Covid-19: Public health agencies review whether vitamin D supplements could reduce riskBMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m2475 (Published 19 June 2020) Cite this as: BMJ 2020;369:m2475
All rapid responses
Re: Covid-19: Public health agencies review whether vitamin D supplements could reduce risk - Most likely they will: not to infection rate but to outcomes
Professor Adrian Martineau is correct when he says that reverse causality might play a role in assessing vitamin D status of people who have become ill with covid-19. In my experience as GP having checked many 25(OH)D levels (1), followed by treatment, those who do have an inflammatory illness have low 25(OH)D levels. There appears to be a “turn over”, vitamin D appears to be “used up”. But treating with D-supplements is still appropriate.
Avoiding vitamin D deficiency within this pandemic isn’t about reducing infection rate, it is about that a healthy 25(OH)D level renders the body to be equipped to battle this infection, it is about preventing the escalation in severity, preventing the need for ventilation and most likely even deaths (2,3). The crucial point is that people must be treated to reach D-sufficiency, that is a serum 25(OH)D of at least 75 nmol/l (30 ng/ml), better even above 100 nmol/l (40 ng/ml) (4-8).
1. Rhein HM. Vitamin D deficiency is widespread in Scotland. BMJ 2008;336June28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440863/
3. Davies G, Garami AR, Byers JC. Evidence Supports a Causal Role for Vitamin D Status in COVID-19 Outcomes. June 2020. medRxiv 2020.05.01.20087965; doi: https://doi.org/10.1101/2020.05.01.20087965
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/
Competing interests: No competing interests
The correlation between questions about Vitamin in diet and sunlight exposure and the circulating level of (25)Vitamin D in populations is poor. The only way to a person's true Vitamin D status and to address its usefulness in Covid 19 is to measure the level before the patient contracts the illness. Second best is at admission. The lack of measuring the level is probably the single most important cause of the often conflicting results in population studies. Do it right or don't do it!
Competing interests: No competing interests
Pandemic - ‘Action This Day’ – Measure Vitamin D in COVID-19 Patients – Time is of Essence – BAME, Elderly and Obese are Disproportionately Dying
Dear Editor 
Vitamin D is suggested for inclusion in WHO COVID-19 road-map.
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. 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  progression: the unknowns are quantum and mechanisms.
OBSERVATIONAL EVIDENCE STRIKING – 10-20 greater D deficiency mortality-risk in some.
Nine observational preprints UK Germany, monitoring COVID-19-positive-patients; papers on, infectivity, hypocalcaemia, and a study in Singapore, taken together, strongly suggest Vitamin D deficiency factors in COVID severity and mortality. No RCTs have reported to date.
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, 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.
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.
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 and Africa, had low levels of these diseases.
CONFOUNDERS – comorbidities increase COVID-19 risk
Martineau 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,”. 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, more-widely Australia, and New Zealand, 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.
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), Asian ‘H2N2’ (1957-1959; 1959 in Peru – seasonal effect?) and Hong Kong ‘H3N2’ (1968-1970), 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; 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; Dexamethasone also changes, Vitamin D and downstream product, levels, logically possibly negatively impacting immune recovery pathways, and time-scales.
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’.
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Competing interests: No competing interests
The 10 mcg (400 IU) vitamin D supplement recommended by Public Health England is verging on the homoeopathic – it would raise blood 25(OH)D levels over 2-3 months by only around 4 nmol/L, leaving someone who is vitamin D deficient still deficient!
Most adults (and especially the elderly, those with dark skins, and those who are overweight or obese) will require much bigger doses to achieve optimal 25(OH)D levels (100-150 nmol/L; 40-60 ng/mL) - 5,000 IU (125 mcg)/day (or even more) is not unusual. (As a general rule of thumb, a dose of 1,000 IU (25 mcg) will raise blood 25(OH)D levels by around 10 nmol/L.) The potential for toxicity from taking vitamin D supplements is low - according to the US National Institutes of Health / Office of Dietary Supplements, ‘most reports suggest a toxicity threshold for vitamin D of 10,000-40,000 IU/day and serum 25(OH)D levels of 500–600 nmol/L (200-240 ng/mL)’ – whereas the potential benefits are huge.
The planned randomised controlled trial of vitamin supplementation to reduce the risk of covid-19 over winter will be a waste of time if inadequate doses are used – let’s hope that the ‘different vitamin D supplementation strategies’ includes some sensible doses such as suggested above
Competing interests: No competing interests
To the vast majority of scientists not contaminated by NICE-speak the fiasco surrounding D3 for COVID must appear inane. The use of RCTs and no other science input has lead NICE into deciding that >25nmol/L 25(OH)D3 is not deficient. Evolution of D3 signalling over 500 million years has refined our innate and adaptive immunity and endowed us with a physiological level of 100 to 150 nmol/L . NICE like Wilberforce are trying to defy evolution . Do they really think that SARS-CoV2 is so enormously different from other viruses to have escaped 500M years of evolutionary combat ? What peculiar train of thought leads NICE to assume that we are safe with just one fifth of the physiological 25(OH)D3 level. in around half the number of cells in our body that comprise immune systems ? Science is all about understanding a system in its totality, not putting on the blinkers of RCTs and ignoring the ca 5000 research papers per annum that put D3 centre-stage in a host of disease conditions, several of which are known co-morbidities for COVID. Hypertension, T2DM, obesity are in that list but also ignored by the NICE D3 panel because......there are no acceptably large RCTs. (The list of discarded conditions is looooong). Unless NICE change their approach to D3 and stop treating it as if it were a xenobiotic it will lose credibility not only with scientists at large but also with the public. Let's see a report that embraces all of D3 relating to immune defences,including observational studies from Indonesia, Philippines, Belgium, Louisiana, India, all pointing to a dramatic reduction in COVID severity or death at >75nmol/L. NICE have already failed miserably by not conducting UK studies months ago. The see British biological expertise out-paced by developing countries is distressing, and NICE's dilatory intransigence is the culprit.
NICE must embrace in their deliberations the fact that African and Asians are less responsive to 25(OH)D3 than caucasians, which compounds the impact of known lower 25(OH)D3 levels. NICE need to do lots of science homework fast.
So....do the job fully NICE, by ditching your fetish for RCTs, or resign. If your terms of office limit you to considering RCTs: resign. If you need help, expand the stakeholder input. Believe me, another trite claim " there is no evidence" will backfire, the pubic at large are now watching. For example:
Competing interests: No competing interests