Abstract
Objectives:
Initial studies suggest HIV-positive persons may be at increased risk for chronic lung diseases such as chronic obstructive pulmonary disease, but have commonly relied on single-center designs, lacked HIV-negative controls, or assessed lung function with only spirometry. We tested differences in spirometry and single-breath diffusing capacity for carbon monoxide (DLCO) in persons with and without HIV.
Design:
Cross-sectional, observational study.
Methods:
Participants were enrolled from the Multicenter AIDS Cohort Study, a longitudinal cohort study of men who have sex with men (both HIV-positive and HIV-negative) at four sites in the United States. Standardized spirometry and DLCO testing were performed in all eligible, consenting participants at routine study visits. We tested associations between HIV status and spirometry and DLCO results, using linear and logistic regression.
Results:
Among 1067 men, median age was 57 years, prevalence of current marijuana (30%), and cigarette (24%) use was high, and another 45% were former cigarette smokers. Median forced expiratory volume in 1 s was 97% of predicted normal and DLCO was 85% of predicted normal. HIV-positive persons demonstrated no statistical difference in forced expiratory volume in 1 s compared with HIV-negative persons, but had worse DLCO (adjusted difference −2.6% of predicted; 95% confidence interval: −4.7 to −0.6%) and a higher risk of DLCO impairment (odds ratio for DLCO < 60% of predicted 2.97; 95% confidence interval: 1.36–6.47). Lower DLCO was associated with lower nadir CD4+ cell counts.
Conclusion:
HIV-positive men are at increased risk of abnormal gas exchange, indicated by low DLCO, compared with men without HIV.
Keywords: chronic obstructive, HIV, pulmonary disease, pulmonary gas exchange, respiratory function tests, spirometry
Introduction
Lung diseases such as chronic obstructive pulmonary disease (COPD) and emphysema are among the leading causes of death and disability worldwide [1,2]. HIV infection has been identified as an independent risk factor for emphysema [3], expiratory airflow limitation [4], gas exchange abnormalities [5,6], and respiratory symptoms [7,8]. Mechanisms are not fully understood, but hypotheses include HIV-induced susceptibility to infections, alterations in respiratory microbiota, abnormal inflammatory responses in the lung, mitochondrial abnormalities, and oxidative stress.
Although many studies have measured lung function in HIV-positive persons [4], nearly all had major limitations such as small sample sizes, lack of HIV-negative controls, and/or limited assessments of lung function. In particular, most studies have only measured spirometry. Spirometry accurately measures airflow mechanics and remains the gold standard for diagnosing COPD, but is unable to assess gas exchange properties of the lung. Diffusing capacity of the lung for carbon monoxide (DLCO) is a sensitive measure of gas exchange, and advances in technology now allow DLCO to be measured in routine clinical settings. Several studies have measured DLCO in HIV populations, but the largest included only 300 HIV-positive men from two clinical centers [6].
We addressed current gaps in knowledge regarding lung function in HIV by measuring spirometry and DLCO in a large, longstanding multicenter cohort study of HIV-positive and HIV-negative men. We tested the hypothesis that compared with HIV-negative men, HIV-positive men would have worse measures of lung airflow mechanics (spirometry) and gas exchange (DLCO).
Methods
Complete details of our methods are provided in the Online Supplement, and a brief description is provided here.
Study design and participants
We implemented this cross-sectional study between 1 April 2017 and 31 March 2018 within the Multicenter AIDS Cohort Study (MACS), an ongoing cohort study of men who have sex with men (MSM) from four sites in the United States (Baltimore, Chicago, Los Angeles, Pittsburgh) enrolled in four waves (1984–1985, 1987–1990, 2001–2003, and 2010+).
Procedures
Informed consent was obtained from all participants. Those with contraindications to pulmonary function testing (PFT) (e.g., recent respiratory infections, chest surgery) were excluded [9,10]. Participants performed spirometry before and after inhaling 360 μg of albuterol via metered-dose inhaler, followed by single-breath DLCO testing (ndd EasyOne Pro, Zurich/Switzerland), in accordance with published standards [9,10]. Predicted values were calculated using National Health and Nutrition Examination Survey equations for spirometry [11] and DLCO [12], accounting for factors such as age, race/ethnicity, and height. DLCO values were corrected for hemoglobin (Hb) and carboxyhemoglobin concentrations [10]. We performed central quality control of all tests and analyzed only tests that passed quality control standards. We assessed patient-reported outcomes using the modified Medical Research Council (mMRC) dyspnea scale and St. George’s Respiratory Questionnaire (SGRQ).
