Vitamin D Supplementation to Prevent COVID-19 Infections and Deaths—Accumulating Evidence from Epidemiological and Intervention Studies Calls for Immediate Action
Hermann Brenner
Nutrients, doi:10.3390/nu13020411
The COVID-19 pandemic poses an unprecedented threat to human health, health care systems, public life, and economy around the globe. The repertoire of effective therapies for severe courses of the disease has remained limited. A large proportion of the world population suffers from vitamin D insufficiency or deficiency, with prevalence being particularly high among the COVID-19 high-risk populations. Vitamin D supplementation has been suggested as a potential option to prevent COVID-19 infections, severe courses, and deaths from the disease, but is not widely practiced. This article provides an up-to-date summary of recent epidemiological and intervention studies on a possible role of vitamin D supplementation for preventing severe COVID-19 cases and deaths. Despite limitations and remaining uncertainties, accumulating evidence strongly supports widespread vitamin D supplementation, in particular of high-risk populations, as well as high-dose supplementation of those infected. Given the dynamics of the COVID-19 pandemic, the benefit-risk ratio of such supplementation calls for immediate action even before results of ongoing large-scale randomized trials become available.
References
Abdollahi, Sarvestani, Rafat, Ghaderkhani, Mahmoudi-Aliabadi et al., The Association Between the Level of Serum 25(OH) Vitamin D, Obesity, and underlying Diseases with the risk of Developing COVID-19 Infection: A case-control study of hospitalized patients in Tehran, Iran, J. Med. Virol,
doi:10.1002/jmv.26726Annweiler, Corvaisier, Gautier, Dubée, Legrand et al., Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study, Nutrients,
doi:10.3390/nu12113377Annweiler, Hanotte, Grandin De L'eprevier, Sabatier, Lafaie et al., Vitamin D and survival in COVID-19 patients: A quasi-experimental study, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2020.105771Brenner, Holleczek, Schöttker, Vitamin, Insufficiency and Deficiency and Mortality from Respiratory Diseases in a Cohort of Older Adults: Potential for Limiting the Death Toll during and beyond the COVID-19 Pandemic?, Nutrients,
doi:10.3390/nu12082488Brenner, Jansen, Saum, Holleczek, Schöttker, Vitamin D Supplementation Trials Aimed at Reducing Mortality Have Much Higher Power When Focusing on People with Low Serum 25-Hydroxyvitamin D Concentrations, J. Nutr,
doi:10.3945/jn.117.250191Brenner, Schöttker, Vitamin D insufficiency may account for almost nine of ten COVID-19 deaths: Time to act, Nutrients,
doi:10.3390/nu12123642Camargo, Jr, Martineau, Vitamin D to prevent COVID-19: Recommendations for the design of clinical trials, FEBS J,
doi:10.1111/febs.15534Cangiano, Fatti, Danesi, Gazzano, Croci et al., Mortality in an Italian nursing home during COVID-19 pandemic: Correlation with gender, age, ADL, vitamin D supplementation, and limitations of the diagnostic tests, Aging
Cantorna, Mechanisms underlying the e_ect of vitamin D on the immune system, Proc. Nutr. Soc
Cantorna, Snyder, Lin, Yang, Vitamin D and 1,25(OH)2D regulation of T cells, Nutrients,
doi:10.3390/nu7043011Cashman, Dowling, Škrabáková, Gonzalez-Gross, Valtueña et al., Vitamin D deficiency in Europe: Pandemic?, Am. J. Clin. Nutr,
doi:10.3945/ajcn.115.120873Castillo, Costa, Barrios, Díaz, Miranda et al., Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study, J. Steroid Biochem. Mol. Biol,
doi:10.1016/j.jsbmb.2020.105751Covid, 19 and Vitamin D Supplementation: A Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin
Faniyi, Lugg, Faustini, Webster, Duffy et al., Vitamin D status and seroconversion for COVID-19 in UK healthcare workers, Eur. Respir. J
Grant, Lahore, Mcdonnell, Baggerly, French et al., Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths, Nutrients,
doi:10.3390/nu12040988Griffin, Wall, Blake, Griffin, Robinson et al., Vitamin D Status of Adults in the Community, in Outpatient Clinics, in Hospital, and in Nursing Homes in the West of Ireland, J. Gerontol. A Biol. Sci. Med. Sci,
doi:10.1093/gerona/glaa010Hastie, Mackay, Ho, Celis-Morales, Katikireddi et al., Vitamin D concentrations and COVID-19 infection in UK Biobank, Diabetes Metab. Syndr,
