Original Article
The association between co-morbidities and physical performance in people with chronic obstructive pulmonary disease: A systematic review
Chronic Respiratory Disease 2014, Vol 11(1) 3–13 ª The Author(s) 2013 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1479972313516879 crd.sagepub.com
Lok Sze Katrina Li1, Gillian E Caughey2 and Kylie N Johnston1
Abstract A systematic review was conducted to examine the association between co-morbidity and physical performance in people with chronic obstructive pulmonary disease (COPD). MEDLINE, EMBASE, CINAHL, SCOPUS and Cochrane Central Register of Controlled Trials were searched from inception to endFebruary 2013, using keywords ‘COPD’, ‘exercise’, ‘physical activity’, ‘rehabilitation’, ‘co-morbidity’ and individual co-morbid conditions. Studies reporting associations of co-morbidities in COPD with at least one objective measure of physical performance were included. Study quality was appraised using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Nine studies met inclusion criteria. Mean (standard deviation (SD)) STROBE score was 16 (3) (maximum score ¼ 21). Four studies examined anxiety as a co-morbid condition; three examined depression; two examined obesity and two examined a range of conditions. Reduced physical performance was associated with higher Charlson score (odds ratio (OR) ¼ 0.72, 95% confidence interval (CI) ¼ 0.54–0.98), metabolic disease (OR ¼ 0.58, 95% CI ¼ 0.49–0.67), anxiety (OR ¼ 0.37, 95% CI ¼ 0.23–0.59) and osteoporosis (OR ¼ 0.28, 95% CI ¼ 0.11–0.70). Depression had minimal association with physical performance but was associated with higher dropout rates from pulmonary rehabilitation programmes. Obesity was negatively associated with baseline physical performance but not with change from an exercise intervention. The presence of co-morbid conditions in people with COPD may negatively affect physical performance and should be identified and accounted for analysis of interventions. Keywords COPD, physical performance, co-morbidity, systematic review
Introduction Chronic obstructive pulmonary disease (COPD) is a progressive condition characterised in the lung by airway inflammation and airflow obstruction which is not fully reversible.1 COPD was ranked as the third leading global cause of death in 2010.2 Clinical features include dyspnoea during physical activity, reduced exercise tolerance and symptom exacerbations that may require hospitalisation. As the condition progresses, dyspnoea and repeated exacerbations result in deterioration in quality of life.3,4 Co-morbidity (the coexistence of one or more conditions in reference to an ‘index’ condition) is common in people with COPD.5 In a US-based study,
Mapel et al.6 reported an average of 3.7 chronic conditions in cases with COPD compared with 1.8 chronic conditions in those without. Common comorbid conditions in COPD include heart failure,7
1 School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia 2 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
Corresponding author: Kylie Johnston, School of Health Sciences, University of South Australia, GPO Box 2471, Adelaide, South Australia 5001, Australia. Email: [email protected]
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Table 1. Systematic search strategy and terms. Database
Search terms
MEDLINE EMBASE
1. COPD (including related terms) 2. Pulmonary rehaba OR exercise OR physical activity (including related terms) 3. 1 or 2 4. Pulmonary 5. Rehabilitata 6. 4 and 5 7. 3 and 6 8. Co-morbida (including related terms) 9. 7 and 8 Replace (8) with congestive heart failure, myocardial or heart infarction, rheumatoid arthritis, peripheral vascular disease, diabetes or diabetes mellitus type2, cardiovascular diseases, depression, hypertension, hyperlipidaemia, osteoarthritis, obesity, kidney or renal disease (all including related terms except kidney or renal disease) 1. COPD OR chronic obstructive pulmonary disease – AND 2. Pulmonary rehaba OR exercise OR physical activity – AND 3. Co-morbida Replace (3) with congestive heart failure, myocardial infarcta, osteoarthritis, rheumatoid arthritis, arthritis, renal or kidney disease, peripheral vascular disease, diabetes, cardiovascular disease, depression, hypertension, hyperlipidaemia or cholesterol, obesity or overweight
CINAHL SCOPUS
COPD ¼ chronic obstructive pulmonary disease. a Truncation, including related terms.
osteoporosis,8 diabetes9 and mental illness.10 The presence of co-morbidity is a major determinant of functional capability, disease severity and patient outcomes for those with COPD.5,11 Co-morbidity may also negatively influence the therapeutic management of COPD. For example, whilst corticosteroids are recommended in guidelines for the maintenance and treatment of acute exacerbations of COPD, approximately 20% of older patients with diabetes will also have COPD, thus corticosteroid use may interfere with blood glucose level and result in poor diabetes control.12 People with multiple chronic conditions including COPD have been reported to prioritise the management of one condition over others,13 creating challenges for management of risk factors including lack of exercise, recognising signs and symptoms of illness and managing medications. A key non-pharmacological intervention in the management of people with COPD is pulmonary rehabilitation (PR) that consists of exercise training, education and psychosocial support. Beneficial effects of PR on exercise tolerance, symptom reduction and quality of life have been demonstrated in people with COPD.14 Whilst depression has been associated with dropout from PR programmes,15 the influence of co-morbidity on degree of improvement gained from rehabilitation, or baseline physical performance in people with COPD, has not been
reviewed. Aspects of physical performance of interest in people with COPD include measures of exercise tolerance, functional exercise capacity16 and physical activity levels.17 Narrative reviews of co-morbidity in COPD have examined possible common disease mechanisms18 and prompted consideration of the impact of comorbidity on physical performance19,20 but have not systematically reviewed existing literature regarding this association. Therefore, the aim of this study was to conduct a systematic review examining the association between co-morbidity and physical performance in people with COPD.
Methods Search strategy and study selection A primary systematic search of electronic databases, namely Cochrane Central Register of Controlled Trials (1996–February 2013), SCOPUS (1996–February 2013), CINAHL (1982–February 2013), MEDLINE (1946–February 2013) and EMBASE (1974–February 2013) was conducted. Search terms used in the major databases are listed in Table 1. Secondary searching examined the reference lists of all full text studies screened. Studies were eligible for inclusion if (a) participants were diagnosed with COPD (or chronic
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Literature search Databases: MEDLINE, CINAHL, EMBASE, SCOPUS, Cochrane Central Register of Controlled Trials
2430 records identified and screenedby title and abstract
2393 records did not meet inclusion criteria on basis of title and abstract
27 duplicates removed
10 full-text articles assessed and reference lists searched 4 did not meet inclusion criteria on basis of full text
3 studies identified from reference lists, full text obtained and included
9 studies included in this review
Figure 1. Flow diagram of study selection.
bronchitis or emphysema), (b) participants had one or more co-morbid conditions documented, (c) the study investigated how co-morbidity in COPD patients affected physical performance, (d) the study reported at least one objective outcome measure related to physical performance and (e) they were written in English.
Quality assessment Two independent reviewers (KJ and KL) critically appraised the included studies using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.21 This tool consists of 22 items that relate to study description, bias, statistical analysis and external validity.22 One item (‘other analyses’) was combined with the ‘main results’ item, resulting in a maximum score of 21.
Data analysis Associations between co-morbidities and measures of physical performance in people with COPD reported in the included articles were summarised. Where odds ratios (ORs) were not reported but significant associations were described using multiple regression, ORs and 95% confidence intervals (CIs) were calculated from the published data by exponentiating the unstandardised b regression coefficient (i.e. OR ¼ exp(b)) to allow comparison of effect size between studies.
