Robles, Priscila Games MSc; Brooks, Dina PhD; Goldstein, Roger MD; Salbach, Nancy PhD; Mathur, Sunita PhD
Pulmonary rehabilitation (PR) has become an established part of the management of chronic obstructive pulmonary disease (COPD).1 Pulmonary rehabilitation addresses a range of nonpulmonary, systemic consequences that may not be adequately addressed by pharmacological therapy alone. There are strong scientific recommendations for the routine use of PR in COPD, with exercise training as the key component.2,3 Pulmonary rehabilitation improves perception of symptoms, exercise capacity, and health-related quality of life (HRQOL), and may reduce the number of hospital days, length of inpatient stay, and other measures of health care utilization.4,5
There are several differences between men and women in the diagnosis, pathophysiology, and presentation of COPD. Women may be at greater risk of smoking-induced lung function impairment for the same level of tobacco exposure6 and are less likely than men to receive a diagnosis of COPD.7 Men are more likely than women to have an emphysema-predominant phenotype, while airway-predominant disease is more common among women.8,9 For a similar degree of airflow limitation, women show greater breathlessness than men.10,11 Some studies have reported that men and women may also show different responses to treatment, including PR.12–15
Sex and gender are currently recognized as determinants of health and disease and as such have been considered both in clinical trials and in service delivery.16–18 The distinction between sex and gender is a conceptual one. The term sex is more commonly used to refer to the biology of human subjects, and gender is for reference to the self-identity and/or social-cultural representation of an individual.19 Although some of the differences between men and women with COPD may have both genetic and biological origins, we will usually refer to gender differences throughout this article to remain consistent.
Given that gender differences in the diagnosis, physiological, or phenotypic presentation and response to the management of COPD may exist, we conducted a systematic review to identify whether the impact of PR differs between men and women.
The review was conducted and reported on the basis of the Centre for Reviews and Dissemination and PRISMA guidelines.20,21 Search strategies were developed and revised for each of the databases MEDLINE/PubMed, EMBASE, CINAHL, and Pedro from October 2011 to May 2012. We maximized search retrieval by using a combination of MeSH headings and free-text terms described in Table 1. One author screened titles and abstracts to select relevant articles. Papers were considered relevant if differences between men and women were examined in the study. Retrieval and review of full-text articles were done by 2 coauthors to determine eligibility. Scanning of reference lists of eligible articles as well as reviews on gender differences in COPD was also performed. Papers were included if they meet the following eligibility criteria: (1) the objective of the study was to assess the differences between men and women on PR outcomes and in which between-gender comparison of pre- and post-PR outcome measures was reported; (2) adults (defined as >19 years), (3) English language, (4) full-text articles available, and (5) studies published between January 1990 and May 2012. We excluded review articles, of conditions other than COPD or if participation in a PR program was not clearly described.
Two coauthors independently appraised the quality of each study, using the scale developed by Down and Black,22 and agreement was reached by consensus on each item. This instrument is a validated scoring scale that has been used to determine the quality of both randomized and nonrandomized clinical trials. It consists of 27 items grouped into 5 subscales that address quality of reporting, external validity; study bias; confounding and selection bias; and power of the study. The maximum total score is 32, with higher scores representing a better methodology. Scores are also expressed as rates out of 32, with 1.00 being the maximum rating possible. For this review, ratings less than 0.50 were considered “weak,” between 0.50 and 0.69 “fair,” between 0.70 and 0.79 “good,” and between 0.80 and 1.00 “very good.”23
Data Extraction and Analysis
One author extracted data, using a standardized form. Data included information regarding source, type of publication (study design and goal), characteristics of trial participants (age, gender), intervention (including training program, setting, duration, and frequency), type of outcome measures (pre/post comparisons), and results of gender comparisons. We retrieved information on method of diagnosis, disease severity, study intervention (ie, PR vs no PR), pharmacological treatment, statistical analysis, and followup. Results are reported as mean (SD) unless otherwise noted. We grouped articles by the outcome measurement used to assess the response to PR and provided a detailed description of studies' contents and results.
