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Massive Review of papers on Vitamin D and COVID-19 - July 3, 2020

A Basic Review of the Preliminary Evidence that Covid-19 Risk and Severity is Increased in Vitamin D Deficiency
ResearchGate preprint (undergoing peer review for publication in Frontiers in Public Health)
Linda L Benskin1,2 LindaBenskin at utexas.edu
Independent researcher for improving health in rural areas of tropical developing countries, Austin, TX, USA
Ferris Mfg. Corp., makers of PolyMem® multifunctional dressings, Ft. Worth, TX, USA
A few of the figures in the PDF
Figure 1
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Figure 5 Retrospective Chart Review by D’Avolio
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Figure 7 Retrospective Chart Review by Glicio
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In the 176 elderly (over age 60) hospitalized individuals tested for both 25(OH)D and Covid-19, vitamin D predicted severity of infection

VitaminDWiki

 Download the ~~#F00:updated Aug 4~~ PDF from VitaminDWiki
Note: The following is from the July Version

As the world’s attention has been riveted upon the growing Covid-19 pandemic, many researchers have written brief reports supporting the hypothesis that vitamin D deficiency is related to the incidence and severity of Covid-19.
The clear common thread among the top risk groups - vitamin D deficiency - may be being overlooked because of previous overstated claims of vitamin D benefits. However, the need to decrease Covid-19 fatalities among high-risk populations is urgent.
Early researchers reported three striking patterns:

  1. The innate immune system is impaired by vitamin D deficiency, which would predispose sufferers to viral infections such as Covid-19. Vitamin D deficiency also increases the activity of the X-chromosome-linked ‘Renin-Angiotensin5 System, making vitamin D deficient individuals (especially men) more susceptible to Covid-19’s deadly “cytokine storm” (dramatic immune system overreaction).
  2. The groups who are at highest risk for severe Covid-19 match those who are at highest risk for severe vitamin D deficiency. This includes the elderly, men, ethnic groups whose skin is naturally rich in melanin (if living outside the tropics), those who avoid sun exposure for cultural and health reasons, those who live in institutions, the obese, and/or those who suffer with hypertension, cardiovascular disease, or diabetes.
  3. The pattern of geographical spread of Covid-19 reflects higher population vitamin D deficiency. Both within the USA and throughout the world, Covid-19 fatality rates parallel vitamin D deficiency rates.

A literature search was performed on PubMed, Google Scholar, and RSMLDS, with targeted Google searches providing additional sources. Although randomized controlled trial results may be available eventually, the correlational and causal study evidence supporting a link between vitamin D deficiency and Covid-19 risks is already so strong that it supports action.
The 141 author groups writing primarily about biological plausibility detailed how vitamin D deficiency can explain every risk factor and every complication of Covid-19, but agreed that other factors are undoubtedly at work. Covid-19 was compared with dengue fever, for which oral vitamin D supplements of 4000IU for 10 days were significantly more effective than 1000IU in reducing virus replication and controlling the “cytokine storm” responsible for fatalities.
Among the 47 original research studies summarized here, chart reviews found that serum vitamin D levels predicted Covid-19 mortality rates (16 studies) and linearly predicted Covid-19 illness severity (8 studies). Two causal modeling studies and several analyses of variance strongly supported the hypothesis that vitamin D deficiency is a causal, rather than a bystander factor, in Covid-19 outcomes. Three of the four studies whose findings opposed the hypothesis relied upon disproven assumptions.
The literature review also found that prophylactically correcting possible vitamin D deficiency during the Covid-19 pandemic is extremely safe. Widely recommending 2000IU of vitamin D daily for all populations with limited ability to manufacture vitamin D from the sun has virtually no potential for harm and is reasonably likely to save many lives.


Introduction

Covid-19 was first recognized in December of 2019.1,2 By January of 2020 it was clear the elderly are by far the most likely succumb to Covid-19 pneumonia, which is caused by a “cytokine storm.”3,4 Later, male sex, obesity, and possessing naturally melanin-rich skin while living outside of the tropics came to be known as the highest risk factors after older age.2,5-13 Unlike influenza, children under age ten are almost completely spared in Covid-19.14,15 This unusual risk factor pattern presented a mystery that spawned studies showing that Covid-19 fatalities are especially high in areas with lower levels of sunshine due to latitude or air pollution, except when population vitamin D intake is high.6,7,9,16-21 In fact, the risk groups for severe Covid-19 match the risk groups for vitamin D deficiency exactly, and there is biological plausibility: vitamin D is known to modulate the immune system, helping prevent both an underreaction that allows upper respiratory infections to be contracted, and the over-reaction referred to in Covid-19 as the “cytokine storm” (see Section 3.2) 16,22,23 This review explores the evidence related to the hypothesis that vitamin D deficiency increases both Covid-19 rates and illness severity.

The Vitamin D Debate

Some popular entertainers and bloggers have noted that the top risk groups for severe Covid-19 complications tend to have vitamin D deficiency Table 1.24-26 And, Trinity College Dublin researchers issued a news release urging the Irish government to change their recommendations for vitamin D supplements in light of evidence of an association between vitamin D levels and Covid-19 mortality.27 However, most governments, medical organizations, and key opinion leaders give one or more of these four reasons not to recommend vitamin D supplements: past claims for vitamin D benefits were overstated, evidence for a link to Covid-19 is insufficient, overdoses are theoretically possible, and the public might believe that taking vitamin D supplements will make them “immune” to Covid-19.28-36
Table 1: : Classification of vitamin D levels (serum 25(OH)D levels):9,37-51
Classification Nanograms Nanomoles Recommended D
danger of toxicity > 100 ng/ml* > 250 nmol/l
normal or optimal > 30 ng/ml > 75 nmol/l 400 - 4000 IU/day
insufficient 21 - 29 ng/ml 51 - 74 nmol/l 4000 - 6000 IU/day
deficient 11 - 20 ng/ml 26 - 50 nmol/l 7000IU/day
severely deficient (often not distinguished from deficient) < 10ng/ml 25 nmol/l 10,000 IU/day x 1 month or 500,000IU x 1
   some sources found that 150ng/ml was not harmful

Although the International Association for Gerontology and Geriatrics (IAGG) Asia/Oceania Region Covid-19 Prevention Statement acknowledged that increasing vitamin D levels could reduce infection risks in elderly individuals whose levels are insufficient they recommended only “getting enough sunlight in the morning” without mentioning supplements.52 Two May 2020 Centre for Evidence-Based Medicine rapid reviews concluded, without discussing any of the recent studies, that there is no evidence to support a role for vitamin D in prevention or treatment of Covid-19 or the cytokine storm.29,53 Alarmed by the media response to a literature review suggesting a link between Covid-19 and vitamin D, two Brazilian medical associations jointly published a note stating that vitamin D supplements are only approved for bone health.54-56 The high mortality rates among minorities are providing momentum for various public health program expansions, which could diminish if vitamin D deficiency, rather than access to care and economic disparities, were found to be even a partial explanation.57-60 In addition, previous studies of dubious quality suggesting that vitamin D can “cure” various chronic illnesses and may be influencing the reluctance to recommend supplements for Covid-19.61
However, despite these concerns, former CDC Chief Dr. Tom Frieden recommended sunshine and up to 2000IU/day of vitamin D as a potential preventative for Covid-19, the British Dietetic Association recommended sunshine (or 400IU/day for those are not able to go outside due to self-isolation), and former vitamin D skeptic Dr. JoAnn Manson5s calls for daily vitamin D supplements (1000 - 2000IU/day) during the Covid-19 pandemic - if vitamin D intake is low and going outdoors is not feasible - were published on both Medscape and WebMD.16,62-65 Medscape published a second review of the topic by McCall, in which correcting possible vitamin D deficiency was characterized as “low hanging fruit” that has no downside.66 Mitchell’s brief review (20 May 2020) in a Lancet-affiliated online journal also supported the vitamin D hypothesis.67 Authors of an early meta-analysis of nine studies found that a high percentage of Covid-19 patients are either vitamin D insufficient or deficient, and that countries with lower population vitamin D status have somewhat higher Covid-19 mortality rates and somewhat lower Covid-19 recovery rates.68 In Qatar, vitamin D for prevention of Covid-19 is being proactively delivered to the homes of high-risk diabetics.69

