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Understanding the impact of chronic obstructive pulmonary disease exacerbations on patient health and quality of life

Open AccessPublished:January 16, 2020DOI:https://doi.org/10.1016/j.ejim.2019.12.014

      Highlights

      • COPD exacerbations represent a significant clinical problem.
      • Lung function, quality of life, comorbidities and mortality outcomes are affected.
      • COPD exacerbations also have a substantial burden on healthcare systems.
      • Improving recognition of COPD exacerbations is key to minimize detrimental effects.
      • Renewed focus on improving clinical practice supported by guidelines is required.

      Abstract

      Exacerbations of chronic obstructive pulmonary disease (COPD) represent a significant clinical problem, and are associated with decreased lung function, worsening quality of life and decreased physical activity levels, with even a single exacerbation having detrimental effects. The occurrence of COPD exacerbations can also have a considerable impact on healthcare costs and mortality rates, with over one-fifth of patients hospitalized for a COPD exacerbation for the first time dying within one year of discharge. This highlights the need for COPD exacerbations to be a major focus in clinical practice. Furthermore, the substantial effect that COPD exacerbations can have on patient mental health should not be underestimated. Despite their clinical importance, COPD exacerbations are poorly recognized and reported by patients, and improving patient understanding and reporting of exacerbations to ensure prompt treatment may minimize their deleterious effects. Renewed focus on improving current clinical practice with support from evidence-based guidelines is required. This also raises a challenge to payors, healthcare systems and government policies to do more to tackle the considerable outstanding burden of COPD exacerbations.

      Keywords

      Abbreviations:

      COPD (chronic obstructive pulmonary disease), GOLD (global initiative for chronic obstructive lung disease)

      Classification

      1. Introduction

      Chronic obstructive pulmonary disease (COPD) was the third leading cause of mortality in 2016 and was responsible for an estimated 3 million deaths worldwide that year, representing a vast global problem [

      World Health Organization, 2018. Global Health Estimates 2016: Deaths by cause, age, sex, by country and by region 2000–2016. Available at: https://www.who.int/healthinfo/global_burden_disease/estimates/en/. Accessed 11 April 2019.

      ]. COPD exacerbations are responsible for the majority of the substantial burden that COPD places on healthcare systems [
      • Blasi F.
      • Cesana G.
      • Conti S.
      • Chiodini V.
      • Aliberti S.
      • Fornari C.
      • et al.
      The clinical and economic impact of exacerbations of chronic obstructive pulmonary disease: a cohort of hospitalized patients.
      ,

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ]. In the USA, the annual cost of COPD management has been shown to increase proportionally with the number of COPD exacerbations, with COPD-related costs, including pharmacy claims for COPD treatments, more than six times higher in patients experiencing frequent (≥2/year) exacerbations ($4361) compared with those who had none ($644) [
      • Patel J.G.
      • Coutinho A.D.
      • Lunacsek O.E.
      • Dalal A.A.
      COPD affects worker productivity and health care costs.
      ].
      The prevalence of COPD exacerbations is high, with over 50% of patients with COPD experiencing exacerbations in multiple long-term studies that lasted 3 years or more [
      • Hoogendoorn M.
      • Feenstra T.L.
      • Boland M.
      • Briggs A.H.
      • Borg S.
      • Jansson S.A.
      • et al.
      Prediction models for exacerbations in different COPD patient populations: comparing results of five large data sources.
      ]. Furthermore, patients can experience multiple COPD exacerbations per year: 23% of patients with a spirometry-confirmed diagnosis of COPD experienced ≥2 moderate/severe exacerbations per year, and 14% of patients experienced ≥3 exacerbations per year [
      • Thomas M.
      • Radwan A.
      • Stonham C.
      • Marshall S.
      COPD exacerbation frequency, pharmacotherapy and resource use: an observational study in UK primary care.
      ,
      • Müllerová H.
      • Shukla A.
      • Hawkins A.
      • Quint J.
      Risk factors for acute exacerbations of COPD in a primary care population: a retrospective observational cohort study.
      ].
      Additionally, exacerbations and hospitalization due to exacerbations were the outcomes that patients with COPD considered to be the most important [
      • Zhang Y.
      • Morgan R.L.
      • Alonso-Coello P.
      • Wiercioch W.
      • Bala M.M.
      • Jaeschke R.R.
      • et al.
      A systematic review of how patients value COPD outcomes.
      ]; therefore, COPD exacerbations should be a major focus in clinical practice. This review will focus on the definition, triggers, reporting and impact of COPD exacerbations.

      2. Search methods

      Relevant articles for this non-systematic, narrative literature review were identified via PubMed searches and from author knowledge. Only articles published in English were included.

      3. Definition

      The definitions for COPD exacerbations vary, but the most commonly used definitions are either symptom-based or event-driven [
      • Hawkins P.E.
      • Alam J.
      • McDonnell T.J.
      • Kelly E.
      Defining exacerbations in chronic obstructive pulmonary disease.
      ]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 report defines COPD exacerbations as acute worsenings of respiratory symptoms that require additional treatment, with dyspnea recognized as the key symptom [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ]. Other characteristics may include increased airway inflammation, mucus production, gas trapping, sputum purulence and volume, cough and wheeze [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ]. Since no diagnostic test is available in routine clinical practice, a COPD exacerbation is diagnosed when other causes of symptom changes in patients with COPD have been excluded [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ,

      Han MK, Dransfield MT, Martinez FJ, 2019. Chronic obstructive pulmonary disease: definition, clinical manifestations, diagnosis, and staging. Available at: https://www.uptodate.com/contents/chronic-obstructive-pulmonary-disease-definition-clinical-manifestations-diagnosis-and-staging#H263049556. Accessed 28 June 2019.

