Skip to main content
Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

The association between HIV infection and pulmonary function in a rural African population

  • Meri R. J. Varkila ,

    Contributed equally to this work with: Meri R. J. Varkila, Alinda G. Vos

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review & editing

    Affiliation Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

  • Alinda G. Vos ,

    Contributed equally to this work with: Meri R. J. Varkila, Alinda G. Vos

    Roles Conceptualization, Formal analysis, Methodology, Project administration, Supervision, Validation, Writing – original draft, Writing – review & editing

    a.g.vos-8@umcutrecht.nl

    Affiliations Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands, Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands, Wits Reproductive Health and HIV Institute, Faculty of Health Sciences, University of the Witwatersrand Johannesburg, Johannesburg, South Africa

  • Roos E. Barth,

    Roles Supervision, Writing – review & editing

    Affiliation Department of Internal Medicine & Infectious Diseases, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

  • Hugo A. Tempelman,

    Roles Resources, Writing – review & editing

    Affiliation Ndlovu Care Group, Groblersdal, South Africa

  • Walter L. J. Devillé,

    Roles Project administration, Resources, Supervision, Writing – review & editing

    Affiliations Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands, Ndlovu Care Group, Groblersdal, South Africa

  • Roel A. Coutinho,

    Roles Supervision, Writing – review & editing

    Affiliation Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

  • Diederick E. Grobbee,

    Roles Supervision, Writing – review & editing

    Affiliations Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands, Julius Clinical Research, Academic Contract Research Organization, Zeist, the Netherlands

  • Kerstin Klipstein-Grobusch

    Roles Conceptualization, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing

    Affiliations Julius Global Health, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands, Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

Abstract

Objectives

HIV infection has been associated with an impaired lung function in high-income countries, but the association between HIV infection and pulmonary function in Sub-Saharan Africa remains unclear. This study aims to investigate the relation between HIV infection and pulmonary function in a rural African population.

Methods

A cross-sectional study was conducted among HIV-positive and HIV-negative adults in a rural area in South Africa, as part of the Ndlovu Cohort Study. A respiratory questionnaire and post-bronchodilator spirometry were performed. Multivariable regression analysis was used to investigate whether HIV was independently associated with a decrease in post-bronchodilator FEV1/FVC ratio considering age, sex, body mass index, respiratory risk factors and a history of a pulmonary infection (tuberculosis (TB) or a pneumonia). Possible mediation by a history of pulmonary infection was tested by removing this variable from the final model.

Results

Two hundred and one consecutive participants were enrolled in the study in 2016, 84 (41.8%) were HIV-positive (82.1% on ART). The median age was 38 (IQR 29–51) years. Following multivariable analysis HIV was not significantly associated to a decline in post-bronchodilator FEV1/FVC ratio (β -0.017, p 0.18). However, upon removal of a history of a pulmonary infection from the final model HIV was significantly related to post-bronchodilator FEV1/FVC ratio, β -0.026, p 0.03.

Conclusions

Pulmonary function is affected by HIV infection which most likely results from co-infection with TB or other pneumonia. Further research should focus on the influence of a pulmonary infection, most notably TB, on pulmonary function, especially as the incidence of TB is high in HIV infection.

Introduction

Human Immunodeficiency virus (HIV) infection remains a major health problem in Sub-Saharan Africa (SSA). With nearly one in every 20 adults (4.9%) living with HIV in this part of the world, HIV/AIDS is the most important cause of morbidity and mortality in SSA [1,2].

Due to increased access to combination antiretroviral therapy (ART) the face of the epidemic is changing. Life expectancy of patients receiving ART is improving and long-term co-morbidities associated with HIV infection are becoming more relevant. Pulmonary emphysema and obstructive lung disease (OLD) are examples of frequently observed co-morbidities in HIV infection [3]. This intercedes with the existing burden of pulmonary diseases, with lower respiratory tract infections and tuberculosis ranking in the top five causes of years of life lost on the African continent [2].

