Intended for healthcare professionals

Rapid response to:

News News analysis

Covid-19: Public health agencies review whether vitamin D supplements could reduce risk

BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m2475 (Published 19 June 2020) Cite this as: BMJ 2020;369:m2475

Rapid Response:

Pandemic - ‘Action This Day’ – Measure Vitamin D in COVID-19 Patients – Time is of Essence – BAME, Elderly and Obese are Disproportionately Dying

Dear Editor [1]

Vitamin D is suggested for inclusion in WHO COVID-19 road-map.[2]

Public Health England (PHE) may wish to consider:

BIOLOGICAL PATHWAYS and EVOLUTION - Vitamin D definitively factors in immune function.

Biological / physiological research powerfully evidences Vitamin D factors in disease immune response, through multiple mechanisms and pathways, including transcription and mitochondrial regulation. Multiple pathways have been identified.[3] Vitamin D is unquestionably built very deep into evolutionary biology.[4. 5]

Consequentially, Vitamin D deficiency inevitably must impact both COVID-19 and Kawasaki-like PIMS-TS [6] progression: the unknowns are quantum and mechanisms.

OBSERVATIONAL EVIDENCE STRIKING – 10-20 greater D deficiency mortality-risk in some.

Nine observational preprints[7] UK[8] Germany[9], monitoring COVID-19-positive-patients; papers on, infectivity,[10] hypocalcaemia,[11] and a study in Singapore,[12] taken together, strongly suggest Vitamin D deficiency factors in COVID severity and mortality. No RCTs have reported to date.[13]

RCTs / POPULATION STUDIES TAKE TIME, months to years - limited pandemic value.

Most RCTs and wider studies including COVIDENCE, will not report until after main pandemic impact,[13] limiting their application-value.

MEASURE VITAMIN D IN COVID-19 PATIENTS: - quick – easy – cheap: and anonymise – follow NICE.

Immediate widespread measurement of Vitamin D levels in plasma of COVID-19 hospital patients would facilitate deficiency repletion per NICE guidelines; and allow fast determination, of Vitamin D deficiency impact on COVID-19, with sufficient certainty sufficient to support timely public health policy adaptation.

INFECTION AND PROGRESSION - governed by different, albeit related, pathways.

Infection statistics will be impacted both by social factors and biology.[1]

Separation of Vitamin D deficiency effect on; COVID-19 infection; and post diagnosis disease progression in hospitalised patients, is important, as driven by different balances of social and biologic factors.

Whilst infection rates will have a social aspect: asymptomacity, severity, and disease progression, must largely depend on biological factors (given equally standards of care); thus, ultimately on; nutritional status, general health and comorbidities, with possible impact of polymorphic genetic components triggered by extrinsic factors.[14]

Consistent with this, comorbidities such as; hypertension, atherosclerosis, and diabetes, are arguably products of poor nutrition, not ‘poverty per se’. Historically groups subject to ‘poverty’ in China[14] and Africa[13], had low levels of these diseases.

CONFOUNDERS – comorbidities increase COVID-19 risk[14]

Martineau[1] suggests, implicitly referring to the 7 observational preprints, that ‘confounding may explain associations’. Indeed: however, many such confounders include a vitamin-D-element, and, in the time-urgency of a pandemic, such considerations are arguably a nicety; given vitamin D deficiency is anyway a defined medical condition. Further effects are so large, and results so stark, it is difficult to conceive confounders could materially impact the direction of the basket-of-outcomes.

REVERSE CAUSALITY – an issue for later - this is a pandemic

Martineau noted, “Reverse causality could also be operating”, “Inflammation itself can disturb Vitamin D metabolism, and actually render somebody deficient,”.[1] This is a valid observation, but it is unclear how it obviates the clinical need to urgently replete Vitamin D deficient patients.

If the issue was dehydration, nobody would demand RCTs to determine if dehydration was due to; low-intake-pre-hospitalisation, or fever-in-hospital, before accepting patients deficient or insufficient in water, required hydration.