      ].
      The severity of COPD exacerbations can be defined as mild, moderate, or severe based on the treatment required and on whether hospitalization is needed [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ]. A mild COPD exacerbation is a worsening of symptoms that can be managed by treatment with short-acting bronchodilators only, although some definitions do not include a requirement for treatment [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ,
      • Wedzicha J.A.
      • Banerji D.
      • Chapman K.R.
      • Vestbo J.
      • Roche N.
      • Ayers R.T.
      • et al.
      Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD.
      ]. Moderate COPD exacerbations require treatment with antibiotics and/or oral corticosteroids [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ]. Severe COPD exacerbations require hospitalization or emergency room visits, and patients may also have acute respiratory failure, which can be life-threatening [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ]. The definition of COPD exacerbation severity should not be confused with the definition of COPD severity, which is classed as mild-to-very severe based on airflow limitation [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ]. Although the classification of exacerbation severity is useful for clinical studies, the severity of a patient's illness in clinical practice should represent a composite of the severity of the underlying disease, the severity and frequency of exacerbations, and any comorbidities. There are also other limitations to these definitions; for example, there are inherent difficulties in validating patient-reported symptoms, patient access to healthcare, the social and financial situation of patients, and the presence of differential diagnoses in patients with COPD, which may mimic an exacerbation [
      • Hurst J.R.
      • Wedzicha J.A.
      What is (and what is not) a COPD exacerbation: thoughts from the new GOLD guidelines.
      ].

      4. Differential diagnosis

      Differential diagnoses of COPD exacerbations include pneumonia, pneumothorax, pleural effusion, pulmonary embolism, cardiac arrhythmias, and cardiac-related pulmonary edema [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ].
      Difficulties in distinguishing between a COPD exacerbation and pneumonia can occur, since symptoms overlap [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ,
      • Hurst J.R.
      Consolidation and exacerbation of COPD.
      ], and a history of COPD exacerbations is significantly associated with the occurrence of pneumonia in patients with COPD [
      • Müllerová H.
      • Chigbo C.
      • Hagan G.W.
      • Woodhead M.A.
      • Miravitlles M.
      • Davis K.J.
      • et al.
      The natural history of community-acquired pneumonia in COPD patients: a population database analysis.
      ]. Additionally, short- and long-term outcomes in hospitalized patients with COPD who have pneumonia and those who have COPD exacerbations are similar [
      • Huerta A.
      • Crisafulli E.
      • Menéndez R.
      • Martinez R.
      • Soler N.
      • Guerrero M.
      • et al.
      Pneumonic and nonpneumonic exacerbations of COPD: inflammatory response and clinical characteristics.
      ]. Pneumonia is frequently underdiagnosed in patients hospitalized with a COPD exacerbation [
      • Hurst J.R.
      Consolidation and exacerbation of COPD.
      ,
      • Finney L.J.
      • Padmanaban V.
      • Todd S.
      • Ahmed N.
      • Elkin S.L.
      • Mallia P.
      Validity of the diagnosis of pneumonia in hospitalised patients with COPD.
      ], and conversely, experience from external adjudication committees, which are often used in clinical trials, has shown that pneumonia can be overdiagnosed (i.e., not confirmed) in patients with COPD. Importantly, findings indicate that patients with COPD who also have pneumonia should potentially be treated differently than those experiencing an exacerbation [
      • Hurst J.R.
      Consolidation and exacerbation of COPD.
      ,
      • Scholl T.
      • Kiser T.H.
      • Vondracek S.F.
      Evaluation of systemic corticosteroids in patients with an acute exacerbation of COPD and a diagnosis of pneumonia.
      ].
      Systematic reviews and meta-analyses highlighted that up to one quarter of patients hospitalized with a suspected COPD exacerbation have a pulmonary embolism [
      • Rizkallah J.
      • Man S.F.P.
      • Sin D.D.
      Prevalence of pulmonary embolism in acute exacerbations of COPD: a systematic review and metaanalysis.
      ,
      • Aleva F.E.
      • Voets L.W.L.M.
      • Simons S.O.
      • de Mast Q.
      • van der Ven A.J.A.M.
      • Heijdra Y.F.
      Prevalence and localization of pulmonary embolism in unexplained acute exacerbations of COPD: a systematic review and meta-analysis.
      ], with similar symptoms observed between patients who did and did not have a pulmonary embolism [
      • Rizkallah J.
      • Man S.F.P.
      • Sin D.D.
      Prevalence of pulmonary embolism in acute exacerbations of COPD: a systematic review and metaanalysis.
      ]. Additionally, many patients with COPD exacerbations have cardiac arrhythmias [
      • Rusinowicz T.
      • Zielonka T.M.
      • Zycinska K.
      Cardiac arrhythmias in patients with exacerbation of COPD.
      ], and the presence of heart failure alongside COPD is common, resulting in diagnostic challenges in these patients since the symptoms for exacerbations of both diseases overlap [
      • Hawkins N.M.
      • Petrie M.C.
      • Jhund P.S.
      • Chalmers G.W.
      • Dunn F.G.
      • McMurray J.J.V.
      Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls and epidemiology.
      ,
      • Minasian A.G.
      • van den Elshout F.J.J.
      • Dekhuijzen P.N.R.
      • Vos P.J.E.
      • Willems F.F.
      • van den Bergh P.J.P.C.
      • et al.
      COPD in chronic heart failure: less common than previously thought?.
      • Hawkins N.M.
      • Virani S.
      • Ceconi C.
      Heart failure and chronic obstructive pulmonary disease: the challenges facing physicians and health services.
      ].
      Therefore, misdiagnosis of COPD exacerbations is a potential risk, which could result in inappropriate treatment. With COPD diagnosis, as is true for all medical conditions, it is important to be aware of the relevant differential diagnoses, and to decide which should be further investigated, depending on their importance and likelihood.