OLD is more common in HIV-positive than in HIV-negative individuals, and HIV infection is independently associated with a decrease in lung function and diffusion capacity [410]. What role ART plays in the development of OLD is an unresolved issue. ART tapers inflammation, possibly reducing immunological damage on alveolar level, but a direct negative effect of ART on pulmonary function was also reported [4,11,12]. However, most data regarding OLD in HIV comes from high-income countries (HIC). Due to marked differences between the settings, such as sex distribution among HIV patients and occupational and environmental risk factors, these data cannot simply be applied to low- and middle-income countries (LMIC). [13,14]

Research into prevalence and pathogenesis of OLD in HIV in SSA is needed to guide medical management of HIV patients in low-resource settings and to reduce the burden of chronic pulmonary disease. This study sets out to investigate the relation between HIV infection and pulmonary function in a rural African population comparing HIV-positive and HIV-negative participants while taking pulmonary co-infection into account.

Methods

Study design and study population

Data was collected in a cross-sectional study, embedded in the Ndlovu Cohort Study (NCS). The NCS is a prospective study including approximately 2000 participants in rural South Africa (Limpopo province). The main aim is to investigate the epidemiology and pathogenesis of cardiovascular disease in the context of HIV infection. [15] Inclusion criteria for the NCS were age (≥18 years) and living in the proximity of the research site. All participants coming for a NCS baseline or follow-up visit in April and May 2016 were considered eligible for participation in this cross-sectional study. Exclusion criteria were myocardial infarction in the last month, surgery in the past six weeks, hypersensitivity to salbutamol or inability to undergo the procedure for any reason. The study was approved by the Human Ethics Research Committee of the University of Pretoria (Reference number 76/2016) and written informed consent was obtained from all subjects prior to study participation. The study was reported according to the STROBE guideline (S1 Appendix).

Baseline data collection

Socio-demographic, lifestyle and anthropometric data, HIV-status and most recent laboratory results (CD4 count and HIV viral load) were collected from the NCS database. Data collection followed standardised procedures as previously described [15]. Additional data on a history of tuberculosis (TB), a history of a pneumonia, smoking, occupational and environmental exposure was collected using an adapted respiratory questionnaire (S2 Appendix) based on The British Medical Research Council Respiratory Questionnaire [16], World Health Survey [17], ATS-DLD-78-A [18], MRC breathlessness scale [19], and questions used in other publications [2022].

Spirometric measurements

Spirometry testing with pre- and post-bronchodilator measurements was performed using a hand-held CareFusion 2009 spirometer and Spida 5 software. Procedures and review of acceptability and repeatability were performed according to American Thoracic Society and European Respiratory Society guidelines [23]. At least three acceptable and repeatable blows were required where the subject performed the manoeuvre with a maximum inspiration, a good start, a smooth continuous exhalation, and maximal effort. In addition, the largest and second-largest values for both forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) had to be within 150 mL of each other. In cases where acceptability and repeatability could not be achieved within three blows, the manoeuvre was repeated up to a maximum of eight times. After the initial measurements, a short-acting bronchodilator (salbutamol 100 μg, 4 doses) was administered using a spacer. Post-bronchodilator spirometry was repeated after a 15-minute waiting time using the same procedure as before. The respiratory parameters measured were: FEV1, FVC and FEV1/FVC ratio. The largest values for post-FEV1 and post-FVC were considered for analysis.

According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) OLD was defined as a FEV1/FVC-ratio below 0.70, post-bronchodilation [24]. As this definition can lead to underestimation of airflow limitation in young people and overestimation in older people, we chose to use a lower limit of normal (LLN) definition [25]. This was defined as a FEV1/FVC-ratio below the 5th percentile of the predicted value. The Global Lung Initiative equation category “Afro-American” was used to define normal values [26]. Reversibility was defined as a post-bronchodilator increase in FEV1 of more than 12% and over 200 ml [27].

Spirometry tests that did not meet acceptability and repeatability criteria, and thus could not be evaluated for the presence of obstruction, were excluded from further analysis (n = 6).

Statistical analysis

Continuous descriptive data was presented as means and standard deviations (SD) for normally distributed data and as medians and interquartile ranges (IQR) for non-normally distributed data. Categorical descriptive data was presented as frequencies and percentages. Selection bias was evaluated by comparing demographics of those who were enrolled in this sub-study to the demographics of the total NCS. The comparison included age, sex, HIV status, education level, marital status and body mass index (BMI). We used a t-test for continuous outcomes and a Chi square test for dichotomous outcomes.

