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January 6, 2021

Sorting Out Whether Vitamin D Deficiency Raises COVID-19 Risk

JAMA. 2021;325(4):329-330. doi:10.1001/jama.2020.24127
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One of the risk factors du jour for coronavirus disease 2019 (COVID-19) has been vitamin D deficiency.

Even Anthony Fauci, MD, has said he takes a vitamin D supplement. Vitamin D “does have an impact on your susceptibility to infection,” Fauci, director of the National Institute of Allergy and Infectious Diseases, told actress Jennifer Garner in a September interview. “I would not mind recommending—and I take it myself—taking vitamin D supplements.”

Most people get some vitamin D from sunlight exposure, although individuals in the US get the nutrient mainly from fortified foods, such as milk, orange juice, and breakfast cereals.

At higher latitudes, people with more melanin content in their skin have lower blood levels of vitamin D because their skin doesn’t produce as much in response to sunlight. A recent article in the Journal of the National Medical Association speculated that vitamin D deficiency “is likely a significant factor” behind disproportionately high COVID-19 cases and deaths among US Black and Latino populations.

An analysis of data from 4962 participants in the National Health and Nutrition Examination Survey found that 1981 (39.92%) were vitamin D deficient, defined as a blood level lower than 20 ng/mL (<50 nmol/L). Vitamin D deficiency was greater in certain subpopulations, such as people with obesity or with type 1 or type 2 diabetes—all 3 of which have been associated with worse COVID-19 outcomes.

Despite Fauci’s recommendation and claims by many supplement sellers, conclusions about vitamin D blood levels’ connection to a host of diseases, including infections, cannot be determined because of mixed or sparse evidence, according to a recent report written for the US Preventive Services Task Force, which is updating its recommendation on vitamin D deficiency screening. The draft updated recommendation, like its 2014 predecessor, concludes that the evidence is insufficient to assess the benefits and harms of screening in asymptomatic adults for any reason.

“Vitamin D might be helpful in that there is evidence it can attenuate immune responses,” which could prevent the “cytokine storms” seen in some patients with COVID-19, A. Catharine Ross, PhD, chair of nutrition sciences at Penn State, wrote in an email. “On the other hand, attenuation might not be beneficial in terms of helping the antibody response.”

Mixed Signals

Research findings about vitamin D and COVID-19 have been mixed and sparse:

  • A study of 77 frail elderly patients hospitalized with COVID-19 in France concluded that vitamin D supplements taken regularly during the year before a COVID-19 diagnosis were associated with less severe disease and better survival than taking no vitamin D or receiving supplementation shortly after diagnosis. And a pilot randomized clinical trial of 76 patients hospitalized with COVID-19 in Spain found that treatment with high-dose vitamin D significantly reduced the risk of intensive care unit admission. However, only larger trials could provide a definitive answer, the authors wrote.

  • On the other hand, a study in a northern Italy hospital found no association between vitamin D and COVID-19. In a review article published in a different journal the same day as their study, the researchers in Italy concluded that poor vitamin D status appears to be linked to an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but age, sex, and comorbidities seem to play a more important role in COVID-19 severity and mortality. Nine days later, a different group of Italian researchers published an observational study of 324 patients with COVID-19 that found taking vitamin D supplements was not linked to risk of hospitalization but was associated with a higher risk of dying if hospitalized.

  • A recent study in JAMA Network Open by University of Chicago researchers linked vitamin D deficiency with a greater likelihood of testing positive for SARS-CoV-2. However, an earlier study of UK Biobank participants found no such connection. The Chicago researchers noted that vitamin D levels examined in the UK study predated COVID-19 diagnoses by at least a decade, so they could have changed by the time SARS-CoV-2 testing took place.

Behind the Headlines

Some of the evidence about vitamin D and COVID-19 doesn’t pass the smell test, according to a July letter to the editor of the British Journal of Nutrition.

