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Available online 15 June 2022
Impact of acute exacerbations of COPD on patients' health status beyond pulmonary function: A scoping review
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A. Machadoa,b,c,d, M. Barussoc,e, J. De Brandtc,d, K. Quadfliegc,d, S. Haesevoetsc,d, M. Daenenf, M. Thomeerf,g, D. Ruttensf,g, A. Marquesa,b, C. Burtinc,d,
Corresponding author
chris.burtin@uhasselt.be

Corresponding author at: REVAL – Rehabilitation Research Center, Faculty of Rehabilitation Sciences, BIOMED Biomedical Research Institute, Hasselt University, Agoralaan Gebouw A, Diepenbeek 3590, Belgium.
a Respiratory Research and Rehabilitation Laboratory (Lab 3R), School of Health Sciences (ESSUA), University of Aveiro, Aveiro, Portugal
b Institute of Biomedicine (iBiMED), University of Aveiro, Aveiro, Portugal
c REVAL – Rehabilitation Research Center, Faculty of Rehabilitation Sciences, BIOMED Biomedical Research Institute, Hasselt University, Agoralaan Gebouw A, Diepenbeek 3590, Belgium
d BIOMED – Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
e Laboratory of Spirometry and Respiratory Physiotherapy—LEFiR, Universidade Federal de São Carlos—UFSCar, São Carlos, São Paulo, Brazil
f Department of Respiratory Medicine, Ziekenhuis Oost-Limburg, Genk, Belgium
g Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium
Received 29 November 2021. Accepted 10 April 2022
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Abstract

This scoping review summarized the evidence regarding the impact of acute exacerbations of COPD (AECOPD) on patients' health status beyond pulmonary function.

PubMed, Embase, and Web of Science were searched. Prospective cohort studies assessing the health status of patients with COPD in a stable phase of the disease and after a follow-up period (where at least one AECOPD occurred) were included. An integrated assessment framework of health status (i.e., physiological functioning, complaints, functional impairment, quality of life) was used.

Twenty-two studies were included. AECOPD acutely affected exercise tolerance, quadriceps muscle strength, physical activity levels, symptoms of dyspnoea and fatigue, and impact of the disease. Long-term effects on quadriceps muscle strength, symptoms of dyspnoea and depression, and quality of life were found. Repeated exacerbations negatively impacted the fat-free mass, levels of dyspnoea, impact of the disease and quality of life. Conflicting evidence was found regarding the impact of repeated exacerbations on exercise tolerance and physical activity levels.

AECOPD have well-established acute and long-term adverse effects on health status beyond pulmonary function; nevertheless, the recovery trajectory and the impact of repeated exacerbations are still poorly studied. Further prospective research is recommended to draw firm conclusions on these aspects.

Keywords:
COPD
Acute exacerbations
Health status
Abbreviations:
6MWD
95%CI
AECOPD
BMI
CAT
CCQ
CES-D
COPD
CRQ
EQ-5D
FACIT-F
FEV1
FFM
GOLD
mMRC
PRISMA-ScR
QMVC
QoL
SF-12
SF-36
SGRQ
VMU
Full Text
Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by the onset of acute exacerbations (AECOPD), defined as an acute worsening of respiratory symptoms that result in additional therapy.1 On average, patients with COPD experience 1 to 4 AECOPD per year,2,3 which account for 50–70% of all COPD related-costs and increase their susceptibility to new AECOPD, hospitalization, and death.1,4,5 These events are associated with increased dyspnoea that usually lasts for 7 to 10 days, although in some cases there is no full recovery after weeks or months.1,6 Even a single AECOPD results in accelerated lung function decline and disease progression.7-9 Evidence also suggests that AECOPD lead to declines in exercise performance, functional status and quality of life (QoL), thus harming health status beyond pulmonary function.1,10-12 In addition, AECOPD are not random events but cluster together in time with a high-risk period for recurrent AECOPD in the 8-weeks following an initial exacerbation.1,13 Some patients are particularly susceptible to these (repeated) exacerbations and are known as the frequent exacerbator phenotype, which can be found across all disease severity groups.1,11 These frequent exacerbators seem to suffer from even more significant declines in lung function and QoL, potentially experiencing a further negative impact on health status.1,11,14-16

Health status can be defined as the impact of health on a person's ability to perform and derive fulfilment from daily life activities.17 Given its complexity, an integrated assessment framework of health status in COPD has been developed, which encompasses four sub-domains: physiological functioning, complaints, functional impairment and QoL.18 These sub-domains are relatively independent, and therefore a comprehensive assessment is essential to understand the impact of AECOPD on all health status domains and tailor interventions to counteract the detrimental effects that each person experiences.16,18-20 However, to date there are no reviews of the available evidence on the impact of AECOPD on the different health status domains. A scoping review to outline the existing evidence on this topic would provide the basis for future research to guide clinical practice on this matter.

Thus, this scoping review aimed to summarize and critically appraise the existing scientific evidence of the impact of AECOPD on the different sub-domains of health status in patients with COPD. Accordingly, our review question was: what do we know about the impact of AECOPD on the different sub-domains of health status in patients with COPD?

Methods

This review followed the updated methodological framework to conduct scoping reviews proposed by Peters and colleagues,21 and is reported according to the Preferred Reporting Items for Systematic reviews and Meta-analyses extension for Scoping Reviews (PRISMA-ScR) checklist guidelines.22

Database and search strategy

One researcher (AM) performed an electronic literature search on PubMed, Embase and Web of Science from inception until January 2021. The following search strategy was used: ((COPD [title/abstract] OR chronic obstructive pulmonary disease [title/abstract/MeSH]) AND (hospital*[title] OR exacerbation [title/abstract])). The search results were imported to EndNote X9 (Clarivate Analytics, Philadelphia, PA, United States of America) and the duplicates were identified and removed.

A single researcher (AM or MSBG or CB) performed the title screening conservatively, i.e., excluding studies which clearly did not fulfil the criteria. Abstract and consequent full-text screening were performed independently by two out of three researchers (AM and CB or MSBG and CB). A consensus-based decision was made after discussion when discrepancies were present.

Selection criteria

Studies were included if they (i) studied patients with COPD that suffered from at least one AECOPD throughout the study; (ii) were prospective cohort studies; (iii) performed at least one type of health status assessment; and (iv) were written in English. Patients had to be assessed at baseline (in a stable phase of the disease) and after a follow-up period. The follow-up assessment(s) could have been conducted immediately after an AECOPD, during the course of a single AECOPD, or over a more extended period of time with the onset of AECOPD during the follow-up period being recorded (e.g., to compare changes in health status in frequent exacerbators vs. non-frequent exacerbators). Given the variability of used definitions of AECOPD in the literature, for the purpose of this review, AECOPD could be defined using symptom-based (i.e., patient-reported worsening of respiratory symptoms either to a healthcare professional or using a diary or tool) or event-based (i.e., change in treatment – medication and/or hospitalization) definitions, or a combination of both.23

Studies reporting on the short-, mid- or long-term effects of any intervention were excluded, unless it was possible to retrieve the data of a control group receiving only standard of care. Abstracts in conference proceedings were also excluded.

Based on the sub-classification of health status previously proposed for patients with COPD,18 we included measures of physiological functioning (exercise tolerance, muscle function and body composition), complaints (subjective complaints, expected dyspnoea and dyspnoea emotions), functional impairment (subjective impairment, behavioural impairment and actual physical activity) and QoL (general QoL, health-related QoL, satisfaction and relations). Measures of pulmonary function were not included.

Data extraction

A customized data collection tool in Microsoft® Excel (Microsoft, Redmond, Washington, United States of America) and a data extraction table in Microsoft® Word (Microsoft, Redmond, Washington, United States of America) were developed to extract the most relevant information from the included studies and facilitate their subsequent analysis and interpretation. Data extraction was performed by AM and MSBG. Information on study design and timing of assessment, sample size, baseline characteristics (age, gender, body mass index (BMI), forced expiratory volume in one second (FEV1)), definition of (frequent) exacerbations used, AECOPD management and setting, measures of health status and main results regarding health status was collected.

Data synthesis

Data are presented in a tabularized format with a narrative summary linking the review results with the aim and review question. Key findings were categorized according to the sub-domains of health status proposed by Vercoulen and colleagues.18 In addition, whenever possible, results synthesis were grouped on acute vs. long-term effects of AECOPD, and on single vs. repeated AECOPD. For the purposes of this review, acute effects combined the results found regarding the onset and first days of an AECOPD, long-term effects combined the data on recovery/sustained changes over time, i.e., data from post-AECOPD periods, annual changes and follow-up times. Numerical summaries for the definition of (frequent) exacerbations, AECOPD characteristics and management, and measures of health status were collated. Schematic overviews were further developed to provide a visual synthesis of the results.

ResultsSearch results

The literature search provided a total of 23,677 records. After the removal of duplicates, 12,662 records were screened for relevant content using titles and abstracts. From these, 12,199 were excluded through title screening and 388 through abstract screening. Thus, the full text of 74 potentially relevant reports was assessed. Twenty-two studies were included in the review. The screening process is visualized in a flow chart (Fig. 1).

Figure 1.

PRISMA flowchart of the included studies.

(0.51MB).
General characteristics

Characteristics of the included studies are shown in Table 1. Studies were conducted between 2004 and 2020.

Table 1.

Influence of exacerbations on changes in health status over time in patients with COPD (n=22).

