Physical function is composed of multiple physiological factors, including endurance, strength, flexibility, and balance, and is an important component to health-related quality of life. Determinants of physical function performance are cardiovascular function, ventilatory capacity, and muscle strength.1,2 Previous studies suggest that HIV-infected patients have greater limitations in physical function compared with HIV-uninfected patients of the same age.3–5 The 6-minute walk test (6-MWT) is a commonly used functional measure that reflects the ability to perform activities of daily living in addition to estimate ambulatory capacity. Performance in the 6-MWT is associated with health-related quality of life and mortality in patients with congestive heart failure,6,7 chronic obstructive pulmonary disease (COPD),8,9 and interstitial lung disease.10–13
A previous study has shown that 6-MWT can be safely used to assess fitness in HIV-infected adults and correlates with objective measures of fitness, such as aerobic capacity.14 An association between chronic lung disease and HIV has been found with greater impairment in self-reported physical function.3,15 These studies, however, did not include an objective measure of physical function and did not objectively assess for the presence of lung disease by measurement of pulmonary function. As HIV-infected patients are aging on effective antiretroviral therapy (ART), pulmonary function abnormalities and chronic lung diseases are increasing in prevalence16 and could contribute to impaired physical function observed in HIV-infected populations. The goal of this report was to determine risk factors for decreased performance on 6-MWT among HIV-infected patients when compared with HIV-uninfected patients, with a specific focus on measures of pulmonary function.
The cohort consisted of HIV-infected and uninfected participants enrolled in the Examinations of HIV Associated Lung Emphysema (EXHALE), a pulmonary substudy of the Veterans Aging Cohort Study.17 EXHALE is an ongoing observational, longitudinal multicenter study conducted at 4 of the 8 Veterans Affairs (VA) Medical Centers participating in Veterans Aging Cohort Study, namely the Atlanta, Bronx, Houston, and Los Angeles VA Medical Centers. Potential participants were approached for enrollment in EXHALE from the General Medicine and Infectious Diseases outpatient clinics; enrollment was stratified by HIV and current smoking status to obtain a similar proportion of current smokers among the HIV-uninfected participants as found in the HIV-infected participants. Those individuals with a history of lung diseases other than COPD or asthma were excluded, as were patients with acute respiratory infections or illness in the 4 weeks before the baseline measurements. Enrollment began in 2009 and is ongoing. Results presented here represent the cross-sectional analysis of baseline data from 180 HIV-infected and 160 HIV-uninfected participants who were enrolled from 2009 through 2012. Institutional Review Boards at all locations approved this study, and participants provided written informed consent.
Baseline study procedures for EXHALE that were included in these analyses consisted of a questionnaire, pulmonary function testing (PFT), and measure of distance covered during 6-MWT. At study entry, all participants self-completed a questionnaire that consisted of a standardized assessment of smoking, drug use, history of lung diseases, and respiratory symptoms.18 Based on survey data, presence of chronic cough symptoms was defined as those who reported cough on most days for 3 consecutive months or more during the year for more than 1 year.
Demographic and pharmacy data, laboratory values, and diagnostic codes (International Classification of Diseases, Ninth Revision [ICD-9]) for existent medical conditions were obtained via the VA national electronic medical records. Variables included age, gender, race, and ART. Laboratory values, including hemoglobin, CD4 cell count, and plasma HIV RNA level, were obtained within 6 months of enrollment. Cardiovascular disease was defined by ICD-9 codes as the composite of coronary artery disease, congestive heart failure, and peripheral vascular disease (all ICD-9 code groupings for medical conditions provided on www.vacohort.org).
