Rapid Response to:
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 doi: https://doi.org/10.1136/bmj.m1548 (Published 20 April 2020)
Robert A Brown, Researcher; Amrita Sakar, PhD., McCarrison Society, Kolkata, West Bengal, India No conflict of interests; McCarrison Society,
La Route de Mont Cochon, St Lawrence, Jersey. C.I.
Dear Editor
BMJ rapid response letters and supporting references [1, 2] posited vitamin D deficiency disease features in COVID-19 severity and mortality risks. [3] Brown and Sakar, [4] in March, suggested vitamin D plasma deficiency differentials may help account for mortality rate differences between European countries.
There are now seven observational preprints (Abstracts and links below), based on COVID-19 positive patient data, indicating vitamin D deficiency and insufficiency, do indeed factor significantly in COVID-19 severity and mortality – for example, and thought provokingly, 10 to 20 times increases were seen in ICU and mortality in Asian studies. [5, 6] One further USA based study observes vitamin D may factor in COVID-19 infection. [7] Whilst differing in, size and exact approach, results of all preprints point clearly in the same direction.
Concerningly, vitamin D is often low in high-risk COVID-19-groups, such as, BAME including African Americans, elderly in care-homes, and the obese. Low vitamin D is also increasingly common in young. [8] Studies suggest low ‘D’ factors in Kawasaki disease [9, 10, 11] ; occurrences are increasingly being linked with COVID-19. [12,13]
Vitamin D is a nutrient-hormone with a multiplicity of roles, well evidenced in voluminous and wide-reaching literature, spanning over a hundred years. The primary, and evolutionarily determined, source of vitamin D, including in; humans (D3), pets, livestock, and plants (D2), is not diet, but appropriate sun exposure. Dietary sources of vitamin D are limited, and particularly so for vegans and non ovo-lacto vegetarians. [14] Twenty minutes of sensible non-burning sunbathing by pale-skinned-humans, can produce 20,000 IU [15]; equivalent to 50 days intake of 400 IU supplementation. Production rate depends on skin pigmentation and other factors including gender. UVB blocking creams inhibit vitamin D production. Fat tissue accretes and stores vitamin D, reducing vitamin D in plasma.
Biology, physiology, and research, has proved that vitamin D has multiple roles, including in regulation of gene transcription, and inter-alia as a crucial factor in immune and respiratory function. The seven observational studies to date, using COVID-19 positive patient data, assessing the impact of vitamin D on COVID-19 severity and mortality, are listed and quoted below:
South Asia (Raharusun) [5]– preprint; ‘Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study’ - 780 COVID-19 positive patient cases concluded, “When controlling for age, sex, and comorbidity, Vitamin D status is strongly associated with COVID-19 mortality outcome of cases.” Unadjusted increased risk of death in ‘D’ insufficient 12.55 (7.63 adjusted) and ‘D’ deficient 19.12 (10.12 adjusted).
South Asia (Alipio) [6] - preprint; ‘Vitamin D supplementation could possibly improve clinical outcomes of patients infected with Coronavirus-2019 (Covid-2019)’ - 212 COVID-19 patients, noted, “the odds of having a mild clinical outcome rather than a severe outcome were approximately 7.94 times (OR=0.126, p<0.001) while interestingly, the odds of having a mild clinical outcome rather than a critical outcome were approximately 19.61 times (OR=0.051, p<0.001).”
India (Glicio) [16]– preprint; ‘Vitamin D Level of Mild and Severe Elderly Cases of COVID-19: A Preliminary Report’ - 176 COVID-19 patients age > 60, noted, “Majority of subjects classified as severe had 25(OH)D level below 30 ng/ml.”
USA (Lau) [17] – preprint; ‘Vitamin D insufficiency is prevalent in severe COVID-19’ – 20 COVID-19 patients noted, “VDI is highly prevalent in severe COVID-19 patients. VDI and severe COVID-19 share numerous associations including hypertension, obesity, male sex, advanced age, concentration in northern climates, coagulopathy, and immune dysfunction.”
Belgium (De Smet) [18] – preprint; ‘Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics’- 186 COVID-19 confirmed patients noted, “Male COVID-19 patients, however, showed markedly higher percentage of vitamin D deficiency than controls (67.0% versus 49.2%, P=0.0006) and this effect was more pronounced with advanced radiological stage ranging from 55.2% in stage 1 to 74% in stage 3.”
Switzerland (D’Avolio) [19] – preprint; ‘25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2’ - 107 patients; 27 were COVID-positive; observed, “significantly lower 25(OH)D levels (p = 0.004) were found in PCR-positive for SARS-CoV-2 (median value 11.1 ng/mL) patients compared with negative patients (24.6 ng/mL); this was also confirmed by stratifying patients according to age >70 years.”
Ireland (Faul) [20] – preprint; ‘Vitamin D Deficiency and ARDS after SARS-CoV-2 Infection’- 33 patients observes, “twelve had a baseline 25OHD level less than 30 nmol.l-1. In patients with SARS-CoV-2 related pneumonia a baseline serum 25OHD level less than 30 nmol.l-1 was associated with a hazard ratio (HR) for intubation of 3.19 (95 percent confidence interval, 1.05 to 9.7), (p = 0.03).”
