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• A Position Statement from the COVID-19 Taskforce of the NNEdPro Global Centre for Nutrition and Health, on Vitamin D and high-risk groups in the COVID-19 pandemic
  Shane McAuliffe, Elaine Macaninch, James Bradfield, Dominic Crocombe and Sumantra Ray
  Published on: 30 December 2020
• Existing meta-analysis of serum vitamin D and pulmonary function across nine population-based cohort studies contributes to the evidence base on vitamin D and respiratory health
  Jiayi Xu, Dana B. Hancock and Patricia A. Cassano
  Published on: 19 June 2020
• POPULATION RESILIENCE We all need optimal back ground immunity, ahead of a second Covid-19 wave
  Helga M Rhein
  Published on: 2 June 2020
• A call for randomized controlled clinical trial, not dismissal, is warranted
  Gennadi V Glinsky
  Published on: 29 May 2020

• Published on: 30 December 2020

  A Position Statement from the COVID-19 Taskforce of the NNEdPro Global Centre for Nutrition and Health, on Vitamin D and high-risk groups in the COVID-19 pandemic

  • Shane McAuliffe, Science Communications Lead NNEdPro Global Centre for Nutrition and Health - Nutrition & Covid-19 Taskforce
  • Other Contributors:
    • Elaine Macaninch, Lead for Patient, Public and Practitioner Outreach
    • James Bradfield, Lead for Education, Awareness, and Implementation
    • Dominic Crocombe, Co-Chair Exec
    • Sumantra Ray, Co-Chair Ex-Officio

  We acknowledge increasing concerns around high-risk groups and COVID-19, about both susceptibility and clinical outcomes. There are many additional factors that are worthy of further research, including the potential role of ethnicity (1-3), inadequate vitamin D status (including both insufficiency and clinical deficiency) (4-6) and inequalities in socio-economic status (7,8). This is not an exhaustive list, and there are many other factors to consider, especially as COVID-19 is a new disease. Our understanding of its interactions, including those with nutrition are continually evolving and with it, so is the evidence base that can inform practice.

  There has been a focus on groups at higher risk during the pandemic, who also tend to be at higher risk of micronutrient deficiencies and poorer overall nutrition, and in such vulnerable groups, diet alone may be insufficient to meet requirements, so micronutrient deficiencies pose a considerable risk to health. In such cases, the immune system may be supported by supplementation, particularly to help correct deficiencies and attenuate the effects of concurrent treatments (9). These observations are particularly prudent in the case of Vitamin D, in which sufficiency is difficult to achieve in the general population at certain times of the year (10) and all year round in vulnerable populations (4,5,11). This is clearly evident for those in residential care, meaning supplementation will be essential to meet requirements....

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  We acknowledge increasing concerns around high-risk groups and COVID-19, about both susceptibility and clinical outcomes. There are many additional factors that are worthy of further research, including the potential role of ethnicity (1-3), inadequate vitamin D status (including both insufficiency and clinical deficiency) (4-6) and inequalities in socio-economic status (7,8). This is not an exhaustive list, and there are many other factors to consider, especially as COVID-19 is a new disease. Our understanding of its interactions, including those with nutrition are continually evolving and with it, so is the evidence base that can inform practice.

  There has been a focus on groups at higher risk during the pandemic, who also tend to be at higher risk of micronutrient deficiencies and poorer overall nutrition, and in such vulnerable groups, diet alone may be insufficient to meet requirements, so micronutrient deficiencies pose a considerable risk to health. In such cases, the immune system may be supported by supplementation, particularly to help correct deficiencies and attenuate the effects of concurrent treatments (9). These observations are particularly prudent in the case of Vitamin D, in which sufficiency is difficult to achieve in the general population at certain times of the year (10) and all year round in vulnerable populations (4,5,11). This is clearly evident for those in residential care, meaning supplementation will be essential to meet requirements.

  In light of considerable interest in the potential role of Vitamin D in COVID-19, our flagship journal BMJ Nutrition, Prevention and Health has published a range of recent peer-reviewed articles on this topic (4,5). In addition to these publications, we have advocated for robust evidence relating to ethnicity and COVID-19, to guide further research, policy and practice (12,13), through a special collection on Nutrition Interactions with COVID-19 (14).

