Serum and Bronchoalveolar Lavage Fluid 25(OH)Vitamin D3 Levels in HIV-1 and Tuberculosis: A Cross-Sectional Study from a Tertiary Care Center in North India

Author(s): Sanjeev Sinha*, Kartik Gupta, Dibyakanti Mandal, B.K. Das, R.M. Pandey

Journal Name: Current HIV Research

Volume 16 , Issue 2 , 2018

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: Vitamin D is an immunomodulator, and its deficiency is associated with Tuberculosis (TB) infection. Bronchoalveolar lavage fluid (BALF) is a rich milieu of macrophages that form the first line of defense against invading TB bacilli. As there is an increased prevalence of vitamin D deficiency in TB and human immunodeficiency virus-1 (HIV-1) subjects, we intend exploring the possibility of a localized deficiency of vitamin D metabolites in BALF of these patients.

Objective: The primary objective was to assess the level of 25D3 in serum and BALF of subjects and look for a significant difference among patients and controls. The secondary objective was to find a correlation between serum and BALF 25D3 levels.

Methods: We performed a cross-sectional study with subjects divided into four groups: Controls (group 1), HIV positive without active TB (group 2), active TB without HIV (group 3), and HIV-TB coinfection (group 4). BALF and serum 25D3 levels were compared between the groups.

Results: Among the 149 (an immunomodulator) successive subjects enrolled, there were 40 subjects in group 1 (HIV-TB-), 48 in group 2 (HIV+TB-), 37 in group 3 (HIV-TB+), and 24 in group 4 (HIV+TB+). Females constituted 31.6% of the study subjects. In groups 3 and 4, there were significantly lower serum 25D3 levels compared to group 1 (p-value group 3: 0.002; group 4: 0.012). In groups 2, 3, and 4, there were significantly lower BALF 25D3 levels compared to group 1 (p-value group 2: 0.000; group 3: 0.000; group 4: 0.001). There was a significant correlation between serum and BALF 25D3 levels (Spearman’s rank correlation coefficient 0.318, p-value = 0.0001).

Conclusion: Lower levels of serum and BALF 25D3 were observed in HIV, TB, and HIV-TB coinfected patients. Localized deficiency of vitamin D metabolites might be associated with increased vulnerability to TB infection.

Keywords: Vitamin 25D3, HIV-1, TB, HIV-1& TB Co-infection, BALF 25D3, Serum.