Post-bronchodilator FEV1 and FVC outcomes, post-bronchodilation FEV1/FVC-ratio and the prevalence of OLD were compared between HIV-positive and HIV-negative individuals.

The association of HIV and FEV1/FVC ratio was assessed using the fixed post- bronchodilator FEV1/FVC ratio. We decided not to use the percentage of predicted FEV1/FVC generated by the GLI equation category “Afro-American”, as it is not certain if these values reflect the normal distribution in a Black African population. The relation between HIV and post-bronchodilator FEV1/FVC ratio was tested in a linear regression analysis. The following baseline variables were considered as confounders and tested in univariable analysis: age, gender, BMI, education, employment, current or ever smoking cigarettes or cigars, current smoking of marijuana, indoor smoking in childhood, a history of TB or pneumonia, use of wood fire outdoors and occupational exposure (mining work, having worked in a dusty job for more than a year or having working with chemicals and fumes for more than one year). All variables with p-value <0.2 in univariable analysis as well as age, sex and BMI (regardless of the p-value) were entered in a multivariable analysis. Second, we assessed mediation by a history of tuberculosis (TB) on the relation between HIV and post-bronchodilator FEV1/FVC ratio by removing TB from the final model. Analysis was performed using SPSS software (IBM Corp. Released 2016. IBM SPSS Statistics for Windows, Version 24.0. Armonk, NY: IBM Corp.).

Results

Two hundred and one participants (50% men) were enrolled in the study, 84 (42%) of whom were HIV-positive (Fig 1, Table 1). The age of participants in this sub-study was the only demographic factor that differed compared to the demographics of the participants in the NCS (the age in this sub-study was on average 2 years higher than the age in the NCS, p = 0.03) (S1 Table). The proportion of men was higher in the HIV-negative group (65%) as compared to the HIV-positive group (30%). HIV-positive participants were slightly older than HIV-negative participants.

Differences in socioeconomic, environmental, and occupational factors between the HIV-positive group and HIV-negative controls were minor. Current smoking was reported by 61 participants; 46 (75%) were HIV negative. Almost all smokers were males (n = 57, 93%). Occupational exposure was generally low and did not differ by HIV status. There were marked differences between men and women: 19% of all men reported having worked in a mine versus 1% of women, 32% of men had worked in a dusty job for more than one year versus 6% of women and 13% of men had worked in a job with exposure to chemical fumes or gases for more than one year compared to 1% of women. A history of pulmonary tuberculosis or pneumonia was reported significantly more often by HIV-positive than by HIV-negative participants (Table 1).

Acceptable spirometry test results could be obtained in 195 (97%) participants. Post-FEV1 and -FEV1/FVC values were significantly lower in the HIV-positive group than the HIV-negative group (Table 2). The prevalence of OLD, according to the LLN, was 10% (n = 8) in HIV-positive participants and 3% (n = 3) in HIV-negative participants (p = 0.06).

HIV was independently associated with a decrease in post- bronchodilator FEV1/FVC ratio following univariable regression analysis, β -0.028, p = 0.03.

Following multivariable regression analysis HIV was not related to post-bronchodilator FEV1/FVC ratio anymore (Table 3). However, when a history of TB or pneumonia was removed from the model the relation between HIV and post-bronchodilator FEV1/FVC ratio became significant again, indicating that the relation between HIV and post-bronchodilator FEV1/FVC ratio was mediated by TB (Table 3).The small number of HIV-positive participants not on ART (n = 15) did not allow us to evaluate the effect of ART on the post- bronchodilator FEV1/FVC ratio.

thumbnail
Table 3. Uni- and multivariable analysis and mediation analysis.

https://doi.org/10.1371/journal.pone.0210573.t003

Discussion

In this African cohort the prevalence of OLD was 10% in HIV-positive participants compared to 3% in the HIV-negative group. HIV infection was not related to the post- bronchodilator FEV1/FVC ratio in multivariable analysis. However, when a history of a pulmonary infection was removed from the final model HIV became significantly associated with a decline in post-bronchodilator FEV1/FVC ratio. This indicates that a history of a pulmonary infection mediates the relation between HIV infection and a decline in pulmonary function.