  However, key messages from emerging articles on Vitamin D have been open to variable interpretation in the media. Furthermore, the most recent NICE/SACN guidance (15) on Vitamin D and COVID-19, whilst advocating Vitamin D supplementation, takes a cautious mass population approach with a relatively conservative upper limit on dosage due to theoretical concerns pertaining to calcium balance amongst other perceived harms associated with higher dose Vitamin D supplements, and as a result this approach is unlikely to be sufficient for those with clinical deficiency.

  Whilst recognising that the pandemic presents a volatile, uncertain, complex and ambiguous environment regarding evidence-based practice, we also believe that in the absence of further primary research data on Vitamin D and COVID-19, reasonable extrapolations from existing data supporting interventions with a much greater likelihood of potential benefit vs harm, such as ensuring population level Vitamin D adequacy, need to be fully explored. In order to provide a balanced picture, we have put together the following points about our knowledge to date, as well as emerging research questions that have arisen:

  • Currently, there is insufficient peer-reviewed and published evidence to support high dose vitamin D supplementation for the prevention or treatment of COVID-19. However, an increasing depth of observational data has resulted in calls for more clinical trials to evaluate a potential therapeutic role of vitamin D in COVID‐19 (16). One pilot trial has recently examined the role of oral supplementation of high dose Calcifediol (25-OH D) alongside combination drug therapy in patients with COVID-19, demonstrating a reduction in critical care admissions in supplemented group (17). This has prompted the initiation of a larger scale trial (18). These come with the caveat that plasma micronutrient concentrations must be interpreted with caution, given that there is consistent evidence that most common measured micronutrients in the plasma are significantly lowered as part of the systemic inflammatory response (19).

  • Due to concerns with potential harm from excessive vitamin D supplementation, the use of high-dose supplements is not advised routinely. This does not mean, however, that high-dose supplements have no role in the prevention or treatment of COVID-19, as their effectiveness has not yet been tested. More recently, questions have been raised about optimal serum measurements for sufficiency and consequently, appropriate recommendations for Vitamin D supplementation in the UK, given the higher requirements stated by the European Food Safety Authority (EFSA) and the American Institute of Medicine (IOM) (20,21).

  • All in all, it is clear that avoiding vitamin D deficiency is important for many aspects of health. For this reason, measures to prevent deficiency should be supported at all times. This is possible through obtaining sufficient sun exposure during applicable seasons of the year, in some food products (particularly those fortified with Vitamin D), and from moderately dosed vitamin D supplements if required, though recent questions about defining optimal doses should be acknowledged and investigated further. At times, severe deficiency may require treatment with higher doses, but is important to note that this should only be done under appropriate clinical supervision.

  Some of these messages have also been echoed by the initial evidence review commissioned by the National Institute for Health & Care Excellence (NICE), in which our dedicated Nutrition & COVID-19 Taskforce had input during the review process (22). We are now beginning to see the findings of these research questions being translated into policy action, with the recent UK expansion in provision of Vitamin D supplementation to vulnerable groups at highest risk during the pandemic (23). Even still, many questions remain to be fully elucidated concerning interindividual differences in requirements, optimal therapeutic doses and in determining individual requirements through screening programmes and testing. More research into the specific role for Vitamin D in the prevention and/or treatment of COVID-19, as well as other infectious diseases and potentially future pandemics, is needed.
  Currently, we also caution against an ultraconservative approach to public health messaging so as not to undermine any potential benefits of achieving adequate Vitamin D status at population level. This requires a combination of mass population approaches combined with clinically supervised supplementation with higher dose supplementation for those with clinical deficiency. This issue has been highlighted by the clinical practice community (21)
  For this reason, it is imperative that the momentum gathered so far during the pandemic continues to be built upon in order to translate what we already know rapidly into risk-manged practice whilst continue to support research to address important questions that remain unanswered.