Surely treatment of Vitamin D deficiency disease patients should be no different. Vitamin D disease is a NICE recognised condition, that requires treatment irrespective of the cause of the deficiency, without exception.

CLINICAL AND NUTRITIONAL ADVICE - determined differently.

Clinical pharmacological applications require RCTs. Current nutritional UK advice restricts itself largely to RCTs, yet decisions on; smoking, handwashing, mask-use, social-distancing, and isolation-polices; as well as historical nutritional policies; were very largely based on judgements, of benefits vs. harms, derived from observation and perceived likely outcomes, rather than RCTs, due to practical difficulties, and ethics of doing human RCT deficiency and infection studies, where potential harm and fatality is involved.

PRAGMATISM - lower Antipodean COVID-19 mortality.

Tasmania,[16] more-widely Australia,[17] and New Zealand,[18] take more pragmatic Vitamin D policy approaches, than the UK, encouraging testing and / or automatic-supplementation (50,000IU month – NZ) for medium-risk patients. Interestingly, Covid -19 mortality per Million, in Australia and New Zealand; and Norway and Finland also with active Vitamin D policies; was much lower than the UK.

NATIONAL AND GLOBAL TRENDS

Infection and mortality incidence, shows signs of both a seasonal and latitudinal aspects, further pointing to Vitamin D factoring in COVID-19 infection and progression.[19]

BAME COVID-19 MORTALITY AND RISK OF VITAMIN D DEFICIENCY – URGENT ISSUES

Facts require facing: BAME Persons including African Americans; Elderly and Obese, are at greatest risk of both, COVID-19 and Vitamin D deficiency: determining if links exists requires urgent measurement of Vitamin D levels in COVID-19 patients.

TIME IS OF ESSENCE in a pandemic.

Evidence based on; Spanish (1918-1920),[20] Asian ‘H2N2’ (1957-1959; 1959 in Peru – seasonal effect?)[21] and Hong Kong ‘H3N2’ (1968-1970),[22] flu pandemics, suggests COVID-19 will likely last 2 years, with a possible 3rd year, latitude-impacted-tail. Historically, the biggest pandemic effect was seen in the second season, suggesting COVID-19 may upsurge this autumn / winter.

DEXAMETHASONE - COMPARE AND CONTRAST

Potential pandemic mitigation strategies, require research and decisive ‘pre-peer-review’ action; as happened with the steroid Dexamethasone[23]; but ironically, not with evolutionary-immune-central-steroid, Vitamin D, despite; high deficiency levels, known biology, low-side-effect-risks and observational studies.

Interestingly, immune pathways activated by Dexamethasone and Vitamin D, overlap, e.g. via VDR[24]; Dexamethasone also changes, Vitamin D and downstream product, levels, logically possibly negatively impacting immune recovery pathways, and time-scales.[25]

CONCLUSION – ‘ACTION THIS COVID-19 DAY’ - Please.

Is failure to collect UK Vitamin D COVID-19 data rational – how can PHE properly and fully consider vitamin D’s role in Covid-19 severity and mortality, without the necessary data?

This is a pandemic – this data is needed now – common sense and pragmatism must prevail – NHS please adopt Churchill’s mantra ‘action this day’- urgently obtain anonymised Vitamin D COVID-19 positive patient data, by addition to testing list / testing of historic samples: record and relate to outcomes - determine if global observational results apply to UK – if the case, PHE please amend Public Health and clinical policy appropriately.

Establishing reduction of Vitamin D deficiency significantly mitigates COVID-19 mortality and severity would be globally ‘game-changing’.