Author(s), year  Study design/ Time of assessment  Population  Exacerbation – definition, treatment & setting  Health status assessment measure  Main results 
Miravitlles et al., 200433  Observational prospective studyTime points:- Baseline- Every 6 months during 2 years  Total sample:n=336; 98% male;66±8 years; FEV1 33.0±8.0 %predicted; BMI 27.4±4.0 kg/m2Frequent exacerbators (≥3 AECOPD in 2 years):n=158; 98% male;66±9 years; FEV1 31.8±8.0 %predicted; BMI 27.0±4.1 kg/m2Infrequent exacerbators (<3 AECOPD in 2 years):n=178; 98% male;67±8 years; FEV1 34.2±8.0 %predicted; BMI 27.8±3.9 kg/m2AECOPD treated with oral steroids: n=189 (41.4%)Patients admitted to the hospital for AECOPD: n=103 (30.7%)  - Defined as a sustained worsening of patient's condition from the stable state characterized by the increase of any combination of three cardinal symptoms: dyspnoea, sputum purulence, and sputum volume, that is acute in onset and necessitates a change in regular medication- Antibiotics and/or oral steroids and/or increased doses of inhaled steroids and bronchodilators- Home or hospital  SGRQ symptoms scoreSGRQ activity scoreSGRQ impact scoreSGRQ total scoreSF-12 physical component scoreSF-12 mental component score  Baseline vs. 6 months vs. 1 year vs. 18 months vs. 2 yearFrequent exacerbators: 52±20 vs. 44 vs. 49 vs. 43 vs. 47±19Infrequent exacerbators: 45±20 vs. 33 vs. 38 vs. 31 vs. 34±19Frequent exacerbators vs. Infrequent exacerbators: p<0.001Frequent exacerbators: 67±19 vs. 65 vs. 69 vs. 66 vs. 68±19Infrequent exacerbators: 59±22 vs. 57 vs. 59 vs. 58 vs. 60±20Frequent exacerbators vs. Infrequent exacerbators: p<0.001Frequent exacerbators: 42±17 vs. 38 vs. 39 vs. 38 vs. 38±18Infrequent exacerbators: 36±18 vs. 29 vs. 30 vs. 28 vs. 30±18Frequent exacerbators vs. Infrequent exacerbators: p<0.001Frequent exacerbators: 51±16 vs. 47 vs. 50 vs. 48 vs. 49±16Infrequent exacerbators: 44±18 vs. 38 vs. 40 vs. 38 vs. 39±17Frequent exacerbators vs. Infrequent exacerbators: p<0.001Patients with moderate COPDInfluence of frequent exacerbations in SGRQ change (compared to infrequent exacerbators): 5.5, p=0.013Annual rate of change: Frequent exacerbators -0.6 vs. Infrequent exacerbators -2.6, p<0.05Influence of hospital admission in SGRQ change (compared to no hospital admission): 1.4, p=0.563Patients with severe COPDInfluence of frequent exacerbations in SGRQ change (compared to infrequent exacerbators): 3.0, p=0.169Influence of hospital admission in SGRQ change (compared to no hospital admission): 5.5, p=0.007Frequent exacerbators:Baseline: 37±8 vs. 2 year: 37±9Infrequent exacerbators:Baseline: 40±10 vs. 2 year: 40±9Frequent exacerbators vs. Infrequent exacerbators: p<0.05Frequent exacerbators:Baseline: 49±13 vs. 2 year: 50±12Infrequent exacerbators:Baseline: 51±12 vs. 2 year: 51±12Frequent exacerbators vs. Infrequent exacerbators: p>0.05 
Donaldson et al., 200527  Observational prospective studyTime points:- Baseline: 8-14 days preceding exacerbation onset- Day of the exacerbation onset- Recovery: 3 day moving average equal or better than baseline- Every year up to 8 years  Total sample:n=147; 69% male;68±8 years; FEV1 40.9±15.7 %predictedPatients with data recorded during exacerbations: n=136AECOPD leading to hospital admission: n=90 (6.2%)  - Recorded in a diary- Defined as an increase in respiratory symptoms for 2 consecutive days, with at least one major symptom (dyspnoea, sputum purulence or sputum volume) plus either another major or a minor symptom (wheeze, cold, sore throat, and cough)- Home or hospital  Days spent indoors (%)Days/week spending all day indoors (n)Time spent outdoors (hours/day)SGRQ symptoms scoreSGRQ activity scoreSGRQ impact scoreSGRQ total score  Baseline: 34.1% vs. AECOPD onset: 44.4% vs. Post AECOPD: 39.7%Baseline: 2 [1; 4] vs. Post AECOPD 3 [1; 5], ↑0 [0; 1], p<0.001Baseline vs. AECOPD: ↓, p=0.021Baseline vs. Post AECOPD: ↓, p=0.024Annual decline: -0.1 (95%CI: -0.2 to -0.1) hours/year, p<0.001Annual decline: -1.3 (95%CI: -2.0 to -0.7), ↓2.0%/year, p<0.001Annual decline: 1.5 (95%CI: 1.0 to 1.1), ↑2.1%/year, p<0.001Annual decline: 1.5 (95%CI: 0.9 to 2.1), ↑3.8%/year, p<0.001Annual decline: 1.0 (95%CI: 0.6 to 1.5), ↑1.9%/year, p<0.001 
Cote et al., 200726  Observational prospective studyTime points:- Baseline- At exacerbation: within 48h of the onset of symptoms- Follow-up: 6 months, 1 and 2 years after exacerbation  Total sample:n=130; 94% male; 67±9 years; FEV1 39.5±15.0 %predicted; BMI 27.4±5.9 kg/m2Subgroups:Single exacerbators (1 exacerbation/year): n=48Frequent exacerbators (≥2 exacerbations/year): n=82Patients admitted to the hospital for AECOPD (during follow-up period): n=50  Defined as an event characterized by a sustained worsening of respiratory symptoms for at least 2 days, requiring:- a visit to a doctor or the emergency department- treatment with antibiotics or systemic steroids or both- no need for hospitalization  6MWD (m)mMRC grade  Total sample:Baseline: 354±119 vs. AECOPD: ↓72 (20.4%) vs. 6 months: ↓37 (10.5%) vs. 1 year: ↓49 (13.9%) vs. 2 years: ↓74 (21.0%), p<0.001Single exacerbators:Baseline: 385±116 vs. AECOPD: ↓77 (20.0%) vs. 1 year: ↓51 (13.0%) vs. 2 years: ↓81 (21.0%)Frequent exacerbators:Baseline: 334±117 vs. AECOPD: ↓69 (21.0%) vs. 1 year: ↓49 (15.0%) vs. 2 years: ↓67 (20.0%)Total sample:Baseline: 2.3±0.9 vs. AECOPD: ↑0.5 (20.6%) vs. 6 months: ↑0.2 (10.5%) vs. 1 year: ↑0.3 (11.0%) vs. 2 years: ↑0.3 (14.5%), p=0.009Single exacerbators:Baseline: 2.1±1.1 vs. AECOPD: ↑0.4 (19.2%) vs. 1 year: ↑0.2 (10.0%) vs. 2 years: ↑0.2 (7.9%)Frequent exacerbators:Baseline: 2.4±0.9 vs. AECOPD: ↑0.5 (21.5%) vs. 1 year: ↑0.3 (11.0%) vs. 2 years: ↑0.4 (16.0%) 
Hopkinson et al., 200730  Observational prospective studyTime points:- Baseline- 1 year follow-up  Total sample:n=64; 66% male;62±9 years; FEV1 36.0±18.4 %predicted; BMI 24.3±5.2 kg/m2Frequent exacerbators (≥2 exacerbations/year): n=36  - Defined as episodes of worsening of respiratory symptoms leading to treatment with antibiotics- Antibiotics  QMVC (kg)QMVC (%predicted)Fat-free mass (kg)  Baseline: 35±2 vs. 1 year: 33±2, p=0.04Not associated with having frequent AECOPDBaseline: 66±18 vs. 1 year: 62±18, p=0.009Not associated with having frequent AECOPDBaseline: 48±8 vs. 1 year: 47±8, p>0.05Correlated with having frequent AECOPD: r=-0.3, p=0.006 
Llor et a., 200832  Observational prospective studyTime points:- Baseline- Every 6 months during 2 years  Total sample:n=136; 96% male;70±10 years; FEV1 48.7±14.5 %predictedPatients with one or more exacerbations:n=90; 97% male;69±10 years; FEV1 47.7±14.6 %predicted  Defined by the symptoms: an increase in dyspnoea, expectoration and/or in the purulence of the sputum  SGRQ total score  Total sample:Baseline: 40±19 vs. 2 years: 38±20, ↑2, p=0.181Patients with exacerbations:Baseline: 41±18 vs. 2 years: ↑0, p=0.781Patients with one exacerbation (n = 32):Baseline vs. 2 years: ↓ 4, p=0.023Patients with two or more exacerbations (n = 58)Baseline vs. 2 years: ↑ 2, p=0.13 
Esteban et al., 200943  Observational prospective studyTime points:- Baseline- 5 years after the initial assessment  Total sample:n=391No hospitalizations during 5 years follow-up:n=287; 65±9 years; FEV1 53.9±13.7 %predicted; BMI 27.8±4.0 kg/m21–2 hospitalizations during 5 years follow-up:n=76; 67±7 years; FEV1 49.5±13.7 %predicted; BMI 28.6±5.4 kg/m23 or more hospitalizations during 5 years follow-up:n=28; 65±9 years; FEV1 44.6±13.3 %predicted; BMI 28.6±4.6 kg/m2  - Information on hospital admissions due to AECOPD was obtained by analysing the database of the hospital, which is the benchmark hospital for the patients enrolled in the study - Hospital  SGRQ symptoms scoreSGRQ activity scoreSGRQ impact scoreSGRQ total scoreSF-36 physical component scoreSF-36 mental component score  No hospitalizations:Baseline: 38±21 vs. 5 years: 39±22, p>0.051–2 hospitalizations:Baseline: 47±21 vs. 5 years: 50±21, p>0.053 or more hospitalizations:Baseline: 47±18 vs. 5 years: 62±19, p<0.05No hospitalizations:Baseline: 48±20 vs. 5 years: 44±24, p<0.051–2 hospitalizations:Baseline: 57±23 vs. 5 years: 55±25, p>0.053 or more hospitalizations:Baseline: 58±21 vs. 5 years: 69±22, p<0.05No hospitalizations:Baseline: 29±19 vs. 5 years: 29±21, p>0.051–2 hospitalizations:Baseline: 34±20 vs. 5 years: 38±21, p>0.053 or more hospitalizations:Baseline: 35±18 vs. 5 years: 50±22, p<0.05No hospitalizations:Baseline: 36±18 vs. 5 years: 35±20, p>0.051–2 hospitalizations:Baseline: 43±19 vs. 5 years: 45±20, p>0.053 or more hospitalizations:Baseline: 44±16 vs. 5 years: 58±20, p<0.05No hospitalizations:Baseline: 46±8 vs. 5 years: 41±9, p<0.051–2 hospitalizations:Baseline: 44±8 vs. 5 years: 37±9, p<0.053 or more hospitalizations:Baseline: 45±6 vs. 5 years: 35±8, p<0.05No hospitalizations:Baseline: 50±11 vs. 5 years: 52±11, p<0.051–2 hospitalizations:Baseline: 50±11 vs. 5 years: 51±12, p>0.053 or more hospitalizations:Baseline: 50±10 vs. 5 years: 46±13, p>0.05 
Nishimura et al., 200934  Observational longitudinal studyTime points:- Baseline- After 6 months. If an exacerbation is present: 6 week exacerbation-free period  Total sample:n=156; 96% male;71±6 years; FEV1 38.1 %predictedPatients with exacerbations:n=48; 96% male;71±7 years; FEV1 40.7±10.9 %predictedPatients with ≥2 AECOPD: n=12  - Defined as a worsening of the respiratory symptoms that required treatment with oral corticosteroids or antibiotics or both- Oral corticosteroids or antibiotics or both  SGRQ symptoms scoreSGRQ activity scoreSGRQ impact scoreSGRQ total scoreCRQ fatigue scoreCRQ emotion scoreCRQ mastery scoreCRQ total score  Patients with exacerbations:Baseline: 54±21 vs. 6 months: ↑5±2, p<0.05Patients with 2 or more exacerbations:Baseline vs. 6 months: ↑12±6, p<0.05Patients with exacerbations:Baseline: 54±20 vs. 6 months: ↑2±1, p>0.05Patients with 2 or more exacerbations:Baseline vs. 6 months: ↑5±2, p<0.05Patients with exacerbations:Baseline: 33±19 vs. 6 months: ↑1±1, p>0.05Patients with 2 or more exacerbations:Baseline vs. 6 months: ↑4±2, p<0.05Patients with exacerbations:Baseline: 45±18 vs. 6 months: ↑2±1, p>0.05Patients with 2 or more exacerbations:Baseline vs. 6 months: ↑6±2, p<0.05Patients with exacerbations:Baseline: 19±5 vs. 6 months: ↓0.4±0.2/question, p<0.05Patients with 2 or more exacerbations:Baseline vs. 6 months: ↓0.5±0.2/question, p<0.05Patients with exacerbations:Baseline: 37±9 vs. 6 months: ↓0.3±0.1/question, p<0.05Patients with 2 or more exacerbations:Baseline vs. 6 months: ↓0.5±0.3/question, p<0.05Patients with exacerbations:Baseline: 22±4 vs. 6 months: ↓0.4±0.2/question, p<0.05Patients with 2 or more exacerbations:Baseline vs. 6 months: ↓0.6±0.3/question, p<0.05Patients with exacerbations:Baseline: 104±20 vs. 6 months: ↓0.3±0.1/question, p<0.05 
Trappenburg et al., 201036  Prospective cohort studyTime points:- Baseline- Every week for 6 weeks  Patients with AECOPD:n=69; 60% male;67±10 years;FEV1 46.0±18.4 %predicted  - Defined as an increase in any two major symptoms (dyspnoea, sputum purulence, sputum volume), or increase in one major and the presence of at least one minor symptom for at least two consecutive days- Increase in inhaled medication, corticosteroids or antibiotics- Home or hospital  CCQ total scoreCCQ symptoms scoreCCQ functional state scoreCCQ mental state score  Mean changes in scoreStable: -0.0 (95%CI -0.1 to 0.0) vs. AECOPD onset: 0.3 (95%CI 0.1 to 0.4), p<0.001Stable: -0.0 (95%CI -0.1 to 0.0) vs. Post-AECOPD: -0.3 (95%CI -0.4 to -0.0), p=0.001AECOPD onset: 0.2 (95%CI 0.0 to 0.4)AECOPD onset: 0.2 (95%CI 0.0 to 0.4)AECOPD onset: 0.3 (95%CI 0.1 to 0.5) 
Ferrari et al., 201129  Observational longitudinal studyTime points:- Baseline - After 3 years  Total sample:n=95; 66% male;64±9 years; FEV1 59.3±23.2 %predicted; BMI 25.9±5.8 kg/m2Patients that suffered at least one exacerbation: 72 (75.8%)  - Defined as an increase in dyspnoea, sputum purulence, and increased sputum volume- Antibiotics or systemic steroids or both– Home or hospital  6MWD (m)SGRQ activity scoreSGRQ total score  Baseline: 438±86 vs. 3 years: 412±100, p=0.001Baseline: 52±21 vs. 3 years: 60±22, p<0.001Baseline: 42±19 vs. 3 years: 44±19, p=0.041Number of AECOPD during the 3 years included in the multiple regression model to predict SGRQ total score: 1.3 (95%CI: 0.1 to 2.5), p=0.031 
Ehsan et al., 201342  Observational longitudinal studyTime points:- Baseline- Every month up to 4 weeks after an AECOPD  Total sample:n=17; 53% male;63±12 years;FEV1 52.0±20.0 %predicted;BMI 25.0±5.0 kg/m2AECOPD leading to hospital admission: n=2  - Recorded in a diary- Defined as an increase greater than 9 points sustained for 3 days or 12 points sustained for 2 days, from baseline score, in the 14-item EXACT; or clinically reported- Home or hospital  PAL (minutes per day in higher level activities, i.e., >3000VMU)  Stable: 157±14 vs. AECOPD 131±13, 26 (17%) p<0.0001 