  References
  1. Khunti K, Singh AK, Pareek M, Hanif W. Is ethnicity linked to incidence or outcomes of covid-19? BMJ 2020; 369 :m1548
  2. Pareek M, Bangash MN, Pareek N, et al. Ethnicity and COVID-19: an urgent public health research priority. Lancet. 2020;395(10234):1421‐1422. doi:10.1016/S0140-6736(20)30922-3
  3. Public Health England: COVID-19: review of disparities in risks and outcomes.
  4. Lanham-New SA, Webb AR, Cashman KD, et al. Vitamin D and SARS-CoV-2 virus/COVID-19 disease. BMJ Nutrition, Prevention & Health 2020;0. doi:10.1136/ bmjnph-2020-000089
  5. Kohlmeier M. Avoidance of vitamin D deficiency to slow the COVID-19 pandemic. BMJ Nutrition, Prevention & Health 2020;0. doi:10.1136/ bmjnph-2020-000096
  6. The Lancet: Vitamin-D and COVID-19: do deficient risk a poorer outcome?
  7. Khalatbari-Soltani S, Cumming RG, Delpierre C, et al. Importance of collecting data on socioeconomic determinants from the early stage of the COVID-19 outbreak onwards. J Epidemiol Community Health Published Online First: 08 May 2020. doi: 10.1136/jech-20
  8. NEJM: Perspective - Covid-19 and Disparities in Nutrition and Obesity
  9. McAuliffe S, Ray S, Fallon E, et al. Dietary micronutrients in the wake of COVID-19: an appraisal of evidence with a focus on high-risk groups and preventative healthcare. BMJ Nutrition, Prevention & Health 2020;0. doi:10.1136/ bmjnph-2020-000100
  10. Almoosawi S, Palla L. Association between vitamin intake and respiratory complaints in adults from the UK National Diet and Nutrition Survey years 1–8. BMJ Nutrition, Prevention & Health 2020;0. doi:10.1136/ bmjnph-2020-000150
  11. Williams J, Williams C. Responsibility for vitamin D supplementation of elderly care home residents in England: falling through the gap between medicine and food. BMJ Nutrition, Prevention & Health 2020;0. doi:10.1136/ bmjnph-2020-000129
  12. NHS launches Race and Health Observatory after BMJ’s call to end inequalities. https://doi.org/10.1136/bmj.m2191
  13. The Lancet: Covid-19 and Ethnicity. Who will research results apply to? https://doi.org/10.1016/S0140-6736(20)31380-5
  14. BMJ Nutrition, Prevention and Health Collections, Call for papers on Nutrition interactions with COVID-19
  15. National Institute for Health and Care Excellence (NICE). COVID-19 rapid guideline: vitamin D (NG187). https://www.nice.org.uk/guidance/ng187/resources/covid19-rapid-guideline...
  16. Vitamin D and Covid-19. Press release from the French National Academy of Medicine. 22 May 2020. https://www.academie-medecine.fr/wp-content/uploads/2020/05/20.5.22-Vita...
  17. Entrenas Castillo, M., Entrenas Costa, L. M., Vaquero Barrios, J. M., Alcalá Díaz, J. F., López Miranda, J., Bouillon, R., & Quesada Gomez, J. M. (2020). "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study". The Journal of steroid biochemistry and molecular biology, 203, 105751. https://doi.org/10.1016/j.jsbmb.2020.105751
  18. Prevention and Treatment With Calcifediol of COVID-19 Induced Acute Respiratory Syndrome (COVIDIOL). ClinicalTrials.gov Identifier: NCT04366908
  19. McMillan DC, Maguire D, Talwar D. Relationship between nutritional status and the systemic inflammatory response: micronutrients. Proc Nutr Soc. 2019 Feb;78(1):56-67. doi: 10.1017/S0029665118002501. Epub 2018 Sep 17. PMID: 30220267.
  20. Griffin G, Hewison M, Hopkin J, Kenny R, Quinton R, Rhodes J, Subramanian S, Thickett D. 2020 Vitamin D and COVID-19: evidence and recommendations for supplementation. R. Soc. Open Sci. 7: 201912. https://doi.org/10.1098/rsos.201912
  21. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, Thickett D. Preventing vitamin D deficiency during the COVID-19 pandemic: UK definitions of vitamin D sufficiency and recommended supplement dose are set too low. Clin Med (Lond). 2020 Nov 6:c
  22. NICE: Vitamin D & COVID-19
  23. UK Gov. At-risk groups to receive free winter supply of vitamin D. https://www.gov.uk/government/news/at-risk-groups-to-receive-free-winter...

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  Conflict of Interest:
  None declared.

