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Goals of COPD treatment: Focus on symptoms and exacerbations

Open ArchivePublished:March 21, 2020DOI:https://doi.org/10.1016/j.rmed.2020.105938

      Highlights

      • Challenges of COPD management include disease heterogeneity and under-diagnosis.
      • The best available tools should be used for COPD diagnosis and assessment.
      • Optimal management of COPD includes recognizing both symptoms and exacerbations.
      • Both pharmacologic and non-pharmacologic treatment strategies should be considered.
      • Novel strategies (e.g. precision medicine, point-of-care testing) may be of value.

      Abstract

      Chronic obstructive pulmonary disease (COPD) is currently a leading cause of death worldwide, and its burden is expected to rise in the coming years. Common COPD symptoms include dyspnea, cough and/or sputum production. Some patients may experience acute worsening of symptoms (known as an exacerbation), and therefore require additional therapy. Exacerbations are mainly triggered by respiratory infections and environmental factors. Healthcare professionals face many challenges in COPD management, including the heterogeneity of the disease and under-reporting of symptoms. The authors review these challenges and provide recommendations for the best methods to assess COPD. The goals of COPD treatment include recognising the impact that both symptoms and exacerbations have on patients’ lives when considering optimal patient-focused management. The review discusses the need for COPD management strategies to include both pharmacologic and non-pharmacologic approaches and provides recommendations for monitoring treatment outcomes and adjusting management strategies accordingly. Novel treatment strategies including precision medicine and point-of-care testing are also discussed.

      Graphical abstract

      Keywords

      Abbreviations

      CAPTURE
      COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease & Exacerbation Risk
      CAT
      COPD Assessment Test
      CCQ
      Clinical COPD Questionnaire
      COPD
      chronic obstructive pulmonary disease
      FEV1
      forced expiratory volume in 1 s
      GOLD
      Global Initiative for Chronic Obstructive Lung Disease
      ICS
      inhaled corticosteroids
      LABA
      long-acting β2-agonist
      LAMA
      long-acting muscarinic antagonist
      MIRROR
      Medical Investigation of Respiratory COPD Perception
      mMRC
      modified Medical Research Council
      SGRQ
      St. George's Respiratory Questionnaire

      1. Introduction

      Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease marked by persistent respiratory symptoms and airflow limitation [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. It was ranked as the third leading cause of death worldwide in 2016 [], and the fourth leading cause of death in the United States in 2017 [
      • Heron M.
      Deaths: leading causes for 2017.
      ]. The prevalence of COPD was reported to be approximately 300 million in 2017 [
      GBD Disease Injury Incidence Prevalence Collaborators, Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.
      ], with the burden of COPD expected to increase further in the coming years due to an aging population and continued exposure to COPD risk factors, including tobacco smoke, occupational dusts and chemicals, biomass fuel and air pollution [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. However, COPD can be prevented by reducing exposure to these risk factors, including avoidance or early cessation of smoking [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • World Health Organization
      ]. The most common respiratory symptoms associated with COPD include dyspnea, cough and/or sputum production [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. In addition to the daily symptom burden, COPD may be punctuated by periods of acute worsening of respiratory symptoms (often referred to as ‘exacerbations’), which account for the greatest proportion of total COPD burden on healthcare systems [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. COPD can be progressive, as indicated by reductions in spirometry measures such as forced expiratory volume in 1 s (FEV1) over time, though patients may progress at different rates [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • Lange P.
      • Celli B.
      • Agusti A.
      • Boje Jensen G.
      • Divo M.
      • Faner R.
      • Guerra S.
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      • Martinez F.D.
      • Martinez-Camblor P.
      • Meek P.
      • Owen C.A.
      • Petersen H.
      • Pinto-Plata V.
      • Schnohr P.
      • Sood A.
      • Soriano J.B.
      • Tesfaigzi Y.
      • Vestbo J.
      Lung-function trajectories leading to chronic obstructive pulmonary disease.
      ].
      This review examines the current goals of COPD management and discusses the challenges that many healthcare professionals face in trying to meet these goals. In the context of the 2020 Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy report [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ], we consider both pharmacologic and non-pharmacologic treatment strategies for the management of symptoms and prevention of exacerbations to improve long-term outcomes and quality of life. Recommendations for monitoring treatment outcomes and adjusting management strategies are also discussed.

