Orthomolecular Nutrition by William B. Grant, PhD
(OMNS June 9, 2020) The evidence that higher vitamin D status is causally linked to lower risk of COVID-19 incidence, severity, and death continues to increase. This brief report outlines what has been learned through early June 2020 and provides links to some of the key references.
It should be noted that acceptance of the role of vitamin D supplementation will probably not be achieved before reports are published that demonstrate randomized controlled trials of vitamin D supplementation significantly reduced COVID-19 incidence or death. Several RCTs and observational studies regarding vitamin D supplementation and COVID-19 incidence and outcomes are either in the planning stage or in progress. The obvious groups to study are those at highest risk: dark-skinned people living at high latitudes, people in nursing homes or health care facilities; prisoners; factory workers such as in meat-packing facilities in the U.S.; health care workers. A major problem is that the powers that be see vitamin D as a threat to income and profit, so use the Disinformation Playbook to suppress positive information on vitamin D. 
In a review published in early April, it was proposed that vitamin D supplementation could reduce the risk of COVID-19. Two mechanisms were identified: 1, reduced survival and replication of viruses through vitamin D-stimulated release of cathelicidin and defensins, and 2, reduced risk of the cytokine storm by reducing production of pro-inflammatory cytokines. 
Reference was also made to the finding that vitamin D supplementation reduces risk of acute respiratory tract infections as demonstrated by randomized controlled trials.  It was recommended that vitamin D supplementation be aimed at increasing serum 25-hydroxyvitamin D [25(OH)D] levels to 40-60 ng/ml (100-150 nmol/l), which would require daily doses up to 4000 to 5000 IU/d vitamin D3. Magnesium should also be supplemented, perhaps 400 mg/d, since the conversion of vitamin D to different metabolites requires the presence of magnesium. This recommendation was based on findings in observational studies such as one conducted by Grassrootshealth.net on influenza-like illness. 
More recently, it was suggested that for those who have not been supplementing with vitamin D that they start supplementing with a large bolus dose of vitamin D of several hundred thousand IU within one-to-two weeks. The rationale is that without the bolus the body would otherwise take several months to achieve the optimum level.  It was also suggested that while vitamin D supplementation could stop COVID-19 from developing at the beginning of symptoms, it probably would not be very useful after lung and organ damage occurs in the acute stage. Most recently, evidence was outlined to show that vitamin D deficiency could explain much of the reason for higher case and mortality rates for Black, Asian, and Minority Ethnic (BAME) residents in England. 
- 1. Grant WB. (2018) Vitamin D acceptance delayed by Big Pharma following the Disinformation Playbook. Orthomolecular Medicine News Service, Oct. 1, 2018. http://orthomolecular.org/resources/omns/v14n22.shtml
- 2. Grant WB, Lahore H, McDonnell SL, et al. (2020) Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients April 2, 2020, 12, 988. https://www.mdpi.com/2072-6643/12/4/988
- 3. Martineau AR, Jolliffe DA, Greenberg L, et al. (2017) Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 356:i6583. https://www.bmj.com/content/356/bmj.i6583
- 4. Grant WB, Lahore H, McDonnell SL, et al., (2020) Vitamin D Supplementation Could Prevent and Treat Influenza, Coronavirus, and Pneumonia Infections" Nutrients preprint, March 14, 2020 https://www.preprints.org/manuscript/202003.0235/v1
- 5. Grant WB, Baggerly CA, Lahore H. (2020) Response to Comments Regarding "Evidence that Vitamin D Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths". Nutrients June 1, 2020, 12(6), 1620. https://www.mdpi.com/2072-6643/12/6/1620
- 6. Grant WB, Boucher BJ. (2020) Vitamin D deficiency due to skin pigmentation and diet may explain much of the higher rates of COVID-19 among BAME in England. BMJ comments, June 6, 2020. https://www.bmj.com/content/369/bmj.m1548/rr-22
- "Of the 212 cases of COVID-19, majority had ordinary clinical outcome. Mean serum 25(OH)D level was 23.8 ng/ml. Serum 25(OH)D level was lowest in critical cases, but highest in mild cases. Serum 25(OH)D levels were statistically significant among clinical outcomes."
- Alipio, MM. (2020) Vitamin D Supplementation Could Possibly Improve Clinical Outcomes of Patients Infected with Coronavirus-2019 (COVID-2019); April 9, 2020. https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3571484
- "A lot of COVID-19 infected patients develop acute respiratory distress syndrome (ARDS), which may lead to multiple organ damage. These symptoms are associated with a cytokine storm syndrome. The aim of this letter is to note the 5 crucial points that vitamin D could have protective and therapeutic effects against COVID-19. For that reason, COVID-19 infection-induced multiple organ damage might be prevented by vitamin D."
