The aging of the HIV-infected population has resulted in a changing spectrum of disease. Mortality related to AIDS-defining conditions has decreased markedly for those on effective antiretroviral therapy (ART),1,2 whereas comorbid non–AIDS-defining conditions now account for the majority of deaths in recent studies.2–6 Since the early days of the AIDS epidemic, pulmonary diseases have been among the most frequent complications of HIV.7–9 Consistent with other comorbid complications, the spectrum of pulmonary diseases now reflects a substantial burden of non–AIDS-defining chronic diseases, especially chronic obstructive pulmonary disease (COPD).10–15
Although some of the burden of pulmonary disease is explained by the high prevalence of smoking, HIV infection seems to confer an independent increase in the risk for chronic lung diseases, particularly COPD.10,11,16–18 Pulmonary function abnormalities and respiratory symptoms are common in HIV-infected patients, with approximately 20% having irreversible airflow obstruction on spirometry and >30% reporting cough, phlegm, wheeze, or dyspnea.14,19,20 However, prior studies directly comparing pulmonary function between HIV-infected and HIV-uninfected persons in the current ART era are limited and importantly have not assessed postbronchodilator spirometry or diffusing capacity of the lung for carbon monoxide (DLCO).12,19,20 A low DLCO was first noted in HIV-infected patients before the combination ART era,21,22 and though recent studies of HIV-infected persons have found that a substantial proportion have an abnormally reduced DLCO,14,20 these have not included an HIV-uninfected comparator group.
Therefore, we sought to determine the pattern and severity of impairment in pulmonary function in a large cohort HIV-infected and HIV-uninfected individuals. We also asked whether pulmonary function was associated with markers of HIV severity. These analyses used data from HIV-infected and HIV-uninfected men participating in 2 clinical centers of the Lung HIV Study,23 a multicenter study of pulmonary disease in HIV infection sponsored by the Lung Division of the National Institutes of Health, National Heart Lung and Blood Institute. Some of these results have been reported previously in the form of an abstract.24
Overview of Population
We performed a cross-sectional analysis of 300 HIV-infected and 289 HIV-uninfected men enrolled from 2009 to 2011 in the Lung HIV Study, a longitudinal cross-cohort collaboration examining pulmonary complications in the ART era.23 Participants from 2 Lung HIV clinical centers who obtained DLCO measurements in HIV-infected and HIV-uninfected patients were included, namely the pulmonary substudy of the Multicenter AIDS Cohort Study (MACS)25 and the Examinations of HIV Associated Lung Emphysema (EXHALE) Study, a substudy of the Veterans Aging Cohort Study (VACS).26,27 The MACS pulmonary study enrolled patients from the Pittsburgh and Los Angeles sites, and the EXHALE study enrolled patients from the Atlanta, Bronx, Houston and Los Angeles Veterans Affairs (VA) Medical Centers. Only men were included in these analyses because MACS is an all-male cohort, and very few women were enrolled in EXHALE. All participants signed written informed consent, and the study was approved by the Institutional Review Boards at each participating center.
HIV-infected and HIV-uninfected outpatients in the MACS and VACS were approached for participation. Those with acute respiratory infections or illnesses in the past 4 weeks were excluded. A history of chronic lung diseases was not required for enrollment. Within the EXHALE study, HIV-infected and -uninfected participants were matched by current smoking status; those with a history of lung diseases other than COPD or asthma, including lung cancer, were excluded. In the MACS substudy, consecutive HIV-infected and -uninfected participants were selected to reflect the distributions within the parent study of smoking and the presence of respiratory symptoms to avoid bias in recruiting primarily smokers or symptomatic individuals who might be more willing to participate in a study of lung function.
