Vitamin D and tuberculosis in children: a role in the prevention or treatment of the disease?

Submitted: October 9, 2021
Accepted: March 24, 2022
Published: March 30, 2022
Abstract Views: 1720
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Authors

Despite the growing number of published studies, the role of vitamin D in the prevention or treatment of tuberculosis remains unclear. In this review we analyze current scientific literature to provide evidence about the relationship between vitamin D and TB, with a special focus on the pediatric population. While in vitro studies have shown relevant antimycobacterial immune-stimulatory and immunosuppressive effects of vitamin D, this has not panned out in vivo with active TB. On the contrary, there is some evidence that this tool could work as prevention – both against TB infection as well as progression from latent to active infection. However, only a few studies have evaluated this correlation in children. The potential link between tuberculosis and vitamin D levels is promising. If effective, vitamin D supplementation of at-risk populations would be an affordable public health intervention, particularly in light of the worldwide increase in identified TB cases and drug-resistance. Vitamin D might represent a new, affordable, safe and easy to access drug for the prevention and treatment of TB. For stronger evidence, considering the features of infection (relative low incidence of reactivation of latent infection in immunocompetent patients) we need clinical trials with large numbers of participants conducted in endemic regions with a prolonged follow-up time.

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Young DB, Gideon HP, Wilkinson RJ. Eliminating latent tuberculosis. Trends Microbiol 2009;17:183-8. DOI: https://doi.org/10.1016/j.tim.2009.02.005
Barry CE 3rd, Boshoff HI, Dartois V, et al. The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 2009;7:845-55. DOI: https://doi.org/10.1038/nrmicro2236
Gideon HP, Flynn JL. Latent tuberculosis: what the host "sees"? Immunol Res 2011;50:202-12. DOI: https://doi.org/10.1007/s12026-011-8229-7
Mtei L, Matee M, Herfort O, et al. High rates of clinical and subclinical tuberculosis among IV-infected ambulatory subjects in Tanzania. Clin Infect Dis 2005;40:1500-7. DOI: https://doi.org/10.1086/429825
Reljic R. IFN-gamma therapy of tuberculosis and related infections. J Interferon Cytokine Res 2007;27:353-64. DOI: https://doi.org/10.1089/jir.2006.0103
Ralph AP, Kelly PM, Anstey NM. L-arginine and vitamin D: novel adjunctive immunotherapies in tuberculosis. Trends Microbiol 2008;16:336-44. DOI: https://doi.org/10.1016/j.tim.2008.04.003
Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008;(1):CD002244. DOI: https://doi.org/10.1002/14651858.CD002244.pub3
Skerry C, Harper J, Klunk M, et al. Adjunctive TNF inhibition with standard treatment enhances bacterial clearance in a murine model of necrotic TB granulomas. PLoS One 2012;7:e39680. DOI: https://doi.org/10.1371/journal.pone.0039680
Ralph AP, Lucas RM, Norval M. Vitamin D and solar ultraviolet radiation in the risk and treatment of tuberculosis. Lancet Infect Dis 2013;13:77-88. Erratum in: Lancet Infect Dis 2013;13:106. Erratum in: Lancet Infect Dis 2013;13:192. DOI: https://doi.org/10.1016/S1473-3099(12)70275-X
Williams B, Williams AJ, Anderson ST. Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr Infect Dis J 2008;27:941-2. DOI: https://doi.org/10.1097/INF.0b013e31817525df
Torun E, Cakir E, Aktas EC, et al. Intracellular cytokine and cathelicidin secretion from monocytes and neutrophils in childhood tuberculosis. Pediatr Infect Dis J 2014;33:224-6. DOI: https://doi.org/10.1097/INF.0000000000000109
