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index.Rmd
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---
title: "Vitamin D and Covid-19"
description: "A comprehensive list of research related to vitamin D and Covid-19"
output:
rmarkdown::html_document:
theme: lumen
---
To make suggestions and changes see the Github repo: [Vitamin_d_covid](https://github.com/GShotwell/vitamin_d_covid/blob/master/index.Rmd)
```{r echo=FALSE, message=FALSE, warning=FALSE}
library(metathis)
meta() %>%
meta_description(
"A comprehensive list of research related to vitamin D and Covid-19"
) %>%
meta_name("github-repo" = "GShotwell/vitamin_d_covid") %>%
meta_viewport() %>%
meta_social(
title = "Vitamin D and Covid",
url = "https://vitamin-d-covid.shotwell.ca/",
image = "https://cdn.pixabay.com/photo/2014/04/05/11/40/pill-316601_960_720.jpg",
image_alt = "Several gold vitamin D pills",
og_type = "website",
og_author = c("Gordon Shotwell"),
twitter_card_type = "summary",
twitter_creator = "@gshotwell"
)
```
# The argument for supplementation
- Vitamin D reduces the risk of [other](https://www.bmj.com/content/356/bmj.i6583) 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](https://www.biorxiv.org/content/10.1101/2020.06.21.162396v1) against the SARS-COV2 virus
- Patients treated with calcifediol are [less likely](https://www.sciencedirect.com/science/article/pii/S0960076020302764?via%3Dihub#tbl0005) 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](https://www.preprints.org/manuscript/202005.0265/v1) an adverse events of vitamin D supplementation can be easily managed by clinicians
# Direct research on vitamin D and Covid
### Supplementation studies
*Randomized*
- A [parallel pilot randomized open label](https://www.sciencedirect.com/science/article/pii/S0960076020302764?via%3Dihub#tbl0005) 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. (Castillo et all, August 2020)
*Non-Randomized*
- A [small cohort trial](https://www.sciencedirect.com/science/article/pii/S0899900720303002) 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. (Chuen Wen Tan, October 2020)
- A [retrospective study](https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3690902) found that hospitalized patients who were treated with vitamin D were less likely to die than those who did not receive vitamin D. (Ling et all, October 2020)
- [A quasi-experimental study](https://www.sciencedirect.com/science/article/pii/S096007602030296X#fig0010) found that French nursing home residents who had recently received a bolus dose of vitamin D were more likely to survive a Covid-19 infection than residents who had not recently received a supplement. 92% of the 57 people who received vitamin D survived, while 66% of the 9 people in the cooperator group survived. (Anweller et. al, October 2020)
### Covid severity associated with serum vitamin D levels
#### Pre-infection blood samples
*Supports link to vitamin D*
1) A [retrospective cohort](https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2770157) study found that Chicago patients who were likely vitamin D deficient were more likely to test positive for Covid-19. (Meltzer et al, May 2020)
1) An [Israeli study](https://febs.onlinelibrary.wiley.com/doi/abs/10.1111/febs.15495) of 7,000 patients with pre-Covid serum vitamin D tests found that vitamin D levels were associated with Covid infection and hospitalization. (Eugene Merzon et al, July 2020)
1) An [analysis](https://www.medrxiv.org/content/10.1101/2020.09.04.20188268v1) of Israeli vitamin D tests performed between 2010 and 2019 found that vitamin D deficiency predicted Covid-19 infection. (Israel et al, August 2020)
1) [An analysis](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239252#pone-0239252-g002) 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. (Kaufman et all, Sept 2020)
*Does not support vitamin D link*
- Vitamin D levels between 2006-2010 [were associated](https://www.sciencedirect.com/science/article/pii/S1871402120301156) 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. (Hastie et al, July 2020)
#### Post-infection blood samples
*Supports vitamin D link*
1) A re-analysis of [107 Swiss blood samples](https://www.mdpi.com/2072-6643/12/5/1359/htm) found that PCR positive patients had 25-hydroxyvitamin D concentrations half that of PCR negatives. This finding held after stratifying for age and gender. (Avolio et 1) l, April 2020)
1) Hospitalized male Covid-19 patients [were found](https://www.medrxiv.org/content/10.1101/2020.05.01.20079376v1) to have lower vitamin D levels than controls. (De Smet et al, May 2019)
1) A observational [study from Belgium](https://www.medrxiv.org/content/10.1101/2020.05.01.20079376v2) found that vitamin D deficiency is correlated with the risk for hospitalization for COVID-19 pneumonia and predisposes to more advanced radiological disease stages. (De Smet, May 2020)
1) Vitamin D deficiency [was more common](https://onlinelibrary.wiley.com/doi/full/10.1111/cen.14276) among ITU Covid patients than the general population in a Newcastle hospital. (Panagiotou et all, June 2020)
1) A [Mexican study](https://www.medigraphic.com/pdfs/sanmil/sm-2020/sm201_2za.pdf) found that patients with vitamin D serum levels bellow 8 ng/mL had 3.68 higher risk of dying from COVID-19. (Arturo Rodríguez Tort et al, April 2020)
1) A [Iranian study](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239799) (Maghbooli et al, September 2020) found there was a significant association between vitamin D sufficiency and reduction in clinical severity. Note that an [expression of concern](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240965) was filed for this publication.
