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Is ethnicity linked to incidence or outcomes of covid-19?

BMJ 2020; 369 doi: (Published 20 April 2020) Cite this as: BMJ 2020;369:m1548

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Vitamin D deficiency due to skin pigmentation and diet may explain much of the higher rates of COVID-19 among BAME in England

Dear Editor:
The recent BMJ editorial by Khunti et al. asks “Is ethnicity linked to incidence or outcomes of covid-19?” [1] Here we outline how ethnicity relates to incidence and outcomes of COVID-19 due, in part, to lack of vitamin D because of increased skin pigmentation and diet.

Public Health England’s (PHE) recent report is a descriptive review of data on the risks, and outcomes, of COVID-19 [2], finding that these risks were higher in Black, Asian, and Minority Ethnic (BAME) groups than with White ethnicity. People in Black ethnic groups had the highest confirmed diagnosis rates, but people of Bangladeshi ethnicity had the highest death rates [80% higher than the death rates with White ethnicity].

The PHE report considered several risk-modifying factors in their analyses [age, sex, deprivation, region, and ethnicity], but not other factors mentioned that might contribute to these disparities [place of birth, occupation, living in care homes, co-morbidities or obesity]. A potentially important factor not considered in the PHE report was vitamin D deficiency, though mounting evidence suggests that vitamin D deficiency is an important risk factor for acute respiratory tract infections and for COVID-19. Meta-analysis of individual participant data from randomized double blind, placebo-controlled trials of vitamin D supplementation showed adjusted odds ratios (OR) of 0.88, [95% confidence interval (CI); 0.81-0.96; P for heterogeneity <0.001] for reduction in acute respiratory tract infection risks with supplementation overall, [3] but reductions were greatest in those with baseline serum 25(OH)D values < 25 nmol/l [deficiency] vs. those with baseline values > 25nmol/l (adjusted OR 0.30 (95% CI; 0.25-0.6) vs. 0.75 (95% CI; 0.60-0.95: P for interaction, 0.006).

Mounting evidence demonstrates that vitamin D has important roles in regulating the immune system that should reduce COVID-19 risks; primarily by reducing survival and replication of the SARS-CoV-2 virus and by reducing the risks of “cytokine storms” by reducing pro-inflammatory cytokine production and increasing anti-inflammatory cytokine productcion [4]. Vitamin D also promotes local ACE2 formation in the lungs, an effect known to reduce the severity of acute respiratory distress syndrome [5]. Furthermore, higher baseline serum 25(OH)D concentrations are currently being reported to be associated with reduced rates of severe COVID-19 and of mortality. 212 COVID-19 patients from three hospitals in southern Asian countries demonstrated an inverse correlation between baseline serum 25(OH)D concentration and clinical outcomes; with mean 25(OH)D values of 78 nmol/l, 69 nmol/l, 53 nmol/l, and 43 nmol/l for ‘mild’, ordinary’, ‘severe’ and ‘critical’ outcomes, respectively, and the differences in those mean 25OH)D values were statistically significant (p<0.001) [6].

An Indonesian study of 780 COVID-19 patients found adjusted OR for death of x7.6 (P<0.001) for 25(OH)D values of 50-75 nmol/l vs. patients with 25(OH)D values >75 nmol/l, rising to x10.1 for 25(OH)D values <50 nmol/l [7].

Nearer England, 25(OH)D concentrations of 186 consecutive COVID-19 patients from Roeselare, Belgium were inversely correlated with COVID-19 severity in males but not females, with median baseline 25(OH)D values in men with Stage 1 disease on CT = 49 nmol/l (P<0.05), with stage 2 = 44 nmol/l, and with CT Stage 3 = 40 nmol/l (P<0.05) versus 51 nmol/l in inpatients with non-covid related illnesses.

BAME in England have higher rates of vitamin D deficiency [25(OH)D concentration <50 nmol/l)] than other UK citizens, for example, the UK-based National Diet and Nutrition Survey for 2008-2012 found that 20.2% of whites aged 18-70 y had serum 25(OH)D concentrations <33 nmol/l vs. 50.5% of BAME 8, the 25(OH)D concentrations being confirmed by accurate modelling of 25(OH)D responses to ultraviolet B exposure and vitamin D intakes [9].

Another recent publication using 25(OH)D concentrations sampled between 2006 and 2010 for the UK Biobank confirmed that values <25 nmol/l were significantly correlated with increased risk for COVID-19 [OR = 1.37 (95% CI; 1.07-1.76)] [10]. Further adjustment for race and ethnicity reduced the OR to 0.92 (95% CI; 0.71-1.21) though median 25(OH)D concentrations were 34 nmol/l in white, 21 nmol/l in black and 14.5 nmol/l in South Asian participants. However, a letter to the editor [in press] points out that adjustment for ethnicity was likely an over-adjustment, since this factor is probably causal rather than a confounder [11].