      5. Triggers

      COPD exacerbations can be triggered by a variety of factors, including respiratory infections (bacteria, fungi and, most importantly, viruses), variations in outdoor temperature and air pollution [
      • Sama S.R.
      • Kriebel D.
      • Gore R.J.
      • DeVries R.
      • Rosiello R.
      Environmental triggers of COPD symptoms: a case cross-over study.
      ]. Consequently, a patient's exacerbation frequency can vary from year to year [
      • Han M.K.
      • Quibrera P.M.
      • Carretta E.E.
      • Barr R.G.
      • Bleecker E.R.
      • Bowler R.P.
      • et al.
      Frequency of exacerbations in patients with chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort.
      ], and also seasonally. The incidence of exacerbations is ~2-fold higher in the winter versus the summer [
      • Jenkins C.R.
      • Celli B.
      • Anderson J.A.
      • Ferguson G.T.
      • Jones P.W.
      • Vestbo J.
      • et al.
      Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study.
      ,
      • Wise R.A.
      • Calverley P.M.A.
      • Carter K.
      • Clerisme-Beaty E.
      • Metzdorf N.
      • Anzueto A.
      Seasonal variations in exacerbations and deaths in patients with COPD during the TIOSPIR trial.
      ], potentially due to an increased prevalence of respiratory viral infections [
      • Jenkins C.R.
      • Celli B.
      • Anderson J.A.
      • Ferguson G.T.
      • Jones P.W.
      • Vestbo J.
      • et al.
      Seasonality and determinants of moderate and severe COPD exacerbations in the TORCH study.
      ,
      • Donaldson G.C.
      • Wedzicha J.A.
      The causes and consequences of seasonal variation in COPD exacerbations.
      ]. Furthermore, exacerbations that occur in the winter, when respiratory viruses are more prevalent in the community, are associated with slow symptom recovery [
      • Aaron S.D.
      • Donaldson G.C.
      • Whitmore G.A.
      • Hurst J.R.
      • Ramsay T.
      • Wedzicha J.A.
      Time course and pattern of COPD exacerbation onset.
      ]. In the UK, the presence of pneumonic infiltrates during an exacerbation was more common in winter than in summer, and was associated with increased systemic inflammation [
      • Williams N.P.
      • Ostridge K.
      • Devaster J.M.
      • Kim V.
      • Coombs N.A.
      • Bourne S.
      • et al.
      Impact of radiologically stratified exacerbations: insights into pneumonia aetiology in COPD.
      ].
      Additional independent risk factors for patients experiencing frequent exacerbations (≥2 per year) have been reported; these include: (i) demographic characteristics (such as being female); (ii) disease characteristics (increased dyspnea, reduced lung function, poorer quality of life, and prior exacerbations [strongest association]); (iii) comorbidities (such as cardiovascular events, depression, and a history of gastroesophageal reflux or heartburn); and (iv) potential biomarkers such as an elevated white blood cell count (Fig. 1) [
      • Müllerová H.
      • Shukla A.
      • Hawkins A.
      • Quint J.
      Risk factors for acute exacerbations of COPD in a primary care population: a retrospective observational cohort study.
      ,
      • McGarvey L.
      • Lee A.J.
      • Roberts J.
      • Gruffydd-Jones K.
      • McKnight E.
      • Haughney J.
      Characterisation of the frequent exacerbator phenotype in COPD patients in a large UK primary care population.
      ,
      • Hurst J.R.
      • Vestbo J.
      • Anzueto A.
      • Locantore N.
      • Müllerová H.
      • Tal-Singer R.
      • et al.
      Susceptibility to exacerbation in chronic obstructive pulmonary disease.
      ].
      Fig 1
      Fig. 1Independent risk factors associated with frequent exacerbations [
      • Müllerová H.
      • Shukla A.
      • Hawkins A.
      • Quint J.
      Risk factors for acute exacerbations of COPD in a primary care population: a retrospective observational cohort study.
      ,
      • McGarvey L.
      • Lee A.J.
      • Roberts J.
      • Gruffydd-Jones K.
      • McKnight E.
      • Haughney J.
      Characterisation of the frequent exacerbator phenotype in COPD patients in a large UK primary care population.
      ,
      • Hurst J.R.
      • Vestbo J.
      • Anzueto A.
      • Locantore N.
      • Müllerová H.
      • Tal-Singer R.
      • et al.
      Susceptibility to exacerbation in chronic obstructive pulmonary disease.
      ,
      • Zeiger R.S.
      • Tran T.N.
      • Butler R.K.
      • Schatz M.
      • Li Q.
      • Khatry D.B.
      • et al.
      Relationship of blood eosinophil count to exacerbations in chronic obstructive pulmonary disease.
      ].
      In addition, high blood eosinophil counts are an independent risk factor for the occurrence of future exacerbations [
      • Zeiger R.S.
      • Tran T.N.
      • Butler R.K.
      • Schatz M.
      • Li Q.
      • Khatry D.B.
      • et al.
      Relationship of blood eosinophil count to exacerbations in chronic obstructive pulmonary disease.
      ], and pulmonary artery enlargement (i.e., a ratio of the diameter of the pulmonary artery to the diameter of the aorta of >1, a marker of pulmonary hypertension) has been significantly associated with an increased risk of future severe exacerbations [
      • Wells J.M.
      • Washko G.R.
      • Han M.K.
      • Abbas N.
      • Nath H.
      • Mamary A.J.
      • et al.
      Pulmonary arterial enlargement and acute exacerbations of COPD.
      ]. However, no plasma or serum protein biomarker has been shown to be independently predictive of the occurrence of COPD exacerbations across different patient cohorts [
      • Keene J.D.
      • Jacobson S.
      • Kechris K.
      • Kinney G.L.
      • Foreman M.G.
      • Doerschuk C.M.
      • et al.
      Biomarkers predictive of exacerbations in the SPIROMICS and COPDGene cohorts.
      ].
      COPD exacerbations are more common in patients with higher severity of airflow limitation, a higher symptom burden and a higher frequency of previous exacerbations. Annual exacerbation rates have been reported to at least double between patients with mild-to-moderate airflow limitation and those with very severe airflow limitation [
      • Thomas M.
      • Radwan A.
      • Stonham C.
      • Marshall S.
      COPD exacerbation frequency, pharmacotherapy and resource use: an observational study in UK primary care.
      ,
      • Overbeek J.A.
      • Penning-van Beest F.J.A.
      • Balp M.M.
      • Dekhuijzen P.N.
      • Herings R.M.C.
      Burden of exacerbations in patients with moderate to very severe COPD in the Netherlands: a real-life study.
      ]. Moreover, in another study, annual exacerbation rates increased ~3-fold between patients with a low symptom burden and exacerbation risk and those with a high symptom burden and exacerbation risk [
      • Merinopoulou E.
      • Raluy-Callado M.
      • Ramagopalan S.
      • MacLachlan S.
      • Khalid J.M.
      COPD exacerbations by disease severity in England.
      ].