TB India 2017 Central TB Division [Internet]. Available from: https: // 1&level=2&sublinkid= 4728&lid=3275 [cited 2018 Apr 11].
Pawlowski A, Jansson M, Sköld M, Rottenberg ME, Källenius G. Tuberculosis and HIV Co-Infection. PLoS Pathog 2012; 8(2): e1002464.
Jambo KC, Banda DH, Kankwatira AM, et al. Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function. Mucosal Immunol 2014; 7(5): 1116-26.
Reardon C, Kim S, Wagner R, Koziel H, Kornfield H. Phagocytosis and growth inhibition of Cryptococcus neoformans by human alveolar macrophages: effects of HIV-1 infection. AIDS 1996; 10: 613-8.
Shellito JE. Failure of host defenses in human immunodeficiency virus. Semin Respir Crit Care Med 2004; 25(1): 73-84.
Patel NR, Zhu J, Tachado SD, et al. HIV impairs TNF-alpha mediated macrophage apoptotic response to Mycobacterium tuberculosis. J Immunol Baltim Md 1950. 2007; 179(10): 6973-80.
Anandaiah A, Sinha S, Bole M, et al. Vitamin D rescues impaired Mycobacterium tuberculosis-mediated tumor necrosis factor release in macrophages of HIV-seropositive individuals through an enhanced Toll-like receptor signaling pathway in vitro. Infect Immun 2013; 81(1): 2-10.
Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J Off Publ Fed Am Soc Exp Biol 2001; 15(14): 2579-85.
Adorini L, Giarratana N, Penna G. Pharmacological induction of tolerogenic dendritic cells and regulatory T cells. Semin Immunol 2004; 16(2): 127-34.
Wu G, Zhao M, Gu X, Yao Y, Liu H, Song Y. The effect of P2X7 receptor 1513 polymorphism on susceptibility to tuberculosis: A meta-analysis. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis 2014; 24: 82-91.
Nava-Aguilera E, Andersson N, Harris E, et al. Risk factors associated with recent transmission of tuberculosis: systematic review and meta-analysis. Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis 2009; 13(1): 17-26.
Lalvani A, Connell DW. Dissecting the immunological, antimicrobial and clinical effects of vitamin D therapy in tuberculosis. Pathog Glob Health 2012; 106(7): 378-9.
Gombart AF. The vitamin D-antimicrobial peptide pathway and its role in protection against infection. Future Microbiol 2009; Nov 4: 1151.
Ramanathan B, Davis EG, Ross CR, Blecha F. Cathelicidins: microbicidal activity, mechanisms of action, and roles in innate immunity. Microbes Infect 2002; 4(3): 361-72.
Liu PT, Stenger S, Tang DH, Modlin RL. Cutting edge: vitamin Dmediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol Baltim Md 1950. 2007; 179(4): 2060-3.
Hewison M. Vitamin D and immune function: an overview. Proc Nutr Soc 2012; 71(1): 50-61.
Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311(5768): 1770-3.
von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol 2010; 11(4): 344-9.
Khoo A-L, Joosten I, Michels M, Woestenenk R, Preijers F, He X-H, et al. 1,25-Dihydroxyvitamin D3 inhibits proliferation but not the suppressive function of regulatory T cells in the absence of antigen-presenting cells. Immunology 2011; 134(4): 459-68.
Nnoaham KE, Clarke A. Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 2008; 37(1): 113-9.
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(5): e0126014.
Maceda EB, Gonçalves CCM, Andrews JR, Ko AI, Yeckel CW, Croda J. Serum vitamin D levels and risk of prevalent tuberculosis, incident tuberculosis and tuberculin skin test conversion among prisoners. Sci Rep 2018; 8(1): 997.
Tenforde MW, Yadav A, Dowdy DW, et al. Vitamin A and D Deficiencies Associated With Incident Tuberculosis in HIV-Infected Patients Initiating Antiretroviral Therapy in Multinational Case-Cohort Study. J Acquir Immune Defic Syndr 2017; 75(3): e71-9.
Garbinski T, Ludewig F. [Sun-ray treatment in pulmonary tuberculosis with antistine protection]. Schweiz Z Tuberk Pneumonol Rev Suisse Tuberc Pneumonol Riv Svizzera Della Tubercolosi E Della Pneumonol 1956; 13(5): 440-8.
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 Lond Engl 2011; 377(9761): 242-50.
Green M. Cod liver oil and tuberculosis. BMJ 2011; 343: d7505.
Naeem Z, Vitamin D. Deficiency- An Ignored Epidemic. Int J Health Sci 2010; 4(1): V-VI.
Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JPA. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ 2014; Apr 1 348: g2035.
Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med 2008; Aug 11 168(15): 1629-37.
Zittermann A, Schleithoff SS, Frisch S, Götting C, Kuhn J, Koertke H, et al. Circulating calcitriol concentrations and total mortality. Clin Chem 2009; 55(6): 1163-70.
Havers F, Smeaton L, Gupte N, et al. 25-Hydroxyvitamin D insufficiency and deficiency is associated with HIV disease progression and virological failure post-antiretroviral therapy initiation in diverse multinational settings. J Infect Dis 2014; 210(2): 244-53.