Pulmonary Function Testing
All participants completed pulmonary function tests (PFTs) at study enrollment per American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines,28,29 including pre- and postbronchodilator spirometry and single-breath DLCO. Within both studies, 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 in the EXHALE study and within research pulmonary function laboratories in the MACS substudy. PFT results were reviewed by site pulmonologists or study investigators for quality control; those not meeting ATS criteria for acceptability and reproducibility were not included in these analyses. Airflow obstruction was defined as a ratio of the postbronchodilator forced expiratory volume in 1 second (FEV1) to the forced vital capacity (FVC) below 0.70.30 In secondary analyses, airflow obstruction was defined as an FEV1/FVC ratio below the lower limit of normal; as results were similar, we present the results using a ratio below 0.70. Predicted normal values (% predicted) for spirometry were determined using the formulas by Hankinson et al31 and formulas of Neas and Schwartz32 for DLCO. Both include adjustments for age, race/ethnicity, gender, and height; percent predicted DLCO values were also corrected for hemoglobin. A positive bronchodilator response was present if the FEV1 and/or FVC increased by at least 12% and 200 mL after bronchodilator administration.33 Severity of airflow obstruction was graded based on the FEV1.30 Impairment in DLCO corrected for hemoglobin was based upon ATS/ERS standards, with a threshold of ≤60% of predicted indicating moderate or greater impairment and ≤40% of predicted reflecting severe impairment.33
Other Data Collection
Participants completed a standardized questionnaire assessing history of lung diseases, smoking, and other exposures using previously published instruments.23 Similar questions were used in the EXHALE and the MACS substudy. Smoking status and pack-years of smoking were defined consistently. Participants who reported <100 lifetime cigarettes were defined as never smokers; as current smokers if they had smoked within the past 12 months; and as former smokers if they had quit >12 months ago. Pack-years were calculated based upon number of cigarettes smoked per day on average and years smoked; never smokers were considered to have zero pack-years of exposure. Within the MACS substudy, recent drug use was defined as within 6 months and within EXHALE, recent use was defined as within 12 months. Questions regarding respiratory symptoms of usual cough, usual phlegm, and prior attacks of wheezing that have been associated with shortness of breath were taken from previously published instruments;34 shortness of breath with activity was quantified using the modified Medical Research Council (MRC) dyspnea score.35,36 The MRC dyspnea score was dichotomized at 2 and above as suggested in published guidelines,30 corresponding to the need to stop for breath when walking at one's own pace on level ground or greater limitation. HIV viral load (copies/mL) and CD4 cell counts (cells/µL) were obtained within 12 months of pulmonary function testing. Recorded nadir CD4 cell count before PFTs was dichotomized as ≥ or <200. ART use was captured from the MACS and VACS datasets.25,26
To ensure that results were similar within each cohort, analyses were first stratified by cohort. As results were consistent with similar associations and magnitude of difference in PFT results by HIV status, we proceeded with the combined EXHALE and MACS cohort analyses. Baseline characteristics in HIV-infected and HIV-uninfected men were compared using t tests and Wilcoxon rank-sum tests for parametric or nonparametric continuous variables, respectively, and χ2 tests for categorical variables. To determine the association of HIV with impairment in pulmonary function, potential risk factors were first examined in bivariate models. Then, multivariable linear regression models were used with percent predicted DLCO as the outcome and included HIV, an indicator variable for clinical center, smoking, and other potential confounders. Predictors that were significant at P < 0.1 in bivariate analyses were included in the multivariable models and were retained if statistically significant at P < 0.05 or if they had a substantive effect on other coefficients.
Because smoking is a major potential confounder, we modeled smoking in several ways, including by deciles of pack-years. The risk of impaired pulmonary function did not increase linearly, but displayed a threshold effect at 35 pack-years; this level was more strongly associated with PFT results than smoking status. Therefore, we modeled smoking exposure as 0, 0–34, and ≥35 pack-years in multivariable analysis.
To determine the association of pulmonary function impairment with markers of HIV, we stratified participants by HIV and CD4 cell count, assuming those without HIV to have a CD4 cell count ≥350 cells per microliter. HIV-infected participants were divided into groups by CD4 cell count ≥350, 200–349, and <200 cells per microliter. Because associations were similar in multivariable regression for those with CD4 cell counts of ≥350 cells per microliter and 200–349 cells per microliter, these groups were combined in the final analysis. We also compared associations with HIV RNA >500 or ≤500 copies per milliliter, using HIV-uninfected participants as the referent group. This study was adequately powered at >80% to detect a 7.5% relative difference in means for FEV1, FVC, FEV1/FVC, and percent predicted DLCO between HIV-infected and HIV-uninfected groups. There was also sufficient power to detect an absolute difference of 10% for FEV1/FVC <0.70 and DLCO ≤60% predicted (power of 82% and 79%, respectively).