1) A [study](https://link.springer.com/article/10.1007/s40618-020-01370-x) 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. (Carpagnano et all, August 2020)
1) A [prospective cohort study](https://www.mdlinx.com/journal-summary/vitamin-d-status-and-outcomes-for-hospitalised-older-patients-with-covid-19/i68lJrN18PCbGXMwzC0tU) 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. (Baktash V et all, August 2020)
1) [A study](https://www.sciencedirect.com/science/article/pii/S0168170220310558) of patients presenting with Covid symptoms at an Iranian hospital found that vitamin D deficiency and ACE dysregulation were more common among those who tested positive for Covid-19. (Mardenia et all, August 2020)
1) [A German Study](https://www.mdpi.com/2072-6643/12/9/2757/htm) found that vitamin D status was associated with need for mechanical ventilation and death. (Radujkovic et al, August 2020)
1) [A small prospective cohort study](https://pmj.bmj.com/content/early/2020/08/26/postgradmedj-2020-138712?s=09) of older adults found that vitamin D deficiency was associated with mechanical ventilation, but not death. (Baktash et all, September 2020)
1) [A Turkish study](https://link.springer.com/article/10.1007/s12603-020-1479-0) found that vitamin D deficiency was associated with mortality. (Karahan & Katkat October 2020)
1) [A study](https://www.medrxiv.org/content/10.1101/2020.10.05.20206706v1) of UK health professionals found that vitamin D deficient individuals were more likely to be seropositive for Covid antibodies. (Aduragbemi et all, October 2020)
1) A study of [Covid positive children](https://onlinelibrary.wiley.com/doi/10.1002/ppul.25106) found that children with Covid had lower vitamin D levels than healthy controls. (Yilmaz & Sen, October 2020)
1) A [case control study](https://www.tandfonline.com/doi/full/10.1080/07315724.2020.1826005) in China found that vitamin D deficiency was higher in Covid patients than healthy controls, and that it was associated with disease severity. (Ye et. al, October, 2020)
1) A retrospective [case control](https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgaa733/5934827) study of 216 hospitalized patients found that 80% of Covid patients were vitamin D deficient, while just 42% of matched controls were deficient. The study did not find that vitamin D deficiency was associated with disease outcome. (Hernández et al, October 2020)
1) A [study](https://link.springer.com/article/10.1007%2Fs00394-020-02411-0) of 74 hospitalized patients found that vitamin D deficiency was associated with Covid lung involvement, and mortality. (Abrishami et all, October 2020)
*Does not support link to vitamin D*
1) A [small trial](https://pubmed.ncbi.nlm.nih.gov/32960622/) did not find an association between vitamin D deficiency and Covid-19 severity. The study did find an association among younger patients. (Macaya et. all, September 2020)
1) A [case-control study](https://www.researchsquare.com/article/rs-96491/v1) did not find that Covid positive patients had lower vitamin D levels than patients hospitalized with non-Covid pneumonia or a set of non-respiratory conditions.
The comparator groups in this study are a bit strange because low vitamin D levels are implicated in almost all of the diagnoses included in this study. See the comments associated with the paper.
### In vitro evidence
- Calcitriol, the active form of Vitamin D [is active](https://www.biorxiv.org/content/10.1101/2020.06.21.162396v1) against the SARS-COV2 virus. (Chee Keng Mok et al, June 2020)
### Non-clinical causal data
*Supports vitamin D*
- Evidence supports a [vitamin-D causal model](https://www.medrxiv.org/content/10.1101/2020.05.01.20087965v1) more than an acausal one. (Davies et al, June 13 2020)
- A [Mendelian randomisation analysis](https://nutrition.bmj.com/content/early/2020/05/20/bmjnph-2020-000096) of excess COVID-19 mortality of African-Americans in the US suggests that vitamin D is a risk factor for Covid Mortality. (Martin Kohlmeier, May 2020)
*Does not support vitamin D*
- A [Mendelian randomization](https://www.medrxiv.org/content/10.1101/2020.08.09.20171280v1.article-info) 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. (Liu et al, August 2020)
- Another [Mendelian randomization](https://www.medrxiv.org/content/10.1101/2020.09.08.20190975v2.full.pdf) based on UK biobank and other genetic datasets found that people of European descent who were genetically predisposed to high vitamin D levels did not change their risk of contracting Covid, but seemed to increase their risk of hospitalization. (Butler-Laporte, September 2020)
### Ecological studies
- A study out of [Northwestern University](https://link.springer.com/article/10.1007%2Fs40520-020-01677-y) 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. (Daneshkhah1 et al, April 2020)
- There was a [strong correlation](https://www.medrxiv.org/content/10.1101/2020.06.24.20138644v1) between vitamin D levels and European mortality which increased over time. (Chuen Wen Tan, June 2020)