Irish Medical Journal debate on vitamin D supplements during the Covid-19 pandemic

The Irish Medical Journal hosted a six-article formal debate on the topic in response to three published reports, including one by the researchers managing Ireland’s part of the 26-country longitudinal study on aging (TILDA), in their May 2020 issue.70-73 All three reports strongly recommended vitamin D supplements to help protect all adults in Ireland from Covid-19 while they are “cocooning” (not going outdoors).70,71 [details in Appendix ]

Debate over reports using “big data”(the UK Biobank and EPIC in the USA, see Results, 3.4.6)

Three research teams (Hastie, et al., Darling, et al., and Raisi-Estabragh, et al.) relied on the 2006-2010 UK Biobank data for the vitamin D levels included in their analyses of the relationship between Covid-19 incidence and vitamin D status.10,74 Roy, et al., challenged the assertion by Hastie, et al., that vitamin D levels are stable over time (important since levels were assessed 10-14 years prior to the pandemic) noting that the cited study (Meng, et al.) only included women and followed up for only 5 years.10,75,76 In fact, Meng, et al., found that, rather than being stable, the mean 25(OH)D increased significantly (p<0.05) over the five years, and that the increase was driven by significant (p<0.05) increases among participants who were initially at risk for deficiency; supplement intake and overall vitamin D intake increased significantly (p<0.05).75 Etsy criticized Hastie’s UK Biobank study’s assumption that, despite government’s recommendations to supplement,the participants failed to correct any vitamin D deficiency revealed by their participation.77 Darling, et al., cited a different study, Jorde, et al., to support their assertion that vitamin D levels are stable over time.10,74,78 However,the Norwegians Jorde, et al., studied had far higher vitamin D levels than the UK Biobank participants at their initial evaluation, a subset increased their 25(OH)D levels significantly (0<0.001) by initiating supplements, and, as in the study by Meng, et al., vitamin D levels did increase significantly for the group as a whole over time (p<0.01).79 Raisi-Estabragh, et al., did not address the issue of the use of potentially no longer accurate 25(OH)D levels.78
During the time frame of these three studies, Covid-19 testing in the UK was extremely limited (Raisi-Estrabragh, et al., stated that most were tested only if hospitalized).76,78 Such limited testing, Roy asserted, raises the possibility that Hastie, et al., accidentally included Covid-19 positive patients who were only moderately ill in their negative group.76 It is also likely that the studies by Darling, et al., and Raisi-Estabragh, et al., compared Covid-19 patients with patients who had serious illnesses such as influenza pneumonia, rather than with healthy individuals.74,78 If vitamin D deficiency increases viral infection risk and severity as hypothesized, the patients in both arms of these studies could be expected to have higher deficiency and insufficiency rates than the general population. In fact, the research teams found high rates of vitamin D insufficiency and deficiency in both of their study groups.74,78
Roy, et al., Yong, and Etsy all pointed out that the UK Biobank studies failed to address the severity of the Covid-19 the patients experienced, which is critical to the question of whether or not vitamin D deficiency contributes to the potentially fatal cytokine storm.10,74,76—78,80 Boucher cautioned against adjusting data for obesity or dark-skinned ethnicity, providing empirical evidence that both directly lower 25(OH)D.81
Grant and McDonnell formally responded to Hastie, et al., asserting that their multivariable model was over-adjusted because causal factors were treated as confounds, suggesting that the authors provide multiple analyses for transparency, including simple and complex models.82 They also requested that the analysis be stratified by ethnicity, citing a previous study in which low 25(OH)D increased risk for preterm birth equally across ethnicities.82 They echoed Roy’s concern that lack of a positive Covid-19 test result did not assure lack of infection in the UK at the time.82 Grant and McDonnell concluded by pointing out that few UK Biobank participants had 25(OH)D levels in the immune-protective range (>40ng/ml), which would decrease the effect.82
In their response, rather than addressing the question of vitamin D deficiency being caused by old age, disability, obesity, etc., Hastie, et al., stated that 25(OH)D cannot be a mediator because it is not the “cause” of old age, disability, etc.82 They asserted that impaired health is more likely associated with reduced outdoor activity than with vitamin D status.82 They presented the nonsignificant results of an “intermediate” model that still included the deficiency-related variables of age, sex, ethnicity, and obesity, omitting only “health-related covariates” (e.g., BP, diabetes) as proof that inclusion of potential mediators did not influence their initial study results.82 Hastie et al., reiterated that there is no statistical interaction between ethnicity and vitamin D deficiency, a positive Covid-19 test would ascertain more severe infections, and concluded by stating that 40ng/ml is not deficient because in the adult UK population mean 25(OH)D levels are only 17.4ng/ml for men under 65 years and 18.9ng/ml for women under 65 years.82
Although vitamin D levels are not drawn routinely, Fox used data from EPIC, a database with 15,000,000 patients across 26 US states, in his analysis of the relationship between vitamin D status and Covid-19 infection, hospitalization, and mortality rates.83 DeFilipps commented succinctly, pointing out because vitamin D deficiency is ubiquitous, assuming patients with no 25(OH)D in their charts were vitamin D sufficient renders the study results unreliable.84 DeFilipps recommended evaluating only the subgroup who were hospitalized for Covid-19 who had pre-existing conditions and known vitamin D deficiency to determine if there was a relationship between their level of deficiency, illness severity, complications, or length of stay.84

Defining appropriate serum vitamin D levels and appropriate supplementation dosages

The 25(OH)D (serum vitamin D level) is the most reliable indicator of functional vitamin D status, but until recently, the test assays varied.85 However, past research study results can be compared by mathematically harmonizing them, and increasingly, labs are adopting LC/MS (D2+D3) as the standard, increasing consistency.85

Controversy concerning risk of overdose

Food fortification was introduced shortly after the discovery of vitamin D. However, there was a dramatic increase in infants with hypercalcemia in the UK, leading to an abrupt scaling back of fortification.86 Later, a rare genetic defect, Williams-Beuren syndrome, was found to be responsible for the hypercalcemia.86 However, vitamin D toxicity concerns remain heightened, with a reluctance to recommend supplements (Figure 1).
Mean Study Author Support for Supplementation (one Author per Country for each Study)
Dietary sources provide UK adults with only about 100IUs of vitamin D per day.87,88 During the Covid-19 pandemic, after concluding that vitamin D is likely to reduce acute respiratory tract infection risk, and that 10,000IU/day is safe, the NHS paradoxically recommended only 400IU/day “to protect bone and muscle health.”34,88
It is not considered possible to achieve toxic levels via the sun alone, and supplementation for prolonged periods brings 25(OH)D to toxic levels only if the dose is consistently extraordinarily high (40,000IU/day for many months).38,86,89,90 The average naturally acquired 25(OH)D among equatorial tribal groups is 46ng/ml.91 Healthy lifeguards typically have 25(OH)D levels of 100- 125ng/ml.39
The Endocrine Society found toxicity symptoms only at levels above 150ng/ml.91 Toxicity is related to high calcium levels; 25(OH)D levels higher than 150ng/ml in conjunction with high calcium levels produce weakness, GI symptoms and accompanying weight loss, arrhythmias, confusion, and kidney damage.38,86,90 Historically, toxic levels of vitamin D (>150ng/ml) have almost exclusively been the result of industrial errors (inaccurate doses in supplements or fortified foods), and the few cases of toxicity from extremely high doses being intentionally taken for prolonged periods of time (sometimes under the direction of a health care practitioner)
were rarely severe.92,93

