Abstract
Background
People with HIV (PWH) are at increased risk for chronic lung disease and may be more susceptible to pulmonary complications following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It remains unclear whether HIV infection modifies long-term pulmonary outcomes after coronavirus disease 2019 (COVID-19). This study assessed longitudinal changes in pulmonary function and respiratory symptoms among PWH and people without HIV (PWoH) with serologically-confirmed SARS-CoV-2 infection.
Methods
We analyzed data from the Multicenter AIDS Cohort Study (MACS)/Women’s Interagency HIV Study (WIHS) Combined Cohort Study (MWCCS), a prospective US cohort of PWH and PWoH. Participants with serologic evidence of past SARS-CoV-2 infection and acceptable pre- and post-SARS-CoV-2 pulmonary function testing (PFT) including spirometry and diffusing capacity for carbon monoxide (DLCO) were included. Annualized changes in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and DLCO were compared by HIV serostatus, stratified by sex. Respiratory symptoms were assessed using the St. George’s Respiratory Questionnaire (SGRQ). Linear regression estimated differences in pulmonary function change by HIV serostatus, stratifying by relevant covariates.
Results
Among 778 participants (204 men; 574 women) exposed to SARS-CoV-2 and who underwent PFTs before and after infection, 66% were PWH. Men with HIV (MWH) had a mean annualized FEV1 decline of -44.3 mL/year versus -33.8 mL/year in men without HIV (MWoH) (mean difference -10.5 mL/year; 95% CI: -30.7, 9.7). Among women, FEV1 declined -19.8 mL/year in PWH vs. -14.8 mL/year in PWoH (mean difference -5.0 mL/year; 95% CI: -18.2, 8.2). Changes in FVC and DLCO were similar across HIV serostatus groups. No consistent differences in respiratory symptom changes were observed between PWH and PWoH. Subgroup analyses did not reveal any HIV-associated differential changes.
Conclusions
Among individuals with serologic evidence of SARS-CoV-2 infection, HIV serostatus was not associated with greater declines in pulmonary function or worsening of respiratory symptoms. Our findings suggest that having HIV alone may not increase the risk for pulmonary impairments following a SARS-CoV-2 infection. Further research is needed to understand how uncontrolled HIV infection and severity of SARS-CoV-2 infection may increase risks of adverse pulmonary outcomes following a SARS-CoV-2 infection.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12931-026-03542-4.
Keywords: Pulmonary function test, SARS-CoV-2 infection, Human immunodeficiency virus
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and became a severe global pandemic affecting over 178 countries [1, 2]. SARS-CoV-2 primarily impacts the respiratory system, with manifestations ranging from asymptomatic infection to severe pneumonia and subsequent acute respiratory distress syndrome [3]. Following resolution of acute infection, individuals can experience persistent pulmonary complications regardless of initial disease severity [4]. Pulmonary impairments following SARS-CoV-2 infection have been documented in individuals without underlying lung conditions, and include abnormalities such as reduced forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO) [5–7].
Individuals living with chronic medical conditions, including those living with HIV, have been identified as disproportionately impacted by SARS-CoV-2 infection [8–10]. People with HIV (PWH) are also susceptible to increased risks of chronic lung impairments unrelated to SARS-CoV-2 infection [11, 12]. Despite effective antiretroviral therapy (ART), PWH may experience lung immune dysregulation [13] and increased susceptibility to respiratory infections. Other mechanisms contributing to adverse pulmonary outcomes include HIV-related structural and immunological changes within the lung, alterations in the lung microbiological milieu, and differential environmental exposures [14]. Chronic lung impairments among PWH manifest as mild abnormalities in pulmonary function testing (PFT) or clinically overt airway diseases (e.g., chronic obstructive pulmonary disease [COPD] and asthma), emphysema, interstitial lung diseases, and pulmonary hypertension [15–19]. PWH experience declines in FEV1 and FVC ranging from 25 to 62 ml/year and 9 to 67 ml/year respectively, depending upon cohort composition and follow-up duration. HIV infection is associated with excess loss of 10–17 ml/year in FEV1, 13 ml/year in FVC, and 0.08 ml/min/mm Hg/year in DLCO, values comparable to the impact of active smoking in the general population [19]. In addition to the pre-existing pulmonary vulnerabilities seen in PWH, this population has biological susceptibilities to adverse outcomes after SARS-CoV-2 infection. PWH demonstrate prolonged SARS-CoV-2 viral shedding, potentially leading to prolonged pulmonary inflammation and tissue damage [20]. Chronic HIV infection is associated with persistent interferon signaling, a process associated with lack of protection against SARS-CoV-2 infection in gut epithelial cells, with similar potential compromised antiviral responses in other epithelial tissues such as the lungs [21]. Finally, reactivation of HIV provirus during SARS-CoV-2 infection has been hypothesized to result in endothelial dysfunction and apoptosis secondary to aberrant HIV protein expression, leading to pulmonary vascular remodeling and diffusion impairments [22]. Impairments in specific pulmonary measures could inform potential causal pathways, with FEV1 measurements reflecting aberrant airways inflammation, FVC measurements reflecting processes impacting interstitial fibrosis, and DLCO measurements capturing pulmonary vascular pathology. Given the respiratory tropism of SARS-CoV-2 and the risk of lung diseases in PWH, improved understanding of how these overlapping conditions impact longitudinal lung health among PWH is critical.
