Evidence does not support vitamin D for reducing respiratory infections, reviews concludeBMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m2629 (Published 30 June 2020) Cite this as: BMJ 2020;369:m2629
All rapid responses
There are several reasons to suspect that vitamin D may be very significant in the pathogenesis of covid-19.
Neonates, infants and children are immunologically sub-optimal but experience relatively mild covid-19 infections. Similarly pregnant women – also immunologically sub-optimal - usually have mild infections with a mortality below c1%. This is in contrast to the severe effects of the H1N1 viral pandemic of 2009 in pregnancy (1).
The elderly are a third group who are immunologically sub-optimal; however, they have a substantial arsenal of antibodies after a lifetime of infections and vaccinations. But - they have a very adverse experience of covid-19 with a mortality of c10%.
It is very clear that two further groups have a very adverse experience of covid-19 – those with pigmented skin and the obese (2).
What common factor links the elderly, the obese and those with pigmented skin? A review of the literature shows that all these three groups are very likely to be vitamin D deficient – as measured by blood concentrations (3-5).
The target system of covid-19 virus is the respiratory tract and it is here that vitamin D plays a significant part in the body’s defence (6).
I suspect many of the excess deaths due in covid-19 infections may be due to vitamin D deficiency. It follows that supplementary vitamin D in these people may be warranted.
There is also the possibility that high doses of the vitamin could be used as part of a treatment regimen.
1. Figueiró-Filho, E A, Oliveira, M L G, Pompilio M A et al. Obstetric, clinical, and perinatal implications of H1N1 viral infection during pregnancy. International Journal of Gynecology and Obstetrics, 116 (2012) 214–218. doi: 10.1016/j.ijgo.2011.10.026
2. Townsend, M J, Kyle, TK, Stanford, F C. Outcomes of COVID-19: disparities in obesity and by ethnicity/race. Int J Obes (Lond) 2020 Jul 9:1–3. doi.org/10.1038/s41366-020-0635-2
3. Samefors, M, Ostgren, C J, Molstad, S et al. Vitamin D deficiency in elderly people in Swedish nursing homes is associated with increased mortality. European Journal of Endocrinology, 170(5), 667–675. doi:10.1530/eje-13-0855
4. Weishaar, T, Rajan, S, Keller, B et al. Probability of Vitamin D Deficiency by Body Weight and Race/Ethnicity. The Journal of the American Board of Family Medicine, 29(2), 226–232. doi:10.3122/jabfm.2016.02.150251
5. Pereira-Santos, M, Costa, P R F, Assis, A et al. Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obesity Reviews, 16(4), 341–349. doi:10.1111/obr.12239
6. Ginde AA, Mansbach JM, Camargo CA Jr. Vitamin D, respiratory infections, and asthma. Curr Allergy Asthma Rep. 2009 Jan;9(1):81-7. doi: 10.1007/s11882-009-0012-7
Competing interests: No competing interests
It is laudable that NICE is open to further evidence. One realistic suggestion might be to apply evidence from existing immunological, metabolic, genetic, observational and epidemiological studies to understand that a well supplied vitamin D store will determine Covid-19 outcomes.
It is all about reaching a healthy physiological 25-hydroxyvitamin D blood level of 30 ng/ml or 75 nmol/l and avoiding insufficient blood levels which are prevalent in the UK.
There is a great wealth of evidence for the benefit of reaching such blood levels (1-7) . A dedicated website on all evidence can be accessed (8) and should be made use of.
Our immune system is only in best working order when such an optimal 25-hydroxyvitamin D is reached. This should be advised by NICE, especially during a pandemic when we rely on a healthy immune reaction. Either a blood test or good sized supplement would be needed.
Some years ago, similar good observational evidence, not RCTs, led to the conclusion that smoking caused lung cancer, but this was suppressed for decades.
Sir Austin Bradford Hill developed criteria how causality can be shown even if RCTs cannot, as is often the case with nutritional substances. One group recently employed mathematical tools successfully to show causality of severe outcomes of Covid-19 infection and lack of vitamin D (9).
