Aim: To review the role of vitamin D in COVID-19.
Background: The COVID-19 pandemic has caused a tremendous social and economic impact worldwide, and rapid outspreading of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still being seen in India. Currently, there are two explanations available for the fatal ARDS in COVID-19 cases. Cytokine storm is characterized by unregulated release of various proinflammatory cytokines, i.e., TNF-α, INF-γ, IL2, IL6, IL8, IL12, CCL2, CCL3, and CXCL10, after interaction between SARS-CoV-2 and host immune cells. On the other hand, bradykinin storm is happening due to downregulation of ACE in the lung tissue. Immunomodulatory effects of vitamin D is proved through various studies. There is no individual therapy and vaccination for the SARS-Cov-2; thus, repurposing of available medicines is crucial now. Antiviral, anti-inflammatory, and immuno-boosting effects of vitamin D has proven in many studies. These effects are very relevant for its putative beneficial effect in SARS-CoV-2.
Review result: Vitamin D has already been used as a repurposed drug in H5N1 pneumonia. Immunomodulatory and antibacterial role of vitamin D is well established. There are studies suggesting toward the cytokine storm as a main culprit behind deadly ARDS in COVID-19. Vitamin D was found as an anti-inflammatory and lung protective substance. Vitamin D was also found protective against bacterial LPS-induced injury by increasing expression of ACE-II and producing antibacterial protein cathelicidin.
Conclusion: Before COVID-19 pandemic, we realized the silent pandemic of vitamin D deficiency. The immunomodulatory, anti-inflammatory, and antibacterial role of vitamin D has been shown in many studies. There are studies which have demonstrated the inverse relationship between vitamin D level and susceptibility to COVID-19. Vitamin-D also plays a crucial role in limiting the fibrosis in the damaged pulmonary tissue and also responsible for deciding overall morbidity of the patient. Thus, it is imperative to think about the potential of vitamin D as a repurposed drug for COVID-19 cases.
Li H, Wang Y, Ji M, et al. Transmission routes analysis of SARS-CoV-2: a systematic review and case report. Front Cell Dev Biol 2020;8:618. DOI: 10.3389/fcell.2020.00618.
Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395(10223):507–513. DOI: 10.1016/S0140-6736(20)30211-7.
Long Q-X, Liu B-Z. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat Med 2020;26(6):845–848. DOI: 10.1038/s41591-020-0897-1.
Lau YL, Malik Peiris JS. Pathogenesis of severe acute respiratory syndrome. Curr Opin Immunol 2005;17(4):404–410. DOI: 10.1016/j.coi.2005.05.009.
Conti P, Ronconi G, Caraffa A, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 2020;34(2):327–331. DOI: 10.23812/CONTI-E.
Chen C, Zhang XR, Ju ZY, et al. Advances in the research of cytokine storm mechanism induced by corona virus disease 2019 and the corresponding immunotherapies. Zhonghua Shaoshang Zazhi 2020;36(6):471–475.
Garvin MR, Alvarez C, Miller JI, et al. A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm. eLife 2020;9:e59177. DOI: 10.7554/eLife.59177.
Zhang Y, Leung DYM, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. J Immunol 2012;188(5):2127–2135. DOI: 10.4049/jimmunol.1102412.
Greiller CL, Martineau AR. Modulation of the immune response to respiratory viruses by vitamin D. Nutrients 2015;7(6):4240–4270. DOI: 10.3390/nu7064240.
Zdrenghea MT, Makrinioti H, Bagacean C, et al. Vitamin D modulation of innate immune responses to respiratory viral infections. Rev Med Virol 2017;27(1). DOI: 10.1002/rmv.1909.
Ardizzone S, Cassinotti A, Trabattoni D, et al. Immunomodulatory effects of 1,25-dihydroxyvitamin D3 on TH1/TH2 cytokines in inflammatory bowel disease: an in vitro study. Int J Immunopathol Pharmacol 2009;22(1):63–71. DOI: 10.1177/039463200902200108.
Palmer MT, Lee YK, Maynard CL, et al. Lineage-specific effects of 1,25-dihydroxyvitamin D (3) on the development of effector CD4 T cells. J Biol Chem 2011;286(2):997–1004. DOI: 10.1074/jbc.M110.163790.
Peterson CA, Heffernan ME. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. J Inflamm (Lond) 2008;5(1):10. DOI: 10.1186/1476-9255-5-10.
Cui C, Xu P, Li G, et al. Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system. Redox Biol 2019;26:101295. DOI: 10.1016/j.redox.2019.101295.
Lin M, Gao P, Zhao T, et al. Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease. Mol Biol Rep 2016;43(5):397–406. DOI: 10.1007/s11033-016-3971-5.
Li YC, Qiao G, Uskokovic M, et al. Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol 2004;89-90(1-5):387–392. DOI: 10.1016/j.jsbmb.2004.03.004.