      2. Challenges in management of COPD

      COPD is a heterogeneous, multifaceted disease that is influenced by genetic and environmental factors [
      • Seifart C.
      • Plagens A.
      Genetics of chronic obstructive pulmonary disease.
      ]. The heterogeneity of COPD has led to much interest in defining different phenotypes based on clinical characteristics [
      • Garudadri S.
      • Woodruff P.G.
      Targeting chronic obstructive pulmonary disease phenotypes, endotypes, and biomarkers.
      ]. For example, the GOLD ABCD classification defines four groups (phenotypes) of patients based on symptom severity and exacerbation history [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. The concept of COPD endotypes refers to the definition of patient subgroups based on underlying biologic differences, for example bacterial colonization, and more controversially, eosinophilic inflammation [
      • Garudadri S.
      • Woodruff P.G.
      Targeting chronic obstructive pulmonary disease phenotypes, endotypes, and biomarkers.
      ,
      • Sidhaye V.K.
      • Nishida K.
      • Martinez F.J.
      Precision medicine in COPD: where are we and where do we need to go?.
      ,
      • Celli B.R.
      • Criner G.J.
      Using the peripheral blood eosinophil count to manage patients with chronic obstructive pulmonary disease.
      ]. Precision medicine refers to the use of both clinical (phenotype) and biologic (endotype) information on an individual basis in order to tailor treatment strategies accordingly [
      • Agusti A.
      • Bel E.
      • Thomas M.
      • Vogelmeier C.
      • Brusselle G.
      • Holgate S.
      • Humbert M.
      • Jones P.
      • Gibson P.G.
      • Vestbo J.
      • Beasley R.
      • Pavord I.D.
      Treatable traits: toward precision medicine of chronic airway diseases.
      ]. Currently, our level of understanding of COPD subtypes is limited, and improvements are needed to better develop novel targeted therapeutic approaches, rather than adopting a ‘one-size-fits-all’ approach to COPD treatment [
      • Garudadri S.
      • Woodruff P.G.
      Targeting chronic obstructive pulmonary disease phenotypes, endotypes, and biomarkers.
      ]. Healthcare professionals need to work with their patients to find the best combination of pharmacologic and non-pharmacologic treatment strategies (including lifestyle changes) to manage the condition [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ].
      Due to environmental and genetic factors, abnormal lung function growth trajectories, beginning at birth, may occur [
      • Agusti A.
      • Faner R.
      Lung function trajectories in health and disease.
      ]. These trajectories have recently been implicated in clinical outcomes, such as the propensity to develop respiratory disease [
      • Agusti A.
      • Faner R.
      Lung function trajectories in health and disease.
      ]. Studies have demonstrated that some patients never reach peak lung function but then experience ‘normal’ rates of decline [
      • Agusti A.
      • Faner R.
      Lung function trajectories in health and disease.
      ]. For others, the period of fastest decline in lung function may occur much earlier than originally thought [
      • Agusti A.
      • Faner R.
      Lung function trajectories in health and disease.
      ], hence early detection and treatment of COPD may be beneficial to reduce associated morbidity and mortality [
      • Csikesz N.G.
      • Gartman E.J.
      New developments in the assessment of COPD: early diagnosis is key.
      ]. Despite these findings, these concepts are not currently routinely considered, and COPD is often perceived as a progressive disease that responds poorly to treatment.
      Evidence suggests that COPD is underdiagnosed, with most cases identified during an exacerbation or after significant loss of lung function [
      • Martinez F.J.
      • Mannino D.
      • Leidy N.K.
      • Malley K.G.
      • Bacci E.D.
      • Barr R.G.
      • Bowler R.P.
      • Han M.K.
      • Houfek J.F.
      • Make B.
      • Meldrum C.A.
      • Rennard S.
      • Thomashow B.
      • Walsh J.
      • Yawn B.P.
      High-Risk-COPD Screening Study Group
      A new approach for identifying patients with undiagnosed chronic obstructive pulmonary disease.
      ]. The US Preventive Services Task Force continues to recommend against screening for COPD with spirometry due to a lack of data to indicate that this impacts long-term outcomes [
      • Guirguis-Blake J.M.
      • Senger C.A.
      • Webber E.M.
      • Mularski R.A.
      • Whitlock E.P.
      Screening for chronic obstructive pulmonary disease: evidence report and systematic review for the US Preventive Services Task Force.
      ], but unfortunately this has been interpreted by some as meaning that identifying and treating COPD is not beneficial. A good option for diagnosing COPD is to use systematic and targeted case-finding approaches. For example, a case-finding methodology was reported [
      • Martinez F.J.
      • Mannino D.
      • Leidy N.K.
      • Malley K.G.
      • Bacci E.D.
      • Barr R.G.
      • Bowler R.P.
      • Han M.K.
      • Houfek J.F.
      • Make B.
      • Meldrum C.A.
      • Rennard S.
      • Thomashow B.
      • Walsh J.
      • Yawn B.P.
      High-Risk-COPD Screening Study Group
      A new approach for identifying patients with undiagnosed chronic obstructive pulmonary disease.
      ] which entailed a brief five-item questionnaire (COPD Assessment in Primary Care to Identify Undiagnosed Respiratory Disease & Exacerbation Risk; CAPTURE) as an initial screen. Peak expiratory flow was then performed on a subset of patients with positive questionnaire results, to increase the accuracy of case identification [
      • Martinez F.J.
      • Mannino D.
      • Leidy N.K.
      • Malley K.G.
      • Bacci E.D.
      • Barr R.G.
      • Bowler R.P.
      • Han M.K.
      • Houfek J.F.
      • Make B.
      • Meldrum C.A.
      • Rennard S.
      • Thomashow B.
      • Walsh J.
      • Yawn B.P.
      High-Risk-COPD Screening Study Group
      A new approach for identifying patients with undiagnosed chronic obstructive pulmonary disease.
      ]. This method is currently being further evaluated in a large primary care patient population [
      • Martinez F.J.
      • Mannino D.
      • Leidy N.K.
      • Malley K.G.
      • Bacci E.D.
      • Barr R.G.
      • Bowler R.P.
      • Han M.K.
      • Houfek J.F.
      • Make B.
      • Meldrum C.A.
      • Rennard S.
      • Thomashow B.
      • Walsh J.
      • Yawn B.P.
      High-Risk-COPD Screening Study Group
      A new approach for identifying patients with undiagnosed chronic obstructive pulmonary disease.
      ]. Another potential approach involves the use of microspirometers such as the PiKo-6® device (nSpire Health, Inc.) [
      • van den Bemt L.
      • Wouters B.C.W.
      • Grootens J.
      • Denis J.
      • Poels P.J.
      • Schermer T.R.
      Diagnostic accuracy of pre-bronchodilator FEV1/FEV6 from microspirometry to detect airflow obstruction in primary care: a randomised cross-sectional study.
      ,
      • Frith P.
      • Crockett A.
      • Beilby J.
      • Marshall D.
      • Attewell R.
      • Ratnanesan A.
      • Gavagna G.
      Simplified COPD screening: validation of the PiKo-6® in primary care.
      ]. Following a postal questionnaire, patients reporting respiratory symptoms can be invited for spirometric assessment to confirm the diagnosis of COPD [
      • Jordan R.E.
      • Lam K.-b.H.
      • Cheng K.K.
      • Miller M.R.
      • Marsh J.L.
      • Ayres J.G.
      • Fitzmaurice D.
      • Adab P.
      Case finding for chronic obstructive pulmonary disease: a model for optimising a targeted approach.
      ]. When full spirometry is not available or practical, for instance during a primary care consultation, then hand-held microspirometers have been shown to reliably and quickly measure pre-bronchodilator FEV1/FEV6, and to therefore identify patients for further spirometric assessment [
      • van den Bemt L.
      • Wouters B.C.W.
      • Grootens J.
      • Denis J.
      • Poels P.J.
      • Schermer T.R.
      Diagnostic accuracy of pre-bronchodilator FEV1/FEV6 from microspirometry to detect airflow obstruction in primary care: a randomised cross-sectional study.
      ,
      • Frith P.
      • Crockett A.
      • Beilby J.
      • Marshall D.
      • Attewell R.
      • Ratnanesan A.
      • Gavagna G.
      Simplified COPD screening: validation of the PiKo-6® in primary care.
      ]. Both of these approaches may have a future role in reducing the underdiagnosis of COPD whilst also increasing the efficiency of full diagnostic spirometry use in primary care.
      Currently, management of COPD focuses on the alleviation of symptoms and prevention of the future risk of exacerbations [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. Challenges relating specifically to the management of symptoms and exacerbations are described in the relevant sections below.