Pulmonary Function Testing
Spirometry pre- and post-bronchodilator was performed according to American Thoracic Society criteria.19,20 Static lung volumes were measured by plethysmography. Diffusing capacity was measured by transfer of carbon monoxide (DLCO) by single breath method.21 PFTs were obtained by certified, trained respiratory technicians or research personnel. PFTs were obtained in the clinical pulmonary function laboratories at the associated medical center. Site pulmonologists or study investigators reviewed PFT results for quality control; results that were not interpretable and did not meet American Thoracic Society criteria for acceptability and reproducibility were not included in these analyses. Fixed airflow obstruction consistent with COPD was defined primarily as a ratio of the post-bronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) below 70%. Predicted normal values for spirometry were determined using Hankinson formulas and for DLCO using Neas formulas.22,23 Both these formulas include adjustments for age, gender, race/ethnicity, and height; percent predicted DLCO was also corrected for hemoglobin concentration. PFTs were interpreted blinded to HIV status, following the European Respiratory Society/American Thoracic Society 2005 recommendations.24
Six-Minute Walk Testing
A standardized 6-MWT was performed by 340 participants in accordance with American Thoracic Society guidelines.25 Participants were coached to walk at their fastest comfortable pace on an even surface for 6 minutes, and the total distance covered was measured; the same protocol was followed for HIV-infected and uninfected participants. We referred to this total distance as the result of 6-MWT. Predicted values were calculated using equations published by Enright and Sherrill,26 which are based on age, gender, and measured body mass index (BMI).
We compared demographic and clinical characteristics and the results of the 6-MWT between HIV-infected and uninfected patients using χ2, Wilcoxon rank sum, and Student t tests as appropriate. Given the increased burden of respiratory symptoms3,27,28 and the interaction between self-reported lung disease and decreased physical function among HIV-infected individuals reported previously, we included an interaction term for HIV and chronic cough in a multivariable linear regression model adjusted for demographic and exposure predictors [patient age, sex, race/ethnicity, BMI category (<25, 25–30, and >30), smoking status, and injection drug use]. To test whether the association between chronic cough and poor 6-MWT performance was explained by pulmonary function, we tested a series of nested models, including individual measures of pulmonary function adjusting for demographic and exposure predictors. For our final model, predictors of poor performance on 6-MWT were chosen a priori based on published studies or if they demonstrated a significant association (P < 0.10) in unadjusted analyses. These included patient age, race, BMI category, smoking status, injection drug use, hemoglobin, cardiovascular disease, and FEV1 percent predicted. Age and all PFT coefficients were presented in 10 unit increments. Tests of statistical significance (P values) and 95% confidence intervals for the measure of association were calculated; a P value of <0.05 was considered statistically significant. All analyses were performed using a statistical software package (Stata version 11; StataCorp, College Station, TX).
The analytic cohort consisted of 340 participants who completed the 6-MWT, 53% of whom were HIV infected. Complete PFT and survey data were available for 323 participants. HIV-infected participants were on average 3 years older than HIV-uninfected participants. Compared with the HIV-uninfected participants, those with HIV were more likely to be men (98% vs. 88%, P < 0.001) and to have a BMI <25 (38% vs. 18%, P < 0.01) (Table 1). Prevalence of current cigarette smoking, number of pack-years, and injection drugs are presented in Table 1. The HIV-infected group had a median CD4 cell count of 431 cells per microliter. Overall, 35% of the HIV-infected patients had a CD4 count below 350 and 14% a CD4 count below 200; 43% had CD4 nadir less than 200, determined by review of all available laboratory records in the VA system. The majority (89%) of the HIV-infected patients were on ART in the 6 months before enrollment.
HIV-infected patients were more likely to report symptoms consistent with chronic cough and compatible symptoms of chronic phlegm and dyspnea. The prevalence of chronic cough was 25% in HIV-infected and 16% in HIV-uninfected participants (P = 0.04). The prevalence of chronic phlegm was 33% and 16% in HIV-infected and HIV-uninfected participants, respectively, and the prevalence of wheeze was 51% in both groups (Table 1). The mean Medical Research Council dyspnea score (range 1–5) for the HIV infected was 1.91 (SD 1.3) and was not significantly different from the mean Medical Research Council dyspnea score (1.75) for HIV uninfected (SD 1.2). Cardiovascular disease, liver failure, and renal insufficiency were equally present in both groups.
Overall, the median distance walked by both groups was 426 m. The median value of the 6-MWT was not statistically different between the HIV-infected and the uninfected participants (426 vs. 421 m, respectively; P = 0.60). Notably, both groups walked less than 576 m, which is the median distance walked by healthy adult men, with ages between 43 and 77 years described in the literature.26
PFT results were generally within the normal range, with the exception of DLCO, which was lower than predicted normal in HIV-infected and uninfected participants. The FEV1 percent predicted, total lung capacity (TLC) percent predicted, and the FEV1/FVC ratio were similar in HIV-infected and uninfected participants (Table 1). Spirometry-defined COPD was found in 30 (19%) of the HIV-infected subjects and in 36 (20%) of the HIV-uninfected subjects. This difference was not statistically significant. The FVC percent predicted, however, was higher and the DLCO percent predicted was significantly lower among the HIV-infected compared with uninfected participants. Approximately 25% of the patients with chronic cough had fixed airflow obstruction, consistent with spirometry-defined COPD.