Hanff TC, Harhay MO, Brown TS, et al. Is there an association between COVID-19 mortality and the renin-angio-tensin system–a call for epidemiologic investigations. Clin Infect Dis 2020(15):ciaa329. DOI: 10.1093/cid/ciaa329.
Li X, Molina-Molina M, Abdul-Hafez A, et al. Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2008;295(1):L178–L185. DOI: 10.1152/ajplung.00009.2008.
Li X, Zhang H, Soledad-Conrad V, et al. Bleomycin-induced apoptosis of alveolar epithelial cells requires angiotensin synthesis de novo. Am J Physiol Lung Cell Mol Physiol 2003;284(3):L501–L507. DOI: 10.1152/ajplung.00273.2002.
Bader M. Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy. Annu Rev Pharmacol Toxicol 2010;50(1):439–465. DOI: 10.1146/annurev.pharmtox.010909.105610.
Lee VY, Schroedl C, Brunelle JK, et al. Bleomycin induces alveolar epithelial cell death through JNK-dependent activation of the mitochondrial death pathway. Am J Physiol Lung Cell Mol Physiol 2005;289(4):L521–L528. DOI: 10.1152/ajplung.00340.2004.
Laird E, Rhodes J, Kenny RA. Vitamin D and inflammation: potential implications for severity of COVID-19. Ir Med J 2020;113:81.
Mark. B. Latitude dependence of the COVID-19 mortality rate-A possible relationship to vitamin D deficiency? SSRN Electro J 2020;26:3561958.
Teymoori-Rad M, Shokri F, Salimi V, et al. The interplay between vitamin D and viral infections. Rev Med Virol 2019;29(2):e2032. DOI: 10.1002/rmv.2032.
Merzon E, Tworowski D, Gorohovski A, et al. Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. MedRxiv 2020. DOI: 10.1101/2020.07.01.20144329.
Hastie CE, Mackay DF, Ho F, et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes MetabSyndr 2020;14(4):561–565. DOI: 10.1016/j.dsx.2020.04.050.
Huang F, Zhang C, Liu Q, et al. Identification of amitriptyline HCl, flavin adenine dinucleotide, azacitidine and calcitriol as repurposing drugs for influenza A H5N1 virus-induced lung injury. PLoS Pathog 2020;16(3):e1008341. DOI: 10.1371/journal.ppat.1008341.
Jiménez-Sousa MÁ, Martínez I, Medrano LM, et al. Vitamin D in human immunodeficiency virus infection: influence on immunity and disease. Front Immunol 2018;9:458. DOI: 10.3389/fimmu.2018.00458.
Jiménez-Sousa MA, Jiménez JL, Fernández-Rodríguez A, et al. VDR rs2228570 polymorphism is related to non-progression to AIDS in antiretroviral therapy naïve HIV infected patients. J Clin Med 2019;8(3):E311. DOI: 10.3390/jcm8030311.
Kong J, Zhu X, Shi Y, et al. VDR attenuates acute lung injury by blocking Ang-2 pathway and rennin angiotensin system. Mol Endocrinol 2013;27(12):2116–2125. DOI: 10.1210/me.2013-1146.
Panagiotou G, Tee SA, Ihsan Y, et al. Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalised with COVID-19 are associated with greater disease severity. Clin Endocrinol (Oxf) 2020(4). DOI: 10.1111/cen.14276.
Xu J, Yang J, Chen J, et al. Vitamin D alleviates lipopolysaccharide-induced acute lung injury via regulation of the renin angiotensin system. Mol Med Rep 2017;16(5):7432–7438. DOI: 10.3892/mmr.2017.7546.
Tsujino I, Ushikoshi-Nakayama R, Yamazaki T, et al. Pulmonary activation of vitamin D3 and preventive effect against interstitial pneumonia. J Clin BiochemNutr 2019;65:245–251.
Croy HE, Abrahams SJ, Raed A, et al. Cathelicidin antimicrobial protein, vitamin D, and risk of death in critically ill patients. Crit Care 2015;19(1):80. DOI: 10.1186/s13054-015-0812-1.
Xiong Y, Liu Y, Cao L, et al. Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients. Emerg Microbes Infect 2020;9(1):761–770. DOI: 10.1080/22221751.2020.1747363.
Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta‐analysis of individual participant data. BMJ 2017;356:i6583. DOI: 10.1136/bmj.i6583.
Jolliffe D, Camargo CA, Sluyter J, et al. Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials. MedRx 2020.
Zhou YF, Luo BA, Qin LL. The association between vitamin D deficiency and community-acquired pneumonia: a meta-analysis of observational studies. Medicine (Baltimore) 2019;98(38):e17252. DOI: 10.1097/MD.0000000000017252.
Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res 2020;32(7):1195–1198. DOI: 10.1007/s40520-020-01570-8.
Mok CK, Ng YL, Ahidjo BA, et al. Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis. MedRxiv 2020.