Our results on the prevalence of OLD are roughly in line with the estimated worldwide prevalence of OLD of 11% [28] and 10.5% in people living with HIV [29]. Studies conducted amongst general populations in African countries reported a prevalence ranging from 4.1% to 24.8% [30], and 6.0% to 22.2% in HIV-positive populations[29,3133]. Although not statistically significant in our cohort, the higher prevalence of OLD in HIV-positive participants is also in line with data from both HIC and LMIC. [5,6,9, 31]

Two recent studies conducted in HIV-positive cohorts found that immune defects as measured by a lower CD4 T cell count may be associated with a decline in FEV1 and FVC [34] and COPD [35]. In a large, international randomized controlled trial, the timing of ART initiation had no effect on rate of lung function decline in ART-naïve individuals with CD4 T cell counts of more than 500 per μL [36]. These findings support the newly updated WHO recommendations that all patients should be treated with ART regardless of their CD4 T cell counts [37]. Data from SSA countries regarding the role of immunomodulation and HIV and the effect of ART on OLD still remains limited.

In TB-endemic regions, such as SSA, the epidemiology of HIV infection and TB tend to be highly intertwined. Up to 65% of South Africans with TB also tested positive for HIV [38], and vice versa, globally approximately 30% of HIV-positive persons are estimated to have (usually latent) M. tuberculosis infection [39]. The risk of active TB doubles within the first year of HIV infection [40] and the life-time risk of active TB for HIV/TB co-infected persons in Africa has been estimated to be around 30–40% [41]. These figures highlight the relationship between HIV infection and pulmonary coinfection in SSA, yet few studies have taken the possible contribution of TB/pneumonia into account when looking at HIV and changes in lung function. Recent work investigating HIV infection, TB and COPD in a Ugandan cohort found a higher prevalence of COPD in HIV-positive individuals with a prior history of TB [33]. These findings are in agreement with our results and suggest decreased lung function in HIV infection in a SSA setting could be attributed to pulmonary co-infection rather than HIV infection.

Whereas associations between prior history of pneumonia and OLD have been established [4244], the pathophysiological mechanisms behind airflow obstruction as a result of pulmonary infection are still incompletely understood. Postulated pathways include the development of bronchiectasis and bronchial stenosis due to aberrant lung tissue remodelling after inflammatory injury [44], as well as chronic inflammation caused by dysregulated macrophages [45]. The pathophysiological interactions of chronic inflammation in HIV infection and lung injury caused by pulmonary infections present interesting topics for future research.

Our analysis also showed that age was robustly associated with a decline in post-bronchodilator FEV1/FVC ratio. This was to be expected as pulmonary function decreases with age [4649]. We also noted that the widely studied OLD-risk factor smoking was not associated with a decline in the post-FEV1/FVC ratio following multivariable analysis (either passive smoking in childhood, or former and current smoking versus never smoking). This may be due to the sample size, as well as different smoking habits between high income settings and low income settings [50, 51]. In our study smoking habits were often described as irregular and highly dependent on fluctuations in participants’ finances (average consumption of 7 cigarettes per day).

Some limitations of our study need to be mentioned. First, as a result of the small sample size we could not investigate the clinically relevant outcome OLD. However, we do not expect that HIV would be associated with OLD, as we found no relation with post-bronchodilator FEV1/FVC when a history of a pulmonary infection was considered. Due to the relatively low number of study participants we were also unable to explore the role of other HIV-related factors, such as ART, CD4 T cell counts and viral loads. Second, as our data collection was constrained to one time-point, studying changes in lung function in HIV infection was beyond the scope of this study. Third, the cross-sectional design limits causal inference. Fourth, participants in this analysis were slightly older than participants in the NCS. However, the other demographic factors did not differ, so it is unlikely that this sub-study is subjected to selection bias. The older age is also unlikely to influence the generalizability of our findings to all cohort participants as there is no reason to assume that the influence of HIV on pulmonary function would change with a small increase in age. Finally, for some of the data we relied on self-reporting, which may have subjected some of our measured parameters to recall or reporting bias.