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• Published on: 19 June 2020

  Existing meta-analysis of serum vitamin D and pulmonary function across nine population-based cohort studies contributes to the evidence base on vitamin D and respiratory health

  • Jiayi Xu, Postdoctoral Fellow Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai
  • Other Contributors:
    • Dana B. Hancock, Senior Genetic Epidemiologist & Director
    • Patricia A. Cassano, Professor & Director

  Lanham-New et al. reviewed current evidence of vitamin D associations with health conditions that are pertinent to SARS-CoV-2 virus/COVID-19 disease. Their review highlighted the importance of a well-balanced diet, including an adequate amount of vitamin D intake, to boost the immune system and to resist viral infection. Lanham-New et al. also noted positive associations reported in a single study between the blood metabolite 25-hydroxyvitamin D (25OHD) and lung function and noted that “formal systematic reviews/meta-analyses of these associations are urgently required.” We would like to draw attention to several published reports of observational cohort studies evaluating the association of serum 25OHD with lung function (1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18) and to our meta-analysis that investigated this association across nine large population-based cohort studies (total N=27,128) (19).
  Our cross-ancestry meta-analysis included adults (age range: 19-95 yrs) living in northern latitudes (e.g. the Netherlands, Iceland, northern part of U.S.) and adults with darker skin tones (i.e., African ancestry participants), who may be at greater risk of vitamin D deficiency given limited sun exposure or slower production of vitamin D in the skin. Prior to combining association results for meta-analysis, the lung function outcomes, exposure (25OHD), and the covariates were harmonized, and the same statistical models were applied across the nine coh...

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  Lanham-New et al. reviewed current evidence of vitamin D associations with health conditions that are pertinent to SARS-CoV-2 virus/COVID-19 disease. Their review highlighted the importance of a well-balanced diet, including an adequate amount of vitamin D intake, to boost the immune system and to resist viral infection. Lanham-New et al. also noted positive associations reported in a single study between the blood metabolite 25-hydroxyvitamin D (25OHD) and lung function and noted that “formal systematic reviews/meta-analyses of these associations are urgently required.” We would like to draw attention to several published reports of observational cohort studies evaluating the association of serum 25OHD with lung function (1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18) and to our meta-analysis that investigated this association across nine large population-based cohort studies (total N=27,128) (19).
  Our cross-ancestry meta-analysis included adults (age range: 19-95 yrs) living in northern latitudes (e.g. the Netherlands, Iceland, northern part of U.S.) and adults with darker skin tones (i.e., African ancestry participants), who may be at greater risk of vitamin D deficiency given limited sun exposure or slower production of vitamin D in the skin. Prior to combining association results for meta-analysis, the lung function outcomes, exposure (25OHD), and the covariates were harmonized, and the same statistical models were applied across the nine cohorts. We reported a statistically significant positive association of 25OHD with lung function, specifically FEV1 and FVC. The positive direction of association was consistent across all cohorts regardless of ancestry. In addition, the positive association of 25OHD with lung function was stronger among current and former smokers, compared with never smokers. Although causality cannot be inferred from the observational studies conducted to date, the indication for a protective effect of vitamin D in individuals with a smoking history, as a vulnerable population, is notable given the current evidence suggesting smoking as a risk factor for worse progression of COVID-19 disease (20). Future prospective studies, including randomized clinical trials, are needed to establish any causal links between 25OHD, cigarette smoking, lung function, and COVID-19 disease. We agree with Lanham-New et al. that the current evidence base is insufficient to include vitamin D supplementation as a prevention or treatment strategy for COVID-19 disease.

  Jiayi Xu, Ph.D.
  Postdoctoral Fellow, Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai

  Dana B. Hancock, Ph.D.
  Senior Genetic Epidemiologist & Director, GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, Research Triangle Institute

  Patricia A. Cassano, Ph.D.
  Professor & Director, Division of Nutritional Sciences, Cornell University

  Reference:

  1. Black PN, Scragg R (2005) Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 128, 3792-3798.
  2. Choi CJ, Seo M, Choi WS et al. (2013) Relationship between serum 25-hydroxyvitamin D and lung function among Korean adults in Korea National Health and Nutrition Examination Survey (KNHANES), 2008-2010. J Clin Endocrinol Metab 98, 1703-1710.
  3. Hansen JG, Gao W, Dupuis J et al. (2015) Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study. Respir Res 16, 81.
  4. Afzal S, Lange P, Bojesen SE et al. (2014) Plasma 25-hydroxyvitamin D, lung function and risk of chronic obstructive pulmonary disease. Thorax 69, 24-31.
  5. Berry DJ, Hesketh K, Power C et al. (2011) Vitamin D status has a linear association with seasonal infections and lung function in British adults. Br J Nutr 106, 1433-1440.
  6. Thuesen BH, Skaaby T, Husemoen LL et al. (2015) The association of serum 25-OH vitamin D with atopy, asthma, and lung function in a prospective study of Danish adults. Clin Exp Allergy 45, 265-272.
  7. Tolppanen AM, Williams D, Henderson J et al. (2011) Serum 25-hydroxy-vitamin D and ionised calcium in relation to lung function and allergen skin tests. Eur J Clin Nutr 65, 493-500.
  8. Shaheen SO, Jameson KA, Robinson SM et al. (2011) Relationship of vitamin D status to adult lung function and COPD. Thorax 66, 692-698.
  9. Niruban SJ, Alagiakrishnan K, Beach J et al. (2015) Association between vitamin D and respiratory outcomes in Canadian adolescents and adults. J Asthma 52, 653-661.
  10. Tolppanen AM, Sayers A, Granell R et al. (2013) Prospective association of 25-hydroxyvitamin d3 and d2 with childhood lung function, asthma, wheezing, and flexural dermatitis. Epidemiology 24, 310-319.
  11. Lange NE, Sparrow D, Vokonas P et al. (2012) Vitamin D deficiency, smoking, and lung function in the Normative Aging Study. Am J Respir Crit Care Med 186, 616-621.
  12. Khan S, Mai XM, Chen Y (2013) Plasma 25-hydroxyvitamin D associated with pulmonary function in Canadian adults with excess adiposity. Am J Clin Nutr 98, 174-179.
  13. Rafiq R, Thijs W, Prein R et al. (2018) Associations of Serum 25(OH)D Concentrations with Lung Function, Airway Inflammation and Common Cold in the General Population. Nutrients 10.
  14. Shim SY, Chae WJ, Kim HC et al. (2018) Association between serum 25-hydroxyvitamin D levels and pulmonary function, among Korean adults, during 2010-2014, by sex, age, and body mass index. Respir Med 140, 32-38.
  15. Moghaddassi M, Pazoki M, Salimzadeh A et al. (2018) Association of Serum Level of 25-Hydroxy Vitamin D Deficiency and Pulmonary Function in Healthy Individuals. ScientificWorldJournal 2018, 3860921.
  16. Mulrennan S, Knuiman M, Walsh JP et al. (2018) Vitamin D and respiratory health in the Busselton Healthy Ageing Study. Respirology 23, 576-582.
  17. Flexeder C, Thiering E, Koletzko S et al. (2017) Higher serum 25(OH)D concentrations are associated with improved FEV1 and FVC in adolescence. The European respiratory journal 49.
  18. Lai SH, Liao SL, Tsai MH et al. (2017) Low cord-serum 25-hydroxyvitamin D levels are associated with poor lung function performance and increased respiratory infection in infancy. PloS one 12, e0173268.
  19. Xu J, Bartz TM, Chittoor G et al. (2018) Meta-analysis across Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium provides evidence for an association of serum vitamin D with pulmonary function. Br J Nutr 120, 1159-1170.
  20. Vardavas CI, Nikitara K (2020) COVID-19 and smoking: A systematic review of the evidence. Tob Induc Dis 18, 20.

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  Conflict of Interest:
  None declared.

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• Published on: 2 June 2020

  POPULATION RESILIENCE We all need optimal back ground immunity, ahead of a second Covid-19 wave

  • Helga M Rhein, retired general practitioner previously Sighthill Health Centre, 380 Calder Road, Edinburgh EH11 4AU

  POPULATION RESILIENCE

  We all need optimal back ground immunity, ahead of a second Covid-19 wave

  In your report (1) you mention the value of sufficient vitamin D for a healthy immune system. You are missing out, however, that the immune function and regulation of appropriate genes and enzymes need a higher vitamin D level (25(OH)D), higher than 25 nmol/l (2-5), as does maximal PTH suppression (6) and is the physiological blood levels in outdoor living people (7). All advocate the optimal blood level to be above 75 nmol/l. An extensive evidence collection is maintained on a specified website (8), and improvements in many conditions have been shown when blood levels were higher (osteomalacia (9), heart disease (10), respiratory tract infections (11), depression (12), COPD (13), cancer survival (14-17) and many more), resulting in the worldwide consensus that levels should be higher than 25 nmol/l. A group of 48 scientists has also published a consensus statement in 2015 that a level of 100 nmol/l should be called sufficient (18). To reach such a level from an average UK level (approx 40 nmol/l) one needs much higher doses of vitamin D than 10 mcg (400 IU).

