Treatable Traits in COPD – A Proposed Approach

References

• Agusti A. The path to personalised medicine in COPD. Thorax. 2014;69(9):857–864. doi:10.1136/thoraxjnl-2014-205507
   PubMed Web of Science ®Google Scholar
• Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med. 2017;195(5):557–582. doi:10.1164/rccm.201701-0218PP
   PubMed Web of Science ®Google Scholar
• Pauwels R. Global initiative for chronic obstructive lung diseases (GOLD): time to act. Eur Respir J. 2001;18(6):901–902. doi:10.1183/09031936.01.0027401
   PubMed Web of Science ®Google Scholar
• Global Initiative for Chronic Obstructive Lung Disease - GOLD. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease; 2021.
   Google Scholar
• Zatloukal J, Brat K, Neumannova K, et al. Chronic obstructive pulmonary disease - diagnosis and management of stable disease; a personalized approach to care, using the treatable traits concept based on clinical phenotypes. Position paper of the Czech Pneumological and Phthisiological Society. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2020;164(4):325–356. doi:10.5507/bp.2020.056
   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. doi:10.7326/0003-4819-142-4-200502150-00005
   PubMed Web of Science ®Google Scholar
• Cranston JM, Crockett AJ, Moss JR, Alpers JH. Domiciliary oxygen for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;4:CD001744. doi:10.1002/14651858.CD001744.pub2
   Web of Science ®Google Scholar
• 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(21):2059–2073. doi:10.1056/NEJMoa030287
   PubMed Web of Science ®Google Scholar
• Lipson DA, Criner GJ, Lomas DA. Single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018;379(6):592–593. doi:10.1056/NEJMc1807380
   PubMedGoogle Scholar
• Chapman KR, Burdon JGW, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360–368. doi:10.1016/S0140-6736(15)60860-1
   PubMed Web of Science ®Google Scholar
• Rahaghi FF, Monk R, Ramakrishnan V, Beiko T, Strange C. Alpha-1 antitrypsin augmentation therapy improves survival in severely deficient patients with predicted FEV1 between 10% and 60%: a retrospective analysis of the NHLBI alpha-1 antitrypsin deficiency registry. Int J Chron Obstruct Pulmon Dis. 2020;15:3193–3199. doi:10.2147/COPD.S263725
   PubMed Web of Science ®Google Scholar
• Vock DM, Durheim MT, Tsuang WM, et al. The survival benefit of lung transplantation in the modern era of lung allocation. Ann Am Thorac Soc. 2017;14:172–181. doi:10.1513/AnnalsATS.201606-507OC
   PubMed Web of Science ®Google Scholar
• Agustí A, Celli B, Faner R. What does endotyping mean for treatment in chronic obstructive pulmonary disease? Lancet. 2017;390(10098):980–987. doi:10.1016/S0140-6736(17)32136-0
   PubMed Web of Science ®Google Scholar
• Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J. 2016;47(2):410–419. doi:10.1183/13993003.01359-2015
   PubMed Web of Science ®Google Scholar
• Agustí A, Bafadhel M, Beasley R, et al. Precision medicine in airway diseases: moving to clinical practice. Eur Respir J. 2017;50(4):1701655. doi:10.1183/13993003.01655-2017
   PubMed Web of Science ®Google Scholar
• Han MK, Agusti A, Calverley PM, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010;182(5):598–604. doi:10.1164/rccm.200912-1843CC
   PubMed Web of Science ®Google Scholar
• Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662–671. doi:10.1164/rccm.201104-0597OC
   PubMed Web of Science ®Google Scholar
• McDonald VM, Fingleton J, Agusti A, et al. Treatable traits: a new paradigm for 21st century management of chronic airway diseases: Treatable Traits Down Under International Workshop report. Eur Respir J. 2019;53:5. doi:10.1183/13993003.02058-2018
   Web of Science ®Google Scholar
• Pérez de Llano L, Miravitlles M, Golpe R, et al. A proposed approach to chronic airway disease (CAD) using therapeutic goals and treatable traits: a look to the future. Int J Chron Obstruct Pulmon Dis. 2020;15:2091–2100. doi:10.2147/COPD.S263430