      3. Goals of COPD treatment: focus on symptoms

      COPD symptoms have a considerable influence on patients' activities, health status and quality of life [
      • Agusti A.
      • Hedner J.
      • Marin J.M.
      • Barbe F.
      • Cazzola M.
      • Rennard S.
      Night-time symptoms: a forgotten dimension of COPD.
      ,
      • Roche N.
      • Chavannes N.H.
      • Miravitlles M.
      COPD symptoms in the morning: impact, evaluation and management.
      ,
      • Tsiligianni I.
      • Metting E.
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      • Chavannes N.
      • Kocks J.
      Morning and night symptoms in primary care COPD patients: a cross-sectional and longitudinal study. An UNLOCK study from the IPCRG.
      ,
      • Doyle T.
      • Palmer S.
      • Johnson J.
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      • Smith P.
      • Mabe S.
      • Welty-Wolf K.
      • Martinu T.
      • Blumenthal J.A.
      Association of anxiety and depression with pulmonary-specific symptoms in chronic obstructive pulmonary disease.
      ,
      • Miravitlles M.
      • Worth H.
      • Soler Cataluna J.J.
      • Price D.
      • De Benedetto F.
      • Roche N.
      • Godtfredsen N.S.
      • van d.M.
      • Löfdahl C.-G.
      • Padullés L.
      • Ribera A.
      Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study.
      ,
      • Lange P.
      • Marott J.L.
      • Vestbo J.
      • Nordestgaard B.G.
      Prevalence of night-time dyspnoea in COPD and its implications for prognosis.
      ,
      • Miravitlles M.
      • Anzueto A.
      • Legnani D.
      • Forstmeier L.
      • Fargel M.
      Patient's perception of exacerbations of COPD – the PERCEIVE study.
      ,
      • Monteagudo M.
      • Rodriguez-Blanco T.
      • Llagostera M.
      • Valero C.
      • Bayona X.
      • Ferrer M.
      • Miravitlles M.
      Factors associated with changes in quality of life of COPD patients: a prospective study in primary care.
      ,
      • Price D.
      • Small M.
      • Milligan G.
      • Higgins V.
      • Gil E.G.
      • Estruch J.
      Impact of night-time symptoms in COPD: a real-world study in five European countries.
      ,
      • Tsiligianni I.
      • Kocks J.
      • Tzanakis N.
      • Siafakas N.
      • van der Molen T.
      Factors that influence disease-specific quality of life or health status in patients with COPD: a review and meta-analysis of Pearson correlations.
      ,
      • Stephenson J.J.
      • Wertz D.
      • Gu T.
      • Patel J.
      • Dalal A.A.
      Clinical and economic burden of dyspnea and other COPD symptoms in a managed care setting.
      ,
      • Rennard S.
      • Decramer M.
      • Calverley P.M.
      • Pride N.B.
      • Soriano J.B.
      • Vermeire P.A.
      • Vestbo J.
      Impact of COPD in North America and Europe in 2000: subjects' perspective of confronting COPD international survey.
      ], and it is this impact that motivates some patients to seek a diagnosis [
      • Miravitlles M.
      • Ribera A.
      Understanding the impact of symptoms on the burden of COPD.
      ]. In particular, dyspnea is responsible for much of the anxiety and disability associated with COPD [
      • Doyle T.
      • Palmer S.
      • Johnson J.
      • Babyak M.A.
      • Smith P.
      • Mabe S.
      • Welty-Wolf K.
      • Martinu T.
      • Blumenthal J.A.
      Association of anxiety and depression with pulmonary-specific symptoms in chronic obstructive pulmonary disease.
      ], as it affects patients with all severities of the disease [
      • Miravitlles M.
      • Worth H.
      • Soler Cataluna J.J.
      • Price D.
      • De Benedetto F.
      • Roche N.
      • Godtfredsen N.S.
      • van d.M.
      • Löfdahl C.-G.
      • Padullés L.
      • Ribera A.
      Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study.
      ,
      • Stephenson J.J.
      • Wertz D.
      • Gu T.
      • Patel J.
      • Dalal A.A.
      Clinical and economic burden of dyspnea and other COPD symptoms in a managed care setting.
      ,
      • Miravitlles M.
      • Ribera A.
      Understanding the impact of symptoms on the burden of COPD.
      ]. The negative impact of COPD symptoms on physical activity promotes muscle deconditioning, which can lead to further dyspnea, thereby promoting a cycle of decline that results in deterioration of health status [
      • Donnell D.E.
      Impacting patient-centred outcomes in COPD: breathlessness and exercise tolerance.
      ,
      • Casaburi R.
      Activity promotion: a paradigm shift for chronic obstructive pulmonary disease therapeutics.
      ,
      • Gea J.
      • Pascual S.
      • Casadevall C.
      • Orozco-Levi M.
      • Barreiro E.
      Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings.
      ,
      • ERS Task Force
      • Palange P.
      • Ward S.A.
      • Carlsen K.H.
      • Casaburi R.
      • Gallagher C.G.
      • Gosselink R.
      • O’Donnell D.E.
      • Puente-Maestu L.
      • Schols A.M.
      • Singh S.
      • Whipp B.J.
      Recommendations on the use of exercise testing in clinical practice.
      ]. Symptoms such as dyspnea affect family life and the patient's ability to perform everyday activities, for instance household chores and walking up stairs [
      • Vermeire P.
      The burden of chronic obstructive pulmonary disease.
      ]. In addition to pulmonary symptoms, COPD can be associated with systemic features such as fatigue, weight loss and sleep disturbance, as well as psychiatric symptoms including depression and anxiety, significantly impacting quality of life [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ,
      • Stage K.B.
      • Middelboe T.
      • Stage T.B.
      • Sorensen C.H.
      Depression in COPD – management and quality of life considerations.
      ].