The Multicenter AIDS Cohort Study (MACS) [23] and Women’s Interagency HIV Study (WIHS) [24], now combined into the MACS/WIHS Combined Cohort Study (MWCCS) [25] are prospective observational cohorts of PWH and people without HIV (PWoH) at increased vulnerability for HIV in the United States. The cohorts conducted repeated PFTs, respiratory symptom assessments, and serological testing for evidence of past SARS-CoV-2 infection. These data provide a unique opportunity to determine whether HIV infection is associated with differential changes in these measures among individuals infected with SARS-CoV-2.
Methods
In this analysis, we described changes in FEV1, FVC, and DLCO as well as respiratory symptoms among MWCCS participants with serological evidence of past SARS-CoV-2 infection. We hypothesized that PWH would have more substantial pulmonary function decline and worsening respiratory symptoms following a SARS-CoV-2 infection compared to PWoH.
Study population
Prior to cohort merging, people enrolled in the MACS and the WIHS attended study visits at 6-month intervals for biospecimen collection and physical examinations, and to respond to questionnaires on sociodemographic, behavioral, and health information, with the same visit structure continued annually in the MWCCS. From April 2017–March 2018, participants in the MACS completed a pulmonary study visit to perform PFTs including pre-and post-bronchodilator spirometry and DLCO [26], and completion of the St. George’s Respiratory Questionnaire (SGRQ) [27]. From April 2018–January 2020, WIHS participants completed a pulmonary visit with similar data collection; DLCO was measured at a subset of six sites. A second pulmonary visit was completed among MWCCS participants between December 2021–January 2025. As described below, all available blood samples collected at MWCCS study visits between November 2020–August 2023 were tested for serological evidence of past SARS-CoV-2 infection.
The cohort for this analysis included MWCCS enrollees with serological evidence of a past SARS-CoV-2 infection who attended a pulmonary visit before SARS-CoV-2 infection and a pulmonary visit at least 6 months after first positive SARS-CoV-2 serology. To compare changes in pulmonary function by HIV serostatus within biological sex, we divided the overall cohort into four groups: (1) men with HIV (MWH) (2), men without HIV (MWoH) (3), women with HIV (WWH), and (4) women without HIV (WWoH).
Ethical approval and informed consent
Written informed consent was obtained from MACS, WIHS, and MWCCS participants. The study was conducted in compliance with United States Health and Human Services human subjects protection requirements and Good Clinical Practice standards. The individual institutional review boards (IRBs) of all participating clinical centers approved all study protocols, and all participants provided written informed consent.
Measures
Baseline characteristics
For all variables, we used the most recent recorded value prior to or on the date of the first positive SARS-CoV-2 serology. Vaccination status, prior hospitalization and diagnoses of asthma and COPD were determined via self-report (see online supplement). Criteria used to determine the presence of other comorbidities and clinical characteristics are included in the online supplement.
SARS-CoV-2 serology
All MWCCS visits occurring between November 2020 and August 2023 with available blood samples were tested for evidence of past SARS-CoV-2 infection using enzyme-linked immunosorbent assays that measured antibodies targeting the receptor-binding domain (RBD) of the spike protein and the full-length nucleocapsid protein, a component of the virus not included in the vaccine formulation available to the study participants [28–30]. Additional details related to assay conduct are included in the online supplement. Participants were categorized as having past SARS-CoV-2 infection if both anti-spike total IgG RBD and anti-nucleocapsid IgG thresholds for seropositivity were met. Participants demonstrating anti-spike total IgG RBD seronegativity but anti-nucleocapsid IgG seropositivity (1.2% of test results in the total MWCCS cohort) were excluded from analyses as this serological combination could represent either SARS-CoV-2 infection or false positive nucleocapsid antibody.
Pulmonary visit data collection
At each PFT visit, spirometry measures included FEV1 and FVC (EasyOne Pro or Easy on-PC, ndd Medical Technologies, Zurich, Switzerland), and were performed pre- and post-bronchodilator (BD) using inhalation of 360 ug of albuterol from a metered-dose inhaler [26, 31]. DLCO assessment followed spirometry measures. Quality for all PFTs was assessed by a central reading center per the American Thoracic Society/European Respiratory Society standards [32]. The online supplement describes PFT time point selection in further detail. We calculated PFT predicted values that accounted for age, sex, and height using race-neutral equations for spirometry [33] and DLCO [34]. DLCO values were adjusted for hemoglobin and carboxyhemoglobin obtained at the time of DLCO testing. Respiratory health status was assessed using the SGRQ [27]. The SGRQ is a 50-item questionnaire with three domains (symptoms, activity, impact) and a total score range of 0-100, with higher scores indicating worse status. The minimal clinically important difference (MCID) for the total score is four points [35].
Statistical analysis
We calculated descriptive statistics for baseline characteristics by HIV serostatus: counts and proportions for categorical variables and means and standard deviations or median and interquartile range (IQR) for continuous variables, including baseline PFT measures. The primary outcomes for this analysis were the annualized change in each PFT measure (FEV1, FVC, and DLCO). FEV1 and FVC were reported using change in absolute ml/year and separately change in % predicted/year. For DLCO, only change in % predicted/year was reported. Annualized change was calculated as the difference between the post- and pre-SARS-CoV-2 infection measurement divided by the number of years between the tests. Density plots were used to visualize these changes for each type of PFT measure by HIV serostatus and mean change with 95% confidence intervals (CIs) were computed using the annualized change contributed by each person for each PFT measure.