Statistical analysis
The primary risk factor of interest was HIV status. The two primary outcome variables were the normalized (percentage of predicted normal) postbronchodilator forced expiratory volume in 1 s (FEV1% predicted) and DLCO corrected for Hb and carboxyhemoglobin (DLCO %predicted). Secondary outcome variables included binary lung function impairment cutpoints of less than 80% of predicted and less than 60% of predicted for both FEV1 and DLCO; forced vital capacity (FVC) %predicted; airflow obstruction as measured by the ratio of FEV1/FVC; spirometry evidence of any COPD [using both common definitions of FEV1/FVC < 0.70 and FEV1/FVC < the 5th percentile of predicted/lower limit of normal (LLN)]; more clinically significant COPD as defined as Global Initiative for Obstructive Lung Disease stage 2–4 disease (FEV1/FVC < 0.70 and FEV1 < 80% of predicted); improvement in FEV1 after bronchodilation (both as a continuous measure and as a binary outcome of >12% and >200 ml increase in FEV1 following albuterol [13]); and the patient-reported outcomes of mMRC and SGRQ scores.
We compared lung function variables and patient-reported outcomes between HIV-positive and HIV-negative participants, first unadjusted, then adjusted for potential confounders that could relate to both HIV status and respiratory outcomes. Models included linear and logistic regression models with robust variance estimators.
In secondary analyses, we restricted our analyses to only the HIV-positive participants, and tested associations between lung function and HIV variables that have been proposed to play a role in HIV-associated lung function impairment. These included current CD4+ T-cell count, nadir CD4+ T-cell count, peak HIV-RNA, cumulative years of exposure to antiretroviral treatment (ART), and prior AIDS.
Results
A total of 1176 out of 1305 (90.1%) MACS participants were seen at their scheduled study visits, met eligibility criteria, and consented to study participation. Quality control standards were met for 90.7% of spirometry tests and 88.7% of DLCO tests, thus providing 1067 FEV1 spirometry tests and 1042 DLCO tests for analyses (Fig. 1).
Fig. 1. Study participant selection for the pulmonary function test substudy of the Multicenter AIDS Cohort Study.
Spirometry and diffusing capacity of the lung for carbon monoxide were performed at routine scheduled Multicenter AIDS Cohort Study visits at visit 67 or visit 68 which occurred between 1 April 2017 and 31 March 2018. Quality control was performed via central review of all spirometry tests, blinded to HIV status.
This cohort of MSM is generally middle-aged [median age of 57 (IQR 49–65) years] with a high prevalence of marijuana use (30%) and current or former cigarette smoking (24 and 45%, respectively) (Table 1).
Table 1.
Demographic and clinical characteristics at the time of pulmonary function testing, by HIV status.
| HIV-positive, n = 591 | HIV-negative, n = 476 | P value | |
|---|---|---|---|
| Age (years) | 55 (47–62) | 61 (53–68) | <0.001 |
| Race | <0.001 | ||
| African-American | 190 (32.2%) | 97 (20.4%) | |
| White | 287 (48.6%) | 331 (69.5%) | |
| Other | 114 (19.3%) | 48 (10.1%) | |
| Education | <0.001 | ||
| 12th grade or less | 133 (23.1%) | 61 (13.0%) | |
| 1–3 years of college | 281 (48.9%) | 216 (46.2%) | |
| 4+ years of college | 161 (28.0%) | 191 (40.8%) | |
| Smoking | 0.032 | ||
| Never | 181 (32.1%) | 144 (31.2%) | |
| Former | 235 (41.7%) | 225 (48.7%) | |
| Current | 148 (26.2%) | 93 (20.1%) | |
| Smoking pack-years, cumulativea | 7.9 (0.8–25.9) | 10.1 (0.2–29.0) | 0.21 |
| Substance use | |||
| Marijuana use | 193 (35.0%) | 113 (24.7%) | <0.001 |
| Cocaine use | 38 (7.0%) | 22 (4.8%) | 0.15 |
| Heroin use | 12 (2.2%) | 5 (1.1%) | 0.18 |
| Any drug injection | 16 (2.8%) | 2 (0.4%) | 0.004 |
| Hepatitis co-infection | |||
| Hepatitis B, chronic | 20 (3.1%) | 5 (1.0%) | 0.012 |
| Hepatitis C, chronic | 45 (7.3%) | 22 (4.3%) | 0.034 |
| HIV characteristics | |||
| CD4+ cell count nadir (cells/μl) | 373 (235–525) | – | – |
| CD4+ cell count current (cells/μl) | 674 (502–885) | – | – |
| HIV-RNA < 50 copies/ml | 497 (88.8%) | – | – |
| Currently on ART | 522 (90.3%) | – | – |
| Cumulative ART years | 12.5 (5.2–17.3) | – | – |
| Peak HIV-RNAb 100 copies/ml | 596 (200–1820) | – | – |
| History of AIDS | 45 (7.6%) | – | – |
| History of Pneumocystis pneumonia | 17 (2.9%) | – | – |
| Cohort of enrollment | <0.001 | ||
| 1984–1985 | 145 (24.5%) | 261 (54.8%) | |
| 1987–1989 | 45 (7.6%) | 19 (4.0%) | |
| 2001–2003 | 251 (42.5%) | 167 (35.1%) | |
| 2010 | 150 (25.4%) | 29 (6.1%) | |
| Site | 0.001 | ||
| Baltimore | 122 (20.6%) | 116 (24.4%) | |
| Chicago | 152 (25.7%) | 91 (19.2%) | |
| Pittsburgh | 161 (27.2%) | 170 (35.7%) | |
| Los Angeles | 156 (26.4%) | 99 (20.8%) |
Results are shown as median (interquartile range) or n(%) unless otherwise specified. ART, antiretroviral treatment.
