Vitamin D and tuberculosis: a review on a hot topic.

Journal of Chemotherapy

ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20

Vitamin D and tuberculosis: a review on a hot topic Ludovica Facchini, Elisabetta Venturini, Luisa Galli, Maurizio de Martino & Elena Chiappini To cite this article: Ludovica Facchini, Elisabetta Venturini, Luisa Galli, Maurizio de Martino & Elena Chiappini (2015) Vitamin D and tuberculosis: a review on a hot topic, Journal of Chemotherapy, 27:3, 128-138 To link to this article: http://dx.doi.org/10.1179/1973947815Y.0000000043

Published online: 18 Dec 2015.

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Date: 27 December 2015, At: 23:52

Review

Vitamin D and tuberculosis: a review on a hot topic Ludovica Facchini, Elisabetta Venturini, Luisa Galli, Maurizio de Martino, Elena Chiappini Anna Meyer Children’s University Hospital, Department of Health Sciences, University of Florence, Florence, Italy

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The aim of this study is to critically summarize the available data on the correlation between vitamin D level and tuberculosis (TB) infection. A literature search covering English language articles published up to 20 October 2014 was conducted in MEDLINE database. Three hundred ninety-seven articles were initially identified, of which 147 studies were initially selected, and other 13 pertinent studies were included. A significant association between low vitamin D levels and susceptibility to TB infection has been found. Keywords: Vitamin D, Tuberculosis, Children, Hypovitaminosis D, Mycobacterium tuberculosis, Immunity

Abbreviations 1,25-OHD 25-OHD DPB IFN IL MTP NK TB TIMP TNF TST VDR

1,25-dihydroxyvitamin D 25-hydroxyvitamin D vitamin D-binding protein interferon interleukin metalloproteinases natural killer tuberculosis metallopeptidase inhibitor tumour necrosis factor tuberculin skin test vitamin D receptor

Introduction Historical aspects In 1651, the clinical features of vitamin D deficiency associated with signs and symptoms suggestive of tuberculosis (TB) were first described. During the nineteenth century, cod liver oil, rich in vitamin D, was largely distributed in TB patients. The first sanatorium opened in Germany in 1859, and subsequently heliotherapy became a common practice in tubercular infection, all over Europe. In 1903, Niel Finsen won the Nobel Prize in Physiology and Medicine for discovery that shortwave ultraviolet light was an effective treatment of cutaneous TB.

Vitamin D and immunity Vitamin D immunomodulating role has been only recently recognized. New findings suggest a key role Correspondence to: Maurizio de Martino, Department of Health Sciences, University of Florence, Anna Meyer Children’s University Hospital, Viale Pieraccini 24, Florence I-50139, Italy. Email: [email protected]

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ß 2015 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947815Y.0000000043

of vitamin D in enhancing immune functions involved in the control of TB infection, it appears to act both as immunostimulator of innate immunity and as immunosuppressor of acquired immunity. Innate immunity The role played by vitamin D in innate immunity is mediated by the nuclear vitamin D receptor (VDR), which stimulates the synthesis of two classes of antibacterial peptides called cathelicidins and beta-defensins. They are produced by monocytes and bronchial epithelial cells, and facilitate the fusion of phagosome containing mycobacteria with intracellular lysosome. These peptides are encoded by CAP-18 gene, the transcription of whom is stimulated by vitamin D.1 Many studies have also revealed an association between TB infection and polymorphisms of the VDR, strengthening the hypothesis of the importance of vitamin D in the immune response to mycobacteria. Moreover, the activation of Toll-like receptor 2 in macrophage and keratinocyte mediated by pathogens lead to the induction of CYP27B1 enzyme, which converts inactive 25-hydroxyvitamin D (25-OHD) to active 1,25-dihydroxyvitamin D (1,25-OHD) in those cells. Vitamin D prevents the arrest of phagosome maturation induced by mycobacteria phagocytised, through the activation of an intracellular signalling pathway, mediated by phosphatidylinositol 3-kinase. An inhibitory effect on TH1 lymphocytes is related to the production of interleukin (IL)-12 and IL-23 by antigen-presenting cells, which have phagocytised mycobacteria. Vitamin D seems also to inhibit metalloproteinases (MTP) involved in the degradation of extracellular matrix and in the development of lung cavitations in active TB.2 This is obtained through