      6. Under-recognition and under-reporting

      Exacerbation recognition and reporting by patients is generally poor. Almost three-quarters of patients have difficulties with understanding the term ‘exacerbation’ [
      • Korpershoek Y.J.G.
      • Vervoort S.C.J.M.
      • Nijssen L.I.T.
      • Trappenburg J.C.A.
      • Schuurmans M.J.
      Factors influencing exacerbation-related self-management in patients with COPD: a qualitative study.
      ], and ~40% of patients do not immediately take action (e.g., contacting their healthcare provider; increasing their medication dose, or taking a different medication; resting; or reducing or stopping smoking) when they experience an exacerbation [
      • Barnes N.
      • Calverley P.M.A.
      • Kaplan A.
      • Rabe K.F.
      Chronic obstructive pulmonary disease and exacerbations: patient insights from the global Hidden Depths of COPD survey.
      ].
      Factors that have the potential to influence exacerbation reporting include access to healthcare, distance from the clinic, availability of personal and public transport, the ability to travel to a clinic (for example, if the patient is on oxygen therapy), and limited resources that may prevent general practitioners from making home visits. Unreported COPD exacerbations are associated with slower recovery [
      • Jones P.W.
      • Lamarca R.
      • Chuecos F.
      • Singh D.
      • Agusti A.
      • Bateman E.D.
      • et al.
      Characterisation and impact of reported and unreported exacerbations: results from ATTAIN.
      ], and prompt recognition, reporting, and treatment of COPD exacerbations reduces the duration of symptoms [
      • Wilkinson T.M.
      • Donaldson G.C.
      • Hurst J.R.
      • Seemungal T.A.
      • Wedzicha J.A.
      Early therapy improves outcomes of exacerbations of chronic obstructive pulmonary disease.
      ]. Patients who do not report COPD exacerbations remain untreated with maintenance or preventive therapies, highlighting the fact that defining exacerbations based on the treatment provided may not provide a complete picture. Furthermore, exacerbations may not be recognized in patients with undiagnosed COPD; for example, a smoker who receives antibiotics or oral corticosteroids for the treatment of bronchitis may be experiencing a COPD exacerbation.

      7. Effect on symptom duration

      Even a single COPD exacerbation has the potential to result in a significant decrease in lung function [
      • Halpin D.M.G.
      • Decramer M.
      • Celli B.R.
      • Mueller A.
      • Metzdorf N.
      • Tashkin D.P.
      Effect of a single exacerbation on decline in lung function in COPD.
      ] and an increase in the risk of further exacerbations [
      • Suissa S.
      • Dell'Aniello S.
      • Ernst P.
      Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality.
      ]. Data collected during a randomized controlled trial showed that patients who had experienced ≥1 exacerbation of any severity since their last study visit had a significantly reduced quality of life, compared with those who had not experienced an exacerbation [
      • Roche N.
      • Wedzicha J.A.
      • Patalano F.
      • Frent S.M.
      • Larbig M.
      • Shen S.
      • et al.
      COPD exacerbations significantly impact quality of life as measured by SGRQ-C total score: results from the FLAME study.
      ]. Additionally, in the 2–3 months following a severe exacerbation, patients were at their greatest risk of suffering from another exacerbation [
      • Suissa S.
      • Dell'Aniello S.
      • Ernst P.
      Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality.
      ]. Each exacerbation further increased the risk of experiencing another event; compared with a first severe exacerbation, the risk of a subsequent severe exacerbation was increased 3-fold following a second severe exacerbation and 24-fold following a tenth severe exacerbation [
      • Suissa S.
      • Dell'Aniello S.
      • Ernst P.
      Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality.
      ]. The duration of an exacerbation is also linked to an increased risk of further exacerbations and poorer health status in patients with COPD exacerbations [
      • Donaldson G.C.
      • Law M.
      • Kowlessar B.
      • Singh R.
      • Brill S.E.
      • Allinson J.P.
      • et al.
      Impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease.
      ]. Exacerbations in which lung function did not recover were associated with viral infection symptoms and an accelerated lung function decline [
      • Donaldson G.C.
      • Law M.
      • Kowlessar B.
      • Singh R.
      • Brill S.E.
      • Allinson J.P.
      • et al.
      Impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease.
      ]. Together, these findings show that even one exacerbation can have harmful effects on the patient and highlight the importance of recognizing COPD exacerbations, as prompt treatment may decrease symptoms and lung function decline. A key aim in clinical practice should be to minimize the rate of exacerbations experienced by patients with COPD.