Controversy over appropriate 25(OH)D goals

In 2014, Veugelers and Ekwaru asserted that the statistical calculations to determine recommendations for vitamin D were incorrectly interpreted, leading to a US RDA (600IU, or 700IU/day for those over 70) that is off by a factor of more than 10.85,94 Heaney, et al., supported the higher level in a reply, citing a recent supplementation study which supported an RDA closer to 7000IU/day.95 All three groups used the goal of 20ng/ml for musculoskeletal health.85. In contrast, the Endocrine Society, aiming to optimize immune health and other aspects of vitamin D function, recommends adults take in 1500IU - 2000IU per day to maintain a 25(OH)D level of 30ng/ml; 30ng/ml is the NIH target level as well.39,85
Controversies regarding appropriate 25(OH)D, are also informed by studies of parathyroid hormone levels.39 Parathyroid hormone levels were not reduced in participants taking 15,000IU/day, even with 25(OH)D levels above 60ng/dl, in a study with a goal of bringing 25(OH)D levels up to at least 40ng/dl.91 Mean serum calcium levels were not increased from baseline.91 25(OH)D levels of up to 120ng/dl appeared safe, and hypercalcemia and hypercalciuria were least common in participants with the highest 25(OH)D levels (calcium was not supplemented).91 Goal 25(OH)D levels were achieved by 70% of the participants with 6000IU/day for normal weight participants, but 7000IU and 8000IU was required for overweight and obese participants, respectively.91
Growing research suggests that 40-60ng/ml is needed for prevention of respiratory infections, and 50-80ng/ml is required to favorably influence hypertension and cardiovascular disease.38 In a 2019 randomized controlled trial, subjects without deficiency (initial 25(OH)D < 25ng/ml) who took 10,000IU/day for 3 years were slightly less likely to suffer a serious adverse event than those taking 400IU/day.96 Mean 25(OH)D levels in the 400IU/day group did not increase, while 25(OH)D for the 10,000IU/day and 4000IU/day groups rose and then plateaued at 58ng/dl and 53ng/dl, respectively.96

Recommended upper limits of vitamin D supplements in the USA were relaxed after several studies demonstrated that 4000IU of vitamin D daily is safe. , , One review showed that 10,000IU daily seemed to be the upper limit of tolerability.73 The Endocrine Society recommends up to 10,000IU/day, particularly for obese individuals.91,97 However, some study participants have taken 15,000IU to 40,000IU daily for at least 6 months without apparent adverse effects.89
The European Society for Clinical Nutrition and Metabolism recommends a one-time dose of 500,000IU IV for ICU patients who are vitamin D deficient (25(OH)D less than 20ng/ml), based upon evidence that this practice decreases length of stay.9,16,98 Giving 500,000IU enterally over 5 days increased 25(OH)D levels and decreased ICU length of stay, but giving the entire 500,000IU in one bolus enterally did not improve 90-day mortality rates.99,100
Grant, et al. crated a firestorm when his early article positing a relationship between Covid-19 and vitamin D recommended 10,000IU/day for one month, followed by 5000IU/day, with a goal 25(OH)D of 40-60ng/ml.16 Although some other researchers agreed, many were outraged Tables 2 and 3, appendix. Kow, et al., questioned both the dose and the goal, citing a robust study in which supplements decreased the incidence of acute respiratory tract infections only when 25(OH)D levels were less than 10ng/ml, and 800IU/day was sufficient.101,102 Grant, et al., replied with several additional studies to support their recommendation of 40-60ng/ml as a goal, but included an example of significantly decreased incidence of respiratory infections with lesser vitamin D3 doses (although 800IU was inferior to 200IU, it still provided significant benefits over the placebo).103,104
Sharma, et al., reviewed the literature informing decisions about Covid-19 and vitamin D3, finding compelling evidence for 10,000IU/day for a month, followed by 5000IU/day to bring 25(OH)D levels up to the target of 40-60ng/ml, then recommended a more modest 1000- 2000IU/day.105 One group, Quesada-Gomez, et al., posited that vitamin D supplementation should be with oral calcifediol.106 However, by far the majority of researchers and commenters recommend vitamin D3 supplements of 1000IU - 4000IU during “Covid-19 times,” with a goal of achieving 25(OH)D levels of 30ng/ml (see citations for Table 1 and Section 4).107
A meta-analysis of vitamin D supplementation to prevent acute respiratory infections found that daily vitamin D supplementation was safe and provided modest protective benefits, rising to a 70% protective effect when deficiency was corrected. , However, studies also found that large bolus doses are not particularly beneficial.102 Effective study doses of vitamin D were most often in the range of 400 - 2000IU (10 - 50mcg), with the higher doses being given to adults.102 A 2020 study of pregnant women also found that daily supplementation is superior to boluses, that 2000IU/day was sufficient to resolve deficiency over time, and that up to 5000IU/day is safe.109

“Covid-19” is the MeSH term for SARS-CoV-2 disease, coronavirus 2019, Covid-19, and derivative terms. The topic of Covid-19 is a relatively new one, with the first reports published only 6 months ago (January 2020). In addition, because vitamin D supplementation is controversial, publication bias is a significant concern. Consequently, a significant percentage of the pertinent literature is found only on preprint services, most of which are captured by Google Scholar. PubMed casts a wider net than MEDLINE. Therefore, initially, PubMed and Google Scholar were searched for “Covid-19 AND “Vitamin D”” (date range, 2020, omitting citations and patents, no language limitations). Repeated searches confirmed the growing interest in the hypothesis that vitamin D deficiency may play an important role in the Covid-19 pandemic.7’9’16’22’40’108’110—125 From May 2 to May 19, Google Scholar hits increased from 49 to 88 and PubMed hits increased from 17 publications to 32. By June 16, the Google Scholar search retrieved 158 possible references and the PubMed publications on the topic had increased to 69. Using the same search terms, the author also accessed the Royal Society of Medicine Library Discovery Service, which, on 16 June, 2020, provided 144 results from academic journals, reports, magazines, and electronic resources.
Duplicates were deleted and full texts obtained for every publication from all three sources as of June 16, 2020, references were scanned for additional sources, and appropriate articles found on ResearchGate and through other internet sources were added to capture how the topic is being addressed in the popular press. Authors of perspectives and studies on this topic span the globe (Figure 2a & b). Most of the research publications are quite brief , and many of the PubMed indexed articles are expert summaries of relevant data supporting the biological plausibility of the hypothesis, rather than reports of original research. Therefore, the author deemed it premature to limit this review to the “best evidence” as one would do in a formal systematic review of the literature. Rather, every publication discussing vitamin D with respect to Covid-19 found by the three formal searches as of June 16, 2020 is included in Table 2 (Original Research, n=47) or Table 3 (Plausibility and In Vitro Studies, n=141). All original research studies (excepting in vitro) are summarized in the Results (Section 3). However, due to space limitations, while many of the Table 3 documents are cited, few are summarized individually.

Results of Searches

Planned Clinical Trials

Formal clinical trials that include Covid-19 and vitamin D (including 16 on clinicaltrials.gov) include: vitamin D boluses plus other medications for Covid-19 positive patients, boluses or moderate daily doses to prevent severe complications in at-risk populations, low-dose vitamin D as a placebo in a drug trial, genetic variant studies focused upon the interaction between vitamin D and Covid-19, and studies of vitamin D levels in patients with differing severities of Covid-19 illness.29,126-143 As late as May 19, 2019, few studies had begun recruiting. Although most of these studies are not designed to determine if daily modest vitamin D supplementation decreases either the risk of contracting Covid-19 or its severity, Dr. Manson plans to test this hypothesis.64
Testing the hypothesis that vitamin D deficiency prior to contracting the virus increases Covid- 19 rates and severity necessitates screening participants for deficiency at enrollment. Failing to correct a deficiency being considered as a potentially significant risk factor for fatal Covid-19 complications would be unethical.144 Therefore, before and after population study designs (recommending supplements to groups known to be vitamin D deficient and observing if the groups’ fatality rates decline) might be more feasible than randomized controlled trials.144

Biological Plausibility Discussions

Many of the reports examining the relationship between vitamin D and Covid-19 present biological plausibility arguments. These reports are summarized in both Table 2 and Table 3. The main arguments are presented concisely here, citing both Covid-19 specific and primary sources.

