A perspective for chronic obstructive pulmonary disease (COPD) management: six key clinical questions to improve disease treatment

References

• Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380(9859):2095–2128. .
   PubMed Web of Science ®Google Scholar
• Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and the prevention of chronic obstructive pulmunary disease. 2020 Report. [cited 2020 Sep 7]. https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf
   Google Scholar
• Pauwels RA, Buist AS, Calverley PM, et al. GOLD scientific committee. global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO global initiative for chronic obstructive lung disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163(5):1256–1276. .
   PubMedGoogle Scholar
• Richards JB. Calculated decisions: mMRC (modified medical research council) Dyspnea scale. Emerg Med Pract. 2017;19(Suppl 10):1–2.
   PubMedGoogle Scholar
• Ghobadi H, Ahari SS, Kameli A, et al. The relationship between COPD assessment test (CAT) scores and severity of airflow obstruction in stable COPD patients. Tanaffos. 2012;11(2):22–26.
   PubMedGoogle Scholar
• Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347–365. .
   PubMed Web of Science ®Google Scholar
• Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and the prevention of Chronic Obstructive Pulmunary Disease. 2017 Report. [cited 2020 Sep 7]. https://goldcopd.org/wp-content/uploads/2017/02/wms-GOLD-2017-FINAL.pdf
   Google Scholar
• Soriano JB, Lamprecht B, Ramírez AS, et al. Mortality prediction in chronic obstructive pulmonary disease comparing the GOLD 2007 and 2011 staging systems: a pooled analysis of individual patient data. Lancet Respir Med. 2015;3(6):443–450.
   PubMed Web of Science ®Google Scholar
• Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(10):1005–1012.
   PubMed Web of Science ®Google Scholar
• Celli BR, Cote CG, Lareau SC, et al. Predictors of Survival in COPD: more than just the FEV1. Respir Med. 2008;102(Suppl1):S27–35.
   PubMedGoogle Scholar
• Sin DD, Man SFP. 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(11):1514–1519.
   PubMed Web of Science ®Google Scholar
• Engström G, Lind P, Hedblad B, et al. Lung function and cardiovascular risk: relationship with inflammation-sensitive plasma proteins. Circulation. 2004;106(20):2555–2560.
   Web of Science ®Google Scholar
• Papi A, Casoni G, Caramori G, et al. COPD increases the risk of squamous histological subtype in smokers who develop non-small cell lung carcinoma. Thorax. 2004;59(8):679–681.
   PubMed Web of Science ®Google Scholar
• Wasswa-Kintu S, Gan WQ, Man SFP, et al. Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Thorax. 2005;60(7):570–575.
   PubMed Web of Science ®Google Scholar
• Malhotra S, Lam S, Man SP, et al. The relationship between stage 1 and 2 non-small cell lung cancer and lung function in men and women. BMC Pulm Med. 2006;6:2.
   PubMedGoogle Scholar
• Agusti A, Calverley PM, Celli B, et al. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res. 2010;11(1):122.
   PubMed 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.
   PubMed Web of Science ®Google Scholar
• Hogg JC, Macklem PT, Thurlbeck WM. Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med. 1968;278(25):1355–1360.
   PubMed Web of Science ®Google Scholar
• Stockley JA, Cooper BG, Stockley RA, et al. Small airways disease: time for a revisit? Int J Chron Obstruct Pulmon Dis. 2017;12:2343–2353.
   PubMed Web of Science ®Google Scholar
• Hogg JC, Chu F, Utokaparch S, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–2653.
   PubMed Web of Science ®Google Scholar
• Burgel PR. The role of small airways in obstructive airway diseases. Eur Respir Rev. 2011;20(119):23–33.
   PubMedGoogle Scholar
• Lee JH, Lee YK, Kim EK, et al. Responses to inhaled long-acting beta-agonist and corticosteroid according to COPD subtype. Respir Med. 2010;104(4):542–549.
   PubMed Web of Science ®Google Scholar
• Nishimura M, Makita H, Nagai K, et al. Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(1):44–52.
   PubMed Web of Science ®Google Scholar
• Johannessen A, Skorge TD, Bottai M, et al. Mortality by level of emphysema and airway wall thickness. Am J Respir Crit Care Med. 2013;187(6):602–608.
   PubMed Web of Science ®Google Scholar
• Mannino DM, Doherty DE, Sonia A. Buist global initiative on obstructive lung disease (GOLD) classification of lung disease and mortality: findings from the atherosclerosis risk in communities (ARIC) study. Respir Med. 2006;100(1):115–122.