In current and former smokers.
In patients with detectable HIV-RNA.
Compared with HIV-negative study participants, the HIV-positive participants were younger, more commonly of African ancestry, more likely to report current smoking and illicit drug use, more commonly coinfected with hepatitis B or C, and less commonly enrolled in the initial 1984–1985 wave of enrollment. Among the HIV-positive participants, 90% were currently on ART, 89% had undetectable HIV-RNA, and median recent CD4+ T-cell count was 674 cells/μl with a nadir of 373 cells/μl. Median duration of ART exposure was 12.5 years.
Median FEV1 was 97% of predicted normal and DLCO was 85% of predicted normal in the overall cohort (Table 2). Spirometric evidence of COPD was present in 5.6 to 9.2% of participants (depending on COPD being defined as FEV1/FVC ratio <5th percentile of predicted or <0.70, respectively).
Table 2.
Differences in lung function (as assessed by spirometry and diffusing capacity of the lung for carbon monoxide), respiratory health status (as assessed by the St. George’s Respiratory Questionnaire), and dyspnea (as assessed by the modified Medical Research Council dyspnea scale) between HIV-positive and HIV-negative men in the Multicenter AIDS Cohort study.
| Continuous outcomes | HIV-positive n = 591 | HIV-negative n = 476 | Differences between HIV-positive and HIV-negative | |
|---|---|---|---|---|
| Median (IQR) | Median (IQR) | Unadjusted | Adjusted | |
| Beta (95% CI) | Beta (95% CI)a | |||
| P value | P value | |||
| FEV1% predicted (coprimary) | 97 (86–107) | 97 (86–107) | −0.2 (−2.3 to 1.8) | −2.2 (−4.5 to 0.2) |
| P = 0.81 | P = 0.067 | |||
| DLCO % predicted (coprimary) | 85 (75 −93) | 86 (78–96) | −2.0 (−3.8 to −0.3) | -2.6 (−4.7 to −0.6) |
| P = 0.023 | P = 0.011 | |||
| FVC % predicted | 95 (86–104) | 95 (86–103) | 0.1 (−0.1 to 0.2) | −0.7 (−2.7 to 1.3) |
| P = 0.43 | P = 0.47 | |||
| FEV1/FVC (%) | 81 (76–84) | 79 (75 −83) | 1.0 (0.1 to 2.0) | −0.5 (−1.6 to 0.6) |
| P = 0.033 | P = 0.36 | |||
| Percentage change in FEV1 after bronchodilator | 3.7 (0.5–7.2) | 3.6 (0.5–6.9) | 0.2 (−0.8 to 1.2) | −0.3 (−1.5 to 0.9) |
| P = 0.69 | P = 0.63 | |||
| SGRQ total score | 8.1 (4.0–17.6) | 6.8 (3.9–13.3) | 1.9 (0.4 to 3.5) | 1.3 (−0.2 to 2.8) |
| P = 0.014 | P = 0.08 | |||
| SGRQ symptom score | 11.1 (2.3–23.8) | 9.6 (2.3–19.7) | 2.6 (0.5 to 4.8) | 2.3 (0.2 to 4.3) |
| P = 0.016 | P = 0.032 | |||
| SGRQ activity score | 6.0 (0–24.2) | 6.0 (0–18.5) | 1.9 (−0.5 to 4.4) | 1.1 (−1.4 to 3.7) |
| P = 0.13 | P = 0.38 | |||
| SGRQ impact score | 4.6 (4.6–12.5) | 4.6 (4.6–8.7) | 1.7 (0.5 to 2.9) | 1.1 (−0.1 to 2.4) |
| P = 0.005 | P = 0.08 | |||
| Binary outcomes | ||||
| n (%) | n (%) | Unadjusted | Adjusted | |
| OR (95% CI) P value |
OR (95% CI)a
P value |
|||
| FEV1 < 80% of predicted | 81 (13.7%) | 70 (14.7%) | 0.92 (0.65 to 1.30) | 1.20 (0.79 to 1.824) |
| P = 0.64 | P = 0.39 | |||
| FEV1 < 60% of predicted | 17 (2.9%) | 11 (2.3%) | 1.25 (0.58 to 2.70) | 2.37 (0.97 to 5.82) |
| P = 0.57 | P = 0.059 | |||
| DLCO < 80% of predicted | 222 (39.0%) | 157 (33.2%) | 1.29 (1.00 to 1.66) | 1.61 (1.18 to 2.18) |
| P = 0.052 | P = 0.002 | |||
| DLCO < 60% of predicted | 33 (5.8%) | 15 (3.2%) | 1.88 (1.01 to 3.51) | 2.97 (1.36 to 6.47) |
| P = 0.047 | P = 0.006 | |||
| COPD (FEV1/FVC < LLN) | 37 (6.8%) | 19 (4.2%) | 1.65 (0.93 to 2.99) | 1.92 (0.97 to 3.82) |