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Vitamin D and tuberculosis in children

a direct effect on the production of MTB in the matrix but also enhancing the production of inhibitors of metalloproteases (TIMP1) by circulating monocytes. Vitamin D stimulates macrophage differentiation, and the production of hydrogen peroxide and nitric oxide, involved in the intracellular killing of Mycobacterium tuberculosis.2 Finally, vitamin D downregulates the production of pro-inflammatory cytokines [IL-1alpha, tumour necrosis factor (TNF)-alpha, TNF-beta, IL-17 and IL-23] controlling the exacerbated inflammatory response that may protect the host from excessive tissue damage at the site of infection.3

that a lower immune response of INF-gamma in the context of vaccination, could be a benefit to the host, preventing an inflammatory response not required.7

Acquired immunity Vitamin D affects acquired immunity by suppressing the proliferation of T lymphocytes, and especially of TH1 lymphocytes producing interferon (IFN)gamma and IL-2. These functions prevent antigens presentation, and consequently, recruitment and proliferation of other T cells.4 The suppression of TH1 lymphocytes led from vitamin D has an inhibitory effect on immunity, as they have a specific role in TB infection recover: indeed after successful therapy and recover from TB has been confirmed the conversion of T cells to TH1 lymphocytes5. Vitamin D has regulatory effects also on the proliferation of TH2 lymphocytes, CD4z and CD25zT cells. However, the role that vitamin D has in these cell lines is not completely understood. According to some authors, the ability of 1,25-OHD to inhibit acquired immunity is involved in regulating the response to self and preventing the development of autoimmunity.4 Moreover, vitamin D has a promoting effect on natural killer (NK) lymphocytes and a suppressing effect on B cell proliferation, immunoglobulin production and differentiation of B cell precursors in plasma cells.6

A literature search covering English language articles published up to 20 October 2014 and concerning children and adults was conducted using multiple keywords and standardized terminology in MEDLINE database. Index terms were used as specified in Appendix 1. Limits were field (Title/Abstract) and language (English). All relevant articles were then evaluated, and pertinent articles were included in this review.

Peculiarity of childhood Considering the differences between the immune system in children and adults, some authors suggested a peculiar role of vitamin D as immunomodulator in children. In the newborn, IFN-gamma, which has a predominant role in the immune response against mycobacterium, is mostly produced by NK cells, whereas in older children and adults by TH1 lymphocytes.7 One study described that IL-2based ELISPOT with AlaDH antigen may be of help in discriminating children with active from those with latent TB rather than INF-gamma, probably according to the different maturity of TH1 lymphocytes in childhood.8 Another study found that high levels of vitamin D in children were related with lower levels of IFN-gamma, valuated after a tuberculin skin test (TST).7 The role of vitamin D in response to vaccination with BCG was assessed by analysing the levels of IFN-gamma, suggesting

Aim To critically summarize the available data on the correlation between vitamin D level and TB infection, focussing on the newest findings and on the need for new studies.

Methods Search strategy

Study selection The primary search was conducted by reviewing titles and abstracts of the studies, after that the full texts of eligible studies were screened for inclusion. An article was included in this review if contained original data from children or adults evaluating a possible correlation between vitamin D level and TB. Study eligibility, quality assessment and data extraction were checked for validity by a second author.

Results Three hundred ninety-seven articles were initially identified, of which 147 studies were initially selected for relevance and pertinence, according to the search strategy. Bibliographies in all relevant articles were then evaluated, and other 13 pertinent studies were included (Appendix 1).

Hypovitaminosis D and susceptibility to TB infection The first study suggesting an association between low vitamin D levels and susceptibility to TB was published in 1985.9 Subsequently, hypovitaminosis D and TB were evaluated in other studies, including a total of 10 450 adults and 572 children. A significant association between low vitamin D levels and susceptibility to TB infection has been found in 29 studies out of 40,7,11,12,15,17,19,24,31,33,37,41,48 as described in Table 1.