Mily A, Rekha RS, Kamal SM, et al. Significant effects of oral phenylbutyrate and vitamin D3 adjunctive therapy in pulmonary tuberculosis: A randomized controlled trial. PLoS One 2015;10:e0138340. DOI: https://doi.org/10.1371/journal.pone.0138340
Tukvadze N, Sanikidze E, Kipiani M, et al. High-dose vitamin D3 in adults with pulmonary tuberculosis: a double-blind randomized controlled trial. Am J Clin Nutr 2015;102:1059-69. DOI: https://doi.org/10.3945/ajcn.115.113886
Ustianowski A, Shaffer R, Collin S, Wilkinson RJ, Davidson RN. Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J Infect 2005;50:432-7. DOI: https://doi.org/10.1016/j.jinf.2004.07.006
Arnedo-Pena A, Juan-Cerdán JV, Romeu-Garcia A, et al. Latent tuberculosis infection, tuberculin skin test and vitamin D status in contacts of tuberculosis patients: a cross-sectional and case-control study. BMC Infect Dis 2011;11:349. DOI: https://doi.org/10.1186/1471-2334-11-349
Desai NS, Tukvadze N, Frediani JK, et al. Effects of sunlight and diet on vitamin D status of pulmonary tuberculosis patients in Tbilisi, Georgia. Nutrition 2012;28:362-6. DOI: https://doi.org/10.1016/j.nut.2011.08.012
Srinivasan A, Syal K, Banerjee D, et al. Low plasma levels of cholecalciferol and 13-cis-retinoic acid in tuberculosis: implications in host-based chemotherapy. Nutrition 2013;29:1245-51. DOI: https://doi.org/10.1016/j.nut.2013.03.018
Mehta S, Mugusi FM, Bosch RJ, et al.. Vitamin D status and TB treatment outcomes in adult patients in Tanzania: a cohort study. BMJ Open 2013;3:e003703. DOI: https://doi.org/10.1136/bmjopen-2013-003703
Sudfeld CR, Giovannucci EL, Isanaka S, et al. Vitamin D status and incidence of pulmonary tuberculosis, opportunistic infections, and wasting among HIV-infected Tanzanian adults initiating antiretroviral therapy. J Infect Dis 2013;207:378-85. DOI: https://doi.org/10.1093/infdis/jis693
Kibirige D, Mutebi E, Ssekitoleko R, et al. Vitamin D deficiency among adult patients with tuberculosis: a cross sectional study from a national referral hospital in Uganda. BMC Res Notes 2013;6:293. DOI: https://doi.org/10.1186/1756-0500-6-293
Joshi L, Ponnana M, Penmetsa SR, et al. Serum vitamin D levels and VDR polymorphisms (BsmI and FokI) in patients and their household contacts susceptible to tuberculosis. Scand J Immunol 2014;79:113-9. DOI: https://doi.org/10.1111/sji.12127
Huaman MA, Sterling TR, Shepherd BE, Fiske CT. 25-Hydroxyvitamin D levels after recovery from tuberculosis: insights into pathogenesis. Tuberculosis (Edinb) 2014;94:51-4. DOI: https://doi.org/10.1016/j.tube.2013.10.009
Glisson F, Bate G, Regemorter A. A treatise of the rickets: being a disease common to children. London: P. Cole; 1651.
Martineau AR. Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis. Proc Nutr Soc 2012;71:84-9. DOI: https://doi.org/10.1017/S0029665111003326
Green M. Cod liver oil and tuberculosis. BMJ 2011;343:d7505. DOI: https://doi.org/10.1136/bmj.d7505
Grad R. Cod and the consumptive: a brief history of cod-liver oil in the treatment of pulmonary tuberculosis. Pharm Hist 2004;46:106-20.
DeLuca HF. Vitamin D: Historical overview. Vitam Horm 2016;100:1-20. DOI: https://doi.org/10.1016/bs.vh.2015.11.001
Roelandts R. The history of phototherapy: something new under the sun? J Am Acad Dermatol 2002;46:926-30. DOI: https://doi.org/10.1067/mjd.2002.121354
Venanzetti M. [Anch'io fui studente al Forlanini. Una giornata con il suo fondatore tra segreti e curiosità].[Book in Italian]. Rome: Scienze e lettere; 2012.
