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

BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1548 (Published 20 April 2020) Cite this as: BMJ 2020;369:m1548

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BAME Children at High Risk of PIMS-TS, a Covid-19 Kawasaki-Like Disease - Vitamin D, a Factor? – Testing and Data Urgently Required

Dear Editor,

Seven observational preprints, [1-8] from a variety of countries, based on COVID-19 positive patients, note significant links between; low vitamin D status and, COVID-19 severity, ICU risk and mortality rates.

Higher rates of COVID-19 are observed in; BAME Persons including African Americans, as well as the Obese, and Elderly.[9]

Similarly, higher occurrence of COVID-19 Kawasaki like disease [10 11] (‘Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2’: PIMS-TS) are reported in BAME children; of 70 admissions, “The Evelina London Children’s Hospital says around 70-80 per cent of the children it has treated for the syndrome are from a black, Asian and minority ethnic background.” Consistent with this, The Necker-Enfants Malades Hospital in Paris, noted BAME children represented 67% of 21 PIMS-TS admissions.[12]

Thus COVID (COVID-19) Kawasaki-like-disease PIMS-TS, in children, appears to be associated with darker skin type, as is Kawasaki disease. Kawasaki disease is reported to be exacerbated by low vitamin D. [13-15] The review ‘Seasonality of Kawasaki Disease: A Global Perspective’ noted, occurrence was higher (40% northern hemisphere extra Tropics, 30% southern hemisphere extra Tropics) in late winter and Spring[16] when vitamin D levels would be expected to be lower. Seasonality may vary by country.[17]

Those with darker skin types living in upper latitudes are widely recognised to be at greater risk of vitamin D deficiency. Vitamin D deficiency rates in the young are often increasing due to more indoor screen-related lifestyles. Low vitamin D risk is significantly greater in African American children,[18] and BAME children in the UK.[19]

Vitamin D is an ancient hormone, derived from exposure of sterols to sunshine (UVB): vitamin D may also be acquired from a limited range of foods. Skin sunshine exposure is the main route of acquisition by most. UVB incident on exposed skin is diminished, when absorbed by melanin. Thus, those with darker skin types are more protected from UVB exposure, but require greater exposure to make an equivalent amount of Vitamin D precursor.

Vitamin D features widely in human physiology including in; immune, metabolic, reproductive, and developmental, pathways; via a multitude of mechanisms including gene transcription, and mitochondrial regulation. Such mechanisms are well and widely reported; some such references may be found in earlier related BMJ Rapid responses.[1, 9] Research is ongoing.

It is inescapable that vitamin D features heavily in disease pathways, because it features at such basal and fundamental levels in human physiology including in immune function. Thus, in relation to COVID-19 and related disease conditions, the question is not; does vitamin D play a role: but, how, by how much, and what is the quantum of impact of insufficiency and deficiency?

On the issue of the often-underappreciated importance of deficiencies, Hugh MacDonald Sinclair FRCP presciently and succinctly observed[20 21]:
“The deficiency of any nutrient which is essential for every tissue will eventually lead to abnormal function in every tissue. That is so incontrovertibly obvious that I am continually astonished by the eminence of the medical scientists to whom it must be forcefully restated.”
“The second is that when deprivation of an essential nutrient occurs, not all tissues will be simultaneously and equally affected, and not all individuals will react in the same way. Which tissue shows symptoms first will depend on the genetic inheritance of the individual and on his or her exposure to environmental factors and lifestyle events. “

At least seven observational studies suggest a link between vitamin D deficiency and COVID-19. If we frail humans are to avoid the risk of a 21st century repetition of the Semmelweis effect, [22 23] it is surely time that vitamin D assay (and even better, also tests for other key nutrients) become standard for all COVID-19, and COVID-19 Kawasaki-like PIMS-TS, patients, so the relationship between, PIMS-TS, COVID-19, Vitamin D and wider nutrients could be better quantified. The information gathered may not generate short term profits, but it might help prevent destruction of economies, lives and social stability.

