Vitamin D for COVID-19: a case to answer?
Authors: Adrian R Martineau, Nita G Forouhi
Journal: The Lancet Diabetes & Endocrinology (2020)

Interest in a potential role for vitamin D in the prevention or treatment of acute respiratory infections dates back to the 1930s, when cod liver oil was investigated as a means to reduce industrial absenteeism due to the common cold. Meta-analyses of randomised controlled trials conducted from 2007–20 reveal protective effects of vitamin D against acute respiratory infections, albeit these effects were of modest size and with substantial heterogeneity.1Jolliffe D Camargo Jr, 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.medRxiv. 2020; (published online July 17.) (preprint)https://doi.org/10.1101/2020.07.14.20152728PubMed Google Scholar The striking overlap between risk factors for severe COVID-19 and vitamin D deficiency, including obesity, older age, and Black or Asian ethnic origin, has led some researchers to hypothesise that vitamin D supplementation could hold promise as a preventive or therapeutic agent for COVID-19. From a mechanistic angle, there are good reasons to postulate that vitamin D favourably modulates host responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), both in the early viraemic and later hyperinflammatory phases of COVID-19. Vitamin D metabolites have long been known to support innate antiviral effector mechanisms, including induction of antimicrobial peptides and autophagy. Laboratory data relating to effects of vitamin D on host responses to SARS-CoV-2 specifically are scarce, but one study that screened four compound libraries for antiviral activity has reported an inhibitory effect of the active vitamin D metabolite 1,25-dihydroxyvitamin D (the steroid hormone and biologically active vitamin D metabolite) in human nasal epithelial cells infected with SARS-CoV-2.2Mok CK Ng YL Ahidjo BA et al.Calcitriol, the active form of vitamin D, is a promising candidate for COVID-19 prophylaxis.medRxiv. 2020; (published online June 22.) (preprint)https://doi.org/10.1101/2020.06.21.162396PubMed Google Scholar Vitamin D has also been shown to regulate immunopathological inflammatory responses in the context of other respiratory infections. The finding that these effects were mediated via regulation of the renin-angiotensin system (RAS) in an animal model3Xu J Yang J Chen J Luo Q Zhang Q Zhang H Vitamin D alleviates lipopolysaccharideinduced acute lung injury via regulation of the reninangiotensin system.Mol Med Rep. 2017; 16: 7432-7438Crossref PubMed Scopus (277) Google Scholar has particular relevance in the context of severe COVID-19, where overactivation of RAS associates with poor prognosis. Epidemiological studies investigating links between circulating levels of 25-hydroxyvitamin D (25[OH]D; the biomarker of vitamin D status) and incidence and severity of COVID-19 are currently limited in number. Two ecological studies have reported inverse correlations between national estimates of vitamin D status and COVID-19 incidence and mortality in European countries.4Laird E Rhodes J Kenny RA Vitamin D and inflammation: potential implications for severity of COVID-19.Ir Med J. 2020; 113: 81PubMed Google Scholar, 5Ilie 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: 1195-1198Crossref PubMed Scopus (518) Google Scholar Lower circulating 25(OH)D concentrations have also been reported to associate with susceptibility to SARS-CoV-2 infection6D'Avolio A Avataneo V Manca A et al.25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.Nutrients. 2020; 12e1359Crossref PubMed Scopus (319) Google Scholar and COVID-19 severity.7Panagiotou 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; (published online July 3.)https://doi.org/10.1111/cen.14276Crossref PubMed Scopus (155) Google Scholar Recently, we have shown that airway diseases are associated with dysregulated vitamin D metabolism,8Jolliffe DA Stefanidis C Wang Z et al.Vitamin D metabolism is dysregulated in asthma and chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2020; (published online March 18.)https://doi.org/10.1164/rccm.201909-1867OCCrossref PubMed Scopus (50) Google Scholar raising the possibility that vitamin D deficiency might arise as a consequence of pulmonary inflammation. Prospective studies can provide insights into the potential for reverse causality, but results from those published to date are conflicting: one retrospective longitudinal study from Israel reported independent associations between low pre-pandemic 25(OH)D levels and subsequent incidence and severity of COVID-19,9Merzon 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; (published online July 3.) (preprint)https://doi.org/10.1101/2020.07.01.20144329Google Scholar but an analogous study in the UK showed no such associations.10Hastie CE Mackay DF Ho F et al.Vitamin D concentrations and COVID-19 infection in UK Biobank.Diabetes Metab Syndr. 2020; 14: 561-565Crossref PubMed Scopus (337) Google Scholar Both of these studies are potentially limited by the use of historic 25(OH)D measurements, which might not reflect concentrations at the time of exposure to SARS-CoV-2. They are also open to residual and unmeasured confounding. Mendelian randomisation studies offer one approach to overcome these problems, but they need to be very large to detect small or moderate effects which might still be of clinical significance. In our view, well powered randomised controlled trials of vitamin D supplementation for the prevention and treatment of COVID-19 are now needed to test for causality. A number of hospital-based treatment trials have been registered to date, but it may prove challenging to detect a signal for vitamin D supplementation in severe COVID-19 for two reasons. First, patients tend to present to hospital in the hyperinflammatory stage of the disease, so it might be too late for them to benefit from any antiviral effects induced by vitamin D supplementation. Second, it could be hard to show the effect of a micronutrient over and above dexamethasone, which has potent anti-inflammatory actions and now represents the standard of care in severe disease. Prevention of SARS-CoV-2 infection also represents an ambitious target, given the highly infectious nature of the pathogen. Perhaps the best hope for showing a clinical benefit lies in a population-based trial investigating prophylactic vitamin D supplementation as a means of attenuating the severity of incident COVID-19, to the extent that it is either asymptomatic or does not result in hospitalisation. The design of such a trial should be informed by findings of meta-analyses of randomised controlled trials of vitamin D to prevent other acute respiratory infections, which suggest that the intervention would work best when given in daily doses of 400–1000 IU to individuals with lower baseline vitamin D status. Pending results of such trials, it would seem uncontroversial to enthusiastically promote efforts to achieve reference nutrient intakes of vitamin D, which range from 400 IU/day in the UK to 600–800 IU/day in the USA. These are predicated on benefits of vitamin D for bone and muscle health, but there is a chance that their implementation might also reduce the impact of COVID-19 in populations where vitamin D deficiency is prevalent; there is nothing to lose from their implementation, and potentially much to gain. NGF has received grant funding from the MRC Epidemiology Unit (MC_UU_12015/5) and NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). The MRC were not involved in the writing of this manuscript, or in the decision to submit it for publication. We declare no competing interests.