Predictors of 6-MWT Among HIV-Infected and Uninfected Participants
To investigate whether respiratory symptoms influence 6-MWT performance and whether this association differs by HIV status, we determined predictors of 6-MWT performance in a multivariable model. The β coefficient for a predictor estimated by these models describes the difference in meters walked in the 6-MWT for a 1 unit change (or otherwise specified) in that predictor, adjusted for other variables in the model. We found that the effect of chronic cough on 6-MWT was modified by HIV infection when adjusting for age, sex, race/ethnicity, BMI, smoking status, and injection drug use, such that an interaction term between HIV infection and chronic cough was significant (β = −51.76, P = 0.04) (Table 2). In this model, age, expressed per 10-year increments (β = −19.39, P < 0.01), BMI >30 (β = −36.75, P < 0.01), and current smoking (β = −46.34, P < 0.01) were also independently associated with poor performance on 6-MWT.
Predictors of 6-MWT Among HIV-Infected Participants
Given the effect modification of HIV infection on the association of chronic cough and 6-MWT performance, we stratified subsequent models by HIV status. Among the HIV-infected participants, older age (β = −32.86, P < 0.001 per 10-year increments), current smoking (β = −49.46, P < 0.01), and injection drug use (β = −30.39 P = 0.02) were significantly associated with poor performance on the 6-MWT in bivariate analyses. Of HIV-specific factors, those with detectable HIV viral load walked on average 27 m less compared with those with undetectable viral load (P = 0.04), whereas CD4 cell count and use of ART were not significant. Symptoms of chronic cough were also associated with 6-MWT performance (β = −41.52, P = 0.003) in bivariate analysis. On objective assessment of pulmonary function, FEV1 percent predicted (β = 12.47, P < 0.001), FVC percent predicted (β = 13.21, P = 0.001), and DLCO percent predicted (β = 8.0, P = 0.04) were all significantly associated with 6-MWT. In contrast, among the HIV-uninfected participants, injection drug use, hemoglobin, symptoms of chronic bronchitis, FEV1 percent predicted, and FVC percent predicted were not significantly associated with 6-MWT (data not otherwise shown).
To understand the association between chronic cough symptoms and 6-MWT among the HIV-infected participants, we generated a series of models. When adjusting for age, gender, race, BMI, injection drug use, and smoking status, chronic cough was independently associated with performance of 6-MWT (β = 31.18, P = 0.03), without inclusion of pulmonary function measures. Then in a series of nested models, we examined whether the association with chronic cough was attenuated when including individual measures of pulmonary function. Because FEV1 and FVC covaried, only FEV1 was used in models. We found that FEV1 percent predicted (β = 10.17, P = 0.002) attenuated the association of chronic cough symptoms with 6-MWT in HIV-infected patients (β = −22.79, P = 0.12), whereas TLC percent predicted (β = 9.16, P = 0.02) or DLCO percent predicted (β = 4.73 P = 0.24) did not attenuate the association with chronic cough (β = −37.58, P = 0.01, and β = −36.54, P = 0.02, respectively) (Table 3).
Finally, we generated a complete multivariable linear regression model, including FEV1 stratified by HIV status. We found that age (β = −24.14, P = 0.01) and FEV1 percent predicted (β = 10.18, P < 0.01) were statistically significant independent predictors of 6-MWT performance when adjusting for age, sex, race/ethnicity, BMI, smoking status, and cardiovascular disease (Table 4) among HIV-infected participants. Detectable HIV viral load and CD4 cell number did not retain significance and were not included in the final model. Current smoking status was a strong independent predictor of poor performance in 6-MWT for both HIV-infected and uninfected groups.