   PubMed Web of Science ®Google Scholar
• van Dijk M, Gan CT, Koster TD, et al. Treatment of severe stable COPD: the multidimensional approach of treatable traits. ERJ Open Res. 2020;6(3):00322–2019. doi:10.1183/23120541.00322-2019
   PubMedGoogle Scholar
• McDonald VM, Higgins I, Wood LG, Gibson PG. Multidimensional assessment and tailored interventions for COPD: respiratory utopia or common sense? Thorax. 2013;68(7):691–694. doi:10.1136/thoraxjnl-2012-202646
   PubMed Web of Science ®Google Scholar
• Mathioudakis AG, Janssens W, Sivapalan P, et al. Acute exacerbations of chronic obstructive pulmonary disease: in search of diagnostic biomarkers and treatable traits. Thorax. 2020;75(6):520–527. doi:10.1136/thoraxjnl-2019-214484
   PubMed Web of Science ®Google Scholar
• McDonald VM, Hiles SA, Godbout K, et al. Treatable traits can be identified in a severe asthma registry and predict future exacerbations. Respirology. 2019;24(1):37–47. doi:10.1111/resp.13389
   PubMed Web of Science ®Google Scholar
• Singh D, Agusti A, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019. Eur Respir J. 2019;53:5. doi:10.1183/13993003.00164-2019
   Web of Science ®Google Scholar
• Miravitlles M, Dirksen A, Ferrarotti I, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α 1 -antitrypsin deficiency. Eur Respir J. 2017;50(5):1700610. doi:10.1183/13993003.00610-2017
   PubMed Web of Science ®Google Scholar
• Lopes AP, Mineiro MA, Costa F, et al. Portuguese consensus document for the management of alpha-1-antitrypsin deficiency. Pulmonology. 2018;24(Suppl 1):1–21. doi:10.1016/j.pulmoe.2018.09.004
   PubMedGoogle Scholar
• Rutgers SR, Timens W, Kaufmann HF, van der Mark TW, Koëter GH, Postma DS. Comparison of induced sputum with bronchial wash, bronchoalveolar lavage and bronchial biopsies in COPD. Eur Respir J. 2000;15(1):109–115. doi:10.1183/09031936.00.15110900
   PubMed Web of Science ®Google Scholar
• Brusselle G, Pavord ID, Landis S, et al. Blood eosinophil levels as a biomarker in COPD. Respir Med. 2018;138:21–31. doi:10.1016/j.rmed.2018.03.016
   PubMed Web of Science ®Google Scholar
• Saha S, Brightling CE. Eosinophilic airway inflammation in COPD. Int J Chron Obstruct Pulmon Dis. 2006;1(1):39–47. doi:10.2147/copd.2006.1.1.39
   PubMedGoogle Scholar
• Vedel-Krogh S, Nielsen SF, Lange P, Vestbo J, Nordestgaard BG. Blood eosinophils and exacerbations in chronic obstructive pulmonary disease. The Copenhagen General Population Study. Am J Respir Crit Care Med. 2016;193(9):965–974. doi:10.1164/rccm.201509-1869OC
   PubMed Web of Science ®Google Scholar
• Kerkhof M, Freeman D, Jones R, Chisholm A, Price DB; Respiratory Effectiveness Group. Predicting frequent COPD exacerbations using primary care data. Int J Chron Obstruct Pulmon Dis. 2015;10:2439–2450. doi:10.2147/COPD.S94259
   PubMed Web of Science ®Google Scholar
• Rogliani P, Ora J, Puxeddu E, Cazzola M. Airflow obstruction: is it asthma or is it COPD? Int J Chron Obstruct Pulmon Dis. 2016;11:3007–3013. doi:10.2147/COPD.S54927
   PubMed Web of Science ®Google Scholar
• Barnes PJ. Inflammatory mechanisms in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2016;138(1):16–27. doi:10.1016/j.jaci.2016.05.011
   PubMed Web of Science ®Google Scholar
• Bafadhel M, Peterson S, De Blas MA, et al. Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Lancet Respir Med. 2018;6(2):117–126. doi:10.1016/S2213-2600(18)30006-7
   PubMed Web of Science ®Google Scholar
• Pascoe S, Barnes N, Brusselle G, et al. Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial. Lancet Respir Med. 2019;7(9):745–756. doi:10.1016/S2213-2600(19)30190-0
   PubMed Web of Science ®Google Scholar
• Singh S, Verma SK, Kumar S, et al. Correlation of severity of chronic obstructive pulmonary disease with potential biomarkers. Immunol Lett. 2018;196:1–10. doi:10.1016/j.imlet.2018.01.004