Results The search strategy yielded 2430 records of which 2393 were excluded based on title or abstract and a further 10 were duplicates. A total of nine studies met the criteria for inclusion (Figure 1).
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Quality assessment Table 2 presents the STROBE checklist score for each included study. Scores ranged between 13 and 20 with a mean (SD) score of 16 (3). A study by Eisner et al.10 reported how the study size was arrived at, whilst none justified sample size with power calculations. Strategies to address potential sources of bias were described in three studies.10,25,29 Only three studies addressed the external validity or generalisability of their study results.24,25,29
Participant characteristics, study design and outcome measures Table 2 presents the participant characteristics, study design and outcome measures of the included studies. The total number of patients included in 9 studies was 7076, ranging from74 to 2962 subjects per study. The mean age of participants in individual studies ranged from 55 to 71 years. The 6-minute walk test distance (6MWD) was used as an outcome measure of physical performance in all studies which met the inclusion criteria. Two types of study design were used in the nine studies. Eisner et al.10 and Giardino et al.25 used crosssectional study designs and found anxiety in COPD patients to be related to poorer health outcomes. The other seven studies15,23,24,26–29 measured participant’s physical performance before and after they participated in a PR programme.
individual co-morbidities in the different studies prevented meta-analysis of findings. In the studies where ORs were reported or calculated, a higher Charlson co-morbidity index score had the largest negative association with physical performance (OR ¼ 0.72, 95% CI ¼ 0.54–0.98)23 followed by the presence of metabolic disease (OR ¼ 0.58, 95% CI ¼ 0.49– 0.67),23 anxiety (OR ¼ 0.37, 95% CI ¼ 0.23–0.59)25 and osteoporosis (OR ¼ 0.28, 95% CI ¼ 0.11– 0.70)24 in descending order. Depression only had a minimal effect on physical performance (OR ¼ 0.003, 95% CI ¼ 0.00–0.25).29 The OR of the two studies on the effect of obesity on performance could not be calculated, however both authors concluded that obesity had a negative association with physical performance in COPD patients.26,27 On the other hand, heart disease had a positive association with physical performance (OR ¼ 2.86, 95% CI ¼ 1.85–3.01).23 These associations are complicated by two issues. First, associations of Charlson index, metabolic disease and heart disease with achievement of minimal clinically important difference in 6MWD reported in a retrospective study by Crisafulli et al.,23 were not replicated in their subsequent prospective study.24 Second, associations of co-morbidity are reported both with baseline measures of 6MWD (for anxiety,10,25,29 depression25,29 and obesity26,27) and with improvements in physical performance after a PR program (for Charlson index,23 metabolic disease,23 heart disease,23 osteoporosis,24 depression15,28 and obesity26,27; Table 4).
Co-morbidities examined Four studies10,25,28,29 examined anxiety as a co-morbid condition; depression was examined in three studies15,28,29 and obesity was examined in two studies.26,27 A range of co-morbid conditions were examined in two studies by Crisafulli et al.23,24 including chronic heart failure, coronary disease, diabetes, osteoporosis, dyslipidaemia and hypertension; however, mental health or obesity were not identified or examined in these studies. Details of co-morbidities examined in each study and how they were identified are included in Table 3.
Associations between co-morbid conditions and physical performance in COPD Table 4 summarises associations reported between co-morbidities and physical performance in people with COPD. Inhomogeneity of statistical analyses for associations between physical performance and
Discussion The findings of this systematic review indicate that the presence of co-morbid anxiety (in two crosssectional studies10,25), osteoporosis (one intervention study24) or obesity (in two cross-sectional studies26,27, one retrospective26) were associated with reduced physical performance in people with COPD. Associations with reduced physical performance were reported for metabolic disease,23 higher Charlson index23 and depression25,28,29 but not found in other included studies of the same co-morbidities.15,24 Obesity did not have an effect on the outcome of PR but was associated with lower baseline 6MWD.26,27 The presence of co-morbid conditions is increasingly recognised as a major clinical consideration in the management of people with COPD, influencing both therapeutic management and clinical outcomes.34 Recommendations made in clinical guidelines for
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71.1 (8.0)
2150/812 49.3 (14.8)
In/outpatient PR (cycle and resistance training); daily sessions up to a minimum of 15. (Not clear how much of programme people attended)
6MWD
Age mean (SD) years
Gender M/F FEV1% predicted mean (SD)
Intervention
Physical performance outcome measures
6MWD
6MWD
66.7 (6.3)
Moderate to severe emphysema
1828
Cross-sectional study
United States 2010 20
Giardino et al.25
47/67 46 (16)
70 (8)
114 (analysis on 98 patients as underweight excluded) Diagnosis of COPD with GOLD classification
Pre–post intervention retrospective
United States 2008 13
Ramachandran et al.26
149/112 46 (15)
Diagnosis of COPD with GOLD classification 65 (8)
Pre–post intervention prospective 261
Canada 2010 17
Sava et al.27
Outpatient PR Nil Outpatient PR Outpatient PR 1-hour exercise Approximately 16 1.5-hour session (walking and sessions, aerobic (cycle and resisresistance trainexercise and strength tance training) ing) þ education training þ education 3 per week 6– session 2 per 12 weeks, but week 7 weeks some of sample þ home exercises did home-based 20 minutes/day programme 5 days/week 6MWD; walk–work; arm 6MWD; CET 6MWD; quadriceps 6MWD; maximum lifts per minute; exercise capacity torque; grip functional activities (cycle ergometer) strength
41/33 1134/694 Mild: 65.7 (20); 27.1 (7.5) moderate: 43 (24.4); severe:38.1 (16.9)
68 (10)
Known diagnosis of COPD
Physician’s diagnosis of COPD
No anxiety: 59(6)’ anxiety: 55 (6.6) 235/81 696/808 49.6 (14) FEV1 in litres reported; COPD no anxiety: 1.78 (0.8); COPD anxiety: 1.88 (0.8); Control no anxiety: 2.73 (0.7); Control anxiety: 3.03 (0.8) Outpatient PR (cycle Nil and resistance training); 3-hour session 3 per week (complete a minimum of 21 sessions)
Diagnosis of COPD with GOLD classification 68.3 (7.6)
74 (analysis on 51 who completed)
Pre–post intervention
Cross-sectional study 1202 (COPD); 302 (control)
United Kingdom 2006 15
Garrod et al.15
United States 2010 19
Eisner et al.10
238
Diagnosis of COPD with GOLD classification 62.0 (9.9)
81 (analysis on 65 who completed)
Diagnosis of COPD with GOLD classification 63 (8)
6MWD
6MWD
Outpatient PR Outpatient PR 2-hour session(cycle, 6-hour session(cycle, walking and resiswalking and resistance training) tance training) 5 3 per week 12 per week 3 weeks weeks
135/103 53.9 (18.1)
Pre–post intervention prospective
Pre–post intervention
Not reported 42 (17)
Germany 2011 18
Von Leupoldt et al.29
United States 2005 15
Trappenburg et al.28
GOLD: Global Initiative of Chronic Obstructive Lung Disease classification; 6MWD: 6-minute walk test distance; FEV1: forced expiratory volume in 1 second, CET: constant work rate cycling exercise test; COPD: chronic obstructive pulmonary disease; STROBE: the Strengthening the Reporting of Observational Studies in Epidemiology.