We used linear regression to assess differences in annualized changes of post-BD FEV1, post-BD FVC, and DLCO by HIV serostatus, where the coefficient for HIV serostatus represented the mean difference in PFT measure changes between PWH and PWoH. Primary analyses were unadjusted for baseline covariates. Additional models adjusted for (1) baseline lung function, (2) current smoking status, and (3) baseline lung function and current smoking status. We also examined differences by HIV serostatus in the change of each pulmonary function measure within the following subgroups: participants who reported current, former, or never smoking; participants > 65 years old; participants diagnosed with asthma or COPD; participants with a body mass index (BMI) > 30 kg/m2; participants with a report of prior hospitalization; and participants with a report of prior SARS-CoV-2 vaccination (receipt of at least one dose of vaccine). All analyses were stratified by biological sex given different underlying characteristics of the MACS and WIHS participants.
We calculated change in SGRQ domains and total score by taking the mean difference between the score measured post-SARS-CoV-2 infection and the score measured pre-SARS-CoV-2 infection, reporting mean change with 95% CIs for each domain by HIV serostatus. We categorized individuals as having worsening of SGRQ domains if score increased by four or more points between first and second assessment.
All analyses were conducted using R (version 4.4.1).
Results
Study cohort
Of the 5220 enrolled MWCCS participants, a total of 778 participants (15%; 204 men and 574 women) had serological evidence of past SARS-CoV-2 infection along with acceptable PFT measurements before and after SARS-CoV-2 infection (Supplementary Figure S1). Supplementary Table S1 summarizes the availability of serologic and pre-SARS-CoV-2 exposure pulmonary function measures among participants. Of the 204 men included, 108 (53%) were MWH. Of the 574 women included, 404 (70%) were WWH. Baseline demographic and clinical characteristics are displayed in Table 1. Compared to MWoH, MWH were younger (median age 58 vs. 65 years) and a higher proportion self-identified as Black (41% vs. 22%), were current smokers (19% vs. 8%), reported low household income (27% vs. 10%), lower proportion obese (25% vs. 29%), and had prevalent comorbidities. Among women, there were no substantial differences by HIV serostatus in age, race, household income, obesity, or comorbidities. WWH were less likely to be current smokers than WWoH (22% vs. 35%). MWH and WWH had median CD4 cell count of 686 and 770 cells/mm3, respectively. In both men and women, approximately 75% of PWH had undetectable HIV viral load. Report of SARS-CoV-2 vaccine receipt was high among men (89% MWH, 95% MWoH) and lower among women (70% WWH, 71% WWoH). Report of hospitalization was 11% among MWH, 7% among MWoH, 7% among WWH, and 8% among WWoH.
Table 1.
Cohort clinical characteristics
| Men | Women | ||||
|---|---|---|---|---|---|
| MWH N = 108 |
MWoH N = 96 |
WWH N = 404 |
WWoH N = 170 |
||
| Demographic Characteristics | |||||
| Age, median (Q1, Q3) | 58 (52, 64) | 65 (59, 69) | 53 (47, 59) | 52 (42, 58) | |
| Race and ethnicity, n (%) | |||||
| Black, non-Hispanic | 44 (40.7) | 21 (21.9) | 325 (80.4) | 134 (78.8) | |
| White, non-Hispanic | 41 (38.0) | 69 (71.9) | 27 (6.7) | 8 (4.7) | |
| Another race, non-Hispanic | 4 (3.7) | 2 (2.1) | 15 (3.7) | 3 (1.8) | |
| Any race, Hispanic | 19 (17.6) | 4 (4.2) | 37 (9.2) | 25 (14.7) | |
| Annual household income ≤ $18,000, n (%) | 28 (27.2) | 9 (10.2) | 197 (53.5) | 83 (50.6) | |
| Region, n (%) | |||||
| West | 28 (25.9) | 16 (16.7) | 9 (2.2) | 13 (7.6) | |
| Northeast | 0 (0.0) | 1 (1.0) | 136 (33.7) | 64 (37.6) | |
| Mid-Atlantic | 39 (36.1) | 26 (27.1) | 29 (7.2) | 10 (5.9) | |
| South | 0 (0.0) | 0 (0.0) | 190 (47.0) | 66 (38.8) | |
| Midwest | 41 (38.0) | 53 (55.2) | 40 (9.9) | 17 (10.0) | |
| Clinical Characteristicsa | |||||
| SARS-CoV-2 vaccination, n (%) | 87 (88.8) | 90 (94.7) | 279 (69.9) | 120 (71.0) | |
| Missing | 10 | 1 | 5 | 1 | |
| Prior hospitalization, n (%) | 11 (10.8) | 6 (6.5) | 29 (7.3) | 13 (7.8) | |
| Missing | 6 | 3 | 9 | 4 | |
| Hypertension, n (%) | 63 (58.3) | 51 (53.7) | 264 (65.5) | 102 (60.0) | |
| Diabetes, n (%) | 35 (32.4) | 15 (15.6) | 116 (28.9) | 41 (24.1) | |
| Myocardial infarction, n (%) | 2 (2.0) | 1 (1.1) | 8 (2.0) | 4 (2.4) | |
| COPD (ever), n (%) | 5 (5.0) | 4 (4.3) | 38 (9.6) | 17 (10.3) | |
| Asthma (ever), n (%) | 11 (10.9) | 7 (7.4) | 94 (23.7) | 41 (24.8) | |
| Kidney disease/renal failure, n (%) | 8 (7.9) | 1 (1.1) | 13 (3.3) | 3 (1.8) | |