Charpy J. [Clinical research on psoriasis therapy].[Article in French]. Ann Dermatol Syphiligr (Paris) 1945;5:227.
Phelan JJ. Calciferol in pulmonary tuberculosis. Lancet 1947;1:764. DOI: https://doi.org/10.1016/S0140-6736(47)91513-4
Ellman P, Anderson KH. Calciferol in tuberculous peritonitis with disseminated tuberculosis. Br Med J 1948;1:394. DOI: https://doi.org/10.1136/bmj.1.4547.394
Okamura WH, Midland MM, Hammond MW, et al. Chemistry and conformation of vitamin D molecules. J Steroid Biochem Mol Biol 1995;53:603-13. DOI: https://doi.org/10.1016/0960-0760(95)00107-B
Zhang R, Naughton DP. Vitamin D in health and disease: current perspectives. Nutr J 2010;9:65. DOI: https://doi.org/10.1186/1475-2891-9-65
Wagner CL, Greer FR, American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008;122:1142-52. Erratum in: Pediatrics 2009;123:197. DOI: https://doi.org/10.1542/peds.2008-1862
Mimouni FB, Shamir R. Vitamin D requirements in the first year of life. Curr Opin Clin Nutr Metab Care 2009;12:287-92. DOI: https://doi.org/10.1097/MCO.0b013e32832a1329
Battersby AJ, Kampmann B, Burl S. Vitamin D in early childhood and the effect on immunity to Mycobacterium tuberculosis. Clin Dev Immunol 2012;2012:430972. DOI: https://doi.org/10.1155/2012/430972
White JH. Vitamin D metabolism and signaling in the immune system. Rev Endocr Metab Disord 2012;13:21-9. DOI: https://doi.org/10.1007/s11154-011-9195-z
Norman AW, Mizwicki MT, Norman DP. Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model. Nat Rev Drug Discov 2004;3:27-41. DOI: https://doi.org/10.1038/nrd1283
Ariganjoye R. Pediatric hypovitaminosis D: Molecular perspectives and clinical implications. Glob Pediatr Health 2017;4:2333794X16685504. DOI: https://doi.org/10.1177/2333794X16685504
Ren S, Nguyen L, Wu S, et al. Alternative splicing of vitamin D-24-hydroxylase: a novel mechanism for the regulation of extrarenal 1,25-dihydroxyvitamin D synthesis. J Biol Chem 2005;280:20604-11. DOI: https://doi.org/10.1074/jbc.M414522200
Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311:1770-3. DOI: https://doi.org/10.1126/science.1123933
Fabri M, Stenger S, Shin DM, et al. Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med 2011;3:104ra102. DOI: https://doi.org/10.1126/scitranslmed.3003045
Hmama Z, Sendide K, Talal A, et al Quantitative analysis of phagolysosome fusion in intact cells: inhibition by mycobacterial lipoarabinomannan and rescue by an 1alpha,25-dihydroxyvitamin D3-phosphoinositide 3-kinase pathway. J Cell Sci 2004;117:2131-40. DOI: https://doi.org/10.1242/jcs.01072
Coussens A, Timms PM, Boucher BJ, et al. 1alpha,25-dihydroxyvitamin D3 inhibits matrix metalloproteinases induced by Mycobacterium tuberculosis infection. Immunology 2009;127:539-48. DOI: https://doi.org/10.1111/j.1365-2567.2008.03024.x
Vidyarani M, Selvaraj P, Jawahar MS, Narayanan PR. 1, 25 Dihydroxyvitamin D3 modulated cytokine response in pulmonary tuberculosis. Cytokine 2007;40:128-34. DOI: https://doi.org/10.1016/j.cyto.2007.08.005
Salamon H, Bruiners N, Lakehal K, et al. Cutting edge: Vitamin D regulates lipid metabolism in Mycobacterium tuberculosis infection. J Immunol 2014;193:30-4. DOI: https://doi.org/10.4049/jimmunol.1400736
