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Although chronic obstructive pulmonary disease (COPD) has a major impact on physical health, the specific impact of COPD on physical functional limitations has not been clearly characterized. We aimed to elucidate the physical functional limitations that are directly attributable to COPD compared to a matched referent group without the condition.
We used the FLOW (Function, Living, Outcomes, and Work) cohort study of adults with COPD (n=1,202) and referent subjects matched by age, sex, and race (n=302) to study the impact of COPD on the risk of a broad array of functional limitations using validated measures: lower extremity function (Short Physical Performance Battery, SPPB), submaximal exercise performance (Six Minute Walk Test, SMWT), standing balance (Functional Reach Test), skeletal muscle strength (manual muscle testing with dynamometry), and self-reported functional limitation (standardized item battery). Multivariate analysis was used to control for confounding by age, sex, race, height, educational attainment, and cigarette smoking.
COPD was associated with poorer lower extremity function (mean SPPB score decrement for COPD vs. referent -1.0 points; 95% CI -1.25 to -0.73 pts) and less distance walked during the SMWT (-334 feet; 95% CI -384 to -282 ft). COPD was also associated with weaker muscle strength in every muscle group tested, including both the upper and lower extremities (p<0.0001 in all cases) and with a greater risk of self-reported functional limitation (OR 6.4; 95% CI 3.7 to 10.9).
A broad array of physical functional limitations were specifically attributable to COPD. COPD affects a multitude of body systems remote from the lung.
Chronic obstructive pulmonary disease (COPD) is being increasingly recognized as a multi-system disease.1 Although pulmonary function decrement is the central physiologic limitation, it does not adequately explain who will become limited or disabled from the condition.2-4 Efforts to prevent COPD-related disability will not succeed until we understand how the disease affects distant body systems. Unfortunately, the impact of COPD on diverse non-pulmonary organ systems has not been well characterized.
Physical functional limitations are central decrements in basic physical actions such as mobility or strength.5 To understand how COPD produces disability, it is important to first determine the disease's impact on a broad array of physical functional limitations. These functional limitations, which represent effects of the disease on body systems distant from the lung, may mediate the disablement process. In a large cohort of adults with well-characterized COPD and a matched referent group recruited from a managed care organization, we elucidated the degree of physical functional limitation directly attributable to COPD.
The FLOW (Function, Living, Outcomes, and Work) study of COPD is an ongoing prospective cohort study of adult members of an integrated health care delivery system with a physician's diagnosis of COPD and a matched referent group without COPD. At baseline assessment, we conducted structured telephone interviews that ascertained COPD status, health status, self-reported functional limitations, sociodemographic characteristics, and physician-diagnosed comorbidities. Subjects then underwent a research clinic visit that included spirometry and other physical assessments. Using these baseline data, we evaluated the functional limitations directly attributable to COPD. The study was approved both by the University of California, San Francisco Committee on Human Research and the Kaiser Foundation Research Institute's institutional review board and all participants provided written informed consent.
We identified all adult members of Kaiser Permanente Medical Care Program (KPMCP) who were recently treated for COPD using a previously described approach.6 The age range was restricted to 40-65 years because a key study outcome includes work disability.7 Using KPMCP computerized databases, we identified all subjects who met each of two criteria: one based on health care utilization and the second based on medication prescribing. The health care utilization criterion was one or more ambulatory visits, emergency department visits, or hospitalizations with a principal International Classification of Disease (ICD-9) diagnosis code for COPD (chronic bronchitis , emphysema , or COPD  during a recent 12 month time period. The medication criterion was two or more prescriptions for a COPD-related medication during a 12 month window beginning 6 months before the index utilization date and ending 6 months after index date. Based on medical record review, we demonstrated that this algorithm is a valid method for identifying adults with COPD.7
A total of 5,800 subjects were initially identified using the computerized algorithm. Of these, 298 died before they could be recruited into the study. Another 1,011 did not meet study inclusion criteria. Among the 2,181 non-respondents, 464 declined by prepaid postcard, 934 declined by telephone, and 783 were not reachable by telephone despite numerous attempts (>10). The completion rate for structured telephone interviews was 2,310 out of a remaining eligible group of 4,419 (51%). This is comparable to our earlier cohort study of adult asthma conducted at KPMCP and compares favorably for other survey-based epidemiologic studies conducted in the U.S.8, 9 Among the 2,310 respondents, 112 were not eligible for the clinic visit (8 were subsequently deceased, 10 were no longer Kaiser members, 85 were physically unable to attend, and 9 moved out of the area). Of the 2,198 eligible subjects, 1,216 completed the research clinic visit (55% of those interviewed and eligible). An additional 10 subjects were excluded because they did not meet the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria for COPD after interviews and spirometry were performed.10 Four additional subjects were excluded from this analysis because they could not perform spirometry due to previous tracheostomy placement. Ultimately, there were 1,202 subjects with COPD who completed both interviews and research clinic visits.