      3.1 Challenges of symptom recognition and management

      Despite the significant impact of COPD symptoms on patients’ lives, there is evidence that the most common respiratory symptoms, such as dyspnea, cough and sputum production, are under-reported [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. In particular, night-time symptoms and sleep disturbance are often under-recognized [
      • Agusti A.
      • Hedner J.
      • Marin J.M.
      • Barbe F.
      • Cazzola M.
      • Rennard S.
      Night-time symptoms: a forgotten dimension of COPD.
      ,
      • Lange P.
      • Marott J.L.
      • Vestbo J.
      • Nordestgaard B.G.
      Prevalence of night-time dyspnoea in COPD and its implications for prognosis.
      ]. Even in those with severe airflow limitation, many patients with COPD do not report symptoms [
      • Agusti A.
      • Calverley P.M.
      • Celli B.
      • Coxson H.O.
      • Edwards L.D.
      • Lomas D.A.
      • MacNee W.
      • Miller B.E.
      • Rennard S.
      • Silverman E.K.
      • Tal-Singer R.
      • Wouters E.
      • Yates J.C.
      • Vestbo J.
      ECLIPSE investigators
      Characterisation of COPD heterogeneity in the ECLIPSE cohort.
      ], and are often slow to discuss them with their physician [
      • Celli B.
      • Blasi F.
      • Gaga M.
      • Singh D.
      • Vogelmeier C.
      • Pegoraro V.
      • Caputo N.
      • Agusti A.
      Perception of symptoms and quality of life – comparison of patients' and physicians' views in the COPD MIRROR study.
      ] or attribute them to factors such as aging, workplace exposure to pollution or smoking [
      • Hansen E.C.
      • Walters J.
      • Baker R.W.
      Explaining chronic obstructive pulmonary disease (COPD): perceptions of the role played by smoking.
      ,
      • Tageldin M.A.
      • Nafti S.
      • Khan J.A.
      • Nejjari C.
      • Beji M.
      • Mahboub B.
      • Obeidat N.M.
      • Uzaslan E.
      • Sayiner A.
      • Wali S.
      • Rashid N.
      • El Hasnaoui A.
      Distribution of COPD-related symptoms in the Middle East and North Africa: results of the BREATHE study.
      ]. Some patients with COPD may adapt their lifestyle to compensate for symptoms, and often only present to physicians when their condition has deteriorated significantly [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. A report describing the burden and impact of COPD in North America and Europe highlighted that even patients with severe dyspnea and significant compromise of daily physical activities requiring exertion tended to underestimate their disease burden, ranking it as mild or moderate [
      • Rennard S.
      • Decramer M.
      • Calverley P.M.
      • Pride N.B.
      • Soriano J.B.
      • Vermeire P.A.
      • Vestbo J.
      Impact of COPD in North America and Europe in 2000: subjects' perspective of confronting COPD international survey.
      ]. In addition, the Medical Investigation of Respiratory COPD Perception (MIRROR) survey recently confirmed that there were differences between the perceptions that patients with COPD have of their disease and those of their physicians [
      • Celli B.
      • Blasi F.
      • Gaga M.
      • Singh D.
      • Vogelmeier C.
      • Pegoraro V.
      • Caputo N.
      • Agusti A.
      Perception of symptoms and quality of life – comparison of patients' and physicians' views in the COPD MIRROR study.
      ]. For instance, patients with severe or very severe COPD perceived their disease to have a greater impact than that perceived by their pulmonologists, particularly in terms of the impact on their quality of life (e.g. daily activities and work) [
      • Celli B.
      • Blasi F.
      • Gaga M.
      • Singh D.
      • Vogelmeier C.
      • Pegoraro V.
      • Caputo N.
      • Agusti A.
      Perception of symptoms and quality of life – comparison of patients' and physicians' views in the COPD MIRROR study.
      ].
      FEV1 is a very important parameter at the population level, for predicting clinical outcomes such as mortality and hospitalizations, or prompting consideration for non-pharmacologic procedures such as lung volume reduction or lung transplantation [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • Duong M.
      • Islam S.
      • Rangarajan S.
      • Leong D.
      • Kurmi O.
      • Teo K.
      • Killian K.
      • Dagenais G.
      • Lear S.
      • Wielgosz A.
      • Nair S.
      • Mohan V.
      • Mony P.
      • Gupta R.
      • Kumar R.
      • Rahman O.
      • Yusoff K.
      • du Plessis J.L.
      • Igumbor E.U.
      • Chifamba J.
      • Li W.
      • Lu Y.
      • Zhi F.
      • Yan R.
      • Iqbal R.
      • Ismail N.
      • Zatonska K.
      • Karsidag K.
      • Rosengren A.
      • Bahonar A.
      • Yusufali A.
      • Lamelas P.M.
      • Avezum A.
      • Lopez-Jaramillo P.
      • Lanas F.
      • O'Byrne P.M.
      • Yusuf S.
      Mortality and cardiovascular and respiratory morbidity in individuals with impaired FEV1 (PURE): an international, community-based cohort study.
      ]. However, it is important to note that, at the individual patient level, FEV1 loses precision and thus cannot be used to determine the most appropriate therapeutic option, as it does not necessarily correlate with all symptoms experienced by patients and their impact on quality of life or exacerbation frequency [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. In addition, some individuals with chronic respiratory symptoms and/or structural evidence of lung disease may have normal spirometry [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • Rodriguez-Roisin R.
      • Han M.K.
      • Vestbo J.
      • Wedzicha J.A.
      • Woodruff P.G.
      • Martinez F.J.
      Chronic respiratory symptoms with normal spirometry: a reliable clinical entity?.
      ]; therefore, healthcare professionals must consider both spirometry and symptoms when assessing patients, to avoid disease progression and the development of acute respiratory events [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. Evidence regarding the impact of COPD symptoms on younger patients (e.g. data on absenteeism, presenteeism and socio-economic status) is sparse; however, it has been reported that COPD likely represents a significant burden for patients of working age [
      • Fletcher M.J.
      • Upton J.
      • Taylor-Fishwick J.
      • Buist S.A.
      • Jenkins C.
      • Hutton J.
      • Barnes N.
      • Van Der Molen T.
      • Walsh J.W.
      • Jones P.
      • Walker S.
      COPD uncovered: an international survey on the impact of chronic obstructive pulmonary disease [COPD] on a working age population.
      ]. Lastly, although the benefits of COPD treatments are well established in terms of pulmonary symptoms, their impact on psychologic symptoms such as confidence, social interaction and sleep quality is less clear [
      • Garrod R.
      • Malerba M.
      • Crisafulli E.
      Determinants of success.
      ]. However, it has recently been shown that behavioral modifications that motivate patients to increase their daily physical activity can also improve anxiety, cognitive function and depression in patients with COPD [
      • Lavoie K.L.
      • Sedeno M.
      • Hamilton A.
      • Li P.-Z.
      • De Sousa D.
      • Troosters T.
      • Maltais F.
      • Bourbeau J.
      Behavioural interventions targeting physical activity improve psychocognitive outcomes in COPD.
      ].