Reasons for South Asian vitamin D deficiency include increased skin pigmentation, providing natural sun-screening, and that many are vegetarians or vegans, but vegetables other than fungi do not contain vitamin D, while animal products [meat, wild oily fish and eggs] contain vitamin D, both as vitamin D3 and its 25(OH)D metabolite [12]. Thus, mean 25(OH)D concentrations in 2109 white men and women in winter were 63 nmol/l for meat eaters, 57 nmol/l for fish eaters, 52 nmol/l for vegetarians, and 38 nmol/l for vegans [13].

There are many further benefits of vitamin D repletion. Secondary analyses of two recent vitamin D RCTs, for example, report significant benefits - reduced cancer rates for supplemented non-obese participants [BMI <25 kg/m2] and reduced rates of cancer deaths with supplementation, overall [14,15]. Reduced risk of progressing from prediabetes to diabetes was found in non-obese participants [BMI<30 kg/m2] and in those not given additional calcium supplements [16,15].

What should be done about this problem? Studies in the UK should assess correlations between baseline serum 25(OH)D values and COVID-19 infection severity; should trial adequate vitamin D supplementation of newly hospitalized patients for effects on disease progression [if not already on-going] [17] and BAME and others populations groups well-known to be at high risk of vitamin D deficiency [indoor and shift workers, the elderly, those in residential care or currently confined to their homes, and the obese] should be advised to take daily supplementation that might reduce COVID-19 severity. Vitamin D is readily available in the UK ‘over the counter’ at supermarkets, chemists and on-line, but could be provided free to those in financial hardship or unable to access supplies. Doses of 1000 IU/day in general and of 4000 IU/day for those at high risk of deficiency, as above, including the BAME groups, should be advised for the duration of the Covid-19 outbreak, since those doses are within NICE safety limits and would help avoid deficiency.

1. Khunti K, Singh AK, Pareek M, et al. Is ethnicity linked to incidence or outcomes of covid-19? BMJ 2020;369:m1548. doi: 10.1136/bmj.m1548
2. Public Health England. Disparities in the risk and outcomes of COVID-19. , 2020:1-89.
3. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583. doi: 10.1136/bmj.i6583
4. Grant WB, Lahore H, McDonnell SL, et al. Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients 2020;12(4):E988. doi: 10.3390/nu12040988
5. Annweiler C, Cao Z, Wu Y, et al. Counter-regulatory 'Renin-Angiotensin' System-based Candidate Drugs to Treat COVID-19 Diseases in SARS-CoV-2-infected patients. Infect Disord Drug Targets 2020 doi: 10.2174/1871526520666200518073329
6. Alipio MM. Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-2019), 2020.
7. Raharusuna P, Priamgada S, Budiarti C, et al. Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study. Coronavirus & Infectious Disease Research eJournal 2020:14. [published Online First: May 6, 2020]
8. Public Health England. National Diet and Nutrition Survey Results from Years 1, 2, 3 and 4 (combined) of the Rolling Programme (2008/2009 – 2011/2012). 14 May 2014 ed: Public Health England, 2017:1-160.
9. O'Neill CM, Kazantzidis A, Kiely M, et al. A predictive model of serum 25-hydroxyvitamin D in UK white as well as black and Asian minority ethnic population groups for application in food fortification strategy development towards vitamin D deficiency prevention. J Steroid Biochem Mol Biol 2017;173:245-52. doi: 10.1016/j.jsbmb.2016.09.010
10. Hastie CE, Mackay DF, Ho F, et al. Vitamin D concentrations and COVID-19 infection in UK Biobank. Diabetes Metab Syndr 2020;14(4):561-65. doi: 10.1016/j.dsx.2020.04.050
11. Grant WB, McDonnell SL. Statistical error in “Vitamin D concentrations and COVID-19 infection in UK Biobank”. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 2020;14
12. Grant WB, Fakhoury HMA, Karras SN, et al. Variations in 25-Hydroxyvitamin D in Countries from the Middle East and Europe: The Roles of UVB Exposure and Diet. Nutrients 2019;11(9):E2065. doi: 10.3390/nu11092065
13. Crowe FL, Steur M, Allen NE, et al. Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study. Public Health Nutr 2011;14(2):340-6. doi: 10.1017/S1368980010002454
14. Manson JE, Cook NR, Lee IM, et al. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med 2019;380(1):33-44. doi: 10.1056/NEJMoa1809944
15. Grant WB, Boucher BJ. Why Secondary Analyses in Vitamin D Clinical Trials Are Important and How to Improve Vitamin D Clinical Trial Outcome Analyses-A Comment on "Extra-Skeletal Effects of Vitamin D, Nutrients 2019, 11, 1460". Nutrients 2019;11(9) doi: 10.3390/nu11092182
16. Pittas AG, Dawson-Hughes B, Sheehan P, et al. Vitamin D Supplementation and Prevention of Type 2 Diabetes. N Engl J Med 2019;381(6):520-30. doi: 10.1056/NEJMoa1900906
17. Grant WB, Baggerly CA, Lahore H. Response to Comments Regarding “Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths”. Nutrients 2020;12(6):1620. doi: 10.3390/nu12061620

Competing interests: WBG receives funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR, USA). BJB has no conflicts of interest to report.

05 June 2020
William B. Grant
Vitamin D researcher
Barbara J. Boucher
Sunlight, Nutrition and Health Research Center
San Francisco, CA, USA