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.
Rapid Response to: Is ethnicity linked to incidence or outcomes of covid-19?
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1548 (Published 20 April 2020)
Discussion of this letter on Reddit 44 comments as of April 28
- COVID-19 more frequent and deadly for those with dark skins (high risk of low vitamin D)
- Virus and Dark Skin in VitaminDWiki
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/
-  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,
-  Rhein, H. (6th March 2020). Re: Preventing a covid-19 pandemic - individuals' defence better if supplied with sufficient vitamin. BMJ368: m810 doi: https://doi.org/10.1136/bmj.m810. https://www.bmj.com/content/368/bmj.m810/rr-9
-  Cobbold, P. (2nd March 2020). BMJ 368: m810 doi: https://doi.org/10.1136/bmj.m810 https://www.bmj.com/content/368/bmj.m810/rr-1
-  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: https://doi.org/10.1136/bmj.m810.https://www.bmj.com/content/368/bmj.m81...
-  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: https://doi.org/10.1136/bmj.m810; https://www.bmj.com/content/368/bmj.m810/rr-42
-  Cobbold, P. (8th March 2020). BMJ 368: m810. doi: https://doi.org/10.1136/bmj.m810; https://www.bmj.com/content/368/bmj.m810/rr-11
-  Silberstein, M. (9th April 2020). Rapid Response: Potential direct therapeutic role for Vitamin D. BMJ 368.https://doi.org/10.1136/bmj.m810. https://www.bmj.com/content/368/bmj.m810/rr-51
-  Smith, F. (2020). Preventing a covid-19 pandemic. Prevention and Cure of Covid 19? – A Discussion about Vitamin D Deficiency. BMJ 368. doi: https://doi.org/10.1136/bmj.m810 https://www.bmj.com/content/368/bmj.m810/rr-49
-  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: https://doi.org/10.1136/bmj.m810. https://www.bmj.com/content/368/bmj.m810/rr-46
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-  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. https://doi.org/10.1002/jbmr.2979
-  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 & immunology 9(3): 80–87. https://doi.org/10.1556/1886.2019.00014
-  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
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-  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.
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-  Silberstein, M. (23 April 2020). Vitamin D: A simpler alternative to tocilizumab for trial in COVID-19? Medical Hypotheses, 109767. https://doi.org/10.1016/j.mehy.2020.109767 (In Press)
-  Alipio, M. (2020). Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-2019). Available at SSRN: https://ssrn.com/abstract=3571484 or http://dx.doi.org/10.2139/ssrn.3571484 https://ssrn.com/abstract=3571484 (Accessed: 24 April 2020).
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COVID-19 is harder for those with dark skins - perhaps due to low vitamin D – April 24, 2020
- Robert A. Brown, ACA, Chair McCarrison Society, Jersey,
- Helga M. Rhein, MD, Retired General Practitioner, Edinburgh, Scotland, UK
- Mark M.Alipio, Clinical Professor, Medical Radiation Scientist, Davao Doctors College, Philippines
- Cedric Annweiler, MD, PhD, Full Professor of Geriatric Medicine and Biology of Aging, Director, School of Medicine, University of Angers, Head, Department of Geriatric Medicine, University Hospital of Angers Director, Research Center on Autonomy and Longevity, France
- Erich Gnaiger, PhD, Chair COST Action CA15203 MitoEAGLE, Medical University of Innsbruck, Department of Visceral, Transplant and Thoracic Surgery, D. Swarovski Research Laboratory, Innsbruck, Austria Disclosure: Founder and CEO of Oroboros Instruments
- Michael F. Holick, Professor, Boston University School of Medicine, Dept of Medicine Endocrinology, Dia-betes, Nutrition & Weight Management Boston, USA. Disclosure: Former consultant for Quest Diagnostics, Consultant Ontometrics Inc. speakers Bureau Abbott Inc.