Diagnosis of COPD with GOLD classification
Study population
Pre–post intervention retrospective
2962
Pre–post intervention prospective 316
Italy 2008 13
Country Year of publication STROBE checklist score Study design
Sample size (n)
Italy 2010 14
Crisafulli et al.23
Author
Crisafulli et al.24
Table 2. Characteristics of study participants, design and outcome measures.
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Table 3. Co-morbidities examined in included studies. Author
Co-morbidities examined
How co-morbidities were identified
Crisafulli et al.23
Medical record extraction Charlson co-morbidity index
Eisner et al.10 Garrod et al.15 Giardino et al.25
Hypertension Congestive heart failure Coronary disease Diabetes Dislipidaemia Osteoporosis/arthrosis Others Chronic heart failure Diabetes Osteoporosis Dyslipidaemia Coronary disease Hypertension Anxiety Depression Anxiety Depression
Ramachandran et al.26
Obesity
Sava et al.27
Overweight and obesity
Trappenburg et al.28 Von Leupoldt et al.29
Anxiety Depression Anxiety Depression
Crisafulli et al.24
Medical record extraction Charlson co-morbidity index
Hospital anxiety and depression scale30,a Brief assessment schedule depression card31,a Beck depression inventory32,a Spielberger state trait anxiety inventory33,a BMI (measured) (normal BMI ¼ 21–24.9 kg/m2, overweight ¼ 25–29.9 kg/m2, obesity ¼ BMI > 30 kg/m2) BMI (measured) (normal BMI ¼ 18.5–24.99 kg/m2, overweight ¼ 25–29.99 kg/m2, obese ¼ BMI > 30 kg/m2) Hospital Anxiety and Depression Scale30,a Hospital Anxiety and Depression Scale30,a
BMI: body mass index. a Validated instrument.
COPD care are based on findings from clinical trials, which often exclude older patients and those with comorbidity. For example, Herland et al.35 found that a ‘typical’ clinical study would only include 17% of the ‘real-life’ asthma or COPD patient population, potentially limiting the generalisation of study findings to ‘real-life’ settings. Changes in physical performance are a common endpoint in COPD studies evaluating pharmacological36 and non-pharmacological37 interventions, and this review demonstrates existing evidence for the potentially confounding influence of co-morbidity on such results. In order to control for the effects of co-morbidity on outcomes of clinical research, indices such as the Charlson co-morbidity index have been used.38 Based on diagnosis of 17 specific conditions, the Charlson co-morbidity index is an established predictor of mortality.38,39 However, the index does not include all conditions (e.g. depression, anxiety and obesity) and is not strongly predictive of other important health outcomes including quality of life40 or health-care utilisation.41 Other co-morbidity scores such as the
medication based Rx-Risk score42,43 may complement the Charlson co-morbidity index, as this includes co-morbid conditions not included in the latter, such as hypertension, anxiety, depression and osteoporosis, which are common in COPD and could negatively impact physical performance. Two cross-sectional studies in this review10,25 reported a negative effect of anxiety and/or depression on COPD patients’ physical performance, two reported no or negligible association28,29 whilst one reported no significant association between baseline depression and change in 6MWD after pulmonary rehabilitation.15 Other studies that examined obesity and multiple co-morbidities did not examine mental health issues.23,24,26,27 If anxiety or depression were present in these patient populations, it may have had a confounding effect on physical performance outcomes. Anxiety and depression are common comorbidities in people with COPD, with prevalence rates as high as 75% for anxiety and 71% for depression.44 Depression has been associated with sedentary lifestyle or lack of adherence to exercise programmes
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Crisafulli et al.23 Achievement of MCID improvement in 6MWD after PRP Achievement of MCID improvement in 6MWD after PRP Achievement of MCID improvement in 6MWD after PRP
Associated physical performance measure
Multiple logistic regression
Multiple logistic regression
Multiple logistic regression
Statistical analysis of association OR ¼ 0.72 (95% CI ¼ 0.54–0.98) p ¼ 0.024 OR ¼ 0.57 (95% CI ¼ 0.49–0.67) p ¼ 0.001 OR ¼ 2.36 (95% CI ¼ 1.85–3.01) p ¼ 0.001
OR 95% CI or effect size
Positive
Negative
Negative
Direction of association with physical performance
Achievement of MCID improvement in 6MWD after PRP
Multiple logistic regression
OR ¼ 0.28 (95% CI ¼ 0.11–0.7) p < 0.01
Negative
Anxiety
Depression
Garrod et al.15
Achievement of clinically significant improvement in either 6MWD or SGRQ after PRP ‘responder’ change in 6MWD after PRP
Cross-sectional 6MWD
Multiple linear 95%CI ¼ 127.3 regression associated to 5.36 feet), with distance of p ¼ 0.033 66.3 feet for anxious versus nonanxious group Univariate and multiple linear regression
None
Negative
(continued)
also examined heart failure, diabetes, hypertension, coronary disease, dyslipidaemia, ‘other diseases’, and heart disease, metabolic disease as groupings: no associations reported
Osteoporosis
also examined self-reported heart failure, diabetes, hypertension, coronary disease, dyslipidaemia, osteoporosis/arthrosis ‘other diseases’, and heart disease, skeletal disease as groupings: no associations reported
Heart disease
Eisner et al.10
Crisafulli et al.24
Higher Charlson index
Authors
Metabolic disease
Co-morbidity examined
Table 4. Associations between co-morbidities and physical performance in people with COPD.
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Depression (HADS depression) Depression (HADS depression)
Trappenburg et al.28 Change in peak workload (cycle) after PRP
Proportion of group who reached MCID in 6MWD after PRP Change in 6MWD after PRP
Change in 6MWD after PRP
Baseline 6MWD
Weak univariate correlation 0.34, p ¼ 0.008
Anxiety (HADS anxiety) Depression (HADS depression) 6MWD after PRP
Baseline 6MWD 6MWD after PRP Baseline 6MWD
Multivariate analysis b ¼ 2.13; SE ¼ 1.43, not significant Multivariate analysis b OR ¼ 0.003 (95% ¼ 5.55; SE ¼ 2.11 CI ¼ 0.00–0.25)a Very similar result to that at baseline.
Slight negative
Slight negative
None
Slight negative
None
Negative
None
Negative
None
Negative
Negative
Negative
Direction of association with physical performance
6MWD: 6-minute walk distance; MCID: minimal clinically important difference; PRP: pulmonary rehabilitation program; b: unstandardised regression coefficient; SE: standard error, OR: odds ratio; CI: confidence interval; HADS: Hospital Anxiety and Depression Scale. a OR and 95% CI calculated from published data (regression coefficient b). All multivariate analyses accounted for effects of age, sex and lung function.
von Leupoldt et al.29
Obesity (BMI > 30 kg/m2)
Sava et al.27
Change in 6MWD after PRP
Baseline 6MWD
OR 95% CI or effect size
OR ¼ 0.37 (95% CI ¼ 0.23–0.59)a p < 0.001 Multiple linear OR ¼ 0.07 (95% regression CI ¼ 0.01–0.38)a p ¼ 0.009 Independent t test, less in obese (203 + 13 m) than non-obese (269 + 11 m, p ¼ 0.0002) Independent t test of change in 6MWD outcome obese versus non-obese. ANOVA: significantly different in obese group (342 + 79 m) from overweight (391 + 78 m) and normal weight groups (407 + 75 m) Multivariate analysis with age, sex, lung function (data not shown) ANOVA: significantly less in obese versus normal weight group (15% vs. 24%, p < 0.01) Multiple linear regression
Statistical analysis of association
Also examined anxiety (HADS anxiety), no associations with 6MWD or peak workload changes.