1.Torjesen, I. (June 19, 2020). ‘Covid-19: Public health agencies review whether Vitamin D supplements could reduce risk’, BMJ,;369(m2475). DOI: 10.1136/bmj.m2475 Available at: https://www.bmj.com/content/369/bmj.m2475 (Accessed: 24 June 2020).
2. Norton, A., De La Horra Gozalo, A., de Colombi, N., Alobo, M., Asego, J. Zainab Al-Rawni Z, ... et al.
The remaining unknowns: A determination of the current research priorities for COVID-19 by the global health research community. (See table 2 clinical management) medRxiv 2020.06.24.20138198; doi: https://doi.org/10.1101/2020.06.24.20138198 Available at: https://www.medrxiv.org/content/10.1101/2020.06.24.20138198v1.full.pdf (Accessed: 24 June 2020).
3. 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., Sarkar, 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: 24 June 2020).
4. Hanel, A., & Carlberg, C. (2020). ‘Vitamin D and evolution: Pharmacologic implications’, Biochem Pharmacol., 173(113595). DOI:10.1016/j.bcp.2019.07.024 Available at: https://www.researchgate.net/profile/Andrea_Hanel/publication/334851051_... (Accessed: 24 June 2020).
5. Ramagopalan, S., Heger, A., Berlanga, A., et al. (2010). ‘A ChIP-seq defined genome-wide map of Vitamin D receptor binding: associations with disease and evolution’, Genome research, 20(10), p.1352–1360. DOI: 10.1101/gr.107920.110
6. Brown, R. (June 10, 2020). ‘BAME Children at High Risk of PIMS-TS, a Covid-19 Kawasaki-Like Disease - Vitamin D, a Factor? – Testing and Data Urgently Required. Is ethnicity linked to incidence or outcomes of covid-19?’, BMJ, 369(m1548) DOI: 10.1136/bmj.m1548. Available at: https://www.bmj.com/content/369/bmj.m1548/rr-25 (Accessed: 24 June 2020).
7. Brown, R. (May 19, 2020). ‘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, 369(m1548). DOI: 10.1136/bmj.m1548 Available at: https://www.bmj.com/content/369/bmj.m1548/rr-19 (Accessed: 24 June 2020).
8. Panagiotou, G., Tee, S., Ihsan, Y., Athar, W., Marchitelli, G., Kelly, D., Boot. C., Stock, N., Macfarlane, J., Martineau, A., Burns, G., Quinton, R. (23 June 2020). Low serum 25-hydroxyvitamin D (25[OH]D) levels in patients hospitalised with COVID-19 are associated with greater disease severity: results of a local audit of practice. medRxiv 2020.06.21.20136903; doi: https://doi.org/10.1101/2020.06.21.20136903 Available at: https://www.medrxiv.org/content/10.1101/2020.06.21.20136903v1.full.pdf (Accessed: 24 June 2020).
9. Brenner, H., Holleczek, B., Schoettker, B. (23 June 2020). Vitamin D insufficiency and deficiency and mortality from respiratory diseases in a cohort of older adults: potential for limiting the death toll during and beyond the COVID-19 pandemic. medRxiv 2020.06.22.20137299; doi: https://doi.org/10.1101/2020.06.22.20137299 Available at: https://www.medrxiv.org/content/10.1101/2020.06.22.20137299v1.full.pdf (Accessed: 25 June 2020)
10. 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, 20095893. DOI: 10.1101/2020.05.08.20095893 Available at: https://www.medrxiv.org/content/10.1101/2020.05.08.20095893v1 (Accessed: 24 June 2020).
11. Liu, J., Han, P,. Wu, J., Gong, J., & Tian, D. (June 22, 2020). ‘Prevalence and predictive value of hypocalcemia in severe COVID-19 patients’, Journal of Infection and Public Health (In Press, Journal Pre-proof). DOI: 10.1016/j.jiph.2020.05.029 Available at: https://www.sciencedirect.com/science/article/pii/S1876034120305323?via%... (Accessed: 24 June 2020).
12. Tan, C., Ho, L., Kalimuddin, S. et al. (June 2, 2020). ‘A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients’, medRxiv, 20112334. DOI: https://doi.org/10.1101/2020.06.01.20112334 Available at: https://www.medrxiv.org/content/10.1101/2020.06.01.20112334v1.full.pdf (Accessed: 24 June 2020).