      8. Effect on lung function

      Many studies have reported the detrimental impact of COPD exacerbations on lung function. COPD exacerbations are associated with accelerated lung function loss, particularly in patients with mild airflow limitation and severe exacerbations [
      • Dransfield M.T.
      • Kunisaki K.M.
      • Strand M.J.
      • Anzueto A.
      • Bhatt S.P.
      • Bowler R.P.
      • et al.
      Acute exacerbations and lung function loss in smokers with and without chronic obstructive pulmonary disease.
      ]. Additionally, patients who have frequent COPD exacerbations are generally the most symptomatic and have the largest decline in lung function [
      • Kania A.
      • Krenke R.
      • Kuziemski K.
      • Czajkowska-Malinowska M.
      • Celejewska-Wojcik N.
      • Kuznar-Kaminska B.
      • et al.
      Distribution and characteristics of COPD phenotypes - results from the Polish sub-cohort of the POPE study.
      ,
      • Donaldson G.C.
      • Seemungal T.A.R.
      • Bhowmik A.
      • Wedzicha J.A.
      Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.
      ].
      Recovery of lung function following an exacerbation can be prolonged, with findings showing that for 25% of exacerbations, lung function does not return to the patients’ pre-exacerbation levels 5 weeks after the event, and that for 7% of exacerbations, lung function does not return to the patients’ pre-exacerbation levels after 3 months [
      • Seemungal T.A.R.
      • Donaldson G.C.
      • Bhowmik A.
      • Jeffries D.J.
      • Wedzicha J.A.
      Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease.
      ]. Therefore, patients should be monitored until they have fully recovered from their COPD exacerbation [
      • Seemungal T.A.R.
      • Donaldson G.C.
      • Bhowmik A.
      • Jeffries D.J.
      • Wedzicha J.A.
      Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease.
      ]. While a long symptom duration during a COPD exacerbation was associated with an increased risk of further exacerbations [
      • Donaldson G.C.
      • Law M.
      • Kowlessar B.
      • Singh R.
      • Brill S.E.
      • Allinson J.P.
      • et al.
      Impact of prolonged exacerbation recovery in chronic obstructive pulmonary disease.
      ], a fast recovery in lung function following treatment has been shown to be significantly associated with a lower risk for COPD exacerbations [
      • Martin A.L.
      • Marvel J.
      • Fahrbach K.
      • Cadarette S.M.
      • Wilcox T.K.
      • Donohue J.F.
      The association of lung function and St. George's Respiratory Questionnaire with exacerbations in COPD: a systematic literature review and regression analysis.
      ].

      9. Effect on quality of life and physical activity

      COPD exacerbations affect many different factors relating to patient quality of life. As expected, patients who experienced frequent exacerbations (≥3/year) had a significantly reduced quality of life compared with patients who experienced less frequent exacerbations (<3/year) [
      • Seemungal T.A.
      • Donaldson G.C.
      • Paul E.A.
      • Bestall J.C.
      • Jeffries D.J.
      • Wedzicha J.A.
      Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease.
      ]. Furthermore, the severity of a COPD exacerbation has been shown to correlate with quality of life. Patients who had a recent severe COPD exacerbation had higher levels of activity impairment and reduced health-related quality of life when compared with those who had a recent moderate COPD exacerbation [
      • Solem C.T.
      • Sun S.X.
      • Sudharshan L.
      • Macahilig C.
      • Katyal M.
      • Gao X.
      Exacerbation-related impairment of quality of life and work productivity in severe and very severe chronic obstructive pulmonary disease.
      ]. However, even a mild COPD exacerbation can adversely impact patient health-related quality of life [
      • Sato M.
      • Chubachi S.
      • Sasaki M.
      • Haraguchi M.
      • Kameyama N.
      • Tsutsumi A.
      • et al.
      Impact of mild exacerbation on COPD symptoms in a Japanese cohort.
      ]. Conversely, a better health-related quality of life has been associated with a lower risk for COPD exacerbations [
      • Martin A.L.
      • Marvel J.
      • Fahrbach K.
      • Cadarette S.M.
      • Wilcox T.K.
      • Donohue J.F.
      The association of lung function and St. George's Respiratory Questionnaire with exacerbations in COPD: a systematic literature review and regression analysis.
      ].
      A global patient survey revealed that the majority of patients with COPD felt that exacerbations prevented them from making plans for the future and impacted daily activities such as walking, sleeping, and speaking [
      • Barnes N.
      • Calverley P.M.A.
      • Kaplan A.
      • Rabe K.F.
      Chronic obstructive pulmonary disease and exacerbations: patient insights from the global Hidden Depths of COPD survey.
      ]. Consistent with this, increased daytime sleepiness, decreased total sleep time, decreased sleep efficiency, and levels of fatigue have been reported during an exacerbation [
      • Vanaparthy R.
      • Mota P.
      • Khan R.
      • Ehsan M.
      • Qureshi A.
      • ZuWallack R.
      • et al.
      A longitudinal assessment of sleep variables during exacerbations of chronic obstructive pulmonary disease.
      ,
      • Baghai-Ravary R.
      • Quint J.K.
      • Goldring J.J.P.
      • Hurst J.R.
      • Donaldson G.C.
      • Wedzicha J.A.
      Determinants and impact of fatigue in patients with chronic obstructive pulmonary disease.
      ]. In addition, COPD has previously been associated with sexual dysfunction in males, particularly erectile dysfunction, with most patients dissatisfied with their current and expected sexual function [
      • Kahraman H.
      • Sen B.
      • Koksal N.
      • Kilinc M.
      • Resim S.
      Erectile dysfunction and sex hormone changes in chronic obstructive pulmonary disease patients.
      ,
      • Collins E.G.
      • Halabi S.
      • Langston M.
      • Schnell T.
      • Tobin M.J.
      • Laghi F.
      Sexual dysfunction in men with COPD: impact on quality of life and survival.
      ]. How COPD exacerbations affect sexual functioning has not yet been fully elucidated, but sex hormone levels have been shown to be markedly altered during a COPD exacerbation [
      • Karadag F.
      • Ozcan H.
      • Karul A.B.
      • Yilmaz M.
      • Cildag O.
      Sex hormone alterations and systemic inflammation in chronic obstructive pulmonary disease.
      ], which may have resulted in sexual dysfunction.
      Hospitalization due to a COPD exacerbation has been shown to result in physical and functional impairment in patients, which deteriorates further between discharge from hospital and 1 month following the exacerbation [
      • Torres-Sánchez I.
      • Cabrera-Martos I.
      • Díaz-Pelegrina A.
      • Valenza-Demet G.
      • Moreno-Ramírez M.P.
      • Valenza M.C.
      Physical and functional impairment during and after hospitalization in subjects with severe COPD exacerbation.
      ]. Exercise capacity and muscle strength were found to decrease when patients suffered even a moderate COPD exacerbation [
      • Alahmari A.D.
      • Kowlessar B.S.
      • Patel A.R.C.
      • Mackay A.J.
      • Allinson J.P.
      • Wedzicha J.A.
      • et al.
      Physical activity and exercise capacity in patients with moderate COPD exacerbations.
      ] and reduced physical activity levels were associated with an increased risk of further exacerbations and mortality [
      • Gimeno-Santos E.
      • Frei A.
      • Steurer-Stey C.
      • de Batlle J.
      • Rabinovich R.A.
      • Raste Y.
      • et al.
      Determinants and outcomes of physical activity in patients with COPD: a systematic review.
      ]. Additionally, patients with COPD exacerbations may have balance impairments that are associated with increased dyspnea and reduced muscle strength, which may contribute to the high incidence of falls experienced by these patients following hospitalization [
      • Oliveira C.C.
      • Lee A.L.
      • McGinley J.
      • Anderson G.P.
      • Clark R.A.
      • Thompson M.
      • et al.
      Balance and falls in acute exacerbation of chronic obstructive pulmonary disease: a prospective study.
      ].
      Hence, a decrease in physical activity levels following a COPD exacerbation can lead to reduced muscle strength, resulting in further physical impairment in patients. The link between COPD exacerbations, physical activity and depression is discussed further on in this review.