Alahmari et al., 201425  Observational prospective studyTime points:- Baseline: starting 2 weeks before the onset of an AECOPD- During AECOPD: starting at the onset- Recovery: 3 day moving average equal or better than baseline  Total sample:n=73; 70% male;71±9 years; FEV1 52.9±16.5 %predicted; BMI 26.8±5.6 kg/m2Subgroups:Infrequent exacerbators (0-1 exacerbations in the preceding year): n=33Frequent exacerbators (≥2 exacerbations in the preceding year): n=40AECOPD management:Antibiotics: n=11Oral corticosteroids: n=7Antibiotics and oral corticosteroids: n=39Untreated: n=22  - Recorded in a diary- Defined as an increase in respiratory symptoms for 2 consecutive days, with at least one major symptom (i.e., dyspnoea, sputum purulence or sputum volume) plus either another major or a minor symptom (i.e., wheeze, cold, sore throat, and cough)- Antibiotics, oral corticosteroids or both- Home  Daily step-count (steps/day)Time outdoors (hours/day)Days on which patients went outdoors (%)Daily step-count (steps/day)  Total sample (stable vs. AECOPD, change from baseline, p-value):4154±2586 vs. 3673±2258, ↓480±1408, p=0.045Days to return to baseline levels: 4 [1; 8]3.4±1.8 vs. 3.2±1.8, ↓0.1±1.1, p=0.51Days to return to baseline levels: 1 [0; 5]84.4±24.2 vs. 79.6±26.1, ↓4.8±18, p=0.13Infrequent vs. frequent exacerbators:-338 (95%CI: -504 to -170) vs. -708 (95%CI: -867 to -549), p=0.002 
Liang et al., 201431  Prospective cohort studyTime points:- Baseline- 1 year follow-up  Total sample:n=450; 69% male;65±11 years; FEV1 48.3±15.8 %predicted; BMI 24.0±4.2 kg/m2No of patients with AECOPD:0: n=1611: n=382: n=43≥3: n=208  - Defined either by a worsening of at least one of three key symptoms (increased sputum amount, changed sputum colour or purulence, and increased dyspnoea), for at least 48h; or by a worsening of at least one key symptom plus a change in at least one of three medications (antibiotics, corticosteroid, and bronchodilator)- Antibiotics and/or corticosteroid and/or bronchodilator  SGRQ symptoms scoreSGRQ activity scoreSGRQ impact scoreSGRQ total score  Baseline: 61±19 vs. 1 year: 55±20, p<0.001Baseline vs. 1 year: p=0.914Baseline: 35±22 vs. 1 year: 30±22, p<0.001Baseline: 46±19 vs. 1 year: 42.±19, p<0.001Influence of AECOPD in SGRQ change at 1 year (compared to no AECOPD): p<0.0011 AECOPD: OR 0.9 (95%CI 0.3 to 2.5), p=0.8652 AECOPD: OR 0.9 (95%CI 0.4 to 2.4), p=0.896≥3 AECOPD: OR 2.9 (95%CI 0.7 to 4.8), p<0.001 
Dreyse et a., 201528  Observational prospective studyTime points:- Baseline- Every 6 months until 2 years follow-up  Total sample:n=100; 58% male;69±8 years; FEV1 52.6±20.6 %predicted; BMI 26.6±3.7 kg/m2Subgroups:Infrequent exacerbators (<2 exacerbations/year): n=51Frequent exacerbators (≥2 exacerbations/year): n=49AECOPD leading to hospital admission: 4%  - Defined as a sustained worsening of the patient's condition from the stable state and beyond normal day-to-day variation, that has an acute onset and necessitates a change in regular medication- Antibiotics or systemic corticosteroids or both- Home or hospital  6MWD (m)CRQ scoremMRC gradeSGRQ score  6MWD and CRQ are lower in frequent exacerbators without differences across time mMRC and SGRQ are higher in frequent exacerbators without differences across time 
Alahmari et al., 201624  Observational prospective studyTime points:- Baseline- At exacerbation (0 day)- 3 and 7 days post exacerbation  Total sample:n=78Protocol 1 (PAL + 6MWD):n=50; 72% male;73±8 years; FEV1 50.7±15.1 %predicted; BMI 26.6±5.6 kg/m2Protocol 2 (QMVC):n=47; 60% male;72±8 years; FEV1 50.1±17.2 %predicted; BMI 25.9±5.6 kg/m2Subgroups:Infrequent exacerbators (0-1 exacerbations in the preceding year)Frequent exacerbators (≥2 exacerbations in the preceding year)AECOPD management:Antibiotics: n=18Oral corticosteroids: n=10Antibiotics and oral corticosteroids: n=68Increased inhaled corticosteroids: n=1  - Recorded in a diary- Defined as an increase in respiratory symptoms for 2 consecutive days, with at least one major symptom (i.e., dyspnoea, sputum purulence or sputum volume) plus either another major or a minor symptom (i.e., wheeze, cold, sore throat, and cough)- Antibiotics, oral corticosteroids or both, increase in inhaled corticosteroids- Home  6MWD (m)QMVC (kg)Functional Assessment of Chronic Illness Therapy-Fatigue scoreTime spent in light activities (hours/day)  Total sample – protocol 1:Baseline: 422 [337; 500] vs. day 3: 373 [265; 450], ↓49 (13.1%), p=0.001Baseline: 422 [337; 550] vs. day 7: 415 [290; 490], ↓7 (1.7%), p=0.103Day 3: 373 [265; 450] vs. day 7: 415 [290; 490], p<0.001GOLD stage 1-2 vs. 3-4 (change from baseline to onset of AECOPD):↓24±14 vs. ↓81±22, p=0.034Total sample – protocol 2:Baseline: 33±3 vs. day 3: 30±3, ↓3 (8.9%), p=0.026Baseline: 33±3 vs. day 7: 29±3, ↓4 (10.7%), p=0.019Day 3: 30±3 vs. day 7: 29±3Total sample:Baseline: 36±2 vs. day 0: 31±2, ↓5 (13.8%), p<0.001Baseline: 36.0±1.5 vs. day 0: 31.0±1.7, ↓5, p<0.001Baseline: 36.0±1.5 vs. day 3: 35.0±1.5, ↓2 (5.4%), p=0.037Total sample – protocol 1:Week 1: 2.2±0.2 vs. week 2: 2.0±0.2, p=0.009Infrequent vs. frequent exacerbators:↓0.1±0.1 vs. ↓0.4±0.1, p=0.048 
Rubinsztajn et al., 201644  Observational prospective studyTime points:- Baseline- After 12 months- After 24 months  Total sample:n=445; 66±9 years; FEV1 50.2±15.8 %predicted; BMI 26.6±5.6 kg/m2Completer after 24 months: n=261Subgroups:0-1 exacerbations/year: n=190≥2 exacerbations/year: n=71  Self-reported and recorded in a diary  mMRC gradeSGRQ symptoms scoreSGRQ activity scoreSGRQ impact scoreSGRQ total score  Total sample:Baseline: 2.1±1.1 vs. 12 months: 2.0±1.0 vs. 24 months: 2.1±1.0, p>0.05Total sample:Baseline: 56±22 vs. 12 months: 59±21 vs. 24 months: 58±22, p>0.05Patients with 0-1 vs. ≥2 exacerbations/year:0-1: 49±20 vs. ≥2: 61±25, p<0.001Total sample:Baseline: 66±2 vs. 12 months: 62 ±3 vs. 24 months: 601±20, p>0.05Patients with 0-1 vs. ≥2 exacerbations/year:0-1: 62±21 vs. ≥2: 76±17, p<0.001Total sample:Baseline: 41±20 vs. 12 months: 40±21 vs. 24 months: 40±19, p>0.05Patients with 0-1 vs. ≥2 exacerbations/year:0-1: 36±18 vs. ≥2: 53±17, p<0.001Total sample:Baseline: 51±18 vs. 12 months: 50±19 vs. 24 months: 49±17, p>0.05Patients with 0-1 vs. ≥2 exacerbations/year:0-1: 46±19 vs. ≥2: 62±14, p<0.001 
Kardos et al., 201738  Observational prospective studyTime points:- Baseline- 1 year follow-up - 2 years follow-up  Total sample:n=3137; 59% male;66±10 years; FEV1 62.9±24.4 %predicted; BMI 27.3±5.6 kg/m2Patients with AECOPD:1 Year: 26.2%; AECOPD rate 0.42 Year: 23.2%; AECOPD rate 0.3Patients admitted to the hospital for AECOPD: 1 Year 1: n=111 (3.5%)Year 2: n=108 (3.4%)  - Defined by prescription of oral steroids and/or antibiotics or hospitalization- Oral steroids and/or antibiotics- Home or hospital  CAT total score  Baseline: 20±8 vs. 1year: ↓2±6 vs 2 years: ↓2±7Improvement ≥MCID, number (%) of patients:1 year = 1554 (49.5%) patients2 years = 1701 (54.2%) patientsWorsening ≥MCID, number (%) of patients:1 year = 918 (29.3%) patients2 years = 710 (22.6%) patientsAECOPD rate was lower in patients with a sustained improvement than in those with a sustained worsening: 0.3 (95%CI 0.3 to 0.4) vs. 0.5 (95%CI 0.4 to 0.6) 
Yohannes et al., 201741  Observational prospective studyTime points:- Baseline- 1 year follow-up - 2 years follow-up- 3 years follow-up  Total sample:n=2059; 64% male;63±7 years;FEV1 48.0±15.6 %predicted; BMI 26.6±5.7 kg/m2  - Defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization- Antibiotic or corticosteroid or both- Home or hospital  Centre for epidemiologic studies depression scale  No exacerbations in the first year:Baseline vs. 3 years follow-up: 0.7 (95%CI: -0.1 to -1.4)1 exacerbation in the first year:Baseline vs. 3 years follow-up: 2.1 (95%CI: 1.2 to -3.0)2 exacerbations in the first year:Baseline vs. 3 years follow-up: 2.8 (95%CI: 1.7 to 3.9)3+ exacerbations in the first year:Baseline vs. 3 years follow-up: 3.7 (95%CI: 2.5 to 4.8) 
Rodrigues et al., 201935  Observational prospective studyTime points:- Baseline- After 1 year- After 2 years- After 3 years- After 6 years  Total sample:n=61; 74% male;64±7 years; FEV1 85.0±16.0 %predicted; BMI 27.0±4.0 kg/m2Completers after 6 years: n=42Patients that suffered ≥1 AECOPD: n=25  Defined as a variation on respiratory symptoms which required a change in medication or hospitalization  CCQ total scoreCAT total score SF-36 physical component scoreSF-36 mental component scoreEQ-5D index scoreEQ-5D visual analog scale score  Yearly change: 0.1 (0.0), p<0.05Exacerbators vs. non-exacerbators:Yearly change: 0.1 (0.0) vs. 0.0 (0.0), p=0.63Yearly change: 0.3 (0.2), p>0.05Exacerbators vs. non-exacerbators:Yearly change: 0.9 (0.2) vs. -0.3 (0.3), p<0.01Yearly change: -1.0 (0.4), p<0.05Exacerbators vs. non-exacerbators:Yearly change: -1.5 (0.5) vs. -0.5 (0.5), p=0.16Yearly change: -0.5 (0.4), p>0.05Exacerbators vs. non-exacerbators:Yearly change: -1.2 (0.5) vs. 0.0 (0.5), p=0.16Yearly change: 0.0 (0.0), p<0.05Exacerbators vs. non-exacerbators:Yearly change: 0.0 (0.0) vs. 0.0 (0.0), p=0.66Yearly change: -0.6 (0.3), p<0.05Exacerbators vs. non-exacerbators:Yearly change: -0.8 (0.5) vs. -0.4 (0.4), p=0.48 
Sievi et al., 201940  Observational prospective studyTime points:- Baseline- Once per year until up to 7 years follow-up  Total sample:n=181; 65% male;64 [59; 69] years; FEV1 46.0 [33.0; 65.0] %predicted; BMI 25.8 [22.6; 28.3] kg/m2Subgroups:Infrequent exacerbators (0-1 exacerbations/year)Frequent exacerbators (2 exacerbations/year)AECOPD leading to hospital admission: n=55  - Defined as an event that led to prescription of antibiotics and/or corticosteroids- Antibiotics and/or corticosteroids- Home or hospital  Daily step-count (steps/day)  Total sample:Annual decline: -479 (95%CI: -634 to -324), p<0.001Frequent vs Infrequent exacerbators:Annual decline: -137 (95%CI: -750 to 473), p=0.660 
Esteban et al., 202045  Observational prospective studyTime points:- Baseline- After 1 year- After 2 years- After 5 years  Total sample that completed 5 years:n=324; 95% male;66±8 years;FEV1 54.3±14.8 %predicted;BMI 27.6±4.8 kg/m2No of patients with hospitalization for AECOPD:0: n=2341: n=402: n=233: n=14>3: n=13  Data on hospitalization for AECOPD was retrieved from the personal electronic clinical record of each patient at every visit- Hospital  SGRQ scoreSGRQ symptoms scoreSGRQ activity scoreSGRQ impact score  Previous hospitalizations for AECOPD were related to 5 to 45% poorer SGRQ scoresInfluence of hospitalizations for AECOPD in SGRQ annual change (compared to no AECOPD):1 AECOPD: 0.2±0.1, p<0.001, OR 1.22 AECOPD: 0.3±0.1, p<0.001, OR 1.3>2 AECOPD: 0.2±0.1, p=0.003, OR 1.21 AECOPD: 0.1±0.0, p=0.021, OR 1.12 AECOPD: 0.3±0.1, p<0.001, OR 1.33 AECOPD: 0.3±0.1, p=0.004, OR 1.3>3 AECOPD: 0.3±0.1, p<0.001, OR 1.41 AECOPD: 0.0±0.0, p=0.294, OR 1.02 AECOPD: 0.3±0.1, p<0.001, OR 1.2>2 AECOPD: 0.2±0.1, p=0.004, OR 1.2 
Kardos et al., 202039  Observational prospective studyTime points:- Baseline- 1 year follow-up - 2 years follow-up  Total sample:n=6075; 59% male;66±10 years; FEV1 61.6±20.3 %predictedPatients with frequent (≥2) or severe (≥1 hospitalization) AECOPD:n=285; 62% male;67±10 years; FEV1 47.3±17.0 %predictedNo of patients with AECOPD: n=1697  - Defined by prescription of oral corticosteroids and/or antibiotics or hospitalization- Antibiotic and/or corticosteroid- Home or hospital  CAT total score  Patients with frequent or severe AECOPD:Baseline vs. 1 year vs. 2 year: no overall changeWorsening ≥MCID: 1 year = 37.5%, 2 year = 37.2%No change: 1 year = 23.2%, 2 year = 22.5%Improvement ≥MCID: 1 year = 39.3%, 2 year = 40.4%Remaining patients:Baseline vs. 1 year vs. 2 year: clinically relevant improvementsWorsening ≥MCID: 1 year = 19.1%, 2 year = 20.5%No change: 1 year = 26.0%, 2 year = 20.5%Improvement ≥MCID: 1 year = 54.9%, 2 year = 59.0%Patients with frequent or severe AECOPD vs. Remaining patients: p<0.001 
Zimmermann et al., 202037  Observational prospective studyTime points:- Baseline- Every day for 8-9 months  Total sample:n=15; 73% male;69±10 years;FEV1 39.0±10.0 %predicted; BMI 22.4±4.8 kg/m2Patients with AECOPD:n=13AECOPD management:Antibiotics: n=17Oral corticosteroids: n=16AECOPD leading to hospital admission: n=4  - Defined by an increase in respiratory symptoms requiring oral corticosteroids and/or antibiotics, with or without medical review and/or hospitalization- Antibiotic and/or corticosteroid- Home or hospital  CAT total score  Mean change from baseline1 day before AECOPD: 1±0, p=0.020AECOPD onset: 1±0, p<0.001Up to 7-days after AECOPD onset: p<0.001 