      3.2 Symptom assessment

      Given the under-reporting and under-recognition of symptoms, there is a need for appropriate tools in clinical practice to identify symptoms and adjust treatment accordingly. The most efficient and accurate way for physicians to assess symptom severity, activity limitation and health-related quality of life is to use a standardized measure, such as a short patient-centered questionnaire [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. A number of questionnaires are available for assessing symptoms, yet uptake is often limited in clinical practice, most likely due to a combination of lack of awareness, difficulty in incorporating questionnaires into practice flow, or lack of electronic medical record support for questionnaires.
      The COPD Assessment Test (CAT) is a useful and practical questionnaire for clinical practice [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. CAT aims to quickly measure the impact of COPD on health-related quality of life and to facilitate patient–physician communication [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. Items covered include physical symptoms such as cough, phlegm, chest tightness, breathlessness when going up hills and stairs, activity limitation at home, and energy, as well as related factors that affect patients’ quality of life, including confidence leaving home and sleep quality [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. CAT has also been shown to be responsive to pulmonary rehabilitation and in assessing recovery from an exacerbation [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ].
      Other questionnaires include the modified Medical Research Council (mMRC) dyspnea scale, Clinical COPD Questionnaire (CCQ) and St. George's Respiratory Questionnaire (SGRQ) [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ,
      • Glaab T.
      • Vogelmeier C.
      • Buhl R.
      Outcome measures in chronic obstructive pulmonary disease (COPD): strengths and limitations.
      ,
      • Cazzola M.
      • MacNee W.
      • Martinez F.J.
      • Rabe K.F.
      • Franciosi L.G.
      • Barnes P.J.
      • Brusasco V.
      • Burge P.S.
      • Calverley P.M.
      • Celli B.R.
      • Jones P.W.
      • Mahler D.A.
      • Make B.
      • Miravitlles M.
      • Page C.P.
      • Palange P.
      • Parr D.
      • Pistolesi M.
      • Rennard S.I.
      • Rutten-van Molken M.P.
      • Stockley R.
      • Sullivan S.D.
      • Wedzicha J.A.
      • Wouters E.F.
      American thoracic society, European respiratory society Task Force on outcomes of COPD, outcomes for COPD pharmacological trials: from lung function to biomarkers.
      ,
      • Cazzola M.
      • Hanania N.A.
      • MacNee W.
      • Rudell K.
      • Hackford C.
      • Tamimi N.
      A review of the most common patient-reported outcomes in COPD – revisiting current knowledge and estimating future challenges.
      ]. Simple to administer, the mMRC dyspnea scale (0–4) is easily used to indicate the extent to which dyspnea impacts on daily activities alone; however, drawbacks include its insensitivity to change (e.g. in response to treatment), and it does not take into account the fact that patients often modify their behavior and the amount of effort exerted due to dyspnea [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. The CCQ enables a more complete understanding of the impact of COPD on patients, including a more comprehensive assessment of activity limitation and emotional dysfunction, and is a useful tool in the everyday clinical setting to assess COPD [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. Areas of assessment include symptoms (e.g. dyspnea, cough and phlegm), functional state and mental state. CCQ has also been shown to be sensitive to clinical improvement after smoking cessation, and during and after exacerbations [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ]. Lastly, while frequently used in clinical trials, the SGRQ includes numerous questions and is not suitable for use in daily clinical practice [
      • van der Molen T.
      • Miravitlles M.
      • Kocks J.W.
      COPD management: role of symptom assessment in routine clinical practice.
      ].

      4. Goals of COPD treatment: focus on exacerbations

      An exacerbation in COPD is defined as an acute worsening of respiratory symptoms that results in additional therapy [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ], and is mainly triggered by respiratory infections (mostly viral, such as rhinovirus, as well as bacterial infections), and environmental factors such as air pollution. Exacerbations associated with viral infections tend to be more severe, last longer, and require more hospitalizations (e.g. during winter) [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. Current treatment goals for exacerbations are to minimize the negative impact of the current exacerbation and reduce the risk of any future exacerbations [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. The majority of patients that experience exacerbations can be managed on an outpatient basis with pharmacologic therapies; however, some patients may require hospitalization for a number of reasons, including severity of symptoms, failure to respond to initial treatment, poor or limited home-based care, and presence of comorbidities [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. As the clinical presentation of exacerbations is heterogeneous, the GOLD report recommends that the determination of severity in hospitalized patients should be based on clinical signs [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ].

