Name: 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.
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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.

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Is ethnicity linked to...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.;Dear EditorCOVID-19 (Coronavirus) mortality disproportionately impacts BAME (Black, Asian and Minority Ethnic) UK individuals, African Americans, Swedish Somalis,[1] and the institutionalised; particularly care-home residents. COVID-19 severity and mortality, appear related to vitamin D deficiency, [2 -12] helping explain higher COVID-19 mortality rates in BAME and the obese.[13]Obesity is a strong COVID-19 risk factor, as are co-morbidities, including diabetes, cardio-vascular disease; and sedentary lifestyle; all are dependent on mitochondrial functionality (Gnaiger).[14] Fat cells accrete vitamin D.[15] The obese consistently have proportionately lower vitamin D status (serum 25-hydroxyvitamin D [25(OH)D]).[16]Vitamin D is a secosteroid hormone with various skeletal and non-skeletal effects including regulation of innate and adaptive immune responses. Vitamin D, by binding to the vitamin D response element in various gene-promoter-regions, decreases expression of pro-inflammatory-cytokines and increases production of antiviral and antibacterial[17] proteins, suggesting an important role in antiviral innate adaptive immunity.[18] Importantly, vitamin D is also involved in renin–angiotensin system regulation,[19] which is regulated by entry of the SARS-Cov-2 virus into cells via the ACE2 receptor, leading to cytokine storms, with subsequent fatal respiratory distress syndrome.[20]Pathways, mechanisms, cell-types, proteins and receptors, 'regulated' by vitamin D include: airway epithelial cell tight-junction function and integrity; lymphocytes, macrophages T cells, T helper cells, Th1, -17; Tregs[21]; related protein cytokines; IL-1, -2, -4, -5, -6 -10, -12; IFN-beta, TNFalpha, ; defensins and cathelicidin; and receptors HLA-DR, CD4, CD8, CD14, CD38.[2] Vitamin D also regulates mitochondrial respiratory inflammatory, oxidative and wider function. [2, 14] RXR and other receptor crosstalk links steroids, retinoids, vitamin D, thyroid hormone, oxidised lipids and peroxisomal pathways during viral and wider immune response.[22, 23, 24] Tocilizumab and vitamin D both may regulate COVID-19 related cytokine storms, through IL-6.[25]A remarkable recent preprint (Alipio),[26] entitled, ‘Vitamin D supplementation could possibly improve clinical outcomes of patients infected with Coronavirus-2019 (COVID-19)’, examines vitamin D status, and hospitalization outcomes in 212 COVID-19 patients, using 4 categories: (1) Mild – without pneumonia, (2) Ordinary – confirmed pneumonia with fever, (3) Severe – hypoxia and respiratory distress, (4) Critical – respiratory failure requiring intensive case monitoring. Alipio observes, “Vitamin D status is significantly associated with clinical outcomes (p&lt;0.001). For each standard deviation increase in serum 25(OH)D, the odds of having a mild clinical outcome rather than a severe outcome were increased approximately 7.94 times; the odds of having a mild clinical outcome rather than a critical outcome were increased approximately 19.61 times,” indicating that, in COVID-19 patients, increased serum 25(OH)D level could improve clinical outcomes, and/or mitigate the worst (severe to critical) outcomes. Conversely, decreased serum 25(OH)D levels could worsen clinical outcomes. Normal 25(OH)D levels were classified as &gt;75 nmol/l (30 ng/ml). Deficient were those below 50 nmol/l (20 ng/ml). Deficiency definitions vary: &lt;25 nmol/L, (10 ng/ml) UK; and 50 nmol/L (20 ng/ml) USA.[26]In Alipio’s preprint, of the 49 patients with mild clinical outcomes, 47 had ‘normal’ (&gt;75 nmol/L) 25(OH)D levels. Conversely only 2 of the 48 critical patients had ‘normal’ (&gt;75 nmol/L) 25(OH)D levels.[26] CRUK expert paper 3 states “70–80 nmol/L (28-32 ng/ml) is ‘optimal’.