The global burden of morbidity and mortality from tuberculosis (TB) is substantial. An estimated one third of the world population is thought to have latent tuberculosis infection (LTBI), and 10% of this cohort will likely progress to active TB during their lifetime. If targets of the World Health Organization’s End TB Strategy are to be met, the prevalence of LTBI must be reduced. Given that primary TB infection is most common during childhood, preventing LTBI infection in children is key to meeting WHO End TB targets.
An association between vitamin D deficiency and the development of TB disease has long been recognized in observational studies. However, whether vitamin D deficiency is a risk factor for or sequelae of TB infection is unclear. The possibility that an existing low-cost, mass-produced drug could be effective in the prevention of TB infection would greatly improve efforts to reduce the global TB burden. But, randomized-controlled clinical trials of preventive measures for TB infection are difficult to perform because enrollment of a large sample of healthy individuals is required. In addition, the probability of progression to TB disease is relatively low, long-term follow up is required to measure TB reactivation as an outcome, and adherence to preventative interventions can be variable in disease-free healthy participants.
For these reasons, a recent phase 3, double-blind, randomized, placebo-controlled trial of vitamin D supplementation in nearly 9000 school-age children living in Mongolia is important. In a previous smaller randomized-controlled trial, the same authors reported that 6 months of vitamin D supplementation decreased the incidence of tuberculin skin test conversion in a similar cohort of children. However, in the current larger trial, vitamin D supplementation did not reduce the risk of TB infection. The authors postulate that the difference in outcomes may reflect the different tests used to identify LTBI infection in the two studies or a type 1 error in the previous study.
Although the results of this study do not support vitamin D supplementation as a preventative measure for TB infection in children, results from a similar ongoing double-blind, placebo-controlled trial in South Africa (ClinicalTrials.gov Identifier: NCT02880982) should help clarify whether vitamin D has a role in TB prevention.
The following NEJM Journal Watch summary further explains the study and findings:
Vitamin D Supplementation Doesn't Prevent Active Tuberculosis
Richard T. Ellison III, MD reviewing Ganmaa D et al. N Engl J Med 2020 Jul 23
Weekly vitamin D didn't reduce the incidence of active tuberculosis in children.
Historically, one of the primary treatment approaches in tuberculosis (TB) sanitariums was heliotherapy — exposure to sunlight. More recent work found that the risks for latent TB and active TB increase with vitamin D deficiency. Moreover, 6 months of vitamin D supplementation appeared to decrease the incidence of tuberculin skin test conversion in Mongolian school-age children. Now, investigators have conducted a randomized, placebo-controlled trial of weekly oral Vitamin D (14,000 IU) to decrease incidence of latent and active tuberculosis and acute respiratory infection in 8851 children in Mongolia aged 6 to 13 years old with negative baseline QuantiFERON-TB Gold (QFT) results.
At 3 years, the mean serum vitamin D concentration was significantly increased in vitamin D recipients, and no adverse effects of supplementation were noted. However, incidences of both conversion to positive QFT results (3.6% vs. 3.3%) and active tuberculosis (0.5% vs. 0.6%) in the vitamin D and placebo groups, respectively, were comparable. Results were also comparable in the subgroup of children with low serum vitamin D level (<10 ng/mL). Similarly, the incidences of symptoms of acute respiratory infection, need for antibiotic therapy, and hospitalization for acute respiratory infections were comparable between the vitamin D and placebo groups.
Comment: Why this well-designed study did not support the findings of the prior trial is unclear, but the findings indicate that this approach to preventing tuberculosis doesn't work.
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James is a 2020-2021 NEJM Editorial Fellow and a graduate of the National University of Ireland, Galway. He has a Masters of Science in Evidence-Based Healthcare from University College London and completed Basic Specialist Training in general internal medicine with the Royal College of Physicians in Ireland.