Human immunodeficiency virus (HIV) infection is a major health public problem worldwide. In 2021, it was estimated that 38.4 million people lived with HIV (PLWH), 1.5 million acquired HIV, and 650,000 died from HIV-related causes.1 HIV is a retrovirus that attacks the immune system causing a depletion of CD4 T lymphocytes, and favoring the appearance of opportunistic infections and neoplasms.

It has been suggested that the lung might serve as an anatomical HIV reservoir.2 HIV can infect bronchial epithelial cells rendering individuals susceptible to lung damage. HIV can also infect alveolar macrophages impairing phagocytosis and immune response to pathogens, and leading to HIV persistence in lungs.3

From detection of the first case of acquired immunodeficiency syndrome in 1982, Pneumocysis jirovecii pneumonia, tuberculosis and other lung infections were frequent in PLWH.4 Later, several studies have reported that lung diseases as airflow limitation, emphysema and respiratory infections are associated with HIV infection.5–7 In the combination antiretroviral therapy era, comorbid lung diseases are important determinants of morbidity and mortality in PLWH.8 A recent meta-analysis estimated a prevalence of chronic obstructive pulmonary disease (COPD) of approximately 10.6% in PLWH, and a multicenter cohort study observed that PLWH have faster lung function decline than matched population controls.9,10 However, research on lung function in PLWH has shown controversial results.

Therefore, we performed a meta-analysis to investigate the effects of HIV infection on pulmonary function comparing lung function tests between PLWH and uninfected controls.

We designed this meta-analysis to determine, in PLWH, the changes on the following parameters of pulmonary function test: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and diffusion capacity of the lung for carbon monoxide (DLCO).

We recorded the protocol for this meta-analysis in the PROSPERO registry (number CRD42023401105) and conducted according to the guidelines of the Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.

The results of our meta-analysis show that all pulmonary function tests were decreased in PLWH. This pulmonary function impairment in PLWH is also observed in nonsmokers and is independent of age, CD4 T-cells count and antiretroviral therapy.

To our knowledge, this is the first meta-analysis on pulmonary function in PLWH. A previously published meta-analysis has focused on prevalence of COPD in PLWH.9 It included 30 studies with 151,686 participants and the overall prevalence of COPD was higher in PLWH than in uninfected controls. Tobacco is a leading cause of lung damage. Worldwide, smoking prevalence among PLWH is higher than in HIV uninfected population.32 Peculiarly, in our meta-analysis, the impairment of pulmonary function remained when we included only those studies with nonsmoker patients.

It is widely known that PLWH have more pulmonary diseases and infections, including pneumonia and tuberculosis.8 The lung is a reservoir for HIV. DNA and RNA of HIV are present in alveolar macrophages in asymptomatic healthy PLWH with systemic viral suppression.33 Besides, there are structural abnormalities in the lung of PLWH that could explain the abnormal pulmonary function test results. Lymphocytic alveolitis, with infiltration of CD4+ and CD8+ T-cells, gamma-delta T-cells and B-cells, is present in untreated PLWH.34 Computed tomographic examinations have detected emphysema and fibrosis-like changes in PLWH that were significantly correlated with HIV viral load.35 Interestingly, one study has shown a telomere shorthening of small airway epithelial cells.36 Inflammation and accelerated immune aging are both proposed to contribute to lung impairment in PLWH.

A decrease in the FEV1/FVC ratio suggests that HIV may be a risk factor for airflow obstruction. This hypothesis is supported by the findings of a meta-analysis by Bigna et al., which found that the prevalence of COPD is higher in PLWH than in the general population.9 While a decrease in FEV1 indicates the presence of obstruction and a decrease in FVC indicates restriction, the simultaneous decline of both parameters could indicate an isolated restrictive pattern or a combined obstructive and restrictive pattern.27 The presence of emphysema and fibrosis observed on computed tomography or lymphocytic alveolitis in lung biopsies of PLWH could explain these alterations. Alveolitis and fibrosis-like changes observed in lungs of PLWH can induce interstitial and vascular abnormalities that compromise the gas exchange. This would manifest as a reduction in DLCO. It has been suggested that HIV-induced inflammation could damage the small airways.27 However, we did not find sufficient data on FEF25–75% to be included in this meta-analysis.

Various immune and biochemical mechanisms have been proposed to explain the pulmonary damage observed in PLWH.2,37 Alexandrova et al. propose that pulmonary immune dysregulation maintains a proinflammatory environment optimal for HIV reservoir persistence.2 Head et al., in a systematic review, described nine immune biomarkers with significant association with lung abnormality, including interleukin-6, tumor necrosis factor α, C-reactive protein, cathelicidin, soluble CD14, soluble CD163, interleukin-2 receptor α chain, endothelin-1, and CD4/CD8 ratio.37 These findings suggest that inflammation, innate immune system, monocyte activation, endothelial dysfunction and general immune health could play a role in HIV-related pulmonary impairment.

The functional impairment observed in PLWH for FEV1 and FVC appear modest but is approximately 180–190mL. Similar differences, 100–150mL, have been considered significant in clinical trials with bronchodilators agents in patients with COPD.38 Therefore, pulmonary function impairment in PLWH is relevant. Longitudinal studies have reported a reduction of DLCO over time, and recently, distinct longitudinal pulmonary function trajectories have been identified.39,40 However, we think that prospective longitudinal studies are still needed to elucidate the progression of pulmonary impairment in PLWH.

Heterogeneity is an important finding in our meta-analysis. There are several possible reasons for it. Firstly, there are differences in participants of studies. The mean age of individuals ranged from 12 to 56 years, the proportion of male included from 0 to 100%, the mean/median CD4 cell/μL count from 371 to 732 and 52–100% PLWH toke antiretroviral therapy. Even there are differences in ethnicity of patients included in various studies conducted in United States. Secondly, we cannot rule out the influence of diverseness in lung function measurement methodology, i.e. equipment and reference equations. Also, the effect estimates of absolute lung function values not stratified by sex and age need to be interpreted with caution. Finally, the funnel plots were asymmetric suggesting a possible publication bias. The existence of not published small studies is the most frequent cause of asymmetry in a funnel plot.

The lack of data on viremia and duration of HIV infection, and the scarce data about CD4 T-cells count and antiretroviral therapy are limitations of this study and the results of meta-regression should therefore be taken with caution and should be validated in future studies. In addition, surprisingly, we have not identified any study from Asian and south American countries.

However, our study has some strengths. We applied the recommended MOOSE guideline for meta-analysis of observational studies. The literature research was exhaustive and comprehensive without language restrictions. We performed a sensitivity analysis, and the pulmonary function test impairment in PLWH were maintained when we differentiated them by study publication year, when we excluded gray literature, and even when we excluded the study with the greatest weight, all of which reinforces the results of the meta-analysis.

In conclusion, HIV infection is associated with pulmonary function impairment. However, further studies from all geographical areas are needed to corroborate these findings, and it is recommendable to include the pulmonary function tests as an additional outcome in clinical trials of new drugs for HIV infection.

None.

The authors declare no conflict of interest