doi:10.1016/j.dsx.2020.04.050Ilie, Stefanescu, Smith, The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality, Aging Clin. Exp. Res,
doi:10.1007/s40520-020-01570-8Jeffery, Burke, Mura, Zheng, Qureshi et al., 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3, J. Immunol,
doi:10.4049/jimmunol.0803217Jungreis, Kellis, Mathematical analysis of Córdoba calcifediol trial suggests strong role for Vitamin D in reducing ICU admissions of hospitalized COVID-19 patients, MedRxiv,
doi:10.1101/2020.11.08.20222638Kaufman, Niles, Kroll, Bi, Holick, SARS-CoV-2 positivity rates associated with circulating 25-hydroxyvitamin D levels, PLoS ONE,
doi:10.1371/journal.pone.0239252Keum, Lee, Greenwood, Manson, Giovannucci, Vitamin D supplementation and total cancer incidence and mortality: A meta-analysis of randomized controlled trials, Ann. Oncol,
doi:10.1093/annonc/mdz059Lemire, Adams, Kermani-Arab, Bakke, Sakai et al., 1,25-Dihydroxyvitamin D3 suppresses human T helper/inducer lymphocyte activity in vitro, J. Immunol
Ling, Broad, Murphy, Pappachan, Pardesi-Newton et al., High-Dose Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-19: A Cross-Sectional Multi-Centre Observational Study, Nutrients,
doi:10.3390/nu12123799Martineau, Jolliffe, Hooper, Greenberg, Aloia et al., Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data, BMJ,
doi:10.1136/bmj.i6583Merzon, Tworowski, Gorohovski, Vinker, Golan Cohen et al., Low plasma 25(OH) vitamin D level is associated with increased risk of COVID-19 infection: An Israeli population-based study, FEBS J,
doi:10.1111/febs.15495Murai, Fernandes, Sales, Pinto, Goessler et al., Effect of Vitamin D 3 Supplementation vs. Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter, Double-blind, Randomized Controlled Trial,
doi:10.1101/2020.11.16.20232397Radujkovic, Hippchen, Tiwari-Heckler, Dreher, Boxberger et al., Vitamin D Deficiency and Outcome of COVID-19 Patients, Nutrients,
doi:10.3390/nu12092757Rastogi, Bhansali, Khare, Suri, Yaddanapudi et al., Short term, high-dose vitamin D supplementation for COVID-19 disease: A randomised, placebo-controlled, study (SHADE study), Postgrad Med. J,
doi:10.1136/postgradmedj-2020-139065Rizzoli, Boonen, Brandi, Bruyère, Cooper et al., Vitamin D supplementation in elderly or postmenopausal women: A 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), Curr. Med. Res. Opin,
doi:10.1185/03007995.2013.766162Spanier, Nashold, Mayne, Nelson, Hayes, Vitamin D and estrogen synergy in Vdr-expressing CD4(+) T cells is essential to induce Helios(+)FoxP3(+) T cells and prevent autoimmune demyelinating disease, J. Neuroimmunol,
doi:10.1016/j.jneuroim.2015.06.015Vassiliou, Jahaj, Pratikaki, Orfanos, Dimopoulou et al., Low 25-Hydroxyvitamin D Levels on Admission to the Intensive Care Unit May Predispose COVID-19 Pneumonia Patients to a Higher 28-Day Mortality Risk: A Pilot Study on a Greek ICU Cohort, Nutrients,
doi:10.3390/nu12123773Wang, Degruttola, Lei, Mayer, Redline et al., The vitamin D for COVID-19 (VIVID) trial: A pragmatic cluster-randomized design, Contemp. Clin. Trials,
doi:10.1016/j.cct.2020.106176Weaver, Alexander, Boushey, Dawson-Hughes, Lappe et al., Calcium plus vitamin D supplementation and risk of fractures: An updated meta-analysis from the National Osteoporosis Foundation, Osteoporos. Int,
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'severe courses of the disease has remained limited. A large proportion of the world '
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'been suggested as a potential option to prevent COVID-19 infections, severe courses, and '
'deaths from the disease, but is not widely practiced. This article provides an up-to-date '
'summary of recent epidemiological and intervention studies on a possible role of vitamin D '
'supplementation for preventing severe COVID-19 cases and deaths. Despite limitations and '
'remaining uncertainties, accumulating evidence strongly supports widespread vitamin D '
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'of those infected. Given the dynamics of the COVID-19 pandemic, the benefit–risk ratio of '
'such supplementation calls for immediate action even before results of ongoing large-scale '
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