The search returned 116 potentially relevant citations and, after checking for duplicates and eligibility, a final number of 11 studies involving gender-associated differences in response to PR program were included in this review (Figure 1). Gender-associated differences in PR outcomes were found in 5 studies24–28 of the 11 studies selected, while 6 articles29–34 did not show any differences (Table 2). The type of publications (study design), quality of the studies, participants' characteristics, and type and duration of the PR interventions were comparable between studies that showed gender-associated differences and those that did not.
Study Quality Appraisal
Quality assessments showed an average score of 16.5 (2.9) (range from 12 to 23 out of maximum 32) that did not improve with more recent years of publication (Table 2). In articles where gender-associated differences were reported, quality scores ranged from 12 to 16 for observational studies25–27 and from 19 to 23 for intervention trials.24–28 No differences between genders were reported in 3 nonintervention studies where quality scores ranged from 14 to 1830–32 and in 3 intervention trials with scores ranging from 13 to 18.29,33,34 Based on the quality assessment instrument, an average rating of 0.55 (0.09) was achieved for studies reporting differences between genders, which was considered “fair.” For those articles showing no differences, a quality rating of 0.49 (0.08) was found, which was considered to be “poor.”
Six studies were nonrandomized controlled trials (5 pre/post observational studies of a cohort of patients25,27,30–32 and 1 retrospective chart review26), 3 were uncontrolled clinical trials29,33,34 and 1 was a controlled clinical trial.28 Only 1 was a randomized controlled trial (RCT).24
The average ratio of men to women among the studies was 1:0.8 and the total sample sizes ranged from 15 to 381 men and 15 to 290 women. The average age of the participants in the studies ranged from 59 to 71 years. Six studies provided age according to gender and, on average, men were aged 64 (4.8) years and women, 64.7 (4.3) years. All articles provided a fair description of the interventions used, which generally involved a multidisciplinary approach with endurance and resistance exercise training, breathing retraining, energy conservation, nutritional counseling, psychosocial support, education, and followups. The frequency of the program varied from 2 to 5 days per week for 3 to 12 weeks duration for short-term programs and 15 to 24 weeks for long-term programs.
Health-related quality of life questionnaires were the most common outcomes used to compare gender-associated differences before and after PR, being described in 9 studies: Chronic Respiratory Questionnaire (CRQ),24–26 St. George's Respiratory Questionnaire,28,29 Medical Outcomes Study 36-item short form,32,33 Perceived Quality of Life Scale,30 and Quality of Life Index-pulmonary version III.32 Field walking tests such as the 6-Minute and 12-Minute Walk Tests25,26,30,32–34 and Incremental Shuttle Walk Test31 were used in 8 studies. Four articles described dyspnea-rating scales as the study outcome: Medical Research Council Dyspnea Scale,31 Transition Dyspnea Index,33 CRQ-dyspnea domain,26 and the University of California at San Diego Shortness of Breath Questionnaire.32 Single studies each reported the use of the State Anxiety Inventory,30 Pulmonary Functional Status Scale,25 Breathing Problems Questionnaire,30 HYRIM Physical Activity Questionnaire,28 and Coping Inventory for Stressful Situations27 to evaluate gender-associated differences after PR.
Health-Related Quality of Life
Greater improvements in HRQOL were showed in women in 2 studies25,26 and greater improvements in men in 2 others.24,28 Although Laviolette et al26 reported higher scores in CRQ dyspnea domain for women after PR, the HRQOL overall scores were no different from those of men. Larger changes in HRQOL scores for women after PR were also reported by Haggerty et al25; however, it was not clearly stated whether scores at PR entry were different between men and women in this study. Skumlien et al28 demonstrated significantly greater increases in scores for men than for women, but pre-PR values were not described. In their study, the available sample size might have been too small to detect gender differences in HRQOL, as only 5 of 15 women and 12 of 18 men were classified as responders. Foy et al24 also found that men improved HRQOL to a greater extent than women after adjusting for baseline values, but only among participants who completed the long-term program.
Four studies reported no differences in HRQOL between genders after PR.29,30,32,33 Haave et al,30 Verrill et al,32 and von Leupoldt et al33 showed that men and women had similar pre-PR HRQOL scores and similar improvements after short-term programs. Verrill et al32 also showed that scores were maintained in the long-term PR participants. Bratås et al29 also reported similar improvements in HRQOL from baseline to followup; however, in the latter study, it was not clear if the scores differed between genders at PR entry.