Data are presented as mean±standard deviation, median [quartile 1; quartile 3] or mean (standard error), unless otherwise stated.

6MWD, 6-min walk distance; 95%CI, 95% confidence interval; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; BMI, body mass index; CAT, COPD assessment test; CCQ, Clinical COPD questionnaire; COPD, chronic obstructive pulmonary disease; CRQ, chronic respiratory disease questionnaire; EQ-5D, EuroQoL 5-dimension questionnaire; EXACT, exacerbations of chronic pulmonary disease tool; FEV1, forced expiratory volume in 1 s; GOLD, global initiative for chronic obstructive lung disease; MCID, minimal clinically important difference; mMRC, modified Medical Research Council dyspnoea questionnaire; OR, odds ratio; PAL, physical activity level; QMVC, quadriceps maximum voluntary contraction; SF-12, 12-item short form health survey; SF-36, 36-item short form health survey; SGRQ, Saint George's respiratory questionnaire; VMU, vector magnitude units.

Most studies (n = 14) defined AECOPD based on an increase in respiratory symptoms24-37 leading to changes in medication (n = 12) (e.g., treatment with antibiotics or systemic steroids)26,28,30,31,33-35,37-41 or to hospitalization (n = 4).35,38,39,41 Follow-up time varied from six weeks up to eight years. Ninety-one percent (n = 20) of the studies25,26,28-45 involved a sample combining patients that suffered a single exacerbation and patients that suffered repeated exacerbations. Severity of exacerbations was usually not reported. Nevertheless, 80% of the studies reporting this information were focused on moderate to severe AECOPD.24,26,28,29,37,40,41,45 Most reported treatment was composed by antibiotics, oral steroids or a combination of both (n = 10).25,26,28,29,34,37-41 Twelve studies included a sample combining patients treated at home with patients treated in the hospital.26-29,33,36-42

Tools used to assess health status

Physiological functioning was assessed in five studies with the six-minute walking distance (6MWD),24,26,28,29 the quadriceps maximum voluntary contraction (QMVC)24,30 and the fat-free mass (FFM).30

Complaints were assessed in nine studies with the modified Medical Research Council dyspnoea questionnaire (mMRC),26,28,44 the COPD assessment test (CAT),35,37-39 the clinical COPD questionnaire (CCQ)35,36 and the functional assessment of chronic illness therapy-fatigue (FACIT-F).24

Functional impairment was assessed in five studies via physical activity levels.24,25,27,40,42 Physical activity was objectively assessed by daily step count25,40 and the time spent in light24 or higher intensity (i.e., >3000 vector magnitude units (VMU))42 activities. The time spent indoors/outdoors25,27 was quantified based on a diary.