Genetic polymorphisms involved in vitamin D metabolism and in susceptibility to TB Genetic variability of the host has been suggested to explain differences in inter-individual susceptibility to Mycobacterium tuberculosis. Polymorphisms in


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Case–control study: 105 adults with active TB, 255 controls

Case–control study: 110 adults with active TB, 110 house-hold contacts, 115 healthy controls Cross-sectional study: 1250 adults with active TB (65,8%, n5823 HIVz), 355 controls

Iftikhar et al., Pakistan30

Joshi et al., India31

Cross-sectional study: 161 patients with TB (81% HIV-positive) Cross-sectional study: 50 HIVz patients, 50 HIVz and TB patients, 50 controls Prospective study: 100 household tuberculosis contacts 28 adults with TB

Williams et al., UK28 Kibirige et al., Uganda29

Friis et al.,Tanzania32

Vitamin D level lower in the group with TB (P50.008), increased TB risk with undetectable levels of vitamin D (P50.009) Median vitamin D level statistically lower in the group with TB (Pv0.05) Median vitamin D levels lower in TB cases. Hypovitaminosis D with equal frequency in both groups Vitamin D levels statistically lower in cases with TB (P50.001)

Vitamin D median levels significantly lower in the TB group (P50.005) Bimodal distribution and median levels of vitamin D are not statistically different in TB and control groups Vitamin D levels significantly lower in patients with TB (Pv0.05) Median levels of vitamin D lower in patients with TB No significant difference in vitamin D levels in the two groups

Main results

Insufficient or deficient vitamin D level in 85% of cases High prevalence of hypovitaminosis D (85.4%). The mean vitamin D level was 22.55 ng/ml (14.59–33.31) Hypovitaminosis D deficiency in 57% of cases and 33% controls (Pv0.0001). Mean vitamin D level lower in active TB patients (Pv0.0001). Mean vitamin D level significantly lower in females with TB (P50.002) High prevalence of hypovitaminosis D in TB patients and household contacts compared with controls Mean vitamin D level higher in TB patients than in controls (110.9 vs 84.4 nmol/l)

Lower vitamin D level in active or latent TB compared to controls

Hypovitaminosis D in most patients No difference in median vitamin D level in the three groups. Vitamin D levels lower in case of coinfection Vitamin D level low in both groups. Increased relative risk of infection in contacts with lower vitamin D level Median vitamin D level insufficient or deficient Vitamin D level lower in the group with active TB

Lower levels of vitamin D in active TB compared with latent TB (P50.007). Higher levels of vitamin D associated with a lower risk of TB disease (P50.001) Cross-sectional study: 506 adults with positive cultures for Mycobacterium Levels of vitamin D lower in cases with positive culture tuberculosis, 129 adults with negative cultures Prospective study: 81 adults with TB tested at diagnosis and at 2 months Sufficient levels of vitamin D in TB patients, median levels increased follow-up after 2 months Case–control study: 72 adults with TB, 72 healthy adults Both high and low vitamin D levels associated with TB.

Retrospective study: 40 adults with active TB, 81 adults with latent TB

Cross-sectional study: 178 cases with TB, 130 healthy cases

Cross-sectional study: 362 adults with TB, 494 healthy adults

Cross-sectional study: 35 adults with TB, 16 healthy adults

Randomized study: 126 adults with TB Cross-sectional study: 178 HIVz and HIV-patients with latent TB 192 HIVz and HIV-patients with active TB Cross-sectional study: 11 children with active TB, 81 children with latent TB, 236 healthy children Prospective study: 28 children with active TB, 38 children with latent TB Cross sectional study: 260 adults with active TB (80%, n5208 HIVz)

Martineau et al., UK25 Martineau et al., South Africa26 Gray et al., Australia27

Talat et al., Pakistan24

Tostman et al., Tanzania20 Nielsen et al., Groenlandia21 Banda et al., Malawi22 Nasera et al., Uganda23

Friis et al., Tanzania19

Wejse et al., Guinea Bissau16 Sita-Lumsden et al., UK17 Gibney et al., Australia18

Sasidharan et al., India

15

Case–control study: 50 adults with active TB, 50 healthy adults Cross-sectional study: 40 adults with TB, 38 healthy adults

Davies et al., UK9 Grange et al., Indonesia10 Davies et al., Kenya11 Davies et al., Thailand12 Chan et al., Hong Kong13 Wilkinson et al., UK14

Case–control study: 15 adults with TB, 15 healthy adults Case–control study: 51 adults with TB, 51 healthy adults Case–control study: 22 adults with TB, 23 adults receiving treatment for non-tuberculosis conditions Case–control study: 103 adults with TB, 43 healthy adults with TB contact

Type of study, patients included

Study (ref.)