Obesity (BMI > 30 kg/m2)
Cross-sectional 6MWD
Depression
Giardino et al.25
Ramachandran et al.26
Cross-sectional 6MWD
Anxiety
Authors
Associated physical performance measure
Co-morbidity examined
Table 4. (continued)
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in the general population.45 Consistent with this finding, Garrod et al.15 in an included study from this review reported greater drop out from a PR programme in participants with depression. Future studies in people with COPD that use a measure of physical performance as an outcome should document anxiety and depression and account for their presence in analysis, as these conditions may confound results and more information on the influence of anxiety and depression is required. In one retrospective study, heart disease was associated with improved 6MWD after PR.23 Cardiac risk factors have been shown to be reduced with a rehabilitation program.46 PR may provide a common exercise pathway to address breathlessness during exercise, skeletal muscle dysfunction and lifestyle changes in chronic heart and lung conditions,47 which may explain this observed association with greater benefit in 6MWD. The primary measure of physical performance in the included studies was distance walked in the 6MWD. Whilst the 6MWD is a validated measure of exercise tolerance in people with COPD,48 it only measures a narrow range of the physical performance spectrum. No studies were identified that examined the relationship of co-morbidities in COPD with other measures of physical performance. Future studies could examine other aspects of physical performance that might be affected by co-morbidities, for example, objective measures of physical activity or functional capacity. Quality assessment of included studies used the STROBE checklist, which was developed to encourage authors to reported adequate information on research methods and data analysis for readers to interpret the results of observational studies with confidence.22 Studies by Giardino et al.,25 Eisner et al.10 (both reporting negative association of anxiety with cross-sectional 6MWD) and von Leupoldt et al.29 (reporting no association of anxiety with crosssectional 6MWD) had the highest scores thus greatest levels of completeness in reporting. Co-morbidities were not identified in a uniform manner across studies included in this systematic review, except for obesity which was defined consistently with the body mass index.26,27 Heterogeneous study designs and statistical analyses in the included studies prevented meta-analysis of associations with physical performance even for the same co-morbid condition. Associations with co-morbidity were reported in some studies with baseline measures of
physical performance, and in other studies with improvement gained after a PR program. These inconsistencies in collecting and analysing comorbidity data make it difficult to compare patient characteristics and results between studies and limit the strength of conclusions able to be drawn from this review. The inclusion of only English-language studies may have limited the completeness of this review.
Conclusion An association between reduced physical performance in people with COPD who also have comorbid anxiety, obesity and osteoporosis and possibly in those with metabolic disease or depression was observed in this study. This highlights the need to identify all co-morbid conditions present in those with COPD, to facilitate the development of specific strategies to ensure optimal participation in physical activity programmes and to improve exercise tolerance and health outcomes. Conflict of interest The authors declared no conflicts of interest.
Funding This project received no specific grant from any funding agency in the public, commercial or not for profit sectors.
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6. Mapel DW, Hurley JS, Frost FJ, et al. Health care utilization in chronic obstructive pulmonary disease: a case-control study in a health maintenance organization. Arch Intern Med 2000; 160: 2653–2658. 7. Tka´cˇ J, Man SFP and Sin DD. Review: systemic consequences of COPD. Ther Adv Respir Dis 2007; 1: 47–59. 8. O’Kelly S, Smith SM, Lane S, et al. Chronic respiratory disease and multimorbidity: prevalence and impact in a general practice setting. Respir Med 2011; 105: 236–242. 9. Sharafkhaneh A, Petersen NJ, Yu HJ, et al. Burden of COPD in a government health care system: a retrospective observational study using data from the US Veterans Affairs population. Int J Chron Obstruct Pulmon Dis 2010; 5: 125–132. 10. Eisner MD, Blanc PD, Yelin EH, et al. Influence of anxiety on health outcomes in COPD. Thorax 2010; 65: 229–234. 11. Mannino DM, Thorn D, Swensen A, et al. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J 2008; 32: 962–969. 12. Caughey GE, Roughead EE, Vitry AI, et al. Comorbidity in the elderly with diabetes: Identification of areas of potential treatment conflicts. Diabetes Res Clin Pract 2010; 87: 385–393. 13. Jowsey T, Jeon YH, Dugdale P, et al. Challenges for co-morbid chronic illness care and policy in Australia: a qualitative study. Aust New Zealand Health Policy 2009; 6: 22–22. 14. Lacasse Y, Goldstein R, Lasserson TJ, et al. Pulmonary rehabilitation for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2006; 4: CD003793. 15. Garrod R, Marshall J, Barley E, et al. Predictors of success and failure in pulmonary rehabilitation. Eur Respir J 2006; 27: 788–794. 16. Eisner MD, Blanc PD, Yelin EH, et al. COPD as a systemic disease: impact on physical functional limitations. Am J Med 2008; 121: 789–796. 17. Watz H, Waschki B, Meyer T, et al. Physical activity in patients with COPD. Eur Respir J 2009; 33: 262–272. 18. Barnes PJ and Celli BR. Systemic manifestations and comorbidities of COPD. Eur Respir J 2009; 33: 1165–1185. 19. Corsonello A, Incalzi RA, Pistelli R, et al. Comorbidities of chronic obstructive pulmonary disease. Curr Opin Pulm Med 2011; 17: S21–S28. 20. Maltais F. Exercise and COPD: therapeutic responses, disease-related outcomes, and activity-promotion strategies. Phys Sportsmed 2013; 41: 66–80.
21. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med 2007; 4: e296. 22. Vandenbroucke JP, von Elm E, Altman DG, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Med 2007; 4: e297. 23. Crisafulli E, Costi S, Luppi F, et al. Role of comorbidities in a cohort of patients with COPD undergoing pulmonary rehabilitation. Thorax 2008; 63: 487–491. 24. Crisafulli E, Gorgone P, Vagaggini B, et al. Efficacy of standard rehabilitation in COPD outpatients with comorbidities. Eur Respir J 2010; 36:1042–1048. 25. Giardino ND, Curtis JL, Andrei A, et al. Anxiety is associated with diminished exercise performance and quality of life in severe emphysema: a cross-sectional study. Respir Res 2010; 11: 29. 26. Ramachandran K, McCusker C, Connors M, et al. The influence of obesity on pulmonary rehabilitation outcomes in patients with COPD. Chron Respir Dis 2008; 5: 205–209. 27. Sava F, Laviolette L, Bernard S, et al. The impact of obesity on walking and cycling performance and response to pulmonary rehabilitation in COPD. BMC Pulm Med 2010; 10: 55. 28. Trappenburg JC, Troosters T, Spruit MA, et al. Psychosocial conditions do not affect short-term outcome of multidisciplinary rehabilitation in chronic obstructive pulmonary disease. Arch Phys Med Rehabil 2005; 86: 1788–1792. 29. von Leupoldt A, Taube K, Lehmann K, et al. The impact of anxiety and depression on outcomes of pulmonary rehabilitation in patients with COPD. Chest 2011; 140: 730–736. 30. Zigmond AS and Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361–370. 31. Yohannes AM, Baldwin RC and Connolly MJ. Depression and anxiety in elderly outpatients with chronic obstructive pulmonary disease: prevalence and validation of the BASDEC screening questionnaire. Int J Geriatr Psychiatry 2000; 15: 1090–1096. 32. Beck AT and Steer RA. Beck depression Inventory, Revised Edition (BDI). San Antonio, TX: The Psychological Corporation, 1971. 33. Speilberger CD. Manual for the state-trait anxiety inventory. Pala Alto, CA: Consulting Psychologists Press, 1983. 34. Schnell K, Weiss CO, Lee T, et al. The prevalence of clinically-relevant comorbid conditions in patients
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with physician-diagnosed COPD: a cross-sectional study using data from NHANES 1999–2008. BMC Pulm Med 2012: 12: 26. Herland K, Akselsen JP, Skjønsberg OH, et al. How representative are clinical study patients with asthma or COPD for a larger ‘real life’ population of patients with obstructive lung disease? Respir Med 2005; 99: 11–19. Troosters T, Weisman I, Dobbels F, et al. Assessing the impact of tiotropium on lung function and physical activity in GOLD stage II COPD patients who are naı¨ve to maintenance respiratory therapy: a study protocol. Open Respir Med J 2011; 15: 1–9. Holland AE, Mahal A, Hill CJ, et al. Benefits and costs of home-based pulmonary rehabilitation in chronic obstructive pulmonary disease: a multi-centre randomised controlled equivalence trial. BMC Pulm Med 2013; 13: 57. Charlson M, Pompei P, Ales K, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373–383. Sundararajan V, Henderson T, Perry C, et al. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. J Clin Epidemiol 2004; 57: 1288–1294. Olomu AB, Corser WD, Stommel M, et al. Do self-report and medical record comorbidity data predict longitudinal functional capacity and quality of life health outcomes similarly? BMC Health Serv Res 2012; 14: 398.
41. Brilleman SL and Salisbury C. Comparing measures of multimorbidity to predict outcomes in primary care: a cross sectional study. Fam Pract 2013; 30: 172–178. 42. Sloan KL, Sales AE, Liu CF, et al. Construction and characteristics of the RxRisk-V: a VA-adapted pharmacybased case-mix instrument. Med Care 2003; 41: 761–774. 43. Lu CY, Barratt J, Vitry A, et al. Charlson and Rx-Risk comorbidity indices were predictive of mortality in the Australian health care setting. J Clin Epidemiol 2011; 64: 223–228. 44. Maurer J, Rebbapragada V, Borson S, et al. Anxiety and depression in COPD: current understanding, unanswered questions, and research needs. Chest 2008; 134: 43S–56S. 45. Roshanaei-Moghaddam B, Katon WJ and Russo J. The longitudinal effects of depression on physical activity. Gen Hosp Psychiatry 2009; 31: 306–315. 46. Thompson DR. Home-based cardiac rehab was as effective as hospital-based rehab in improving cardiac risk factors. Evid Based Nurs 2009; 12: 83. 47. Evans RA, Singh SJ, Collier R, et al. Generic, symptom based, exercise rehabilitation; integrating patients with COPD and heart failure. Respir Med 2010; 104: 1473–1481. 48. Cote CG, Casanova C, Marin JM, et al. Validation and comparison of reference equations for the 6-min walk distance test. Eur Respir J 2008; 31: 571–578.
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The association between co-morbidities and physical performance in people with chronic obstructive pulmonary disease: A systematic review
Chronic Respiratory Disease 2014, Vol 11(1) 3–13 ª The Author(s) 2013 Reprints and permission: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1479972313516879 crd.sagepub.com
Lok Sze Katrina Li1, Gillian E Caughey2 and Kylie N Johnston1
Abstract A systematic review was conducted to examine the association between co-morbidity and physical performance in people with chronic obstructive pulmonary disease (COPD). MEDLINE, EMBASE, CINAHL, SCOPUS and Cochrane Central Register of Controlled Trials were searched from inception to endFebruary 2013, using keywords ‘COPD’, ‘exercise’, ‘physical activity’, ‘rehabilitation’, ‘co-morbidity’ and individual co-morbid conditions. Studies reporting associations of co-morbidities in COPD with at least one objective measure of physical performance were included. Study quality was appraised using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Nine studies met inclusion criteria. Mean (standard deviation (SD)) STROBE score was 16 (3) (maximum score ¼ 21). Four studies examined anxiety as a co-morbid condition; three examined depression; two examined obesity and two examined a range of conditions. Reduced physical performance was associated with higher Charlson score (odds ratio (OR) ¼ 0.72, 95% confidence interval (CI) ¼ 0.54–0.98), metabolic disease (OR ¼ 0.58, 95% CI ¼ 0.49–0.67), anxiety (OR ¼ 0.37, 95% CI ¼ 0.23–0.59) and osteoporosis (OR ¼ 0.28, 95% CI ¼ 0.11–0.70). Depression had minimal association with physical performance but was associated with higher dropout rates from pulmonary rehabilitation programmes. Obesity was negatively associated with baseline physical performance but not with change from an exercise intervention. The presence of co-morbid conditions in people with COPD may negatively affect physical performance and should be identified and accounted for analysis of interventions. Keywords COPD, physical performance, co-morbidity, systematic review
Introduction Chronic obstructive pulmonary disease (COPD) is a progressive condition characterised in the lung by airway inflammation and airflow obstruction which is not fully reversible.1 COPD was ranked as the third leading global cause of death in 2010.2 Clinical features include dyspnoea during physical activity, reduced exercise tolerance and symptom exacerbations that may require hospitalisation. As the condition progresses, dyspnoea and repeated exacerbations result in deterioration in quality of life.3,4 Co-morbidity (the coexistence of one or more conditions in reference to an ‘index’ condition) is common in people with COPD.5 In a US-based study,
Mapel et al.6 reported an average of 3.7 chronic conditions in cases with COPD compared with 1.8 chronic conditions in those without. Common comorbid conditions in COPD include heart failure,7
1 School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia 2 School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia
Corresponding author: Kylie Johnston, School of Health Sciences, University of South Australia, GPO Box 2471, Adelaide, South Australia 5001, Australia. Email: [email protected]
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Table 1. Systematic search strategy and terms. Database
Search terms
MEDLINE EMBASE
1. COPD (including related terms) 2. Pulmonary rehaba OR exercise OR physical activity (including related terms) 3. 1 or 2 4. Pulmonary 5. Rehabilitata 6. 4 and 5 7. 3 and 6 8. Co-morbida (including related terms) 9. 7 and 8 Replace (8) with congestive heart failure, myocardial or heart infarction, rheumatoid arthritis, peripheral vascular disease, diabetes or diabetes mellitus type2, cardiovascular diseases, depression, hypertension, hyperlipidaemia, osteoarthritis, obesity, kidney or renal disease (all including related terms except kidney or renal disease) 1. COPD OR chronic obstructive pulmonary disease – AND 2. Pulmonary rehaba OR exercise OR physical activity – AND 3. Co-morbida Replace (3) with congestive heart failure, myocardial infarcta, osteoarthritis, rheumatoid arthritis, arthritis, renal or kidney disease, peripheral vascular disease, diabetes, cardiovascular disease, depression, hypertension, hyperlipidaemia or cholesterol, obesity or overweight
CINAHL SCOPUS
COPD ¼ chronic obstructive pulmonary disease. a Truncation, including related terms.