  But your report says a blood level of 25 nmol/l is sufficient and the majority would only need 10 mcg of a D-supplement.
  However, the Institute of Medicine in the US has declared the level of sufficiency as 50 nmol/l, and they advise also higher D-supplement intake. In contrast to the UK where suf...

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  POPULATION RESILIENCE

  We all need optimal back ground immunity, ahead of a second Covid-19 wave

  In your report (1) you mention the value of sufficient vitamin D for a healthy immune system. You are missing out, however, that the immune function and regulation of appropriate genes and enzymes need a higher vitamin D level (25(OH)D), higher than 25 nmol/l (2-5), as does maximal PTH suppression (6) and is the physiological blood levels in outdoor living people (7). All advocate the optimal blood level to be above 75 nmol/l. An extensive evidence collection is maintained on a specified website (8), and improvements in many conditions have been shown when blood levels were higher (osteomalacia (9), heart disease (10), respiratory tract infections (11), depression (12), COPD (13), cancer survival (14-17) and many more), resulting in the worldwide consensus that levels should be higher than 25 nmol/l. A group of 48 scientists has also published a consensus statement in 2015 that a level of 100 nmol/l should be called sufficient (18). To reach such a level from an average UK level (approx 40 nmol/l) one needs much higher doses of vitamin D than 10 mcg (400 IU).

  But your report says a blood level of 25 nmol/l is sufficient and the majority would only need 10 mcg of a D-supplement.
  However, the Institute of Medicine in the US has declared the level of sufficiency as 50 nmol/l, and they advise also higher D-supplement intake. In contrast to the UK where sufficiency is declared at a lower leveI of 25 nmol/l and just half as much of supplement is recommended. I can therefore not understand how your report can be called a 'consensus' statement with these glaring differences in recommendation between countries.
  In addition it seems quite illogical for any nutrient to be given to all age groups at the same supplement size, babies or adults, but the UK advisory bodies recommend just that, one dose for all: 10 mcg. You don’t seem to criticise this.

  To the frequently posed question: was the vitamin D-deficiency the cause or the symptom of the disease? It clearly is both! A cancer patient will most likely be found to be D-deficient due to the disease process having gone on for some years, but blood level, symptoms and survival can be improved with supplements (14-17). Cancer patients appear to need more, they have a higher turnover, like people with other inflammatory conditions.
  You quote “the most recent Vitamin D Assessment Study and the Vitamin D and Omega-3 Fatty Acid Study did not show a mortality effect in vitamin D-replete adults” (19) but the same authors did publish in their update a significant cancer survival (14). Why is this ignored?
  This trial you quoted is an illustration why randomised controlled trials will not necessarily show a benefit in a normal, mostly replete population (US). However, cancer patients represent a mostly deficient cohort, a survival benefit could therefore be found, even if the design of the study was not based on achieved vitamin D blood level (which it really should have been) and all participants received the same dose (when some would have needed much bigger doses than others to reach the same sufficiency level).

  There have been to date 7 preliminary results of studies in different parts of the world, summarised in a BMJ rapid response (20). All showed much better outcomes in Covid-19 illness when vitamin D levels were higher than 75 nmol/l. This does of course not prove the benefit of higher vitamin D blood levels to fend off Covid-19, but it is a definite suggestion.