| P = 0.084 | P = 0.062 | |||
| COPD (FEV1/FVC < 0.7) | 53 (9.7%) | 39 (8.7%) | 1.13 (0.73 to 1.75) | 1.70 (0.98 to 2.95) |
| P = 0.57 | P = 0.058 | |||
| COPD, GOLD Stage 2–4 (FEV1/FVC < 0.7 and FEV1 < 80% of predicted) | 32 (5.9%) | 23 (2.1%) | 1.16 (0.67 to 2.01) | 1.62 (0.80 to 3.29) |
| P = 0.61 | P = 0.18 | |||
| Positive bronchodilator response | 34 (6.5%) | 29 (6.6%) | 0.98 (0.59 to 1.63) | 0.93 (0.47 to 1.85) |
| P = 0.93 | P = 0.85 | |||
| mMRC ≥ 2 | 76 (13.1%) | 44 (9.3%) | 1.56 (1.19 to 2.06) | 1.33 (0.98 to 1.81) |
| P = 0.002 | P = 0.07 | |||
Continous outcomes are shown in the top section, with beta coefficients (95% CI) indicating the estimated difference of the outcome (row variable) for the HIV-positive participants, relative to the HIV-negative participants. Binary outcomes are shown in the lower section, with odds ratios (95% CI) indicating the odds of the outcome (row variable) for the HIV-positive participants, relative to the HIV-negative participants. Adjusted results statistically significant at P < 0.05 are highlighted in boldtext. CI, confidence interval; COPD, chronic obstructive pulmonary disease; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; mMRC, modified Medical Research Council dyspnea scale; SGRQ, St. George’s Respiratory Questionnaire.
Adjusted for age, race, education, smoking (categorized as current/former/never), chronic hepatitis B or C coinfection, illicit drug use (self-reported marijuana, cocaine, heroin, or any injection drug use), cohort of enrollment, and study site with robust variance estimator. Due to skewness, SGRQ data were additionally analyzed using bootstrapped modeling.
FEV1% predicted was similar between the HIV-positive and HIV-negative study participants in unadjusted analysis but after adjusting for potential confounders, FEV1% predicted appeared worse in HIV-positive persons, although the confidence interval (CI) of this difference crossed zero (adjusted difference of −2.2% of predicted; 95% CI: −4.5 to +0.2%; P = 0.067).
HIV-positive participants had lower DLCO %predicted (adjusted difference of −2.6% of predicted; 95% CI: −4.7 to −0.6%; P = 0.011). When analyzing DLCO and FEV1 as binary outcomes, HIV-positive participants had significantly higher odds of DLCO impairment, defined as DLCO less than 80% of predicted (P = 0.002) or DLCO less than 60% of predicted (P = 0.006). There was no difference in odds for FEV1 less than 80% of predicted, although odds for FEV1 less than 60% of predicted was of borderline statistical significance (P = 0.059).
There were no significant differences by HIV status in the secondary outcomes of FVC, FEV1/FVC, or bronchodilator responses, although COPD prevalence was borderline higher in HIV (P = 0.058 and 0.062 depending on the COPD definition used).
We also observed no overall differences by HIV status in the patient-reported outcomes of SGRQ respiratory health status or mMRC dyspnea scale. The 95% CI for the fully adjusted difference in SGRQ total score between the HIV-positive and HIV-negative participants (−0.2 to +2.8 points) also excluded the minimal clinically important difference of four points for the total SGRQ score. The HIV-positive participants reported statistically worse symptom domain scores of the SGRQ, but there is no established minimal clinically important difference for SGRQ domain scores.