- Barbara J Boucher, MD, FRCP, Hon Prof, The Blizard Institute, SMD, Queen Mary University of London, London, UK
- Gustavo Duque, MD, PhD, FRACP, FGSA, Professor and Chair of Medicine, Director - Australian Institute for Musculoskeletal Science (AIMSS), Melbourne Medical School- Western Campus, The University Of Mel-bourne& Western Health, Australia
- François Féron, Professor, Faculty of Medicine, INP, CNRS UMR 7051, Marseille, France, Leader of the team «NOSE: Nasal Olfactory Stemness and Epigenesis», Coordinator of the European University CIVIS, Director of NeuroSchool, Graduate school in Neuroscience, Manager of clinical trials in neural therapy (Bio-therapy unit, AP-HM)
- Rose Anne Kenny MD, Chair of Medical Gerontology, Trinity College, Dublin, Ireland
- Manuel Montero-Odasso, MD, PhD, FRCPC, AGSF, FGSA, Professor, Departments of Medicine, and Epi-demiology and Biostatistics, Faculty Scholar, The University of Western Ontario, London, ON. Canada Secretary-Treasurer, Canadian Geriatrics Society (CGS), Co-Chair, CGS Covid-19 Working Group
- Salvatore Minisola, Professor of Internal Medicine, Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, “Sapienza” University, Rome, Italy. Disclosure: Served as speaker for Abiogen, Amgen, Bruno Farmaceutici, Diasorin, Eli Lilly, Shire, Sandoz, Takeda. He also served in advisory board of Abiogen, Kyowa Kirin, Pfizer, UCB.
- Jonathan Rhodes MD FRCP FMedSci, Emeritus Professor of Medicine, Institute of Translational Medicine. With the University of Liverpool and Provexis UK Disclosure: holds a patent for use of a soluble fibre preparation as maintenance therapy for Crohn’s disease plus a patent for its use in antibiotic-associated diarrhoea. Patent also held with the University of Liverpool and others in relation to use of modified heparins in cancer therapy.
- Afrozul Haq, Professor, Ph.D., FIABS, Former Dean, School of Interdisciplinary Sciences and Technology (SIST), Department of Food Technology, Jamia Hamdard University, New Delhi-110062, India
- Susanne Bejerot, Professor, MD, Örebro University, School of Medical Sciences, Örebro, Sweden
- Lina A.J. Reiss, PhD, Associate Professor, Otolaryngology-Head and Neck Surgery and Biomedical Engi-neering, Oregon Health & Science University, USA
- Lina Zgaga, Associate Professor of Epidemiology, Trinity College Dublin, University of Dublin, Ireland Michael A Crawford, Visiting Professor Michael A Crawford, PhD, FRSB, FRCPath, The Department of Me-tabolism, Digestion and Reproduction. Imperial College, London.
- Rosemary A. Fricker, BSc (Hons), PhD., Visiting Professor of Neurobiology, Keele University, School of Medicine. UK
- Peter Cobbold, PhD, Emeritus Professor, University of Liverpool, UK
- Henry W Lahore, Founder of VitaminDWiki, USA
- Mats B. Humble, MD, PhD., Örebro University, School of Medical Sciences, Örebro, Sweden
- Amrita Sakar, PhD., McCarrison Society, Kolkata, West Bengal, India
- Spiros Karras, MD, PHD Academic Researcher – National Scholarships Foundation, Thessaloniki, Greece
- Javier Iglesias-Gonzalez, PhD, Principal Investigator Oroboros Instruments, Innsbruck, Austria
- Duygu Gezen-Ak Ph.D., Brain and Neurodegenerative Disorders Research Laboratories, Department of Medical Biology, Cerrahpasa Faculty of Medicine, Istanbul University, Turkey
- Erdinc Dursun Ph.D., Brain and Neurodegenerative Disorders Research Laboratories, Department of Medi-cal Biology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
- Isabella Cooper, FnDNutr., BSc (Hons), AMRSB, AfPHYS, AfENDO, Doctoral Researcher, Anatomy, Physiology & Pathology, School of Life Sciences, University of Westminster, London, UK
- David Grimes, Retired consultant physician, Blackburn, Manchester, UK
- Dr Cedric W.B. de Voil, MB.,ChB. (St Andrews). Retired GP, Arbroath, Scotland, UK
- McCarrison Society. La Route de Mont Cochon, St Lawrence, Jersey. C.I.
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