   PubMed Web of Science ®Google Scholar
• Wei X, Shi Z, Cui Y, et al. Impulse oscillometry system as an alternative diagnostic method for chronic obstructive pulmonary disease. Medicine (Baltimore). 2017;96(46):e8543.
   PubMed Web of Science ®Google Scholar
• Reilly JJCOPD. and declining FEV1–time to divide and conquer? N Engl J Med. 2008;359(15):1616–1618.
   PubMed Web of Science ®Google Scholar
• Jarenbäck L, Ankerst J, Bjermer L, et al. Flow-volume parameters in COPD related to extended measurements of lung volume, diffusion, and resistance. Pulmonary Med. 2013;2013:782052.
   PubMedGoogle Scholar
• Radovanovic D, Contoli M, Marco FD, et al. Clinical and functional characteristics of COPD patients across GOLD classifications: results of a multicenter observational study. COPD. 2019;16(3–4):215–226.
   PubMedGoogle Scholar
• Han MK, Kazerooni EA, Lynch DA, et al. Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology. 2011;261(1):274–282.
   PubMed Web of Science ®Google Scholar
• Milne S, King GG. Advanced imaging in COPD: insights into pulmonary pathophysiology. J Thorac Dis. 2014;6(11):1570–1585.
   PubMed Web of Science ®Google Scholar
• Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367(10):913–921.
   PubMed Web of Science ®Google Scholar
• Lowe KE, Regan EA, Anzueto A, et al. COPDGene® 2019: redefining the diagnosis of chronic obstructive pulmonary disease. Chronic Obstr Pulm Dis. 2019;6(5):384–399.
   PubMed Web of Science ®Google Scholar
• Woodruff PG, Barr RG, Bleecker E, et al. Clinical significance of symptoms in smokers with preserved pulmonary function. N Engl J Med. 2016;374(19):1811–1821.
   PubMed Web of Science ®Google Scholar
• Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and the prevention of Chronic Obstructive Pulmunary Disease. 2006 report. [cited 2020 Sep 7]. https://www.who.int/respiratory/copd/GOLD_WR_06.pdf
   Google Scholar
• Enright PL, Beck KC, Sherrill DL. Repeatability of spirometry in 18,000 adult patients. Am J Respir Crit Care Med. 2004;169(2):235–238.
   PubMed Web of Science ®Google Scholar
• Jones PW, Donohue JF, Nedelman J, et al. Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis. Respir Res. 2011;12:161.
   PubMed Web of Science ®Google Scholar
• Martin AL, Marvel J, Fahrbach K, et al. The association of lung function and St. George’s respiratory questionnaire with exacerbations in COPD: a systematic literature review and regression analysis. Respir Res. 2016;17:40.
   PubMed Web of Science ®Google Scholar
• Dransfield MT, Bourbeau J, Jones PW, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med. 2013;1(3):210–223.
   PubMed Web of Science ®Google Scholar
• Decramer M, Celli B, Kesten S, et al. UPLIFT investigators. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet. 2009;374(9696):1171–1178.
   PubMed Web of Science ®Google Scholar
• Zhou Y, Zhong NS, Li X, et al. Tiotropium in early-stage chronic obstructive pulmonary disease. N Engl J Med. 2017;377(10):923–935.
   PubMed Web of Science ®Google Scholar
• Formiga MF, Vital I, Urdaneta G, et al. The BODE index and inspiratory muscle performance in COPD: clinical findings and implications. SAGE Open Med. 2018;6:2050312118819015.
   Web of Science ®Google Scholar
• Bhatt SP, Soler X, Wang X, et al. Association between functional small airway disease and FEV1 decline in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2016;194(2):178–184.
   PubMed Web of Science ®Google Scholar
• Kirby M, Tanabe N, Tan WC, et al. Total airway count on computed tomography and the risk of chronic obstructive pulmonary disease progression. Findings from a population-based study. Am J Respir Crit Care Med. 2018;197(1):56–65.
   PubMed Web of Science ®Google Scholar
• Tantucci C, Pini L. COPD: it is time to change! Int J Chron Obstruct Pulmon Dis. 2015;10:2451–2457.
   PubMed Web of Science ®Google Scholar
• Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3): 89–95. .
   PubMed Web of Science ®Google Scholar
• Sin DD, Vestbo J. Biomarkers in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;6(6):543–545.