[27]In respiratory-tract-infections more generally, in the deficient (&lt;25 nmol/L), vitamin D supplements reduce infection,[28] and deficiency links with poor respiratory outcomes, in COPD,[29, 30] asthma[31] and bronchiectasis.[32] Poor conversion from “25(OH)D to 1,25(OH)2D”, results in deficiency of 1,25(OH)2D.[33]Currently, no effective COVID-19 treatment exists. Vaccines present enormous possibilities, but equally-large hurdles, and require time. Vitamin D biology, is a mature well-researched field, dating back 100 years. Doses, and risks, within clinical parameters, are established and well quantified. Governmental intake guidance exists. Vitamin D deficiency is a medically accepted condition, requiring treatment. Existing blood samples from COVID-19 hospitalized patients could be retrospectively tested for 25(OH)D and linked to outcomes.[25]We and others (Grant, Lahore)[9, 34] hypothesize vitamin D may have clinical COVID-19 relevance. Vitamin D deficiency may biomark risk of sepsis in all populations; 25(OH)D was significantly lower in patients that died within 30 days.[35, 36] A French clinical RCT recently started, testing effects of a large single vitamin D dose, administered early in infection, compared to a standard dose, on the mortality of older COVID-19 infected adults deficient in vitamin D (Annweiler).[37]Whilst clinical studies have potential, vitamin D deficiency is an existing, ubiquitous and pressing issue. Deficiency is variable, but widespread globally. BAME people in high latitudes are a group at high risk of deficiency, as observed by NICE[38] and others (Rhein).[39] Surprisingly, vitamin D may be a larger relative COVID-19 causative agent than socioeconomic-factors.[40] Importantly, vitamin D supplementation determinants should include basal level, genetic background, metabolic status and gender.Albeit vitamin D deficiency most likely accounts for a greater COVID-19 impact on BAME, older, institutionalised and obese persons, COVID-19 severity would undoubtedly be exacerbated by, often socioeconomic related, general micro-nutrient inadequacies.[41, 42]Dr Hugh Sinclair almost 100 years ago observed; “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 it must be repeatedly forcefully restated.”Recognition (subject to proof by research), that vitamin D deficiency contributes to COVID-19 infection, progression, severity and mortality would demand policy rethinking on: the seasonality of COVID-19,[43] outdoor access, motivation for physical exercise, food fortification, supplementation, clinical treatment, and provision of free vitamin D supplements to institutions, front-line health and care workers. Sensible (according to latitude and weather) sun exposure is free, available to all and quickly improves vitamin D status, but is inhibited by lock-down.Alipio’s results, viewed in the context of earlier recent vitamin D and COVID-19 publications,[2 9] must now lead to urgent research (Brown).[2, 13] Human nature is such that simple solutions to complex issues, for example vitamin C for scurvy, and hand washing prior to baby delivery, are often not readily embraced; but surely the scale and impact of the COVID-19 pandemic demands all avenues are fully explored; more so when no other effective treatment strategies as yet exist. A safe simple step, the correction of a deficiency state, vitamin D this time, convincingly holds out a potential, significant, feasible ‘COVID-19 mitigation remedy.[1] Bejerot, S., Humble, M. (19 March 2020). BMJ Rapid Response: Inhabitants of Swedish-Somali origin are at great risk for covid-19. BMJ 368 doi:[2] Brown, R., Sarkar, A. (29th Feb. 2020 –posted 24th). 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.