The authors focused on an Indonesian retrospective study linking low vitamin D levels to a higher risk of dying from COVID-19. Although the publication had not been peer-reviewed, “it has taken the internet by storm,” garnering thousands of tweets, not to mention headlines in major news outlets, the letter writers noted.

The problem, they said, was that they couldn’t track down the authors of the study, which didn’t mention the names or number of hospitals involved. Plus, vitamin D levels aren’t routinely checked in Indonesia, so it’s unclear how the authors would have acquired that information retrospectively. Although the paper is no longer on SSRN, the preprint repository, it can still be found online.

In mid-October, the editors of PLoS One issued an “expression of concern” about a vitamin D study they had published 3 weeks earlier, which found that among patients hospitalized with COVID-19, those with vitamin D levels lower than 30 ng/mL were twice as likely to die than the others.

Only 31.06% of study participants had a laboratory-confirmed COVID-19 diagnosis and potential confounders might not have been adequately addressed. “Vitamin D levels may be indicative of comorbidities that may themselves impact COVID outcomes,” explained the editors, who said they are reassessing the article.

The editors also questioned the authors’ declaration of no competing interests. Public information suggests that corresponding author Michael Holick, MD, PhD, of the Boston University School of Medicine, does have competing interests, including consulting work, industry funding, and authorship of books (such as 2011’s The Vitamin D Solution), the editors wrote.

Conflicts of Interest?

By early December 2020, dozens of studies examining vitamin D and COVID-19, most of which had not yet started recruiting participants, were listed on ClinicalTrials.gov.

Whether any of these studies can settle the debate isn’t clear. The “sponsors and collaborators” section for several planned US studies lists parties that stand to profit if vitamin D deficiency is shown to worsen COVID-19 outcomes, raising the specter of conflicts of interest. In addition, at least 3 US studies plan to test vitamin D in conjunction with hydroxychloroquine, which has repeatedly been shown to be ineffective against COVID-19, most recently in JAMA.

“The credibility of clinical trials requires a hands-off approach from funders,” Ross noted. For that reason, she said, research sponsored by the National Institutes of Health (NIH) is preferred to that funded by the supplement industry.

However, none of the vitamin D and COVID-19 studies on ClinicalTrials.gov appears to be NIH-funded.

JoAnn Manson, MD, chief of preventive medicine at the Brigham and Women’s Hospital, is a principal investigator for one of the largest. In July, Manson coauthored a “call to action” to eliminate vitamin D deficiency during the pandemic. Two of the 11 sources it cited were the questionable preprint from Indonesia and a BMJ “Rapid Response” that also cited the preprint. Tishcon Corporation, a vitamin supplement manufacturer, and Quest Diagnostics, which markets a $69 vitamin D test directly to consumers, are among the sponsors and collaborators of Manson’s study, as are Sweden’s prestigious Karolinska Institute and Harvard Medical School.

Pediatrician Carol Wagner, MD, of the Medical University of South Carolina, is leading a study with 2 sponsors and collaborators that have a vested interest in the findings. ZRT Laboratory, a Beaverton, Oregon, company, sells a $75 vitamin D test directly to consumers. Grassroots Health Nutrient Research Institute operates “D*action,” “a global vitamin D population intervention program” that charges participants $65 for a vitamin D test. Holick serves on the institute’s International Scientists Panel.

The Upshot

Regardless of whether vitamin D protects against COVID-19, adequate levels are important for bone health.

“Avoiding vitamin D deficiency is always a goal,” Ross wrote. “If the diet doesn’t include vitamin D fortified milk or natural products like fish, then a supplement of the RDA [recommended dietary allowance] amount (600-1000 IU per day) provides good assurance. I consider this a ‘good idea,’ but I don’t want to leave the impression that diet cannot be sufficient.”