Demographic information was available for non-interviewed subjects from Kaiser computerized databases. Compared to subjects who were eligible but not interviewed, interviewed subjects were slightly older (mean 0.7 years), more likely to be female (59 vs. 51%), and more likely to be white (69 vs. 56%). In terms of race-ethnicity, the two largest minority subgroups were slightly over-represented among those who completed interviews: (African American 14% vs. 11%, Hispanic 9% vs. 4%). Most of the differences in race were driven by limitations inherent in the Kaiser computerized databases: the prevalence of unknown race was much higher among those who did not complete interviews (17% vs 0.3%).
We aimed to recruit 300 referent subjects without COPD. Recruitment methods were identical to those used to recruit the COPD group, except that we excluded subjects with any history of utilization for COPD (i.e., no ambulatory visits, emergency department visits, or hospitalizations with any ICD-9 diagnosis code for COPD). We initially identified 373 referent subjects with no history of utilization for COPD who were matched to subjects with COPD by age, sex, and race. By design, we subsequently excluded 71 subjects who had evidence of airway obstruction (FEV1/FVC <0.70) at the time of research clinic evaluation leaving 302 referent subjects. Referent subjects were similar to COPD cases in terms of age, sex, and race (p>0.20) (Table 1).
To assess respiratory impairment, we conducted spirometry according to American Thoracic Society (ATS) Guidelines.11, 12 We used the EasyOne™ Frontline spirometer (ndd Medical Technologies, Chelmsford, MA), which meets ATS criteria. To calculate percent predicted pulmonary function values, we used predictive equations derived from NHANES III.13 Based on FEV1, FEV1/FVC ratio, and respiratory symptoms, COPD severity was staged based on National Heart, Lung, and Blood Institute / World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria (stage 0 to IV).10, 14 Because research clinic examinations were conducted by trained non-medical personnel, we did not administer bronchodilators for study purposes. However, 90% of subjects had taken their own short-acting bronchodilator within 4 hours of spirometry or had taken a long-acting bronchodilator earlier in the same day.
We assessed functional limitations, which are decrements in basic physical actions, using a multifaceted evaluation that combined a survey-based measure (self-reported functional limitation as described below) and physical assessment. Submaximal exercise performance was measured using the Six Minute Walk Test, which was developed by Guyatt and has been widely used in studies of COPD.15, 16 We used the American Thoracic Society protocol.17
Lower extremity function was measured using the validated Short Physical Performance Battery (SPPB).18-20 This battery includes 3 performance measures, each scored from 0 to 4 points. The standing balance test asks subjects to maintain their feet in a side-by-side, semi-tandem stand, or tandem stand for 10 seconds. A test of walking speed requires subjects to walk 4 meters at their normal pace. Participants are assigned a score from 1 to 4 based on the quartile of length of time needed to complete the test. The chair stand test, which reflects lower extremity extensor muscle strength, measures the time required for the subject to stand up and sit down from a chair 5 times with arms folded across the chest. Scores from 1 to 4 are assigned based on quartile of length of time to complete the task. A summary performance score integrates the 3 performance measures, ranging from 0 to 12. Previous work indicates that the battery has excellent inter-observer reliability, test-retest reliability, and predictive validity.18-20
In addition to the balance component of the SPPB, we measured balance with the functional reach test. This test measures how far a subject can reach forward beyond arm's length while maintaining a fixed base of support in the standing position, without losing balance.21 The functional reach test has excellent test-retest reliability and validity.21-24
Isometric skeletal muscle strength was evaluated following standard manual muscle testing procedures.25 A hand-held dynamometer was used to improve the objectivity of the force estimates (MicroFet2 dynamometer (Saemmons Preston, Bolingbrook, IL).25 The examiners were trained in manual muscle testing by the same experienced physical therapist. Each of the examiners practiced testing control subjects until there was agreement between the raters 90% of the time within 5 pounds of force. Power grip strength was measured using a Jamar Hydraulic Hand Dynamometer (Stoelting, Wood Dale, IL) according to the protocol of the American Society of Hand Therapists.26, 27 Three trials were performed of each muscle group in alternating fashion. The maximum of three trials on the dominant side was selected for analysis.