Table 1 Association between tuberculosis (TB) and hypovitaminosis D9–48.


No

Yes

Yes

Yes Yes

Yes

Yes

Yes

No No

No

No

Yes

Yes

Yes

No

Yes

Yes

Yes Yes No

Yes No

Association TB-hypovitaminosis D

Facchini et al. Vitamin D and tuberculosis in children

Cohort study: 677 adults with TB (51%, n5344 HIVz)

Observational retrospective study: 86 adults with active TB; 80 adults with latent TB Case–control study: 165 adults with active TB, 197 healthy controls

Observational prospective study: 1103 adults HIVz

Mehta et al.,Tanzania34

Esteve et al., Spain35

Sudfeld et al., Tanzania37 Koo et al., South Korea38 Desai et al., Georgia39

Median vitamin D level lower in TB patients compared to controls (P50.01). Black race, enrolment in winter and previous TB disease related with lower vitamin D level Vitamin D insufficiency was associated with a 66% higher risk of TB relapse Hypovitaminosis D, male and black skin were independently correlated with TB Vitamin D level significantly lower in TB patients than in controls (Pv0.005) Vitamin D deficiency significantly associated with TB (P50.027)

Main results

Mean vitamin D level not different in TB patients and controls at diagnosis (13.2 vs 13.2 ng/ml; P50.97) Observational prospective study: 85 adults with active TB Mean vitamin D levels were 14.5+ 7.0 ng/ml, and vitamin D insufficiency occurred in 97% of subjects Observational study 38 HIVz adults: 19 with active TB, 19 controls 8% (15/19) of both cases and controls were vitamin D deficient. Steenhoff et al., The absolute difference of 1.3 nmol/l in 25-OHD levels between HIVz Botswana40 patients and controls was not consistent Cross-sectional and case–control study: 202 adults (contacts of active TB) No association between latent TB status and serum 25-OHD was Armedo-Pena et al., found in 50 patients but a sufficient 25-OHD level was a protector Spain41 against TST later conversion (P50.019). The mean of serum level 25OHD in TST conversion cases was lower than controls,17.5+ 5.6 ng/ml vs 25.9+ 13.7 ng/ml (P50.041) Case–control study 166 TB patients: 219 controls Higher prevalence of vitamin D insufficiency in TB male patients than Ho-Pham et al., in controls (35.4 vs 19.5%, P50.01), but not in women Vietnam42 Hypovitaminosis D was found in 86% patients, with a baseline serum Yamshchikov et al., USA Observational study: 95 adults with active TB 25-OHD level of 20.4 ng/ml and Canada43 76% were 25-OHD deficient and 56% had undetectable levels Ustianowsky et al., UK44 Observational study: 210 adults with active TB Vitamin D levels in plasma and pleural fluid of TB patients and Srinivasan et al., India45 Case–control observational study: 22 adults with TB 22 healthy controls healthy controls were, respectively, 67.45 (10.71) nmol/l and 21.40 (8.58) nmol/l compared with 117.43 (18.40) nmol/l (Pv0.001) and 94.73 (33.34) nmol/l (P50.0049) Prospective cohort study: 247 participants exposed to TB The means of VitD concentration in the TB infection conversion Arnedo-Pena A et al., (TBIC) cases and the non-cases were, respectively, 20?7+ 11?9 and Spain46 27?2+ 11?4 ng/ml (P50.028). A higher serum VitD concentration was associated with low incidence of TBIC (P trend 0.005), and an increase of 1 ng/ml VitD concentration decreased the incidence of TBIC by 6% (relative risk 0?94, 95% confidence interval 0.90–0.99, P50.015) Jubulis et al., India47 Prospective case–control study: 60 children with TB (probable or Both groups had high levels of vitamin D deficiency (55 vs 50%, confirmed) and 118 healthy controls P50.53). In multivariable analysis, TB was not associated with vitamin D deficiency (aOR 1.00, 95%CI 0.38–2.66) Case–control study: 94 TB cohort subjects and 282 Korean national The median baseline 25-hydroxyvitamin D (25[OH]D) level in the TB Hong et al., South survey participants group (9.86 ng/ml, IQR 7.19–14.15) was lower than in controls Korea48 (16.03 ng/ml, IQR 12.38–20.30, Pv0.001)