Strengths to be mentioned are the comparison between HIV-positive and HIV-negative individuals, the rural setting and the extensive evaluation of pulmonary risk factors like smoking in childhood and occupational exposure. As a result, our study contributes to the current understanding on the influence of HIV on post-bronchodilator FEV1/FVC ratio and it highlights the influence of a history of a pulmonary infection on pulmonary function in a rural SSA setting

In conclusion, HIV infection is associated with a decline in pulmonary function measured with post-bronchodilator FEV1/FVC ratio, but this effect seems to be mediated by a history of a pulmonary infection, notably TB. TB is still highly prevalent, especially in the HIV-positive population and may pose a significant burden of pulmonary disease in these patients. We would therefore recommend to investigate the influence of TB on pulmonary function, considering HIV infection, in a larger cohort using the clinically more relevant outcome ‘OLD’. In the meantime, the regular contact of HIV-positive participants with the health care system should be used to direct clinical care towards prevention and early treatment of TB infections.

Supporting information

S1 Table. Comparison of demographics between the current study and the total cohort Ndlovu Cohort Study).

https://doi.org/10.1371/journal.pone.0210573.s003

(DOCX)

Acknowledgments

We would like to acknowledge P. Zanen, lung physiologist in the UMC Utrecht, The Netherlands, for a quality check of the spirometries and the Ndlovu Research Consortium (South Africa and The Netherlands) for hosting this project.

