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Systemic Inflammation, Immune Activation and Impaired Lung Function Among People Living with HIV in Rural Uganda

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Systemic Inflammation, Immune Activation and Impaired Lung Function Among People Living with HIV in Rural Uganda HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author J Acquir Manuscript Author Immune Defic Manuscript Author Syndr. Author manuscript; available in PMC 2019 August 15. Published in final edited form as: J Acquir Immune Defic Syndr. 2018 August 15; 78(5): 543–548. doi:10.1097/QAI.0000000000001711. Systemic Inflammation, Immune Activation and Impaired Lung Function among People Living with HIV in Rural Uganda Crystal M. North1,2, Daniel Muyanja3, Bernard Kakuhikire3, Alexander C. Tsai1, Russell P. Tracy4, Peter W. Hunt5, Douglas S. Kwon1,6, David C. Christiani1,2, Samson Okello2,3,7, and Mark J. Siedner1,3 1Massachusetts General Hospital, Boston, MA 2Harvard. T. H. Chan School of Public Health, Boston, MA 3Mbarara University of Science and Technology, Mbarara, Uganda 4University of Vermont 5University of California, San Francisco 6Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 7University of Virginia Abstract Background—Although both chronic lung disease and HIV are inflammatory diseases common in sub-Saharan Africa, the relationship between systemic inflammation and lung function among people living with HIV (PLWH) in sub-Saharan Africa is not well described. Methods—We measured lung function (using spirometry) and serum high sensitivity C-reactive protein, IL-6, sCD14 and sCD163 in 125 PLWH on stable antiretroviral therapy and 109 age and sex-similar HIV-uninfected controls in rural Uganda. We modeled the relationship between lung function and systemic inflammation using linear regression, stratified by HIV serostatus, controlled for age, sex, height, tobacco and biomass exposure. Results—Half of subjects (46%, [107/234]) were women and the median age was 52 years (IQR 48–55). Most PLWH (92%, [115/125]) were virologically suppressed on first-line antiretroviral therapy. Median CD4 count was 472 cells/mm3. In multivariable linear regression models stratified by HIV serostatus, an interquartile range increase in IL-6 and sCD163 were each inversely associated with lung function (mL, 95% confidence interval) among PLWH (IL-6: FEV1 −18.1 (−29.1, −7.1), FVC −17.1 (−28.2, −5.9); sCD163: FVC −14.3 (−26.9, −1.7)). hsCRP (>3mg/L vs. <1mg/L) was inversely associated with lung function among both PLWH and HIV- uninfected controls (PLWH: FEV1 −39.3 (−61.7, −16.9), FVC −44.0 (−48.4, −6.4); HIV- uninfected: FEV1 −37.9 (−63.2, −12.6), FVC −58.0 (−88.4, −27.5)). sCD14 was not associated with lung function, and all interaction terms were insignificant. Corresponding Author: Crystal M. North, MD, Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, 55 Fruit Street, BUL-148, Boston, MA 02114, Phone: 617-726-8854, Fax: 617-724-6878, [email protected]. Presentation of Data: Presented at the 2018 Conference on Retroviruses and Opportunistic Infections; March 2018; Boston, MA AUTHOR CONTRIBUTIONS CMN conceived of the study design, conducted the data analysis and wrote the first draft of the manuscript. DCC and MJS provided methodological guidance. SO, MJS, BK and ACT led study procedures and data collection. RT and DSK led biomarker-related testing. All authors reviewed and critiqued the final manuscript. North et al. Page 2 Conclusions—Macrophage activation and systemic inflammation are associated with lower lung Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author function among PLWH on stable antiretroviral therapy in rural Uganda. Future work should focus on underlying mechanisms and public health implications. Keywords AIDS; Spirometry; Respiratory; Africa; Biomarker INRODUCTION People living with HIV (PLWH) are at increased risk for chronic obstructive pulmonary disease (COPD)1–3 through various poorly understood mechanisms including direct virus- related pulmonary toxicity, persistent systemic inflammation, and accelerated immune senescence. The lungs are an HIV reservoir, even among PLWH with undetectable viral loads.4,5 HIV-infected pulmonary macrophages, lymphocytes and airway epithelial cells cause lymphocytic alveolitis, cellular apoptosis and lung parenchymal damage,6–9 which are associated with pulmonary complications among PLWH.10 Although alveolar viral load and inflammation decrease with antiretroviral therapy (ART),11 the parenchymal damage may be irreversible. Concurrently, intestinal barrier dysfunction and microbial translation are associated with systemic inflammation and immune activation12 that persists despite ART, 13–15 although the causality of this relationship has not been fully elucidated. Lastly, accelerated immune senescence may result from continuous, low-grade immune