[3] Ilie, P., Stefanescu, S., Smith, L. (8th April 2020) The role of Vitamin D in the prevention of Coronavirus Disease 2019 infection and mortality. Square Research. Preprint. DOI:10.21203/rs.3.rs-21211/v1.McCartney, D., Byrne, D. (2020). Optimisation of Vitamin D Status for Enhanced Immuno-protection Against Covid-19. Issue: [4] Ir Med J; 113(4): P58. immuno-protection-against-covid-19/[5] Isaia, G. (25th March 2020). Possibile ruolo preventivo e terapeutico della vitamina D nella gestione della pan-demia da COVID-19. Enzo Medico, Università degli Studi di Torino, Torino,[6] Rhein, H. (6th March 2020). Re: Preventing a covid-19 pandemic - individuals' defence better if supplied with sufficient vitamin. BMJ368: m810 doi: .[7] Cobbold, P. (2nd March 2020). BMJ 368: m810 doi:[8] Maestri, E., Formoso, G., Da Cas R., Mammarella, F.,Trotta, F. (12th March 2020).Vitamin D against COVID 19: Clinicians need more than observations and hope. BMJ 368: m810 doi:[9] Grant, W. (1st April 2020). Re: Preventing a covid-19 pandemic: Can vitamin D supplementation reduce the spread of COVID-19? Try first with health care workers and first responders. BMJ 2020;368:m810 doi:[10] Cobbold, P. (8th March 2020). BMJ 368: m810. doi:[11] Silberstein, M. (9th April 2020). Rapid Response: Potential direct therapeutic role for Vitamin D. BMJ 368..[12] Smith, F. (2020). Preventing a covid-19 pandemic. Prevention and Cure of Covid 19? – A Discussion about Vitamin D Deficiency. BMJ 368. doi:[13] Brown, R. (7th April 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: .[14] Gnaiger, E. (2009). Capacity of oxidative phosphorylation in human skeletal muscle. New perspectives of mitochondrial physiology. Int J Biochem Cell Biol 41: 1837-45.[15] Garg, S., Kim, L., Whitaker, M., et al. (2019). Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease — COVID-NET, 14 States, March 1–30, 2020. MMWR Morb Mortal Wkly Rep 69: 458–464. DOI:[16] Carrelli, A., Bucovsky, M., Horst, R., Cremers, S., Zhang, C., … et al. (2017). Vitamin D Storage in Adipose Tissue of Obese and Normal Weight Women. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 32(2): 237–242.[17] Golpour, A., Bereswill, S., Heimesaat, M. M. (2019). Antimicrobial and Immune-Modulatory Effects of Vitamin D Provide Promising Antibiotics-Independent Approaches to Tackle Bacterial Infections - Lessons Learnt from a Literature Survey. European journal of microbiology &amp; immunology 9(3): 80–87.[18] Fabbri, A., Infante, M., Ricordi, C. (2020). Editorial – Vitamin D status: a key modulator of innate immunity and natural defense from acute viral respiratory infections. Eur Rev Med Pharmacol Sci.. 24(7): 4048- 4052 DOI: 10.26355/eurrev_202004_20876[19] Ajabshir. S., Asif, A., Nayer, A., (2014). The effects of vitamin D on the renin-angiotensin system. J Nephropathol. 3(2): 41–43. doi: 10.12860/jnp.2014.09[20] Dijkman. R., Jebbink, F., Deijs, M., Milewska, A., Pyrc K, … et. al. (2012). Replication-Dependent Downregulation of Cellular Angiotensin-Converting Enzyme 2 Protein Expression by Human Coronavirus NL63. J Gen Virol 93(Pt 9): 1924-1929. DOI: 10.1099/vir.0.043919-0[21] Fisher, S., Rahimzadeh, M., Brierley, C., Gration, B., Doree, C., … et. Al. (2019). The role of vitamin D in increasing circulating T regulatory cell numbers and modulating T regulatory cell phenotypes in patients with inflammatory disease or in healthy volunteers: A systematic review. PLoS One 14(9): e0222313. doi: 10.1371/journal.pone.0222313.[22] Evans, R., Mangelsdorf, D. (2014). Nuclear Receptors, RXR, and the Big Bang. Cell 157(1): 255–266.[23] Gopal, R., Mendy, A., Marinelli, M., Richwalls, L., Seger, P. … et.al. (2019). Peroxisome Proliferator-Activated Receptor Gamma (PPARg) Suppresses Inflammation and Bacterial Clearance during Influenza-Bacterial Super-Infection. Viruses 11(6): 505.[24] Jean Beltran, P., Cook, K., Hashimoto, Y., Galitzine, C., Murray, L., Vitek, O., &amp; Cristea, I. M. (2018). Infection-Induced Peroxisome Biogenesis Is a Metabolic Strategy for Herpesvirus Replication. Cell host &amp; microbe 24(4): 526–541.[25] Silberstein, M. (23 April 2020). Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? Medical Hypotheses, 109767. (In Press)[26] Alipio, M. (2020). Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-2019). Available at SSRN: or (Accessed: 24 April 2020).[27] Cancer Research UK (2010). Vitamin D. Expert paper 3. Available at: (Accessed: 24 April 2020).[28] Martineau, A., Jolliffe, D., Hooper, R., Lauren, G., Aloia, J., Bergman, P., … et al. (2017). Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data BMJ 356 :i6583[29] Jolliffe, D., Greenberg, L., Hooper, R., … et al. (2019). Vitamin D to prevent exacerbations of COPD: systematic review and meta-analysis of individual participant data from randomised controlled trials.Thorax 74: 337-345.[30] Janssens, W., Bouillon, R., Claes, B., … et al. (2010). Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax 65: 215-220.[31] Jolliffe. D., Greenberg, L., Hooper, R., Griffiths, C., Camargo, Jr., C, … et. al. (2017). Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med. 5(11): 881-890. doi: 10.1016/S2213-2600(17)30306-5. Epub 2017 Oct 3[32] Chalmers, J., McHugh, B., Docherty, C., et. al. Vitamin-D deficiency is associated with chronic bacterial colonisation and disease severity in bronchiectasis. (2013). Thorax 68:39-47.[33] Pletz, M., Terkamp, C., Schumacher, U., Rohde, G., Schütte, H., Welte, T., Bals, R, (2017). CAPNETZ-Study Group. Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25(OH)2 D are associated with disease severity. Respir Res. 15: 53. doi: 10.1186/1465-9921-15-53.[34] Grant, W., Lahore, H., McDonnell, S., Baggerly, C., French, C., Aliano, J., &amp; Bhattoa, H. (30th March 2020 2nd version). Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients,12: 988.[35] Zhou, W., Mao, S., Wu, L., Yu, J. (2018). Association Between Vitamin D Status and Sepsis. Clin Lab. 64(4): 451-460. doi: 10.7754/Clin.Lab.2017.170919.[36] Parekh, D., Patel, J., Scott, A., Lax, S., Dancer, R. C. et. al. (2017). Vitamin D Deficiency in Human and Murine Sepsis. Critical care medicine 45(2): 282–289.[37] Annweiler, C. (n.d.). COvid-19 and Vitamin D Supplementation: a Multicenter Randomized Controlled Trial of High Dose Versus Standard Dose Vitamin D3 in High-risk COVID-19 Patients. (CoVitTrial). NCT04344041. DCRI., Angers, France.[38] NICE. (2018). Vitamin D deficiency in adults - treatment and prevention. Available at: (Accessed 20 April 2020).[39] Rhein, H. (2008). Vitamin D deficiency is widespread in Scotland. BMJ. 336(7659): 1451.DOI: 10.1136/bmj.39619.479155.3A[40] Bäcker, A., (10th April 2020). Why COVID-19 May Be Disproportionately Killing African Americans: Black Overrepresentation among COVID-19 Mortality Increases with Lower Irradiance, Where Ethnicity Is More Predictive of COVID-19 Infection and Mortality Than Median Income. Available at SSRN: or (Accessed 24 April 2020).[41] Muthayya, S., Rah, J., Sugimoto, J., Roos, F., Kraemer, K., &amp; Black, R. E. (2013). The global hidden hunger indices and maps: an advocacy tool for action. PloS one, 8(6): e67860.[42] Brough. L., Rees, G., Crawford, M., Morton, R., Dorman, E. (2010). Effect of multiple-micronutrient supplementation on maternal nutrient status, infant birth weight and gestational age at birth in a low-income, multi-ethnic population. Br J Nutr. 104(3): 437-45. doi: 10.1017/S0007114510000747. Epub 2010 Apr 23.[43] Rhodes, J., Subramanian S., Laird, E., Kenny, R. (April 2020) Letter: Covid-19, and vitamin D. Alimentary Pharmacology &amp; Therapeutics 9(00): 1-3, DOI: 10.1111/apt.15752Competing interests:As listed on Author listResearcherMcCarrison SocietyLa Route de Mont Cochon, St Lawrence, Jersey. C.I.

Is ethnicity linked to...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.;Dear EditorCOVID-19 (Coronavirus) mortality disproportionately impacts BAME (Black, Asian and Minority Ethnic) UK individuals, African Americans, Swedish Somalis,[1] and the institutionalised; particularly care-home residents. COVID-19 severity and mortality, appear related to vitamin D deficiency, [2 -12] helping explain higher 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.

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