osteoporosis,8 diabetes9 and mental illness.10 The presence of co-morbidity is a major determinant of functional capability, disease severity and patient outcomes for those with COPD.5,11 Co-morbidity may also negatively influence the therapeutic management of COPD. For example, whilst corticosteroids are recommended in guidelines for the maintenance and treatment of acute exacerbations of COPD, approximately 20% of older patients with diabetes will also have COPD, thus corticosteroid use may interfere with blood glucose level and result in poor diabetes control.12 People with multiple chronic conditions including COPD have been reported to prioritise the management of one condition over others,13 creating challenges for management of risk factors including lack of exercise, recognising signs and symptoms of illness and managing medications. A key non-pharmacological intervention in the management of people with COPD is pulmonary rehabilitation (PR) that consists of exercise training, education and psychosocial support. Beneficial effects of PR on exercise tolerance, symptom reduction and quality of life have been demonstrated in people with COPD.14 Whilst depression has been associated with dropout from PR programmes,15 the influence of co-morbidity on degree of improvement gained from rehabilitation, or baseline physical performance in people with COPD, has not been
reviewed. Aspects of physical performance of interest in people with COPD include measures of exercise tolerance, functional exercise capacity16 and physical activity levels.17 Narrative reviews of co-morbidity in COPD have examined possible common disease mechanisms18 and prompted consideration of the impact of comorbidity on physical performance19,20 but have not systematically reviewed existing literature regarding this association. Therefore, the aim of this study was to conduct a systematic review examining the association between co-morbidity and physical performance in people with COPD.
Methods Search strategy and study selection A primary systematic search of electronic databases, namely Cochrane Central Register of Controlled Trials (1996–February 2013), SCOPUS (1996–February 2013), CINAHL (1982–February 2013), MEDLINE (1946–February 2013) and EMBASE (1974–February 2013) was conducted. Search terms used in the major databases are listed in Table 1. Secondary searching examined the reference lists of all full text studies screened. Studies were eligible for inclusion if (a) participants were diagnosed with COPD (or chronic
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Literature search Databases: MEDLINE, CINAHL, EMBASE, SCOPUS, Cochrane Central Register of Controlled Trials
2430 records identified and screenedby title and abstract
2393 records did not meet inclusion criteria on basis of title and abstract
27 duplicates removed
10 full-text articles assessed and reference lists searched 4 did not meet inclusion criteria on basis of full text
3 studies identified from reference lists, full text obtained and included
9 studies included in this review
Figure 1. Flow diagram of study selection.
bronchitis or emphysema), (b) participants had one or more co-morbid conditions documented, (c) the study investigated how co-morbidity in COPD patients affected physical performance, (d) the study reported at least one objective outcome measure related to physical performance and (e) they were written in English.
Quality assessment Two independent reviewers (KJ and KL) critically appraised the included studies using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist.21 This tool consists of 22 items that relate to study description, bias, statistical analysis and external validity.22 One item (‘other analyses’) was combined with the ‘main results’ item, resulting in a maximum score of 21.
Data analysis Associations between co-morbidities and measures of physical performance in people with COPD reported in the included articles were summarised. Where odds ratios (ORs) were not reported but significant associations were described using multiple regression, ORs and 95% confidence intervals (CIs) were calculated from the published data by exponentiating the unstandardised b regression coefficient (i.e. OR ¼ exp(b)) to allow comparison of effect size between studies.
Results The search strategy yielded 2430 records of which 2393 were excluded based on title or abstract and a further 10 were duplicates. A total of nine studies met the criteria for inclusion (Figure 1).
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Quality assessment Table 2 presents the STROBE checklist score for each included study. Scores ranged between 13 and 20 with a mean (SD) score of 16 (3). A study by Eisner et al.10 reported how the study size was arrived at, whilst none justified sample size with power calculations. Strategies to address potential sources of bias were described in three studies.10,25,29 Only three studies addressed the external validity or generalisability of their study results.24,25,29
Participant characteristics, study design and outcome measures Table 2 presents the participant characteristics, study design and outcome measures of the included studies. The total number of patients included in 9 studies was 7076, ranging from74 to 2962 subjects per study. The mean age of participants in individual studies ranged from 55 to 71 years. The 6-minute walk test distance (6MWD) was used as an outcome measure of physical performance in all studies which met the inclusion criteria. Two types of study design were used in the nine studies. Eisner et al.10 and Giardino et al.25 used crosssectional study designs and found anxiety in COPD patients to be related to poorer health outcomes. The other seven studies15,23,24,26–29 measured participant’s physical performance before and after they participated in a PR programme.
individual co-morbidities in the different studies prevented meta-analysis of findings. In the studies where ORs were reported or calculated, a higher Charlson co-morbidity index score had the largest negative association with physical performance (OR ¼ 0.72, 95% CI ¼ 0.54–0.98)23 followed by the presence of metabolic disease (OR ¼ 0.58, 95% CI ¼ 0.49– 0.67),23 anxiety (OR ¼ 0.37, 95% CI ¼ 0.23–0.59)25 and osteoporosis (OR ¼ 0.28, 95% CI ¼ 0.11– 0.70)24 in descending order. Depression only had a minimal effect on physical performance (OR ¼ 0.003, 95% CI ¼ 0.00–0.25).29 The OR of the two studies on the effect of obesity on performance could not be calculated, however both authors concluded that obesity had a negative association with physical performance in COPD patients.26,27 On the other hand, heart disease had a positive association with physical performance (OR ¼ 2.86, 95% CI ¼ 1.85–3.01).23 These associations are complicated by two issues. First, associations of Charlson index, metabolic disease and heart disease with achievement of minimal clinically important difference in 6MWD reported in a retrospective study by Crisafulli et al.,23 were not replicated in their subsequent prospective study.24 Second, associations of co-morbidity are reported both with baseline measures of 6MWD (for anxiety,10,25,29 depression25,29 and obesity26,27) and with improvements in physical performance after a PR program (for Charlson index,23 metabolic disease,23 heart disease,23 osteoporosis,24 depression15,28 and obesity26,27; Table 4).
Co-morbidities examined Four studies10,25,28,29 examined anxiety as a co-morbid condition; depression was examined in three studies15,28,29 and obesity was examined in two studies.26,27 A range of co-morbid conditions were examined in two studies by Crisafulli et al.23,24 including chronic heart failure, coronary disease, diabetes, osteoporosis, dyslipidaemia and hypertension; however, mental health or obesity were not identified or examined in these studies. Details of co-morbidities examined in each study and how they were identified are included in Table 3.