      10. Mortality

      COPD exacerbations have a major impact on mortality [
      • Suissa S.
      • Dell'Aniello S.
      • Ernst P.
      Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality.
      ,
      • Ho T.W.
      • Tsai Y.J.
      • Ruan S.Y.
      • Huang C.T.
      • Lai F.
      • Yu C.J.
      • et al.
      In-hospital and one-year mortality and their predictors in patients hospitalized for first-ever chronic obstructive pulmonary disease exacerbations: a nationwide population-based study.
      ]. Mortality after a severe exacerbation has been found to peak in the first week following hospitalization [
      • Suissa S.
      • Dell'Aniello S.
      • Ernst P.
      Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality.
      ], and a UK national audit in 2014 determined an inpatient mortality rate of 4.3% in patients hospitalized for a COPD exacerbation [

      Stone A, Holzhauer-Barrie J, Lowe D, McMillan V, Saleem Khan M, Searle L, et al., 2017. COPD: Who cares when it matters most? National Chronic Obstructive Pulmonary Disease (COPD) Audit Programme: Outcomes from the clinical audit of COPD exacerbations admitted to acute units in England 2014. Results and data analysis. Available at: https://www.rcplondon.ac.uk/projects/outputs/copd-who-cares-when-it-matters-most-outcomes-report-2014. Accessed 9 May 2019.

      ]. Furthermore, a meta-analysis of studies that followed patients for at least 1.5 years after hospital admission reported a predicted case fatality rate of 16%, defined as the ‘excess mortality that results from a COPD exacerbation’ [
      • Hoogendoorn M.
      • Hoogenveen R.T.
      • Rutten-van Molken M.P.
      • Vestbo J.
      • Feenstra T.L.
      Case fatality of COPD exacerbations: a meta-analysis and statistical modelling approach.
      ]. In patients with COPD hospitalized for an exacerbation for the first time, more than one in five died within 1 year of discharge [
      • Ho T.W.
      • Tsai Y.J.
      • Ruan S.Y.
      • Huang C.T.
      • Lai F.
      • Yu C.J.
      • et al.
      In-hospital and one-year mortality and their predictors in patients hospitalized for first-ever chronic obstructive pulmonary disease exacerbations: a nationwide population-based study.
      ] and only one-half of patients were alive within 3.6 years [
      • Suissa S.
      • Dell'Aniello S.
      • Ernst P.
      Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality.
      ]. Moderate and severe exacerbations were associated with an increased mortality risk, which increased with exacerbation frequency [
      • Soler-Cataluña J.J.
      • Martínez-García M.A.
      • Román Sánchez P.
      • Salcedo E.
      • Navarro M.
      • Ochando R.
      Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.
      ,
      • Rothnie K.J.
      • Mullerova H.
      • Smeeth L.
      • Quint J.K.
      Natural history of chronic obstructive pulmonary disease exacerbations in a general practice-based population with chronic obstructive pulmonary disease.
      ].