Observational prospective study: 116 patients with active TB; 86 controls

Case–control study: 29 adults with previous TB, 36 controls

Huamam et al., USA33

Kim et al., Korea36


Study (ref.)

Table 1 Continued



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Yes

Yes

Yes

No

Yes

No

Yes

Yes

Yes

Yes

Yes

Association TB-hypovitaminosis D


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genes related to vitamin D have been analysed, and in particular in VDR gene. The VDR gene is located on chromosome 12 and is susceptible to various polymorphisms. A correlation between susceptibility to active TB and specific variants of VDR gene has been investigated. An increased risk of active TB has been identified in carriers of the variant T of the TaqI allele of VDR and in carriers of the variant FF of FokI allele of VDR.14,49 A better response to antitubercular therapy has been described in presence of polymorphisms T of TaqI, FF of FokI and AA of ApaI. Recently, a correlation between VDR and lipid metabolism in infected macrophages has been speculated. Vitamin D treatment of infected macrophages reduced infection-induced accumulation of lipid droplets, required for intracellular Mycobacterium tuberculosis growth.50 A possible link between variants of vitamin D-binding protein (DPB) and active TB was also investigated by other authors. Vitamin D-binding protein is a serum glycoprotein encoded by the DPB gene, located on chromosome 4. The most common gene polymorphism affects codon 416 and 420 within exon 11, with the production of three DPB variants identifiable with electrophoresis (groupspecific component 1-fast, 1-slow and 2-slow). A higher affinity for 25-OHD has been described in variants 1-fast and 1-slow compared to variant 2-slow.49 Moreover, polymorphisms in CYP27B1 gene, which encodes for a1-hydroxylase, seem not to be correlated with susceptibility to TB.

Role of vitamin D in prevention of active TB disease At present, no randomized controlled trial on the use of vitamin D in the prevention of TB disease is available in literature. The main reason for the lack of studies on this topic is that the annual risk of reactivation of latent TB is low in immunocompetent subjects. Therefore, a very large number of people should follow up for a long time to have reliable information. Some studies have tried to circumvent these obstacles, assessing the response to mycobacteria with a blood assay (BCG-lux assay) in patients receiving vitamin D supplementation. In this test, the blood’s ability to minimize the luminescence and then the growth of a recombinant mycobacterium is measured in vitro.49 The results available so far show that the treatment with vitamin D increases the response to stimulation with tubercular antigen compared to placebo, but do not influence the secretion of IFN-gamma, stimulated by the antigen BCG. A double-blind study has been conducted in Mongolia in 120 school-aged children, evaluating the effect of vitamin D supplementation (400 IU daily for 6 months) on the seroconversion to a positive TST. In the group receiving supplementation,

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a lower rate of TST positivization and an increase in vitamin D levels were found.51

Role of supplementation with vitamin D in the treatment of active TB disease Multiple studies investigated the response to anti-tubercular treatment in association to vitamin D supplementation. At present, 12 studies, one of which on paediatric population, are available in literature, including a total of 1449 subjects (1401 adults and 48 children).26,52,62 Seven studies were randomized controlled trials. The main results are described in Table 2. Results are discordant among studies. While a significant benefit from vitamin D supplementation was found in six studies,25,54,58,60,62 no correlation was observed in the remaining six studies. Discrepancies may be due to several reasons: the doses of vitamin D used in different studies largely varied and in some studies,52,53,55,57,59 they were significantly lower compared to those historically used in the complementary treatment of TB infection. Moreover, the study designs, the study populations largely differ since the settings include UK and USA as well as India, Japan and African countries. Finally, the effect of vitamin D supplementation in the presence of specific polymorphisms of VDR was not investigated.