Gender differences were reported only by Skumlien et al,28 where the authors showed statistically significant differences between improvement in 6-minute walk distances (6MWD) for men and the lack of change in this outcome for women, even after correcting for pre-PR walk distances.
Seven articles reported that physical capacity improved to a similar extent in men and women.25,26,30–34 Haave et al30 reported a statistically significant increase in distance after PR for both genders with or without controlling for differences in lung function, but the average improvement did not reach clinical relevance for either group (conservatively estimated to be 54 m).35 Lizak et al31 also showed equal benefits in exercise capacity after PR although women had worse pre-PR values than men. Haggerty et al25 and Verrill et al32 showed that, although men walked farther than women at baseline, both genders improved to a similar degree following PR.
More pronounced reductions in dyspnea were reported in women only by Laviolette et al,26 although women had greater dyspnea scores at baseline and the overall scores improved equivalently and significantly in both genders after PR in this study. Three articles showed no gender differences in this outcome after PR.31–33 Lizak et al31 observed equal improvements in dyspnea scores for both genders despite lower pre- and post-PR values for women. von Leupoldt et al33 and Verrill et al32 reported equal baseline dyspnea scores and confirmed similar benefits from PR for both genders.
Among the studies that reported coping styles and functional status as PR outcomes, 2 found gender-associated differences upon completion of the programs25,27 and other 2 showed that improvements were independent of gender.28,30 Haggerty et al25 showed that after baseline adjustments, improvements in overall functional status were similar. Although men reported less improvement in psychological subscore, the authors argued that a greater decrease in the anxiety section scores in women might have accounted for most of this difference. Ninot et al27 reported higher emotion-focused coping scores for women, higher problem-focused coping scores for men whereas avoidance scores were not different between genders at PR entry. Upon completion of the program, only the avoidance scores were significantly increased in women. Increases in avoidance strategies are indicative of intention and behavior to keep away from stressful situations. Haave et al30 observed that men and women showed similar anxiety levels and health status at PR entry and equal, yet small, improvements following PR. Likewise, Skumlien et al28 found no improvements in health status for either men or women.
We reviewed 11 studies that investigated gender-associated differences in response to PR in people with COPD. Five studies reported differences in response to PR programs between men and women in outcomes such as dyspnea (n = 3), exercise capacity (n = 5), and HRQOL (n = 4) whereas 6 studies showed no gender effects in dyspnea (n = 1), exercise capacity (n = 3), HRQOL (n = 3), health status (n = 2), and coping styles (n = 1). Although there was little variability in study characteristics for articles showing and not showing gender differences, heterogeneity among the articles such as study design, patient baseline characteristics, and outcome measurements may have accounted for conflicting results.
Differences in health outcomes between men and women have already been demonstrated in cardiac36,37 and stroke rehabilitation.38 However, it is unclear whether these differences exist in PR. Because of the rapid increase in the incidence and prevalence of COPD among women,39 researchers in respiratory field have started to explore the differences between men and women in the expression and outcomes of COPD including responses to PR.
Investigators examining the impact of COPD in men and women have reported significantly higher degrees of dyspnea, significantly lower disease-related quality of life, worse exercise performance, and poorer functional and psychological status for women than men with COPD for the same degree of airflow obstruction (forced expiratory volume in the first second of expiration).9–11,40,41 As responses to therapeutic interventions might reflect these differences in men and women, investigators have suggested that women are more likely to benefit in terms of dyspnea, health, and psychological status whereas men in exercise capacity.10,11,41
Despite that, some studies included in this review reported no gender differences in such characteristics and PR outcomes. Among those describing pre-PR values, only Laviolette et al26 and Lizak et al31 showed that women self-reported more dyspnea than men, and only Haggerty et al25 and Verrill et al32 showed that men walked farther when entering PR programs. Except for coping styles, the studies showed no difference in health and functional status between genders prior to PR. With regard to HRQOL, either the studies showed no gender differences for men and women or baseline characteristics were not clearly reported by the authors.