Vitamin D enhances resistance to viral illnesses

Early studies of vitamin D supplementation for acute respiratory tract infections produced conflicting results.38,102 Most studies of vitamin D for influenza prevention were conducted on healthy populations with high baseline levels, rather than on the deficient populations who would benefit most.16’41’119’123’145 Despite this, some found that higher 25(OH)D linearly enhance the innate immune response to acute winter respiratory infections, halving the incidence and significantly reducing the duration of illness.42’146’147
In 2017’ 25 international researchers from 23 institutions performed a meta-analysis of individual participant data from 25 high-quality randomized controlled trials of vitamin D supplementation to prevent acute respiratory tract infections to determine why the results were inconsistent.102 They found that bolus doses were not consistently protective’ even in severely vitamin D deficient populations.102 Removing bolus-dose data led to consistent findings of benefit’ regardless of initial vitamin D status.102 Daily or weekly vitamin D supplementation was most beneficial for participants with baseline 25(OH)D <10ng/ml (severe deficiency)’ providing more statistically significant (p<0.001) protection than the (p<0.02) protection vitamin D provided less deficient participants.102 The authors found that response to vitamin D supplementation is so variable that studies should base findings on changes in 25(OH)D levels’ rather than relying upon the vitamin D dose given to each participant.41’102 They also found that vitamin D supplementation is extremely safe: even large doses did not increase risk of serious adverse events’ such as renal stones.102
Historical data provides modest support for the hypothesis that populations with high vitamin D deficiency rates allow new pandemic viral strains to propagate more freely. The only recorded time period void of new strains of pandemic influenza is 1920 - 1957’ and vitamin D food supplementation was most prevalent during the middle of that time period: from 1930 to 1950.61 The Covid-19 pandemic began in Wuhan during a particularly dark January: 42% darker than their average January in 13 years (2007 - 2020).148
Several studies have shown that vitamin D decreases the severity of dengue fever.149 Oral vitamin D supplements of 4000IU for 10 days were significantly more effective than 1000IU in reducing dengue virus replication and controlling the damaging cytokine hyper-reaction.149-152 Vitamin D supplementation also reduced rotavirus replication in pigs.152 A recent review article by Sharma’ et al.’ summarized biological plausibility arguments and found that vitamin D deficiency is associated with a wide range of viral illnesses’ and that vitamin D supplementation was both preventative and decreased severity’ limiting hyper-inflammatory complications.105
In the lungs’ formation of the peptide LL37’ an innate immune system component that’ among other things’ attacks enveloped viruses such as SARS-CoV-2 and modulates the immune system’ 38 43 115 153 requires sufficient vitamin D levels. ’ ’ ’ LL37 is inhibited by carbon and other nanoparticles in air pollution.43 Therefore, vitamin D deficient individuals can be expected to be at increased risk of both developing Covid-19 and experiencing the “cytokine storm” if they become infected, particularly in areas of the world with high levels of air pollution.43,115

How vitamin D may decrease serious Covid-19-associated complications

During the “Spanish flu” pandemic of 1918-1919, deaths were substantially reduced when patients were treated in “open air” hospitals with access to sunlight, perhaps due to vitamin D5s “cytokine storm” suppression.61,148,154 In the deep south, dramatically increased incidence of pneumonia led to much higher Spanish flu case fatality rates for African Americans than for whites.16 Covid-19 usually produces mild symptoms in the seemingly-vulnerable homeless, who are disproportionately outdoors, despite the population skew towards older males and African Americans.155-157 Prior to antibiotics, successful treatments for tuberculosis were cod liver oil, UVB phototherapy, and sunshine: all vitamin D sources.97
Vitamin D enhances the innate immune response while, paradoxically, protecting against inappropriate prolonged inflammation by suppressing TNFa and the cytokines (e.g. IL-6, IL-17) implicated in severe Covid-19, and elevating anti-inflammatory IL-10.16’29’38’42’44’89’147’158—167 Many of the articles referenced here include detailed descriptions of the role of vitamin D in preventing a “cytokine storm” and several authors, including Meftahi, et al., and Biesalski, added a series of cartoons to their papers to simplify the concept.165,166
Given that vitamin D decreases pro-inflammatory IL-6 and that IL-6 is implicated in the Covid- 19 “cytokine storm,”168 and finding that mean IL-6 levels are higher in males and African Americans and increase with age and obesity (groups with increased risk for Covid-19 mortality), Silberstein went on to evaluate the possibility that vitamin D deficiency causes upregulation of IL-in high risk individuals prior to exposure to Covid-19, increasing their likelihood of developing fatal Covid-19 complications.169 Using detailed IL-6 data from Tuscany, Italy, Silberstein found a strong correlation between age stratified Covid-19 deaths in Italy and mean IL-6 levels (r(6)=0.9837, p=0.00025).169 Data for a similarly detailed analysis for sex, obesity, and ethnicity was not available.169 The authors note that IL-6 is generally low in children, but it is high for a brief time in early childhood, which could explain the Kawasaki-like Covid-19 sequela in some children.169 Intense exercise can cause dramatic increases in IL-6, which could explain the paradoxical severity of Covid-19 infection in athletes.169 They suggest vitamin D supplements for all to decrease pre-existing pro-inflammatory states.169
Vitamin D also helps prevent viral infections from progressing to pneumonia by tightening cell junctions. 16,38,163,170 And, vitamin D's influence on the coagulation pathway decreases risk of acute respiratory distress syndrome as it decreases thrombosis risks.112,125,155,160,167,171 Therefore, correcting vitamin D deficiency might help prevent Covid-19 illness AND help limit complications when prevention is unsuccessful.22,38,112,167
Daneshkhah, et al., proposed that Vitamin D deficiency causes C-reaction protein (CRP) levels to rise, thus increasing the likelihood of a cytokine storm.172 The authors found that CRP and vitamin D status are inversely related in healthy individuals.172 CRP levels were increased in severe Covid-19 patients, but because CRP is a marker for inflammation, it was unclear if this was a cause or an effect.172 The authors used population data from 10 countries to show a possible link between vitamin D status and the adaptive average case mortality ratio.172 A great deal of information was presented in support of the hypothesis.172 The authors proposed further studies to determine if Covid-19 patients with high CRP are deficient in vitamin D.172

Risk for Severe Covid-19 Parallels Risk for Vitamin D Deficiency

Many authors, some with compelling statistical analyses, propose vitamin D deficiency from low sunlight levels (Nordic countries have high vitamin D intake) to explain the geographic distribution of severe Covid-19.6’7’23’45’110’120’148 Italy and Spain have very high vitamin D deficiency rates.9’37’45’61’120’173 First-generation non-Western immigrants, even in countries with low overall rates’ are often vitamin D deficient.174-176 Vitamin D deficiency is especially common in the elderly, in part because synthesis from sunlight is muted in old age.16’42’45’114’120’177-180. Naturally melanin-rich skin increases vitamin D deficiency risks’ particularly in high latitudes.10’45’110’114’120’146’179 It takes five times as much sunlight exposure for someone with dark skin to attain the benefits that someone with lighter skin receives.11 Lower 25(OH)D is associated with diabetes’ hypertension’ cardiovascular disease’ and COPD risk.16’22’42’45’181 Dialysis patients are often severely vitamin D deficient.182 Up to 50% of US nursing home patients’ and 75% of institutionalized people in general’ are vitamin D deficient.120’180’183
The UK5s low sunlight levels could explain why health workers with naturally melanin-rich skin (mostly nurses and physicians) are so disproportionately represented on the Telegraph’s tribute wall.184’185 The only postpartum Covid-19 fatality in the UK was a vitamin D deficient diabetic Pakistani woman who suffered a thrombotic complication.186
Current increased “stay at home” regulations and increased boredom and stress can be expected to result in eating patterns which increase obesity and the comorbidities with which it is associated.187 In part because vitamin D is fat-soluble’ obese individuals have increased daily vitamin D intake requirements and are often deficient. ’’’’’ ’ In addition’ vitamin D deficiency causes the body to store more fat by increasing parathyroid hormone levels.190 Obesity is a major risk factor for fatal Covid-19 complications’ particularly in younger adults.45’188 Ekiz’ et al.’ found that increasing vitamin D levels makes it easier to lose excess weight’ which could lower individual Covid-19 risk.190 Increasing milk intake could help decrease stress eating by increasing tryptophan’ and could help improve immune function.187
Recent studies in Ireland and Switzerland both found that older males are at even higher risk of vitamin D deficiency than older females.70’122 Vitamin D deficiency increases the X-chromosome linked ‘Renin-Angiotensin’ System (RAS) activity, making men more susceptible to ACE2 receptor dysregulation and theoretically’ to increased Covid-19 morbidity.22’44’121’163’191’192 Although vitamin D deficiency is not universal in severe Covid-19’ every deleterious symptom can be explained by RAS over-reaction’ which would occur more easily in individuals without sufficient vitamin D to control the RAS.22’124’163’181

Evidence Informing the Hypotheses that Vitamin D Deficiency Influences Covid-19

While data from randomized controlled trials is superior, the hypothesis that vitamin D deficiency is a major contributor in Covid-19 risk and severity is already supported by twenty population-data analyses, both causal inference modeling reports, four case studies/series, one prospective correlational study, one case control study, one cohort observational study, and ten retrospective chart reviews.. One population-data analysis and three retrospective chart reviews supported the dissenting view. One population-data analysis, one retrospective chart review, and the lone systematic review were neutral. Recognizing that truth is not exposed by the mere tallying of positions, but rather, by evaluating the specifics of the data and the strength of the study designs, all 47 studies are summarized here and in Table 2.