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    12 Comments for this article
    EXPAND ALL
    25 D3 Levels
    H Silverstein, MD | Preventive Medicine Center
    The dose of D3 is likely irrelevant: while a blood level > 30 nanograms per mL (ng/mL) has been considered the dividing line for health, there are many who support 50-66 ng/mL as the desirable 25 hydroxy-vitamin D3 level, including this author. Such a value is generally achieved with a dose of 5,000 international units 5 to 7 days a week taken for more than 6 months. High doses given over short periods of time may furnish the desired blood levels but may not create sustained whole-body equilibrium presumed essential for normal physiology.
    CONFLICT OF INTEREST: None Reported
    Following the Potential Vitamin D Correlation for Months Understanding Correlation Does Not Equal Causation
    John Lambiase, Associate Science | ASCP
    As a clinical laboratorian I take interest in this subject matter. When Tom Frieden posted his op ed in March about Vitamin D being potentially helpful I wanted to know why.

    Scouring through as much data on all available servers there is a significant amount of data regarding correlation between Vitamin D and respiratory Illness in general.

    I absolutely agree with Dr. Silverstein in his comment regarding relevance of dose. There are many variables that can stymie supplementation and normal physiological levels between 40-60 ng/mL appear to be plausible and I say that
    from experience.

    I work night shift in a clinical lab and we all analyzed our levels in late March. Those who were not supplementing had vitamin D levels < 14 ng/mL. (We reside between the 30th line of latitude)

    We started dosing with 10,000 IU for the first week and dropped down to 5000 IU for the following week and that brought our levels in the ballpark of 20 ng/mL. On 5000 IU daily since we were able to achieve levels >40 <60 by the end of the April (Surprised it took that long).

    While maintaining this dosage my personal summer peak was 59 ng/mL for (25OHD) and this included vacationing to Florida. Calcium levels never became a factor.

    Three weeks ago while on the same 5000 IU daily dosage I was surprised that my personal level of 25(OH)D fell by 17-18% to 48 ng/mL and was likely attributed to lower direct sunlight as we approached winter solstice.

    It made me wonder about people at higher latitudes who in the summer might have been straddling the line of clinical deficiency. What would their levels look like if they dropped 17% from summer to winter? It also begs to ask, could the drop be greater at higher latitudes given the less direct sun angle?

    Given the lockdown orders and the fact that people are scared to go outside it might be reasonable to think that the RDA's on vitamin D might be too low to be of any benefit to first help people maintain a replete state going into winter from summer or even worse try to correct a deficiency in any reasonable amount of time.

    The whole study on Vitamin D is very interesting regarding Innate and adaptive Immune signaling which includes modulation of mitochondrial oxidative stress in many studies in general. Something that could be seemingly important as well is the type of fat intake while supplementing vitamin D to aid in absorption. Monounsaturated (MUFA) fats like real olive, avocado, and high oleic acid safflower oil has been studied to be better over polyunsaturated and saturated fats for aiding in Vitamin D absorption. MUFA's have also shown to lower LDL cholesterol mitochondrial oxidative stress as well which might be beneficial to those who have insulin resistance (1-3).

    References

    (1) https://academic.oup.com/qjmed/article/93/2/85/1517901
    (2) https://www.nature.com/articles/nrendo.2011.150
    (3) https://doi.org/10.1210/jc.2013-2103
    CONFLICT OF INTEREST: None Reported
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    Vitamin D Brouhaha
    William Bayer, MD | Clinical Associate Professor Family Medicine University of Rochester Medical School
    I have seen over the years that when there has been so much discussion about the benefits of a medical intervention, usually that means the medical intervention is not very effective. I don’t believe there is any definitive evidence about the benefits of vitamin D for bone health. Historically societies with some of the greatest bone strength have had very little consumption of vitamin D and calcium.Until there is a really good study vitamin D should go by the wayside of other vitamins minerals and supplements which have had their day in court and failed to stand up to scrutiny.
    CONFLICT OF INTEREST: None Reported
    Effects of Vitamin D supplementation my depend on baseline levels and geographic region
    Johannes Scholl, Dr. med. | Dr. Scholl Prevention First GmbH, Private Practice for Preventive Medicine
    I agree with the author that many publications about COVID19 and vitamin D are of low study quality or may be biased by sponsor´s interests.

