Vitamin D accelerates clinical recovery from tuberculosis: results of the SUCCINCT Study [Supplementary Cholecalciferol in recovery from tuberculosis]. A randomized, placebo-controlled, clinical trial of vitamin D supplementation in patients with pulmonary tuberculosis'

Abstract

Background: Vitamin D enhances host protective immune responses to Mycobacterium tuberculosis by suppressing Interferon-gamma (IFN-g) and reducing disease associated inflammation in the host. The objectives of this study were to determine whether vitamin D supplementation to patients with tuberculosis (TB) could influence recovery.

Methods: Two hundred and fifty nine patients with pulmonary TB were randomized to receive either 600,000 IU of Intramuscular vitamin D3 or placebo for 2 doses. Assessments were performed at 4, 8 and 12 weeks. Early secreted and T cell activated 6 kDa (ESAT6) and Mycobacterium tuberculosis sonicate (MTBs) antigen induced whole blood stimulated IFN-g responses were measured at 0 and 12 weeks. Statistical comparisons between outcome variables at 0 and 12 weeks were performed using Student's t-test and Chi2 tests.

Results: After 12 weeks, the vitamin D supplemented arm demonstrated significantly greater mean weight gain (kg)+3.75, (3.16-4.34) versus+2.61 (95% CI 1.99-3.23) p 0.009 and lesser residual disease by chest radiograph; number of zones involved 1.35 v/s 1.82 p 0.004 (95% CI 0.15, 0.79) and 50% or greater reduction in cavity size 106 (89.8%) v/s 111 (94.8%), p 0.035. Vitamin D supplementation led to significant increase in MTBs-induced IFN-g secretion in patients with baseline 'Deficient' 25-hydroxyvitamin D serum levels (p 0.021).

Conclusions: Supplementation with high doses of vitamin D accelerated clinical, radiographic improvement in all TB patients and increased host immune activation in patients with baseline 'Deficient' serum vitamin D levels. These results suggest a therapeutic role for vitamin D in the treatment of TB.

Trial registration: ClinicalTrials.gov; No. NCT01130311; URL: clinicaltrials.gov.

Figure 1

Study Flowchart. Study Drug (Cholecalciferol) and Placebo (Normal Saline) matched for colour and volume of contents. ² ‘Completed treatment’; administration of 2 doses of study drug/placebo (over first 2 months), with follow up assessments complete at all visits over a total duration of 3 months. * Includes all patients who completed treatment at end of 3 months, as well as those who died during, or defaulted from, treatment before completion (indicated for each treatment arm). Flow Diagram adapted from the CONSORT 2010 Statement: updated guidelines for reporting parallel group randomized trials.

Figure 2

Mycobacterial-antigen stimulated IFN-g responses in TB patients according to disease severity and circulating 25-hydroxyvitamin D levels. Diluted whole blood cells were stimulated with ESAT6 and M. tuberculosis sonicate (MTBs) and IFN-g measured in cell supernatants after 6 days of culture. The graphs depict IFN-g responses in patients classified into severity according to their TB scores (a-b); Severity Class I (TB score 0 to 5), Class II (TB score 6 – 7) and Class III (TB score ≥ 8) in response to stimulation with (a) ESAT6 and (b) MTBs, or according to their vitamin D levels (c-d); Optimal (>30 nmol/ml), Insufficient (20–30 nmol/ml) or Deficient (< 20 nmol/ml) in response to stimulation with (c) ESAT6 and (d) MTBs. The box and whiskers plots depict cytokine responses in the 10th to 90th percentiles with the horizontal bar indicating the median levels of each group.

Figure 3

MTBs-induced IFN-g secretion is increased in the Vitamin D treatment arm after 12 weeks of anti-tuberculous therapy. Diluted whole blood cells were stimulated with M. tuberculosis sonicate (MTBs) and IFN-g measured in cell supernatants after 6 days of culture. The box and whiskers plots depict cytokine responses in the 10th to 90th percentiles with the horizontal bar indicating the median levels of each group. ‘*' Denotes values significantly different p < 0.05 between levels at 0 and 12 weeks respectively as determined by paired t test analysis.

Figure 4

MTBs- stimulated IFN-g levels are increased post-therapy in TB patients with deficient more severe TB. Whole blood cells were stimulated with MTBs and IFN-g measured in cell supernatants and compared between patients classified into TB severity classes I, II and III. Responses at 0 and 12 weeks were compared in each group by paired t test analysis. The box and whiskers plots depict cytokine responses in the 10th to 90th percentiles with the horizontal bar indicating the median levels of each group. a, Placebo arm b, Drug intervention arm. ‘*' Denotes p <0.05 between levels at 0 and 12 weeks respectively.

Figure 5

MTBs- stimulated IFN-g levels are increased post-therapy in TB patients with deficient Vitamin D levels. Whole blood cells were stimulated with MTBs and IFN-g measured in cell supernatants at 6 days post-stimulation. Vitamin D levels >30 ng/ml, Optimal; 20–30 ng/ml, Insufficient; <20 ng/nl, Deficient. a, Placebo arm b, Drug intervention arm. The box and whiskers plots depict cytokine responses in the 10th to 90th percentiles with the horizontal bar indicating the median levels of each group. ‘*' Denotes p <0.05 between levels at 0 and 12 weeks respectively as determined by paired t test analysis.