| Race-free eGFR < 60, n (%) | 17 (17.2) | 8 (8.7) | 71 (18.3) | 10 (6.2) | |
| HIV viral load, n (%) | |||||
| Undetectable: no signal | 57 (52.8) | 244 (60.4) | |||
| Undetectable: under lower limit | 20 (18.5) | 57 (14.1) | |||
| Detectable | 31 (28.7) | 103 (25.5) | |||
| CD4 cells/mm3, median (Q1, Q3) |
686 (495, 913) |
770 (573, 997) |
|||
| BMI, median (Q1, Q3) | 27 (24, 30) | 27 (25, 31) | 33 (27, 39) | 32 (27, 37) | |
| Underweight (< 18.5) | 3 (2.8) | 0 (0.0) | 0 (0.0) | 2 (1.2) | |
| Healthy weight (18.5 to < 25) | 37 (34.3) | 26 (27.1) | 56 (13.9) | 19 (11.2) | |
| Overweight (25 to < 30) | 41 (38.0) | 42 (43.8) | 98 (24.3) | 42 (24.7) | |
| Obese (30+) | 27 (25.0) | 28 (29.2) | 250 (61.9) | 107 (62.9) | |
| Hepatitis C, n (%) | 5 (4.6) | 2 (2.1) | 8 (2.0) | 4 (2.4) | |
| Hepatitis B, n (%) | 7 (6.5) | 1 (1.0) | 5 (1.2) | 1 (0.6) | |
| Behavioral Characteristics | |||||
| Current tobacco smoking, n (%) | 18 (18.9) | 7 (8.0) | 85 (22.1) | 56 (35.2) | |
| Ever tobacco smoking, n (%) | 70 (64.8) | 59 (61.5) | 227 (56.2) | 111 (65.3) | |
| Pack-years, median (Q1, Q3) | 15 (4, 32) | 9 (4, 22) | 7 (3, 16) | 8 (4, 17) | |
COPD Chronic obstructive pulmonary disease, eGFR Estimated glomerular filtration rate, Q1 First quartile, Q3 Third quartile, MWH Men with HIV, MWoH Men without HIV, WWH Women with HIV, WWoH Women without HIV
aSee methods and supplementary information for comorbidity definitions
Pulmonary function testing prior to SARS-CoV-2 infection
In men, pre- and post-BD FEV1 and FVC were largely normal, with mean values in MWH and MWoH ranging from 94 to 102% predicted (Table 2). When compared to MWoH, MWH had lower pre- and post-BD FEV1% predicted (pre-BD: 93.8% vs. 98.6% predicted; post-BD: 96.1% vs. 100.9% predicted). Similar magnitudes of difference were seen in pre- and post-BD FVC% predicted. MWH had lower adjusted DLCO% predicted than MWoH (93.7% vs. 96.0% predicted). Women had lower pre- and post- BD FEV1 and FVC than men, with mean values in WWH and WWoH ranging from 80–87% predicted. When compared to WWoH, WWH had lower pre- and post-BD FEV1% predicted (pre-BD: 80.2% vs. 82.5% predicted; post-BD: 82.5% vs. 84.5% predicted). Similar magnitudes of difference were seen in pre- and post-BD FVC% predicted. WWH had lower adjusted DLCO% predicted than WWoH (89.9% vs. 93.6% predicted).
Table 2.
Pulmonary function before SARS-CoV-2 infection by HIV serostatus and source cohort
| Men | Women | |||
|---|---|---|---|---|
| MWH N = 108 |
MWoH N = 96 |
WWH N = 404 |
WWoH N = 170 |
|
| Pre-BD | ||||
| FEV1, L | 3.3 (0.7) | 3.2 (0.6) | 2.1 (0.5) | 2.2 (0.5) |
| FEV1% predicted | 93.8 (15.8) | 98.6 (15.9) | 80.2 (15.9) | 82.5 (16.2) |
| FVC, L | 4.3 (1.0) | 4.2 (0.7) | 2.7 (0.6) | 2.9 (0.6) |
| FVC % predicted | 97.9 (15.1) | 101.9 (14.8) | 83.9 (15.0) | 86.9 (15.0) |
| FEV1/FVC | 0.8 (0.1) | 0.8 (0.1) | 0.8 (0.1) | 0.8 (0.1) |
| Post-BD | ||||
| FEV1, L | 3.3 (0.8) | 3.3 (0.7) | 2.2 (0.5) | 2.3 (0.6) |
| FEV1% predicted | 96.1 (17.2) | 100.9 (17.0) | 82.5 (16.1) | 84.5 (17.8) |
| FVC, L | 4.2 (1.0) | 4.3 (0.8) | 2.7 (0.6) | 2.8 (0.6) |
| FVC % predicted | 96.3 (16.4) | 101.1 (15.0) | 83.3 (14.7) | 86.0 (15.7) |
| FEV1/FVC | 0.8 (0.1) | 0.8 (0.1) | 0.8 (0.1) | 0.8 (0.1) |
| Adjusteda DLCO % predicted | 93.7 (19.1) | 96.0 (14.7) | 89.9 (17.1) | 93.6 (21.2) |
All values mean (SD) unless otherwise indicated. BD Bronchodilator, DLCO Diffusing capacity of the lung for carbon monoxide, FVC Forced vital capacity, FEV1 Forced expiratory volume in one second, MWH Men with HIV, MWoH Men without HIV, PFT Pulmonary function test, WWH Women with HIV, WWoH Women without HIV
aAdjusted for hemoglobin and carboxyhemoglobin
Missingness ranges from 4% (MWoH FEV1) to 68% (WWH Adjusted DLCO). Full details are in Supplementary Table S1
Change in pulmonary function after SARS-CoV-2 infection
Figure 1 displays the timing of baseline and follow-up PFTs compared with the first positive SARS-CoV-2 antibody test. Among men, the median (IQR) time between PFTs was 66 (62–72) months for MWH and 68 (63–73) months for MWoH. The median (IQR) time from baseline PFT to first positive SARS-CoV-2 antibody test was 54 (49–59) months. The median (IQR) time from first positive SARS-CoV-2 antibody test to follow-up PFT was 13 9–17 months. Among women, the median (IQR) time between PFT tests was 60 (55–65) months for WWH and 58 (53–64) months for WWoH. The median (IQR) time from baseline PFT to first positive SARS-CoV-2 serology test was 39 (31–45) months. The median (IQR) time from the first positive SARS-CoV-2 serology test to follow-up PFT was 20 14–26 months.