    One aspect that has been ignored frequently in previous RCTs of Vitamin D is the baseline level of 25(OH)D and the geographic region. Whereas in the U.S. most of the population are living below 41 degrees of latitude thus getting enough UVB radiation for vitamin D production via the skin all year long, this is not the case for European countries. Depending on the latitude in Europe there may be a "vitamin
    D winter" of 5-7 months duration, where there isn´t any vitamin D production via the skin.

    In our own unpublished data from Germany with thousands of measurements during the year, average 25(OH)D was 12 ng/ml in March and 24 ng/ml in September with a SD +/-5 ng/ml. So the effect of vitamin D supplementation may be different in different geographic regions due to different baseline levels of vitamin D.

    Previous studies and a Cochrane meta-analysis have shown that compared to very low baseline levels of vitamin D, supplementing vitamin D to achieve levels >30 ng/ml will reduce the risk of acquiring respiratory infections and seasonal influenza. Mechanisms that mediate a better immune response of T-cells have been published, as well as an effect of vitamin D on insulin sensitivity. Insulin resistance of T8-helper-cells is one aspect of a slower immune response to seasonal influenza and other viral infections, as T-cells are lacking the "energy boost" mediated by insulin in the first phase response to an infection.

    Part of the higher COVID19 risk in black and hispanic patients, obesity, diabetes and older age may be mediated by the observed lower vitamin D levels in these populations. This was suggested by a recent paper in Nature Scientific Reviews:

    "Vitamin D deficiency markedly increases the chance of having severe disease after infection with SARS Cov-2. The intensity of inflammatory response is also higher in vitamin D deficient COVID-19 patients. This all translates to increase morbidity and mortality in COVID-19 patients who are deficient in vitamin D. Keeping the current COVID-19 pandemic in view authors recommend administration of vitamin D supplements to population at risk for COVID-19." (1)

    What we would need is a rigorous RCT with early / high-dose vitamin D supplementation like 2 x 40 000 IU in week 1 vs. placebo at hospital admission in a high-risk population for severe course of COVID19. It would be easy to undertake, but unlike trials with largely inefficient drugs like remdesivir there is no relevant economic interest in undertaking such a study.

    Reference

    1. Jain, A., Chaurasia, R., Sengar, N.S. et al. Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep 10, 20191 (2020). https://doi.org/10.1038/s41598-020-77093-z
    CONFLICT OF INTEREST: None Reported
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    Misquoted Italian reference.
    Jan van der Meulen, M.D., Ph.D. | General Practice deJagerweg, Dordrecht, the Netherlands.
    In the paragraph “Mixed signals” an Italian observational study of 324 patients with COVID-19 is misquoted (1). The author of the paragraph concludes that taking vitamin D supplements was associated with a higher risk of dying if hospitalized. Reading the study, one may wonder whether the conclusion of an association between vitamin D supplements and in-hospital mortality is correct? The study provides the following figures: the adjusted OR (95% CI) is 2,42 (0,78-7,49) with an adjusted p-value of 0,13.

    Furthermore, one may question whether it is correct that the above-mentioned figures were obtained by pooling data of two
    studies. The first study, published in June, was performed between March and May 12th, 2020. It regarded 105 Parkinson's patients and 92 of their family members with COVID-19 (2). The conclusion of the study was that COVID-19 patients were younger, more likely to suffer from chronic obstructive pulmonary disease and obesity, and not using vitamin D supplements than unaffected patients.

    The second study, not published, was performed later and regarded 127 consecutive COVID-19 patients admitted to a hospital. In this group of patients, 40% has ischemic heart disease versus 5% and 4% in the Parkinson group respectively the family members and 20% has cancer versus 1% and 2% in the Parkinson group respectively the family members.

    References

    1. Cereda E, Bogliolo L, Lobascio F, Barichella M, Zecchinelli AL, Pezzoli G, et al. Vitamin D supplementation and outcomes in coronavirus disease 2019 (COVID-19) patients from the outbreak area of Lombardy, Italy. Nutrition 00 (2020) 111055.