   PubMed Web of Science ®Google Scholar
• Schleich F, Corhay J-L J-L, Louis R. Blood eosinophil count to predict bronchial eosinophilic inflammation in COPD. Eur Respir J. 2016;47(5):1562–1564. doi:10.1183/13993003.01659-2015
   PubMed Web of Science ®Google Scholar
• Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. 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. doi:10.1016/S2213-2600(15)00106-X
   PubMed Web of Science ®Google Scholar
• Papi A, Vestbo J, Fabbri L, et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet. 2018;391(10125):1076–1084. doi:10.1016/S0140-6736(18)30206-X
   PubMed Web of Science ®Google Scholar
• Roche N, Chapman KR, Vogelmeier CF, et al. Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment. Data from the FLAME trial. Am J Respir Crit Care Med. 2017;195(9):1189–1197. doi:10.1164/rccm.201701-0193OC
   PubMed Web of Science ®Google Scholar
• Brightling CE, Bleecker ER, Panettieri RA, et al. Benralizumab for chronic obstructive pulmonary disease and sputum eosinophilia: a randomised, double-blind, placebo-controlled, phase 2a study. Lancet Respir Med. 2014;2(11):891–901. doi:10.1016/S2213-2600(14)70187-0
   PubMed Web of Science ®Google Scholar
• Butler A, Walton GM, Sapey E. Neutrophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease. COPD. 2019;15(4):392–404. doi:10.1080/15412555.2018.1476475
   Google Scholar
• Baines KJ, Simpson JL, Gibson PG. Innate immune responses are increased in chronic obstructive pulmonary disease. PLoS One. 2011;6(3):e18426. doi:10.1371/journal.pone.0018426
   PubMed Web of Science ®Google Scholar
• Parr DG, White AJ, Bayley DL, Guest PJ, Stockley RA. Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study. Respir Res. 2006;7:136. doi:10.1186/1465-9921-7-136
   PubMed Web of Science ®Google Scholar
• Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(2):349–355. doi:10.1164/ajrccm.163.2.2003122
   PubMed Web of Science ®Google Scholar
• Martinez FJ, Calverley PMA, Goehring U-M, Brose M, Fabbri LM, Rabe KF. 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. doi:10.1016/S0140-6736(14)62410-7
   PubMed Web of Science ®Google Scholar
• Lopez-Campos JL, Miravitlles M, de la Rosa Carrillo D, Cantón R, Soler-Cataluña JJ, Martinez-Garcia MA. Current challenges in chronic bronchial infection in patients with chronic obstructive pulmonary disease. J Clin Med. 2020;9(6):1639. doi:10.3390/jcm9061639
   PubMed Web of Science ®Google Scholar
• Dima E, Kyriakoudi A, Kaponi M, et al. The lung microbiome dynamics between stability and exacerbation in chronic obstructive pulmonary disease (COPD): current perspectives. Respir Med. 2019;157:1–6. doi:10.1016/j.rmed.2019.08.012
   PubMed Web of Science ®Google Scholar
• Cui L, Lucht L, Tipton L, et al. Topographic diversity of the respiratory tract mycobiome and alteration in HIV and lung disease. Am J Respir Crit Care Med. 2015;191(8):932–942. doi:10.1164/rccm.201409-1583OC
   PubMed Web of Science ®Google Scholar
• Man WH, de Steenhuijsen Piters WAA, Bogaert D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol. 2017;15(5):259–270. doi:10.1038/nrmicro.2017.14
   PubMed Web of Science ®Google Scholar
• Su YC, Jalalvand F, Thegerström J, Riesbeck K. The interplay between immune response and bacterial infection in COPD: focus upon non-typeable Haemophilus influenzae. Front Immunol. 2018;9:2530. doi:10.3389/fimmu.2018.02530
   PubMed Web of Science ®Google Scholar
• Sze MA, Dimitriu PA, Hayashi S, et al. The lung tissue microbiome in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1073–1080. doi:10.1164/rccm.201111-2075OC
   PubMed Web of Science ®Google Scholar
• Galiana A, Aguirre E, Rodriguez JC, et al. Sputum microbiota in moderate versus severe patients with COPD. Eur Respir J. 2014;43(6):1787–1790. doi:10.1183/09031936.00191513