6-MWT has features that make it ideal for testing functional performance in both outpatient and inpatient settings. In this cross-sectional study, we compared the 6-MWT in HIV-infected patients with uninfected patients with similar clinical characteristics. Consistent with previous studies, we found that older age, current smoking, and obesity were significantly associated with poor performance on 6-MWT. Among HIV-infected but not HIV-uninfected participants, symptoms of chronic cough were significantly associated with decreased 6-MWT performance. Airflow limitation (as defined by FEV1 percent predicted) seemed to explain this association, and the FEV1 was an independent predictor of 6-MWT in the HIV-infected patients in multivariable models.
These data highlight the significant role that airflow limitation, as reflected by symptoms of chronic cough and decreased FEV1, plays in the physical performance of HIV-infected individuals. These factors seem to play a stronger role in 6-MWT performance in HIV-infected patients compared with those without HIV. Reasons for this difference are uncertain, but we have previously demonstrated that HIV-infected patients may experience a greater degree of respiratory symptoms for a similar limitation in lung function when compared with HIV-uninfected patients.29 Whether greater inflammation systemically or within the airways of HIV-infected patients plays a role in this relationship requires further investigation.
Clinically, chronic cough symptoms are an easy-to-elicit marker that may signal an increased risk for poor 6-MWT performance among HIV-infected patients and can serve as a prompt for clinicians to consider evaluation of physical function and pulmonary function. Not unique to the veteran population, chronic cough and other respiratory symptoms are prevalent in other studies of HIV-infected patients as well.27,28 These data further raise the possibility that appropriate treatment of respiratory symptoms and airway obstruction in HIV-infected individuals could have an impact on physical function and as a result could also confer improvement in health-related quality of life.30
In healthy individuals, the most important predictor of 6-MWT has been described as age, evident in patients older than 60 years,31 followed by sex.26,31 In COPD patients, multiple predictors have been shown to independently influence 6-MWT performance, including degree of airflow limitation, sex, race, age, and BMI.32 Our data suggest, when comparing coefficients in models stratified by HIV status, that age may play a stronger role in decline in 6-MWT in HIV-infected than in HIV-uninfected participants. These data underscore the need to better understand the decrements in physical function associated with aging in HIV.
Our study adds to the knowledge of factors that influence physical function in HIV-infected patients. Previous reports have shown that HIV-infected patients on ART have preserved capacity to perform activities of daily life but are limited in vigorous activities.15,33 Several studies support that HIV infection is associated with limitations in self-reported34 and measured physical function.35 Our results suggest that risk factors for poor 6-MWT performance vary by HIV status, although HIV infection itself and variables related to HIV disease control were not independent predictors of 6-MWT performance.
Novel findings in our work are that HIV-infected participants with chronic cough walk on average 42 m less than HIV-infected patients without chronic cough in unadjusted analyses and further that there was a significant interaction between HIV and chronic cough, such that distance walked among HIV-infected participants with chronic cough was nearly 52 m less compared with those without HIV or chronic cough in multivariable analysis. This association between chronic cough and 6-MWT performance is mostly explained by airflow limitation (FEV1) rather than by restrictive disease (TLC) or gas exchange impairment (DLCO) in the HIV-infected participants. These findings are notable, despite the fact that the majority of patients with chronic cough did not meet spirometric criteria for COPD, based on the most recent GOLD criteria guidelines,36 yet had demonstrable decreases in 6-minute walk distance that approach the clinically meaningful difference of 50 m. Our data also underscore the significant impact of current smoking as a strong predictor of low 6-MWT in both HIV-infected and uninfected patients, in concordance with previous reports in the literature,5,37,38 and highlight the need for improved smoking cessation in this population.
Some of the limitations in this study include the predominantly male veteran population, the relatively young age of the participants, and the lack of an objective measure for cardiovascular disease. Future studies incorporating longitudinal analysis and objective measurements of cardiovascular disease with 6-MWT performance are needed. Nonetheless, to our knowledge, this is the first report on quantification and characterization of the impact of chronic lung disease on physical function as measured by 6-MWT in HIV-infected patients.
In conclusion, we found that airflow limitation, as reflected by symptoms of chronic cough and as objectively measured by decreased FEV1 percent predicted, is independently associated with poor performance on 6-MWT among HIV-infected patients. Early detection and preventative measures, such as smoking cessation and management of airflow limitation, may decrease the impact of chronic lung disease on physical function in HIV.
The authors would like to acknowledge the contribution of the study participants and project staff involved with the EXHALE study.
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