   PubMedGoogle Scholar
• Agusti A, Gea J, Faner R. Biomarkers, the control panel and personalized COPD medicine. Respirol Carlton Vic. 2016;21(1):24–33.
   PubMed Web of Science ®Google Scholar
• Sin DD, Pahlavan PS, Man SFP. Review: surfactant protein D: A lung specific biomarker in COPD? Ther Adv Respir Dis. 2008;2(2):65–74.
   PubMedGoogle Scholar
• Lacoma A, Prat C, Andreo F, et al. Biomarkers in the management of COPD. Eur Respir Rev. 2009;18(112):96–104.
   PubMedGoogle Scholar
• Lock-Johansson S, Vestbo J, Sorensen GL. Surfactant protein D, club cell protein 16, pulmonary and activation-regulated chemokine, C-reactive protein, and fibrinogen biomarker variation in chronic obstructive lung disease. Respir Res. 2014;15(1):147.
   PubMedGoogle Scholar
• Mannino DM, Tal-Singer R, Lomas DA, et al. Plasma fibrinogen as a biomarker for mortality and hospitalized exacerbations in people with COPD. Chronic Obstr Pulm Dis. 2015;2(1):23–34.
   PubMed Web of Science ®Google Scholar
• Fermont JM, Masconi KL, Jensen MT, et al. Biomarkers and clinical outcomes in COPD: a systematic review and meta-analysis. Thorax. 2019;74(5):439–446.
   PubMed Web of Science ®Google Scholar
• Leung JM, Mayo J, Tan W, et al. Plasma pro-surfactant protein B and lung function decline in smokers. Eur Respir J. 2015;45(4):1037–1045.
   PubMed Web of Science ®Google Scholar
• Pavasini R, d’Ascenzo F, Campo G, et al. Cardiac troponin elevation predicts all-cause mortality in patients with acute exacerbation of chronic obstructive pulmonary disease: systematic review and meta-analysis. Int J Cardiol. 2015;191:187–193.
   PubMed Web of Science ®Google Scholar
• Pavasini R, Tavazzi G, Biscaglia S, et al. Amino terminal pro brain natriuretic peptide predicts all-cause mortality in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis. Chron Respir Dis. 2017;14(2):117–126.
   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.
   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.
   PubMed Web of Science ®Google Scholar
• Pascoe S, Locantore N, Dransfield MT, et al. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med. 2015;3(6):435–442.
   PubMed Web of Science ®Google Scholar
• Brusselle GG, Bracke K, Lahousse L. Targeted therapy with inhaled corticosteroids in COPD according to blood eosinophil counts. Lancet Respir Med. 2015;3(6):416–417.
   PubMed Web of Science ®Google Scholar
• Barnes NC, Sharma R, Lettis S, et al. Blood eosinophils as a marker of response to inhaled corticosteroids in COPD. Eur Respir J. 2016;47(5):1374–1382.
   PubMed Web of Science ®Google Scholar
• Agusti A, Fabbri LM, Singh D, et al. Inhaled corticosteroids in COPD: friend or foe? Eur Respir J. 2018;52:6.
   Web of Science ®Google Scholar
• Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol–glycopyrronium versus salmeterol–fluticasone for COPD. N Engl J Med. 2016;374(23):2222–2234.
   PubMed Web of Science ®Google Scholar
• Kardos P, Wencker M, Glaab T, et al. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(2):144–149. .
   PubMed Web of Science ®Google Scholar
• Watz H, Tetzlaff K, Wouters EF, et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med. 2016;4(5):390–398.
   PubMed Web of Science ®Google Scholar
• Chapman KR, Hurst JR, Frent SM, et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in patients with chronic obstructive pulmonary disease (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198(3):329–339.
   PubMed Web of Science ®Google Scholar
• Nici L, Mammen MJ, Charbek E, et al. Pharmacologic management of chronic obstructive pulmonary disease. An official american thoracic society clinical practice guideline. Am J Respir Crit Care Med. 2020;201(9):e56–e69.
   PubMed Web of Science ®Google Scholar
• Chalmers JD, Laska IF, Franssen FME, et al. Withdrawal of inhaled corticosteroids in COPD: a European respiratory society guideline. Eur Respir J. 2020 2020 Jun 4;55(6):2000351. Published.
   PubMed Web of Science ®Google Scholar
• Ferguson GT, Rabe KF, Martinez FJ, et al. Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Lancet Respir Med. 2018;6(10):747–758.
