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.
COVID-19 (Coronavirus) mortality disproportionately impacts BAME (Black, Asian and Minority Ethnic) UK individuals, African Americans, Swedish Somalis, 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.
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). Fat cells accrete vitamin D. The obese consistently have proportionately lower vitamin D status (serum 25-hydroxyvitamin D [25(OH)D]).
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 proteins, suggesting an important role in antiviral innate adaptive immunity. Importantly, vitamin D is also involved in renin–angiotensin system regulation, 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.
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; 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. 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.
A remarkable recent preprint (Alipio), 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<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 >75 nmol/l (30 ng/ml). Deficient were those below 50 nmol/l (20 ng/ml). Deficiency definitions vary: <25 nmol/L, (10 ng/ml) UK; and 50 nmol/L (20 ng/ml) USA.
In Alipio’s preprint, of the 49 patients with mild clinical outcomes, 47 had ‘normal’ (>75 nmol/L) 25(OH)D levels. Conversely only 2 of the 48 critical patients had ‘normal’ (>75 nmol/L) 25(OH)D levels. CRUK expert paper 3 states “70–80 nmol/L (28-32 ng/ml) is ‘optimal’.
In respiratory-tract-infections more generally, in the deficient (<25 nmol/L), vitamin D supplements reduce infection, and deficiency links with poor respiratory outcomes, in COPD,[29, 30] asthma and bronchiectasis. Poor conversion from “25(OH)D to 1,25(OH)2D”, results in deficiency of 1,25(OH)2D.
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.
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).
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 and others (Rhein). Surprisingly, vitamin D may be a larger relative COVID-19 causative agent than socioeconomic-factors. 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, 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.
 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: https://doi.org/10.1136/bmj.m1101 https://www.bmj.com/content/368/bmj.m1101/rr-10
 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. https://www.mitofit.org/index.php/Brown_2020_MitoFit_Preprint_Arch
 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:  Ir Med J; 113(4): P58. http://imj.ie/optimisation-of-vitamin-d-status-for-enhanced- immuno-protection-against-covid-19/
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Competing interests: As listed on Author list