- Aygun H. (2020) Vitamin D can prevent COVID-19 infection-induced multiple organ damage. Naunyn Schmiedebergs Arch Pharmacol. 2020 May 25:1-4. https://pubmed.ncbi.nlm.nih.gov/32451597
- "Timely implementation of vitamin D supplementation programmes worldwide is critical; initial priority should be given to those who are at the highest risk, including the elderly, immobile, homebound, BAME and healthcare professionals. Population-wide vitamin D sufficiency could prevent seasonal respiratory epidemics, decrease our dependence on pharmaceutical solutions, reduce hospitalisations, and thus greatly lower healthcare costs while significantly increasing quality of life."
- Davies G, Garami AR, Byers J. (2020) Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes. 1 May, updated 3 June, 2020. https://www.medrxiv.org/content/10.1101/2020.05.01.20087965v2.full.pdf
- "We retrospectively investigated the 25-hydroxyvitamin D (25(OH)D) concentrations in plasma obtained from a cohort of patients from Switzerland. In this cohort, significantly lower 25(OH)D levels (p = 0.004) were found in PCR-positive for SARS-CoV-2 (median value 11.1 ng/mL) patients compared with negative patients (24.6 ng/mL)."
- D'Avolio A, Avataneo V, Manca A, et al. (2020) 25-Hydroxyvitamin D Concentrations Are Lower in Patients with Positive PCR for SARS-CoV-2. Nutrients. 2020 May 9;12(5):E1359. https://pubmed.ncbi.nlm.nih.gov/32397511
- "COVID-19 patients showed lower median 25(OH)D (18.6 ng/mL, IQR 12.6-25.3, versus 21.5 ng/mL, IQR 13.9-30.8; P=0.0016) and higher vitamin D deficiency rates (58.6% versus 45.2%, P=0.0005). Surprisingly, this difference was restricted to male COVID-19 patients who had markedly higher deficiency rates than male controls (67.0% versus 49.2%, P=0.0006) that increased with advancing radiological stage and were not confounded vitamin D-impacted comorbidities."
- De Smet D, De Smet K, Herroelen P, et al. (2020) (2020) Vitamin D deficiency as risk factor for severe COVID-19: a convergence of two pandemics, May 5, 2020. https://www.medrxiv.org/content/10.1101/2020.05.01.20079376v2
- "The RAS, which includes ACE and ACE2, is a complex network that has a major role in various biological functions 31. Chronic vitamin D deficiency may induce RAS activation lung fibrosis through activation of the RAS 35; therefore, increasing evidence indicates that 1,25(OH)2D3 may also be a negative endocrine regulator of the RAS. Inducing the expression of renin, ACE, Ang II and AT1R, and inhibiting ACE2 expression could result in acute lung injury. Vitamin D inhibits renin, ACE and Ang II expression, and induces ACE2 levels in ALI."
- Ghavideldarestani M, Honardoost M, Khamseh ME. (2020) Role of Vitamin D in Pathogenesis and Severity of COVID-19 Infection https://www.preprints.org/manuscript/202004.0355/v1
- "We performed a retrospective study in two tertiary medical centers in South Asia. The medical records of COVID19 patients were reviewed and a total of 176 subjects included were the elderly whose age is at least 60 years, We reported that majority of the subjects had 25(OH)D level below 30 ng/ml, most of them were male, had diabetes, and were classified as severe. Most of the male and female subjects had 25(OH)D level below 30 ng/ml."
- Glicio, EJ.(2020) Vitamin D Level of Mild and Severe Elderly Cases of COVID-19: A Preliminary Report (May 5, 2020). SSRN: https://ssrn.com/abstract=3593258
- Several recent publications and preprints report multi-country studies based of COVID-19 case or death rates with respect to country mean 25(OH)D concentration. One concern regarding such studies is that the 25(OH)D concentrations used are probably not related to those most likely to develop COVID-19 at the time of incidence. However, a more serious problem is that life expectancy has a much stronger correlation (direct) than does 25(OH)D as discussed in this preprint. I have confirmed their findings using more recent COVID-19 case and death rate data.
- Kumar V, Srivastaa A. (2020) Spurious Correlation? A review of the relationship between Vitamin D and Covid-19 infection and mortality. https://www.medrxiv.org/content/10.1101/2020.05.25.20110338v1.full.pdf
- This article presents retrospective results for 780 patients in Indonesia. Compared to 25(OH)D >30 ng/ml, 25(OH)D between 20 and 30 ng/ml had an odds ratio for death of 7.6 (P<0.001), while 25(OH)D <20 ng/ml had an odds ratio for death of 10.1 (P<0.001).
- Raharusun, P, Priambada S, Budiart C, Agung E, Budi C. (2020) Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study (April 26, revised 6 May, 2020). SSRN. https://ssrn.com/abstract=3585561
- The recommended dietary allowance of vitamin D is 600-800 IU/daily, but during this period,| a multivitamin or supplement containing 1000-2000 IU/daily of vitamin D would be reasonable. https://www.medscape.com/viewarticle/930152
- JoAnn E. Manson, MD, DrPH, (2020) Does Vitamin D Protect Against COVID-19? MEDSCAPE, May 11, 2020
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