      4.1 Challenges of exacerbation management

      The long-term prognosis following hospitalization for exacerbations is poor, especially in patients with additional risk factors such as older age, comorbidities, lower body mass index and poorer quality of life [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. Some patients with COPD are particularly susceptible to frequent exacerbations, and these patients have been shown to have worse health status, morbidity and mortality than those with less frequent exacerbations [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • 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.
      ]. Despite this, many patients do not report their exacerbations to healthcare professionals [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. Patient education on when to seek medical attention for exacerbations is of vital importance. A recent Cochrane review reported that COPD self-management interventions, which include written negotiated action plans for worsening symptoms, lead to a lower probability of respiratory-related hospitalization and all-cause hospitalizations [
      • Lenferink A.
      • Brusse-Keizer M.
      • van der Valk P.D.
      • Frith P.A.
      • Zwerink M.
      • Monninkhof E.M.
      • van der Palen J.
      • Effing T.W.
      Self-management interventions including action plans for exacerbations versus usual care in patients with chronic obstructive pulmonary disease.
      ]. However, there have been concerns that health benefits from self-management programs in COPD could be counterbalanced by increased mortality [
      • Fan V.S.
      • Gaziano J.M.
      • Lew R.
      • Bourbeau J.
      • Adams S.G.
      • Leatherman S.
      • Thwin S.S.
      • Huang G.D.
      • Robbins R.
      • Sriram P.S.
      • Sharafkhaneh A.
      • Mador M.J.
      • Sarosi G.
      • Panos R.J.
      • Rastogi P.
      • Wagner T.H.
      • Mazzuca S.A.
      • Shannon C.
      • Colling C.
      • Liang M.H.
      • Stoller J.K.
      • Fiore L.
      • Niewoehner D.E.
      A comprehensive care management program to prevent chronic obstructive pulmonary disease hospitalizations: a randomized, controlled trial.
      ,
      • Peytremann-Bridevaux I.
      • Taffe P.
      • Burnand B.
      • Bridevaux P.O.
      • Puhan M.A.
      Mortality of patients with COPD participating in chronic disease management programmes: a happy end?.
      ], although this should be interpreted with caution, as not all studies have been able to replicate the data [
      • Lenferink A.
      • Brusse-Keizer M.
      • van der Valk P.D.
      • Frith P.A.
      • Zwerink M.
      • Monninkhof E.M.
      • van der Palen J.
      • Effing T.W.
      Self-management interventions including action plans for exacerbations versus usual care in patients with chronic obstructive pulmonary disease.
      ,
      • Zwerink M.
      • Brusse-Keizer M.
      • van der Valk P.D.
      • Zielhuis G.A.
      • Monninkhof E.M.
      • van der Palen J.
      • Frith P.A.
      • Effing T.
      Self management for patients with chronic obstructive pulmonary disease.
      ]. Self-management programs are not intended to replace other components of patient care; however, the authors suggest that inappropriate use of self-managed therapies by patients may delay acute healthcare, with the potential of ultimately increasing the use of in-hospital healthcare.
      COPD exacerbations are usually identified based on an increase in a variety of symptoms, including increased breathlessness and/or increased sputum production [
      • Sapey E.
      • Bafadhel M.
      • Bolton C.E.
      • Wilkinson T.
      • Hurst J.R.
      • Quint J.K.
      Building toolkits for COPD exacerbations: lessons from the past and present.
      ]. However, there are no objective criteria for measuring exacerbations, and this increase in symptoms may be an extension of regular COPD symptoms [
      • Agusti A.
      • Faner R.
      • Celli B.
      • Rodriguez-Roisin R.
      Precision medicine in COPD exacerbations.
      ]. It may also be difficult to distinguish true increased symptoms versus the patient's perception of symptoms. It has been reported that the sensation of dyspnea is enhanced in patients with COPD who experience frequent acute exacerbations and is blunted in those who suffer from exacerbations infrequently [
      • Scioscia G.
      • Blanco I.
      • Arismendi E.
      • Burgos F.
      • Gistau C.
      • Foschino Barbaro M.P.
      • Celli B.
      • O'Donnell D.E.
      • Agusti A.
      Different dyspnoea perception in COPD patients with frequent and infrequent exacerbations.
      ].
      Identifying exacerbation triggers in COPD patients is often difficult in practice. Pulmonary inflammation varies greatly between individuals, and this has proven challenging in terms of biomarker evaluation or inflammation-targeted therapeutic intervention [
      • Sapey E.
      • Bafadhel M.
      • Bolton C.E.
      • Wilkinson T.
      • Hurst J.R.
      • Quint J.K.
      Building toolkits for COPD exacerbations: lessons from the past and present.
      ]. Unlike COPD exacerbations [
      • Agusti A.
      • Faner R.
      • Celli B.
      • Rodriguez-Roisin R.
      Precision medicine in COPD exacerbations.
      ], other acute presentations of chronic diseases (e.g. myocardial infarction) have specific and sensitive diagnostic toolkits, such as biomarkers and imaging techniques, that are used in routine management of patients [
      • Sapey E.
      • Bafadhel M.
      • Bolton C.E.
      • Wilkinson T.
      • Hurst J.R.
      • Quint J.K.
      Building toolkits for COPD exacerbations: lessons from the past and present.
      ].
      Exacerbations can also be difficult to recognize, and many patients presenting with a COPD exacerbation have comorbid conditions, which complicates evaluation and management. Indeed, it may be that events recorded as exacerbations are actually a presentation of a comorbidity [
      • Kim V.
      • Aaron S.D.
      What is a COPD exacerbation? Current definitions, pitfalls, challenges and opportunities for improvement.
      ]. Some studies suggest that clinicians are less likely to diagnose comorbidities (e.g. heart failure and myocardial infarction) if there is an existing diagnosis of COPD [
      • Rothnie K.J.
      • Quint J.K.
      Chronic obstructive pulmonary disease and acute myocardial infarction: effects on presentation, management, and outcomes.
      ,
      • de Miguel Diez J.
      • Chancafe Morgan J.
      • Jimenez Garcia R.
      The association between COPD and heart failure risk: a review.
      ]. Additionally, the presence of a comorbidity has been shown to increase the duration of an exacerbation and lead to longer hospital stays [
      • Patel A.R.C.
      • Donaldson G.C.
      • Mackay A.J.
      • Wedzicha J.A.
      • Hurst J.R.
      The impact of ischemic heart disease on symptoms, health status, and exacerbations in patients with COPD.
      ,
      • Baker E.H.
      • Janaway C.H.
      • Philips B.J.
      • Brennan A.L.
      • Baines D.L.
      • Wood D.M.
      • Jones P.W.
      Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease.
      ], while there is evidence to suggest that comorbidities (e.g. asthma) may contribute to more frequent severe exacerbations [
      • Jeong S.H.
      • Lee H.
      • Carriere K.C.
      • Shin S.H.
      • Moon S.M.
      • Jeong B.-H.
      • Koh W.-J.
      • Park H.Y.
      Comorbidity as a contributor to frequent severe acute exacerbation in COPD patients.
      ].
      Many novel treatments have failed to prevent exacerbations. This may be due to the use of inappropriate or ineffective molecules, or because the concept of a single medicine treating a heterogeneous disease such as COPD is unrealistic [
      • Singh D.
      • Martin U.
      Biologics for chronic obstructive pulmonary disease: present and future.
      ]. However, personalized medicine may have a role in preventing exacerbations in some COPD patients [
      • Sidhaye V.K.
      • Nishida K.
      • Martinez F.J.
      Precision medicine in COPD: where are we and where do we need to go?.
      ,
      • Agusti A.
      • Bel E.
      • Thomas M.
      • Vogelmeier C.
      • Brusselle G.
      • Holgate S.
      • Humbert M.
      • Jones P.
      • Gibson P.G.
      • Vestbo J.
      • Beasley R.
      • Pavord I.D.
      Treatable traits: toward precision medicine of chronic airway diseases.
      ,
      • Leung J.M.
      • Obeidat M.
      • Sadatsafavi M.
      • Sin D.D.
      Introduction to precision medicine in COPD.
      ,
      • Cazzola M.
      • Calzetta L.
      • Rogliani P.
      • Matera M.G.
      The challenges of precision medicine in COPD.
      ,
      • Agusti A.
      • Bafadhel M.
      • Beasley R.
      • Bel E.H.
      • Faner R.
      • Gibson P.G.
      • Louis R.
      • McDonald V.M.
      • Sterk P.J.
      • Thomas M.
      • Vogelmeier C.
      • Pavord I.D.
      s. on behalf of all participants in the, Precision medicine in airway diseases: moving to clinical practice.
      ]. Blood eosinophil counts can help healthcare professionals to predict the probability of clinical benefit with the addition of inhaled corticosteroids (ICS) to maintenance bronchodilators [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. Treatment with macrolides may also have a role in COPD therapy. Low-dose erythromycin therapy for 12 months reduced the frequency and severity of exacerbations in patients with moderate-to-severe COPD, with an acceptable tolerability [
      • 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.
      ]. Daily azithromycin therapy has also been shown to reduce COPD exacerbations, and has been recommended for use in patients who are at risk of recurrent exacerbations [
      • 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.
      ,
      • Albert R.K.
      • Connett J.
      • Bailey W.C.
      • Casaburi R.
      • Cooper J.A.D.
      • Criner G.J.
      • Curtis J.L.
      • Dransfield M.T.
      • Han M.K.
      • Lazarus S.C.
      • Make B.
      • Marchetti N.
      • Martinez F.J.
      • Madinger N.E.
      • McEvoy C.
      • Niewoehner D.E.
      • Porsasz J.
      • Price C.S.
      • Reilly J.
      • Scanlon P.D.
      • Sciurba F.C.
      • Scharf S.M.
      • Washko G.R.
      • Woodruff P.G.
      • Anthonisen N.R.
      Azithromycin for prevention of exacerbations of COPD.
      ]. However, besides the potential to generate resistant microbes, azithromycin has been associated with a small increased risk of hearing decrements, as well as cardiovascular events relating to QT-interval prolongation in some patients with concurrent risk factors [
      • Albert R.K.
      • Connett J.
      • Bailey W.C.
      • Casaburi R.
      • Cooper J.A.D.
      • Criner G.J.
      • Curtis J.L.
      • Dransfield M.T.
      • Han M.K.
      • Lazarus S.C.
      • Make B.
      • Marchetti N.
      • Martinez F.J.
      • Madinger N.E.
      • McEvoy C.
      • Niewoehner D.E.
      • Porsasz J.
      • Price C.S.
      • Reilly J.
      • Scanlon P.D.
      • Sciurba F.C.
      • Scharf S.M.
      • Washko G.R.
      • Woodruff P.G.
      • Anthonisen N.R.
      Azithromycin for prevention of exacerbations of COPD.
      ,
      • Taylor S.P.
      • Sellers E.
      • Taylor B.T.
      Azithromycin for the prevention of COPD exacerbations: the good, bad, and ugly.
      ]. Additional subgroup analyses suggest that chronic azithromycin therapy may not benefit current smokers [
      • Han M.K.
      • Tayob N.
      • Murray S.
      • Dransfield M.T.
      • Washko G.
      • Scanlon P.D.
      • Criner G.J.
      • Casaburi R.
      • Connett J.
      • Lazarus S.C.
      • Albert R.
      • Woodruff P.
      • Martinez F.J.
      Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy.
      ]. Furthermore, data on macrolide treatment for longer than 12 months, and the use of other antibiotics for the treatment of COPD, are currently lacking.

