fuhrman C.R.
        • Weissfeld J.L.
        • et al.
        Radiographic emphysema predicts low bone mineral density in a tobacco-exposed cohort.
        Am J Respir Crit Care Med. 2011; 183: 885-890
        • Boschetto P.
        • Miniati M.
        • Miotto D.
        • et al.
        Predominant emphysema phenotype in chronic obstructive pulmonary.
        Eur Respir J. 2003; 21: 450-454
        • Damiano V.V.
        • Tsang A.
        • Kucich U.
        • et al.
        Immunolocalization of elastase in human emphysematous lungs.
        J Clin Invest. 1986; 78: 482-493
        • Haruna A.
        • Muro S.
        • Nakano Y.
        • et al.
        CT scan findings of emphysema predict mortality in COPD.
        Chest. 2010; 138: 635-640
        • Dawkins P.A.
        • Dowson L.J.
        • Guest P.J.
        • Stockley R.A.
        Predictors of mortality in α1-antitrypsin deficiency.
        Thorax. 2003; 58: 1020-1026
        • Martinez F.J.
        • Foster G.
        • Curtis J.L.
        • et al.
        Predictors of mortality in patients with emphysema and severe airflow obstruction.
        Am J Respir Crit Care Med. 2006; 173: 1326-1334
        • Bon J.M.
        • Leader J.K.
        • Weissfeld J.L.
        • et al.
        The influence of radiographic phenotype and smoking status on peripheral blood biomarker patterns in chronic obstructive pulmonary disease.
        PLoS ONE. 2009; 4: e6865
        • Matsuoka S.
        • Yamashiro T.
        • Diaz A.
        • et al.
        The relationship between small pulmonary vascular alteration and aortic atherosclerosis in chronic obstructive pulmonary disease: quantitative CT analysis.
        Acad Radiol. 2011; 18: 40-46
        • Barr R.G.
        • Bluemke D.A.
        • Ahmed F.S.
        • et al.
        Percent emphysema, airflow obstruction, and impaired left ventricular filling.
        N Engl J Med. 2010; 362: 217-227