Among HIV-positive participants, a higher current CD4+ T-cell count was associated with lower FEV1% predicted and higher odds of FEV1 impairment (FEV1 < 80% of predicted), but lower odds of DLCO impairment (DLCO < 80% of predicted) (Table 3). A higher nadir CD4+ T-cell count was associated with higher DLCO %predicted and lower risk of DLCO impairment. Increasing years of ART exposure appeared to potentially associate with worse DLCO %predicted and higher odds of DLCO impairment, but statistical significance was borderline (P = 0.057 and 0.079, respectively). Peak viral load was not associated with either FEV1 or DLCO. Prior AIDS was associated with worse FEV1% predicted (−6.8% predicted; 95% CI: −12.2 to −1.3% predicted; P = 0.016), but no difference in DLCO (Supplemental Table E3, http://links.lww.com/QAD/B702).
Table 3.
Relationship between HIV variables and percentage of predicted normal forced expiratory volume in 1 s and diffusing capacity of the lung for carbon monoxide.
| Current CD4+ (square root) | Nadir CD4+ (square root) | Years of ART exposure | Peak HIV-RNA (natural log) | |
|---|---|---|---|---|
| Standardized beta (95% CI) P value, adjusteda | ||||
| FEV1% predicted | −0.11 (−0.20 to −0.02) | 0.03 (−0.05 to 0.10) | −0.02 (−0.11 to 0.08) | 0.007 (−0.06 to 0.01) |
| P = 0.013 | P = 0.54 | P = 0.70 | P = 0.86 | |
| DLCO % predicted | 0.05 (−0.05 to 0.22) | 0.11 (0.01 to 0.20) | −0.09 (−0.19 to 0.003) | −0.03 (−0.10 to 0.05) |
| P = 0.25 | P = 0.032 | P = 0.057 | P = 0.49 | |
| OR (95% CI) P value, adjusteda | 1.06 (1.007 to 1.11) | 0.99 (0.95 to 1.04) | 1.17 (0.89 to 1.55) | 0.97 (0.86 to 1.10) |
| FEV1< 80% of predicted | P = 0.025 | P = 0.72 | P = 0.26 | P = 0.62 |
| DLCO < 80% of predicted | 0.96 (0.93 to 0.995) | 0.97 (0.94 to 0.999) | 1.20 (0.98 to 1.47) | 1.00 (0.92 to 1.10) |
| P = 0.026 | P = 0.049 | P = 0.079 | P = 0.94 | |
Continous outcomes are shown in the top section and binary outcomes are shown in the lower section. Results statistically significant at p < 0.05 are highlighted in bold text. Due to skewness, CD4+ and HIV-RNA measures required transformation. ART, antiretroviral treatment; CI, confidence interval; DLCO, diffusing capacity for carbon monoxide; FEV1, forced expiratory volume in 1 s; OR, odds ratio.
Adjusted for age, race, education, smoking (categorized as current/former/never), chronic hepatitis B or C coinfection, illicit drug use (self-reported marijuana, cocaine, heroin, or any injection drug use), and cohort of enrollment.
In exploratory analyses (Supplemental Tables E1–E3, http://links.lww.com/QAD/B702), current and nadir CD4+ and prior AIDS related to lung function in the pre-ARTera cohort, but not in the post-ART cohort, while increasing years of ARTexposure related to lung function in only the post-ART cohort. Nadir CD4+ T-cell count only related to DLCO in current or former smokers, but not never-smokers. Interaction P values were all more than 0.05, but many were in the P = 0.05 to 0.10 range.
Discussion
We measured spirometry and DLCO in a large, multisite cohort of men with and without HIV. Our major finding was that HIV status was more closely associated with impairments in measures of gas exchange (DLCO) than measures of airflow obstruction (FEV1 and FEV1/FVC). Our data add to the growing evidence base that HIV-positive persons are at higher risk for pulmonary function impairment. Furthermore, our data suggest that DLCO testing may be a more sensitive test for underlying lung abnormalities than spirometry.
FEV1 and airflow obstruction (i.e. COPD) tended to be worse among HIV-positive persons than HIV-negative persons, although the differences were not statistically significant. These results are less clear than several previous observational studies that reported significantly higher odds of COPD among HIV-positive persons compared with HIV-negative persons, as reviewed in a systematic review and meta-analysis [4]. This meta-analysis of 11 publications showed that HIV was associated with higher odds of having COPD. Based on the COPD prevalence we observed, power for detecting a difference in COPD prevalence between the HIV-positive and HIV-negative participants in our study was low at 46% for FEV1/FVC less than LLN and only 10% for FEV1/FVC less than 0.70, possibly explaining the marginal statistical significance results.