      5. Recommendations for COPD treatment

      5.1 Control of risk factors and non-pharmacologic management

      It is important to identify and reduce COPD risk factors in the prevention and treatment of COPD [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. For instance, smoking cessation is a key intervention, and healthcare professionals are therefore encouraged to deliver smoking cessation messages and interventions to patients, such as using counseling, financial incentive programs and patient education [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • Celli B.R.
      • Wedzicha J.A.
      Update on clinical aspects of chronic obstructive pulmonary disease.
      ]. Therapies for tobacco dependence, including varenicline, sustained-release bupropion, nortriptyline, nicotine gum, nicotine inhaler, nicotine nasal spray, and nicotine patches, can be effective as quitting aids and are recommended in the absence of contraindications [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • Cahill K.
      • Stevens S.
      • Perera R.
      • Lancaster T.
      Pharmacological interventions for smoking cessation: an overview and network meta‐analysis.
      ]. In addition, reducing exposure to indoor and outdoor pollution, including biomass fuel and occupational inhalants, may require public policy changes, as well as protective steps taken by individuals [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ].
      Pulmonary rehabilitation should be considered an important component of integrated patient management [
      • Celli B.R.
      • Wedzicha J.A.
      Update on clinical aspects of chronic obstructive pulmonary disease.
      ] in combination with pharmacologic therapies. A Cochrane meta-analysis of 65 randomized controlled trials involving 3822 patients has reported that pulmonary rehabilitation can relieve dyspnea and fatigue, improve emotional function and enhance the sense of control that patients have over their condition [
      • McCarthy B.
      • Casey D.
      • Devane D.
      • Murphy K.
      • Murphy E.
      • Lacasse Y.
      Pulmonary rehabilitation for chronic obstructive pulmonary disease.
      ]. The effect with pulmonary rehabilitation was larger for quality of life domains (Chronic Respiratory Questionnaire) than the minimal clinically important difference of 0.5 units [
      • McCarthy B.
      • Casey D.
      • Devane D.
      • Murphy K.
      • Murphy E.
      • Lacasse Y.
      Pulmonary rehabilitation for chronic obstructive pulmonary disease.
      ]. In addition, statistically significant improvements were noted in all domains of the SGRQ, and both functional and maximal exercise showed statistically significant improvements [
      • McCarthy B.
      • Casey D.
      • Devane D.
      • Murphy K.
      • Murphy E.
      • Lacasse Y.
      Pulmonary rehabilitation for chronic obstructive pulmonary disease.
      ]. Similarly, another Cochrane review including 1477 patients suggested that pulmonary rehabilitation after an exacerbation can improve health-related quality of life and exercise capacity [
      • Puhan M.A.
      • Gimeno-Santos E.
      • Cates C.J.
      • Troosters T.
      Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease.
      ].
      It has been reported that patients who undertake regular physical activity have a lower risk of exacerbations, COPD hospital admissions and all-cause mortality [
      • Gimeno-Santos E.
      • Frei A.
      • Steurer-Stey C.
      • de Batlle J.
      • Rabinovich R.A.
      • Raste Y.
      • Hopkinson N.S.
      • Polkey M.I.
      • van Remoortel H.
      • Troosters T.
      • Kulich K.
      • Karlsson N.
      • Puhan M.A.
      • Garcia-Aymerich J.
      • consortium P.R.
      Determinants and outcomes of physical activity in patients with COPD: a systematic review.
      ,
      • Garcia-Aymerich J.
      • Lange P.
      • Benet M.
      • Schnohr P.
      • Antó J.M.
      Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study.
      ]. Health education can also help patients cope with their illness, and it may be effective in influencing behavioral changes (e.g. smoking cessation) and attainment of certain treatment goals [
      • World Health Organization
      ]. Lastly, influenza and pneumococcal (PCV13 and PPSV23) vaccinations are recommended for patients with COPD, in particular older patients [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. Vaccination can reduce serious illness, and some studies have shown reductions in the total number of exacerbations [
      • Wongsurakiat P.
      • Maranetra K.N.
      • Wasi C.
      • Kositanont U.
      • Dejsomritrutai W.
      • Charoenratanakul S.
      Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study.
      ,
      • Walters J.A.E.
      • Tang J.N.Q.
      • Poole P.
      • Wood‐Baker R.
      Pneumococcal vaccines for preventing pneumonia in chronic obstructive pulmonary disease.
      ,
      • Poole P.
      • Chacko E.E.
      • Wood‐Baker R.
      • Cates C.J.
      Influenza vaccine for patients with chronic obstructive pulmonary disease.
      ].

