1
Dear Editor,
Tuberculosis (TB) is one of the most important infectious diseases and considered
among the top 10 causes of death in the world. According to World Health Organization
(WHO) report in 2020, about 10 million infected cases of TB and also 1.5 million death
occurred form this disease in 2019 [1], [2]. Moreover, about one fourth of infected
patients by Mycobacterium tuberculosis (Mtb) are involved with more severe complications
such as infection by drug-resistant TB (DR-TB) strains, co-infection with HIV virus,
as well as latent TB (LTBI) infection. Although individuals affected by LTBI are asymptomatic
and cannot infect others, but in general, some of them may develop to active-TB form
that it is accounted as a concern for health services [3], [4], [5]. In addition,
the standard treatment of TB is also a time consuming process and in some cases such
as co-infection with HIV, DR-TB, and cases with side effects, therapeutic protocols
may face with serious limitations. Therefore, it seems we will require to develop
the novel therapeutic agents which reduce the course of treatment, and can cover the
other problems in treating TB [5], [6], [7]. Vitamin D was first used by Williams
in the beginning of 1849; he noticed that the fish liver oil improves the appetite
and strength of the TB patients [8]. Rook et al. (1986) showed that calcitriol, the
active biological form of Vitamin D, has in vitro anti-TB effects [9]. Based on the
evidence, vitamin D influences the host immune system responses. It can activate the
monocytes and lymphocytes of human through their vitamin D receptors (VDRs). For instance,
this vitamin stimulates the physiological processes such as monocytes activities,
restraining the proliferation of lymphocytes, stimulation of the immunoglobulin and
cytokine production, stimulation of the reactive nitrogen and oxygen stress responses,
restraining the matrix metalloproteinase activity, autophagy stimulation, and production
of human antimicrobial peptides (AMPs) [10], [11]. In recent studies, it has been
demonstrated that the serum level of vitamin D has a significant relationship with
susceptibility rate to TB [10], [11], [12]. Furthermore, it has been shown that the
polymorphisms such as Taql in the VDR gene also affect the development of TB [10].
Thus, it seems that vitamin D by improving the immune system responses causes the
shorten course of TB treatment, increasing the intercellular elimination of Mtb, reducing
transmissibility, and also improvement of the intensity and strength of infection
by DR-TB strains [13].
Several clinical trials have so far been done about the effects of vitamin D on the
treatment of TB, but some of which have shown controversial results. Moreover, the
role of vitamin D supplement in the treatment of TB has not properly determined in
the meta-analysis studies. The aim of this study was to evaluate the role of vitamin
D on reducing the sputum conversion time in the patients with drug-susceptible TB
and multi-drug resistant TB (MDR-TB). The polymorphism of Taql can also modify the
effect of vitamin D supplement on time conversion.
Using the key words “Tuberculosis” and “Vitamin D”, the clinical trial studies related
to our study were searched from the clinical trial website (
https://clinicaltrials.gov/
). Then, the free access documents were retrieved for the clinical trial studies.
The required information from these studies were extracted and listed in Table 1.
Table 1
Characteristics of included studies.
Author
Publish year
Setting
Clinical trials register No.
Intervention vitamin D3
Dosage
Female/MaleAge
Statistics of studies
Refs.
case
control
p-value
Martineau
2011
UK
NCT00419068
vitamin D32.5 mg
2, 4 and 6 weeks
NA30.6
36 (95% CI 31.8–40.2)
43.5(95% CI 36.5–50.5)
HR: 1.39; 95% CI 0.90–2.16, P = 0.41
[10]
Daley
2015
India
NCT00366470
vitamin D32.5 mg
0, 2, 4, and 6 weeks
58/18942.65
43·0 (33·3–52·8)
42·0 (33·9–50·1)
0·952
[12]
Mily
2015
Bangladesh
NCT01580007
vitamin D3500 mg
Once daily for 2 months
23/1927.4 ± 12
61.3% (38/62)
42.2%(27/64)
0.032
[14]
Salahuddin
2013
Saudi Arabia
NCT01130311
vitamin D3600,000 IU
2 doses
118/14128.05 ± 61
6.68 ± 2.04, 6.3–7.03
6.85 ± 2.50, 6.4–7.29
0.16
[15]
Tukvadze
2015
Georgia
NCT00918086
vitamin D31.25 mg
Thrice weekly for 8 week
72/12733.25
29; 95% CI:24, 36
27; 95% CI: 23, 36
HR: 0.86; 95% CI: 0.63, 1.18; P = 0.33
[16]
Bekele
2018
Ethiopia
NCT01698476
vitamin D35000 IU
FOR 16 weeks
147/20130.47
1.07 0.43–2.65P = 0.879
1.05 0.42–2.63P = 0.904
NA
[17]
Ganmaa
2017
Mongolia
NCT01657656
vitamin D33.5 mg
four oral doses
134/25633
NA
NA
Adjusted hazard ratio, 1.09; 95% confidence interval,0.86–1.36; P = 0.48.
[18]
Ralph
2013
Indonesia
NCT00677339
vitamin D350,000 IU
Once daily for 4 weeks
69/13127.5
59%(44/75)
65%(52/80)
Risk difference 7%, 95% CI 29 to 22%.
