https://github.com/GShotwell/vitamin_d_covid
Snapshot as of Sept 20, 2020

The argument for supplementation

• Vitamin D reduces the risk of other (Martineau et al, February 2017) acute respiratory infections. One interesting finding of this meta-analysis is that people who were very deficient (less than 25 nmol/L) saw the largest protective effect with an adjusted odd ratio of 0.58 and a 95% CI of 0.40 to 0.82. These are the same populations which seem to be at risk for severe Covid-19
• Calcitriol, the active form of Vitamin D is active (Chee Keng Mok et al June 22, 2020) against the SARS-COV2 virus
• Patients treated with calcifediol are less likely to be admitted to the ICU than controls
• Several studies have now observed lower vitamin D levels among severe Covid-19 patients
• Vitamin D is very low risk (McCullough et al, May 2020, preprint) an adverse events of vitamin D supplementation can be easily managed by clinicians

Direct research on vitamin D and Covid

Intervention studies

Randomized - A parallel pilot randomized open label (Castillo et all, August 2020) trial of 76 patients in Spain found that the administration of calcifediol reduced ICU admission and mortality. Of the 50 patients treated with calcifediol. 13/26 patients in the control group required ICU care compared with 1 in the intervention group. Cohort - A small cohort trial (Chuen Wen Tan, June 10 2020) found that just 16% of patients who received vitamin D, magnesium, and vitamin B12 required oxygen compared with 61.5% of the previous cohort who did not receive DBM supplementation.

In vitro evidence

• Calcitriol, the active form of Vitamin D is active (Chee Keng Mok et al, June 2020) against the SARS-COV2 virus.

Covid severity associated with serum vitamin D levels

Post-infection blood samples

Supports vitamin D link

• A re-analysis of 107 Swiss blood samples (Avolio et al, April 2020) found that PCR positive patients had 25-hydroxyvitamin D concentrations half that of PCR negatives. This finding held after stratifying for age and gender.
• Hospitalized male Covid-19 patients were found (De Smet et al, May 2019) to have lower vitamin D levels than controls
• A observational study from Belgium(De Smet, May 2020) found that vitamin D deficiency is correlated with the risk for hospitalization for COVID-19 pneumonia and predisposes to more advanced radiological disease stages.
• Vitamin D deficiency was more common (Panagiotou eet all, June 2020) among ITU Covid patients than the general population in a Newcastle hospital.
• A Mexican study (Arturo Rodríguez Tort et al, April 2020) found that patients with vitamin D serum levels bellow 8 ng/mL had 3.68 higher risk of dying from COVID-19.
• A Iranian study (Maghbooli et al, July 14 2020) found there was a significant association between vitamin D sufficiency and reduction in clinical severity.
• A study (Carpagnano et all, August 2020) of 42 COVID-19 patients in a respiratory ICU found that 50% of vitamin D deficient patients died after 10 days compared with 5% of non-deficient patients.
• A prospective cohort study (Baktash V et all, August 2020) found that vitamin D deficiency was more common among Covid positive patients presenting with Covid symptoms than Covid negative patients, and suggested that it could be considered as a diagnostic tool.
• A study (Mardenia et all, August 2020) of patients presenting with Covid symptoms at an Iranian hospital found that vitamin D deficiency and ACE disregulation were more commone among those who tested positive for Covid-19.
• A Germnan Study (Radujkovic et al, August 2020) found that vitamin D status was associated with need for mechanical ventilation and death.
• A smallprospective cohort study (Baktash et all, September 2020) of older adults found that vitamin D deficiency was associated with mechanical ventilation, but not deatha.

Pre-infection blood samples

Supports link to vitamin D

• A retrospective cohort (Meltzer et al, May 2020) study found that Chicago patients who were likely vitamin D deficient were more likely to test positive for Covid-19.
• An Israeli study (Eugene Merzon et al, July 2020) of 7,000 patients with pre-Covid serum vitamin D tests found that vitamin D levels were associated with Covid infection and hospitalization.
• An analysis (Isreal et al, August 2020) of Isreali vitamin D tests performed between 2010 and 2019 found that vitamin D deficiency predicted Covid-19 infection.
• An analysis (Kaufman et all, Sept 2020) of 190,000 patients found that the probability of testing positive was associated with vitamin D levels. This association held across all age groups, ethnicities and geographies.

Contradicts vitamin D link

• Vitamin D levels between 2006-2010 were associated (Hastie et al, July 2020) with Covid-19 mortality, but not after controlling for other variables in the data set. It's hard to make inferences from 10 year old blood samples because there's a causal story in which low vitamin D in 2010 increases vitamin D in 2020 because that group is likely to supplement.

Mendelian randomization

• A Mendelian randomisation analysis (Martin Kohlmeier, May 2020) of excess COVID-19 mortality of African-Americans in the US suggests that vitamin D is a risk factor for Covid Mortality
• A Mendelian randomization (Liu et al, August 2020) using genes associated with vitamin D deficiency did not support a causal connection between vitamin D and Covid-19 mortality. It appears that this study used UK Biobank data, but the date of the samples were not disclosed.

Ecological studies

• A study out of Northwestern University (Daneshkhah1 et al, April 2020) found that the vitamin D status of a country's elderly population was associated with the number of severe cases of Covid-19 in that country.
• There was a strong correlation (Chuen Wen Tan, June 2020) between vitamin D levels and European mortality which increased over time.
• UVB radiation, which the skin uses to manufacture vitamin D is associated (Moozhipurath et al, May 1st 2020) with lower death rates and case fatality rates.
• Covid-19 deaths-per-million appears to vary by latitude (Rhodes et al, June 2020).
• Latitude was not associated (Jüni et al, June 2020) with a proportional increase in cases during one week of March.
• Latitude is a significant predictor of Covid mortality after controlling for age (Rhodes et al, July 2020).
• Vitamin D levels were inversely associated with cases per million in Europe, but not with deaths per million. (Sing, Kaur, Kumar Sigh, August 2020).