Self-reported functional limitation was measured during interviews using a previously validated approach used by Sternfeld and colleagues, which was based on questions from the Framingham Disability Study, Established Populations for Epidemiologic Studies of the Elderly, the Nagle scale, and Rosow and Breslau scales.28 The scale is comprised of 10 questions that assess the degree of difficulty in multiple domains of basic physical functioning such as pushing, stooping, kneeling, getting up from a standing position, lifting lighter or heavier objects, standing, sitting, standing from a seated position, walking up stairs, and walking in the neighborhood (see Appendix). Subjects who indicate “a lot of difficulty” with one or more functions or not doing a function because they were unable or they were told by a doctor not to do so are defined by this measure as having a self-reported functional limitation.28
In addition, two additional questions were derived from the SF-36 scale to measure functional limitation.29 These items ask whether the respondent's health limits him or her a lot, a little, or not at all in moderate activities (e.g., moving a table, pushing a vacuum cleaner, bowling, or playing golf) or climbing several flights of stairs. Subjects who indicated “a lot” of limitation were defined as having functional limitation on each item.
Statistical analysis was conducted using SAS software, version 9.1 (SAS Institute, Inc, Cary, NC). We used linear regression analysis to elucidate the association between COPD status (vs. referent group) and performance on the SPPB, SMWT, functional reach test, and skeletal muscle strength tests. To examine potential confounding we controlled for age, sex, height, race (white, non-hispanic vs. other), educational attainment, and smoking status (current or past vs. never). Logistic regression was used to analyze the relationship between COPD status and the risk of self-reported functional limitations in analogous fashion. Income was not included as a covariate because it may be the outcome of COPD health status (i.e., COPD may lead to work disability and diminished income). We calculated the population attributable fraction (PAR%) for the impact of COPD on self-reported functional limitations.30
To evaluate the more severe spectrum of COPD, we repeated the analysis after redefining COPD as an FEV1/FVC ratio <0.70 and FEV1 < 80% predicted (i.e., GOLD stage II or greater) which is consistent with the Burden of Lung Disease (BOLD) Study approach.31
The relationship between cardiovascular disease, COPD, and functional limitation is complex. Smoking is a major risk factor for both cardiovascular disease and COPD. COPD itself appears to be a risk factor for cardiovascular disease.7 Moreover, pulmonary function impairment is associated with cardiovascular disease even among lifelong never smokers.32 Because the causal pathway is complex, controlling for cardiovascular disease in the analyses would likely “overadjust” the estimates for COPD as a risk factor for functional limitation. Nonetheless, we performed an additional analysis in which we additionally controlled for cardiovascular disease (congestive heart failure, coronary artery disease, myocardial infarction, or stroke) and diabetes.
By design, subjects with and without COPD were similar in age, sex, and race-ethnicity (p>0.20 in all cases) (Table 1). The prevalence of lifetime smoking was much higher among those with COPD (87%) than in the referent group (48%) (p<0.0001). Persons with COPD also had lower social class, as evidenced by lower educational attainment and household income. As expected, pulmonary function was markedly poorer in the COPD group (Table 2). The prevalence of cardiovascular disease (22 vs. 3%) and diabetes (21 vs 14%) were higher in the COPD group than among referents (p<0.05 in both cases). Among subjects with COPD, the distribution of GOLD stages was stage 0 (31%), stage 1 (7%), stage 2 (32%), stage 3 (21%), AND stage 4 (9%)
Compared to the matched referent group, a diagnosis of COPD was associated with substantively poorer lower extremity function after controlling for age, sex, race, height, smoking history, and educational attainment (mean score decrement on SPPB -1.0 points; 95% CI -1.25 to -0.73) (Table 3). COPD was also related to much worse performance on the SMWT (-334 feet; 95% CI -384 to -282 feet) and standing balance (-3.0 cm in functional reach; 95% CI -4.2 to -1.8 cm). These COPD-related decrements in physical function correspond to a 9% reduction in mean lower extremity function, 20% reduction in SMWT performance, and 9% decrease in functional reach compared to the referent group.
COPD was related to weaker skeletal muscle strength in all muscle groups tested (Table 4). Both upper and lower extremity strength were affected. Compared to the referent group, the decrement in mean muscle strength was 18% for quadriceps, 18% for hip flexors, 15% for hip abductors, 17% for elbow flexion, and 10% for grip strength.
