Vitamin D Supplements for Prevention of Tuberculosis Infection and Disease

Abstract

BACKGROUND Vitamin D metabolites support innate immune responses to Mycobacterium tuberculosis. Data from phase 3, randomized, controlled trials of vitamin D supplementation to prevent tuberculosis infection are lacking. METHODS We randomly assigned children who had negative results for M. tuberculosis infection according to the QuantiFERON-TB Gold In-Tube assay (QFT) to receive a weekly oral dose of either 14,000 IU of vitamin D 3 or placebo for 3 years. The primary outcome was a positive QFT result at the 3-year follow-up, expressed as a proportion of children. Secondary outcomes included the serum 25-hydroxyvitamin D (25[OH]D) level at the end of the trial and the incidence of tuberculosis disease, acute respiratory infection, and adverse events. RESULTS A total of 8851 children underwent randomization: 4418 were assigned to the vitamin D group, and 4433 to the placebo group; 95.6% of children had a baseline serum 25(OH)D level of less than 20 ng per milliliter. Among children with a valid QFT result at the end of the trial, the percentage with a positive result was 3.6% (147 of 4074 children) in the vitamin D group and 3.3% (134 of 4043) in the placebo group (adjusted risk ratio, 1.10; 95% confidence interval [CI], 0.87 to 1.38; P = 0.42). The mean 25(OH)D level at the end of the trial was 31.0 ng per milliliter in the vitamin D group and 10.7 ng per milliliter in the placebo group (mean between-group difference, 20.3 ng per milliliter; 95% CI, 19.9 to 20.6). Tuberculosis disease was diagnosed in 21 children in the vitamin D group and in 25 children in the placebo group (adjusted risk ratio, 0.87; 95% CI, 0.49 to 1.55). A total of 29 children in the vitamin D group and 34 in the placebo group were hospitalized for treatment of acute respiratory infection (adjusted risk ratio, 0.86; 95% CI, 0.52 to 1.40). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS Vitamin D supplementation did not result in a lower risk of tuberculosis infection, tuberculosis disease, or acute respiratory infection than placebo among vitamin Ddeficient schoolchildren in Mongolia. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02276755.

Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials

“…This difference reflects the inclusion of null data from four new RCTs in which vitamin D was given in relatively high doses at weekly or monthly intervals over 2-5 years. 41,42,44,45 Null results of these studies contrast with protective effects reported from earlier trials in which smaller daily doses of vitamin D were given over shorter periods. 8,9,13,16 These differing findings suggest that the frequency, amount and duration of vitamin D supplementation may be key determinants of its protective efficacy.…”

“…The current study has several strengths: it contains the very latest RCT data available in this fast-moving field, including findings from three large phase 3 trials published in 2020 41,42,44 as well as some as-yet unpublished studies. 46,47 The inclusion of additional studies allowed us to analyse results of placebo-controlled studies vs. high-dose / low-dose studies separately, and gave us the power to investigate reasons for heterogeneity of effect observed across trials.…”

Vitamin D and COVID-19: evidence and recommendations for supplementation

“…Infection with tuberculosis as defined by a positive QuantiFERON-TB test was the primary outcome with the incidence of clinical tuberculosis and ARIs as secondary outcomes. The weekly vitamin D bolus had no significant impact on any of these outcomes [ 85 ]. This contrasts with a previous study in 247 Mongolian schoolchildren in which daily ingestion of milk fortified with 300 IU of vitamin D3 resulted in a 50% reduction in participant-reported ARIs during the winter [ 86 ].…”

Is There Proof of Extraskeletal Benefits From Vitamin D Supplementation From Recent Mega Trials of Vitamin D?

“…( 73 ) However, a recent large trial of 8851 Mongolian children found that a weekly vitamin D dose of 14,000 IU taken over 3 years did not prevent acute respiratory or tuberculosis infections, even in those with baseline 25(OH)D <25 nmol/L. ( 74 ) Other trials that have included respiratory infections as an outcome include the CAPS, VITAL, and DO‐Health studies, which gave a daily vitamin D dose, and D‐Health, which gave a monthly bolus dose (Supplemental Table S1). Their results when published are expected to provide further important information about the effect of vitamin D in preventing acute respiratory infections.…”