Finally, QoL was assessed in twelve studies with the Saint George's respiratory questionnaire (SGRQ),27-29,31-34,43-45 the chronic respiratory disease questionnaire (CRQ),28,34 the 36-item short form health survey (SF-36),35,43 the 12-item short form health survey (SF-12),33 the EuroQoL 5-dimension questionnaire (EQ-5D)35 and the centre for epidemiologic studies depression scale (CES-D).41

Fig. 2 provides an overview of the outcome measures used to assess each health status subdomain. No study assessed all the domains that compose health status. Instead, the majority of studies25,30-34,36-43,45 (n = 15) focused on a single health status domain.

Figure 2.

Schematic overview of the outcome measures used to assess each health status subdomain. *, activities >3000 vector magnitude units; 6MWD, six-minute walking distance; CAT, COPD assessment test; CCQ, clinical COPD questionnaire; CES-D, centre for epidemiological studies depression scale; CRQ, chronic respiratory disease questionnaire; EQ-5D, EuroQoL 5-dimension questionnaire; FACIT-F, functional assessment of chronic illness therapy-fatigue; mMRC, modified Medical Research Council dyspnoea questionnaire; QMVC, quadriceps maximum voluntary contraction; SF-12, 12-item short form health survey; SF-36, 36-item short form health survey; SGRQ, Saint George's respiratory questionnaire.

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Influence of exacerbations on physiological function

Two studies24,26 reported a significant reduction in the 6MWD in the first two to three days after the onset of an AECOPD, which was found to be more pronounced in patients with severe to very severe disease (GOLD stages 3 and 4).24 In addition, studies exploring the effects of repeated AECOPD26,28,29 also found a consistent decline in the 6MWD however, the recovery trajectory was conflicting. One study24 reported that the 6MWD increased back to the pre-exacerbation status after seven days, whereas more extended studies26,28 found that the observed decrease in 6MWD was maintained up to two years of follow-up, with inconsistent results regarding a lower 6MWD in frequent exacerbators (i.e., two or more AECOPD per year).26,28

QMVC was significantly reduced three and seven days after the onset of AECOPD symptoms.24 A decline in QMVC over a 1-year follow-up was also observed but with no correlation with having frequent exacerbations (i.e., two or more per year).30 Yet, frequent exacerbators had a more pronounced decline in FFM.30

Influence of exacerbations on complaints

A consistent worsening of complaints at the onset of an AECOPD was found across all outcome measures.24,26,36,37

There was an increase (worsening) in the mMRC score within 48 h of the onset of an AECOPD, which was more pronounced in patients suffering from repeated exacerbations.26 Furthermore, this increase was sustained at 1- and 2-years follow-up in frequent exacerbators (i.e., two or more AECOPD per year), but not in single exacerbators.26 A second study also corroborated these findings by reporting higher mMRC scores in frequent exacerbators.28

Similarly, a significant increase (worsening) in the CAT total score was found at the onset of an AECOPD, which was already noticeable one day before and was sustained for up to seven days after the onset of the exacerbation.37 Consistently, a faster deterioration in the CAT score (yearly change) was found in patients with exacerbations in comparison to non-exacerbators.35 In addition, patients presenting a sustained worsening on CAT score (i.e., increase ≥2 points) had a higher number of exacerbations.38,39

An increase (worsening) in the CCQ total score was found at the onset of an AECOPD, which recovered in the post-AECOPD assessment.36 This worsening was consistent across all CCQ domains.36 The CCQ score also deteriorated over time but without differences between exacerbators and non-exacerbators.35

A significant reduction (worsening) of 5 points in the FACIT-F score was observed at the onset of an AECOPD, which recovered to a 2 points reduction at day 3 in comparison to stable phase.24

Influence of exacerbations on functional impairment

Daily step count was reduced during the first 7 days of an AECOPD compared to a stable week.25 Further analysis of these data showed that it took a median of 3.5 days return to baseline levels, and patients with the largest falls in daily step count during the exacerbation were the ones taking longer to recover.25 Conflicting results were found regarding the annual decline, with one study25 finding a significantly faster decline in frequent exacerbators (i.e., two or more AECOPD per year) in comparison to infrequent exacerbators, and another study40 finding no differences between the decline of steps in frequent and infrequent exacerbators.

Time spent in activities >3000 VMU was reduced during AECOPD in comparison to the preceding or subsequent weeks.42 This decline was significant during the first week of exacerbation, with no further decline on the second week, and tended to increase back to baseline levels in the two subsequent weeks.42 In line with these results, time spent in light activities was higher during the first week post-exacerbation than the second week, with frequent exacerbators (i.e., two or more AECOPD in the preceding year) presenting a more considerable reduction in time spent in light activities from week 1 to week 2 in comparison to infrequent exacerbators.24

There was an increase in time spent indoors during exacerbations, which was sustained in the post-exacerbation period (days 1 to 35 after the onset) in comparison to the stable phase.27 A decrease in outdoors time during AECOPD that continues in the post-exacerbation period was also found, with frequent exacerbators (i.e., at least 2.5 AECOPD per year) presenting a faster annual decline in daily time outdoors than infrequent exacerbators.27 However, inconsistent results were found as in another study,25 in patients with a similar severity of AECOPD but better baseline lung function, the fall in time and percentage of days outdoors during exacerbations did not reach statistical significance.

Influence of exacerbations on quality of life

A consistent increase (worsening) in the SGRQ score with exacerbations27,29,34,43,45 was reported, with frequent exacerbators presenting faster and more pronounced declines in QoL.28,29,31,33,34,43-45 In a study with a 2-year follow-up, patients who suffered a single AECOPD improved in SGRQ score by −3.8 points while frequent exacerbators (i.e., two or more AECOPD per year) worsened +2.4 points.32

A similar pattern for QoL has also been found in the CRQ, SF-36 and SF-12. Patients with AECOPD presented a decline in CRQ, SF-36 and SF-12 scores, which was more pronounced in frequent exacerbators across all CRQ domains and in the physical component of SF-36 and SF-12.28,33-35,43 The EQ-5D was found to decline annually in exacerbators and non-exacerbators, similarly.35

A strong relationship between the number of AECOPD during the first year of follow-up and the change in depression score (i.e., CES-D) over 3-years has been found, with patients who suffered from more exacerbations presenting the most significant declines.41

A summary of the acute and long-term effects of AECOPD and the impact of single and repeated exacerbations on health status can be found in Fig. 3.

Figure 3.

Effects of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) on patients’ health status. (a) acute and long-term effects of AECOPD on health status. (b) effects of single and repeated AECOPD on health status. ↑, increase; ↓, decrease; ↑↑, greater increase than in single AECOPD; ↓↓, greater decrease than in single AECOPD; *, only in repeated AECOPD; (?), conflicting results found.

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Discussion

This scoping review summarized the acute and long-term effects of AECOPD and the impact of repeated exacerbations on the health status of patients with COPD. Acute effects included a worsening of symptoms and impact of the disease, and a reduction of exercise capacity, quadriceps muscle strength and physical activity levels. Long-term negative effects were reported on complaints, quadriceps muscle strength and quality of life. Repeated exacerbations negatively impacted FFM and resulted in further worsening of complaints (i.e., dyspnoea and impact of the disease) and QoL (i.e., health related QoL and depression). The impact of repeated exacerbations on exercise tolerance and physical activity levels is less clear.

Impact of exacerbations on complaints

An AECOPD is defined by an acute worsening of respiratory symptoms and it is usually characterized by increased airway inflammation, mucus production and air trapping.1 A recent proposal on an updated definition of AECOPD states that these events are characterized by dyspnoea and/or cough and sputum that worsens over up to 14 days, possibly accompanied by tachypnoea and/or tachycardia, and often associated with increased local and systemic inflammation.46 Not surprisingly, an acute worsening of complaints (i.e., dyspnoea and fatigue) during exacerbations was found.24,26 During this period, the worsening of airway obstruction results in increased work of breathing, dynamic hyperinflation and hypoxaemia, leading to symptoms of dyspnoea and fatigue.47-49 These symptoms usually recover following the exacerbation,47,49 yet persistent (up to 2 years) and higher increases in dyspnoea levels were found in frequent exacerbators,26,28 emphasizing the high impact of these events on patients’ life. In fact, the impact of the disease, as assessed by the CAT, has been found higher during either single or repeated exacerbations and on the long-term,35,37-39 and associated to the worsening of lung function, systemic inflammation and functional status.50,51

Impact of exacerbations on physiological function

Exacerbations result in physiological impairment. There is an immediate reduction in QMVC three and seven days after the onset of exacerbation symptoms.24 The increased systemic inflammation appears to contribute to this, as QMVC has been correlated with systemic levels of IGF-I and CXCL8 in AECOPD52; and pro-inflammatory cytokines activate pathways leading to atrophy and inflammation-induced muscle dysfunction.53,54 The reduced physical activity levels and medication used (e.g., corticosteroids) during this period seem to also play a role in QMVC reduction.53,55 Moreover, the increased cost of ventilation during exacerbations increases resting energy expenditure, with negative consequences on body weight and muscle mass,55 highlighting a potential role of nutritional support in these patients.56 Over the 1-year follow-up, one study found that frequent exacerbations were associated with FFM decline,30 possibly indicating a cumulative effect of AECOPD on muscle mass depletion – the main constituent of FFM.57 Furthermore, the same study found that the decline in FFM was also associated with the use of maintenance oral corticosteroids,30 which has been described in steroid-induced myopathy.58,59 Given the known relationship between reduced muscle mass and muscle strength impairment,58,60,61 one could expect that frequent AECOPD would also be associated with QMVC decline. Nevertheless, no association was found,30 showing that muscle mass and muscle strength are not always reduced in the same proportion.62 Further research is therefore needed to enhance our understanding on the impact of AECOPD on muscle dysfunction.

