Research Article: Vitamin D status and risk of incident tuberculosis disease: A nested case-control study, systematic review, and individual-participant data meta-analysis

Date Published: September 11, 2019

Publisher: Public Library of Science

Author(s): Omowunmi Aibana, Chuan-Chin Huang, Said Aboud, Alberto Arnedo-Pena, Mercedes C. Becerra, Juan Bautista Bellido-Blasco, Ramesh Bhosale, Roger Calderon, Silvia Chiang, Carmen Contreras, Ganmaa Davaasambuu, Wafaie W. Fawzi, Molly F. Franke, Jerome T. Galea, Daniel Garcia-Ferrer, Maria Gil-Fortuño, Barbará Gomila-Sard, Amita Gupta, Nikhil Gupte, Rabia Hussain, Jesus Iborra-Millet, Najeeha T. Iqbal, Jose Vicente Juan-Cerdán, Aarti Kinikar, Leonid Lecca, Vidya Mave, Noemi Meseguer-Ferrer, Grace Montepiedra, Ferdinand M. Mugusi, Olumuyiwa A. Owolabi, Julie Parsonnet, Freddy Roach-Poblete, Maria Angeles Romeu-García, Stephen A. Spector, Christopher R. Sudfeld, Mark W. Tenforde, Toyin O. Togun, Rosa Yataco, Zibiao Zhang, Megan B. Murray, Paul Garner

Abstract: BackgroundFew studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk.Methods and findingsWe assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected four controls from among contacts who did not develop TB disease, matching on gender and year of age. We also conducted a one-stage individual-participant data (IPD) meta-analysis searching PubMed and Embase to identify prospective studies of vitamin D and TB disease until June 8, 2019. We included studies that assessed vitamin D before TB diagnosis. In the primary analysis, we defined vitamin D deficiency as 25–(OH)D < 50 nmol/L, insufficiency as 50–75 nmol/L, and sufficiency as >75nmol/L. We estimated the association between baseline vitamin D status and incident TB using conditional logistic regression in the Lima cohort and generalized linear mixed models in the meta-analysis. We further defined severe vitamin D deficiency as 25–(OH)D < 25 nmol/L and performed stratified analyses by HIV status in the IPD meta-analysis. In the Lima cohort, we analyzed 180 cases and 709 matched controls. The adjusted odds ratio (aOR) for TB risk among participants with baseline vitamin D deficiency compared to sufficient vitamin D was 1.63 (95% CI 0.75–3.52; p = 0.22). We included seven published studies in the meta-analysis and analyzed 3,544 participants. In the pooled analysis, the aOR was 1.48 (95% CI 1.04–2.10; p = 0.03). The aOR for severe vitamin D deficiency was 2.05 (95% CI 0.87–4.87; p trend for decreasing 25–(OH)D levels from sufficient vitamin D to severe deficiency = 0.02). Among 1,576 HIV-positive patients, vitamin D deficiency conferred a 2-fold (aOR 2.18, 95% CI 1.22–3.90; p = 0.01) increased risk of TB, and the aOR for severe vitamin D deficiency compared to sufficient vitamin D was 4.28 (95% CI 0.85–21.45; p = 0.08). Our Lima cohort study is limited by the short duration of follow-up, and the IPD meta-analysis is limited by the number of possible confounding covariates available across all studies.ConclusionOur findings suggest vitamin D predicts TB disease risk in a dose-dependent manner and that the risk of TB disease is highest among HIV-positive individuals with severe vitamin D deficiency. Randomized control trials are needed to evaluate the possible role of vitamin D supplementation on reducing TB disease risk.

Partial Text: The global burden of tuberculosis (TB) remains high, with approximately one-fourth to one-third of the world’s population infected with Mycobacterium tuberculosis (MTB), and the World Health Organization (WHO) estimates 10 million people developed TB disease in 2017 [1]. Concurrently, vitamin D deficiency (VDD) is a widespread problem globally, with a high degree of geographic variability; reported adult prevalence of VDD ranges from 10% in North America to >80% in parts of Asia [2,3]. Vitamin D is an important regulator of the immune system [4], and in vitro studies have elucidated multiple mechanisms by which vitamin D influences the pathogenesis of TB infection or disease [5–8]. At the level of the macrophage, vitamin D is involved in cathelicidin- and interferon gamma (IFN-γ)-mediated activity against mycobacteria, [5,6], induction of oxidative species [7], and the promotion of phagolysosome fusion, which leads to degradation of mycobacteria [8]. Discoveries about the various ways vitamin D modulates specific host immune responses to TB infection have focused attention on the possibility that low vitamin D levels may contribute to TB disease progression.

Our IPD meta-analysis provides consistent support for a modest dose-dependent effect of vitamin D on future progression of TB disease across multiple studies conducted in diverse contexts. In the IPD, the association of low serum 25–(OH)D levels with increased TB disease risk was most pronounced among HIV-positive individuals with severe VDD.



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