    2. Fasano A, Cereda E, Barichella M, Cassani E, Ferri V, Zecchinelli AL, et al. COVID-19 in Parkinson’s Disease Patients Living in Lombardy, Italy. Movement Disorders, 2020; 35: 1089-1093.
    CONFLICT OF INTEREST: None Reported
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    Funding Conflicts
    James Leo, MD | MemorialCare Health System
    The author cites a statement by Ross that studies of vitamin D should be free of industry funding conflicts. While this would be an ideal state for all research, why is there no such statement made for all Pharma-sponsored research? Let’s be even-handed, and let’s continue to look critically at the methods and validity of all studies - with an extra long and deep look at those that are subject to bias, whether financial, intellectual, or otherwise.
    CONFLICT OF INTEREST: None Reported
    Recent Vitamin D Systematic Review
    Janek Kuziemski, M.D, Ph.D | Essex Partnership University NHS Trust, Princess Alexandra Hospital, Derwent Centre, Harlow, UK
    A systematic review of studies researching evidence for Vitamin D's "anti-COVID" properties was recently published (1). It included 9 studies, 7 of them with 40 - 1000 participants, 1 with >1000, and 1 with 1million participants according to the authors (Table1) Based on results of 7 studies (including the one with 1 million participants) the authors concluded that "blood vitamin D status can determine the risk of being infected with COVID-19, seriousness of COVID-19, and mortality from COVID-19." However the study with 1 million participants (2) was based on correlations between average Vitamin D levels in populations of different European countries (unknown number of participants, historical data), and the incidence of COVID infections per 1 million population in European countries in April and May 2020, which varied from 93 to 4730 (April) and 372 to 5980 (May) per one million population. The authors conclude that “a significant correlation was observed for levels of mean vitamin D with COVID-19 cases (p=0.033) but not with death (P=0.123) per million population”. An interesting question then arises: "What is current difference in COVID-19 incidence and related death rate between two countries included in Ali's study with the lowest (Portugal – 39 nmol/l) and the highest (Slovakia - 81.5) average level of Vitamin D in Europe?" Current statistics (from 21st Jan 2020) shows that the incidence of COVID is 41 900 / 1 millions for Slovakia (the highest level of Vit D3 in Europe) and 57 000 / 1 million population for Portugal (the lowest level). The difference may seem significant (and most likely is, even if we control these results for various confounders), but the point is that the lower mortality incidence than in Slovakia is seen in 8 countries in Europe (all having lower Vitamin D levels in their populations), and is higher than in Portugal in as many as 11 countries (all having higher Vitamin D levels in their populations). So the conclusions formulated in the review (1) do not appear in line with the observed epidemiology in Europe.

    References

    1. Yisak H et al. Effects of Vitamin D on COVID-19 Infection and Prognosis: A Systematic Review. Risk Manag Healthc Policy. 2021 Jan 7;14:31-38. 

    2. Ali N. Role of vitamin D in preventing of COVID-19 infection, progression and severity. J Infect Public Health. 2020 Oct;13(10):1373-1380.

    Dr Grzegorz Wisniewski (aka Jan Kuziemski on Facebook)
    CONFLICT OF INTEREST: None Reported
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    Response to Rubin
    Nathaniel Hupert, MD MPH | Weill Medical College and Cornell Institute for Disease and Disaster Preparedness, Cornell University
    Rubin asks whether the disproportionate morbidity of COVID-19 among Black and Latino populations and other at-risk groups (e.g., diabetics) might be attributable to vitamin D deficiency. Her conclusion: vitamin D supplementation is probably good for…bone health? Given the global devastation wrought by COVID-19, a more dispositive answer to the question is necessary -- and possible. Rubin’s analysis has two important limitations. First, it fails to consider fully the manifold risk groups disproportionately affected by COVID-19, especially individuals with limited daylight exposure (e.g., those in long-term care, carceral facilities, and daytime indoor shift-workers). Second, it includes only three studies: Meltzer’s cohort study showing decreased infection, Annweiller’s quasi-experimental nursing home study showing doubled survival, and Castillo’s randomized controlled trial (RCT) showing dramatic reductions in ICU requirements.