- UVB radiation, which the skin uses to manufacture vitamin D is [associated](https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3586555#.XrA5awDBBLE.twitter) with lower death rates and case fatality rates. (Moozhipurath et al, May 1st 2020)
- Covid-19 deaths-per-million appears to [vary by latitude](https://www.ncbi.nlm.nih.gov/pubmed/32311755). (Rhodes et al, June 2020)
- Latitude [was not associated](https://www.cmaj.ca/content/192/21/E566) with a proportional increase in cases during one week of March. (Jüni et al, June 2020)
- Latitude is a significant predictor of Covid mortality after [controlling for age](https://nutrition.bmj.com/content/3/1/118). (Rhodes et al, July 2020)
- Vitamin D levels were [inversely associated](https://link.springer.com/article/10.1007/s40520-020-01619-8) with cases per million in Europe, but not with deaths per million. (Sing, Kaur, Kumar Sigh, August 2020)
- The fall 2020 outbreaks in Europe [appear to be correlated](https://www.medrxiv.org/content/10.1101/2020.10.28.20221176v2) with latitude but not temperature. (Warland, November 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](https://pubmed.ncbi.nlm.nih.gov/28202713/) (Martineau et al, February 2017)
- An [2020 meta analysis](https://www.medrxiv.org/content/10.1101/2020.07.14.20152728v1) found that while vitamin D supplementation did reduce the rate of ARI, there was evidence of publican bias in the research. (Jolliffe et all, July 2020)
- Vitamin D and Influenza — [Prevention or Therapy?](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121423/) (Gruber-Bzura, August 2018)
- Vitamin D and [the anti-viral state](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3308600/) (Beard et al, January 2011)
# Government guidance
*Supports supplementation*
- [Israel](https://www.theyeshivaworld.com/news/headlines-breaking-stories/1911344/health-ministry-urges-israelis-to-take-vitamin-d-to-fight-covid-19.html) started recommending vitamin D in October 2020.
- The United Kingdom [changed its guidance](https://inews.co.uk/news/politics/vitamin-d-supplements-recommended-matt-hancock-covid-19-725284) to recommend vitamin D.
- [Slovenia](https://www.bmj.com/content/369/bmj.m1820/rr) has begun administering vitamin D to residents of nursing homes and health care workers.
- The French National Academy of Medicine now [recommends](http://www.academie-medecine.fr/wp-content/uploads/2020/05/20.5.22-Vitamine-D-et-coronavirus-ENG.pdf) 800 to 1,000 IU/day of vitamin D supplementation as a preventative and adjuvant therapy for Covid-19 infection.
- A Swiss expert panel [recommends](https://www.sge-ssn.ch/media/Nutritional-status-in-supporting-a-well-functioning-immune-system-for-optimal-health-with-a-recommendation-for-Switzerland-1.pdf) that people supplement with 2,000 IU of vitamin D per day.
- New Zealand [provides](https://www.cambridge.org/core/services/aop-cambridge-core/content/view/859AD0FC45E96D4300180B5C571959CD/S1368980016001683a.pdf/vitamin_d_status_and_its_predictors_in_new_zealand_agedcare_residents_eligible_for_a_governmentfunded_universal_vitamin_d_supplementation_programme.pdf) 50,000 IU monthly vitamin D supplementation to all aged care residents.
*Does not support supplementation*
- NICE, an English clinical research group, [does not recommend](https://www.nice.org.uk/advice/es28/chapter/Key-messages) vitamin D supplementation. (Nice.org.u, June 29 2020)
# 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](https://www.frontiersin.org/articles/10.3389/fpubh.2020.00513/full) note that this review only included studies which were available prior to July 2020, so did not include the COVIDIOL pilot RCT. (Benskin, Sept 2020)
*Other reviews*
- [This review](https://www.preprints.org/manuscript/202005.0265/v1) 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. (McCullough, May 15 2020)
- A [review in Nature](https://www.nature.com/articles/s41430-020-0661-0) suggests that all patients should be monitored and potentially treated for vitamin D deficiency. (Ebadi et al, May 2020)
- A [bmj report](https://nutrition.bmj.com/content/3/1/106) 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. (Lanham-new, May 2020)
- A quarantine hospital in Egypt has [started providing](https://www.egypttoday.com/Article/1/88198/Doctors-in-Egypt%E2%80%99s-quarantine-hospitals-to-receive-million-Vitamin-D) (Egypt Today, News source, June 1st 2020) vitamin D to fronting medical workers.
- A [review of the evidence](https://nutrition.bmj.com/content/bmjnph/early/2020/05/13/bmjnph-2020-000089.full.pdf) 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. (Lanham-New et al, April 2020)
- a [Commentary](https://www.metabolismjournal.com/article/S0026-0495(20)30186-4/) in Metabolism Journal calling for action to eliminate Vitamin D deficiencies, and recommending a higher Vitamin D advice during the pandemic of 1000-2000 IU a day. (Manson et al, July 23, 2020)