   PubMed Web of Science ®Google Scholar
• Pragman AA, Kim HB, Reilly CS, Wendt C, Isaacson RE. The lung microbiome in moderate and severe chronic obstructive pulmonary disease. PLoS One. 2012;7(10):e47305. doi:10.1371/journal.pone.0047305
   PubMed Web of Science ®Google Scholar
• Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med. 2008;359(22):2355–2365. doi:10.1056/NEJMra0800353
   PubMed Web of Science ®Google Scholar
• Mammen MJ, Sethi S. COPD and the microbiome. Respirology. 2016;21(4):590–599. doi:10.1111/resp.12732
   PubMed Web of Science ®Google Scholar
• Garcha DS, Thurston SJ, Patel ARC, et al. Changes in prevalence and load of airway bacteria using quantitative PCR in stable and exacerbated COPD. Thorax. 2012;67(12):1075–1080. doi:10.1136/thoraxjnl-2012-201924
   PubMed Web of Science ®Google Scholar
• Oliveira AS, Munhá J, Bugalho A, et al. Identification and assessment of COPD exacerbations. Pulmonology. 2017. doi:10.1016/j.rppnen.2017.10.006
   Web of Science ®Google Scholar
• Yii ACA, Loh CH, Tiew PY, et al. A clinical prediction model for hospitalized COPD exacerbations based on “treatable traits”. Int J Chron Obstruct Pulmon Dis. 2019;14:719–728. doi:10.2147/COPD.S194922
   PubMed Web of Science ®Google Scholar
• Bafadhel M, McKenna S, Agbetile J, et al. Aspergillus fumigatus during stable state and exacerbations of COPD. Eur Respir J. 2014;43(1):64–71. doi:10.1183/09031936.00162912
   PubMed Web of Science ®Google Scholar
• Hammond EE, McDonald CS, Vestbo J, Denning DW. The global impact of Aspergillus infection on COPD. BMC Pulm Med. 2020;20(1):241. doi:10.1186/s12890-020-01259-8
   PubMed Web of Science ®Google Scholar
• Linden D, Guo-Parke H, Coyle PV, et al. Respiratory viral infection: a potential “missing link” in the pathogenesis of COPD. Eur Respir Rev. 2019;28(151):180063. doi:10.1183/16000617.0063-2018
   PubMed Web of Science ®Google Scholar
• Brode SK, Campitelli MA, Kwong JC, et al. The risk of mycobacterial infections associated with inhaled corticosteroid use. Eur Respir J. 2017;50(3):1700037. doi:10.1183/13993003.00037-2017
   PubMed Web of Science ®Google Scholar
• Dubé BP, Guerder A, Morelot-Panzini C, Laveneziana P. The clinical relevance of the emphysema-hyperinflated phenotype in COPD. COPD Res Pract. 2015;2(1):1. doi:10.1186/s40749-015-0017-7
   Google Scholar
• Kitaguchi Y, Fujimoto K, Kubo K, Honda T. Characteristics of COPD phenotypes classified according to the findings of HRCT. Respir Med. 2006;100(10):1742–1752. doi:10.1016/j.rmed.2006.02.003
   PubMed Web of Science ®Google Scholar
• Hackx M, Gyssels E, Severo Garcia T, et al. Chronic obstructive pulmonary disease: CT quantification of airway dimensions, numbers of airways to measure, and effect of bronchodilation. Radiology. 2015;277(3):853–862. doi:10.1148/radiol.2015140949
   PubMed Web of Science ®Google Scholar
• Refaee T, Wu G, Ibrahim A, et al. The emerging role of radiomics in COPD and lung cancer. Respiration. 2020;99(2):99–107. doi:10.1159/000505429
   PubMed Web of Science ®Google Scholar
• Grydeland TB, Dirksen A, Coxson HO, et al. Quantitative computed tomography: emphysema and airway wall thickness by sex, age and smoking. Eur Respir J. 2009;34(4):858–865. doi:10.1183/09031936.00167908
   PubMed Web of Science ®Google Scholar
• de Jong PA, Müller NL, Paré PD, Coxson HO. Computed tomographic imaging of the airways: relationship to structure and function. Eur Respir J. 2005;26(1):140–152. doi:10.1183/09031936.05.00007105
   PubMed Web of Science ®Google Scholar
• Madani A, Zanen J, de Maertelaer V, Gevenois PA. Pulmonary emphysema: objective quantification at multi-detector row CT–comparison with macroscopic and microscopic morphometry. Radiology. 2006;238(3):1036–1043. doi:10.1148/radiol.2382042196
   PubMed Web of Science ®Google Scholar
• Gonçalves I, Guimarães MJ, van Zeller M, et al. Clinical and molecular markers in COPD. Pulmonology. 2018;24(4):250–259. doi:10.1016/j.pulmoe.2018.02.005
