As part of the adaptive immune response, different types of T cells exist to provide protection for the human body. T helper (Th) cells are one of the major types of T cells that release specific cytokines to mediate immune responses. Specifically, Th1 cells are critical for regulating intracellular infections from Mtb
[42]. Vitamin D and 1,25 (OH)
2D inhibit the proliferation of Th1 and Th17 cells and their pro-inflammatory cytokines such as IL-2, IFN-γ, IL-17 secretion, as well as induce T regulatory responses
[42]. While the inhibition of Th1 and Th17 CD4 T cell responses would allow the pathogen to replicate and cause active disease, Vitamin D has a role in the innate immune response, which reduces the viability of Mtb (
Figure 1). A 2006 paper showed that when human macrophages were activated by Toll-like receptors (TLR) there was an overexpression of vitamin D receptor (VDR) and the vitamin D-1-hydroxylase genes. This overexpression led to the destruction of Mtb via induction of the antimicrobial peptide cathelicidin
[43]. This study showed that when human macrophages that had been infected with Mtb were treated with 1,25 (OH)
2D
3, there was a reduction in the number of viable bacilli
[43]. While the innate immune system is responsible for the first-line defense, the adaptive immune response has a larger role in pathogen neutralization. Vitamin D is a primary target for antigen-presenting cells (APCs), a critical component of the adaptive immune system
[44]. In addition, 1,25 (OH)
2D
3 regulates the cytokines and chemokines released by dendritic cells (DC) by inhibiting IL-12 and IL-23 cytokines from Th1 while upregulating IL-10 cytokine, which shows anti-inflammatory properties
[44]. Due to Vitamin D’s involvement in the inflammatory process, it is worth evaluating its efficacy in combating TB disease. In a vast majority of patients with TB, 25(OH)D levels fall below 20 ng/mL
[45]. In 2018, a meta-analysis was conducted to investigate the association between vitamin D levels and children with TB showed that children with latent TB had significantly lower Vitamin D levels than controls
[46]. A 2019 study performed to determine the impact of vitamin D levels and risk of TB disease showed vitamin D predicts TB disease in a dose-dependent manner
[47]. Before antibiotic use, vitamin D was already used to treat TB as seen in an 1848 study that evaluated the role of sun exposure and administration of cod liver oil, both rich in Vitamin D
[45]. In the study, 18% of patients who were treated with cod liver oil were stabilized, compared to 6% of the control group
[48]. In 1998, a study showed that in children who took vitamin D supplementation along with first-line anti-TB drugs, clinical improvement occurred at a quicker rate
[45]. Salahuddin et al. demonstrated that vitamin D supplemented in high doses leads to improvements in radiographs and weight gain in patients with TB. The study was limited in the fact that it did not show a difference in sputum conversion rates, a clinical tool used to assess the efficacy of treatments
[49]. However, there have also been studies that did not support clinical improvements.
Table 1 summarizes the findings of key studies. A meta-analysis conducted in 2019 to analyze the effectiveness of vitamin D supplementation on pulmonary TB, indicated that vitamin D did not have any beneficial effect on anti-TB treatment. However, in participants with a tt genotype, sputum culture conversion times were shortened
[50]. Based on the analyzed studies, vitamin D was most effective in shortening sputum conversion times but given the conflicting results, more randomized control trials are needed to establish its clinical efficacy. Therefore, the use of vitamin D supplementation is not unambiguously correlated to an enhanced anti-TB response.
Figure 1. Immunomodulatory effects of 1,25 (OH)2D.
Table 1. Overview of major clinical studies.
Author |
Population |
Vitamin D Dose |
Duration |
Findings |
Martineau et al. (Mathyssen, Carolien et al., 2017) |
146 adults |
2.5 mg at start, and at days 14, 28, and 42 |
56 days |
No effect on sputum culture conversion on the overall population. |
Wejse et al. (Mathyssen, Carolien et al., 2017) |
365 adults |
100,000 IU at start, 3 months, 5 months, and 8 months |
1 year |
No effect on clinical outcome/mortality |
Tukvadze et al. (Mathyssen, Carolien et al., 2017) |
199 adults |
50,000 IU 3×/week for 8 weeks, followed by every other week for another 8 weeks |
16 weeks |
No improvement in sputum TB clearance |
Ganmaa et al. (Ganmaa, Davaasambuu et al., 2020) [51] |
8851 children |
14,000 IU vitamin D | 3 | or placebo |
3 years |
Not lower risk of TB infection |
Sudfeld et al. (Sudfeld, Christopher R et al., 2020) [52] |
6250 HIV+ adults |
50,000 IU Vitamin D | 3 | for first month of ART followed by 2000 IU Vitamin D | 3 | daily |
3 years |
No overall effect of supplementation on mortality risk. No difference in incidence of pulmonary TB between Vitamin D | 3 | vs. placebo |
Morcos et al. [41] (Mathyssen, Carolien et al., 2017) |
24 children (<13 y/o) |
1000 IU daily. No placebo implemented |
8 weeks |
Clinical improvement in radiography (X-ray and Ultrasound). Weight gain in patients |
Nursyam et al. [41] (Mathyssen, Carolien et al., 2017) |
67 patients (15–59 y/o) |
0.25 mg daily × 6 weeks |
12 weeks |
Increased rate of sputum conversion. Improved radiologic findings |
Salahuddin et al. [41] (Mathyssen, Carolien et al., 2017) |
259 patients (>16 y/o) |
2 IM injections of 600,000 IU given at 1 month apart |
12 weeks |
Faster clinical and radiographic improvement. Enhanced host immune activation |
Hassanein et al. [41] (Mathyssen, Carolien et al., 2017) |
60 adults |
1 IM injection of 200,000 IU |
8 weeks |
Enhanced TB score and more rapid sputum conversion rates |