How big would be the effect size? Possibly significant, judging by the observation that those at highest risk of severe vitamin D deficiency are the same group who are at highest risk of Covid-19 mortality (people with dark skin types, those older, overweight or with underlying conditions)
Why would we want to wait for RCT’s when significant valuable evidence already exists? RCTs risk negative outcomes due to incorrect design, (variable base line 25-hydroxyvitamin-D, same dose for all, etc)
Denying present knowledge, not using the inexpensive, safe, D-supplements, not recognising the potential of replenishing a deficient population means failing those at highest risk of severe outcomes.
This is the time, when our advisory NHS bodies should act, before a second wave. Summertime UVB is good but still not enough, (due to indoor habits), 10 mcg insufficient. NICE, SACN, PHE should not miss the opportunity to give clear messages to a majority in the UK who have below optimal 25-hydroxyvitamin D levels.
What possible reason might there be why this should not be advised?
The remit must be: “Treat vitamin D deficiency”.
Sufficiency must be defined as 25-hydroxyvitamin D above 30 ng/ml or 75 nmol/l.
A licensed supplement can be prescribed by GPs to high risk groups, I did this for many years: 20,000 IU weekly, for adults. If given on repeat prescription for 8 weeks, as is usual, then only 8 tablets are prescribed when requested and any, even if only remote, risk of overdose would thereby be completely eliminated.
1. R.F. Chun, P.T. Liu, R.L. Modlin, J.S. Adams, M. Hewison
Impact of vitamin D on immune function: lessons learned from genome-wide analysis
Front. Physiol., 5 (2014), p. 151 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000998/
3. Hanel A, Carlberg C. Vitamin D and evolution: pharmacologic implications. Biochemical Pharmacology 2020; 173: https://doi.org/10.1016/j.bcp.2019.07.024
4. Vieth R. Best Pract Res Clin Endocrinol Metab. 2011 Aug;25(4):681-91. Why the Minimum Desirable Serum 25-hydroxyvitamin D Level Should Be 75 nmol/L (30 Ng/Ml) https://www.sciencedirect.com/science/article/abs/pii/S1521690X1100073X
5. Holick MF et al. Endocrine Society: Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011, 96 (7):1911 https://academic.oup.com/jcem/article/96/7/1911/2833671
6. Mendes MM, Hart KH, Lanham-New SA, Botelho PB. Suppression of Parathyroid Hormone as a Proxy for Optimal Vitamin D Status: Further Analysis of Two Parallel Studies in Opposite Latitudes. Nutrients. 2020;12(4):E942. Published 2020 Mar 28. https://www.mdpi.com/2072-6643/12/4/942
7. Luxwolda MF, Kuipers RS, Kema IP, van der Veer E, Dijck-Brouwer DA, Muskiet FA. Vitamin D status indicators in indigenous populations in East Africa. Eur J Nutr. 2013;52(3):1115‐1125 https://pubmed.ncbi.nlm.nih.gov/22878781/
9. Evidence Supports a Causal Role for Vitamin D Status in COVID-19 Outcomes
Gareth Davies, Attila R Garami, Joanna C Byers. June 2020.
medRxiv 2020.05.01.20087965; doi: https://doi.org/10.1101/2020.05.01.20087965
Competing interests: No competing interests
The reviews have pulled together various studies and trials of vitamin D and respiratory infections. The variation in the doses used for vitamin D means it is not clear what optimum dose is effective in preventing or treating respiratory infections from a small number of studies. We know that the dose response relationship between vitamin D supplementation and serum 25(OH)D is exponential in healthy subjects. However the dose response of vitamin D3 in obese subjects is significantly lower than in healthy subjects (1,2).
Factors such as obesity and being overweight contribute significantly to serum 25(OH)D levels and hence body weight specific recommendations need to be considered to achieve the required serum vitamin D levels in research studies of vitamin D dose response in respiratory infections. The extent to which this is addressed in the studies to date is not clear.
1. Ekwaru, J.P. et al (2014). The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers. PLoS One. 2014; 9(11): e111265.
2. Dhaliwal, R. et al (2014). The Vitamin D Dose Response in Obesity. Endocr Prac 2014. 20(12):1258-64.
Competing interests: No competing interests