      5.2 Pharmacologic treatment

      Pharmacologic therapy for COPD is used to treat symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance and health status [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. The classes of medications commonly used to treat COPD include long-acting β2-agonists (LABAs), long-acting muscarinic antagonists (LAMAs) and ICS [
      • Celli B.R.
      • Wedzicha J.A.
      Update on clinical aspects of chronic obstructive pulmonary disease.
      ]. The choice within each class depends on the availability of medication and patients’ responses and preferences [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ].
      Once the clinical and spirometric diagnosis of COPD is confirmed, clinical guidance from the GOLD strategy report can be applied for initial pharmacologic treatment using the best available evidence, emphasizing the importance of selecting the correct treatment from the start [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. The model, involving the individualized assessment of symptoms and exacerbation risk using the ABCD assessment scheme, is shown in Fig. 1 [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. Rescue medication with short-acting bronchodilators should be prescribed for immediate symptom relief, but use of these is not generally recommended on a regular basis [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. A long-acting bronchodilator is then usually offered. In some patients, a combination treatment such as LAMA/LABA (e.g. for patients with severe breathlessness) or LABA/ICS (for patients with a high risk of exacerbations and higher blood eosinophil counts) may be offered as initial treatment [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ].
      Fig. 1
      Fig. 1Initial pharmacologic treatment of COPD.
      © 2020, Global Initiative for Chronic Obstructive Lung Disease, reproduced with permission.
      CAT, COPD Assessment Test; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; mMRC, modified Medical Research Council dyspnea scale.

      5.3 The management cycle

      Following initiation of therapy, patients should be followed up for achievement of treatment goals, and adjustments made where necessary (Fig. 2) [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. If response to initial treatment is not appropriate, it is important to consider whether symptoms or exacerbations are the predominant characteristic, and follow the most appropriate pharmacologic path, as per Fig. 3 [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. The addition of a long-acting bronchodilator is used for dyspnea; for exacerbations, either a long-acting bronchodilator or an ICS is added. Factors that favor adding an ICS include more frequent exacerbations, higher eosinophil counts, or the coexistence of bronchial asthma [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ].
      Fig. 2
      Fig. 2The management cycle of patients with COPD.
      © 2020, Global Initiative for Chronic Obstructive Lung Disease, reproduced with permission.
      Fig. 3
      Fig. 3Follow-up of pharmacologic management in patients with COPD in whom dyspnea or exacerbations predominate.
      © 2020, Global Initiative for Chronic Obstructive Lung Disease, reproduced with permission.
      Consider if eos ≥300 or ≥100 AND ≥2 moderate exacerbations or 1 hospitalization; ** Consider de-escalation of ICS or switch if pneumonia, inappropriate original indication or lack of response to ICS.
      eos, eosinophils; FEV1, forced expiratory volume in 1 s; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist.
      As most COPD pharmacotherapies are inhaled, proper inhaler technique is key [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. A recommendation in the GOLD report is that the choice of inhaler device needs to be individually tailored based on access, as well as the patient's ability and preference [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ]. Good instructions and demonstrations are critical, and technique should be assessed at each visit [
      • Global Initiative for Chronic Obstructive Lung Disease
      Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2020 report).
      ,
      • Melani A.S.
      • Bonavia M.
      • Cilenti V.
      • Cinti C.
      • Lodi M.
      • Martucci P.
      • Serra M.
      • Scichilone N.
      • Sestini P.
      • Aliani M.
      • Neri M.
      Gruppo Educazionale Associazione Italiana Pneumologi Ospedalieri, Inhaler mishandling remains common in real life and is associated with reduced disease control.
      ]. A significant relationship has been identified between poor inhaler use and symptom control in patients with COPD [
      • Melani A.S.
      • Bonavia M.
      • Cilenti V.
      • Cinti C.
      • Lodi M.
      • Martucci P.
      • Serra M.
      • Scichilone N.
      • Sestini P.
      • Aliani M.
      • Neri M.
      Gruppo Educazionale Associazione Italiana Pneumologi Ospedalieri, Inhaler mishandling remains common in real life and is associated with reduced disease control.
      ], although education can improve inhalation techniques in some patients [
      • Melani A.S.
      • Bonavia M.
      • Cilenti V.
      • Cinti C.
      • Lodi M.
      • Martucci P.
      • Serra M.
      • Scichilone N.
      • Sestini P.
      • Aliani M.
      • Neri M.
      Gruppo Educazionale Associazione Italiana Pneumologi Ospedalieri, Inhaler mishandling remains common in real life and is associated with reduced disease control.
      ,
      • Rootmensen G.N.
      • van Keimpema A.R.
      • Jansen H.M.
      • de Haan R.J.
      Predictors of incorrect inhalation technique in patients with asthma or COPD: a study using a validated videotaped scoring method.
      ]. Errors in delivery device use include low inhalation flow, multiple breaths, and exhalation into the inhaler [
      • Sulaiman I.
      • Cushen B.
      • Greene G.
      • Seheult J.
      • Seow D.
      • Rawat F.
      • MacHale E.
      • Mokoka M.
      • Moran C.N.
      • Sartini Bhreathnach A.
      • MacHale P.
      • Tappuni S.
      • Deering B.
      • Jackson M.
      • McCarthy H.
      • Mellon L.
      • Doyle F.
      • Boland F.
      • Reilly R.B.
      • Costello R.W.
      Objective assessment of adherence to inhalers by patients with chronic obstructive pulmonary disease.
      ]. Thus, inhaler technique and adherence should be assessed before concluding that the current therapy requires modification.

      6. Summary and conclusions

      Although COPD imposes a significant burden in terms of mortality and morbidity, it is both preventable (by reduction of exposure to risk factors) and treatable (by reducing COPD symptoms and exacerbations). The goals of COPD treatment include recognizing the significance of both symptoms and exacerbations when considering optimal management. The authors recommend using the best tools available to diagnose and assess COPD (including comorbidities), and combining both pharmacologic and non-pharmacologic measures for effective COPD management.

      Funding

      This work was supported by Boehringer Ingelheim .

      Declaration of competing interest

      CFV reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Mundipharma and Novartis, personal fees from Berlin Chemie/Menarini, CSL Behring, Nuvaira and Teva, and grants from the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), outside the submitted work. MR-R reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Menarini, Mundipharma, Novartis, Pfizer, Teva and Bial, and grants and personal fees from GlaxoSmithKline, outside the submitted work. DS reports personal fees from Apellis, Cipla, Genentech, Peptinnovate and Skyepharma, and grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Glenmark, Merck, Mundipharma, Novartis, Pfizer, Pulmatrix, Teva, Theravance and Verona, outside the submitted work. MKH reports personal fees from Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim and Mylan, and other from Novartis and Sunovion, outside the submitted work. RR-R has nothing to disclose. GTF reports grants, personal fees and non-financial support from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Boehringer Ingelheim, Novartis, AstraZeneca, Pearl Therapeutics and Sunovion; personal fees from Verona, Mylan, Innoviva, GlaxoSmithKline and Circassia; and grants and personal fees from Theravance, outside the submitted work.

      Acknowledgments

      Dave Singh is supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC) . Editorial support was provided by MediTech Media, London, UK and was funded by Boehringer Ingelheim .

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