Demographic and Clinical Characteristics
Our cohort included 300 HIV-infected and 289 HIV-uninfected men with a mean age of 54 (Table 1); 51% were enrolled in EXHALE from Veterans Affairs sites. The EXHALE and MACS patients were comparable, although the EXHALE patients were slightly older and more likely to be current smokers (data not otherwise shown). The combined cohort was racially and ethnically diverse. Overall, more HIV-infected men were current smokers compared with HIV-uninfected men (47% vs. 35%, P = 0.007) and had more pack-years of smoking. HIV-infected men were also more likely to have smoked marijuana and used injection drugs (Table 1). As very few participants had used injection drugs recently, current and former use were combined into a composite variable reflecting ever use in subsequent analyses. HIV-infected men were also more likely to report a history of prior bacterial or Pneumocystis pneumonia.
Prevalence of PFT Abnormalities in HIV-Infected Compared With HIV-Uninfected Men
The majority of both HIV-infected and HIV-uninfected men had normal airflow on spirometry (Table 2), with an average FEV1 postbronchodilator of >90% of predicted. There was no significant difference in the proportion of HIV-infected compared with HIV-uninfected participants with an FEV1/FVC <0.70 postbronchodilator or with a positive bronchodilator response. Overall, 18% of HIV-infected and 16% of HIV-uninfected men met criteria for airflow obstruction (P = 0.5).
Mean DLCO was significantly lower in HIV-infected men compared with HIV-uninfected men (Table 2). Overall, 30% of HIV-infected participants had a DLCO that was ≤60% of predicted compared with 18% of HIV-uninfected participants (P = 0.001). HIV-infected participants were also more likely to have greater DLCO impairment across all ATS/ERS severity categories of DLCO (Fig. 1). Patients with a DLCO ≤60% predicted were significantly more likely to have ever smoked compared with those with a higher DLCO. Among HIV-infected participants, 92% of those with a DLCO ≤60% vs. 66% of those with a DLCO >60% had ever smoked (P < 0.005).
The predominant pulmonary function abnormality observed was an isolated reduction in DLCO. An equal proportion (61%) of HIV-infected and HIV-uninfected participants with a DLCO ≤60% of predicted did not have concomitant airflow obstruction. Among participants with airflow obstruction, the mean % predicted DLCO was substantially lower among those with HIV compared with those without, with a mean (SD) of 56 (21) vs. 67 (22) respectively, P = 0.008. Among participants without airflow obstruction, the mean percent predicted DLCO (SD) was also significantly lower among HIV-infected compared with HIV-uninfected men: 73 (17) vs. 77 (17), P = 0.005.
PFT Results Stratified by Markers of HIV Disease Severity
In bivariate analyses stratified by HIV and CD4 cell count, airflow obstruction was present in 36% of HIV-infected men with a CD4 cell count <200 cells per microliter compared with 16% with a CD4 cell count of 200–349 cells per microliter, 17% with a CD4 cell count ≥350 cells per microliter, and 16% of HIV-uninfected men (P = 0.09) (Fig. 2). There was no statistically significant relationship in the prevalence of airflow obstruction according to HIV viral load: 24% with HIV viral load >500 copies per milliliter had airflow obstruction compared with 17% with viral load ≤500 copies per milliliter and 16% of HIV-uninfected participants (P = 0.4).
However, DLCO was associated with both recent and nadir CD4 cell count; the relationship seemed more strongly related to recent CD4 cell count (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A464). HIV-infected men with a recent CD4 cell count <200 cells per microliter and those with a CD4 between 200 and 349 cells per microliter had a significantly lower DLCO when compared with HIV-infected men with a CD4 cell count ≥350 cells and to HIV-uninfected men (Fig. 2). The percent predicted DLCO [mean (SD)] was 58 (12) in HIV-infected men with CD4 <200 cells per microliter; 67 (17) in those with CD4 200 to <350 cells per microliter; 72 (19) in those with CD4 ≥350 cells per microliter; and 76 (18) in HIV-uninfected men, P = 0.001.
