NICE evidence review summary: Vitamin D for COVID-19

With much written in the media about the potential benefits of supplementing with vitamin D to help either prevent or treat COVID-19, NICE has produced an evidence review of the available data to inform on the value of this intervention, which is summarised below.

The primary research questions posed by the review are:

1. What is the effectiveness and safety of vitamin D supplementation for the treatment of COVID-19 in adults, young people and children?
2. What is the effectiveness and safety of vitamin D supplementation for the prevention of COVID-19 in adults, young people and children?
3. Is vitamin D status associated with susceptibility to COVID-19 in adults, young people and children?
4. From the evidence selected, are there subgroups of people who may benefit from vitamin D supplementation more than the wider population of interest?

Background
The majority of vitamin D is produced by the action of sunlight on the skin and the main circulating metabolite is 25-hydroxyvitamin D (25(OH)D) which is used to provide a measure of vitamin D status. In 2016, the Scientific Advisory Committee on Nutrition (SACN) produced a report on vitamin D1 and defined a vitamin D level of less than 25nmol/l as being associated with an increased risk of poor musculoskeletal health outcomes, for example, rickets or osteomalacia (that is, soft bones). The SACN report recommended that serum vitamin D should not fall below 25nmol/l throughout the year and advice from the NHS2 suggests that during the autumn and winter, adults and children over 5 years should take a supplement containing 10mcg vitamin D. Interestingly, the SACN report in 2016 also reviewed the evidence on vitamin D and the risk of infections and concluded that it did not generally show a beneficial effect. More recently, SACN has reviewed the evidence since 2016 and once again concluded that the evidence does not support recommending vitamin D supplementation3 to prevent acute respiratory infections in the general UK population.

Clinical studies reviewed
NICE identified a total of five studies which examined the potential relationship between vitamin D status and COVID-19. All of the studies were observational in nature.

None of these studies were able to provide sufficient evidence to answer the first and second research questions.

In relation to the third question, three studies sought to examine the relationship between vitamin D status and COVID-19. The study by D’Avolio et al4 examined differences in vitamin D levels among those testing positive vs negative for COVID-19. The results showed that that patients testing positive for COVID-19 had a significantly lower vitamin D level compared to those testing negative (27.75 nmol/l vs 61.5 nmol/l, p = 0.004). However, the study was subject on selection bias, that is, it is unclear how the patients were identified and recruited and only those who were symptomatic were included. In addition, other potential confounders which are known to be important in COVID-19 such as body mass index, ethnicity, smoking status were not recorded.

The second study5 used logistic regression models to examine the relationship between vitamin D levels and ethnicity for the development of COVID-19. The study included positive COVID-19 tests from 1474 individuals and then compared these with serum 25(OH)D levels contained in a large UK Biobank. The results of the modelling (which was adjusted for recognised confounders such as smoking status, weight and several other factors) found no significant relationship between baseline 25(OH)D levels and the development of COVID-19 infection. In addition, there was also no relationship between ethnicity and COVID-19 infection. A limitation of the study was the vitamin D levels were recorded historically and may have changed at the time of participant assessment.

The third study6 examined the association between vitamin D levels and the number of deaths in 20 European countries. The study observed a moderate degree of negative correlation (r = -0.44, p = 0.05) between serum 25(OH)D levels and the number of cases of COVID-19 per 1 million population. However, reported vitamin D levels for this study were taken from a single earlier study and in some cases, the data was over 15 years old. Furthermore, other factors which might have influenced the association were not considered.

The final observational study7 also examined vitamin D levels and deaths from COVID-19 this time across 12 European countries. The authors reviewed published vitamin D levels in older adults in these countries which they correlated with the reported number of COVID-19-related deaths. The concluded that low 25(OH)D levels were correlated with increased mortality from COVID-19 although the correlation coefficient is not reported. As with the previous European study, historical vitamin D levels were used and there was no consideration of potential confounders.

One other included study was a case-controlled telephone survey of 1,486 people with Parkinson’s disease8 designed to explore whether such patients were more at risk from COVID-19. The results showed no significant increased risk but those with Parkinson’s disease were statistically less likely to be taking vitamin D supplements. Again, limitations include no adjustment was made for confounders and COVID-19 status was self-reported.

Summary
The NICE evidence review has concluded that to date, there is no good evidence for either a preventative or protective role of vitamin D in relation to COVID-19. Nevertheless, given the importance of vitamin D for bone and muscle health, NICE recommends that individuals continue to follow the advice advocated by SACN.

The review is available online at www.nice.org.uk/advice/es28/chapter/Key-messages.

References

1. GOV.UK. SACN vitamin D and health report. www.gov.uk/government/publications/sacn-vitamin-d-and-health-report.
2. NHS Vitamin D. www.nhs.uk/conditions/vitamins-and-minerals/vitamin-d/.
3. Scientific Advisory Committee on Nutrition. Vitamin D and acute respiratory tract infections. June 2020. https://app.box.com/s/g0ldpth1upfd7fw763ew3aqa3c0pyvky.
4. D’Avolio A et al. 25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2 Nutrients 2020; 12(5):1359.
5. Hastie CE et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr 2020;14(4):561–5.
6. Llie 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;May 6:1–4.
7. Laird E, Rhodes J, Kenny RA. Vitamin D and inflammation: potential implication for severity of Covid-19. Ir Med J 2020;113(5):81–8.
8. Fasano A et al. COVID-19 in Parkinson’s disease patients living in Lombardy, Italty. Movement Disord 2020;Jun 2:10: doi: 10.1002/mds.28176.