#VisualAbstract: Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease

1. After 3 years of weekly vitamin D supplementation, the proportion of children who tested positive on interferon-gamma release assays was similar to that of the placebo group

2. No between-group differences were detected in the incidences of tuberculosis disease or acute respiratory infection during this period.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Although tuberculosis disease usually arises in adulthood, asymptomatic latent infection often takes root in childhood, and the treatment of active disease alone is insufficient to achieve prompt global tuberculosis control as called for by the World Health Organization. As such, it is important to identify strategies to reduce the number of youths who acquire latent infection. Vitamin D deficiency has been found to be associated with susceptibility to tuberculosis infection; conversely, single-dose supplementation appears to improve immunity to mycobacteria. This phase 3 trial was designed to assess the effects of long-term vitamin D supplementation on the risk of both tuberculosis infection and tuberculosis disease. Nearly 9000 children participated in the study, and the percentage who experienced a conversion to a positive QuantiFERON-TB test (QFT) result at the 3-year follow-up was similar between groups. Additionally, tuberculosis disease and acute respiratory infection were diagnosed at similar rates in both groups throughout the study. No adverse events related to the treatment regimen were noted. These findings contrasted with those of previous studies involving the same population, suggesting that the apparent inconsistencies may have been due to differences in dosage or duration. One limitation of this study was the use of the relatively low threshold for conversion recommended by the manufacturer of the assay kit. In post hoc analysis, application of a more conservative threshold suggested a potential effect in those with especially low serum 25-hydroxyvitamin D, or 25(OH)D.

Click here to read the study, published today in NEJM

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

In-Depth [randomized controlled trial]: In this double-blind, placebo-controlled trial that began in September 2015, 8851 children between the ages of 6 and 13 years with negative QFT results were stratified by school and randomly assigned in a 1:1 ratio to receive either 14,000 IU of vitamin D or placebo every week for 3 years. At the end of the study, 3.6% (147 of 4074 children) of the vitamin D group and 3.3% (134 of 4043) of the placebo group had a positive QFT result, defined as an interferon-gamma level of 0.35 IU/mL or greater (adjusted RR, 1.10; 95% CI, 0.87 to 1.38; P=0.42). However, post hoc subgroup analysis at the threshold of 4.0 IU/mL revealed a lower risk of conversion versus placebo among children in the vitamin D group who had baseline 25(OH)D concentrations below 10 ng/mL (adjusted RR, 0.41; 95% CI, 0.17 to 0.99). Active tuberculosis occurred in a total of 46 children but was distributed evenly between groups (adjusted RR, 0.87; 95% CI, 0.49 to 1.55), as was acute respiratory infection, which occurred in a total of 63 children (adjusted RR, 0.86; 95% CI, 0.52 to 1.40). Both non-fatal adverse events (142 vs. 182) and deaths (4 vs. 6) occurred numerically more frequently in the placebo group, but no events were judged to be related to the treatment regimen.

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