Analyses of population data

Backer asked whether temperature or radiance could explain the speed and level of geographic spread of Covid-19.148 Every location with over 2000 cases by March 15, 2020 had an average temperature of 10°C or lower.148 And, over a longer time period, locations with 4-week temperature averages under 14°C when they reached 100 cases all had faster growth than any of the warmer locations (p=0.0001).148 The same analysis using deaths instead of cases yielded a similar negative correlation (p<0.02).148 However, Finland, Norway, and Russia, all reaching 2000 cases after March 15, did not conform to the pattern, leading to a study of sunlight.148 Indeed, irradiance and cloudopacity better accounted for all the of data (p<0.01).148 Increased cloudiness and air pollution can explain why in Korea, Daegu had ten times as many cases of Covid-19 as more internationally-connected Seoul, and in Italy, Lombardy had over ten times as many cases as more internationally-connected Lazio (Rome).148 Multivariate regression found that the best independent predictor of Covid-19 case (p<0.001) and death (p<0.001) growth rates was the average zenith (most direct sun rays) when the location reached its 100th case.148 Zenith, correlated with both irradiation (p<0.01) and temperature (p<0.001), explained the lower growth rate in Finland, Norway, and Russia, and fully accounted for the variance from both.148 No association with increased travel or visiting was found.148 Backer concluded that sunlight leads to less Covid-19 transmission, likely due to both the direct result of irradiation and increased vitamin D, and thus, advising people to stay indoors rather than opening up outdoor recreation areas during the Covid-19 pandemic appears to be a poor choice.148 Rather, people should spend this coming winter in areas of their countries with more direct overhead sunshine.148
In contrast, Yao, et al., found no association between Covid-19 transmission rates and temperature or UV radiation across the 62 cities (of 224) in China with at least 50 cases at the peak of the outbreak (10 Feb) and at least 10 cases remaining on 9 March.193 However, the authors note that their study examined data from early January to early March, 2020, a time during which strict travel restrictions were put into place to prevent Covid-19 transmission in China.193,194 It is possible that many of the cities in which UV light or temperature effectively reduced transmission were eliminated from the study because they no longer had the minimum of 10 cases by 9 March.
Two statistical analyses of geographical areas in the USA addressed the question of whether high Covid-19 fatality rates in African Americans could be explained by income levels.11,195 Backer’s initial statistical analysis from 8 cities and states that provide a racial breakdown of Covid-19
victims found that race-based fatality rate differences diminish in direct proportion to available sunlight, with Covid-19 deaths among blacks in Detroit at 193% higher than the percent-black area population, but only 7% higher in Florida (Pearson -0.76, p<0.05).11 African Americans comprise 26% of Milwaukee County,s population, half of their Covid-19 cases, and 81% of its deaths.11 This led to an exploration of the hypothesis that rather than socioeconomics (lower incomes, jobs that do not permit social distancing) being solely responsible, irradiance may play a large role in the disproportionate Covid-19 morbidity and mortality rates among African Americans in the USA.11 In Michigan, the state with the highest racial disparity in Covid-19 deaths, a county-by-county analysis showed that percent African American, but not percent over 65 years, median income, median age, or number of people per household, significantly (p<0.05) correlated with Covid-19 morbidity.11
Similarly, Li, et al., focused on US counties with at least 50 Covid-19 cases (661 counties) and those with at least 10 deaths (221 counties), grouping them into quartiles and comparing highest to lowest.195 Multivariate analysis demonstrated that “percent black” predicted county cases and fatalities, even after controlling for other demographics, socioeconomics, and comorbidities.195 Higher daily temperatures decreased county case numbers, but not mortality rate.195 They proposed vitamin D deficiency among black Americans as a “unifying theory” to explain their results.195 The team’s institution went on to conduct a retrospective review of vitamin D in Covid-19 patients.195
Laird, et al., plotted Covid-19 mortality/million against mean 25(OH)D levels for twelve European countries, finding a significant correlation (p=0.046).37 Panarese and Shahini ranked the 108 countries with at least 100 Covid-19 cases on 2 April 2020 by latitude, demonstrating visually that, overall, deaths per million were higher in the northern-most countries, whose citizens would be the most likely to be vitamin D deficient from the dark winter.196 Following up on Panarese and Shahini’s work, Rhodes, et al., compared the 120 countries with more than 150 Covid-19 cases by 15 April 2020, finding that Covid-19 mortality rates were significantly correlated with latitude (r=0.53, p<0.0001)23 Rhodes, et al., used a simple scatter-graph to illustrate that the Covid-19 mortality rates per million population were dramatically lower in countries with capitals south of 35°N, where sunshine in the time immediately preceding the pandemic made maintaining vitamin D levels possible.23
Ilie, et al., reported a significant correlation between low mean vitamin D levels across 20 European countries and both Covid-19 fatalities/million population (p=0.05) and Covid-19 cases/million population (p=0.050).120 Kumar and Srivastava protested against the study by Ilie, et al., stating that the correlation was being stretched by the media to claim that vitamin D supplements may reduce Covid-19 mortality rates by 50%.197 Purportedly concerned that this exaggerated claim would lead to fatal overdoses, the authors conducted a statistical analysis of Covid-19 case and death rates and life expectancy using the data from Ilie, et al. ’ The authors asserted that because vitamin D deficiency increases with age, controlling for life expectancy would reveal the true relationship between vitamin D and Covid-19 infection and fatality rates.197 The researchers found that life expectancy was a better predictor of both Covid-19 mortality and case rates than vitamin D. The authors called for clinical trials of vitamin D supplements.
Citing Ilie, et al., Singh, et al., compared mean 25(OH)D levels and Covid-19 cases and deaths per million population for 20 European countries on 8 April and again on 12 May.198 The significance of the inverse correlation between vitamin D and case rates increased from p=0.0501 in April to p=0.0119 in May.198 However, the inverse correlation for death rates decreased from p=0.0535 to p=0.0860.198 Singh, et al., did not discuss the possibility that vitamin D levels increased between April and May as sunshine increased, potentially protecting patients from the “cytokine storm.,,198
Notari and TorrierTs much larger,more detailed, comprehensive 126 country data review found that most of the 24 identified potential risk factors for Covid-19 propagation, including blood type, life expectancy, and even greeting habits, were significantly correlated with one another.199 Prevalence of Type-I diabetes,BCG vaccination,and vitamin D levels were the only “almost independent factors.”199 In the 42-country subset with vitamin D data and high GDP, lower mean annual levels of vitamin D were linearly related to increased Covid-19 risk (p=0.006), with seasonal values (March) demonstrating even more significance (p=0.002).199
Kara, et al., mapped the population prevalence of vitamin D deficiency (<20ng/ml) and severe deficiency (<10ng/ml) against Covid-19 total fatalities for the 40 most affected countries, worldwide, finding a clear relationship.45 Regression analyses demonstrated a quadratic relationship between prevalence of vitamin D deficiency and insufficiency and Covid-19 cases.45 A histogram with regression lines illustrated the relationship between latitude, population vitamin D status, and country rank (by number of cases).45 Finding vitamin D deficiency and Covid-19 to be related pandemics, they agreed with Grant, et al., in recommending vitamin D (without high calcium) supplementation, as well as encouraging fortified food intake and increased sun (UVB) exposure.45