References

  1. 1. Joint United Nations Program on HIV/AIDS (UNAIDS) (2012). Global Report: UNAIDS report on the global AIDS epidemic, 2012. Geneva: UNAIDS. Available from: http://www.unaids.org/sites/default/files/media_asset/20121120_UNAIDS_Global_Report_2012_with_annexes_en_1.pdf.
  2. 2. GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017; 390(10100):1151–1210. pmid:28919116
  3. 3. Deeks SG, Lewin SR, Havlir DV. The End of AIDS: HIV infection as a chronic disease. Lancet. 2013; 382(9903):1525–33. pmid:24152939
  4. 4. Diaz PT, Wewers MD, Pacht E, Drake J, Nagaraja HN, Clanton TL. Respiratory symptoms among HIV-seropositive individuals. Chest. 2003; 123(6):1977–82. pmid:12796177
  5. 5. Crothers K, Butt AA, Gibert CL, Rodriguez- Barradas MC, Crystal S, Justice AC. Increased COPD among HIV-positive compared to HIV-negative veterans. Chest. 2006; 130(5):1326–33. pmid:17099007
  6. 6. Crothers K, Huang L, Goulet JL, Goetz MB, Brown ST, Rodriguez-Barradas MC, et al. HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era. Am J Respir Crit Care Med. 2011; 183(3):388–95. pmid:20851926
  7. 7. Petrache I, Diab K, Knox KS, Twigg HL 3rd, Stephens RS, Flores S, et al. HIV associated pulmonary emphysema: a review of the literature and inquiry into its mechanism. Thorax. 2008; 63(5):463–9. pmid:18443163
  8. 8. Kristoffersen US, Lebech AM, Mortensen J, Gerstoft J, Gutte H, Kjaer A. Changes in lung function of HIV-infected patients: a 4.5-year follow-up study. Clin Physiol Funct Imaging. 2012; 32(4):288–95. pmid:22681606
  9. 9. Drummond MB, Kirk GD, Astemborski J, Marshall MM, Mehta SH, McDyer JF, et al. Association between obstructive lung disease and markers of HIV infection in a high-risk cohort. Thorax. 2012; 67(4):309–14. pmid:22090038
  10. 10. Drummond MB, Huang L, Diaz PT, Kirk GD, Kleerup EC, Morris A, et al. Factors associated with abnormal spirometry among HIV-infected individuals. AIDS. 2015; 29(13):1691–700. pmid:26372280
  11. 11. Twigg HL, Knoz KS. HIV-related lung disorders. Drug Discov Today Dis Mech. 2007; 4(2): 95–101. pmid:18709181
  12. 12. George MP, Kannass M, Huang L, Sciurba FC, Morris A. Respiratory symptoms and airway obstruction in HIV-infected subjects in the HAART era. PLoS One. 2009; 4(7):e6328. pmid:19621086
  13. 13. UNAIDS: The Gap Report. Geneva 2014. Available at: http://www.unaids.org/en/resources/documents/2014/20140716_UNAIDS_gap_report.
  14. 14. Institute for Health Metrics and Evaluation, Human Development Network, The World Bank. The Global Burden of Disease: Generating evidence, guiding policy—Sub-Saharan Africa Regional Edition. Seattle, WA: IHME, 2013.
  15. 15. Vos AG, Tempelman H, Devillé W, Barth R, Wensing A, Kretzschmar M, et al. HIV and risk of cardiovascular disease in Sub-Saharan Africa: Rationale and design of the Ndlovu Cohort Study. Eur J Prev Cardiol. 2017; 24(10):1043–1050. pmid:28379043
  16. 16. Cotes JE. Medical Research Council Questionnaire on respiratory symptoms. Lancet. 1987; 2:1028
  17. 17. World Health Organization, Evidence and Information for Policy. World Health Survey 2002. B–Individual Questionnaire, Rotation A. Available from: http://www.who.int/healthinfo/survey/whslongindividuala.pdf
  18. 18. Ferris B. Epidemiology standardization project (American Thoracic Society). Am Rev Respir Dis. 1978 Dec; 118:1–120.
  19. 19. Stenton C. The MRC breathlessness scale. Occup Med (Lond). 2008; 58(3):226–7.
  20. 20. Mengersen K, Morawska L, Wang H, Murphy N, Tayphasavanh F, Darasavong K, et al. The effect of housing characteristics and occupant activities on the respiratory health of women and children in Lao PDR. Sci Total Environ. 2011; 409(8):1378–84. pmid:21300397
  21. 21. Isara AR, Aigbokhaode AQ. Household cooking fuel use among residents of a sub-urban community in Nigeria: Implications for indoor air pollution. Eurasian J Med. 2014; 46(3):203–8 pmid:25610326
  22. 22. Van Gemert F, Kirenga B, Chavannes N, Kamya M, Luzige S, Musinguzi P, et al. Prevalence of chronic obstructive pulmonary disease and associated risk factors in Uganda (FRESH AIR Uganda): a prospective cross-sectional observational study. Lancet Glob Health. 2015; 3(1):e44–51 pmid:25539969
  23. 23. Miller MR, Hankinson J, Brusasco V et al. ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005; 26(2):319–38. pmid:16055882
  24. 24. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2016. Available from: http://goldcopd.org/.
  25. 25. Bakke PS, Ronmark E, Eagan T, Pistelli F, Annesi-Maesano I, Maly M, et al. Recommendations for epidemiological studies on COPD. Eur Respir J. 2011; 38(6):1261–77 pmid:22130763
  26. 26. Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al, and the ERS Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3–95 year age range: the global lung function 2012 equations. Eur Respir J. 2012; 40(6):1324–43. pmid:22743675
  27. 27. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J. 2005; 26(5):948–68. pmid:16264058