COPD was also associated with a greater risk of self-reported functional limitation (OR 6.4; 95 CI 3.7 to 10.9), moderate activity limitation (OR 7.6; 95% CI 4.0 to 14.4), and limitation in stair climbing (OR 11.7; 95% CI 7.3 to 18.6) compared to those without COPD.
When COPD was redefined as GOLD stage II or greater, the results were highly similar for all analyses (Tables 3, ,4,4, and and5).5). For both COPD definitions, the population attributable fraction for self-reported functional limitations was 82%. In addition, controlling for cardiovascular disease and diabetes slightly attenuated the risk estimates, but the overall pattern of results was very similar.
COPD was related to a broad array of physical functional limitations compared to a matched referent group without the disease, including lower extremity functioning, exercise performance, skeletal muscle strength, and self-reported limitation in basic physical actions. These physical functional limitations are directly attributable to COPD, because patients with and without COPD were recruited from the same source population of managed care patients and were matched by age, sex, and race. For distance walked in 6 minutes, the COPD-related decrement amounted to more than the length of a football field.
These findings are important because they indicate that COPD has impacts on diverse body systems remote from the lung. Although previous studies have characterized physical function in COPD patients, they have not been able to estimate a broad array of decrements specifically attributable to the disease. Prior studies have either evaluated a limited spectrum of function or lacked an appropriate referent group.16, 33-46 Moreover, many of these studies included a highly selected group of persons with COPD, often on the severe end of the disease spectrum. These results from the FLOW study advance the field by establishing the multiple physical functional decrements that are directly attributable to COPD among persons with a broad range of disease severity.
In our theoretical framework, which is based on the work of Verbrugge and Jette, the development of functional limitations is the first step in the pathway to developing disability in COPD.5 Poorer lower extremity function, submaximal exercise performance, and muscle strength may result in disability from the disease. We are prospectively following the matched cohort of patients with and without COPD to determine the eventual impact of functional limitations on disability.
The role of cardiovascular comorbities in the development of functional limitations in COPD is complex, because both conditions share risk factors (e.g., smoking) and COPD itself appears to predispose to adverse cardiovascular outcomes.7,32 When we controlled for cardiovascular comorbidities and diabetes, the estimates for functional limitation attributable to COPD were only slightly attenuated. It is likely that these analyses overadjusted the risk estimates. Future longitudinal analyses may better elucidate this complex inter-relationship.
A study strength is the large sample of COPD patients who have a broad spectrum of disease severity, ranging from mild to severe. Our study is, to our knowledge, the largest prospective COPD cohort study to systematically evaluate a broad range of functional limitations compared to an appropriate matched control group. Recruitment from a large health plan should also help ensure genearlizability to patients who are being treated for COPD in clinical practice. Availability of interview data, pulmonary function tests, and extensive physical characterization allows robust conclusions about physical functioning.
Our study is also subject to several limitations. Although the inclusion criteria required health care utilization for COPD, misclassification of asthma could have occurred. Our COPD definition required concomitant treatment with COPD medications to increase the specificity of the definition. In addition, all patients had a physician diagnosis of COPD and reported having the condition. The observed lifetime smoking prevalence was similar to that in other population-based epidemiologic studies of COPD, supporting the diagnosis of COPD rather than asthma.47, 48 We also previously demonstrated the validity of our approach using medical record review.7 When we limited the definition of COPD to more severe disease (GOLD Stage II or greater), however, the results were not substantively affected. In sum, we have a high degree of confidence that our results are not affected by misclassification bias.
Because our ultimate focus is on disability prevention, we intentionally sampled younger adults with COPD. Therefore, these results may underestimate the impact of COPD on functional limitation among older patients. In addition, Kaiser Permanente members, because they have health care access, may also be different than the general population of adults with COPD. Mitigating these limitations, the sociodemographic characteristics of Northern California Kaiser Permanente members are similar to those of the regional population, with some under-representation of income extremes.49, 50 Moreover, selection bias could have been introduced by non-participation in the study. There were some differences among subjects who did and did not participate in the interviews, but they were modest in scope and not likely to affect the results.
In conclusion, a broad array of physical functional limitations could be attributed directly to COPD. Prospective follow-up will determine the impact of these functional limitations on the risk of disability. Strategies to prevent COPD, or to treat it effectively, have potential to reduce physical functional limitation, and perhaps disability, in the general population.
Funded by: NHLBI / NIH R01HL077618
The next questions ask about difficulties that you might have with common activities. For the next items, please tell me what level of difficulty you have had during the past month: a lot of difficulty, some difficulty, a little difficulty, or no difficulty.
During the past month, how much difficulty have you had….
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