Braiman noted that as of March 22, 2020, although 10% of the Covid-19 cases lived south of the Tropic of Cancer, they represented only 1% of the fatalities.144 The three exceptions could all be explained by mean population vitamin D levels.144 Nordic countries have vitamin D deficiency rates below 1% (due to diet or supplementation) and impressively low Covid-19 fatality rates, except Sweden.144,200 In Stockholm, severe vitamin D deficiency is common among displaced Somalis, who with less than 1% of the population have suffered 40% of the Covid-19 fatalities.7,176,201 Indonesia straddles the equator, but its predominately Muslim women have vitamin D levels that are only half that of notoriously low Italy.144 Sunscreen use is popular in the Philippines, which may account for the high levels of vitamin D deficiency there.144 Braiman recommended ethical testing of the hypothesis that vitamin D and Covid-19 outcomes are related by encouraging supplementation in deficient populations and evaluating death rate changes.144
Although Latinos and African Americans were found to be at higher risk of Covid-19 mortality in New York City, it is difficult to determine the influence of Latino ethnicity versus race (over 75% of Latinos identify as non-white), because New York City does not provide sufficiently detailed data.202 In contrast, Georgia does break down Covid-19 data by both ethnicity and race.202 Black Latino Covid-19 morbidity was 123% higher than white Latino morbidity (p<0.001),supporting researcher Backer5s hypothesis that a darker complexion decreases sun exposure benefits.202 Covid-19 morbidity is 37% higher for white non-Latinos than for white Latinos (p<0.0001), 689% higher for Native American non-Latinos than for their Latino counterparts (p<0.01), and there were no cases of Covid-19 among Latino Asians.202 Latinos spend more time outdoors than any other racial group (85% more than African Americans) which could explain why Latinos defied externally-imposed racial disparity explanations.202The author concluded that irradiance exposure seems to help prevent Covid-19.202
Countries with higher rates of vitamin D-rich sea fish consumption or food supplementation have lower Covid-19 mortality rates than adjacent countries.180 The elderly, especially in nursing homes, where 84 - 93% of residents in the US are vitamin D insufficient, are at highest risk for severe Covid-19.180 Backer and Mageswaran evaluated vitamin D deficiency rates among elderly females and Covid-19 deaths prior to May 31st in 32 countries, finding that case fatality rates were up to twice as high in countries with high vitamin D deficiency rates (p<0.04).180 They also found that case fatality rates were significantly higher (p<0.026) in countries with a high percentage of black inhabitants.180 Noting many biological plausibility arguments and vitamin D deficiency and insufficiency race disparities, the authors recommend Covid-19 prevention and treatment studies.180
Li, et al., used machine learning to produce logistic models to predict case rates, death rates, and case fatality rates in all 50 US states and 154 countries listed on the Johns Hopkins Covid-19 dashboard on 15 May 2020, assessing the interdependence of the 57 factors LASSO identified as potentially influencing Covid-19 outcomes.203 Among their many findings, Lee, et al., determined that higher population vitamin D intake is an independent factor in reduced Covid-19 cases.
Kohlmieir performed a Mendelian randomization to test the effect of latitude (a proxy for vitamin D) on rates of African American Covid-19 deaths in the 22 reporting states with more than 15 African American deaths as of 16 April 2020, finding a strong relationship (r=0.427).204 A correlational analysis found that excess mortality rates were significantly higher (r=0.435, p=0.02) in states with higher latitudes.204 The highest excess mortality rates were all in states near or above 40° N, where UVB intensity in winter and spring is too low to provide vitamin D.204 The African American fatality over-representation was 5.6-fold in Wisconsin compared with 1.3-fold in Florida.204
Adding the proposed relationship between latitude and Covid-19 to knowledge that ozone filters the ultraviolet-B radiation the body requires to produce vitamin D, Alipio evaluated data from all 34 countries with April 2019 ozone data available on an open-access database.205 Kendall rank correlation test found that ozone concentration significantly (P<0.001) positive correlated with Covid-19 cases, but latitude and Covid-19 cases appeared to have no relationship.205
Recognizing the advantages of comparing cities within a single country with varied UV radiation, altitude, and weather patterns, such as consistent policies, culture, and genetic factors, Skutsch, et al., conducted a multiple regression analysis of data from 45 cities in Mexico, comparing the rate of increase in cumulative Covid-19 cases and fatalities.206 Despite extremely high Covid-19 population vulnerability rates, as of 3 May there had been only 3332 Covid-19 deaths and hospitals had not been overwhelmed.206 Even as late as 14 May, only hospitals in Mexico City were full; infection rates were increasing at a slower rate in Mexico than in many
other countries.206 Data from January was included because, while UV light’s sterilization effect would be immediate, physiologic vitamin D formation precedes its impact on infection and mortality rates.206 Skutsch, et al., found a negative relationship between rate of transmission and altitude (r=-0.354, p=0.014), but temperature, relative humidity, and latitude were insignificant.206 UV levels in January correlated a bit more strongly with transmission rates (r=- 0.369, p=0.014) than UV levels during the transmission period (r=-0.32, p=0.032), supporting the hypothesis that the influence of UV is due to vitamin D rather than sterilization.206 In contrast, UV was only marginally associated with rates of mortalities.206 Mexico City’s air pollution may have explained this.206 Surprisingly, altitude and UV levels were not significantly interrelated, but their combined effect accounted for 18% of transmission rate variation (p=0.0062).206 Data for 834 individuals scattered across 561 municipalities showed that lower altitude is a highly significant (r=-0.35, p=0.0005) predictor of vitamin D levels, perhaps influenced by the high levels of UV light in coastal cities and the cooler climate of higher altitude cities leading to more clothing coverage.206
Noting that all five US states with fatalities greater than 5000 and four of the five states with cases over 90,000 are in latitudes above 37°N, Li, et al., used latitude as an indicator to evaluate the relationship between sunlight, vitamin D, and Covid-19 case and death rates per 1000,000 population.207 Aggregate data (22 Jan - 23 May 2020) showed that states in latitudes above 37°N, when compared with states at lower latitudes, had significantly higher case rates (702 vs 255/100K) and death rates (43 vs 11 deaths/100K) (p<0.001).207 The higher case rates were not attributable to higher test rates.207 The authors suggested sunlight and vitamin D as the explanation, calling for studies to evaluate the impact of vitamin D on the prevention of Covid- 19.207
In a less detailed study, Marik, et al., evaluated the case fatality rates for all 50 US States, mapping the results to illustrate that, with the exception of states with very low population densities and Louisiana, case fatality rates increased with increasing latitude.208 The cumulative summary case fatality rate for states over 40°N was significantly higher than for states below 40°N (6.0% vs 3.5%, p<0.001).208 Attributing the differences to vitamin D’s dampening of excessive inflammation, they advocated for standard vitamin D supplement doses and further studies.208
Moozhipurath, et al., obtained UVB radiation data for 108 days (through 8 May 2020) in the 152 countries with more than 20 Covid-19 cases, beginning when the country had over 20 cases, analyzing the relationship between daily UV index (UVI - a surrogate for UVB), Covid-19 deaths, and Covid-19 cases, controlling for weather variables, including ozone levels.21 UVI increase was associated with a 1.2% decrease in the daily growth rate of cumulative Covid-19 deaths (p<0.01) and a 1.0% decrease in the daily growth rate of cumulative Covid-19 case fatality rates (p<0.05).21 The authors asserted that their methods led to very conservative estimates of the effect of UVB on Covid-19 deaths, and advocated for “sensible” increased exposure to sunlight, particularly for people at high risk of vitamin D deficiency.21
A statistical analysis by Davies, et al., found that Covid-19 outbreaks with large fatality rates occurred exclusively above 30°N, with a 55:1 ratio between 30°N - 55°N and more southern latitudes.61 The Epidemic Severity Index was greater than 2.5 in nine of 239 locations, all above 30°N.61 Northern outliers all had higher vitamin D population levels, southern countries with the most severe outbreaks (Philippines and Brazil) have a high vitamin D deficiency prevalence, and fatality rates are doubled by naturally melanin-rich skin in the USA and UK.61 Iran, where religious full-body clothing is worn and vitamin D deficiency is common, fared far worse than Israel, whose vitamin D deficiency prevalence is relatively low.61