   PubMed Web of Science ®Google Scholar
• Kim YW, Lee CH, Hwang HG, et al. Resting hyperinflation and emphysema on the clinical course of COPD. Sci Rep. 2019;9(1):3764. doi:10.1038/s41598-019-40411-1
   PubMedGoogle 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. doi:10.1164/rccm.200407-867OC
   PubMed Web of Science ®Google Scholar
• O’Donnell DE, Laveneziana P. Physiology and consequences of lung hyperinflation in COPD. Eur Respir Rev. 2006;15(100):61–67. doi:10.1183/09059180.00010002
   Google Scholar
• Cardoso J, Coelho R, Rocha C, Coelho C, Semedo L, Bugalho Almeida A. Prediction of severe exacerbations and mortality in COPD: the role of exacerbation history and inspiratory capacity/total lung capacity ratio. Int J Chron Obstruct Pulmon Dis. 2018;13:1105–1113. doi:10.2147/COPD.S155848
   PubMed Web of Science ®Google Scholar
• D’Ascanio M, Viccaro F, Calabrò N, et al. Assessing static lung hyperinflation by whole-body plethysmography, helium dilution, and impulse oscillometry System (IOS) in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2020;15:2583–2589. doi:10.2147/COPD.S264261
   PubMed Web of Science ®Google Scholar
• Rossi A, Aisanov Z, Avdeev S, et al. Mechanisms, assessment and therapeutic implications of lung hyperinflation in COPD. Respir Med. 2015;109(7):785–802. doi:10.1016/j.rmed.2015.03.010
   PubMed Web of Science ®Google Scholar
• Young RP, Hopkins RJ. Update on the potential role of statins in chronic obstructive pulmonary disease and its co-morbidities. Expert Rev Respir Med. 2013;7(5):533–544. doi:10.1586/17476348.2013.838018
   PubMed Web of Science ®Google Scholar
• Gan WQ, Man SFP, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59(7):574–580. doi:10.1136/thx.2003.019588
   PubMed Web of Science ®Google Scholar
• Agustí A, Edwards LD, Rennard SI, et al. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS One. 2012;7(5):e37483. doi:10.1371/journal.pone.0037483
   PubMed Web of Science ®Google Scholar
• Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(10):982–988. doi:10.1164/rccm.201206-1113OC
   PubMed Web of Science ®Google Scholar
• Li WF, Huang YQ, Huang C, Feng YQ. Statins reduce all-cause mortality in chronic obstructive pulmonary disease: an updated systematic review and meta-analysis of observational studies. Oncotarget. 2017;8(42):73000–73008. doi:10.18632/oncotarget.20304
   PubMedGoogle Scholar
• Lu Y, Chang R, Yao J, Xu X, Teng Y, Cheng N. Effectiveness of long-term using statins in COPD - A network meta-analysis. Respir Res. 2019;20(1):17. doi:10.1186/s12931-019-0984-3
   PubMedGoogle Scholar
• Hiles SA, Gibson PG, Agusti A, McDonald VM. Treatable traits that predict health status and treatment response in airway disease. J Allergy Clin Immunol Pract. 2020. doi:10.1016/j.jaip.2020.09.046
   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. doi:10.1164/rccm.201201-0034OC
   PubMed Web of Science ®Google Scholar
• Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular disease in patients with chronic obstructive pulmonary disease, Saskatchewan Canada cardiovascular disease in COPD patients. Ann Epidemiol. 2006;16(1):63–70. doi:10.1016/j.annepidem.2005.04.008
   PubMed Web of Science ®Google Scholar
• Trinkmann F, Saur J, Borggrefe M, Akin I. Cardiovascular comorbidities in chronic obstructive pulmonary disease (COPD)-current considerations for clinical practice. J Clin Med. 2019;8(1):69. doi:10.3390/jcm8010069
   PubMed Web of Science ®Google Scholar
• Pascual-Guardia S, Badenes-Bonet D, Martin-Ontiyuelo C, et al. Hospital admissions and mortality in patients with COPD exacerbations and vertebral body compression fractures. Int J Chron Obstruct Pulmon Dis. 2017;12:1837–1845. doi:10.2147/COPD.S129213
   PubMed Web of Science ®Google Scholar