Looman KIM, Jansen MAE, Voortman T, et al. The role of vitamin D on circulating memory T cells in children: The Generation R study. Pediatr Allergy Immunol 2017;28:579-87. DOI: https://doi.org/10.1111/pai.12754
Afsal K, Selvaraj P, Harishankar M. 1, 25-dihydroxyvitamin D3 downregulates cytotoxic effector response in pulmonary tuberculosis. Int Immunopharmacol 2018;62:251-60. DOI: https://doi.org/10.1016/j.intimp.2018.07.018
Facchini L, Venturini E, Galli L, et al. Vitamin D and tuberculosis: a review on a hot topic. J Chemother 2015;27:128-38. DOI: https://doi.org/10.1179/1973947815Y.0000000043
Gough ME, Graviss EA, May EE. The dynamic immunomodulatory effects of vitamin D3 during Mycobacterium infection. Innate Immun 2017;23:506-23. DOI: https://doi.org/10.1177/1753425917719143
Kampmann B, Gaora PO, Snewin VA, et al. Evaluation of human antimycobacterial immunity using recombinant reporter mycobacteria. J Infect Dis 2000;182:895-901. DOI: https://doi.org/10.1086/315766
Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A single dose of vitamin D enhances immunity to mycobacteria. Am J Respir Crit Care Med 2007;176:208-13. DOI: https://doi.org/10.1164/rccm.200701-007OC
Yesudian PD, Berry JL, Wiles S, et al. The effect of ultraviolet B-induced vitamin D levels on host resistance to Mycobacterium tuberculosis: a pilot study in immigrant Asian adults living in the United Kingdom. Photodermatol Photoimmunol Photomed 2008;24:97-8. DOI: https://doi.org/10.1111/j.1600-0781.2008.00339.x
Coussens AK, Wilkinson RJ, Hanifa Y, et al. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc Natl Acad Sci USA 2012;109:15449-54. DOI: https://doi.org/10.1073/pnas.1200072109
Lalvani A, Connell DW. Dissecting the immunological, antimicrobial and clinical effects of vitamin D therapy in tuberculosis. Pathog Glob Health 2012;106:378-9. DOI: https://doi.org/10.1179/2047772412Z.00000000087
Reeme AE, Robinson RT. Dietary vitamin D3 suppresses pulmonary immunopathology associated with late-stage tuberculosis in C3HeB/FeJ mice. J Immunol 2016;196:1293-304. DOI: https://doi.org/10.4049/jimmunol.1500931
Davies PD. A possible link between vitamin D deficiency and impaired host defence to Mycobacterium tuberculosis. Tubercle 1985;66:301-6. DOI: https://doi.org/10.1016/0041-3879(85)90068-6
Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 2008;37:113-9. DOI: https://doi.org/10.1093/ije/dym247
Zeng J, Wu G, Yang W, et al. A serum vitamin D level <25nmol/l pose high tuberculosis risk: a meta-analysis. PLoS One 2015;10:e0126014. DOI: https://doi.org/10.1371/journal.pone.0126014
Gou X, Pan L, Tang F, et al. The association between vitamin D status and tuberculosis in children: A meta-analysis. Medicine (Baltimore) 2018;97:e12179. DOI: https://doi.org/10.1097/MD.0000000000012179
Davies PD, Church HA, Brown RC, Woodhead JS. Raised serum calcium in tuberculosis patients in Africa. Eur J Respir Dis 1987;71:341-4.
Davies PD, Church HA, Bovornkitti S. Altered vitamin D homeostasis in tuberculosis. Int Med Thailand 1988;4:45-47.
Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 2000;355618-21. DOI: https://doi.org/10.1016/S0140-6736(99)02301-6
Sasidharan PK, Rajeev E, Vijayakumari V. Tuberculosis and vitamin D deficiency. J Assoc Physicians India 2002;50:554-8.
Sita-Lumsden A, Lapthorn G, Swaminathan R, Milburn HJ. Reactivation of tuberculosis and vitamin D deficiency: the contribution of diet and exposure to sunlight. Thorax 2007;62:1003-7. DOI: https://doi.org/10.1136/thx.2006.070060
Gibney KB, MacGregor L, Leder K, et al. Vitamin D deficiency is associated with tuberculosis and latent tuberculosis infection in immigrants from sub-Saharan Africa. Clin Infect Dis 2008;46:443-6. DOI: https://doi.org/10.1086/525268
Ho-Pham LT, Nguyen ND, Nguyen TT, et al. Association between vitamin D insufficiency and tuberculosis in a Vietnamese population. BMC Infect Dis 2010;10:306. DOI: https://doi.org/10.1186/1471-2334-10-306
Grange JM, Davies PD, Brown RC, et al. A study of vitamin D levels in Indonesian patients with untreated pulmonary tuberculosis. Tubercle 1985;66:187-91. DOI: https://doi.org/10.1016/0041-3879(85)90035-2
Chan TY, Poon P, Pang J, et al. A study of calcium and vitamin D metabolism in Chinese patients with pulmonary tuberculosis. J Trop Med Hyg 1994;97:26-30.
Martineau AR, Leandro AC, Anderson ST, et al. Association between Gc genotype and susceptibility to TB is dependent on vitamin D status. Eur Respir J 2010;35:1106-12. DOI: https://doi.org/10.1183/09031936.00087009
Nielsen NO, Skifte T, Andersson M, et al. Both high and low serum vitamin D concentrations are associated with tuberculosis: a case-control study in Greenland. Br J Nutr 2010;104:1487-91. DOI: https://doi.org/10.1017/S0007114510002333
Mastala Y, Nyangulu P, Banda RV, et al. Vitamin D deficiency in medical patients at a central hospital in Malawi: a comparison with TB patients from a previous study. PLoS One 2013;8:e59017. DOI: https://doi.org/10.1371/journal.pone.0059017
Buonsenso D, Focarelli B, Scalzone M, et al. Chest wall TB and low 25-hidroxy-vitamin D levels in a 15-month-old girl. Ital J Pediatr 2012;38:12. DOI: https://doi.org/10.1186/1824-7288-38-12
Talat N, Perry S, Parsonnet J, et al. Vitamin d deficiency and tuberculosis progression. Emerg Infect Dis 2010;16:853-5. DOI: https://doi.org/10.3201/eid1605.091693
Yani FF, Lipoeto NI, Supriyatno B, et al. Vitamin D status in under-five children with a history of close tuberculosis contact in Padang, West Sumatra. Asia Pac J Clin Nutr 2017;26:S68-72.
Koh GC, Hawthorne G, Turner AM, et al. Tuberculosis incidence correlates with sunshine: an ecological 28-year time series study. PLoS One 2013;8:e57752. DOI: https://doi.org/10.1371/journal.pone.0057752
Margalit I, Block C, Mor Z. Seasonality of tuberculosis in Israel, 2001-2011. Int J Tuberc Lung Dis 2016;20:1588-93. DOI: https://doi.org/10.5588/ijtld.16.0306
Gray K, Wood N, Gunasekera H, et al. Vitamin d and tuberculosis status in refugee children. Pediatr Infect Dis J 2012;31:521-3. DOI: https://doi.org/10.1097/INF.0b013e3182456c55
Gupta A, Montepiedra G, Gupte A, et al. Low vitamin-D levels combined with PKP3-SIGIRR-TMEM16J host variants is associated with tuberculosis and death in HIV-infected and -exposed infants. PLoS One 2016;11:e0148649. DOI: https://doi.org/10.1371/journal.pone.0148649
Walker VP, Modlin RL. The vitamin D connection to pediatric infections and immune function. Pediatr Res 2009;65:106R-113. DOI: https://doi.org/10.1203/PDR.0b013e31819dba91
Yamshchikov AV, Kurbatova EV, Kumari M, et al. Vitamin D status and antimicrobial peptide cathelicidin (LL-37) concentrations in patients with active pulmonary tuberculosis. Am J Clin Nutr 2010;92:603-11. DOI: https://doi.org/10.3945/ajcn.2010.29411
Iftikhar R, Kamran SM, Qadir A, et al. Vitamin D deficiency in patients with tuberculosis. J Coll Physicians Surg Pak 2013;23:780-3.