Among our HIV-positive participants, COPD prevalence was 9.7% (using the FEV1/FVC < 0.70 criteria). This prevalence is similar to the findings of the meta-analysis above, where pooled data from 16 studies (n = 4717 HIV-positive persons with spirometry) showed COPD prevalence of 10.6%. Given the impact of COPD on mortality, quality of life, and work productivity, the presence of COPD in nearly 10% of HIV-positive persons should prompt further research into HIV-specific case finding, treatment, and prevention strategies. Longitudinal data in our cohort and other cohorts will allow for richer analyses and better understanding of how HIV might uniquely affect COPD pathogenesis, progression, and outcomes such as exacerbations of COPD, which some studies suggest are more common in HIV [14] and which may contribute to COPD pathognenesis and progression [15].
Prior studies suggest the importance of DLCO impairment. Among a general population of cohort of 1564 current and former smokers, each decrease in DLCO of 10% of predicted was associated with worse quality of life, worse exercise capacity, and higher respiratory disease exacerbation rates, even after adjusting for FEV1 and emphysema, suggesting that DLCO is a unique and clinically important marker of lung disease [16]. Smokers with normal spirometry and low DLCO are also at increased risk for developing subsequent COPD [17]. The adjusted difference in DLCO between our HIV-positive and HIV-negative participants was 2.6% of predicted (P = 0.011), which might appear small, but DLCO has no established minimal clinically important difference. Furthermore, when we categorized results into more severe forms of DLCO impairment (e.g., <60% predicted) those with HIV had approximately triple the risk of DLCO impairment which has been associated with poor clinical outcomes. A study from three cities in the USA (Los Angeles, Pittsburgh, San Francisco) measured DLCO in 391 HIV-positive participants and demonstrated that DLCO less than 60% of predicted was associated with increased risk of mortality over a median follow-up time of 69 months (adjusted hazard ratio of 2.28; 95% CI: 1.08–4.82; P = 0.03) [18]. The prevalence of DLCO less than 60% of predicted was 28.6% in that study, suggesting that DLCO impairment might be a major and clinically important abnormality in HIV-positive patients.
Other studies have reported DLCO less than 60% of predicted in 30% of HIV-positive USA men at two MACS sites and four Veterans Affairs sites [6], and 37% of women at the San Francisco site of the USA Women’s Interagency HIV Study cohort [5]. Other studies have reported abnormal DLCO using different criteria such as DLCO less than 80% of predicted, which was present in 52% of HIV-positive persons in Mallorca, Spain [19] and 64% in Pittsburgh, USA [20]; DLCO less than 5th percentile of predicted normal was present in 42% of HIV-positive persons at a single site in Copenhagen, Denmark [21]. Compared with these other studies, we demonstrated a high prevalence of DLCO less than 80% of predicted in our HIV-positive men (39%), but prevalence of DLCO less than 60% of predicted was only 5.8%, which is low, but still approximately double that seen in our HIV-negative men.
The much lower prevalence of severe DLCO impairment in our cohort might reflect our study design where all persons in the longstanding MACS cohort were offered PFT testing (and where 80% agreed to participate and provided good-quality data), rather than being selectively enrolled from a convenience sample of clinic or research settings, where those who participate in research might be at higher risk for underlying diseases. Our low prevalence of more severe DLCO impairment might also reflect survival bias, where those with low DLCO may not have survived to the current PFT visit, or might result from cohort differences in overall health, socioeconomic status, and risk behaviors. Importantly, our data support findings from previous smaller studies that have shown that HIV-positive persons have higher risk for DLCO impairment than HIV-negative persons.
We are aware of only two publications to report longitudinal DLCO measures in HIV-positive persons. One study was a sample of MACS participants in Pittsburgh and San Francisco and found that faster decline of DLCO in HIV (n = 70) over 3 years of follow-up was associated with smoking and higher concentrations of blood endothelin-1 and soluble CD163 [22]. Another study of HIV-positive men and women (n = 277) in Los Angeles, Pittsburgh, and San Francisco found that over a median follow-up time of 6.3 years, DLCO declined in 20% of participants and was associated with pneumonia and smoking [23]. Longitudinal follow-up of our MACS cohort is planned, allowing us to eventually more definitively address critical questions regarding how DLCO impairment evolves over time, risk factors for (and protective factors against) progression of DLCO impairment, and the clinical impact of DLCO impairment.