With reference to the response to the PR, half of the studies in this review reported similar benefits in men and women for outcomes such as dyspnea, exercise capacity (walk distances), and psychological status. Only Laviolette et al26 reported greater improvements in CRQ dyspnea domain for women; however, the larger change could have just reflected that women had more dyspnea at baseline. Greater improvement in 6-minute walk distances was described in men only by Skumlien et al.28 Haggerty et al25 described similar improvements in overall functional status for both genders with women showing lower anxiety subscores than men after PR. In the study by Ninot et al,27 although women with COPD seemed to cope with their disease in ways that were more deleterious when compared with men, both men and women tended to benefit equally from participation in PR programs with regard to these outcomes.
Benefits of PR in HRQOL between men and women seem to be equivalent but the results from literature are less consistent. Haggerty et al25 and Laviolette et al26 found that women experienced larger improvements in subscales of the HRQOL questionnaires when compared with men whereas Skumlien et al28 and Foy et al24 described significant changes for only men; although in the latter study both women and men improved their quality of life right after the short-term program while women gained no additional benefit from the extended duration of the PR program. In this review, improvements after PR were found to be independent of gender in half of the studies.
The aim of PR is to improve patient functional level42,43 and, therefore, it should focus on a holistic approach to health rather than on single outcomes. It is also important to recognize that physical tests do not completely reflect the impact of COPD and how patients cope with the disease in their daily lives. In the same way, self-report measures such as generic and disease-specific HRQOL questionnaires and perceived dyspnea scales are not complete measures of physical or functional status. Although the majority of the studies included in this review did use more than 1 health outcome, the results were inconsistent even among those studies using same outcome measurement tools. Nevertheless, if PR benefits were to be achieved differently between men and women, one could assume that the type or magnitude of such differences would be more accurately captured through various measures as opposed to individual outcome.
A comprehensive PR program for people with COPD includes exercise training, nutritional and psychosocial counseling, and self-management education.4,5,43 Our review showed that PR programs, even though slightly different, were comparable among studies regardless of whether or not they reported a gender-associated difference in outcomes. In addition, all programs targeted control of symptoms, improvement of health status and quality of life, and optimization of functional and physical capacities. Programs were designed in accordance with international guidelines for PR; however, we could not establish whether PR was delivered differently to men and women among the studies.
Studies included in this review predominantly used a nonrandomized design to address gender differences in PR outcomes and assessing the quality of these studies presents a challenge, as there are few quality assessment tools for nonrandomized studies.22 We have used an alternative approach for rating the quality of both randomized and nonrandomized studies that examines the importance of individual quality components (eg, reporting internal and external validity). Regardless of the study design, our results showed no differences in quality ratings between studies that reported gender-associated effects on PR outcomes and those that did not. The present systematic review is limited by methodological variability among studies. Although studies other than RCTs remain important for evaluating diagnostic and prognostic strategies, as well as impacts of interventions,44 the role of such studies in formulating recommendations remains unclear. Authors should consider the potential sources of bias in their comparisons and whether or not they can be minimized with well-conducted, nonrandomized studies. Randomized controlled trials with large sample sizes could confirm results reported by multiple observational studies on gender-associated differences in response to PR.
It remains unclear whether men and women experience the impact of PR similarly. Conflicting results noted in this review could possibly be attributable to differences among programs, settings, and outcome assessments. Besides reporting multiple PR outcomes, studies could ensure the use of assessment tools designed to allow comparisons between men and women. To improve consistency and accuracy of between-gender comparisons, studies could also ensure baseline homogeneity and/or account for variation in these outcome measures when reporting their results.45
Quantitative and qualitative investigations would help better understand whether programs meet the needs of men and women given their physiological and functional differences in disease presentation and whether a customized treatment will result in better outcomes. It seems reasonable to assume that men and women may encounter similar benefits in PR, but some fundamental differences might exist regarding how these benefits are perceived. Qualitative and mixed-method research designs could be used to better understand this question.