Vitamin D background and previous studies

• Vitamin D Supplementation to Prevent Acute Respiratory Tract Infections: Systematic Review and Meta-Analysis of Individual Participant Data (Martineau et al, February 2017)
• An 2020 metaanalysis (Jolliffe et all, July 2020) found that while vitamin D supplementation did reduce the rate of ARI, there was evidence of publican bias in the research.
• Vitamin D and Influenza — Prevention or Therapy? (Gruber-Bzura, August 2018)
• Vitamin D and the anti-viral state (Beard et al, January 2011)

Lit reviews and clinical guidance

If you only have time for one review

• A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in Vitamin D Deficiency (Benskin, Sept 2020) note that this review only included studies which were available prior to July 2020, so did not include the COVIDIOL pilot RCT.

Other revies

• This review (McCullough, May 15 2020) of potential vitamin D mechanisms of action provides some useful history on the origin of vitamin D dosing recommendations. They also review their clinical guidelines after treating several thousand patients with 5000-10000 IU/day, including recognizing and resolving hypercalcemia or other adverse events.
• Slovenia has begun administering vitamin D to residents of nursing homes and health care workers.
• A review in Nature (Ebadi et al, May 2020) suggests that all patients should be monitored and potentially treated for vitamin D deficiency.
• A bmj report (Lanham-new, May 2020)) which is generally critical of the connection between Covid-19 and vitamin D nevertheless concludes that supplementation according to government health guidelines (no more than 4,000 IU/day) is sensible for most people.
• Evidence supports a vitamin-D causal model (Davies et al, june 13 2020) more than an acausal one.
• A quarantine hospital in Egypt has started providing (Egypt Today, News source, June 1st 2020) vitamin D to frontline medical workers.
• The French National Academy of Medicine now recommends (Website French National Academy, May 22 2020) vitamin D supplementation as a preventative and adjuvent therapy for Covid-19 infection.
• NICE, an English clinical research group, does not recommend (Nice.org.uk, June 29 2020) vitamin D supplementation.
• A review of the evidence (Lanham-New et al, April 2020) finds that supplementing with vitamin D in accordance with government guidelines is a good idea, but there is no evidence to support supplementation rates higher than 4,000 IU/day
• a A Basic Review(Linda Benskin, preprint, July 2020) of the Preliminary Evidence that Covid-19 Risk and Severity is Increased in Vitamin D Deficiency, stating that The evidence strongly suggests that vitamin D deficiency is an easily modifiable risk factor and correcting it is potentially life-saving
• a Commentary(Manson et al, July 23, 2020) in Metabolism Journal calling for action to eliminate Vitamin D deficencies, and recommending a higher Vitamin D advice during the pandemic of 1000-2000 IU a day

Race and Covid

• Black and Asian (Williamson et al, July 2020) populations are at a high risk of Covid morality. Some studies (Carolina Bonilla et al, June 2012) have found a relationship between skin pigmentation an vitamin D levels, but others (Powe et al, November 2013) have found that there is no difference in bio-available vitamin D because of differences in genetic polymorphisms related to vitamin D–binding protein. Interestingly, vitamin D binding protein is itself associated (Chishimba et al, November 2013) with infectious lung diseases.
• There are lots of other factors (Bhala et al, November 2013) which vary by race and which make Covid mortality more likely. These do not fully explain the race gap.
• BAIPO, which represents UK doctors of Indian origin wrote to the NHS (Letter, Google Drive, April 22 2020) advocating for vitamin D testing and supplementation for front line staff. They are providing all members with vitamin D on request.
• Black people are 5 Times More Likely (DiMaggio et al May 2020) to Develop COVID-19: Spatial Modeling of New York City ZIP Code-level Testing Results
• Excess African-American mortality in the US was higher (Kohlmeier, May 2020) in northern states than southern states.
• A dataset of 6 million US veterans (Rentsch et al, May 2020) found that Black and Hispanic had higher rates of Covid-19 which were not explained by medical conditions or where they live or receive care.
• An analysis(Drefahl et al, July 2020) found that immigrants to Sweden from low and middle income countries were 1.5-2.5 times more likely to die from Covid.
• An analysis of census(McLaren, June 2020) data found that for all minorities, the minority's population share is strongly correlated with total COVID-19 deaths.
• Middle eastern and African immigrants to Sweden were at a much higher risk of covid-19 mortality than the Swedish-born population. (Rostilla et al, August 2020)

Potential Mechanisms

• This is the best overview (Quesada-Gomez et al, 2020) of potential vitamin D mechanisms with respect to Covid-19.
• Vitamin D helps regulate the renin angiotensin system(YouTube video, Channel Found my Fitness, Rhonda Patrick PhD , April 14 2020)) which includes the ACE2 receptor that Covid-19 binds to.
• Vitamin D may bind (Dasgupta, May 2020) to the non-structural protein nsp7 on the SARS-CoV-2 virus.
• An article in Nature (Ebady et al, May 2020) outlines a number of potential mechanisms.
• The Essential Role of Vitamin D in the Biosynthesis of Endogenous Antimicrobial Peptides May Explain Why Deficiency Increases Mortality Risk in COVID-19 Infections
• Vitamin D is essential (McCullough et al, May 2020) to the formation of antimicrobial peptides such as cathelicidin and beta defensins.
  
• Lungs as Target of COVID-19 Infection: Protective Common Molecular Mechanisms of Vitamin D and Melatonin as a New Potential Synergistic Treatment (Giménez, August 2020)