  It has also become obvious that those with dark skin types who are well known to be more D-deficient than those with light skin types (21) are at particular risk of Covid-19 including high mortality if not having blood levels that are adequate. A 10 mcg D-supplement is highly inadequate.
  Back to your rather unhelpful, negative formulation of 'mega supplements'. In order to reach adequate blood levels which can be effective for a healthy immunity most people in the UK would need doses of 3-5000 IU daily, or 10,000 IU for the first few weeks to increase the level. I presume those were the dose sizes which you call ‘mega’. These doses are perfectly safe (22). It will take 3 months to reach a blood level plateau. I have worked as GP in Scotland until recently and for the past 15 years I have treated many people with vitamin D deficiency with such doses and even higher. I have never seen an overdose of vitamin D and I would like to challenge the authors to give me evidence for their postulation. By mentioning the dangers of ‘mega supplements’, which occurred in many headlines of the world press following your publication, you simply frighten people off taking an appropriate dose of vitamin D as if it was a dangerous substance. In fact you are doing quite the opposite from protecting the public: it is dangerous to let the public remain ignorant to the point that they are afraid to take more than 10 mcg of vitamin D.

  With our UK prevalence of D-deficiency being one of the highest in Europe, isn’t it ethically obligatory to act? Firstly, you might want to propose to research the links between Covid-19 and Vitamin D, by testing hospitalised patients’ blood for 25(OH)D.
  But, more importantly, with all the existing evidence in front of us and the absence of any danger associated with reasonably sized supplements, the balance of evidence is heavily loaded towards a fast vitamin D replacement programme. It would be negligent to allow a large proportion of society to continue to be vitamin D deficient despite better knowledge. As others have pointed out (23) even if a population wide optimal vitamin D level would not have any beneficial effect on Covid-19 outcomes, at least it would lead most likely to significant health benefits.

  Public health bodies have an obligation to pass on this knowledge and implement effective methods which will lead to better vitamin D status population-wide and thereby an improved background immunity and the building of resilience in our population ahead of a much feared second wave of Covid-19.

  1. Lanham-New SA, Webb AR, Cashman KD, et al. Vitamin D and SARS-CoV-2 virus/COVID-19 disease BMJ Nutrition, Prevention & Health 2020;bmjnph-2020-000089 https://nutrition.bmj.com/content/early/2020/05/15/bmjnph-2020-000089.ci...
  2. 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
  3. 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
  4. Heaney RP. Vitamin D in Health and Disease. Clin J Am Soc Nephrol 2008 Sep;3(5):1535-41 https://pubmed.ncbi.nlm.nih.gov/18525006/
  5. Hanel A, Carlberg C. Vitamin D and evolution: Pharmacologic implications. Biochem Pharmacol. 2020;173:113595. https://pubmed.ncbi.nlm.nih.gov/31377232/
  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/
  8. https://vitamindwiki.com
  9. Uday S, Högler W. Spot the silent sufferers: A call for clinical diagnostic criteria for solar and nutritional osteomalacia. J Steroid Biochem Mol Biol. 2019 Apr;188:141-146 https://pubmed.ncbi.nlm.nih.gov/30654108/
  10. Gholami, F., Moradi, G., Zareei, B. et al. The association between circulating 25-hydroxyvitamin D and cardiovascular diseases: a meta-analysis of prospective cohort studies. BMC Cardiovasc Disord 19, 248 (2019) https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-01...
  11. 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 https://www.bmj.com/content/356/bmj.i6583
  12. Robert Briggs, Kevin McCarroll, Aisling O'Halloran, Martin Healy, Rose Anne Kenny, Eamon Laird. Vitamin D Deficiency Is Associated With an Increased Likelihood of Incident Depression in Community-Dwelling Older Adults. Journal of the American Medical Directors Association, 2018 https://www.sciencedaily.com/releases/2018/12/181205134045.htm
  13. Martineau AR et al. Vitamin D3 supplementation in patients with chronic obstructive pulmonary disease (ViDiCO): a multicentre, double-blind, randomised controlled trial. The Lancet, Respiratory Medicine, Volume 3, Issue 2, February 2015, Pages 120-130 https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(14)70255-3/fulltext
  14. Manson JE, Bassuk SS, Buring JE; VITAL Research Group. Principal results of the VITamin D and OmegA-3 TriaL (VITAL) and updated meta-analyses of relevant vitamin D trials. J Steroid Biochem Mol Biol. 2019 Nov 13;198:105522. https://pubmed.ncbi.nlm.nih.gov/31733345/
  15. Keum N1, Lee DH, Greenwood DC, Manson JE, Giovannucci E. Vitamin D supplementation and total cancer incidence and mortality: a meta-analysis of randomized controlled trials. Ann Oncol. 2019 May 1;30(5):733-743. https://www.ncbi.nlm.nih.gov/pubmed/30796437
  16. Zhang Y, Fang F, Tang J, Jia L, Feng Y, Xu P, et al. Association between vitamin D supplementation and mortality: systematic review and meta-analysis. BMJ. 2019;366:l4673 https://www.ncbi.nlm.nih.gov/pubmed/31405892
  17. Varun Samji, Tarek Haykal, Yazan Zayed, et al. Role of vitamin D supplementation for primary prevention of cancer: Meta-analysis of randomized controlled trials.. Journal of Clinical Oncology, 2019; 37: 1534 https://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.1534
  18. 10/16/2015 GrassrootsHealth, A Public Health Promotion Organization https://www.grassrootshealth.net/project/our-scientists/
  19. Manson JE, Cook NR, Lee I-M, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med 2019;380:33–44 https://www.nejm.org/doi/full/10.1056/NEJMoa1809944
  20. Brown R, Sakar A. 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. https://www.bmj.com/content/369/bmj.m1548/rr-19
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  23. Howarth M. https://www.scottishreview.net/MarkHowarth526a.html