Fig. 1.
Timing of pulmonary function tests relative to first positive SARS-CoV-2 serology in men (red) and (blue) source cohorts
The cohort-level distributions of post-BD FEV1, post-BD FVC, and DLCO change stratified by HIV serostatus are displayed in Fig. 2. The annualized change in absolute post-BD FEV1 was - 44.3 ml/year among MWH compared to -33.8 ml/year among MWoH [mean difference - 10.5 ml/year (95% CI -30.7 to 9.7) (Table 3). The annualized change in absolute post-BD FEV1 was - 19.8 ml/year among WWH compared to -14.8 ml/year among WWoH [mean difference - 5.0 ml/year (95% CI -18.2 to 8.2 )]. Changes in % predicted measures of FEV1 and FVC were similar. Among men, annualized change in % predicted DLCO was similar comparing MWH to MWoH [-0.1 vs. 0.1%/year; mean difference − 0.2%/year (95% CI -0.9 to 0.5)]. Similarly, among women annualized change in % predicted DLCO was not different comparing WWH to WWoH [0.1 vs. -0.1%/year; mean difference 0.1%/year (95% CI -1.2 to 1.4)]. Models adjusting for baseline FEV1 and current smoking status, separately or combined, yielded similar results (Supplementary Table S3, Supplementary Figures S8-S10).
Fig. 2.
Distributions of annualized changes in percent predicted pulmonary function tests pulmonary function before and after SARS-CoV-2 infection by HIV serostatus (DLCO adjusted for hemoglobin and carboxyhemoglobin. PWH People with HIV, PWoH People without HIV, DLCO Diffusing capacity of the lungs for carbon monoxide)
Table 3.
Annualized changes in pulmonary function, measured by FEV1, FVC, and DLCO, before and after SARS-CoV-2 infection, by HIV serostatus
| Men | Women | |||||||
|---|---|---|---|---|---|---|---|---|
| MWH Mean (95% CI) |
MWoH Mean (95% CI) |
Difference (95% CI) |
WWH Mean (95% CI) |
WWoH Mean (95% CI) |
Difference (95% CI) |
|||
| FEV1 ml/year | ||||||||
| Pre-BD | -35.6 (-48.1, -23.0) | -30.7 (-39.1, -22.3) | -4.8 (-20.2, 10.5) | -18.6 (-24.0, -13.1) | -17.4 (-25.6, -9.3) | -1.1(-11.0, 8.8) | ||
| Post-BD | -44.3 (-60.8, -27.8) | -33.8 (-44.5, -23.1) | -10.5 (-30.7, 9.7) | -19.8 (-27.0, -12.5) | -14.8 (-25.1, -4.5) | -5.0 (-18.2, 8.2) | ||
| FEV1% predicted/year | ||||||||
| Pre-BD | -0.3 (-0.7, 0.1) | -0.1 (-0.3, 0.2) | -0.2 (-0.7, 0.3) | 0.0 (-0.2, 0.2) | 0.0 (-0.3, 0.3) | -0.0 (-0.4, 0.4) | ||
| Post-BD | -0.5 (-0.9, 0.0) | -0.1 (-0.5, 0.2) | -0.3 (-0.9, 0.3) | -0.0 (-0.3, 0.2) | 0.1 (-0.3, 0.5) | -0.2 (-0.7, 0.3) | ||
| FVC mL/year | ||||||||
| Pre-BD | -26.5 (-40.4, -12.7) | -17.2 (-28.1, -6.3) | -9.3 (-27.0, 8.3) | -17.3 (-23.8, -10.9) | -16.2 (-26.2, -6.3) | -1.1 (-12.9, 10.8) | ||
| Post-BD | -20.2 (-33.7, -6.7) | -22.7 (-34.3, -11.0) | 2.5 (-15.5, 20.5) | -14.5 (-21.2, -7.8) | -10.2 (-21.7, 1.2) | -4.3 (-17.3, 8.8) | ||
| FVC % predicted/year | ||||||||
| Pre-BD | -0.0 (-0.4, 0.3) | 0.2 (-0.0, 0.5) | -0.3 (-0.7, 0.2) | 0.0 (-0.2, 0.3) | 0.1 (-0.3, 0.4) | -0.0 (-0.4, 0.4) | ||
| Post-BD | 0.1 (-0.2, 0.5) | 0.1 (-0.2, 0.4) | 0.0 (-0.4, 0.5) | 0.1 (-0.1, 0.3) | 0.2 (-0.1, 0.6) | -0.1 (-0.5, 0.3) | ||
| DLCOa % predicted/year | -0.1 (-0.6, 0.4) | 0.1 (-0.4, 0.6) | -0.2 (-0.9, 0.5) | 0.1 (-0.5, 0.6) | -0.1 (-1.5, 1.4) | 0.1 (-1.2, 1.4) | ||
BD Bronchodilator, CI Confidence interval, DLCO Diffusing capacity of the lung for carbon monoxide, FEV1 Forced expiratory volume in one second, FVC Forced vital capacity, MWH Men with HIV, MWoH Men without HIV, PFT Pulmonary function test, WWH Women with HIV, WWoH Women without HIV
aAdjusted for hemoglobin and carboxyhemoglobin
Pulmonary function sensitivity analyses
Stratifying cohorts by key demographic and clinical characteristics (age, smoking status, pre-existing obstructive lung disease, BMI, prior hospitalization, report of SARS-CoV-2 vaccine receipt) did not identify any factors consistently associated with differential annual change in FEV1 or FVC by HIV serostatus (Supplementary Figs. 2–5). There were no demographic or clinical characteristics associated with differential annual change in % predicted DLCO by HIV serostatus in men (Supplementary Fig. 6). Among women aged 65 + years, greater decline was seen among WWoH compared to WWH (mean difference 5.4%/year; 95% CI 3.0 to 7.7) (Supplementary Fig. 7). Within each cohort we compared the 10% with the largest decline in % predicted FEV1 to the remaining 90% of the cohort. Those with the largest decline in % predicted FEV1 were more likely to be current smokers, have lower income, and report prior hospitalization compared to the remaining 90% of individuals within each cohort. Additionally, among women, worst decliners were more likely to have obesity and chronic obstructive pulmonary disease (Supplementary Table S4).