13. ‘28. Studies found for: vitamin d | covid-19’. U.S National Library of Medicine Clinical Trials.gov (Not yet reported: many not yet recruiting: not all related to vitamin D: many will likely not report before 2021) Available at: https://clinicaltrials.gov/ct2/results?term=vitamin+d&cond=covid-19 (Accessed: 24 June 2020).
14. Brown, R. (June 17, 2020). ‘Is ethnicity linked to incidence or outcomes of covid-19? High BAME COVID-19 Mortality - Ethnicity a Factor? – Yet: Cardiovascular Disease – Hypertension – Diabetes - were rare in 1920-60’s in Indigenous Africans – Vitamin D an underrated factor?’, BMJ, 369(m1548). DOI: https://doi.org/10.1136/bmj.m1548 Available at: https://www.bmj.com/content/369/bmj.m1548/rr-26 (Accessed: 24 June 2020).
15. Campbell, T. (May 11, 2006). ‘The China Study: The Most Comprehensive Study of Nutrition Ever Conducted And the Startling Implications for Diet, Weight Loss, And Long-term Health’, BenBella Books; 1 edition ISBN-10: 1932100660 (quoted for the data it contains – no authors viewpoint should be implied as to wider content of this citation) (the data was derived from the China Cornell Oxford Project - but data links are not working https://web.archive.org/web/20090223222003/http://www.nutrition.cornell....)
16. ‘Vitamin D Advice for Clinicians Department of Health Tasmania’. Available at: https://www.dhhs.tas.gov.au/publichealth/healthy_communities/vitamin_d/v... (Accessed: 24 June 2020).
17. ‘Health Direct Free Australian health advice you can count on’. Available aat: https://www.healthdirect.gov.au/vitamin-d-deficiency (Accessed: 24 June 2020).
18. Carr, H., Galtry. J., & Clark S. (March, 2012). ‘Ministry of Health and Cancer Society of New Zealand’. Consensus Statement on Vitamin D and Sun Exposure in New Zealand. Wellington: Ministry of Health. Available at: https://www.health.govt.nz/system/files/documents/publications/vitamind-... (Accessed: 24 June 2020).
19. Davies, G., Garami, A., & Byers, J. (June 13 2020). Evidence Supports a Causal Role for Vitamin D Status in COVID-19 Outcomes. medRxiv 2020.05.01.20087965; doi: https://doi.org/10.1101/2020.05.01.20087965 Available at: https://www.medrxiv.org/content/10.1101/2020.05.01.20087965v3.full.pdf (Accessed: 24 June 2020).
20. Wikipedia contributors. (June, 2020). ‘Spanish flu’. Available at: https://en.wikipedia.org/w/index.php?title=Spanish_flu&oldid=963876583 (Accessed: 24 June 2020).
21. Wikipedia contributors. (June, 2020). ‘Asian Flu. 1957–1958 influenza pandemic’. Available at: https://en.wikipedia.org/w/index.php?title=1957%E2%80%931958_influenza_p... (Accessed: 24 June 2020).
22. Wikipedia contributors. (June, 2020). ‘Hong Kong flu’. Available at: https://en.wikipedia.org/w/index.php?title=Hong_Kong_flu&oldid=963601908 (Accessed: 24 June 2020).
23. Horby, P., Lim, W., Emberson, J. et al. (June 2, 2020). ‘Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report’medRxiv,20137273. DOI: 10.1101/2020.06.22.20137273
24. Kulkarni, N. N., Gunnarsson, H. I., Yi, Z. et al. (2016). ‘Glucocorticoid Dexamethasone Down-Regulates Basal and Vitamin D3 Induced Cathelicidin Expression in Human Monocytes and Bronchial Epithelial Cell Line’, Immunobiology, 221(2), p.245-252. DOI: 10.1016/j.imbio.2015.09.001.
25. Alabsi, S., DeVore, K., Willson, R. (no date). ‘Guidelines for the Use of DEXAMETHASONE (Decadron). UnityPoint’. Available at: https://www.unitypoint.org/blankchildrens/filesimages/for%20providers/ni... (Accessed: 24 June 2020).

Competing interests: No competing interests

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