Shepherd L, Souberbielle J-C, Bastard J-P, et al. Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons. J Infect Dis 2014; 210(2): 234-43.
Viard J-P, Souberbielle J-C, Kirk O, et al. Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study. AIDS Lond Engl 2011 Jun 19; 25(10): 1305-15.
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(1): 3-5.
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(9): 843-50.
Grobler L, Nagpal S, Sudarsanam TD, Sinclair D. Nutritional supplements for people being treated for active tuberculosis. Cochrane Infectious Diseases Group, editor. Cochrane Database Syst Rev [Internet]. 2016 Jun 29 [cited 2018 Apr 11]; Available from: http: //
Rennard SI, Basset G, Lecossier D, et al. Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol Bethesda Md (1985) 1986; 60(2): 532-8.
IndianJMedRes1273207-2847408_075434.pdf [Internet]. [cited 2018 Apr 11]. Available from: http: // temp/ IndianJMedRes1273207-2847408_075434.pdf
Talat N, Perry S, Parsonnet J, Dawood G, Hussain R, Vitamin D. Deficiency and Tuberculosis Progression. Emerg Infect Dis 2010; 16(5): 853-5.
Ho-Pham LT, Nguyen ND, Nguyen TT, et al. Association between vitamin D insufficiency and tuberculosis in a Vietnamese population. BMC Infect Dis 2010; Oct 25 10: 306.
Huang S-J, Wang X-H, Liu Z-D, et al. Vitamin D deficiency and the risk of tuberculosis: a meta-analysis. Drug Des Devel Ther 2016; 11: 91-102.
Haug C, Müller F, Aukrust P, Frøland SS. Subnormal serum concentration of 1,25-vitamin D in human immunodeficiency virus infection: correlation with degree of immune deficiency and survival. J Infect Dis 1994; 169(4): 889-93.
JE L JS A. Vitamin D in HIV-Infected Patients. Curr HIV/AIDS Rep 2011; 8(3): 133-41.
Villamor E. A potential role for vitamin D on HIV infection? Nutr Rev 2006; 64(5 Pt 1): 226-33.
Tsai KS, Wahner HW, Offord KP, Melton LJ, Kumar R, Riggs BL. Effect of aging on vitamin D stores and bone density in women. Calcif Tissue Int 1987; 40(5): 241-3.
Czernichow S, Fan T, Nocea G, Sen SS. Calcium and vitamin D intake by postmenopausal women with osteoporosis in France. Curr Med Res Opin 2010; 26(7): 1667-74.
Lamberg-Allardt CJ, Outila TA, Kärkkainen MU, Rita HJ, Valsta LM. Vitamin D deficiency and bone health in healthy adults in Finland: could this be a concern in other parts of Europe? J Bone Miner Res Off J Am Soc Bone Miner Res 2001; 16(11): 2066-73.
Wilkinson RJ, Llewelyn M, Toossi Z, Patel P, Pasvol G, Lalvani A, 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 Lond Engl 2000; 355(9204): 618-21.
Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ. 1,25(OH)2D2 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest 1990; 85(5): 1588-93.
Cadranel J, Hance AJ, Milleron B, Paillard F, Akoun GM, Garabedian M. Vitamin D metabolism in tuberculosis. Production of 1,25(OH)2D3 by cells recovered by bronchoalveolar lavage and the role of this metabolite in calcium homeostasis. Am Rev Respir Dis 1988; 138(4): 984-9.
Barnes PF, Modlin RL, Bikle DD, Adams JS. Transpleural gradient of 1,25-dihydroxyvitamin D in tuberculous pleuritis. J Clin Invest 1989; 83(5): 1527-32.
Cadranel JL, Garabédian M, Milleron B, et al. Vitamin D metabolism by alveolar immune cells in tuberculosis: correlation with calcium metabolism and clinical manifestations. Eur Respir J 1994; 7(6): 1103-10.
Ralph AP, Rashid Ali MRS, William T, et al. Vitamin D and activated vitamin D in tuberculosis in equatorial Malaysia: a prospective clinical study. BMC Infect Dis [Internet]. 2017 Apr 27 [cited 2018 Apr 14]; 17. Available from: https: // pmc/articles/PMC5408363/
Owolabi O, Agbla S, Owiafe P, et al. Elevated serum 25-hydroxy (OH) vitamin D levels are associated with risk of TB progression in Gambian adults. Tuberculosis (Edinb) Scotl 2016; 98: 86-91.
Friis H, Range N, Changalucha J, et al. Vitamin D Status among Pulmonary TB Patients and Non-TB Controls: A Cross-Sectional Study from Mwanza, Tanzania. PLoS One 2013; 8(12): e81142.
Flauzino T, Simao ANC, de Almeida ERD, et al. Association between Vitamin D Status, Oxidative Stress Biomarkers and Viral Load in Human Immunodeficiency Virus Type 1 Infection. Curr HIV Res 2017; 15(5): 336-44.
Liu MC, Xiao H-Q, Brown AJ, Ritter CS, Schroeder J. Association of vitamin D and antimicrobial peptide production during late-phase allergic responses in the lung. Clin Exp Allergy J Br Soc Allergy Clin Immunol 2012; 42(3): 383-91.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2018
Published on: 15 August, 2018
Page: [167 - 173]
Pages: 7
DOI: 10.2174/1570162X16666180528112924
Price: $65

Article Metrics

PDF: 23