It is thus urgent, even arguably imperative, vitamin-D-levels in COVID-19 patients in hospitals and care-homes, particularly the most at risk including, BAME, the elderly, obese, and young including those presenting with Kawasaki disease, are collected, related to outcomes, and reported, to determine if the above preprint data holds more widely.
Observations, not RCTs, resolved human deficiency related diseases, such as, goitre, rickets, beriberi, pellagra, and scurvy. RCTs were not completed before; parachute deployment, recommendations to drink only ‘clean’ water, sun cream approval, social distancing, steps to discourage smoking, or hand washing for infection control. [21, 22]
Vitamin D deficiency/insufficiency is referred to by some as a pandemic, and is a recognised disorder obliging prescribed existing recommended treatments and protocols, including by NICE. [23]
References
- 1. 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)
- 2. Brown, R. (April 7, 2020). ‘Rapid Response: Re: Preventing a COVID-19 pandemic - COVID-19: Vitamin D deficiency; and, death rates; are both disproportionately higher in elderly Italians, Spanish, Swedish Somali, and African Americans? A connection? Research urgently required!’, BMJ, 368(m810). DOI: 10.1136/bmj.m810 Available at: https://www.bmj.com/content/368/bmj.m810/rr-46 (Accessed: 18 May 2020).
- 3. Grant, W., Lahore, H., McDonnell, S., Baggerly, C., French, C., Aliano, J. & Bhattoa, H. (March 30, 2020; 2nd version). ‘Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths’, Nutrients, 12(988). Available at: https://www.preprints.org/manuscript/202003.0235/v2 (Accessed: 18 May 2020).
- 4. Brown, R. & Sarkar, A. (March 24, 2020). ‘Vitamin D deficiency: a factor in COVID-19, progression, severity and mortality? – An urgent call for research’, MitoFit Preprint Arch. DOI: 10.26124/mitofit:200001. Available at: https://www.mitofit.org/index.php/Brown_2020_MitoFit_Preprint_Arch (Accessed: 18 May 2020).
- 5. 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: 18 May 2020).
- 6. 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: 18 May 2020).
- 7. Meltzer, D., Best T., Zhang, H., Vokes, T., Arora, V. & Solway, J. (May 13, 2020). ‘Association of Vitamin D Deficiency and Treatment with COVID-19 Incidence’, MedRxiv. DOI: 10.1101/2020.05.08.20095893 Available at: https://www.medrxiv.org/content/10.1101/2020.05.08.20095893v1 (Accessed: 18 May 2020).
- 8. Buttriss, J. & Lanham‐New, S. (May 18, 2020). ‘Is a vitamin D fortification strategy needed?’, Nutrition Bulletin, p. 1-8. DOI: 10.1111/nbu.12430
- 9. 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.
- 10. 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.
- 11. 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
- 12. 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] https://hosppeds.aappublications.org/content/hosppeds/early/2020/04/06/h...
- 13. 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’. Available at: https://www.aa.com.tr/en/europe/new-global-trend-of-covid-19-linked-dise... (Accessed: 19 May 2020).
- 14. Schmid, A. & Walther, B. (2013). ‘Natural vitamin D content in animal products’, Advances in nutrition (Bethesda, Md.), 4(4), p.453–462. DOI: 10.3945/an.113.003780
- 15. Holick, M. (2011). ‘Vitamin D: a d-lightful solution for health’, Journal of investigative medicine : the official publication of the American Federation for Clinical Research, 59(6), p.872–880. DOI: 10.2310/JIM.0b013e318214ea2d
- 16. Glicio, El, J. (May 5, 2020). ‘Vitamin D Level of Mild and Severe Elderly Cases of COVID-19: A Preliminary Report’, SSRN. Available at: https://ssrn.com/abstract=3593258 (Accessed: 18 May 2020).
- 17. 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: 18 May 2020).
- 18. De Smet, D., De Smet, K., Herroelen, P., Gryspeerdt, S. & Martens, D. (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: 18 May 2020).
- 19. 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
- 20. 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: 18 May 2020)
- 21. Davis R. The Doctor Who Championed Hand-Washing and Briefly Saved Lives. NPR Your Health. Available at https://www.npr.org/sections/health-shots/2015/01/12/375663920/the-docto.... (Accessed: 18 May 2020).
- 22. Acknowledgement: Thanks to William Grant referenced above note 3 for the parachute analogy, and his wider contribution to finding and sharing papers, and to Henry Lahore of https://vitamindwiki.com/for his tireless cataloguing of all things Vitamin D, with dogged unceasing determination, over very many years.
- 23. National Institute for Health and Care Excellence (2020). ‘Vitamin D deficiency in adults - treatment and prevention’. Last revised in September 2018. Next planned review by November 2021. Available at: https://cks.nice.org.uk/vitamin-d-deficiency-in-adults-treatment-and-pre... (Accessed: 18 May 2020).
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