Respiratory symptoms prior to SARS-CoV-2 infection
Before SARS-CoV-2 infection, men had relatively mild respiratory health impairment, with mean values of SGRQ domains ranging from 5.2 to 17.9 among MWH and 2.7 to 12.8 among MWoH (Supplementary Table S2). All domains were higher (worse) among MWH compared to MWoH, with highest scores seen in the symptom domain (MWH: 17.9; MWoH 12.8). Among women, overall respiratory impairment was worse compared to men, with mean values of SGRQ domains ranging from 8.1 to 30.2 among WWH and 9.0 to 28.6 among WWoH. Among women, pre-positive-SARS-CoV-2 serology SGRQ domain scores were similar between HIV serostatus groups.
Change in respiratory symptoms after SARS-CoV-2 infection
Among MWH and MWoH, neither individual SGRQ domains nor total score demonstrated a clinically significant change from the assessment prior to SARS-CoV-2-infection to the assessment after (Table 4). Moreover, there were no meaningful differences when comparing across serostatus groups. Similarly, among WWH and WWoH, none of the individual SGRQ domains or total score had a clinically significant change from the assessment prior to SARS-CoV-2 infection to the assessment after. Among women, the SGRQ activity domain had the most substantial change by HIV serostatus: in WWH, the activity score decreased (improved) by 3.1 points, while among WWoH the activity score increased (worsened) by 2.1 points [difference: -5.2 points (95% CI -10.0 to -0.4)]. Other domains and total score of the SGRQ among women did not differ comparing WWH to WWoH.
Table 4.
Changes in St. George’s Respiratory Questionnaire domains comparing post- to pre- SARS-CoV-2 infection, with differences by HIV serostatus
| Domain | Men | Women | |||||
|---|---|---|---|---|---|---|---|
| Mean (SD) | Difference (95% CI) | Mean (SD) | Difference (95% CI) |
||||
| MWH | MWoH | WWH | WWoH | ||||
| Symptoms | -2.7 (21.7) | -0.1 (16.5) | -2.6 (-8.1, 2.9) | -1.9 (20.9) | -1.2 (23.6) | -0.7 (-4.6, 3.3) | |
| Activity | 2.0 (19.9) | 0.1 (18.7) | 1.9 (-3.6, 7.4) | -3.1 (27.0) | 2.1 (25.2) | -5.2 (-10.0, -0.4) | |
| Impacts | -0.4 (9.3) | -0.6 (8.2) | 0.2 (-2.3, 2.7) | -0.3 (14.5) | -0.4 (13.0) | 0.2 (-2.4, 2.7) | |
| Total | 0.1 (11.9) | -0.2 (10.7) | 0.3 (-3.0, 3.5) | -1.8 (16.0) | -0.2 (15.2) | -1.6 (-4.5, 1.2) | |
CI Confidence interval, MWH Men with HIV, MWoH Men without HIV, SD Standard deviation, WWH Women with HIV, WWoH Women without HIV
The proportions of men and women experiencing a 4 or more-point increase (worsening) in SGRQ score domains or total score after infection with SARS-CoV-2 are displayed in Fig. 3 and summarized in Supplementary Table S5. There were numerically higher proportions of MWH compared to MWoH experiencing worsening total SGRQ (27% vs. 20%), activity (35% vs. 29%), and impact (16% vs. 12%) scores. Among women, the directionality was opposite, with numerically higher proportions of WWoH compared to WWH experiencing worsening symptoms (36% vs. 29%) and activity (43% vs. 35%) scores.
Fig. 3.
Percentage of people with SGRQ scores that worsen (increase) at least 4 points from pre-SARS-CoV-2 infection pulmonary visit to post-SARS-CoV-2 infection pulmonary visit, by sex and HIV serostatus. (PWH People with HIV, PWoH People without HIV, SGRQ St. George’s Respiratory Questionnaire)
Discussion
In this prospective analysis from the multisite MWCCS participants with pre- and post-SARS-CoV-2 infection pulmonary function testing and St. George’s Respiratory Questionnaire, we observed that among individuals with serological evidence of SARS-CoV-2 infection, there were no differences in pulmonary function changes comparing PWH to PWoH. Moreover, there were no consistent differences in changes in respiratory symptom burden comparing PWH to PWoH. These findings suggest that HIV infection is not an independent risk factor for worsening pulmonary outcomes following a SARS-CoV-2 infection.
