Should vitamin D supplementation be recommended to prevent COVID-19?

From BMJ.

"Should vitamin D supplementation be recommended to prevent COVID-19?

Dear Editor,

The Intensive Care and National Audit and Research Centre (ICNARC) Report on COVID-19 showed that 35% of critically ill patients in the UK were from black and minority ethnic backgrounds (BME).[1] Only 14% of the population in England and Wales are from BME backgrounds,[2] suggesting that they are disproportionately affected by COVID-19. A number of reasons have been postulated, such as higher rates of socioeconomic deprivation, multigenerational living, and cardiometabolic disease in BME communities. Furthermore, major cities like London and Birmingham have been hit hardest by COVID-19 due, in part, to urban density and international travel, but they also have a greater ethnic diversity than the rest of the country.

One alternative hypothesis is the higher prevalence of vitamin D deficiency in those from BME backgrounds. Vitamin D deficiency is common in South Asians and African-Caribbeans in the UK, particularly in inner cities. One study in Birmingham found serum 25-hydroxyvitamin D levels below 10 nanograms/mL (25 nmol/L) in one in four African-Caribbeans and one in three Asians.[3] An analysis of UK primary care records found that two-thirds of Asian/Asian British and half of Black/Black British adults had 25-hydroxyvitamin D levels below 30nmol/L.[4]

Vitamin D is principally obtained following skin exposure to sunlight, leading to ultraviolet (UV) light induction of dermal vitamin D synthesis. Relatively few foods provide a dietary source of vitamin D. The current lock-down to control COVID-19 could potentially exacerbate vitamin D deficiency by reducing UV light exposure at a time of the year when the vitamin D status of most of the UK population is at its lowest following the decline in vitamin D production during the winter.

The effect of vitamin D on immune function and respiratory health has been known for some time. Vitamin D reduces pulmonary inflammation and enhances innate and adaptive immunity to respiratory pathogens.[5,6] Epithelial cells lining the respiratory tract contain enzymes which convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which in turn induces expression of various antibacterial proteins by cells, such as macrophages, from the innate immune system.[7]

Vitamin D also increases the phagocytic potential of macrophages and inhibits the maturation of dendritic cells, which dampens the response of pro-inflammatory cytokines (e.g. IL-12 and IL-23) and enhances the expression of anti-inflammatory cytokines, such as IL-10, thereby shifting the T cell response from pro-inflammatory T helper (TH1) towards a tolerogenic TH2 based profile through support from regulatory T cells.[6] Vitamin D inhibits a potentially harmful chemokine and cytokine response while maintaining antiviral activity,[8] which may prove particularly important in COVID-19, in which critically ill patients experience a cytokine storm.

A number of observational studies have shown independent associations between vitamin D deficiency and incidence of respiratory tract infections (RTIs).[8] A large cohort study in US citizens found that lower vitamin D levels were independently associated with the likelihood of a recent upper respiratory tract infection (URTI) with a clear dose-response relationship.[9] In patients with asthma and COPD, the association between vitamin D deficiency and URTIs was stronger still (odds ratio 5.67 and 2.26, respectively).[9] Vitamin D deficiency is associated with a higher risk of community-acquired pneumonia [10] and independently predicts mortality and ICU admission among these patients.[11] The extent to which vitamin D deficiency specifically contributes to viral infections has not yet been fully established [12] although H5N1 virus-infected mice models do suggest a protective effect of calcitriol (an active form of vitamin D) on reducing acute lung injury.[13]

Vitamin D deficiency is common among patients with acute respiratory distress syndrome,[14] which is a hallmark of severe COVID-19 infection,[15] and patients with lower vitamin D levels have a higher odds of developing acute respiratory failure (odds ratio 1.84, 95% CI 1.22 to 2.77).[16] Vitamin D deficiency is associated with increased alveolar inflammation and damage, which may be ameliorated by vitamin D supplementation.[14]

A systematic review and individual patient data meta-analysis of high-quality randomised controlled trials showed that daily or weekly vitamin D supplementation at a standard dose significantly reduces the risk of RTIs.[18] The number needed-to-treat to prevent one RTI was only four when regular vitamin D supplementation is used at a daily dose of under 20 micrograms or 800 IU, among people with vitamin D deficiency. Systematic reviews of RCTs of vitamin D supplementation for patients with asthma and COPD similarly conclude that vitamin D supplementation prevents exacerbations in patients who are vitamin D deficient.[19][20] Use of high or bolus doses of vitamin D appear to have no effect on preventing RTIs and may even disrupt vitamin D metabolism, and the effect is only statistically significant in people with vitamin D deficiency.[18]

Trials for vitamin D supplementation for the treatment of COVID-19 are currently underway, providing hope that its efficacy for protecting patients from SARS-Coronavirus-2 will be more definitively resolved.[22,23] However, given the substantial epidemiological evidence that vitamin D supplementation is effective at preventing respiratory tract infections and that vitamin D deficiency may be causally related to ARDS, a strong argument could be made to recommend empirical preventative treatment with standard-dose (400 to 800 IU or 10-20 micrograms daily) vitamin D supplementation for high-risk groups, such as people from BME backgrounds, patients with chronic respiratory disease such as COPD and asthma, and any other population groups at risk of vitamin D deficiency.

Regular intake of standard-dose vitamin D is not associated with adverse effects such as hypercalcaemia or renal stones.[18] This would be a safe intervention to recommend to at-risk population groups and strengthens the argument for increased vitamin D fortification at a population level. It is highly questionable to wait for the results of RCTs before this recommendation should be made.

Shamil Haroon, Clinical Lecturer in Primary Care, Institute of Applied Health Research.

Jennifer Cooper, Academic Clinical Fellow, Institute of Applied Health Research.

Astha Anand, Academic Clinical Fellow, Institute of Applied Health Research.

Krishnarajah Nirantharakumar, Senior Clinical Lecturer, Insitute of Applied Health Research.

Martin Hewison, Professor of Molecular Endocrinology, Institute of Metabolism and Systems Research."