Exacerbations (single or repeated) also result in an acute decrease in functional exercise tolerance, which was expected since the breathing load is acutely increased and patients experience breathlessness even when performing low-intensity activities.47,63 Moreover, fatigue and quadriceps muscle weakness also play a role as limiting factors of exercise performance.64 Surprisingly, although it is often assumed that AECOPD leads to a permanent impairment on exercise performance, it is still unclear if the decrease in exercise tolerance recovers after a few days,24 alongside with symptomatic recovery,6,47,65 or whether it is sustained on a long-term, with studies26,28 even suggesting a sustained impairment 2 years after the exacerbation. It is known that (i) different types of AECOPD result in distinct clinical findings, prognosis and responses to treatment66,67; (ii) hospitalized patients with AECOPD are the ones presenting worse prognosis68; and (iii) the use of antibiotics and corticosteroids presents inconsistent benefits depending on the clinical setting and severity of AECOPD.68 Since in one study24 only community managed AECOPD were included and patients were mostly treated with a combination of antibiotics and oral corticosteroids, while the other two studies26,28 involved a percentage of AECOPD that resulted in hospital admission and did not report the exact number of patients treated with each medications, it is likely that these factors may have contributed to the disparity of the findings. Moreover, the six-minute walk test presents a significant learning effect and evidence shows the necessity of conducting the test twice in AECOPD.69,70 Therefore, differences in the methodology regarding the frequency and timing of assessments and the number of tests performed, might have also contributed to the inconsistency in the results. Future studies with robust methodologies are needed to clarify the long-term effects of AECOPD on exercise tolerance.

Impact of exacerbations on functional impairment

Exacerbations lead to functional impairment observed by reduced physical activity levels,24,25,27,42 which seems to be more accentuated in repeated AECOPD. An acute decrease in physical activity levels is associated with the severe inactivity and low amount of time spent in weight-bearing activities during hospitalization for AECOPD, general immobility and tendency to become housebound.16,71,72 The worsening of symptoms - particularly dyspnoea at rest - hypoxaemia, muscle weakness and loss of exercise capacity might also reduce physical activity levels.71,73,74 In turn, reduced physical activity levels lead to further skeletal muscle deconditioning and reduction of exercise capacity, bringing patients into a vicious cycle of symptoms and inactivity.74-77 It has been hypothesized that this vicious cycle could explain the long-term effect of AECOPD on physical activity levels.74 Nevertheless, conflicting evidence was found,74,78 with studies showing that physical activity levels can either recover in a few days/weeks or may not return to pre-exacerbation levels, especially in the case of frequent exacerbators.25,27,40,42,79 The differences in the timepoints of assessment and outcome measures used (e.g., objective vs. subjective measures) might have contributed to the heterogeneity in the results found.80 Further studies, following the international recommendations on how to measure physical activity in patients with COPD,81 are needed to better understand the impact of AECOPD on physical activity over time.

Impact of exacerbations on quality of life

The effects of exacerbations on QoL were the most studied. A long-term decline (up to 8 years) in QoL due to AECOPD was found,27,29,33,34,43,45 which was more pronounced in frequent exacerbators,28,29,31,33-35,43-45 suggesting a cumulative effect of repeated exacerbations in this domain. It is known that AECOPD have a huge impact on patients' everyday activities (e.g., walking, sleeping, work) and, consequently, they feel unable to maintain their lifestyle and make plans.82-84 Given these reasons and all the consequences of AECOPD mentioned above on complaints, physiological functioning and functional impairment, the decline on QoL was expected.

Implications of the findings for research

In sum, heterogeneity amongst the presentation and trajectory of recovery of exacerbations was found, and there is at least a subset of patients presenting a sustained worsening of health status after (repeated) exacerbations. This heterogeneity might have been influenced by the variety of AECOPD definitions found, as it is known that even small changes in the definition used affect the incidence rate, type and classification of exacerbations, with event-based AECOPD being usually considerably less identified and in specific groups of patients.23,85,86 The underlying cause of the AECOPD (e.g., viral exacerbations are known for being more severe and taking a longer recovery time),87 its severity, treatment setting (e.g., hospital vs. home), the standard of care provided (i.e., pharmacological treatment), presence of comorbidities, socioeconomic status and/or knowledge about the disease, might have also contributed to the heterogeneity found.67,87-93 A more accurate definition of AECOPD and understanding of its aetiology and diagnosis is, therefore, critical to better recognise exacerbations’ clinical impacts and improve treatment strategies. Despite this heterogeneity, AECOPD are usually treated uniformly (i.e., bronchodilators, systemic corticosteroids and/or antibiotics) without considering the different underlying outcomes and treatment needs.94 Since one size does not fit all, comprehensive health status assessments that allow the identification of distinct treatable traits amongst individuals are crucial to personalize treatments, contributing to improved AECOPD recovery and prevention.95 In this review, we have found that no study assessed all the domains that compose health status, thus future studies should explore the effects of AECOPD on patients’ health status using comprehensive measures. Moreover, early pulmonary rehabilitation is a safe intervention for the management of patients with AECOPD that has been shown to improve QoL, and reduce the length of hospitalization, hospital readmissions and mortality in these patients, while targeting several treatable traits (e.g., physical activity, exercise capacity, muscle weakness, dyspnoea) that are associated with exacerbation recurrence.4,96-98 Evidence suggests that pulmonary rehabilitation may be offered to patients with AECOPD to recover their pre-exacerbation health status.99 Pulmonary rehabilitation seems particularly important to those presenting a late recovery or who never recover to pre-exacerbation levels.90 Future studies should focus on personalizing pulmonary rehabilitation programs to target the different identified treatable traits during AECOPD.94,95

Methodological considerations

This scoping review has some strengths and limitations that need to be acknowledged. To our knowledge, this is the first review of the impact of AECOPD in the different sub-domains of health status in patients with COPD. A thorough search and screening were performed, and rigorous methodological and reporting frameworks (JBI and PRISMA-ScR) were followed. Nevertheless, we did not publish a protocol of the study before conducting this scoping review, thus the methods were not peer-reviewed prior to our search. Several concepts have been used to define health status and numerous tools were designed to assess the different aspects of this comprehensive measure. To ensure clarity, this work followed a previously published assessment framework for health status in patients with COPD.18 Additionally, the summary of the impacts of AECOPD on the different domains of health status was challenging due to the diversity in exacerbation definition and diagnosis, timepoints of assessment, outcome measures used, and lack of clarity of some results found. Most studies included a population combining different AECOPD severities, treatments and/or treatment settings, which prevented the presentation of these results separately. All these aspects have hampered results synthesis. Lastly, since most of the studies included were focused on moderate to severe AECOPD, the findings of this review cannot be translated to mild AECOPD.

Conclusion

Exacerbations of COPD result in both acute and long-term impairments in all health status domains. Acutely, there is a worsening of symptoms and impact of the disease, and a reduction in exercise capacity, quadriceps muscle strength and physical activity levels. Long-term negative effects are noticed on complaints, quadriceps muscle strength and quality of life. Repeated exacerbations result in a reduction of FFM and further worsening of complaints and QoL. However, the impact of repeated exacerbations on exercise tolerance and physical activity levels, and the trajectory of patients' recovery, is less clear due to the lack of studies and conflicting evidence found. Future research focused on these aspects is therefore warranted.

Funding

This work was funded by Programa Operacional de Competitividade e Internacionalização – POCI, through Fundo Europeu de Desenvolvimento Regional - FEDER (POCI-01–0145-FEDER-007,628), Fundação para a Ciência e Tecnologia (SFRH/BD/147,200/2019) and under the project UIDB/04,501/2020. In addition, Ana Machado's work is supported by Bijzonder Onderzoeksfonds – Bilaterale Samenwerking (BOF BILA) from Hasselt University (BOF BILA reference: DOC/SCHL-BOSE/190/522). Jana De Brandt is funded by the Flemish government through the Research Foundation – Flanders (FWO) grant #11B4718N. Sarah Haesevoets is supported by Bijzonder Onderzoeksfonds (BOF) from Hasselt University (BOF reference: BOF21KP15).

