As healthcare professionals, you might be receiving questions on vitamin D for prevention and treatment of COVID-19. This brief summarises the current evidence, following the literature review conducted by the National Institute for Health and Care Excellence (NICE), Scientific Advisory Committee on Nutrition (SACN), and Public Health England (PHE)1,2.
A link between vitamin D and COVID-19 has been suggested because factors associated with low vitamin D status overlap with COVID-19 incidence and severity, such as age, ethnicity, and care home residence1. Vitamin D is thought to moderate the immune system response. Therefore, it has been hypothesised that vitamin D may play a role in COVID-191.
Vitamin D has a well-established role in musculoskeletal health through regulation of calcium and phosphate3. Vitamin D can prevent rickets and osteomalacia, and it is implicated in immunomodulation3. Food sources of vitamin D are insufficient for most. The main source of vitamin D is endogenous synthesis within the skin following ultraviolent (UV)-B radiation3. Vitamin D is usually measured as 25 hydroxyvitamin D (25[OH]D)2. Deficiency is defined as 25[OH]D levels less than 25nmol/litre2. Two forms of vitamin D are licensed in the UK for treatment and prevention of vitamin D deficiency: vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol)1.
NICE develop evidence-based guidelines for health and social care practitioners, including public health4. SACN provide evidence-informed dietary recommendations5. The evidence review conducted by NICE, PHE, and SACN asked three questions, detailed below. For all questions, all formulations, doses, and regimens of vitamin D were included1.
The review concluded that there is insufficient evidence to recommend vitamin D supplementation with the sole intention to prevent SARS-CoV-2 transmission or treat COVID-192.
1. What is the clinical effectiveness and safety of vitamin D supplementation for the treatment of COVID-19 in adults, young people and children?
One study was identified from Spain. Vitamin D was associated with a beneficial OR of 0.003 (95% CI 0.003-0.250). The study was graded very low quality due to its small size (n=76); differences between the two groups with regards to patient comorbidities; and the absence of blinding. The study used a formulation not commonly used in the UK at very high doses. Differences in “standard care” between Spain and the UK limit generalisability1,2.
2. What is the clinical effectiveness and safety of vitamin D supplementation for the prevention of SARS CoV2 infection (and subsequent COVID-19) in adults, young people and children?
No eligible studies were identified1,2.
3. Is vitamin D status independently associated with susceptibility to developing COVID-19, severity of COVID-19, and poorer outcomes from COVID-19 in adults, young people and children?
There is an association between low vitamin D status and severe outcomes from COVID-191. However, many risk factors are the same for both low vitamin D and severe COVID-19, and so causality cannot be established. In addition, vitamin D is a negative acute phase reactant meaning levels reduce during inflammation, which could be seen in COVID-192.
The quality was considered “very low” of all 13 included studies, meaning any estimate of effect is very uncertain1,2. Studies were observational; there were no randomised controlled trials. Limitations included high risk of bias, differences in factors adjusted for, residual confounding, and variation in population demographics. Use of different assays may result in 15-20% variation in measured vitamin D levels3. Vitamin D levels were measured at different time points in different studies: at admission, within the preceding 3-12 months, or 10-14 years prior1,2. Two studies used history of vitamin D supplementation and blood levels were not measured. Vitamin D levels were analysed differently: using blood levels on a linear scale, or supra-/sub-threshold (note thresholds varied between studies).
Six studies investigated COVID-19 incidence: four demonstrated a significant association (two using a linear scale; one with a threshold of <50nmol/l; one using 75nmol/l as a threshold). Two studies found no association, using a linear scale.
Seven studies investigated COVID-19 severity. Various outcome measures were used. Two studies found no association between vitamin D levels and composite outcome measures; whereas another (using a <30nmol/l threshold) did find a significant association. One study found that vitamin D <50nmol/l was associated with severe COVID-19. Another study demonstrated levels <75nmol/l were not associated with hospitalisation. Two studies found that lower vitamin D levels were associated with increased mortality. Another study demonstrated the supplementation in the year preceding COVID-19 diagnosis was associated with reduced mortality, but that supplementation at the time of diagnosis was not beneficial compared to no supplementation.
Lastly, NICE considered the SACN review on vitamin D supplementation and acute respiratory tract infections (excluding COVID-19). A systematic review and meta-analysis demonstrated a protective effect of 10-25 micrograms (400-1000 units) per day, in those aged 1-16 years (Joliffe, 2020)1. Limitations of this study included differences in vitamin D regimens, participants, context, and assessment of outcomes in the included studies.
Given these inconsistent findings from a small number of low-quality heterogeneous studies, it is not possible to advocate vitamin D supplements for the purpose of preventing COVID-19. However, randomised controlled trials investigating the role of vitamin D supplementation in COVID-19 are ongoing and guidance will be updated with the publication of trial results1.
• Public Health advice remains unchanged: vitamin D supplementation is recommended for everyone living in the UK in order to promote musculoskeletal health3,5. For most people, supplementation between October-March is sufficient. Supplementation is advised all year round for people who:
• This recommendation is even more important during the COVID-19 pandemic as people are spending more time indoors than usual.
• A dose of 10 micrograms (400 units) per day is recommended for all aged 4 years and over, including pregnant and breastfeeding women. This dose is effective for 97.5% of the population in preventing deficiency and maintaining 25[OH]D levels >25nmol/l even when UVB exposure is low2,3,5.
• A tolerable upper intake limit of 100 micrograms (4000 units) is set for adults1,3.
• Adverse effects of high dose vitamin D (over 100 micrograms daily) include hypercalcaemia. Patients with medical conditions predisposing to renal impairment or hypercalcaemia should discuss vitamin D supplementation with their healthcare professional and consider monitoring2.