Dataset Information

Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.

ABSTRACT: BACKGROUND:By modulating immune function, vitamin D might increase innate immunity and inhibit the growth of initial bacterial invasion and protect against tuberculosis infection. OBJECTIVE:We examined the effect of vitamin D supplementation on tuberculin skin test (TST) conversion. DESIGN:A double-blind, placebo-controlled study was conducted in 120 Mongol schoolchildren. We estimated the prevalence of latent tuberculosis infection at baseline and examined the effect of vitamin D (800 IU/d) on serum concentrations of 25-hydroxyvitamin D [25(OH)D] and TST conversion. RESULTS:At baseline, the mean (±SD) 25(OH)D concentration was 7 ± 4 ng/mL, and all concentrations were <20 ng/mL. Vitamin D supplementation increased serum 25(OH)D by a mean of 12.7 ng/mL compared with placebo (P < 0.0001). At baseline, 16 children in the vitamin D group and 18 in the placebo group were TST positive (P = 0.7). Over 6 mo, TSTs converted to positive in 5 (11%) children receiving vitamin D compared with 11 (27%) receiving placebo (RR: 0.41; 95% CI: 0.16, 1.09; P = 0.06). Only one TST conversion occurred among those whose serum 25(OH)D concentration increased to >20 ng/mL, whereas 8 TST conversions occurred in those whose final 25(OH)D concentration remained <10 ng/mL (P = 0.05). The mean increase in stature was 2.9 ± 1.6 cm in the vitamin D group and 2.0 ± 1.7 cm in the placebo group (95% CI: 2.16, 2.81; P < 0.003). CONCLUSIONS:Vitamin D supplementation for 6 mo had significant favorable effects on serum 25(OH)D concentrations and on growth in stature. A trend was seen toward fewer TST conversions in the vitamin D group. This trial was registered at clinicaltrials.gov as NCT01244204.

SUBMITTER: Ganmaa D

PROVIDER: S-EPMC3396446 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.

Ganmaa Davaasambuu D Giovannucci Edward E Bloom Barry R BR Fawzi Wafaie W Burr Winthrop W Batbaatar Dulguun D Sumberzul Nyamjav N Holick Michael F MF Willett Walter C WC

The American journal of clinical nutrition 20120703 2

<h4>Background</h4>By modulating immune function, vitamin D might increase innate immunity and inhibit the growth of initial bacterial invasion and protect against tuberculosis infection.<h4>Objective</h4>We examined the effect of vitamin D supplementation on tuberculin skin test (TST) conversion.<h4>Design</h4>A double-blind, placebo-controlled study was conducted in 120 Mongol schoolchildren. We estimated the prevalence of latent tuberculosis infection at baseline and examined the effect of vi ...[more]

PMID: 22760564

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Project description:Heavy exposure to Mycobacterium tuberculosis, the etiologic agent of tuberculosis (TB) and among the top infectious killers worldwide, results in infection that is cleared, contained, or progresses to disease. Some heavily exposed tuberculosis contacts show no evidence of infection using the tuberculin skin test (TST) and interferon gamma release assay (IGRA); yet the mechanisms underlying this "resister" (RSTR) phenotype are unclear. To identify transcriptional responses that distinguish RSTR monocytes, we performed transcriptome sequencing (RNA-seq) on monocytes isolated from heavily exposed household contacts in Uganda and gold miners in South Africa after ex vivo M. tuberculosis infection. Gene set enrichment analysis (GSEA) revealed several gene pathways that were consistently enriched in response to M. tuberculosis among RSTR subjects compared to controls with positive TST/IGRA testing (latent TB infection [LTBI]) across Uganda and South Africa. The most significantly enriched gene set in which expression was increased in RSTR relative to LTBI M. tuberculosis-infected monocytes was the tumor necrosis factor alpha (TNF-α) signaling pathway whose core enrichment (leading edge) substantially overlapped across RSTR populations. These leading-edge genes included candidate resistance genes (ABCA1 and DUSP2) with significantly increased expression among Uganda RSTRs (false-discovery rate [FDR], <0.1). The distinct monocyte transcriptional response to M. tuberculosis among RSTR subjects, including increased expression of the TNF signaling pathway, highlights genes and inflammatory pathways that may mediate resistance to TST/IGRA conversion and provides therapeutic targets to enhance host restriction of M. tuberculosis intracellular infection. IMPORTANCE After heavy M. tuberculosis exposure, the events that determine why some individuals resist TST/IGRA conversion are poorly defined. Enrichment of the TNF signaling gene set among RSTR monocytes from multiple distinct cohorts suggests an important role for the monocyte TNF response in determining this alternative immune outcome. These TNF responses to M. tuberculosis among RSTRs may contribute to antimicrobial programs that result in early clearance or the priming of alternative (gamma interferon-independent) cellular responses.

Project description:BackgroundA high prevalence (50-80%) of Tuberculin Skin Test Positivity (TST+ >or=10 mm indurations) has been reported in TB endemic countries. This pool forms a huge reservoir for new incident TB cases. However, immune biomarkers associated with TST conversion are largely unknown. The objective of this study was to identify immune biomarkers associated with TST conversion after acute Mycobacterium tuberculosis (MTB) exposure.Methodology/principal findingsA 24 month longitudinal study was carried out in a recently MTB exposed cohort of household contacts (HC = 93; 75% TST+). Control group consisted of unexposed community controls (EC = 59; 46%TST+). Cytokine secretion was assessed in whole blood cultures in response to either mycobacterial culture filtrate (CF) antigens or mitogens (PHA or LPS) using Elisa methodology. Compared to the EC group, the HC group at recruitment (Kruskal-Wallis Test) showed significantly suppressed IFN gamma (p = 0.0001), raised IL-10 (p = 0.0005) and raised TNF alpha (p = 0.001) in response to CF irrespective of their TST status. Seventeen TST-HC, showed TST conversion when retested at 6 months. Post TST conversion (paired t tests) significant increases were observed for CF induced IFN gamma (p = 0.038), IL-10 (p = 0.001) and IL-6 (p = 0.006). Cytokine responses were also compared in the exposed HC group with either recent infection [(TST converters (N = 17)] or previous infection [TST+ HC (N = 54)] at 0, 6, 12 and 24 months using ANOVA on repeated measures. Significant differences between the exposed HC groups were noted only at 6 months. CF induced IFN gamma was higher in previously infected HC group (p = 0.038) while IL-10 was higher in recently infected HC group (p = 0.041). Mitogen induced cytokine secretion showed similar differences for different group.Conclusions/significanceOur results suggest that TST conversion is associated with early increases in IFN gamma and IL-10 responses and precedes latency by several months post exposure.

Dataset Information

Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.

Publications

Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial.

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