DLCO was also significantly associated with HIV viral load (see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/A464). The mean percent predicted DLCO (SD) in HIV-infected participants with a viral load of >500 copies per milliliter was 66 (18) compared with 71 (19) in the HIV-infected participants who were virally suppressed and 76 (18) in the HIV-uninfected (P = 0.001). Overall, 34% of HIV-infected men with a viral load >500 copies per milliliter had a DLCO ≤60% of predicted normal, compared with 30% of HIV-infected men with HIV RNA below this level and 18% of HIV-uninfected men, P = 0.002.
HIV as an Independent Risk Factor for Decreased DLCO
After evaluating factors associated with DLCO in bivariate analyses, we determined independent risk factors for percent predicted DLCO, corrected for hemoglobin, in multivariable linear regression (Tables 3). Although prior Pneumocystis pneumonia, tuberculosis, and injection drug use were significantly associated with DLCO in bivariate analyses, they were no longer significant in multivariable analyses. HIV viral load and CD4 cell count were both associated with DLCO but were collinear; CD4 was chosen because the association with DLCO was stronger. Thus, after adjusting for race-ethnicity, pack-years of smoking, and clinical center, we found that HIV status remained significantly associated with a decreased DLCO percent predicted. Stratifying participants by HIV and recent CD4 cell count, DLCO was significantly lower in the HIV-infected groups with a CD4 cell count <200 cells per microliter [beta-coefficient −11.6, 95% confidence interval: −18.4 to −4.8] and with a CD4 cell count ≥200 cells per microliter (beta-coefficient −3.7, 95% confidence interval: −6.4 to −0.88) when compared with those without HIV infection.
Association of PFT Results With Respiratory Symptoms
To assess the clinical significance of abnormal PFT results with patient-reported outcomes, we compared the association between respiratory symptoms and abnormalities in PFTs. Compared with HIV-uninfected participants, HIV-infected participants were significantly more likely to report usual cough (28 vs. 20%, P = 0.03) and usual phlegm (33% vs. 24%, P = 0.03), whereas the prevalence of wheezing was similar (26% vs. 24%, P = 0.7). HIV-infected participants tended to have greater dyspnea on exertion (15 vs. 10% with MRC dyspnea score of 2 or greater, P = 0.058). HIV-infected participants with abnormal lung function defined by an FEV1/FVC ratio <0.70 or a DLCO ≤60% of predicted were significantly more likely to have usual cough, phlegm, and dyspnea compared with HIV-infected participants who did not meet criteria for fixed airflow obstruction or who had a higher DLCO (Table 4). In contrast, the difference between the proportions of HIV-uninfected participants with respiratory symptoms according to PFT results was not as marked. Restricted to those with a DLCO ≤60% predicted, HIV-infected participants compared with HIV-uninfected participants were more likely to have cough (43% vs. 26%, P = 0.04), although the difference in those with phlegm (42% vs. 29%, P = 0.1) and dyspnea (29% vs. 16%, P = 0.1) was not statistically significant. Restricted to those with an FEV1/FVC <0.70, HIV-infected participants compared with HIV-uninfected participants were significantly more likely to have cough (53% vs. 21%, P = 0.001), phlegm (59% vs. 20%, P < 0.001), and dyspnea (31% vs. 11%, P = 0.02), whereas the proportions with wheezing were similar. Among persons without pulmonary function abnormalities, the prevalence of respiratory symptoms was equivalent by HIV status.
In the first large-scale and multicenter cohort to examine pulmonary function including DLCO in HIV-infected and HIV-uninfected men in the current ART era, we found that HIV infection was an independent predictor of decreased DLCO after accounting for smoking and other potential confounders. Additionally, markers of greater HIV severity, including higher HIV viral load, recent CD4 cell count, and a nadir CD4 cell count <200 cells per microliter were all associated with lower DLCO. In multivariable models, DLCO was significantly lower in the HIV-infected groups with a CD4 cell count <200 cells per microliter and with a CD4 cell count ≥200 cells per microliter when compared with those without HIV infection. Measures of airflow and the likelihood of airflow obstruction were similar in HIV-infected and HIV-uninfected participants, although the proportion with airflow obstruction tended to be greater in those with a CD4 cell count <200 cells per microliter. Notably, our cohort had a high prevalence of smoking, even in the HIV-uninfected participants that was substantially higher than the general population.