[19]
The Odds Ratio (OR) and Hazard Ratio (HR) indices at 95% confidence intervals were
used to evaluate the relationship between the vitamin D supplementation as adjunctive
therapy and the sputum conversion. Using OR the effect of polymorphism of Taql gene
on the time of sputum conversion was also measured. Pooling the data was done in the
present study by use of the Comprehensive Meta-Analysis (CMA) software, version 2.2
(Biostat, Englewood, NJ). Based on Dersimonian and Laird method, the random effect
models was used for the cases with high levels of heterogeneity (I
2 index >25% and Cochran’s Q-test p-value <0.05) [3].
Overall, eight studies that had been fulfilled between 2011 and 2018 were matched
with our criteria studies. We evaluated the information about 1811 people, so that
34.29% of them were women and the rest were men. Also, the mean age of the patients
was measured 31.6 ± 15. In the study by Ralph et al. (2013), they used of both L-arginine
and vitamin D for some groups, but we omitted the information of L-arginine groups
in order to merely to evaluate the pure effect of vitamin D on TB.
Based on the primary statistical analysis, vitamin D supplementation increases the
sputum smear and culture conversion (OR: 3.197; 2.39–4.26 with 95% CIs; I2
: 64.44; Q value: 11.24 and Egger’s intercept: 1.81). However, the consumption of
that had no impact on the time of sputum smear and culture conversion (HR: 1.05; 0.88–1.25
with 95% CIs; I2
: 38.11; Q value: 3.23; Eggers’ intercept: 1.29). According to the secondary analysis,
vitamin D had no impacts on the sputum conversion in the MDR-TB patients (OR: 0.91;
0.58–1.41 with 95% CIs; p-value: 0.69). In addition, we did not find a significant
relationship between the effect of Taql gene polymorphism in adjunctive therapy of
vitamin D and shortening the duration of sputum conversion (tt allele with OR: 1.12
and p value: 0.61; Tt allele with OR: 1.03 and p value: 0.86; TT allele with OR: 1.23
and p value: 0.31). Moreover, Taql polymorphism had no impacts on shortening the duration
of sputum smear and culture conversion (HR: 1.43; 0.90–2.26 with 95% CIs; p value:
0.12). Regarding the statistical analysis, we also performed a supplementary analysis
about the impact of vitamin D supplementation on the size of the lung cavity, total
white blood cells (WBC) as well as deaths, although there was not found the significant
relationship in this respect. For the three recent items, the statistical analysis
results was OR: 0.92; p value: 0.49, OR: 1.18; p value: 0.145, and OR: 1.1; p value:
0.76 respectively. Vitamin D is one of the most well-known bioactive compounds that
has an important effect on the reduction of pathogenesis of infectious diseases by
modulating the immune system responses (Fig. 1).
Fig. 1
The crucial role of vitamin D in the immunopathogenesis of TB. Vitamin D has immunomodulatory
effects on the immune-system, so that it suppresses Th1, Th17, B cell as well as DCs
maturation. However, it also stimulates the proliferation of T regulatory (T reg)
cells, which in turn inhibit the excessive T cell-mediated immunity and tissue damage.
In the other hand, it also has a specific receptor on the macrophages, vitamin D receptor
(VDR). After the binding to the VDR, vitamin D triggers the processes such as the
production of natural human antimicrobial peptides (AMPs), nitric oxide synthesis
and chemotaxis to provoke immune response for clearance of M. tuberculosis (Mtb).
By restraining the CD4+ T cell proliferation, inducing the IFN-γ, IL-2, and formation
of VDR-RXR complex, vitamin D can shift the immune system response towards Th2/T regulatory
(T reg) cells, and indeed effects on the final outcome of the infection by Mtb
[20]. In the present study we demonstrated that vitamin D as adjunctive substance
increases the sputum smear and culture conversion (OR: 3.19; p value: 0.01). However,
based on our analysis, the consumption of vitamin D had no impact on the time of the
sputum smear and culture conversion (HR: 1.05; p-value: 0.54). Furthermore, we observed
no significant relationship between the vitamin D supplementation and sputum conversion
in MDR-TB cases, total white blood cell counts, reduction of lung cavity size, death,
and Taql polymorphism; previous studies had also controversial results. Jolliffe et
al. (2019) showed that vitamin D supplementation can accelerate sputum smear conversion
in the MDR-TB patients (aHR 1.15), but our findings were in contradiction with their
results [21]. Wu et al. (2018) showed that vitamin D can increase the sputum smear
and culture conversion (OR 1.21, p value: 0.007) and our results was also consistent
with their results. However, Wu et al. stated that consuming vitamin D had a significant
relationship with increasing the lymphocyte counts in the TB patients, but our findings
was contradictory with the previous studies [22]. Wu et al. (2018) showed that vitamin
D supplementation had no impact on the increasing of sputum conversion, but their
results was not consistent with our results [22]. Nonetheless, the difference in the
results could be due to the low sample size and limited studies. Although in the present
study the existing clinical trials was evaluated up to April 2020, but we require
more studies and more volunteers to evaluate the validity of the present study results.
In summary, we demonstrated that vitamin D supplementation increases the sputum smear
and culture conversion in the TB patients. However, vitamin D has no impact on shortening
the duration of sputum conversion in the TB patients. Regarding the present studies,
it seems that vitamin D supplementation can increase the sputum conversion by improving
the disinfecting activity of the macrophages. Hence, it can be concluded that vitamin
D can be recommended for the adjunctive therapy in treating and prevention of TB,
in combination with the anti-tuberculosis drugs and for the prophylactic aims.
Ethical Statement
Ethical Statement is not applicable for this manuscript.