In persons without HIV, findings on the impacts of SARS-CoV-2 infection on pulmonary function measurements are inconsistent. Lewis and colleagues observed that among a cohort of 80 individuals with mild to moderate COVID-19 disease, FEV1, FVC or DLCO measured within one year after SARS-CoV-2 infection did not differ from pre-infection values [36]. A separate analysis of 52 individuals from the Copenhagen General Population Study observed that individuals with mild COVID-19 infection had adjusted excess decline in FEV1 of 13.0 mL/year in the two years post-infection compared to uninfected participants [37]. The RECoVERED Study group reported that among a cohort of 301 individuals, one year after hospitalized or non-hospitalized SARS-CoV-2 infection, 25% of participants had impaired pulmonary function [38]. To our knowledge, our analysis represents the first and the largest description of changes in objective and subjective pulmonary measures comparing PWH and PWoH with serological evidence of SARS-CoV-2 infection. We add to the literature our findings that there was no observe differences in longitudinal pulmonary outcomes comparing PWH to PWoH with median follow-up times of 13 and 20 months after SARS-CoV-2 infection in men and women, respectively.
In the MWCCS, the annual change in absolute FEV1 among PWoH with serological evidence of SARS-CoV-2 infection ranged from - 15 to -34 ml/year, and when measured using % predicted values ranged 0.1% to -0.1% predicted. These ranges are similar to the unadjusted magnitude of change reported by Lewis et al. (0.2% predicted) but are less than those reported in the two-year follow-up study by Iversen et al. (-46 ml/year). The lack of longitudinal change in DLCO % predicted observed in our analysis also aligns with the reports of Lewis and Iversen. Taken together, the pulmonary function trajectories observed in our SARS-CoV-2 seropositive PWoH group align with those reported in other cohorts of PWoH.
The lack of differential pulmonary function changes among PWH has several potential explanations. First, HIV infection simply may not be an independent risk factor for worse pulmonary outcomes after SARS-CoV-2 infection. It is noteworthy that the majority of MWCCS participants contributing data to this analysis have well-controlled HIV as measured by an undetectable HIV viral load and robust CD4 cell count. The additive impact of HIV infection on the background risk of accelerated pulmonary decline following SARS-CoV-2 infection may be attenuated with effective HIV treatment. The distribution of FEV1 decline in MWH has more outliers with reduced lung function. It is possible that among individuals with uncontrolled HIV, a subset experiences greater declines in pulmonary function measures compared to PWoH, but we are underpowered to study this hypothesis in our cohort. A second possible explanation for our findings is that the duration of follow-up between SARS-CoV-2 infection and post-infection PFT may have been insufficient to detect longitudinal changes. However, in the study by Iversen et al., differences in pulmonary function between those with and without SARS-CoV-2 infection were observed as early as six months, with changes persisting up to 24 months, making the duration of follow-up less likely a factor. Third, the wide range of time between the first positive SARS-CoV-2 serology and the follow-up PFT in this observational cohort study may have impacted the ability to detect differences in pulmonary function changes between PWH and PWoH. Studies have reported an initial decline in pulmonary function early post-infection that recovers one year after infection [39, 40], highlighting the dynamic nature of lung damage and recovery after SARS-CoV-2 infection. Finally, the MWCCS participants included in this analysis had largely normal pulmonary function prior to SARS-CoV-2 infection. Pre-existing lung disease is associated with worse long-term pulmonary outcomes after SARS-CoV-2 infection [41]. It is possible that a similar analysis in a cohort of individuals with and without HIV, and with pre-existing lung disease, would yield different results.
Our findings of no differences in change in respiratory symptom burden after SARS-CoV-2 infection between PWH to PWoH aligns with our pulmonary function findings. The overall symptom burden in the analytical cohort prior to SARS-CoV-2 infection was low, affording the opportunity to detect worsening symptoms after SARS-CoV-2 infection. Despite this, we did not see any consistent trends in the worsening or improving of respiratory symptoms after SARS-CoV-2 infection. Similar to our pulmonary function findings, the lack of associations between HIV serostatus and changes in respiratory symptoms after SARS-CoV-2 infection may be due to a lack of biological impact of HIV infection on symptom domains or related to the specific characteristics of the MWCCS analytical cohort.
This analysis has limitations. The timing of PFT assessment before and after SARS-CoV-2 serological testing was variable in the setting of an observational cohort study. The variable time windows create heterogeneity in our assessments of the impacts of SARS-CoV-2 infection on longitudinal outcomes. While we did not observe an impact of hospitalization on pulmonary outcomes, the MWCCS did not systematically collect data on the presence of pneumonia nor the severity or treatment of SARS-CoV-2 infection among all participants, an important potential modifier of longitudinal pulmonary outcomes. Therefore, it is possible our findings would differ if we were able to better assess severity of SARS-CoV-2 infection (e.g., people requiring oxygen support). Moreover, this analysis is only among those individuals who returned for a MWCCS visit; hence, excluding individuals who may have died due to SARS-CoV-2 infection. Due to factors such as antibody fading and asymptomatic infection, we were not able to accurately identify individuals with no history of SARS-CoV-2 infection to compare lung function changes between those with and without SARS-CoV-2 infection. Finally, the analytical cohort was comprised largely of PWH who had controlled HIV infection. This prevents the generalization of our findings to populations where access to HIV treatment is poor.