The cause of DLCO impairment in HIV requires further study. DLCO is a sensitive measure of gas exchange properties of the lungs, but is nonspecific. We corrected for common factors affecting DLCO (blood concentrations of Hb and carboxyhemoglobin), but other causes of DLCO impairment include abnormalities in lung structure/function (e.g. obstructive airways disease, emphysema, pulmonary fibrosis), heart failure, and pulmonary vascular disease (e.g. right heart failure, pulmonary hypertension). One of the first studies to report DLCO impairment in HIV was a pre-ARTera case series of four individuals in Columbus, USA with severe DLCO impairment, but no history of pneumonia or AIDS [24]. Spirometry showed minimal airflow obstruction, but computed tomography imaging showed significant emphysema and bullous changes of the lungs in three of the four patients. In further support of DLCO impairment in HIV potentially being driven by emphysema, a study of 158 HIV-positive persons in Pittsburgh, USA (2009– 2011), comprehensively assessed causes of DLCO impairment in HIV with echocardiograms, plasma NT-proBNP assays, sputum analysis for airway inflammation, and chest computed tomography evaluation for interstitial lung disease (which was not found in any participants) and quantitative lung density measurements for emphysema [25]. In that relatively small study, DLCO impairment was associated with only emphysema and FEV1 in smokers, and with only FVC and sputum lymphocytes and neutrophils in nonsmokers. We did not collect such comprehensive assessments in our study, so we were unable to address causes of DLCO impairment, but such research should be a high priority in the future.
In addition to physiologic measures of lung function, we also collected patient-reported outcomes of mMRC and SGRQ. Although HIV-positive persons reported more dyspnea on the mMRC scale in unadjusted analysis, this difference was NS after adjusting for potential confounders, suggesting that HIV does not uniquely contribute to dyspnea. SGRQ total scores also did not differ by HIV status and excluded a minimal clinically important difference (MCID) of four points on the 100-point scale of SGRQ. However, we found that HIV-positive participants reported worse scores on the SGRQ symptom domain. The SGRQ symptom domain does not have an accepted MCID, so the clinical impact of this difference is not clear.
The rich historical data in this cohort, with up to 34 years of twice-yearly study visits, allowed us to perform uniquely detailed analyses of historical HIV-related variables. Our data confirm a previously reported association between lower nadir CD4+ cell counts and worse DLCO in a subset of 300 HIV-positive men from two MACS sites and four Veterans Affairs sites [6]. Mechanisms for this relationship are currently not clear, but future studies should address biologically plausible mechanisms such as alterations in the airway microbiome, establishment of latent airway epithelial cell infection by HIV, or coinfections with other chronic viruses such as cytomegalovirus or human herpesviruses. We did not confirm findings of other studies where lower nadir CD4+ cell counts were associated with worse FEV1 [26,27], although several other studies also did not find an association between nadir CD4þ and FEV1 [28,29].
Results suggested that more years of ARTexposure might be associated with worse DLCO, but had no association with FEV1. These data could suggest a potential harmful pulmonary effect of ART or impact of immune reconstitution on gas exchange, though we urge caution in interpreting these analyses due to borderline statistical associations and the cross-sectional study design. The Strategic Timing of Antiretroviral Treatment Pulmonary Substudy found no evidence of pulmonary harm among HIV-positive, ART-naive persons randomized to begin ART immediately or deferred until their CD4+ cell counts were 350 cells/μl [30]. However, the investigators measured only FEV1 and did not measure DLCO, so potential effects of ARTon gas exchange remain possible and requires further study.
Unexpectedly, higher current CD4+ cell counts were associated with worse FEV1. We are unaware of any previous studies reporting this association, as most have found no association between current CD4+ and FEV1 [29,31]. Although higher current CD4+ cell counts were associated worse FEV1, they were associated with better DLCO. Reasons for the discrepancy between current CD4þ and measures of mechanics (e.g. FEV1) versus gas exchange (e.g. DLCO) are not clear, but could reflect complex relationships between immune function and different COPD phenotypes such as airway-predominant COPD (for which FEV1 will be more sensitive than DLCO) and emphysema-predominant COPD (for which DLCO will be more sensitive than FEV1).
Due to complex relationships we observed between the historical HIV data and PFT outcomes, we undertook a post-hoc analysis to test for interactions by ART era and by smoking status. We caution that these were exploratory and likely underpowered analyses, but results suggested that relationships between CD4+ cell counts and low DLCO might only be present in the so-called legacy cohort of persons infected in the era prior to effective ART. If this is true, DLCO effects could be related to long duration of HIV, toxic and ineffective early ART regimens, or starting ART at very low CD4+ cell counts. Analyses by smoking status suggested that low nadir CD4+ was associated with low DLCO in only former/current smokers, so cigarette smoke might also play a role in these associations. Analyses by prior AIDS similarly suggested potential differences in strengths of these relationships by ART era and smoking. In total, these exploratory analyses suggest a complex relationship between HIV infection, HIV treatment, smoking, and pulmonary function. Such factors will need to be considered in future work regarding HIV and lung diseases.