• Chen W, Lin CW, Chen YY, Chen YJ, Liang CY, Lin MS. Prevalence, risk factors, and health-related quality of life of osteoporosis in patients with COPD at a community hospital in Taiwan. Int J Chron Obstruct Pulmon Dis. 2015;1493. doi:10.2147/COPD.S85432
   PubMed Web of Science ®Google Scholar
• Donaldson GC, Seemungal TAR, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847–852. doi:10.1136/thorax.57.10.847
   PubMed Web of Science ®Google Scholar
• Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925–931. doi:10.1136/thx.2005.040527
   PubMed Web of Science ®Google Scholar
• Rothnie KJ, Müllerová H, Smeeth L, Quint JK. Natural history of chronic obstructive pulmonary disease exacerbations in a general practice-based population with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;198(4):464–471. doi:10.1164/rccm.201710-2029OC
   PubMed Web of Science ®Google Scholar
• García-Sanz MT, Cánive-Gómez JC, Senín-Rial L, et al. One-year and long-term mortality in patients hospitalized for chronic obstructive pulmonary disease. J Thorac Dis. 2017;9(3):636–645. doi:10.21037/jtd.2017.03.34
   PubMed Web of Science ®Google Scholar
• Jernberg T, Hasvold P, Henriksson M, Hjelm H, Thuresson M, Janzon M. Cardiovascular risk in post-myocardial infarction patients: nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J. 2015;36(19):1163–1170. doi:10.1093/eurheartj/ehu505
   PubMed Web of Science ®Google Scholar
• Halpin DM, Miravitlles M, Metzdorf N, Celli B. Impact and prevention of severe exacerbations of COPD: a review of the evidence. Int J Chron Obstruct Pulmon Dis. 2017;20:2891–2908. doi:10.1186/s12931-019-0984-3
   Web of Science ®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. doi:10.1056/NEJMoa0909883
   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. doi:10.1164/rccm.201412-2269OC
   PubMed Web of Science ®Google Scholar
• David B, Bafadhel M, Koenderman L, De Soyza A. Eosinophilic inflammation in COPD: from an inflammatory marker to a treatable trait. Thorax. 2020. doi:10.1136/thoraxjnl-2020-215167
   PubMed Web of Science ®Google Scholar
• MacDonald MI, Osadnik CR, Bulfin L, et al. Low and high blood eosinophil counts as biomarkers in hospitalized acute exacerbations of COPD. Chest. 2019;156(1):92–100. doi:10.1016/j.chest.2019.02.406
   PubMed Web of Science ®Google Scholar
• MacDonald M, Beasley RW, Irving L, Bardin PG. A hypothesis to phenotype COPD exacerbations by aetiology. Respirology. 2011;16(2):264–268. doi:10.1111/j.1440-1843.2010.01908.x
   PubMed Web of Science ®Google Scholar
• MacDonald M, Korman T, King P, Hamza K, Bardin P. Exacerbation phenotyping in chronic obstructive pulmonary disease. Respirology. 2013;18(8):1280–1281. doi:10.1111/resp.12197
   PubMed Web of Science ®Google Scholar
• McDonald VM, Osadnik CR, Gibson PG. Treatable traits in acute exacerbations of chronic airway diseases. Chron Respir Dis. 2019;16:1479973119867954. doi:10.1177/1479973119867954
   Web of Science ®Google Scholar
• Prins HJ, Duijkers R, van der Valk P, et al. CRP-guided antibiotic treatment in acute exacerbations of COPD in hospital admissions. Eur Respir J. 2019;53(5):1802014. doi:10.1183/13993003.02014-2018
   PubMed Web of Science ®Google Scholar
• Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2012;186(1):48–55. doi:10.1164/rccm.201108-1553OC
   PubMed Web of Science ®Google Scholar
• Sivapalan P, Lapperre TS, Janner J, et al. Eosinophil-guided corticosteroid therapy in patients admitted to hospital with COPD exacerbation (CORTICO-COP): a multicentre, randomised, controlled, open-label, non-inferiority trial. Lancet Respir Med. 2019;7(8):699–709. doi:10.1016/S2213-2600(19)30176-6
   PubMed Web of Science ®Google Scholar
• Roede BM, Bindels PJ, Brouwer HJ, Bresser P, de Borgie CA, Prins JM. Antibiotics and steroids for exacerbations of COPD in primary care: compliance with Dutch guidelines. Br J Gen Pract. 2006;56(530):662–665.