Associations between co-morbid conditions and physical performance in COPD Table 4 summarises associations reported between co-morbidities and physical performance in people with COPD. Inhomogeneity of statistical analyses for associations between physical performance and
Discussion The findings of this systematic review indicate that the presence of co-morbid anxiety (in two crosssectional studies10,25), osteoporosis (one intervention study24) or obesity (in two cross-sectional studies26,27, one retrospective26) were associated with reduced physical performance in people with COPD. Associations with reduced physical performance were reported for metabolic disease,23 higher Charlson index23 and depression25,28,29 but not found in other included studies of the same co-morbidities.15,24 Obesity did not have an effect on the outcome of PR but was associated with lower baseline 6MWD.26,27 The presence of co-morbid conditions is increasingly recognised as a major clinical consideration in the management of people with COPD, influencing both therapeutic management and clinical outcomes.34 Recommendations made in clinical guidelines for
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71.1 (8.0)
2150/812 49.3 (14.8)
In/outpatient PR (cycle and resistance training); daily sessions up to a minimum of 15. (Not clear how much of programme people attended)
6MWD
Age mean (SD) years
Gender M/F FEV1% predicted mean (SD)
Intervention
Physical performance outcome measures
6MWD
6MWD
66.7 (6.3)
Moderate to severe emphysema
1828
Cross-sectional study
United States 2010 20
Giardino et al.25
47/67 46 (16)
70 (8)
114 (analysis on 98 patients as underweight excluded) Diagnosis of COPD with GOLD classification
Pre–post intervention retrospective
United States 2008 13
Ramachandran et al.26
149/112 46 (15)
Diagnosis of COPD with GOLD classification 65 (8)
Pre–post intervention prospective 261
Canada 2010 17
Sava et al.27
Outpatient PR Nil Outpatient PR Outpatient PR 1-hour exercise Approximately 16 1.5-hour session (walking and sessions, aerobic (cycle and resisresistance trainexercise and strength tance training) ing) þ education training þ education 3 per week 6– session 2 per 12 weeks, but week 7 weeks some of sample þ home exercises did home-based 20 minutes/day programme 5 days/week 6MWD; walk–work; arm 6MWD; CET 6MWD; quadriceps 6MWD; maximum lifts per minute; exercise capacity torque; grip functional activities (cycle ergometer) strength
41/33 1134/694 Mild: 65.7 (20); 27.1 (7.5) moderate: 43 (24.4); severe:38.1 (16.9)
68 (10)
Known diagnosis of COPD
Physician’s diagnosis of COPD
No anxiety: 59(6)’ anxiety: 55 (6.6) 235/81 696/808 49.6 (14) FEV1 in litres reported; COPD no anxiety: 1.78 (0.8); COPD anxiety: 1.88 (0.8); Control no anxiety: 2.73 (0.7); Control anxiety: 3.03 (0.8) Outpatient PR (cycle Nil and resistance training); 3-hour session 3 per week (complete a minimum of 21 sessions)
Diagnosis of COPD with GOLD classification 68.3 (7.6)
74 (analysis on 51 who completed)
Pre–post intervention
Cross-sectional study 1202 (COPD); 302 (control)
United Kingdom 2006 15
Garrod et al.15
United States 2010 19
Eisner et al.10
238
Diagnosis of COPD with GOLD classification 62.0 (9.9)
81 (analysis on 65 who completed)
Diagnosis of COPD with GOLD classification 63 (8)
6MWD
6MWD
Outpatient PR Outpatient PR 2-hour session(cycle, 6-hour session(cycle, walking and resiswalking and resistance training) tance training) 5 3 per week 12 per week 3 weeks weeks
135/103 53.9 (18.1)
Pre–post intervention prospective
Pre–post intervention
Not reported 42 (17)
Germany 2011 18
Von Leupoldt et al.29
United States 2005 15
Trappenburg et al.28
GOLD: Global Initiative of Chronic Obstructive Lung Disease classification; 6MWD: 6-minute walk test distance; FEV1: forced expiratory volume in 1 second, CET: constant work rate cycling exercise test; COPD: chronic obstructive pulmonary disease; STROBE: the Strengthening the Reporting of Observational Studies in Epidemiology.
Diagnosis of COPD with GOLD classification
Study population
Pre–post intervention retrospective
2962
Pre–post intervention prospective 316
Italy 2008 13
Country Year of publication STROBE checklist score Study design
Sample size (n)
Italy 2010 14
Crisafulli et al.23
Author
Crisafulli et al.24
Table 2. Characteristics of study participants, design and outcome measures.
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Table 3. Co-morbidities examined in included studies. Author
Co-morbidities examined
How co-morbidities were identified
Crisafulli et al.23
Medical record extraction Charlson co-morbidity index
Eisner et al.10 Garrod et al.15 Giardino et al.25
Hypertension Congestive heart failure Coronary disease Diabetes Dislipidaemia Osteoporosis/arthrosis Others Chronic heart failure Diabetes Osteoporosis Dyslipidaemia Coronary disease Hypertension Anxiety Depression Anxiety Depression
Ramachandran et al.26
Obesity
Sava et al.27
Overweight and obesity
Trappenburg et al.28 Von Leupoldt et al.29
Anxiety Depression Anxiety Depression
Crisafulli et al.24
Medical record extraction Charlson co-morbidity index
Hospital anxiety and depression scale30,a Brief assessment schedule depression card31,a Beck depression inventory32,a Spielberger state trait anxiety inventory33,a BMI (measured) (normal BMI ¼ 21–24.9 kg/m2, overweight ¼ 25–29.9 kg/m2, obesity ¼ BMI > 30 kg/m2) BMI (measured) (normal BMI ¼ 18.5–24.99 kg/m2, overweight ¼ 25–29.99 kg/m2, obese ¼ BMI > 30 kg/m2) Hospital Anxiety and Depression Scale30,a Hospital Anxiety and Depression Scale30,a
BMI: body mass index. a Validated instrument.
