In 2018, there were an estimated 37.9 million persons living with HIV (PLWH), of whom approximately 70% resided in sub-Saharan Africa (SSA).¹ The coverage of antiretroviral treatment (ART), resulting in viral suppression, has increased in the last decades.^2,3,4 Currently, ART coverage in adults with HIV in South Africa is 79%.¹ Consequently, the life expectancy of PLWH has increased, and HIV is becoming a chronic disease with an increased risk of age-related comorbidities.^2,3,4

One of the comorbid complications noted among ART-compliant HIV patients is reduced pulmonary function, including obstructive lung disease (OLD), which comprises asthma and chronic obstructive pulmonary disease (COPD).^5,6,7,8 While HIV was found to be independently associated with COPD, the relationship between HIV and asthma remains ambiguous.^5,9,10 The burden of these chronic diseases is high and increasing; a review by Drummond and Kirk indicates an OLD prevalence of 16% – 20% in PLWH.¹¹ The underlying biological mechanisms are not yet entirely understood. Direct virus-related pulmonary toxicity, persistent systemic inflammation, a modified antioxidant/oxidant balance resulting in oxidative stress, and expedited immune deterioration are among the complex mechanisms that may explain the increased risk of OLD.^12,13 Even in patients who achieve viral suppression on ART, these mechanisms may still continue, or the damage that occurred during uncontrolled HIV viraemia may be irreversible.^12,13

Symptoms of OLD include cough, wheezing, dyspnoea and mucus production.^{5,6,7,8,13,14} These symptoms are often reported to be worse in HIV-positive individuals as compared to HIV-negative individuals.^{5,6,7,8,13,14} Furthermore, OLD onset is commonly earlier in this population as opposed to the HIV-negative population.¹⁵ A recent study suggests potential higher mortality resulting from airflow obstruction in COPD patients living with HIV compared to those without HIV infection.³ Undetected OLD may result in more frequent and serious exacerbations.^16,17 Additionally, it increases the risk of comorbidities such as lower respiratory tract infections.^16,17

In general, the failure to diagnose OLD prevents timely treatment and impacts quality of life and mortality.^16,17 Obtaining reliable spirometry results requires adequate clinical resources and is time-consuming.¹⁸ Screening the vast number of HIV patients in SSA is impossible in often-overburdened healthcare systems. Hence, we aimed to identify the predictive factors for impaired lung function specific to the HIV-positive population in SSA, to allow the appropriate selection of HIV patients who would benefit most from screening for OLD by means of spirometry.

All participants were of black African descent and consisted of 98 ART-naïve participants, 85 participants on first-line ART and 189 participants on second-line ART (Table 1). Of the participants, 64 (17.2%) had impaired lung function. Of the 64 impaired lung function cases, 46 had an FEV1/FVC ratio below the 20th percentile, which included 13 COPD cases according to the GOLD and LLN 5th-percentile cut-offs and 10 cases who also met the GINA criteria for asthma. The remaining 18 cases were found solely to have asthma, as they did not have a reduced FEV1/FVC ratio below the 20th percentile and did not meet the criteria for COPD. There was no difference in age or sex between participants with or without impaired pulmonary function (P > 0.1 for both comparisons). Most impaired lung function was found in participants who were on second-line ART (62.5%). Dyspnoea was the most common symptom for both the patient group with normal lung function and those with impaired lung function (23.4% and 28.1%, respectively; P = 0.40). Other symptoms were relatively uncommon.

Following the linear regression analysis, three variables were identified as predictors of a lower FEV1/FVC ratio: age (β = –0.003, P < 0.01), male sex (β = –0.016, P = 0.03) and history of TB or pneumonia (β = –0.024, P < 0.01) (Table 2). The logistic regression analyses, after bootstrapping, included female sex and a history of TB or pneumonia as predictors of impaired lung function (odds ratio for female sex = 1.44, 95% confidence interval [CI] = 0.78–2.66; odds ratio for history of lung disease = 2.58, 95% CI = 1.47–4.52). Only a history of TB or of pneumonia remained a statistically significant predictor (P < 0.001) (Table 3). The logistic regression analyses resulted in the following diagnostic model: probability of impaired lung function = 1/(1 + exp (–2.24 + 0.37 × female sex + 1.01 × history of pneumonia or TB). The ROC curve is presented in Figure 1. After bootstrapping, the AUC was 0.64 (95% CI = 0.56–0.70), which indicates that the prediction rule is able to identify participants with impaired lung function at an acceptable level, although not very well. The Hosmer–Lemeshow test yielded a P-value of 0.97.

We have explored and internally validated, by means of bootstrapping, the predictors of impaired lung function in an HIV-positive population situated in urban SSA. Combining the results from the linear and logistic regressions suggested that a history of TB or pneumonia predicts impaired lung function in the current population. Male sex and increasing age were also associated with a decrease in lung function in the linear regression analyses.