   PubMed Web of Science ®Google Scholar
• Roede BM, Bresser P, Prins JM, Schellevis F, Verheij TJM, Bindels PJE. Reduced risk of next exacerbation and mortality associated with antibiotic use in COPD. Eur Respir J. 2009;33(2):282–288. doi:10.1183/09031936.00088108
   PubMed Web of Science ®Google Scholar
• Aggarwal D, Mohapatra PR, Aggarwal P. Significance of sputum purulence to guide antibiotic therapy in exacerbations of COPD. Eur Respir J. 2013;41(1):248. doi:10.1183/09031936.00083112
   PubMed Web of Science ®Google Scholar
• Butler CC, Gillespie D, White P, et al. C-reactive protein testing to guide antibiotic prescribing for COPD exacerbations. N Engl J Med. 2019;381(2):111–120. doi:10.1056/NEJMoa1803185
   PubMed Web of Science ®Google Scholar
• Chen K, Pleasants KA, Pleasants RA, et al. Procalcitonin for antibiotic prescription in chronic obstructive pulmonary disease exacerbations: systematic review, meta-analysis, and clinical perspective. Pulm Ther. 2020;6(2):201–214. doi:10.1007/s41030-020-00123-8
   PubMedGoogle Scholar
• 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(9):1618–1623. doi:10.1164/ajrccm.164.9.2105011
   PubMed Web of Science ®Google Scholar
• Papi A. Pathophysiology of exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006;3(3):245–251. doi:10.1513/pats.200512-125SF
   PubMedGoogle Scholar
• Kolsum U, Donaldson GC, Singh R, et al. Blood and sputum eosinophils in COPD; relationship with bacterial load. Respir Res. 2017;18(1):88. doi:10.1186/s12931-017-0570-5
   PubMed Web of Science ®Google Scholar
• Bafadhel M, Davies L, Calverley PMA, Aaron SD, Brightling CE, Pavord ID. Blood eosinophil guided prednisolone therapy for exacerbations of COPD: a further analysis. Eur Respir J. 2014;44(3):789–791. doi:10.1183/09031936.00062614
   PubMed Web of Science ®Google Scholar
• Aleva FE, Voets LWLM, Simons SO, de Mast Q, van der Ven AJAM, Heijdra YF. Prevalence and localization of pulmonary embolism in unexplained acute exacerbations of COPD. Chest. 2017;151(3):544–554. doi:10.1016/j.chest.2016.07.034
   PubMed Web of Science ®Google Scholar
• Ra SW, Sin DD. Should we screen for pulmonary embolism in severe COPD exacerbations? Not just yet, primum non nocere. Chest. 2017;151(3):523–524. doi:10.1016/j.chest.2016.09.018
   PubMed Web of Science ®Google Scholar
• Kunisaki KM, Dransfield MT, Anderson JA, et al. Exacerbations of chronic obstructive pulmonary disease and cardiac events. A post hoc cohort analysis from the SUMMIT randomized clinical trial. Am J Respir Crit Care Med. 2018;198(1):51–57. doi:10.1164/rccm.201711-2239OC
   PubMed Web of Science ®Google Scholar
• Ni Y, Shi G, Yu Y, Hao J, Chen T, Song H. Clinical characteristics of patients with chronic obstructive pulmonary disease with comorbid bronchiectasis: a systemic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015;10:1465–1475. doi:10.2147/COPD.S83910
   PubMed Web of Science ®Google Scholar
• Olalde I, Mallick S, Patterson N, et al. The genomic history of the Iberian Peninsula over the past 8000 years. Science (80-). 2019;363(6432):1230–1234. doi:10.1126/science.aav4040
   PubMed Web of Science ®Google Scholar
• Miravitlles M, Guerrero T, Mayordomo C, Sánchez-Agudo L, Nicolau F, Segú JL. Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: a multiple logistic regression analysis. The EOLO Study Group. Respiration. 2000;67(5):495–501. doi:10.1159/000067462