Discussion A clear role of vitamin D as immunomodulator in fighting mycobacterium infection has been showed in both in vitro and in vivo studies.1–6 Extensive data are available on the correlation between vitamin D and TB infection, showing an increased risk of active TB in hypovitaminosis D. Recently, some authors tried to establish a possible use of vitamin D supplementation as an adjunctive treatment in TB infection and prophylaxis in TB contact. According to the existing literature,52–63 the use of vitamin D supplementation during the anti-tubercular therapy is not clearly correlated to a better response in TB clearance. Further randomized controlled trial are needed to clarify the beneficial effect of vitamin D supplementation in TB patients. These studies should be designed using adequate doses of vitamin D and considering the more recent knowledge about vitamin D response related to genetic polymorphisms. Furthermore, the majority of the studies available on vitamin D and TB are done in adults, with the exception of four studies in 1438 children.27,28,57,63 Considering the peculiarity of the immune system in childhood, vitamin D could act differently in those patients.7,8 New data are needed to confirm the correlation between hypovitaminosis D and TB infection in this population, in order to better clarify a possible role of vitamin D supplementation in prevention and treatment of TB also in this group of patients.

Increased vitamin D levels of 79 nmol/l in the treated group (P50.0001) Not reported

100 000 UI of D3 in four doses (0–2–4–6 weeks)


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Not reported

Different mean clinical outcome in the study arms [mean weight gain(kg)z3.75 vsz2.61 (P50.009) and less residual disease detected by chest x-ray in supplemented arm (P50.035)] Sputum culture conversion was achieved in 44/75 (59%) in the vitamin D arm vs 52/80 (65%) in the placebo arm. The mean clinical outcome was not different between study arms Median time to sputum conversion in the intervention arm significantly shorter than in the control arm (P50.04) Sputum smear conversion of 6 weeks in vitamin D group vs 8 weeks in placebo group (P50.067) In 23 patients treated with the standard TB regimen, vitamin D levels showed a shorter time taken to obtain three consecutive negative sputum smears or TB bacteria cultures

No change in weight or in symptoms

Increase of sputum conversion rate in the subpopulation of tt VDR TaqI (P50.02)

Increased sputum conversion rate after 6 weeks (P50.002)

Yes

Yes

Yes

No

Yes

No

Yes

Yes

a: Vitamin D supplement used non reported; TB: tuberculosis; VDR: vitamin D receptor; UI: international units (1 UI50.000025 mg); X-ray: radiography; DM: diabetes mellitus; D2: ergocalciferol; D3: colecalciferol.

Not done

Case-control study: 44 adults with active TB (with DM) treated with vitamin D or placebo Observational prospective study: 38 adults with active TB

Kota et al., India63

Sato et al., Japan53

100 000 UI D3 in four doses Non reported (1–2–3–6 weeks after the beginning of anti-TB therapy) 60 000 UI/weeks Not reported

Randomized double-blind placebo controlled trial: 146 adults with active TB

Coussens et al., UK56

Not reported

50 000 UI, four times a week for 8 weeks

600 000 UI D3 in two doses intramuscular (0–1 month)

1000 UI/diea

Not reported

Average increase in vitamin D Hypovitaminosis D relapse in 10 of 11 patients No levels of 22 nmol/l after one after 8 weeks; increase of vitamin D levels in dose in the treated group TB patients compared to healthy adults, no detection of hypercalcaemia Increase of vitamin D levels of No positive clinical effect on TB, no effect on No 25 nmol/l in both groups mortality in the vitamin D group

100 000 UI of D2 in a single dose

100 000 UI of D3 in three doses (0–5–8 months)

Not reported

No

10 000 UI/diea

Hypercalcaemia in 63% of treated cases

Not reported

No

400–4000 UI/diea

No variation in calcium

Not reported

Main results

In summary: has vitamin d a role in vitamin D receptor (TB) treatment?