Simple observations have greatly factored in remediation of impactful diseases – is it not time to let the sunlight in?[24]

1. Brown, R., & Sarkar, A. (19th May 2020). Is ethnicity linked to incidence or outcomes of covid-19? Low vitamin D: high risk COVID-19 mortality? Seven preprints suggest that is case. Does low ‘D’ put BAME and elderly, at particular COVID-19 risk? Testing and Data Required. BMJ 2020;369:m1548 doi: https://doi.org/10.1136/bmj.m1548 Available from https://www.bmj.com/content/369/bmj.m1548/rr-19
2. Alipio, M. (April 9, 2020). ‘Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-19)’, SSRN. DOI: 10.2139/ssrn.3571484 Available at: https://ssrn.com/abstract=3571484 (Accessed 2nd June 2020).
3. Raharusun, P., Sadiah, P., Cahni, B., Erdie, A., Cipta, B. (April 26, 2020). ‘Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study’, SSRN. DOI: 10.2139/ssrn.3585561 Available at: https://ssrn.com/abstract=3585561 (Accessed 2nd June 2020).
4. Lau, F., Majumder, R., Torabi, R., Saeg, F., Hoffman, R., Cirillo, J. & Greiffenstein, P. (April 28, 2020). ‘Vitamin D Insufficiency is Prevalent in Severe COVID-19’, MedRxiv. DOI: 10.1101/2020.04.24.20075838 Available at: https://www.medrxiv.org/content/10.1101/2020.04.24.20075838v1 (Accessed 2nd June 2020).
5. De Smet, D., De Smet, K., Herroelen, P., Gryspeerdt, S. & Martens, D. (Version 1 May 5, 2020). ‘Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics’, MedRxiv. DOI: 10.1101/2020.05.01.20079376 Available at: https://www.medrxiv.org/content/10.1101/2020.05.01.20079376v1 (Accessed: 2nd June 2020).
(Version 2 19 May 2020). https://doi.org/10.1101/2020.05.01.20079376
6. D’Avolio, A., Avataneo, V., Manca A., Cusato, J., De Nicolò, A., Lucchini, R., Keller, F. & Cantù, M. (2020). ‘25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2’, Nutrients, 12(5) 1359, p. 1-7. DOI: 10.3390/nu12051359 Available at https://www.mdpi.com/2072-6643/12/5/1359/htm (Accessed: 2nd June 2020).
7. Faul, J., Kerley, C., Love, B., O’Neill, E., Cody. C., Tormey, W., Hutchinson, K., Cormican, L. & Burke, C. (2020). ‘Vitamin D Deficiency and ARDS after SARS-CoV-2 Infection’, Ir Med J, 113(5), P84. Available at: http://imj.ie/wp-content/uploads/2020/05/Vitamin-D-Deficiency-and-ARDS-a... (Accessed: 2nd June 2020).
8. Lau, F., Majumder, R., Torabi, R., Saeg, F., Hoffman, R., Cirillo, J. & Greiffenstein, P. (April 28, 2020). ‘Vitamin D Insufficiency is Prevalent in Severe COVID-19’, MedRxiv. DOI: 10.1101/2020.04.24.20075838 Available at: https://www.medrxiv.org/content/10.1101/2020.04.24.20075838v1 (Accessed 2nd June 2020).
9. Brown, R., Rhein, H., Alipio, M., Annweiler, C., Gnaiger, E., Holick M., Boucher, B., Duque, G., Feron, F., Kenny, R., Montero-Odasso, M., Minisola, M., Rhodes, J., Haq., A, Bejerot, S., Reiss, L., Zgaga, L., Crawford, M., Fricker, R., Cobbold, P., Lahore, H., Humble, M., Sakar, A., Karras, S., Iglesias-Gonzalez, J., Gezen-Ak, D., Dursun E., Cooper, I., Grimes, D. & de Voil C. (April 20, 2020). ‘Rapid response re: Is ethnicity linked to incidence or outcomes of COVID-19?’: COVID-19 ’ICU’ risk – 20-fold greater in the Vitamin D Deficient. BAME, African Americans, the Older, Institutionalised and Obese, are at greatest risk. Sun and ‘D’-supplementation – Game-changers? Research urgently required. BMJ, 369(m1548). DOI: 10.1136/bmj.m1548. Available at: https://www.bmj.com/content/369/bmj.m1548/rr-6 (Accessed: 18 May 2020)
10. Jones, V., Mills, M., Suarez, D., Hogan, C., Yeh, D., Bradley Segal, J., Nguyen, E., Barsh, G., Maskatia, S. & Mathew, R. (April 7, 2020). ‘COVID-19 and Kawasaki Disease: Novel Virus and Novel Case’, Hosp Pediatr. pii: hpeds.2020-0123. doi: 10.1542/hpeds.2020-0123. [Epub ahead of print] Available from https://hosppeds.aappublications.org/content/hosppeds/early/2020/04/06/h...