Despite guidelines for PR being the same for men and women with COPD, there is little information regarding whether or not they benefit from PR in the same way. Some studies in this review suggest that women improve more from PR in terms of dyspnea, functional and health status, and coping styles whereas men tend to benefit more in their exercise capacity. Benefits of PR on HRQOL outcomes between men and women seem to be equivalent, but the results are less consistent. These findings, however, are not conclusive and might have been limited by heterogeneity in design and outcome measures as well as by small sample sizes of the studies included in this review. The impact of gender-related differences on the outcome of PR and how these differences may affect the delivery of PR programs remains to be defined.
1. Lacasse Y, Maltais F, Goldstein RS. Pulmonary rehabilitation: an integral part of the long-term management of COPD. Swiss Med Wkly. 2004;134:601–605.
2. Nici L, Donner C, Wouters E, et al. American Thoracic Society/European Respiratory Society Statement on Pulmonary Rehabilitation. Am J Respir Crit Care Med. 2006;173:1390–1413.
3. O'Donnell DE, Aaron S, Bourbeau J, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease—2007 update. Can Respir J. 2007;14(suppl B):5B–32B.
4. Lacasse Y, Martin S, Lasserson TJ, Goldstein RS. Meta-analysis of respiratory rehabilitation in chronic obstructive pulmonary disease. A Cochrane systematic review. Eura Medicophys. 2007;43:475–485.
5. Ries AL, Bauldoff GS, Carlin BW, et al. Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based clinical practice guidelines. Chest. 2007;131:4S–42S.
6. Sørheim I-C, Johannessen A, Gulsvik A, Bakke PS, Silverman EK, DeMeo DL. Gender differences in COPD: are women more susceptible to smoking effects than men? Thorax. 2010;65:480–485.
7. Chapman KR, Tashkin DP, Pye DJ. Gender bias in the diagnosis of COPD. Chest. 2001;119:1691–1695.
8. Kanner RE, Connett JE, Altose MD, et al. Gender difference in airway hyperresponsiveness in smokers with mild COPD. The Lung Health Study. Am J Respir Crit Care Med. 1994;150:956–961.
9. Martinez FJ, Curtis JL, Sciurba F, et al. Sex differences in severe pulmonary emphysema. Am J Respir Crit Care Med. 2007;176:243–252.
10. de Torres JP, Casanova C, Hernandez C, Abreu J, Aguirre-Jaime A, Celli BR. Gender and COPD in patients attending a pulmonary clinic. Chest. 2005;128:2012–2016.
11. Watson L, Vestbo J, Postma DS, et al. Gender differences in the management and experience of chronic obstructive pulmonary disease. Respir Med. 2004;98:1207–1213.
12. Camp PG, Goring SM. Gender and the diagnosis, management, and surveillance of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4:686–691.
13. Han MK, Postma D, Mannino DM, et al. Gender and chronic obstructive pulmonary disease: why it matters. Am J Respir Crit Care Med. 2007;176:1179–1184.
14. van Haren-Willems J, Heijdra Y. Increasing evidence for gender differences in chronic obstructive pulmonary disease. Women's Health. 2010;6:595–600.
15. Varkey AB. Chronic obstructive pulmonary disease in women: exploring gender differences. Curr Opin Pulm Med. 2004;10:98–103.
16. Einecke U. [Gender medicine becomes constantly more important. No disease is gender neutral]. MMW Fortschr Med. 2008;150:12–14.
17. Kim AM, Tingen CM, Woodruff TK. Sex bias in trials and treatment must end. Nature. 2010;465:688–689.
18. Tingen CM, Kim AM, Wu P-H, Woodruff TK. Sex and sensitivity: the continued need for sex-based biomedical research and implementation. Women's Health. 2010;6:511–516.
19. Torgrimson BN, Minson CT. Sex and gender: what is the difference? J Appl Physiol. 2005;99:785–787.
20. Booth AM, Wright KE, Outhwaite H. Centre for Reviews and Dissemination databases: value, content, and developments. Int J Technol Assess Health Care. 2010;26:470–472.
21. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62:e1–e34.
22. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52:377–384.
23. Salgado TM, Moles R, Benrimoj SI, Fernandez-Llimos F. Pharmacists' interventions in the management of patients with chronic kidney disease: a systematic review. Nephrol Dial Transplant. 2012;27:276–292.