Despite these limitations, our study has several strengths. First, the MWCCS is a multicenter cohort with well-characterized participants including epidemiologically well-matched comparator PWoH. This cohort affords the important opportunity to robustly isolate the potential impacts of HIV infection on pulmonary outcomes. Second, we determined SARS-CoV-2 infection using a biological marker (positive serology) rather than self-report. This approach permitted the inclusion of asymptomatic infections, which are largely excluded from prior reports of hospitalized and treated individuals. Finally, the collection of both physiologic and patient-reported pulmonary domains permitted a comprehensive analysis of the impacts of HIV infection on pulmonary outcomes after SARS-CoV-2 infection.
Conclusions
In conclusion, our study found that among individuals with serological evidence of SARS-CoV-2 infection, PWH did not have differential longitudinal changes in objective or subjective changes in pulmonary outcomes compared to PWoH. This study suggests that the long-term respiratory impacts of SARS-CoV-2 infection may not be worse in PWH than in PWoH. Further research is needed to understand how uncontrolled HIV infection and severity of SARS-CoV-2 infection may increase risks of adverse pulmonary outcomes following a SARS-CoV-2 infection.
Supplementary Information
Acknowledgements
The authors gratefully acknowledge the contributions of the study participants and dedication of the staff at the MWCCS sites.
Abbreviations
- ART
Antiretroviral therapy
- BD
Bronchodilator
- BMI
Body mass index
- CI
Confidence interval
- COPD
Chronic obstructive pulmonary disease
- COVID-19
Coronavirus disease 2019
- DLCO
Diffusing capacity for carbon monoxide
- FEV1
Forced expiratory volume in one second
- FVC
Forced vital capacity
- IQR
Interquartile range
- MACS
Multicenter AIDS Cohort Study
- MCID
Minimal clinically important difference
- MWCCS
MACS/WIHS Combined Cohort Study
- MWH
Men with HIV
- MWoH
Men without HIV
- PFT
Pulmonary function testing
- PWH
People with HIV
- PWoH
People without HIV
- SARS-CoV-2
Severe acute respiratory syndrome coronavirus-2
- SGRQ
St. George’s Respiratory Questionnaire
- WIHS
Women’s Interagency HIV Study
- WWH
Women with HIV
- WWoH
Women without HIV
Authors’ contributions
CAW, AE, KMK, AM, AD, CR, SRC, MAF and MBD were responsible for conception and design of work. BES, VS, IZB, MCM, JAD, MLA, SKC, SJG, DGL, RFF, DBR, LH, AM, CR, LP, MAF, MBD were responsible for acquisition of data. CAW, AE, KMK, CR, SRC, MAF and MBD drafted the work. All authors substantially revised the draft manuscript, read, and approved the final manuscript.
Funding
Data in this manuscript were collected by the MACS/WIHS Combined Cohort Study (MWCCS). The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). 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, David Hanna, 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 Topper), U01-HL146193; Chicago-Cook County CRS (Mardge Cohen, Audrey French, and Ryan Ross), U01-HL146245; Chicago-Northwestern CRS (Steven Wolinsky, Frank Palella, and Valentina Stosor), U01-HL146240; Northern California CRS (Bradley Aouizerat, Jennifer Price, and Phyllis Tien), U01-HL146242; Los Angeles CRS (Roger Detels and Matthew Mimiaga), 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, James B. Brock, Emily Levitan, and Deborah Konkle-Parker), U01-HL146192; UNC CRS (M. Bradley Drummond and Michelle Floris-Moore), 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 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), National Institute on Minority Health and Health Disparities (NIMHD), and in coordination and alignment with the research priorities of the National Institutes of Health, Office of AIDS Research (OAR). MWCCS data collection is also supported by UL1-TR000004 (UCSF CTSA), UL1-TR003098 (JHU ICTR), UL1-TR001881 (UCLA CTSI), P30-AI-050409 (Atlanta CFAR), P30-AI-073961 (Miami CFAR), P30-AI-050410 (UNC CFAR), P30-AI-027767 (UAB CFAR), P30-AI-124414 (ERC-CFAR), P30-MH-116867 (Miami CHARM), UL1-TR001409 (DC CTSA), KL2-TR001432 (DC CTSA), and TL1-TR001431 (DC CTSA). This material is also the result of work supported with resources and the use of facilities at the Boise VA Medical Center.
Data availability
Access to individual-level data from the MACS/WIHS Combined Cohort Study Data (MWCCS) may be obtained upon review and approval of a MWCCS concept sheet. Links and instructions for online concept sheet submission are on the study website (https:/statepi.jhsph.edu/mwccs/work-with-us) .
Declarations
Ethics approval and consent to participate
Written informed consent was obtained from MACS, WIHS, and MWCCS participants. The study was conducted in compliance with United States Health and Human Services human subjects protection requirements and Good Clinical Practice standards. The individual institutional review boards (IRBs) of all participating clinical centers approved all study protocols, and all participants provided written informed consent.
Consent for publication
Not applicable.
Competing interests
CAW, AE, VS, IZB, JAD, MLA, SKC, SJG, DGL, RFF, DBR, LH, KMK, AD, CR, SRC, LP, MAF and MBD report no relevant conflicts of interest related to this manuscript. AM has received funding from Pfizer, Inc. unrelated to this manuscript. MCM is a member of the medical advisory board of ndd Medical Technologies and receives fees for medical education from MGC Diagnostics. BES reports grant support from Gilead Sciences, Inc.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Access to individual-level data from the MACS/WIHS Combined Cohort Study Data (MWCCS) may be obtained upon review and approval of a MWCCS concept sheet. Links and instructions for online concept sheet submission are on the study website (https:/statepi.jhsph.edu/mwccs/work-with-us) .