Causal inference modeling reports

Davies, et al., also analyzed three potential root causes for their influence on Covid-19 outcomes, categorizing factors as lowering vitamin D, negatively influenced by low vitamin D, or vitamin D neutral.61 Environmental conditions hostile to the virus and environmental measures (e.g., distancing) decrease Covid-19 spread, but do not influence case fatality rates.61 If vitamin D is a “bystander” variable (simply a marker of bad health), case fatality rates would correlate best with vitamin D-neutral comorbidities.61 The authors provide a detailed analysis of the known Covid- 19 epidemiological, latitude, and environmental data.61 A table illustrates that 16 predictions of the causal model accurately match the known facts, while 14 predictions of the bystander model strongly contradict the data and two more are not supported.61 The remaining three predictions for each model could not be determined.61 The analysis strongly supports the hypothesis Figure 3.61
Annweiler, et al.,used Hill’s methodology for determining causality, which states that the more of the seven criteria are met, the stronger the claim, to evaluate the hypothesis that vitamin D is causally linked to Covid-19 outcomes.209 Vitamin D met six of the criteria, failing only on specificity (because vitamin D deficiency is high in the general population).209 Concluding that vitamin D deficiency is highly likely to be a cause of poor Covid-19 outcomes, the authors suggest that these results, coupled with the excellent safety profile of vitamin D and lack of other treatments, support testing vitamin D as an adjuvant treatment and prophylaxis for the general population.209

Case Studies and Case Series in which vitamin D is mentioned

Ahmed, et al., reported that a Covid-19 positive maternity patient with diabetic ketoacidosis, vitamin D deficiency, and a history of asthma developed a fatal thrombosis four days post extubation.186 Horowitz, et al., reported on two Covid-19 pneumonia patients with histories of immunosuppression from Lyme disease who responded to repeated doses of glutathione, along with a multitude of other drugs and remedies. One had a history of low vitamin D. Bossoni, et al., reported on a 72-year-old thyroidectomized Covid-19 positive patient who experienced sudden onset severe hypocalcemia.211 Her parathyroid level was low, and she was extremely vitamin D deficient (8ng/ml).211 Bossoni, et al., noted that home confinement can worsen vitamin D deficiency, increasing the risk of systemic infections and potentially life-threatening hypocalcemia.211
Vitamin D deficiency is common in Indonesia, affecting 35.1% of elderly institutionalized women and 23% of the general population.212 Pinzon, et al., tested ten PCR-positive Covid-19 patients in Indonesia, finding that nine were vitamin D deficient (25(OH)D <10ng/ml) and the remaining patient was insufficient (25(OH)D=20.5).212 Finding no clinical evidence to inform the decision to provide vitamin D supplements to prevent or treat Covid-19 in their review of the literature, they called for randomized controlled trials and now prescribe all patients 2000IU/day.212

Prospective correlational study, case-controlled survey, and cohort observational study

Vitamin D deficiency is common among Irish males (median 25(OH)D of 18.8 ng/ml for ages 40 -60).213 Faul, et al., drew 25(OH)D in 33 Covid-19 positive Caucasian males over the age of 40 who were admitted to the hospital in respiratory failure without cancer, diabetes, cardiovascular disease, or chronic immunosuppressant intake in Ireland in March of 2020.213 The twelve requiring mechanical ventilation (including all four fatalities) had mean serum 25(OH)D levels of 10.8 ng/ml, compared with 16.4 ng/ml for those requiring only oxygen (p=0.03).213. Patients with 25(OH)D <12 ng/ml had a hazard ratio for requiring ventilator care of 3.19 (p=0.03).213 The authors concluded that low vitamin D is either a marker for poor health, or it permits pro- inflammatory changes that lead to severe Covid-19: “a thought worthy of further study.”213
Concerned about the effects of Covid-19 on their community-dwelling Parkinson5 s Disease patients in Lombardy, Italy, Fasano, et al., conducted telephone interviews with 1486 patients and 1207 family-member case controls.214 The 105 Parkinson’s patients with Covid-19 and 92 family members with Covid-19 differed only in decreased shortness of breath (p=0.004) and decreased hospitalization rates (p=0.018) for the Parkinson’s patients.214 The authors adjusted the data for the age differences between groups, thought to be due to aggressive protective measures for the elderly in the area.214 Parkinson’s, hypertension, and COPD medications did not influence the likelihood of developing Covid-19, while Vitamin D supplementation was protective (p=0.048).
Tan, et al., compared the 26 consecutive patients 50 years or older not requiring oxygen on admission who were hospitalized immediately prior to initiation of a daily oral combination of 1000IU vitamin D3, 150mg magnesium, and 500mcg vitamin B12 with the next 17 consecutive patients meeting the same criteria to determine if these supplements altered oxygen or intensive care support needs.215 Remarkably, of the 9 patients supplemented within a week of symptom onset, only one required oxygen, and that was within 24 hours of supplement initiation.215 Of the 8 patients supplemented over a week after symptom onset, one required ICU care within 24 hours of supplement initiation, and one required oxygen three days later.215 Of the 16 control group patients requiring oxygen, 8 progressed to requiring ICU care.215 Supplementation reduced the need for any oxygen (17.6% vs 61.5%, p=0.006) and for ICU care (5.9% vs 30.8%).215

Retrospective chart reviews favoring the hypothesis

Alipio performed a chart review using de-identified data from 212 Covid-19 patients with recorded pre-Covid-19 25(OH)D levels from three hospitals in Southern Asia in which 25(OH)D was tested initially and weekly.40 Individuals’ 25(OH)D levels did not vary significantly during hospitalization, confirming that battling Covid-19 does not, in and of itself, deplete vitamin D40 Vitamin D status (3 categories: >30ng/ml, 21-29ng/ml, or <20ng/ml) correlated significantly and linearly with more critical Covid-19 illness (4 levels clearly defined by previous researchers).40 For each standard deviation increase in serum 25(OH)D, the odds of having a mild, rather than a critical, case of Covid-19 were almost 20 times as great (OR=0.051, p<0.001).40 [Figure 4]
A statistical analysis by D’Avolio, et al.,of records in a Swiss clinic’s database for 107 symptomatic individuals obtaining a SARS-CoV-2 PCR test found that the 27 PCR-positive patients had significantly lower (p = 0.004) 25(OH)D (11.1ng/ml) when compared with testnegative subjects (24.6 ng/ml).122 PCR-positive patients were 70.4% male, while PCR-negative patients were only 48.8% male, with similar ages.122 Differences between 2019 median 25(OH)D verses PCR-positive 2020 median 25(OH)D were significant for both women (25.6ng/ml vs. 9.3ng/ml, p = 0.019) and men (22.9ng/ml vs. 11.4ng/ml, p = 0.005), but not for PCR-negative for either gender [Figure 5].122
Lau, et al., found that among all 20 Covid-19 patients with recorded 25(OH)D at a New Orleans hospital, every ICU patient under age 75 had vitamin D insufficiency.155 Eleven of 13 ICU patients had vitamin D insufficiency verses 4 of 7 patients with milder Covid-19.155 Seven ICU patients had critically low 25(OH)D (<20ng/mL) and three had levels below 10ng/mL).155 Patients with the lowest 25(OH)D levels were African American Figure 6.155
In Jakarta, Indonesia, hospitals are designed to provide patients sunlight and home patients exercise outdoors.216 In this setting, daily minutes of sunshine were compared with patient recovery, death rates, and incidence.216 Asary and Veruswati found sunshine was not related to prevention, but Covid-19 patient recovery briskness was significantly (Spearmen’s a = 0.05) correlated with sunnier days.216