The prevalence of a decreased DLCO, despite the fact that 89% of the HIV-infected men were on ART, was striking. A DLCO less than 60% of predicted, which is consistent with moderate to severe impairment, was significantly more likely in HIV-infected compared with HIV-uninfected men and was present in 30% of those with HIV. The prevalence of a reduced DLCO is important to consider in light of published guidelines and common clinical practice that often involve only screening spirometry to evaluate for respiratory disease.30 In our cohort, spirometry alone would have missed a substantial gas exchange abnormality in many of the HIV-infected and HIV-uninfected participants; considering HIV-infected individuals, 61% of those with moderately to severely reduced DLCO had an isolated reduction without accompanying airflow obstruction.
These data are significant because both FEV1 and DLCO are important clinical indicators of patient outcomes. The FEV1, in particular, is an established measure associated with increased mortality.30,37 However, a DLCO <85% predicted, in the absence of other pulmonary impairment, is also associated with increased mortality in the general population.38 Of PFT measures, DLCO was most closely associated with mortality in a recent study.39 DLCO has been predictive of morbidity and mortality in a number of specific pulmonary diseases as well.40–42
However, the clinical implications of reduced pulmonary function are not fully understood in HIV-infected population. We found that HIV-infected patients with a low DLCO or airflow obstruction were significantly more likely to have increased respiratory symptoms, including usual cough, phlegm, and dyspnea compared with HIV-infected patients with higher DLCO and with no airflow obstruction. Further, respiratory symptoms were notably more prominently expressed among HIV-infected patients with abnormal pulmonary function than among HIV-uninfected patients. A DLCO ≤80% predicted has been associated with a greater prevalence of respiratory complaints in HIV-infected persons in another study.14 In addition, a reduced DLCO could play a role in the decreased functional capacity43 and aerobic capacity in HIV-infected persons.44 Additional longitudinal studies of patient outcomes are required to fully evaluate the significance of our findings.
There are multiple diseases that can contribute to impaired DLCO. The differential diagnosis includes emphysema, interstitial lung diseases, pulmonary vascular diseases (such as pulmonary arterial hypertension, chronic thromboembolic disease, or from injection drug use), and nonpulmonary diseases, such as congestive heart failure with pulmonary edema. Our data suggest that the impairment in DLCO may not be attributable solely to emphysema, given that many participants had an isolated reduction in DLCO with normal airflow. Nonetheless, emphysema may still be a significant contributor, as a greater prevalence of radiographic emphysema in the absence of airflow obstruction among HIV-infected compared with uninfected persons has been reported early in the combination ART era.16,45,46 An increased risk of interstitial lung diseases,10 pulmonary arterial hypertension,13,47 and congestive heart failure48 have also been reported in HIV-infected persons. Combined emphysematous and interstitial changes, as a consequence of smoking may also occur,49 although the extent to which this manifests among HIV-infected persons has not been explored. Of note, patients in the EXHALE study were more likely to have a lower DLCO compared with MACS participants; this finding may reflect unmeasured confounding related to socioeconomic status, occupational or environmental exposures, and extent of drug use that Veterans may share in common, but that differ from MACS participants. Additional work understanding which disease processes are causing the decrease in DLCO will have significant implications for appropriate management of HIV-infected persons.