      11. Impact on mental health

      In one study, COPD exacerbations were associated with moderate-to-severe depression in nearly half of patients who had experienced exacerbation episodes in the previous year, moderate-to-severe anxiety in more than two-thirds of patients, and post-traumatic stress symptoms in one-third of patients [
      • Teixeira P.J.
      • Porto L.
      • Kristensen C.H.
      • Santos A.H.
      • Menna-Barreto S.S.
      • Do Prado-Lima P.A.S.
      Post-traumatic stress symptoms and exacerbations in COPD patients.
      ]. Symptoms of anxiety, depression, and post-traumatic stress have been more commonly reported in patients with frequent COPD exacerbations (≥2) versus patients with ≤1 COPD exacerbation in the previous year [
      • Kania A.
      • Krenke R.
      • Kuziemski K.
      • Czajkowska-Malinowska M.
      • Celejewska-Wojcik N.
      • Kuznar-Kaminska B.
      • et al.
      Distribution and characteristics of COPD phenotypes - results from the Polish sub-cohort of the POPE study.
      ,
      • Teixeira P.J.
      • Porto L.
      • Kristensen C.H.
      • Santos A.H.
      • Menna-Barreto S.S.
      • Do Prado-Lima P.A.S.
      Post-traumatic stress symptoms and exacerbations in COPD patients.
      ]. However, a study comparing the results of patient interviews with physician assessments found that physicians may underestimate the psychological impact of exacerbations on patients [
      • Kessler R.
      • Ståhl E.
      • Vogelmeier C.
      • Haughney J.
      • Trudeau E.
      • Lofdahl C.G.
      • et al.
      Patient understanding, detection, and experience of COPD exacerbations: an observational, interview-based study.
      ], highlighting the importance of raising physician awareness of these comorbid mental health issues.
      Depression and anxiety are also associated with a decrease in physical activity and worsening health-related quality of life, and with increased respiratory symptoms and risk of hospitalization, mortality, and further exacerbations [
      • Atlantis E.
      • Fahey P.
      • Cochrane B.
      • Smith S.
      Bidirectional associations between clinically relevant depression or anxiety and COPD: a systematic review and meta-analysis.
      ,
      • Pooler A.
      • Beech R.
      Examining the relationship between anxiety and depression and exacerbations of COPD which result in hospital admission: a systematic review.
      • Lou P.
      • Zhu Y.
      • Chen P.
      • Zhang P.
      • Yu J.
      • Zhang N.
      • et al.
      Prevalence and correlations with depression, anxiety, and other features in outpatients with chronic obstructive pulmonary disease in China: a cross-sectional case control study.
      ]. Decreases in physical activity have also been associated with higher levels of depression in patients with a moderate COPD exacerbation [
      • Alahmari A.D.
      • Kowlessar B.S.
      • Patel A.R.C.
      • Mackay A.J.
      • Allinson J.P.
      • Wedzicha J.A.
      • et al.
      Physical activity and exercise capacity in patients with moderate COPD exacerbations.
      ]. These findings suggest that, for some patients, decreased physical activity after a COPD exacerbation may result in them becoming housebound, which may, in turn, increase patient depression, thereby creating a vicious cycle, which could lead to further impairments in physical activity for the patient (Fig. 2).
      Fig 2
      Fig. 2Downward spiral of COPD exacerbations.
      COPD, chronic obstructive pulmonary disease.
      Prescription data in hospice patients with end-stage COPD – who most likely have severe or very severe airflow limitation, a high symptom burden, and a high risk of exacerbations – have shown that 58.5% were prescribed anxiolytics, 42.4% were prescribed antipsychotics, 19.1% were prescribed antidepressants, and 3.1% were prescribed nonbenzodiazepine hypnotics [
      • Afrane M.
      • Sera L.
      • Holmes H.M.
      • McPherson M.L.
      Commonly prescribed medications among patients in hospice care for chronic obstructive pulmonary disease.
      ]. These data indicate that mental health issues may be prevalent in hospice patients with end-stage COPD who are at high risk of COPD exacerbations. However, it has been proposed that time-limited anxiety and depression symptoms that occur during COPD exacerbations do not require treatment [
      • Tselebis A.
      • Pachi A.
      • Ilias I.
      • Kosmas E.
      • Bratis D.
      • Moussas G.
      • et al.
      Strategies to improve anxiety and depression in patients with COPD: a mental health perspective.
      ], since the exacerbation may be resolved by the time these treatments exert their effects.
      COPD not only affects the mental health of patients with COPD; almost two-thirds of people caring for patients with COPD reported anxiety symptoms and approximately one-third reported depression symptoms [
      • Jácome C.
      • Figueiredo D.
      • Gabriel R.
      • Cruz J.
      • Marques A.
      Predicting anxiety and depression among family carers of people with chronic obstructive pulmonary disease.
      ]. Perceived caregiver burden and patient activity limitation were identified as predictors of anxiety and depression symptoms in caregivers [
      • Jácome C.
      • Figueiredo D.
      • Gabriel R.
      • Cruz J.
      • Marques A.
      Predicting anxiety and depression among family carers of people with chronic obstructive pulmonary disease.
      ].