  28. 28. Adeloye D, Chua S, Lee C, Basquill C, Papana A, Theodoratou E, et al. Global Health Epidemiology Reference Group (GHERG). Global and regional estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health. 2015; 5(2):020415 pmid:26755942
  29. 29. Bigna JJ, Kenne AM, Asangbeh SL, Sibetcheu AT. Prevalence of chronic obstructive pulmonary disease in the global population with HIV: a systematic review and meta-analysis. Lancet Glob Health. 2018;6(2):e193–e202. pmid:29254748
  30. 30. Finney LJ, Feary JR, Leonardi-Bee J, Gordon SB, Mortimer K. Chronic obstructive pulmonary disease in sub-Saharan Africa: a systematic review. Int J Tuberc Lung Dis. 2013; 17(5):583–9. pmid:23394105
  31. 31. Akanbi MO, Taiwo BO, Achenbach CJ, Ozoh OB, Obaseki DO, Sule H, et al. HIV-associated chronic obstructive pulmonary disease in Nigeria. J AIDS Clin Res. 2015; 6(5).
  32. 32. Pefura-Yone EW, Fodjeu G, Kengne AP, Roche N, Kuaban C. Prevalence and determinants of chronic obstructive pulmonary disease in HIV infected patients in an African country with low level of tobacco smoking. Respir Med. 2015; 109(2):247–54. pmid:25538018
  33. 33. North CM, Allen JG, Okello S, Sentongo R, Kakuhikire B, Ryan ET, et al. HIV Infection, Pulmonary Tuberculosis, and COPD in Rural Uganda: A Cross-Sectional Study. Lung. 2018;196(1):49–57. pmid:29260309
  34. 34. Risso K, Guillouet-de-Salvador F, Valerio L, Puglièse P, Naqvi A, Durant J, et al. COPD in HIV-Infected Patients: CD4 Cell Count Highly Correlated. PLoS One. 2017;12(1):e0169359. pmid:28056048
  35. 35. Ronit A, Lundgren J, Afzal S, Benfield T, Roen A, Mocroft A, et al. Airflow limitation in people living with HIV and matched uninfected controls.Thorax. 2018;73(5):431–438. pmid:29331988
  36. 36. Kunisaki KM, Niewoehner DE, Collins G, Aagaard B, Atako NB, Bakowska E et al. Pulmonary effects of immediate versus deferred antiretroviral therapy in HIV-positive individuals: a nested substudy within the multicentre, international, randomised, controlled Strategic Timing of Antiretroviral Treatment (START) trial. Lancet Respir Med. 2016;4(12):980–989. pmid:27773665
  37. 37. WHO. Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Geneva, Switzerland: World Health Organization, 2015.
  38. 38. Mayosi BM, Lawn JE, van Niekerk A, Bradshaw D, Abdool Karim SS, Coovadia HM; Lancet South Africa team. Health in South Africa: changes and challenges since 2009. Lancet. 2012;380(9858):2029–43. pmid:23201214
  39. 39. Getahun H, Gunneberg C, Granich R, Nunn P. HIV infection-associated tuberculosis: the epidemiology and the response. Clin Infect Dis. 2010;50 Suppl 3:S201–7.
  40. 40. Sonnenberg P, Glynn JR, Fielding K, Murray J, Godfrey-Faussett P, Shearer S. How soon after infection with HIV does the risk of tuberculosis start to increase? A retrospective cohort study in South African gold miners. J Infect Dis. 2005;191(2):150–8. pmid:15609223
  41. 41. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003;163(9):1009–21. pmid:12742798
  42. 42. Amaral AF, Coton S, Kato B, Tan WC, Studnicka M, Janson C et al. Tuberculosis associates with both airflow obstruction and low lung function: BOLD results. Eur Respir J. 2015;46(4):1104–12. pmid:26113680
  43. 43. Hayden LP, Hobbs BD, Cohen RT, Wise RA, Checkley W, Crapo JD, et al. Childhood pneumonia increases risk for chronic obstructive pulmonary disease: the COPDGene study. Respir Res. 2015; 16(1):115.
  44. 44. Gautam SS, O’Toole RF. Convergence in the Epidemiology and Pathogenesis of COPD and Pneumonia. COPD. 2016;13(6):790–798. pmid:27310416
  45. 45. Chakrabarti B, Calverley PM, Davies PD. Tuberculosis and its incidence, special nature, and relationship with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2007;2(3):263–72. pmid:18229564
  46. 46. Lalley PM. The aging respiratory system—pulmonary structure, function and neural control. Respir Physiol Neurobiol. 2013;187(3):199–210. pmid:23570957
  47. 47. Janssens JP. Aging of the respiratory system: impact on pulmonary function tests and adaptation to exertion. Clin Chest Med. 2005;26(3):469–84, vi-vii. pmid:16140139
  48. 48. Brändli O, Schindler C, Künzli N, Keller R, Perruchoud AP. Lung function in healthy never smoking adults: reference values and lower limits of normal of a Swiss population. Thorax. 1996;51(3):277–83. pmid:8779131
  49. 49. Dockery DW, Ware JH, Ferris BG Jr, Glicksberg DS, Fay ME, Spiro A 3rd, Speizer FE. Distribution of forced expiratory volume in one second and forced vital capacity in healthy, white, adult never-smokers in six U.S. cities. Am Rev Respir Dis. 1985;131(4):511–20. pmid:3873193
  50. 50. Pampel F. Tobacco use in sub-Sahara Africa: estimates from the demographic health surveys. Soc Sci Med. 2008;66(8):1772–83. pmid:18249479
  51. 51. Sreeramareddy CT, Harper S, Ernstsen L. Educational and wealth inequalities in tobacco use among men and women in 54 low-income and middle-income countries. Tob Control. 2018; 27(1):26–34 pmid:27885168