5000 UI daily of D2

Randomized double blind control trial: 101 TB adults treated with vitamin D; 99 TB adults treated with vitamin D

Randomized double blind control trial: 132 adults with active TB treated with vitamin D; 127 adults with active TB not treated with vitamin D

Randomized controlled trial: 187 adults with TB treated with vitamin D; 180 adults with TB treated with placebo Randomized controlled trial: 62 adults with active TB treated with vitamin D, 64 adults with active TB treated with placebo Randomized controlled trial: 24 children treated vitamin D: 24 untreated children

Randomized controlled trial: 23 adults with TB treated with vitamin D; 23 adults treated without vitamin D Randomized controlled trial: 30 adults with TB treated with vitamin D; 30 adults not treated with vitamin D Randomized controlled trial: 33 adults with TB treated with vitamin D; 32 adults with TB ptreated with placebo Randomized controlled trial: 25 adults with TB treated with vitamin D; 25 healthy adults not treated

Dose of vitamin d

Increase of vitamin D blood level

Ralph et al., Indonesia61

Morcos et al., Egypt59 Salahuddin et al.55

Wejse et al., Guinea Bissau62 Martineau et al., UK30

Nursyam et al., Indonesia54 Martineau et al., UK58

Narang et al., India57

Gwinup et al., USA52

Study (ref.)


Table 2 Role of vitamin D supplementation in the anti-tubercular treatment30,52–62.



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Disclaimer Statements Contributors All authors have made substantial contributions to this review: MdM and EC in the conception and design of the study, LF and EV in the acquisition of data and analysis and interpretation of data; EV and LG in drafting the article, EC and LG in revising it critically for important intellectual content; all the authors in the final approval of the version to be submitted. Funding None. Conflicts of interest The authors declare that they have no competing interests.


Ethics approval No ethics approval was required for this review article.

Appendix 1 Search strategy ((vitamin[Title/Abstract] AND D[Title/Abstract]) AND tuberculosis[Title/Abstract]) OR ((1[Title/Abstract] AND 25-dihydroxyvitamin[Title/Abstract]

AND

D[Title/Abstract])

AND

tuberculosis[Title/Abstract]) OR ((25-hydroxyvitamin[Title/Abstract] AND D[Title/Abstract]) AND tuberculosis[Title/Abstract]) OR ((hypovitaminosis[Title/Abstract] AND D[Title/Abstract]) AND tuberculosis[Title/Abstract]) OR ((vitamin[Title/Abstract] AND D[Title/Abstract] AND deficiency[Title/Abstract]) AND tuberculosis[Title/Abstract]) OR ((vitamin[Title/Abstract] AND D[Title/ Abstract] AND receptor[Title/Abstract]) AND tuberculosis[Title/ Abstract])

OR

(VDR[Title/Abstract] AND tuberculosis[Title/

Abstract]) OR ((vitamin[Title/Abstract] AND D[Title/Abstract] AND supplementation[Title/Abstract]) AND tuberculosis[Title/ Abstract]) OR ((vitamin[Title/Abstract] AND D[Title/Abstract] AND supplementation[Title/Abstract]) AND (tuberculosis[Title/ Abstract] AND treatment[Title/Abstract])) AND English[lang] Articles initially identified: 397. Study selected: 147.1,3,7,15–31,33– 34,37–51,54–56,58–62,64–165.

References 1 Selvaraj P, Prabhu Anand S, Harishankar M, Alagarasu K. Plasma 1,25 dihydroxy-vitamin D3 level and expression of vitamin d receptor and cathelicidin in pulmonary tuberculosis. J Clin Immunol. 2009;29:470–8. 2 Adorini L. Intervention in autoimmunity: the potential of vitamin D receptor agonists. Cell Immunol. 2005;233:115–24. 3 Harishankar M, Afsal K, Banurekha VV, Meenakshi N, Selvaraj P. 1,25-Dihydroxy vitamin D3 downregulates proinflammatory cytokine response in pulmonary tuberculosis. Int Immunopharmacol. 2014;23:148–52. 4 Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P, et al. Extra-renal 25-hydroxyvitamin D3 1alphahydroxylase in human health and disease. J Steroid Biochem Mol Biol. 2007;103:316–21. 5 Marchant A, Amedei A, Azzurri A, Vekemans J, Benagiano M, Tamburini C, et al. Polarization of PPDSpecific T-cell response of patients with tuberculosis from Th0 to Th1 profile after successful antimycobacterial therapy or in vitro conditioning with Interferon-a or Interleukin-12. Am J Respir Cell Mol Biol. 2001;24:187–94. 6 Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007;179:1634–47.

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