11. El-Bar, K. (May 14, 2020). ‘New global trend of COVID-19 linked disease in children. Italian doctors report in new article that Kawasaki disease among some patients may be linked to COVID-19. Anadolu Agency’. https://www.aa.com.tr/en/europe/new-global-trend-of-covid-19-linked-dise... (Accessed: 8th June 2020).
12. McNamara A. (4th June 2020) BAME children ‘more at risk’ of rare COVID-19-related syndrome. PA Science. BBC Science Focus Magazine. https://www.sciencefocus.com/news/bame-children-more-at-risk-of-rare-cov... (Retrieved 4th June 2020)
13. Stagi, S., Rigante, D., Lepri, G., Matucci Cerinic, M. & Falcini, F. (2016). ‘Severe vitamin D deficiency in patients with Kawasaki disease: a potential role in the risk to develop heart vascular abnormalities?’, Clin Rheumatol., 35(7), p.1865-1872. DOI: 10.1007/s10067-015-2970-6.
14. Yang, X. & Dong, X. Y. (2016). ‘Research advances in association between vitamin D and Kawasaki disease and related mechanisms of action’, Zhongguo Dang dai er ke za zhi = Chinese Journal of Contemporary Pediatrics, 18(12), p.1319-1323.
Jun, J., Jung, Y. & Lee, D. (2017). ‘Relationship between vitamin D levels and intravenous immunoglobulin resistance in Kawasaki disease’, Korean Journal of Pediatrics, 60(7), p.216-220. DOI: 10.3345/kjp.2017.60.7.216
15. Burns, J. C., Herzog, L., Fabri, O., Tremoulet, A. H., Rodó, X., et.al. Kawasaki Disease Global Climate Consortium (2013). Seasonality of Kawasaki disease: a global perspective. PloS one, 8(9), e74529. https://doi.org/10.1371/journal.pone.0074529
16. Burgner, D., & Harnden, A. (2005). Kawasaki disease: What is the epidemiology telling us about the etiology? International Journal of Infectious Diseases 9, 4, 185-194. https://doi.org/10.1016/j.ijid.2005.03.002. Available from https://www.sciencedirect.com/science/article/pii/S1201971205000597
17. Atkinson, M., Melamed, L., Kumar, J., Roy, N., Miller, R., 3rd, Furth, L., & Fadrowski, J. (2014). Vitamin D, race, and risk for anemia in children. The Journal of pediatrics, 164(1), 153–158.e1. https://doi.org/10.1016/j.jpeds.2013.08.060 Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872204/
18. Basatemur, E., Horsfall, L., Marston, L., Rait, G., & Sutcliffe, A. (2017). Trends in the Diagnosis of Vitamin D Deficiency. Pediatrics, 139(3), e20162748. https://doi.org/10.1542/peds.2016-2748 Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337117/
Wikipedia. Hugh Macdonald Sinclair. (Retrieved 8th June 2020) https://en.wikipedia.org/w/index.php?title=Hugh_Macdonald_Sinclair&oldid...
19. Cannon G. (Ed.) (ND) The Founders of Modern Nutrition – Sinclair. The McCarrison Society. Available from https://docs.google.com/viewerng/viewer?url=https://mccarrison.com/wp-co... (Retrieved 8th June 2020)
20. Wikipedia. (2020). Semmelweis reflex. https://en.wikipedia.org/w/index.php?title=Semmelweis_reflex&oldid=95501... (Retrieved 6th June 2020)
21. Scully, S. (2017) Women were dying from childbirth at hospitals. This 19th-century doctor figured out why. Upworthy. (Retrieved 6th June 2020) https://www.upworthy.com/women-were-dying-from-childbirth-at-hospitals-t...
22. Howarth, M. (27th May 2020). We need sunshine back in our lives. Scottish review. Available at https://www.scottishreview.net/MarkHowarth526a.html

Competing interests: No competing interests

10 June 2020
Robert A Brown
Reasearcher
McCarrison Society
La Route de Mont Cochon, St Lawrence, Jersey. C.I.