Martineau AR, Honecker FU, Wilkinson RJ, Griffiths CJ. Vitamin D in the treatment of pulmonary tuberculosis. J Steroid Biochem Mol Biol 2007;103:793-8. DOI: https://doi.org/10.1016/j.jsbmb.2006.12.052
Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2009;179:843-50. DOI: https://doi.org/10.1164/rccm.200804-567OC
Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 2011;377:242-50. DOI: https://doi.org/10.1016/S0140-6736(10)61889-2
Nursyam EW, Amin Z, Rumende CM. The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion. Acta Med Indones 2006;38:3-5.
Salahuddin N, Ali F, Hasan Z, et al. 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'. BMC Infect Dis 2013;13:22. DOI: https://doi.org/10.1186/1471-2334-13-22
Morcos MM, Gabr AA, Samuel S, et al. Vitamin D administration to tuberculous children and its value. Boll Chim Farm 1998;137:157-64.
Ganmaa D, Giovannucci E, Bloom BR, et al. Vitamin D, tuberculin skin test conversion, and latent tuberculosis in Mongolian school-age children: a randomized, double-blind, placebo-controlled feasibility trial. Am J Clin Nutr 2012;96:391-6. DOI: https://doi.org/10.3945/ajcn.112.034967
Khandelwal D, Gupta N, Mukherjee A, et al. Vitamin D levels in Indian children with intrathoracic tuberculosis. Indian J Med Res 2014;140:531-7.
Mukherjee A, Saini S, Kabra SK, et al. Effect of micronutrient deficiency on QuantiFERON-TB Gold In-Tube test and tuberculin skin test in diagnosis of childhood intrathoracic tuberculosis. Eur J Clin Nutr 2014;68:38-42. DOI: https://doi.org/10.1038/ejcn.2013.216
Balcells ME, Yokobori N, Hong BY, et al. The lung microbiome, vitamin D, and the tuberculous granuloma: A balance triangle. Microb Pathog 2019;131:158-63. DOI: https://doi.org/10.1016/j.micpath.2019.03.041
Buonsenso D, Lancella L, Delogu G, et al. A twenty-year retrospective study of pediatric tuberculosis in two tertiary hospitals in Rome. Pediatr Infect Dis J 2012;31:1022-6. DOI: https://doi.org/10.1097/INF.0b013e3182615270
Danilo Buonsenso, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario “Agostino Gemelli”, Rome

Department of Basic Biotechnological Sciences, Intensive and Perioperative Clinics, Catholic University of the Sacred Heart, Rome, Italy.
Center for Global Health Research and Studies, Catholic University of Sacred Heart, Rome, Italy.

How to Cite

Buonsenso, Danilo, Davide Pata, Arianna Turriziani Colonna, Vittoria Ferrari, Gilda Salerno, and Piero Valentini. 2022. “Vitamin D and Tuberculosis in Children: A Role in the Prevention or Treatment of the Disease?”. Monaldi Archives for Chest Disease 92 (4). https://doi.org/10.4081/monaldi.2022.2112.