The pathologic mechanisms by which HIV may contribute independently to a decrease in DLCO are uncertain. The increased inflammation observed in HIV-infected individuals, particularly when more severely immunosuppressed,50,51 may play a significant role. Higher circulating peripheral neutrophil counts, reflective of greater inflammation, have been associated with a reduced DLCO in the general population.32 Lymphocytic alveolitis in HIV-infected persons may play a role in reduced DLCO, particularly among those with lower CD4 cell counts.52 Upregulation of matrix metalloproteinase expression in alveolar macrophages may be particularly important in HIV-associated emphysema.53 In addition, the presence of subacute infection or greater likelihood of colonization with microorganisms may contribute to the pathogenesis of increased lung inflammation and impaired DLCO. Although prior studies have found that a declining DLCO in HIV-infected patients with acute respiratory symptoms is suggestive of Pneumocystis pneumonia,54 it is important to note that our population consisted of stable HIV-infected outpatients without a recent change in respiratory symptoms.
The association of HIV infection with airflow obstruction remains controversial. Although we have previously shown that COPD prevalence is increased in HIV-infected persons based on International Classification of Diseases, Ninth Revision (ICD-9) or self-reported diagnoses,55 there was no difference in the prevalence of airflow obstruction defined by spirometry when comparing HIV-infected men with HIV-uninfected men in our current cohort. These results are similar to the work by Drummond et al12 although these authors did find an association between airflow obstruction and substantially higher HIV viral load, defined as >200,000 copies per milliliter, suggesting a potential pathogenetic role of HIV. There were too few participants with an HIV viral load >200,000 copies per milliliter (n = 2) in our cohort to use this stratification, which may account for the differences between these 2 studies. Other studies have found an association between airflow obstruction and ART use.14,20 Because 89% of the HIV-infected patients were on ART, we had limited power to examine the relationship between ART and pulmonary function.
In contrast to our results and those of Drummond et al,12 Madeddu et al15 from Italy found a lower FEV1, FEV1/FVC ratio, and increased prevalence of airflow obstruction in HIV-infected individuals compared with age- and smoking-matched HIV-uninfected controls (23% vs. 8%, P = 0.008) that remained significant in multivariable analysis. The majority of these patients had undetectable viral load. Although residual confounding or other unmeasured factors between our cohorts may explain these differences, the Italian cohort was significantly younger, with a mean age of 42. One possible explanation is that HIV infection may contribute to a decline in lung health through accelerated cellular senescence, resulting in an earlier presentation of COPD that was more pronounced in their younger cohort. It is also possible that in our older cohort, men with more severely compromised lung function have already died, minimizing differences between those with and without HIV, as the mortality rate among HIV-infected individuals still exceeds that of the HIV-uninfected individuals.
Our study has a number of strengths. This is the first study to compare results of pre- and postbronchodilator spirometry and DLCO in HIV-infected and -uninfected men in the current era. The participants were enrolled from the MACS and VACS, 2 large and multicenter ongoing HIV cohort studies with carefully characterized clinical data. PFTs were measured systematically in a standardized fashion. Our cohort was also racially and geographically diverse, with centers located throughout the United States.
Our study has certain limitations. Due to technical issues, we were unable to systematically obtain measures of carboxyhemoglobin at all sites and therefore were unable to adjust the DLCO for carboxyhemoglobin. However, all participants were asked to refrain from smoking for at least 6 hours before testing, DLCO was corrected for hemoglobin and adjusted for other potential confounders in multivariable models. Pulmonary function testing was of necessity performed at multiple laboratories, but all laboratories operated per ATS standards, trained personnel obtained PFTs at each site, and we included an adjustment for clinical center.28,29,56 Finally, our results may not be generalizable to other studies or populations, as our cohort was a research cohort restricted to men.
In summary, HIV-infected men had a significantly decreased DLCO compared with HIV-uninfected men even after adjusting for smoking and other potential confounders, and despite widespread use of ART. Overall, 30% of HIV-infected men had a DLCO ≤60% of predicted normal, with the majority having an isolated reduction in diffusing capacity. Furthermore, a lower CD4 cell count was associated with a greater likelihood of a decreased DLCO. An impaired DLCO and fixed airflow obstruction were also more likely to be associated with chronic cough, phlegm, and dyspnea in HIV-infected compared with uninfected participants. Whether the decreased DLCO is due to emphysema or other processes such as pulmonary vascular disease or interstitial lung disease requires further evaluation and will have significant implications for patient care and for our understanding of the pathogenesis of HIV-related lung disease.
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