COPD care are based on findings from clinical trials, which often exclude older patients and those with comorbidity. For example, Herland et al.35 found that a ‘typical’ clinical study would only include 17% of the ‘real-life’ asthma or COPD patient population, potentially limiting the generalisation of study findings to ‘real-life’ settings. Changes in physical performance are a common endpoint in COPD studies evaluating pharmacological36 and non-pharmacological37 interventions, and this review demonstrates existing evidence for the potentially confounding influence of co-morbidity on such results. In order to control for the effects of co-morbidity on outcomes of clinical research, indices such as the Charlson co-morbidity index have been used.38 Based on diagnosis of 17 specific conditions, the Charlson co-morbidity index is an established predictor of mortality.38,39 However, the index does not include all conditions (e.g. depression, anxiety and obesity) and is not strongly predictive of other important health outcomes including quality of life40 or health-care utilisation.41 Other co-morbidity scores such as the
medication based Rx-Risk score42,43 may complement the Charlson co-morbidity index, as this includes co-morbid conditions not included in the latter, such as hypertension, anxiety, depression and osteoporosis, which are common in COPD and could negatively impact physical performance. Two cross-sectional studies in this review10,25 reported a negative effect of anxiety and/or depression on COPD patients’ physical performance, two reported no or negligible association28,29 whilst one reported no significant association between baseline depression and change in 6MWD after pulmonary rehabilitation.15 Other studies that examined obesity and multiple co-morbidities did not examine mental health issues.23,24,26,27 If anxiety or depression were present in these patient populations, it may have had a confounding effect on physical performance outcomes. Anxiety and depression are common comorbidities in people with COPD, with prevalence rates as high as 75% for anxiety and 71% for depression.44 Depression has been associated with sedentary lifestyle or lack of adherence to exercise programmes
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Crisafulli et al.23 Achievement of MCID improvement in 6MWD after PRP Achievement of MCID improvement in 6MWD after PRP Achievement of MCID improvement in 6MWD after PRP
Associated physical performance measure
Multiple logistic regression
Multiple logistic regression
Multiple logistic regression
Statistical analysis of association OR ¼ 0.72 (95% CI ¼ 0.54–0.98) p ¼ 0.024 OR ¼ 0.57 (95% CI ¼ 0.49–0.67) p ¼ 0.001 OR ¼ 2.36 (95% CI ¼ 1.85–3.01) p ¼ 0.001
OR 95% CI or effect size
Positive
Negative
Negative
Direction of association with physical performance
Achievement of MCID improvement in 6MWD after PRP
Multiple logistic regression
OR ¼ 0.28 (95% CI ¼ 0.11–0.7) p < 0.01
Negative
Anxiety
Depression
Garrod et al.15
Achievement of clinically significant improvement in either 6MWD or SGRQ after PRP ‘responder’ change in 6MWD after PRP
Cross-sectional 6MWD
Multiple linear 95%CI ¼ 127.3 regression associated to 5.36 feet), with distance of p ¼ 0.033 66.3 feet for anxious versus nonanxious group Univariate and multiple linear regression
None
Negative
(continued)
also examined heart failure, diabetes, hypertension, coronary disease, dyslipidaemia, ‘other diseases’, and heart disease, metabolic disease as groupings: no associations reported
Osteoporosis
also examined self-reported heart failure, diabetes, hypertension, coronary disease, dyslipidaemia, osteoporosis/arthrosis ‘other diseases’, and heart disease, skeletal disease as groupings: no associations reported
Heart disease
Eisner et al.10
Crisafulli et al.24
Higher Charlson index
Authors
Metabolic disease
Co-morbidity examined
Table 4. Associations between co-morbidities and physical performance in people with COPD.
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Depression (HADS depression) Depression (HADS depression)
Trappenburg et al.28 Change in peak workload (cycle) after PRP
Proportion of group who reached MCID in 6MWD after PRP Change in 6MWD after PRP
Change in 6MWD after PRP
Baseline 6MWD
Weak univariate correlation 0.34, p ¼ 0.008
Anxiety (HADS anxiety) Depression (HADS depression) 6MWD after PRP
Baseline 6MWD 6MWD after PRP Baseline 6MWD
Multivariate analysis b ¼ 2.13; SE ¼ 1.43, not significant Multivariate analysis b OR ¼ 0.003 (95% ¼ 5.55; SE ¼ 2.11 CI ¼ 0.00–0.25)a Very similar result to that at baseline.
Slight negative
Slight negative
None
Slight negative
None
Negative
None
Negative
None
Negative
Negative
Negative
Direction of association with physical performance
6MWD: 6-minute walk distance; MCID: minimal clinically important difference; PRP: pulmonary rehabilitation program; b: unstandardised regression coefficient; SE: standard error, OR: odds ratio; CI: confidence interval; HADS: Hospital Anxiety and Depression Scale. a OR and 95% CI calculated from published data (regression coefficient b). All multivariate analyses accounted for effects of age, sex and lung function.
von Leupoldt et al.29
Obesity (BMI > 30 kg/m2)
Sava et al.27
Change in 6MWD after PRP
Baseline 6MWD
OR 95% CI or effect size
OR ¼ 0.37 (95% CI ¼ 0.23–0.59)a p < 0.001 Multiple linear OR ¼ 0.07 (95% regression CI ¼ 0.01–0.38)a p ¼ 0.009 Independent t test, less in obese (203 + 13 m) than non-obese (269 + 11 m, p ¼ 0.0002) Independent t test of change in 6MWD outcome obese versus non-obese. ANOVA: significantly different in obese group (342 + 79 m) from overweight (391 + 78 m) and normal weight groups (407 + 75 m) Multivariate analysis with age, sex, lung function (data not shown) ANOVA: significantly less in obese versus normal weight group (15% vs. 24%, p < 0.01) Multiple linear regression
Statistical analysis of association
Also examined anxiety (HADS anxiety), no associations with 6MWD or peak workload changes.
Obesity (BMI > 30 kg/m2)
Cross-sectional 6MWD
Depression
Giardino et al.25
Ramachandran et al.26
Cross-sectional 6MWD
Anxiety
Authors
Associated physical performance measure
Co-morbidity examined
Table 4. (continued)
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in the general population.45 Consistent with this finding, Garrod et al.15 in an included study from this review reported greater drop out from a PR programme in participants with depression. Future studies in people with COPD that use a measure of physical performance as an outcome should document anxiety and depression and account for their presence in analysis, as these conditions may confound results and more information on the influence of anxiety and depression is required. In one retrospective study, heart disease was associated with improved 6MWD after PR.23 Cardiac risk factors have been shown to be reduced with a rehabilitation program.46 PR may provide a common exercise pathway to address breathlessness during exercise, skeletal muscle dysfunction and lifestyle changes in chronic heart and lung conditions,47 which may explain this observed association with greater benefit in 6MWD. The primary measure of physical performance in the included studies was distance walked in the 6MWD. Whilst the 6MWD is a validated measure of exercise tolerance in people with COPD,48 it only measures a narrow range of the physical performance spectrum. No studies were identified that examined the relationship of co-morbidities in COPD with other measures of physical performance. Future studies could examine other aspects of physical performance that might be affected by co-morbidities, for example, objective measures of physical activity or functional capacity. Quality assessment of included studies used the STROBE checklist, which was developed to encourage authors to reported adequate information on research methods and data analysis for readers to interpret the results of observational studies with confidence.22 Studies by Giardino et al.,25 Eisner et al.10 (both reporting negative association of anxiety with cross-sectional 6MWD) and von Leupoldt et al.29 (reporting no association of anxiety with crosssectional 6MWD) had the highest scores thus greatest levels of completeness in reporting. Co-morbidities were not identified in a uniform manner across studies included in this systematic review, except for obesity which was defined consistently with the body mass index.26,27 Heterogeneous study designs and statistical analyses in the included studies prevented meta-analysis of associations with physical performance even for the same co-morbid condition. Associations with co-morbidity were reported in some studies with baseline measures of
physical performance, and in other studies with improvement gained after a PR program. These inconsistencies in collecting and analysing comorbidity data make it difficult to compare patient characteristics and results between studies and limit the strength of conclusions able to be drawn from this review. The inclusion of only English-language studies may have limited the completeness of this review.
Conclusion An association between reduced physical performance in people with COPD who also have comorbid anxiety, obesity and osteoporosis and possibly in those with metabolic disease or depression was observed in this study. This highlights the need to identify all co-morbid conditions present in those with COPD, to facilitate the development of specific strategies to ensure optimal participation in physical activity programmes and to improve exercise tolerance and health outcomes. Conflict of interest The authors declared no conflicts of interest.
Funding This project received no specific grant from any funding agency in the public, commercial or not for profit sectors.
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