References
[1]
The Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention Chronic Obstructive Pulmonary Disease. 2021. (acessed 2021 June 14) Available from: https://goldcopd.org/wp-content/uploads/2020/11/GOLD-REPORT-2021-v1.0-11Nov20_WMV.pdf
[2]
L. Boer, E. Bischoff, X. Borgijink, J. Vercoulen, R. Akkermans, H. Kerstjens, et al.
‘Exacerbation-free time’to assess the impact of exacerbations in patients with chronic obstructive pulmonary disease (COPD): a prospective observational study.
NPJ Prim Care Respir Med, 28 (2018), pp. 1-6
[3]
T.A Seemungal, J.R. Hurst, J.A. Wedzicha.
Exacerbation rate, health status and mortality in COPD–a review of potential interventions.
Int J Chron Obstr Pulm Dis, 4 (2009), pp. 203-223
[4]
M.A. Puhan, E. Gimeno-Santos, C.J. Cates, T. Troosters.
Pulmonary rehabilitation following exacerbations of chronic obstructive pulmonary disease.
Cochrane Database Syst Rev, 12 (2016),
[5]
B.R. Celli, W. MacNee, A. Agusti, A. Anzueto, B. Berg, A.S. Buist, et al.
Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.
Eur Respir J, 23 (2004), pp. 932-946
[6]
T.A. Seemungal, G.C. Donaldson, A. Bhowmik, D.J. Jeffries, J.A. Wedzicha.
Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med, 161 (2000), pp. 1608-1613
[7]
M.T. Dransfield, K.M. Kunisaki, M.J. Strand, A. Anzueto, S.P. Bhatt, R.P. Bowler, et al.
Acute exacerbations and lung function loss in smokers with and without chronic obstructive pulmonary disease.
Am J Respir Crit Care Med, 195 (2017), pp. 324-330
[8]
D.M. Halpin, M. Decramer, B.R Celli, A. Mueller, N. Metzdorf, D.P. Tashkin.
Effect of a single exacerbation on decline in lung function in COPD.
Respir Med, 128 (2017), pp. 85-91
[9]
J.A. Wedzicha.
Mechanisms of chronic obstructive pulmonary disease exacerbations.
Ann Am Thorac Soc, 12 (2015), pp. S157-S1S9
[10]
A. Anzueto.
Impact of exacerbations on COPD.
Eur Respir Rev, 19 (2010), pp. 113-118
[11]
J.R. Hurst, J. Vestbo, A. Anzueto, N. Locantore, H. Müllerova, R. Tal-Singer, et al.
Susceptibility to exacerbation in chronic obstructive pulmonary disease.
N Engl J Med, 363 (2010), pp. 1128-1138
[12]
M.A. Spruit, S.J. Singh, C. Garvey, R. ZuWallack, L. Nici, C. Rochester, et al.
An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation.
Am J Respir Crit Care Med, 188 (2013), pp. e13-e64
[13]
J.R. Hurst, G.C. Donaldson, J.K. Quint, J.J. Goldring, R. Baghai-Ravary, J.A. Wedzicha.
Temporal clustering of exacerbations in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med, 179 (2009), pp. 369-374
[14]
G. Donaldson, T.A. Seemungal, A. Bhowmik, JA. Wedzicha.
Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease.
Thorax, 57 (2002), pp. 847-852
[15]
T.A. Seemungal, G.C. Donaldson, E.A. Paul, J.C. Bestall, D.J. Jeffries, J.A. Wedzicha.
Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med, 157 (1998), pp. 1418-1422
[16]
J.R. Hurst, N. Skolnik, G.J. Hansen, A. Anzueto, G.C. Donaldson, M.T. Dransfield, et al.
Understanding the impact of chronic obstructive pulmonary disease exacerbations on patient health and quality of life.
Eur J Intern Med, 73 (2020), pp. 1-6
[17]
J. Curtis, D. Patrick.
The assessment of health status among patients with COPD.
Eur Respir J, 21 (2003), pp. 36s-45s
[18]
J.H. Vercoulen, L. Daudey, J. Molema, P.J. Vos, J.B. Peters, M. Top, et al.
An Integral assessment framework of health status in chronic obstructive pulmonary disease (COPD).
Int J Behav Med, 15 (2008), pp. 263-279
[19]
A. Agustí, P.M. Calverley, M. Decramer, R.A. Stockley, J.A. Wedzicha.
Prevention of exacerbations in chronic obstructive pulmonary disease: knowns and unknowns.
Chron Obstr Pulm Dis, 1 (2014), pp. 166-184
[20]
E.E. Vincent, E.J. Chaplin, J.E. Williams, T. Harvey-Dunstan, N.J. Greening, M.C. Steiner, et al.
Experiences of patients undergoing pulmonary rehabilitation during an exacerbation of chronic respiratory disease.
Chron Respir Dis, 14 (2017), pp. 298-308
[21]
M.D. Peters, C. Marnie, A.C. Tricco, D. Pollock, Z. Munn, L. Alexander, et al.
Updated methodological guidance for the conduct of scoping reviews.
JBI Evid Synth, 18 (2020), pp. 2119-2126
[22]
A.C. Tricco, E. Lillie, W. Zarin, K.K. O’Brien, H. Colquhoun, D. Levac, et al.
PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation.
Ann Intern Med, 169 (2018), pp. 467-473
[23]
V. Kim, S.D. Aaron.
What is a COPD exacerbation? Current definitions, pitfalls, challenges and opportunities for improvement.
[24]
A.D. Alahmari, B.S. Kowlessar, A.R. Patel, A.J. Mackay, J.P. Allinson, J.A. Wedzicha, et al.
Physical activity and exercise capacity in patients with moderate COPD exacerbations.
Eur Respir J, 48 (2016), pp. 340-349
[25]
A.D. Alahmari, A.R. Patel, B.S. Kowlessar, A.J. Mackay, R. Singh, J.A. Wedzicha, et al.
Daily activity during stability and exacerbation of chronic obstructive pulmonary disease.
BMC Pulm Med, 14 (2014), pp. 98
[26]
C.G. Cote, L.J. Dordelly, B.R. Celli.
Impact of COPD exacerbations on patient-centered outcomes.
Chest, 131 (2007), pp. 696-704
[27]
G.C. Donaldson, T.M. Wilkinson, J.R. Hurst, W.R. Perera, J.A. Wedzicha.
Exacerbations and time spent outdoors in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med, 171 (2005), pp. 446-452
[28]
J. Dreyse, O. Díaz, P.B. Repetto, A. Morales, F. Saldías, C. Lisboa.
Do frequent moderate exacerbations contribute to progression of chronic obstructive pulmonary disease in patients who are ex-smokers?.
Int J Chron Obstr Pulm Dis, 10 (2015), pp. 525-533
[29]
R. Ferrari, S.E. Tanni, L.M. Caram, C.R. Naves, I. Godoy.
Predictors of health status do not change over three-year periods and exacerbation makes difference in chronic obstructive pulmonary disease.
Health Qual Life Outcomes, 9 (2011), pp. 112
[30]
N.S. Hopkinson, R.C. Tennant, M.J. Dayer, E.B. Swallow, T.T. Hansel, J. Moxham, et al.
A prospective study of decline in fat free mass and skeletal muscle strength in chronic obstructive pulmonary disease.
Respir Res, 8 (2007), pp. 25
[31]
L. Liang, Y. Lin, T. Yang, H. Zhang, J. Li, C. Wang.
Determinants of health-related quality of life worsening in patients with chronic obstructive pulmonary disease at one year.
Chin Med J, 127 (2014), pp. 4-10
[32]
C. Llor, J. Molina, K. Naberan, J. Cots, F. Ros, M. Miravitlles, et al.
Exacerbations worsen the quality of life of chronic obstructive pulmonary disease patients in primary healthcare.
Int J Clin Pract, 62 (2008), pp. 585-592
[33]
M. Miravitlles, M. Ferrer, A. Pont, R. Zalacain, J. Alvarez-Sala, F. Masa, et al.
Effect of exacerbations on quality of life in patients with chronic obstructive pulmonary disease: a 2 year follow up study.
Thorax, 59 (2004), pp. 387-395
[34]
K. Nishimura, S. Sato, M. Tsukino, T. Hajiro, A. Ikeda, H. Koyama, et al.
Effect of exacerbations on health status in subjects with chronic obstructive pulmonary disease.
Health Qual Life Outcomes, 7 (2009), pp. 69
[35]
F.M. Rodrigues, H. Demeyer, M. Loeckx, M. Hornikx, H. Van Remoortel, W. Janssens, et al.
Health status deterioration in subjects with mild to moderate airflow obstruction, a six years observational study.
[36]
J.C. Trappenburg, I. Touwen, G.H. de Weert-van Oene, J. Bourbeau, E.M. Monninkhof, T.J. Verheij, et al.
Detecting exacerbations using the Clinical COPD Questionnaire.
Health Qual Life Outcomes, 8 (2010), pp. 1-9
[37]
S.C. Zimmermann, J. Huvanandana, C.D. Nguyen, A. Bertolin, J.C. Watts, A. Gobbi, et al.
Day-to-day variability of forced oscillatory mechanics for early detection of acute exacerbations in COPD.
Eur Respir J, 56 (2020),
[38]
P. Kardos, C. Vogelmeier, H. Worth, R. Buhl, N.S. Lossi, C. Mailänder, et al.
A two-year evaluation of the ‘real life’impact of COPD on patients in Germany: the DACCORD observational study.
Respir Med, 124 (2017), pp. 57-64
[39]
P. Kardos, C.F. Vogelmeier, H. Worth, R. Buhl, V. Obermoser, C.P. Criée.
COPD assessment test changes from baseline correlate with COPD exacerbations: a longitudinal analysis of the DACCORD observational study.
[40]
N.A. Sievi, M. Kohler, R. Thurnheer, J.D. Leuppi, S. Irani, M. Frey, et al.
No impact of exacerbation frequency and severity on the physical activity decline in COPD: a long-term observation.
Int J Chron Obstr Pulm Dis, 14 (2019), pp. 431-437
[41]
A.M. Yohannes, H. Mülerová, K. Lavoie, J. Vestbo, S.I. Rennard, E. Wouters, et al.
The association of depressive symptoms with rates of acute exacerbations in patients with COPD: results from a 3-year longitudinal follow-up of the ECLIPSE cohort.
J Am Med Dir Assoc, 18 (2017), pp. 955-959
[42]
M. Ehsan, R. Khan, D. Wakefield, A. Qureshi, L. Murray, R. ZuWallack, et al.
A longitudinal study evaluating the effect of exacerbations on physical activity in patients with chronic obstructive pulmonary disease.
Ann Am Thorac Soc, 10 (2013), pp. 559-564
[43]
C. Esteban, J.M. Quintana, J. Moraza, M. Aburto, M. Egurrola, P.P. España, et al.
Impact of hospitalisations for exacerbations of COPD on health-related quality of life.
Respir Med, 103 (2009), pp. 1201-1208
[44]
R. Rubinsztajn, T. Przybyłowski, M. Maskey-Warzęchowska, K. Karwat, R. Chazan.
Exacerbations of chronic obstructive pulmonary disease and quality of life of patients.
Pathophysiology of Respiration: Springer, (2015), pp. 69-74
[45]
C. Esteban, I. Arostegui, A. Aramburu, J. Moraza, J. Najera-Zuloaga, M. Aburto, et al.
Predictive factors over time of health-related quality of life in COPD patients.
Respir Res, 21 (2020), pp. 1-11
[46]
B.R. Celli, L.M. Fabbri, S.D. Aaron, A. Agusti, R. Brook, G.J. Criner, et al.
An updated definition and severity classification of COPD exacerbations: the rome proposal.
Am J Respir Crit Care Med, 204 (2021), pp. 1251-1258
[47]
C. Parker, N. Voduc, S. Aaron, K. Webb, D. O’Donnell.
Physiological changes during symptom recovery from moderate exacerbations of COPD.
Eur Respir J, 26 (2005), pp. 420-428
[48]
M. Roca, A. Verduri, L. Corbetta, E. Clini, L.M. Fabbri, B. Beghé.
Mechanisms of acute exacerbation of respiratory symptoms in chronic obstructive pulmonary disease.
Eur J Clin Investig, 43 (2013), pp. 510-521
[49]
R. Baghai-Ravary, J.K. Quint, J.J. Goldring, J.R. Hurst, G.C. Donaldson, J.A. Wedzicha.