Existing models of OLD focus on the added values of other diagnostic tools, such as different types of computed tomography and magnetic resonance imaging, or of capnography to enable an earlier or more reliable diagnosis.^38,39,40,41 Other models aim to predict the prognosis or exacerbations of OLD.^38,39,40,41 However, none of these models focused on the diagnostic value of easily collected predictors, and none of the models was developed in an HIV-positive, SSA population. Our diagnostic model has only modest capacity to distinguish between normal lung function and impaired lung function. Hence, as our model is the first to use readily available clinical data, it establishes the foundation for further development of a diagnostic model of OLD in the current population.

Our findings on individual predictors are in line with previous research that has been conducted in HIV-positive populations in diverse countries.^{9,28,29,30,31,42,43,44,45,46,47} Increasing age, a history of TB, and prior bacterial or Pneumocystis pneumonia have been associated with COPD, asthma and lower FEV1/FVC ratios in multiple studies.^{9,28,29,30,42,43,44,45,46,47} Most evidence has been generated by research conducted in high-income countries. Only a limited number of studies conducted in SSA have analysed the association between HIV and impaired lung function.^{9,29,48,49,50} The factors associated with impaired lung function in the SSA population were older age and a history of TB.^9,49,50 Sex, viral load, smoking status and ART duration have not been conclusively identified as impaired lung function predictors.^9,29,49,50 Furthermore, a systematic review by Finney et al. found that most of the studies conducted in SSA focus on the prevalence of impaired lung function rather than identifying the predictors.⁴⁸ Most studies aiming to identify the predictors had a limited sample size^9,29,49 or a low prevalence of impaired lung function,^29,50 so the robustness of the findings has to be confirmed in other research.

A vast body of research has established male sex as a risk factor for airflow obstruction.^{42,43,44,45,46,47} This association was confirmed through our linear regression analyses. However, a significant association between sex and impaired lung function was not found in the logistic regression. This is likely the result of limited statistical power in the dichotomous analysis. Another possible explanation is the inclusion of asthma cases in the impaired lung function outcome. Previous studies conducted in HIV-positive populations have found asthma patients to be more frequently female.^30,51 The asthma cases were not included in the linear regression, as these analyses focused on the FEV1/FVC ratio. Hence, the influence of male sex on the impaired lung function outcome may have been counterbalanced by the association between female sex and asthma.

Strikingly, smoking was not related to impaired lung function, while a vast body of previous research has established smoking as a strong predictor of and risk factor for OLD in PLWH.^{44,45,52,53,54} Nevertheless, two studies analysing HIV-infected populations have found similar results as those currently reported.^9,55 This may be explained by inconsistent smoking behaviour as a result of insufficient finances.^56,57 Furthermore, smoking behaviour is usually assessed through inhaled smoking, while in the current population, chewing tobacco and the use of snuff are common as well.^56,57 Hence, there may be unmeasured smoking behaviour that is not being taken into account. Furthermore, it has been suggested that the pathogenesis of OLD may be independent of smoking behaviour in the HIV-positive population, attributable to a state of chronic inflammation, but evidence is lacking.⁵⁸

The current study has not identified ART duration as a predictive factor of impaired lung function. Research has not reached a consensus regarding the effect of ART on OLD.^44,45 Some evidence has identified ART as an independent factor for airway obstruction in HIV patients.^44,45 The underlying biological mechanism may be related to immune reconstruction inflammatory syndrome or the initiation of pulmonary autoimmunity.⁵⁸ Other studies have found no significant effect of ART on OLD. Reasons for these conflicting findings may be related to the HIV stage and time of ART initiation, as well as differences in the study population.^30,59

This study has several strengths. Our model is based on comprehensive and detailed data from an HIV-positive population in an urban SSA setting and is the first to use readily available clinical data. Missing data were limited, and standardised methods of assessment were used to obtain the predictors and outcome data. Our study responds to the need for identifying the predictive factors for impaired lung function as called for in recent articles.^9,31,58 Limitations include that the current data set had too few COPD and asthma cases according to the GINA, GOLD and LLN criteria to develop a model for OLD. Hence, we used a FEV1/FVC ratio below the 20th percentile, which inherently leads to over-diagnosis of clinical OLD and results in limited generalisability. A larger data set with more clinical OLD cases would allow for verification of the identified predictors. The AUC indicates that the current model misses other important predictors that are necessary to improve the model performance. Assessment of smoking may have misrepresented current smoking behaviour, as no information on chewing tobacco was collected. Additionally, the study population was recruited from RCTs and might therefore not represent the general HIV-positive population in Johannesburg. However, we do not foresee bias in the current study, as RCT participation is attractive to the general population in Johannesburg because of the convenient logistics (no long queues) and the quality of medical services involved.

A history of TB or pneumonia predicted impaired lung function in the current population. Male sex and increasing age in years were associated with a decrease in lung function. The model does not yet allow adequate risk stratification to guide clinical management, but clinicians should be aware of possible impaired lung function in HIV-positive patients with a history of TB or pneumonia and consider early spirometry testing for this group. More research is needed to confirm the identified predictors and to add others in order to develop a model that is specific and sensitive enough to rule out or rule in OLD.