Our study had several notable strengths, including its multicenter design, relatively large sample size, inclusion of HIV-positive and HIV-negative controls, detailed historical HIV data, and collection of centrally quality-controlled spirometry and DLCO data (corrected for both Hb and carboxyhemoglobin) in an ongoing cohort without regard to clinical care or respiratory symptoms. Limitations include our lack of detailed lung imaging, which is emerging as an important tool for assessing lung disease phenotypes [32–35]. We lacked functional outcomes such as 6-min walk testing, so we are unable to determine the clinical significance of lung function impairment in HIV. A prior study that included a subset of MACS participants found that FEV1, FVC, DLCO, and smoking were related to decreased 6-min walk distance in HIV [36]. Our MACS cohort also studied only men in the USA (specifically MSM), so our results should not be widely extrapolated to women or persons with HIV in low-to-middle income countries. The USA-based Women’s Interagency HIV Study (WIHS) is collecting spirometry and DLCO measures to address the paucity of data regarding lung disease in women with HIV. Finally, we have collected only cross-sectional PFT measures and we did not correct for multiple statistical comparisons, but future work in the newly combined MACS-WIHS Combined Cohort Study will collect PFT measures longitudinally, thereby allowing validation using longitudinal data, a better understanding of the rate of change in lung function, and mechanistic pathways leading to the development of lung disease in HIV-positive men and women.
Conclusion
Compared with men without HIV, HIV-positive men are at increased risk of abnormal pulmonary gas exchange as measured by DLCO. Reasons for this difference are not clear, but our analyses suggest a complex relationship between lung function abnormalities, HIV infection, HIV treatment, cigarette smoking, and immune function.
Supplementary Material
Acknowledgements
The study team expresses our gratitude to each of the MACS participants for their contributions to our scientific understanding of lung health in HIV.
Footnotes
Data in this article were collected by the Multicenter AIDS Cohort Study (MACS), now the MACS/WIHS Combined Cohort Study (MWCCS). MWCCS (Principal Investigators): Atlanta CRS (Ighovwerha Ofotokun, Anandi Sheth, and Gina Wingood), U01-HL146241; Baltimore CRS (Todd Brown and Joseph Margolick), U01-HL146201; Bronx CRS (Kathryn Anastos and Anjali Sharma), U01-HL146204; Brooklyn CRS (Deborah Gustafson and Tracey Wilson), U01-HL146202; Data Analysis and Coordination Center (Gypsyamber D’Souza, Stephen Gange and Elizabeth Golub), U01-HL146193; Chicago-Cook County CRS (Mardge Cohen and Audrey French), U01-HL146245; Chicago-Northwestern CRS (Steven Wolinsky), U01-HL146240; Connie Wofsy Women’s HIV Study, Northern California CRS (Bradley Aouizerat and Phyllis Tien), U01-HL146242; Los Angeles CRS (Roger Detels), U01-HL146333; Metropolitan Washington CRS (Seble Kassaye and Daniel Merenstein), U01-HL146205; Miami CRS (Maria Alcaide, Margaret Fischl, and Deborah Jones), U01-HL146203; Pittsburgh CRS (Jeremy Martinson and Charles Rinaldo), U01-HL146208; UAB-MS CRS (Mirjam-Colette Kempf and Deborah Konkle-Parker), U01-HL146192; UNC CRS (Adaora Adimora), U01-HL146194. The MWCCS is funded primarily by the National Heart, Lung, and Blood Institute (NHLBI), with additional co-funding from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Human Genome Research Institute (NHGRI), National Institute on Aging (NIA), National Institute of Dental & Craniofacial Research (NIDCR), National Institute of Allergy And Infectious Diseases (NIAID), National Institute of Neurological Disorders And Stroke (NINDS), National Institute of Mental Health (NIMH), National Institute on Drug Abuse (NIDA), National Institute of Nursing Research (NINR), National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). MWCCS data collection is also supported by UL1-TR000004 (UCSF CTSA), P30-AI-050409 (Atlanta CFAR), P30-AI-050410 (UNC CFAR), and P30-AI-027767 (UAB CFAR). The Minneapolis Veterans Affairs Healthcare System and Veterans Health Administration Office of Research and Development also provided protected research time in support of this study.
Conflicts of interest
All authors have received grant support from NIH for the work presented here. K.M.K. has received consultancy fees from GlaxoSmithKline and Nuvaira, Inc. outside the work presented here; has received contracted clinical trial support from AstraZeneca and Sanofi outside the work presented here. R.J. has received consultancy fees from ndd Medical Technologies. D.C., G.D., M.E.F., V.S., and A.M.: nothing to declare. M.C.M. has received consultancy fees from GlaxoSmithKline and royalties from UpToDate outside the work presented here.
The views expressed in this article are those of the authors and do not reflect the views of the United States Government, the National Institutes of Health, the Department of Veterans Affairs, the funders, the sponsors, or any of the authors’ affiliated academic institutions.
Portions of these data were presented as a poster abstract at the 2019 Conference on Retroviruses and Opportunistic Infections (March 2019, Seattle/USA).
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