24. Foy CG, Rejeski WJ, Berry MJ, Zaccaro D, Woodard CM. Gender moderates the effects of exercise therapy on health-related quality of life among COPD patients. Chest. 2001;119:70–76.
25. Haggerty MC, Stockdale-Woolley R, ZuWallack R. Functional status in pulmonary rehabilitation participants. J Cardiopulm Rehabil Prev. 1999;19:35–42.
26. Laviolette L, Lacasse Y, Doucet M, et al. Chronic obstructive pulmonary disease in women. Can Respir J. 2007;14:93–98.
27. Ninot G, Fortes M, Poulain M, et al. Gender difference in coping strategies among patients enrolled in an inpatient rehabilitation program. Heart Lung. 2006;35:130–136.
28. Skumlien S, Skogedal EA, Bjortuft O, Ryg MS. Four weeks' intensive rehabilitation generates significant health effects in COPD patients. Chron Respir Dis. 2007;4:5–13.
29. Bratås O, Espnes G, Rannestad T, Walstad R. Pulmonary rehabilitation reduces depression and enhances health-related quality of life in COPD patients—especially in patients with mild or moderate disease. Chron Respir Dis. 2010;7:229–237.
30. Haave E, Skumlien S, Hyland ME. Gender considerations in pulmonary rehabilitation. J Cardiopulm Rehabil Prev. 2008;28:215–219.
31. Lizak MK, Singh S, Lubina S, Zembala M. Female and male chronic obstructive pulmonary disease patients with severe dyspnea do not profit less from pulmonary rehabilitation. Pol Arch Med Wewn. 2008;118:413–418.
32. Verrill D, Barton C, Beasley W, Lippard WM. The effects of short-term and long-term pulmonary rehabilitation on functional capacity, perceived dyspnea, and quality of life. Chest. 2005;128:673–683.
33. von Leupoldt A, Hahn E, Taube K, Schubert-Heukeshoven S, Magnussen H, Dahme B. Effects of 3-week outpatient pulmonary rehabilitation on exercise capacity, dyspnea, and quality of life in COPD. Lung. 2008;186:387–391.
34. Zu Wallack RL, Patel K, Reardon JZ, Clark BA III, Normandin EA. Predictors of improvement in the 12-minute walking distance following a six-week outpatient pulmonary rehabilitation program. Chest. 1991;99:805–808.
35. Wise RA, Brown CD. Minimal clinically important differences in the Six-Minute Walk Test and the Incremental Shuttle Walking Test. COPD. 2005;2:125–129.
36. Lieberman L, Meana M, Stewart D. Cardiac rehabilitation: gender differences in factors influencing participation. J Womens Health. 1998;7:717–723.
37. Marzolini S, Brooks D, Oh PI. Sex differences in completion of a 12-month cardiac rehabilitation programme: an analysis of 5922 women and men. Euro J Cardiovasc Prev Rehabil. 2008;15:698–703.
38. Paolucci S, Bragoni M, Coiro P, et al. Is sex a prognostic factor in stroke rehabilitation? Stroke. 2006;37:2989–2994.
39. Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523–532.
40. Cote CG, Chapman KR. Diagnosis and treatment considerations for women with COPD. Int J Clin Pract. 2009;63:486–493.
41. de Torres JP, Casanova C, Hernandez C, et al. Gender associated differences in determinants of quality of life in patients with COPD: a case series study. Health Qual Life Outcomes. 2006;4:72.
42. ACCP/AACVPR Pulmonary Rehabilitation Guidelines Panel. Pulmonary rehabilitation. Chest. 1997;112:1363–1396.
43. Marciniuk DD, Brooks D, Butcher S, et al. Optimizing pulmonary rehabilitation in chronic obstructive pulmonary disease—practical issues: a Canadian Thoracic Society Clinical Practice Guideline. Can Respir J. 2010;17:159–168.
44. Norris SL, Atkins D. Challenges in using nonrandomized studies in systematic reviews of treatment interventions. Ann Intern Med. 2005;142:1112–1119.
45. Senn S. Testing for baseline balance in clinical trials. Stat Med. 1994;13:1715–1726.
chronic obstructive pulmonary disease; exercise; gender differences; systematic review