   PubMed Web of Science ®Google Scholar
• Kim V, Han MK, Vance GB, et al. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene study. Chest. 2011;140(3):626–633. doi:10.1378/chest.10-2948
   PubMed Web of Science ®Google Scholar
• Burgel PR, Nesme-Meyer P, Chanez P, et al. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest. 2009;135(4):975–982. doi:10.1378/chest.08-2062
   PubMed Web of Science ®Google Scholar
• 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(3):325–331. doi:10.1164/rccm.200912-1869OC
   PubMed Web of Science ®Google Scholar
• Gunduz C, Basoglu OK, Tasbakan MS. Prevalence of overlap syndrome in chronic obstructive pulmonary disease patients without sleep apnea symptoms. Clin Respir J. 2018;12(1):105–112. doi:10.1111/crj.12493
   PubMed Web of Science ®Google Scholar
• Shorofsky M, Bourbeau J, Kimoff J, et al. Impaired sleep quality in COPD is associated with exacerbations: the CanCOLD cohort study. Chest. 2019;156(5):852–863. doi:10.1016/j.chest.2019.04.132
   PubMed Web of Science ®Google Scholar
• Iyer AS, Bhatt SP, Garner JJ, et al. Depression is associated with readmission for acute exacerbation of chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2016;13(2):197–203. doi:10.1513/AnnalsATS.201507-439OC
   PubMed Web of Science ®Google Scholar
• Hoong JM, Ferguson M, Hukins C, Collins PF. Economic and operational burden associated with malnutrition in chronic obstructive pulmonary disease. Clin Nutr. 2017;36(4):1105–1109. doi:10.1016/j.clnu.2016.07.008
   PubMed Web of Science ®Google Scholar
• Pitta F, Troosters T, Probst VS, Spruit MA, Decramer M, Gosselink R. Physical activity and hospitalization for exacerbation of COPD. Chest. 2006;129(3):536–544. doi:10.1378/chest.129.3.536
   PubMed Web of Science ®Google Scholar
• Garcia-Rio F, Rojo B, Casitas R, et al. Prognostic value of the objective measurement of daily physical activity in patients with COPD. Chest. 2012;142(2):338–346. doi:10.1378/chest.11-2014
   PubMed Web of Science ®Google Scholar
• Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM. Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study. Thorax. 2006;61(9):772–778. doi:10.1136/thx.2006.060145
   PubMed Web of Science ®Google Scholar
• Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011;105(6):930–938. doi:10.1016/j.rmed.2011.01.005
   PubMed Web of Science ®Google Scholar
• Maricoto T, Monteiro L, Gama JMR, Correia-de-sousa J, Taborda-Barata L. Inhaler technique education and exacerbation risk in older adults with asthma or chronic obstructive pulmonary disease: a meta-analysis. J Am Geriatr Soc. 2019;67(1):57–66. doi:10.1111/jgs.15602
   PubMed Web of Science ®Google Scholar
• Viniol C, Vogelmeier CF. Exacerbations of COPD. Eur Respir Rev. 2018;27:147. doi:10.1183/16000617.0103-2017
   Web of Science ®Google Scholar
• Ozyilmaz E, Kokturk N, Teksut G, Tatlicioglu T. Unsuspected risk factors of frequent exacerbations requiring hospital admission in chronic obstructive pulmonary disease. Int J Clin Pract. 2013;67(7):691–697. doi:10.1111/ijcp.12150
   PubMed Web of Science ®Google Scholar
• Agustí A, Calverley PM, Decramer M, Stockley RA, Wedzicha JA. Prevention of exacerbations in chronic obstructive pulmonary disease: knowns and unknowns. Chronic Obstr Pulm Dis. 2014;1(2):166–184. doi:10.15326/jcopdf.1.2.2014.0134
   PubMedGoogle Scholar