      12. Association with other comorbidities

      COPD exacerbations have been linked to many different comorbidities, with the presence and number of comorbidities significantly associated with the length and cost of hospitalization [
      • Terzano C.
      • Colamesta V.
      • Unim B.
      • Romani S.
      • Meneghini A.
      • Volpe G.
      • et al.
      Chronic obstructive pulmonary disease (COPD) exacerbation: impact of comorbidities on length and costs during hospitalization.
      ]. Additionally, patients with two mild or one severe comorbidity are at an increased risk of exacerbation recurrence [
      • Almagro P.
      • Cabrera F.J.
      • Diez J.
      • Boixeda R.
      • Alonso Ortiz M.B.
      • Murio C.
      • et al.
      Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de Medicina Interna (ESMI) study.
      ].
      Alongside mental health comorbidities, physical comorbidities such as hypertension, diabetes mellitus, chronic heart failure, ischemic heart disease, anemia, and dyslipidemia are common in patients hospitalized for a COPD exacerbation [
      • Almagro P.
      • Cabrera F.J.
      • Diez J.
      • Boixeda R.
      • Alonso Ortiz M.B.
      • Murio C.
      • et al.
      Comorbidities and short-term prognosis in patients hospitalized for acute exacerbation of COPD: the EPOC en Servicios de Medicina Interna (ESMI) study.
      ]. COPD exacerbations have been found to increase the risk of cardiovascular disease, including myocardial infarction and stroke [
      • Donaldson G.C.
      • Hurst J.R.
      • Smith C.J.
      • Hubbard R.B.
      • Wedzicha J.A.
      Increased risk of myocardial infarction and stroke following exacerbation of COPD.
      ,
      • Kunisaki K.M.
      • Dransfield M.T.
      • Anderson J.A.
      • Brook R.D.
      • Calverley P.M.A.
      • Celli B.R.
      • et al.
      Exacerbations of chronic obstructive pulmonary disease and cardiac events. A post hoc cohort analysis from the SUMMIT randomized clinical trial.
      • Goto T.
      • Shimada Y.J.
      • Faridi M.K.
      • Camargo Jr., C.A.
      • Hasegawa K.
      Incidence of acute cardiovascular event after acute exacerbation of COPD.
      ].
      Additionally, heart failure, visual impairment, lung cancer, depression, prostate disorders, asthma, osteoporosis, diabetes, gastroesophageal reflux, and peripheral vascular disease are significantly associated with frequent (≥2 per year) exacerbations [
      • Hurst J.R.
      • Vestbo J.
      • Anzueto A.
      • Locantore N.
      • Müllerová H.
      • Tal-Singer R.
      • et al.
      Susceptibility to exacerbation in chronic obstructive pulmonary disease.
      ,
      • Westerik J.A.M.
      • Metting E.I.
      • van Boven J.F.M.
      • Tiersma W.
      • Kocks J.W.H.
      • Schermer T.R.
      Associations between chronic comorbidity and exacerbation risk in primary care patients with COPD.
      ]. Coexisting asthma has also been shown to significantly increase the frequency of severe exacerbations [
      • Lee H.
      • Rhee C.K.
      • Lee B.J.
      • Choi D.C.
      • Kim J.A.
      • Kim S.H.
      • et al.
      Impacts of coexisting bronchial asthma on severe exacerbations in mild-to-moderate COPD: results from a national database.
      ].

      13. Discussion and conclusion

      In conclusion, COPD exacerbations represent a significant clinical problem, with deleterious effects on many aspects of patient health status, such as lung function, quality of life, comorbidities, and mortality. Furthermore, patients may take several weeks to recover following a COPD exacerbation.
      Improving physician and patient recognition, and increasing awareness of the impact of COPD exacerbations, are key to minimizing detrimental effects. Patient education initiatives are needed to increase their understanding and reporting of COPD exacerbations, allowing swift identification and treatment.
      The occurrence of a COPD exacerbation increases the risk of further exacerbations and can result in a progressive cycle of patient decline. Therefore, understanding the predictors of an increased exacerbation risk and prevention of COPD exacerbations should be a key focus of COPD clinical research. Although current treatment options for the prevention and treatment of COPD exacerbations are outlined in the GOLD 2020 report [

      Global Initiative for Chronic Obstructive Lung Disease, 2020. 2020 Report: Global Strategy for the Diagnosis, Management and Prevention of COPD. Available at: https://goldcopd.org. Accessed 5 November 2019.

      ], further research is required on approaches to better predict and, therefore, prevent COPD exacerbations. To reduce the significant burden of COPD, a concerted effort from healthcare providers, payors, and policymakers is needed to drive early identification of those at risk, improve reporting and increase preventative care.

      Role of the funding source

      AstraZeneca provided funding for medical writing support and employees of AstraZeneca were involved in the writing of this review article and the decision to submit for publication.

      Declaration of Competing Interest

      J.R. Hurst reports grants, personal fees and non-financial support from pharmaceutical companies that make medicines to treat COPD. N. Skolnik reports nonfinancial support from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Sanofi; personal fees from AstraZeneca, Boehringer Ingelheim and Eli Lilly; and has served on advisory boards for AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Intarcia, Janssen Pharmaceuticals, Merck, Mylan, Sanofi and Teva Pharmaceutical. G.J. Hansen reports no conflicts of interest. A. Anzueto reports grants or fees from AstraZeneca, Boehringer Ingelheim, Forest Laboratories, GlaxoSmithKline and Novartis. G.C. Donaldson reports personal fees from the American Thoracic Society, AstraZeneca, Micom Ltd and the Research Foundation Flanders (FWO) outside the submitted work. M.T. Dransfield reports grants from the American Lung Association, the Department of Defense, the Department of Veterans Affairs and the National Heart, Lung, and Blood Institute; personal fees from Mereo and Quark; personal fees and other from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and PneumRx; and other from Boston Scientific, Pulmonx, Novartis and Yungjin. P. Varghese is an employee of AstraZeneca.

      Acknowledgments

      This work was supported by AstraZeneca. Medical writing support, under the direction of the authors, was provided by Pauline Craig, PhD, of CMC Connect, a division of McCann Health Medical Communications Ltd, Glasgow, UK, funded by AstraZeneca, Gaithersburg, USA in accordance with Good Publication Practice (GPP3) guidelines [
      • Battisti W.P.
      • Wager E.
      • Baltzer L.
      • Bridges D.
      • Cairns A.
      • Carswell C.I.
      • et al.
      Good publication practice for communicating company-sponsored medical research: GPP3.
      ].

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