    Seven additional peer-reviewed studies showing positive associations are omitted: 1) Ling’s observational study where high-dose vitamin D therapy (~3,000 IU/day) reduced mortality >80%; 2) Katz’s large (>100,000 person) observational study finding ~5-fold COVID-19 risk increase among patients with inadequate vitamin D; 3) Kaufman’s cohort study showing an inverse association between infection risk and vitamin D levels; 4) Merzon’s cohort study finding a 50% increase in SARS CoV-2 positivity among vitamin D-deficient patients; 5) Tan’s cohort study showing vitamin D supplementation decreased supplemental oxygen requirements; 6) Rastogi’s small treatment RCT showing quicker viral clearance among COVID-19 patients who received vitamin D; and 7) Pereira’s systematic review/meta-analysis concluding vitamin D deficiency was associated with COVID-19 hospitalization, severity, and mortality.

    Though such comparisons are difficult, these positive studies arguably present stronger evidence than the two negative observational studies Rubin cites: one failed to account for well-documented hypovitaminosis D in non-COVID respiratory disease; the other failed to adjust for unsuccessful repletion in the vitamin D-treated group (an error that Meltzer et al. carefully avoided).

    Of the many prominent US public health physicians who have voiced support for investigating potential vitamin D-COVID-19 links (including a former CDC Director and former U.S. Surgeon General) Rubin mentions only Dr. Fauci’s endorsement. Unfortunately, federally funded research has yet to begin. Rubin notes that none of the vitamin D trials listed on clinicaltrials.gov are government funded, but does not mention that, through 1/17/2021, not one of the 607 NIH COVID-19-related notices of grant policies, guidelines, and funding opportunity announcements even mentions vitamin D.

    Rubin cautions that, given this absence of federal funding, commercial bias may influence vitamin D/COVID-19 research. A more pertinent conclusion would be to ask why, in the face of considerable published evidence and high-level interest, the U.S. government has yet to direct its considerable resources to confirming whether an inexpensive and virtually risk-free intervention (vitamin D supplementation) can modulate SARS CoV-2 infection and COVID-19.
    CONFLICT OF INTEREST: None Reported
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    Vitamin D is a negative acute phase reactant
    Julia Powers, MD |
    Numerous study authors appear to be unaware of research pointing to vitamin D as a negative acute phase reactant. That is, just as ferritin rises in the acute phase of illness, vitamin D drops in the acute phase of illness. Vitamin D levels drawn when someone is admitted sick to the hospital, like ferritin levels, could possibly be an interesting biomarker for the current level of inflammation, but they do not say anything about the person's premorbid vitamin D status (1, 2).

    With a few exceptions, most of the studies that have been circulating thus do not
    address the question of whether vitamin D supplementation is helpful, either prophylactically or as a treatment.

    References

    1. https://pubmed.ncbi.nlm.nih.gov/23454726/
    2. https://pubmed.ncbi.nlm.nih.gov/25631715/ 
    CONFLICT OF INTEREST: None Reported
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    Low Insolation Date Determines Autumn COVID-19 Surge Dates in Europe
    Clement Kent, Ph.D. | York University, Toronto
    At a national level, Walrand analyses the date of fall 2020 COVID-19 surges compared to the date when the country sun UVB daily dose drops lower than 34% of that at latitude 0° (1). The two are highly correlated (R-squared = 0.9993 - Figure 5). Walrand considers two factors related to insolation: outdoors virus inactivation and 25(OH)D concentration, and concludes "a low 25(OH)D concentration should be considered a contributing factor to COVID-19 severity".