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  Conflict of Interest:
  None declared.

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• Published on: 29 May 2020

  A call for randomized controlled clinical trial, not dismissal, is warranted

  • Gennadi V Glinsky, MD, Ph.D. University of California San Diego

  Multiple lines of strong circumstantial arguments supporting the putative role of Vitamin D as candidate pandemic mitigation agents have been made based on unbiased genomics-guided tracing of SARS-CoV-2 targets in human cells which generated some quite unexpected findings. The title of the paper reporting observations is “Tripartite combination of candidate pandemic mitigation agents: Vitamin D, Quercetin, and Estradiol manifest properties of medicinal agents for targeted mitigation of the COVID-19 pandemic defined by the genomics-guided tracing of SARS-CoV-2 targets in human cells”. One of the end points of this contribution is the identification of the tripartite combination of candidate pandemic mitigation agents comprising of Vitamin D/Quercetin/Estradiol. After the completion of the genomics screens, it was really quite unexpected conclusion to reach. However, after the follow-up analyses of available experimental and clinical observations it seems to make more sense. Please see the link below to the paper

  https://doi.org/10.3390/biomedicines8050129

  One of the main conclusions of the paper is that the randomized controlled clinical trial should be conducted to assess the potential clinical efficacy of the tripartite combination.

  Best regards,

  Dr. Gennadi V. Glinsky, MD, Ph.D.
  Correspondence: gglinskii@ucsd.edu
  Web:...

  Show More

  Multiple lines of strong circumstantial arguments supporting the putative role of Vitamin D as candidate pandemic mitigation agents have been made based on unbiased genomics-guided tracing of SARS-CoV-2 targets in human cells which generated some quite unexpected findings. The title of the paper reporting observations is “Tripartite combination of candidate pandemic mitigation agents: Vitamin D, Quercetin, and Estradiol manifest properties of medicinal agents for targeted mitigation of the COVID-19 pandemic defined by the genomics-guided tracing of SARS-CoV-2 targets in human cells”. One of the end points of this contribution is the identification of the tripartite combination of candidate pandemic mitigation agents comprising of Vitamin D/Quercetin/Estradiol. After the completion of the genomics screens, it was really quite unexpected conclusion to reach. However, after the follow-up analyses of available experimental and clinical observations it seems to make more sense. Please see the link below to the paper

  https://doi.org/10.3390/biomedicines8050129

  One of the main conclusions of the paper is that the randomized controlled clinical trial should be conducted to assess the potential clinical efficacy of the tripartite combination.

  Best regards,

  Dr. Gennadi V. Glinsky, MD, Ph.D.
  Correspondence: gglinskii@ucsd.edu
  Web: http://iem.ucsd.edu/people/profiles/guennadi-v-glinskii.html

  Best regards,

  Dr. Gennadi V. Glinsky, MD, Ph.D.

  Correspondence: gglinskii@ucsd.edu
  Web: http://iem.ucsd.edu/people/profiles/guennadi-v-glinskii.html

  Show Less

  Conflict of Interest:
  None declared.

  • Back to top