   PubMed Web of Science ®Google Scholar
• Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018;378(18):1671–1680.
   PubMed Web of Science ®Google Scholar
• Crim C, Calverley PM, Anderson JA, et al. Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results. Eur Respir J. 2009;34(3):641–647.
   PubMed Web of Science ®Google Scholar
• Contoli M, Pauletti A, Rossi MR, et al. Long-term effects of inhaled corticosteroids on sputum bacterial and viral loads in COPD. Eur Respir J. 2017;50:4.
   Web of Science ®Google 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.
   PubMedGoogle Scholar
• Contoli M, Corsico A, Santus P, et al. Use of ICS in COPD: from blockbuster medicine to precision medicine. COPD. 2017;14(6):641–647.
   PubMedGoogle Scholar
• Pantzaris ND, Spilioti DX, Psaromyalou A, et al. The use of serum procalcitonin as a diagnostic and prognostic biomarker in chronic obstructive pulmonary disease exacerbations: a literature review update. J Clin Med Res. 2018;10(7):545–551. .
   PubMedGoogle 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.
   PubMed Web of Science ®Google Scholar
• Corrado A, Rossi A. How far is real life from COPD therapy guidelines? An Italian observational study. Respir Med. 2012;106(7):989–997.
   PubMed Web of Science ®Google Scholar
• Palmiotti GA, Lacedonia D, Liotino V, et al. Adherence to GOLD guidelines in real-life COPD management in the Puglia region of Italy. Int J Chron Obstruct Pulmon Dis. 2018;13:2455–2462.
   PubMed Web of Science ®Google Scholar
• Brusselle G, Price D, Gruffydd-Jones K, et al. The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK. Int J Chron Obstruct Pulmon Dis. 2015;10:2207–2217.
   PubMed Web of Science ®Google Scholar
• Vestbo J, Vogelmeier C, Small M, et al. Understanding the GOLD 2011 strategy as applied to a real-world COPD population. Respir Med. 2014;108(5):729–736.
   PubMed Web of Science ®Google Scholar
• Contoli M, Rogliani P, Di Marco F, et al. Satisfaction with chronic obstructive pulmonary disease treatment: results from a multicenter, observational study. Ther Adv Respir Dis. 2019;13:1753466619888128.
   Web of Science ®Google Scholar
• Wurst KE, Punekar YS, Shukla A. Treatment evolution after COPD diagnosis in the UK primary care setting. Plos One. 2014;9(9):e105296.
   PubMed Web of Science ®Google Scholar
• Di Marco F, Santus P, Terraneo S, et al. Characteristics of newly diagnosed COPD patients treated with triple inhaled therapy by general practitioners: a real world Italian study. NPJ Prim Care Respir Med. 2017;27(1):51.
   PubMed Web of Science ®Google Scholar
• Ghosh S, Anderson WH, Putcha N, et al. Alignment of inhaled chronic obstructive pulmonary disease therapies with published strategies. analysis of the global initiative for chronic obstructive lung disease recommendations in SPIROMICS. Ann Am Thorac Soc. 2019;16(2):200–208.
   PubMed Web of Science ®Google Scholar
• Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775–789.
   PubMed Web of Science ®Google Scholar
• Burge PS, Calverley PM, Jones PW, et al. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ. 2000;320(7245):1297–1303.
   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.
   PubMed Web of Science ®Google Scholar
• Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016;388(10048):963–973.
   PubMed Web of Science ®Google Scholar
• Newton R, Giembycz MA. Understanding how long‐acting β2‐adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma – an update. Br J Pharmacol. 2016;173(24):3405–3430.
   PubMedGoogle Scholar
• Cazzola M, Dahl R. Inhaled combination therapy with long-acting beta 2-agonists and corticosteroids in stable COPD. Chest. 2004;126(1):220–237.
   PubMed Web of Science ®Google Scholar
• Cataldo D, Derom E, Liistro G, et al. Overuse of inhaled corticosteroids in COPD: five questions for withdrawal in daily practice. Int J Chron Obstruct Pulmon Dis. 2018;13:2089–2099.
   PubMed Web of Science ®Google Scholar
• Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42(6):1484–1494.
   PubMed Web of Science ®Google Scholar
• Matera MG, Page CP, Calzetta L, et al. Pharmacology and therapeutics of bronchodilators revisited. Pharmacol Rev. 2020;72(1):218–252.