    Walrand's analysis is strong but inference at a patient level from national data is not possible. Also, Nordic countries have mandated vitamin D supplementation
    in food but still followed the insolation date trend, so further factors must be at work. Foods most commonly supplemented with vitamin D are dairy products and margarines; research in subpopulations who do not benefit from this is warranted.

    Reference

    1. Nature Scientific Reports, 21 Jan. 2021, "Autumn COVID-19 surge dates in Europe correlated to latitudes, not to temperature-humidity, pointing to vitamin D as contributing factor."
    CONFLICT OF INTEREST: None Reported
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    Vitamin D's Mechanism
    George Henderson | Auckland University of Technology
    Dr Bayer states "Historically societies with some of the greatest bone strength have had very little consumption of vitamin D and calcium", however these are societies with very high sunlight exposure. Evolution has arranged things so that peoples in higher latitudes have had to subsist on the fatty animal foods that supply vitamin D during their winter months.

    We can understand the value of vitamin D as a drug by comparing it with dexamethasone. Both drugs release hepatic selenium stores and supply Se to monocytes in circulation (1,2). Selenium increase in immune cells allows improved function and in endothelial
    circulatory cells is anti-inflammatory. Selenium intake and status has been associated with COVID-19 mortality - and with mutation rates of other RNA viruses (3,4)

    The conversion of vitamin D3 to active hormone requires magnesium, iron and vitamin C - cellular handling of these nutrients is impaired in diabetes and chronic illness, so that use of pre-formed D may be essential in critical illness.

    References

    [1] Schütze N, Fritsche J, Ebert-Dümig R, et al. The selenoprotein thioredoxin reductase is expressed in peripheral blood monocytes and THP1 human myeloid leukemia cells--regulation by 1,25-dihydroxyvitamin D3 and selenite. Biofactors. 1999;10(4):329-338. doi:10.1002/biof.5520100403

    [2] Rock C, Moos PJ. Selenoprotein P regulation by the glucocorticoid receptor. Biometals. 2009;22(6):995-1009. doi:10.1007/s10534-009-9251-2

    [3] Zhang J, Taylor EW, Bennett K, Saad R, Rayman MP. Association between regional selenium status and reported outcome of COVID-19 cases in China, The American Journal of Clinical Nutrition, Volume 111, Issue 6, June 2020, Pages 1297–1299, https://doi.org/10.1093/ajcn/nqaa095

    [4] Moghaddam A, Heller RA, Sun Q et al. L. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients 2020, 12, 2098.
    CONFLICT OF INTEREST: None Reported
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    Update
    Janek Kuziemski, M.D, Ph.D. | Essex Partnership University NHS Trust, Princess Alexandra Hospital, Derwent Centre, Harlow, UK
    In my previous comment I concluded that, based on data re: COVID-related mortality in Europe, it can not be claimed that a blood level of vitamin D reduces mortality. This was because 8 countries in Europe (all having lower vitamin D levels in their populations than Slovakia where levels are highest) had a lower mortality incidence, and as many as 11 countries (all having higher vitamin D levels in their populations than in Portugal where this level is the lowest in Europe) the mortality rate was higher.

    However, data re COVID-related biweekly mortality as per 20th Feb are even
    contraindicating a hypothesis that blood vitamin D level may reduce mortality, as Slovakia has the highest biweekly COVID mortality in the world (236.1/million). On the other side, a second country with the highest biweekly mortality in the world is indeed Portugal (190.55/million).

    Based on these data only it would be premature to suggest that vitamin D causes higher COVID-related mortality. Probably more likely is a hypothesis that its blood level has no impact on mortality, but I think that this topic needs urgent attention, taking into account number of people taking vitamin D who believe that this supplement may protect them from COVID infection and its potentially fatal consequences.

    Dr Grzegorz Wisniewski (aka Jan Kuziemski on Facebook)

    References:

    1. https://ourworldindata.org/grapher/biweekly-covid-deaths-per-million-people?stackMode=absolute&country=CAN~FRA~DEU~IND~GBR~USA®ion=World
    CONFLICT OF INTEREST: None Reported
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