activation due to repeated antigenic stimulation among PLWH.16 Indices of immune senescence, including markers of T cell activation and telomere shortening, are similarly associated with lung function abnormalities.17,18 Among patients with COPD, systemic inflammation is associated with disease severity, exacerbations and overall mortality.19,20 Biomarkers of macrophage activation and systemic inflammation have also been associated with impaired lung function and parenchymal abnormalities in U.S. and European HIV cohorts.17,21–23 However, these findings may not be applicable to sub-Saharan Africa, where PLWH present for HIV care at advanced disease stages 24 and air pollution rather than smoking is the major chronic lung disease risk factor25–28 To address this knowledge gap, we measured lung function, systemic inflammation (high sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6)) and macrophage activation (soluble CD14 (sCD14) and soluble CD163 (sCD163)) among a mixed cohort of older-age PLWH and population-based, HIV-uninfected controls in rural Uganda. We hypothesized that systemic inflammation and macrophage activation would be associated with lower lung function, the effect of which would be the greatest among PLWH. METHODS Participants were enrolled in the Uganda Non-Communicable Diseases and Aging Cohort (UGANDAC; NCT02445079), a mixed cohort of PLWH and population-based HIV- uninfected controls described in detail previously.29,30 In brief, a convenience sample of PLWH were recruited from the HIV outpatient clinic at the Mbarara Regional Referral J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2019 August 15. North et al. Page 3 Hospital who were at least 40 years of age and had been on antiretroviral therapy for at least Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author three years. HIV-uninfected controls were recruited from the complete population census of a cluster of 8 villages approximately 20 kilometers from the HIV clinic, were sex- and age- matched (by age quartile) to PLWH, and were confirmed to be HIV negative prior to study visits. We collected data on demographics, medical history, socioeconomic status (SES)31, tobacco exposure32 and respiratory symptoms.33 We measured serum concentrations of hsCRP by latex immunoturbidimetry (LabCorp, Burlington, NC) and plasma concentrations of IL-6 (MesoScale Discovery, Rockville, MD), sCD14 and sCD163 (R&D Systems, Minneapolis, MN) with ELISA according to manufacturer instructions at the Laboratory for Clinical Biochemistry Research at the University of Vermont. We defined HIV viral suppression as a viral load below the assay detection limit (plasma: <40 copies/uL; dried blood spot: <550 copies/uL; Roche Cobas® assay, Pleasanton, CA; assay limitations changed due to local clinical practice modification). Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were measured by trained research assistants using the EasyOne® Plus handheld spirometer (ndd Medical Technologies Inc., Andover MA) in accordance with American Thoracic Society (ATS) guidelines.34,35 Four puffs of albuterol (Ventolin, GlaxoSmithKline, Philadelphia, PA) were administered to participants with FEV1/FVC<0.7 and spirometry was repeated after 10 minutes. Spirometry was interpreted by two pulmonologists (CMN, DCC) using National Health and Nutrition Examination Survey III (NHANES III) prediction equations with African American correction factors,36 given their similarity to East African prediction 37 equations. COPD was defined as post-bronchodilator FEV1/FVC<0.7, and obstruction severity was defined using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria.38 Statistical Analysis Cohort characteristics were compared by HIV serostatus using parametric and non- parametric tests as indicated by covariate distributions. To evaluate for selection bias, demographics were compared between those who completed and those who declined spirometry, and between those with and without ATS-acceptable spirometry. Our primary outcome of interest was lung function (in mL), as measured by FEV1 and FVC. Secondary outcomes of interest included self-reported respiratory symptoms, defined as self- reported cough, phlegm production, wheezing or dyspnea. Our explanatory variables of interest were systemic inflammation and macrophage activation, which included blood levels of hsCRP, IL-6, sCD14 and sCD163. Serum biomarkers were log transformed and divided by the interquartile range (IQR) of the distribution,39 except for hsCRP, which was categorized according to clinical risk (<1 mg/L, 1–3 mg/L, or >3 mg/L) as previously described.40 We fit multivariable linear regression models to evaluate the relationship between our outcomes of interest and an IQR increase in IL-6, sCD14 or sCD163, and hsCRP risk category. Models were stratified by HIV serostatus and adjusted
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