   PubMed Web of Science ®Google Scholar
• Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet. 2017;389(10082):1919–1929.
   PubMed Web of Science ®Google Scholar
• Crim C, Dransfield MT, Bourbeau J, et al. Pneumonia risk with inhaled fluticasone furoate and vilanterol compared with vilanterol alone in patients with COPD. Ann Am Thorac Soc. 2015;12(1):27–34.
   PubMed Web of Science ®Google Scholar
• Yang M, Chen H, Zhang Y, et al. Long-term use of inhaled corticosteroids and risk of upper respiratory tract infection in chronic obstructive pulmonary disease: a meta-analysis. Inhal Toxicol. 2017;29(5):219–226.
   PubMed Web of Science ®Google Scholar
• Price D, Yawn B, Brusselle G, et al. Risk-to-benefit ratio of inhaled corticosteroids in patients with COPD. Prim Care Respir J. 2013;22(1):92–100.
   PubMedGoogle Scholar
• Bai C, Ichinose M, Lee SH, et al. Lung function and long-term safety of tiotropium/olodaterol in East Asian patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2017;12:3329–3339.
   PubMed Web of Science ®Google Scholar
• Mahler DA, Kerwin E, Ayers T, et al. FLIGHT1 and FLIGHT2: efficacy and safety of QVA149 (Indacaterol/Glycopyrrolate) versus its monocomponents and placebo in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(9):1068–1079.
   PubMed Web of Science ®Google Scholar
• Martinez FJ, Fabbri LM, Ferguson GT, et al. Baseline symptom score impact on benefits of glycopyrrolate/formoterol metered dose inhaler in COPD. Chest. 2017;152(6):1169–1178.
   PubMed Web of Science ®Google Scholar
• Tashkin DP, Strange C. Inhaled corticosteroids for chronic obstructive pulmonary disease: what is their role in therapy? Int J Chron Obstruct Pulmon Dis. 2018;13:2587–2601.
   PubMed Web of Science ®Google Scholar
• Rossi A, van der Molen T, Del Olmo R, et al. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD. Eur Respir J. 2014;44(6):1548–1556.
   PubMed Web of Science ®Google Scholar
• Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. N Engl J Med. 2014;371(14):1285–1294.
   PubMed Web of Science ®Google Scholar
• Calzetta L, Matera MG, Braido F, et al. Withdrawal of inhaled corticosteroids in COPD: a meta-analysis. Pulm Pharmacol Ther. 2017;45:148–158.
   PubMed Web of Science ®Google Scholar
• Wouters EF, Postma DS, Fokkens B, et al. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial. Thorax. 2005;60(6):480–487.
   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.
   PubMed Web of Science ®Google Scholar
• Fingleton J, Hardy J, Beasley R. Treatable traits of chronic airways disease. Curr Opin Pulm Med. 2018;24(1):24–31.
   PubMed Web of Science ®Google Scholar
• Diab N, Gershon AS, Sin DD, et al. Underdiagnosis and overdiagnosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2018;198(9):1130–1139.
   PubMed Web of Science ®Google Scholar
• Nardini S, Annesi-Maesano I, Simoni M, et al. Accuracy of diagnosis of COPD and factors associated with misdiagnosis in primary care setting. E-DIAL (Early DIAgnosis of obstructive lung disease) study group. Respir Med. 2018;143:61–66.
   PubMed Web of Science ®Google Scholar
• Pecchiari M, Radovanovic D, Santus P, et al. Airway occlusion assessed by single breath N2 test and lung P-V curve in healthy subjects and COPD patients. Respir Physiol Neurobiol. 2016;234:60–68.
   PubMed Web of Science ®Google Scholar
• Katsoulis K, Kostikas K, Kontakiotis T. Techniques for assessing small airways function: possible applications in asthma and COPD. Respir Med. 2016;119:e2–e9.
   PubMedGoogle 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.
   PubMed Web of Science ®Google Scholar
• Fragoso E, André S, Boleo-Tomé JP, et al. Understanding COPD: A vision on phenotypes, comorbidities and treatment approach. Rev Port Pneumol. 2016;22(2):101–111.
   PubMed Web of Science ®Google Scholar
• Chai CS, Liam CK, Pang YK, et al. Clinical phenotypes of COPD and health-related quality of life: a cross-sectional study. Int J Chron Obstruct Pulmon Dis. Published. 2019;14:565–573. 2019 Mar 1.
   PubMed Web of Science ®Google Scholar