Determinants and impact of fatigue in patients with chronic obstructive pulmonary disease.
Respir Med, 103 (2009), pp. 216-223
[50]
A.A. Gulart, A.B. Munari, Q. APAd, K.C. Cani, D.L. Matte, A.F. Mayer.
Does the COPD assessment test reflect functional status in patients with COPD?.
Chron Respir Dis, 14 (2017), pp. 37-44
[51]
A.J. Mackay, G.C. Donaldson, A.R. Patel, P.W. Jones, J.R. Hurst, J.A. Wedzicha.
Usefulness of the chronic obstructive pulmonary disease assessment test to evaluate severity of COPD exacerbations.
Am J Respir Crit Care Med, 185 (2012), pp. 1218-1224
[52]
M.A. Spruit, R. Gosselink, T. Troosters, A. Kasran, G. Gayan-Ramirez, P. Bogaerts, et al.
Muscle force during an acute exacerbation in hospitalised patients with COPD and its relationship with CXCL8 and IGF-I.
Thorax, 58 (2003), pp. 752-756
[53]
H.R. Gosker, R.C. Langen, S.O. Simons.
Role of acute exacerbations in skeletal muscle impairment in COPD patients.
Expert Rev Respir Med, (2020), pp. 103-115
[54]
T. Crul, D. Testelmans, M.A. Spruit, T. Troosters, R. Gosselink, I. Geeraerts, et al.
Gene expression profiling in vastus lateralis muscle during an acute exacerbation of COPD.
Cell Physiol Biochem, 25 (2010), pp. 491-500
[55]
R.M. Abdulai, T.J. Jensen, N.R. Patel, M.I. Polkey, P. Jansson, B.R. Celli, et al.
Deterioration of limb muscle function during acute exacerbation of chronic obstructive pulmonary disease.
Am J Respir Crit Care Med, 197 (2018), pp. 433-449
[56]
P.F. Collins, I.A. Yang, Y.C. Chang, A. Vaughan.
Nutritional support in chronic obstructive pulmonary disease (COPD): an evidence update.
J Thorac Dis, 11 (2019), pp. S2230-S22S7
[57]
A. Bosy-Westphal, M. Müller.
Identification of skeletal muscle mass depletion across age and BMI groups in health and disease—There is need for a unified definition.
Int J Obes, 39 (2015), pp. 379-386
[58]
M. Decramer, V. De Bock, R. Dom.
Functional and histologic picture of steroid-induced myopathy in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med, 153 (1996), pp. 1958-1964
[59]
A. Couillard, C. Prefaut.
From muscle disuse to myopathy in COPD: potential contribution of oxidative stress.
Eur Respir J, 26 (2005), pp. 703-719
[60]
R. Ferrari, L.M. Caram, M.M. Faganello, F.F. Sanchez, S.E. Tanni, I. Godoy.
Relation between systemic inflammatory markers, peripheral muscle mass, and strength in limb muscles in stable COPD patients.
Int J Chron Obstr Pulm Dis, 10 (2015), pp. 1553-1558
[61]
S. Bernard, P. LeBLANC, F. Whittom, G. Carrier, J. Jobin, R. Belleau, et al.
Peripheral muscle weakness in patients with chronic obstructive pulmonary disease.
Am J Respir Crit Care Med, 158 (1998), pp. 629-634
[62]
M. Decramer, L.M. Lacquet, R. Fagard, P. Rogiers.
Corticosteroids contribute to muscle weakness in chronic airflow obstruction.
Am J Respir Crit Care Med, 150 (1994), pp. 11-16
[63]
D. O’donnell, C. Parker.
COPD exacerbations• 3: pathophysiology.
Thorax, 61 (2006), pp. 354-361
[64]
L. Nici.
Mechanisms and measures of exercise intolerance in chronic obstructive pulmonary disease.
Clin Chest Med, 21 (2000), pp. 693-704
[65]
A. Oliveira, V. Afreixo, A. Marques.
Enhancing our understanding of the time course of acute exacerbations of COPD managed on an outpatient basis.
Int J Chron Obstr Pulm Dis, 13 (2018), pp. 3759-3766
[66]
Y. Kandemir, N.Ö. Doğan, E. Yaka, M. Pekdemir, S. Yılmaz.
Clinical characteristics of neutrophilic, eosinophilic and mixed-type exacerbation phenotypes of COPD.
Am J Emerg Med, 45 (2021), pp. 237-241
[67]
I.D. Pavord, P.W. Jones, P.R. Burgel, K.F. Rabe.
Exacerbations of COPD.
Int J Chron Obstr Pulm Dis, 11 (2016), pp. 21-30
[68]
F.W. Ko, K.P. Chan, D.S. Hui, J.R. Goddard, J.G. Shaw, D.W. Reid, et al.
Acute exacerbation of COPD.
Respirology, 21 (2016), pp. 1152-1165
[69]
A.E. Holland, M.A. Spruit, T. Troosters, M.A. Puhan, V. Pepin, D. Saey, et al.
An official European respiratory society/american thoracic society technical standard: field walking tests in chronic respiratory disease.
Eur Respir J, 44 (2014), pp. 1428-1446
[70]
C.R. Osadnik, R.C. Borges, C.F. McDonald, C.R. Carvalho, A.E. Holland.
Two 6-minute walk tests are required during hospitalisation for acute exacerbation of COPD.
J COPD Found, 13 (2016), pp. 288-292
[71]
C. Esteban, S. Garcia-Gutierrez, M.J. Legarreta, A. Anton-Ladislao, N. Gonzalez, I. Lafuente, et al.
One-year mortality in COPD after an exacerbation: the effect of physical activity changes during the event.
J COPD Found, 13 (2016), pp. 718-725
[72]
F. Pitta, T. Troosters, V.S. Probst, M.A. Spruit, M. Decramer, R. Gosselink.
Physical activity and hospitalization for exacerbation of COPD.
Chest, 129 (2006), pp. 536-544
[73]
R.C. Borges, C.R.F. Carvalho.
Physical activity in daily life in Brazilian COPD patients during and after exacerbation.
J COPD Found, 9 (2012), pp. 596-602
[74]
H. Demeyer, M. Costilla-Frias, Z. Louvaris, E. Gimeno-Santos, M. Tabberer, R.A. Rabinovich, et al.
Both moderate and severe exacerbations accelerate physical activity decline in COPD patients.
Eur Respir J, 51 (2018),
[75]
A. Anzueto, M. Miravitlles.
Pathophysiology of dyspnea in COPD.
Postgrad Med, 129 (2017), pp. 366-374
[76]
D.E O’Donnell, K.M. Milne, M.D. James, J.P. de Torres, J.A. Neder.
Dyspnea in COPD: new mechanistic insights and management implications.
[77]
M.A. Ramon, G. Ter Riet, A.E. Carsin, E. Gimeno-Santos, A. Agustí, J.M. Antó, et al.
The dyspnoea–inactivity vicious circle in COPD: development and external validation of a conceptual model.
[78]
N.A. Sievi, M. Kohler, R. Thurnheer, J.D. Leuppi, S. Irani, M. Frey, et al.
No impact of exacerbation frequency and severity on the physical activity decline in COPD: a long-term observation.
Int J Chron Obstr Pulm Dis, 14 (2019), pp. 431
[79]
H. Watz, F. Pitta, C.L. Rochester, J. Garcia-Aymerich, R. ZuWallack, T. Troosters, et al.
An official European Respiratory Society statement on physical activity in COPD.
Eur Respir Soc, (2014),
[80]
C. Burtin, D. Mohan, T. Troosters, H. Watz, N.S. Hopkinson, J. Garcia-Aymerich, et al.
Objectively measured physical activity as a COPD clinical trial outcome.
Chest, 160 (2021), pp. 2080-2100
[81]
H. Demeyer, D. Mohan, C. Burtin, A. Vaes, M. Heasley, R. Bowler, et al.
Objectively measured physical activity in patients with COPD: recommendations from an international task force on physical activity.
Chron Obstr Pulm Dis, 8 (2021), pp. 528-550
[82]
J. Haughney, M. Partridge, C. Vogelmeier, T. Larsson, R. Kessler, E. Ståhl, et al.
Exacerbations of COPD: quantifying the patient’s perspective using discrete choice modelling.
Eur Respir J, 26 (2005), pp. 623-629
[83]
N. Barnes, P.M. Calverley, A. Kaplan, K.F. Rabe.
Chronic obstructive pulmonary disease and exacerbations: patient insights from the global Hidden Depths of COPD survey.
BMC Pulm Med, 13 (2013), pp. 54
[84]
C.T. Solem, S.X. Sun, L. Sudharshan, C. Macahilig, M. Katyal, X. Gao.
Exacerbation-related impairment of quality of life and work productivity in severe and very severe chronic obstructive pulmonary disease.
Int J Chron Obstr Pulm Dis, 8 (2013), pp. 641-652
[85]
M. Montes de Oca, M.E. Laucho-Contreras.
Is it time to change the definition of acute exacerbation of chronic obstructive pulmonary disease? What Do we need to add?.
Med Sci, 6 (2018), pp. 50
[86]
J. Trappenburg, A. Van Deventer, T. Troosters, T. Verheij, A. Schrijvers, J.J. Lammers, et al.
The impact of using different symptom-based exacerbation algorithms in patients with COPD.
Eur Respir J, 37 (2011), pp. 1260-1268
[87]
J.A. Wedzicha, T.A. Seemungal.
COPD exacerbations: defining their cause and prevention.
[88]
J.L. Lopez-Campos, A. Agustí.
Heterogeneity of chronic obstructive pulmonary disease exacerbations: a two-axes classification proposal.
Lancet Respir Med, 3 (2015), pp. 729-734
[89]
A. Zhou, Z. Zhou, Y. Zhao, P. Chen.
The recent advances of phenotypes in acute exacerbations of COPD.
Int J Chron Obstr Pulm Dis, 12 (2017), pp. 1009-1018
[90]
M.A. Spruit, F.M. Franssen, E.P. Rutten, S. Wopereis, E.F. Wouters, L.E. Vanfleteren.
A new perspective on COPD exacerbations: monitoring impact by measuring physical, psychological and social resilience.
Eur Respir Soc, (2016), pp. 1024-1027
[91]
M.R. Crutsen, S.J. Keene, D.J. Nakken, M.T. Groenen, S.M. van Kuijk, F.M. Franssen, et al.
Physical, psychological, and social factors associated with exacerbation-related hospitalization in patients with COPD.
J Clin Med, 9 (2020), pp. 636
[92]
M.D. Eisner, P.D. Blanc, T.A. Omachi, E.H. Yelin, S. Sidney, P.P. Katz, et al.
Socioeconomic status, race and COPD health outcomes.
J Epidemiol Community Health, 65 (2011), pp. 26-34
[93]
P. Galiatsatos, H. Woo, L.M. Paulin, A. Kind, N. Putcha, A.J. Gassett, et al.
The association between neighborhood socioeconomic disadvantage and chronic obstructive pulmonary disease.
Int J Chron Obstr Pulm Dis, 15 (2020), pp. 981-993
[94]
A.G. Mathioudakis, W. Janssens, P. Sivapalan, A. Singanayagam, M.T. Dransfield, J.U.S. Jensen, et al.
Acute exacerbations of chronic obstructive pulmonary disease: in search of diagnostic biomarkers and treatable traits.
[95]
V.M. McDonald, C.R. Osadnik, P.G. Gibson.
Treatable traits in acute exacerbations of chronic airway diseases.
Chron Respir Dis, 16 (2019), pp. 1-16
[96]
C. Burtin, M. Decramer, R. Gosselink, W. Janssens, T. Troosters.
Rehabilitation and acute exacerbations.
Eur Respir J, 38 (2011), pp. 702-712
[97]
C.K. Ryrsø, N.S. Godtfredsen, L.M. Kofod, M. Lavesen, L. Mogensen, R. Tobberup, et al.
Lower mortality after early supervised pulmonary rehabilitation following COPD-exacerbations: a systematic review and meta-analysis.
BMC Pulm Med, 18 (2018), pp. 154
[98]
A. Machado, P.M. Silva, V. Afreixo, C. Caneiras, C. Burtin, A. Marques.
Design of pulmonary rehabilitation programmes during acute exacerbations of COPD: a systematic review and network meta-analysis.
Eur Respir Rev, 29 (2020),
[99]
D.M. Halpin, M. Miravitlles, N. Metzdorf, B. Celli.
Impact and prevention of severe exacerbations of COPD: a review of the evidence.
Int J Chron Obstr Pulm Dis, 12 (2017), pp. 2891-2908
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