Noticing that critically ill Covid-19 patients in a hospital in Wuhan, China, tended to be severely hypocalcemic, Sun, et al., conducted a 241 patient retrospective chart review, using standardized definitions of mild, moderate, severe, and critical Covid-19. 217 On admission, 74.7% of patients were hypocalcemic.217 Noting that vitamin D deficiency can cause hypocalcemia, they found a median 25(OH)D of 10.20ng/ml (severe deficiency) among the 26 patients tested; none were vitamin D sufficient.217 These 26 patients had worse CRP (p<0.001), D-dimer (p<0.001), and parathyroid hormone (p=0.048) levels.217 Calcium levels positively correlated with 25(OH)D levels (p = 0.004), and lower calcium levels correlated linearly with lower SpO2 levels (p<0.001), higher complication rates (p<0.001), and higher 28-day mortality rates (p<0.001).217 Vitamin D deficiency and hypoproteinemia were associated with increased mortality in critically ill patients.217
Cunat, et al., found that although recommended for all ICU patients, vitamin D was tested in only 17 of the 226 consecutive Covid-19 patients admitted to their hospital in Spain.218 All 17 were vitamin D deficient (25(OH)D <20ng/ml), 13 had <12.5ng/ml, and three had <5ng/ml.218 Of these 17 patients, 35.2% had hypocalcemia and 64.7% had hypophosphatemia.218 The incidence of nosocomial infections was very high (76.5%).218 The authors stated that vitamin D deficiency is especially problematic for Covid-19 ICU patients because vitamin D reduces pro- inflammatory and increases anti-inflammatory cytokines.218
Raharusuna, et al., conducted a retrospective chart review of 780 hospitalized test-confirmed Covid-19 patients in Indonesia.46 After controlling for age, sex, and comorbidity, both insufficient (odds ratio 7.63) and deficient vitamin D (odds ratio 10.12) were significantly associated with Covid-19 mortality (p<0.001 for each).46 Fatalities were 4.1% in patients with normal 25(OH)D, 87.8% with insufficiency, and 98.9% with deficiency.46
In India, Glicio, et al., performed a statistical analysis on the data from the 176 Covid-19 patients 60 years or older in two tertiary medical centers whose medical records included body mass index (BMI), sex, comorbidities, clinical characteristics, and pre-hospitalization 25(OH)D.47 Over 80% were vitamin D insufficient or deficient, and of those, 72% were male.47 Inadequate 25(OH)D was strongly associated with chronic kidney disease, hypertension, and diabetes.47 Vitamin D levels were lower, with a linear distribution, in older patients (oldest age was 85).47
Insufficient 25(OH)D was found in 45% of the 24 patients with mild Covid-19 versus 86% of the 131 patients with severe outcomes.47 As age increased, vitamin D levels correlated linearly with outcomes, with patients over 70 suffering severe Covid-19 only if they were vitamin D insufficient.47 In contrast with obese patients, those with healthy BMIs tended to have severe Covid-19 only if they were vitamin D deficient (also a linear correlation) Figure 7.47
De Smet, et al., found endemic vitamin D deficiency in their area of Belgium, with lower mean levels in men than women except in summer (p<0.05).219 Children under age 18 had lower deficiency rates (p<0.05). Comparing 186 consecutive test-positive Covid-19 patients (109 male) with the 2717 consecutive age-matched controls whose 25(OH)D was tested during the same season in 2019, they found that vitamin D deficiency was prevalent in controls (45.2%), but significantly (p<0.05) more common in the hospitalized Covid-19 patients (58.6%).219 The median 25(OH)D for Covid-19 patients was 18.6 ng/ml, compared with 21.5 ng/ml for controls (p=0.0016). Male patients were more likely than their control counterparts to be deficient (67.0% vs 49.2%, p=0.0006).219 Vitamin D deficiency was strongly associated with more severe Covid- 19 pneumonia in males (55.2% with stage 1, 66.7% with stage 2, and 74% with stage 3, p=0.001), but not in females.219 Vitamin D was stable across all stages of Covid-19 for females, suggesting that the illness itself does not deplete vitamin D.219 The authors argue that as a whole, their data supports a causal role for vitamin D deficiency in Covid-19.219
Meltzer,et al.,analyzed data from their US facility’s Covid-19 positive patients with documented 25(OH)D levels in EPIC within the previous two years to determine if deficiency increases Covid-19 incidence.220 Data for the most recent 25(OH)D and treatment (dose and time span) led to four categories 1) likely still deficient, 2) likely sufficient, 3) likely deficient but improved since testing, and 4) uncertain status.220 Known risk factors and factors that influence vitamin D activation were evaluated.220 A multivariate analysis found that, of patients with 25(OH)D levels within the previous year, those likely to still be deficient (category 1) were more likely (RR=1.77, p<0.02) to test positive for Covid-19 than those likely to be vitamin D sufficient (category 2).220 Older age, non-white race, and immunosuppression were the only other factors associated with testing positive for Covid-19.220 Hypertension, obesity, and diabetes were not covariates with vitamin D.220 Vitamin D deficiency was associated with supplement type and dose (p<0.01), unless the relatively few patients receiving 2000IU or more of vitamin D3 were omitted (indicating that lower doses, D2, and calcitrol did not improve deficiency).220 The authors concluded that the relatively low doses of vitamin D usually given to correct deficiency in their institution decreased the apparent benefit of supplementation on Covid-19 rates, and that 4000-5000IU/day may be indicated for Covid-19 prevention.220
Retrospective chart reviews that are neutral or strongly oppose the hypothesis
Fox and Sizemore evaluated the Electronic Health Records of over 15,000,000 patients in EPIC across 26 US states, finding 28,185 patients with documented 25(OH)D (of which, 86% were deficient) and Covid-19 status.83 No association was found between vitamin D deficiency (defined by each lab) and Covid-19 rates, hospitalizations, or fatalities.83 In contrast with the study by Meltzer, et al., no date limits were placed on the testing; the authors noted that vitamin D levels are usually drawn to confirm suspected deficiency.83 The authors recognized this limitation and recommended future studies including patients with normal vitamin D levels, along with studies to assess the effect of vitamin D supplementation on prevention or treatment of Covid-19.83
Hastie, et al., evaluated data from the 1474 participants in the UK Biobank study whose Covid- 19 test results were available to them.10 Rather than comparing the 1025 PCR-negative participants to the 449 PCR-positive patients, every person in the 348,598 database without a PCR-positive test result was assumed negative.10 The 25(OH)D levels obtained 10-14 years prior were significantly lower in blacks and South Asians.10 Black or South Asian ethnicity was also strongly associated (p < 0.001) with confirmed Covid-19 infection.10 Median 25(OH)D was significantly lower (p = 0.013) for those with confirmed Covid-19 infection, and 25(OH)D predicted infection univariably.10 In contrast, the multivariate analysis did not find 25(OH)D was significant.10 Unlike most other studies of Covid-19, the authors found no association between diabetes or hypertension and Covid-19 risk, raising concerns that important variables were factored out in their analysis.10,82
Another review using 2006 - 2010 data from the UK Biobank was conducted by Darling, et al., who compared the vitamin D status, BMI, ethnicity, and lifestyle factors of 580 Covid-19 positive cases (including outpatients) with 723 negative controls of similar age.74 25(OH)D levels were 3.6ng/ml lower (p<0.001) in patients who were obese and 6.4ng/ml lower for those whose ethnicity was not white (p<0.001).74 Covid-19 risk was increased for non-smokers, London dwellers, males, and non-whites.74 After factoring out overweight and obesity (the factor with the highest odds ratio), and after grouping participant data into quartiles rather than using individual data, 25(OH)D did not independently predict Covid-19 risk.74
Raisi-Estabragh, et al., conducted a third multivariate analysis on the UK Biobank participants, including all 4510 who had positive (1326) or negative (3184) Covid-19 tests from 16 March to
May 2020, almost all of whom were hospitalized.78 The researchers used the baseline data from 10-14 years ago for age, sex, deprivation, BMI, and 25(OH)D levels, adjusting the 25(OH)D levels for seasonality and ethnicity.78 Compared with the 497,996 untested participants of the UK Biobank study, men and non-white ethnicities were over-represented in the test group, with black ethnicity being 3.5 times more likely to be test positive than the untested cohort.78 Men and whites had higher average 25(OH)D levels than women and non-white ethnicities78 Evaluating data from males and females independently, statistical significance was reached for males only for non-white ethnicity, more deprivation, and higher BMI.78 For women, in addition to these three factors, lower 25(OH)D, more overcrowding, and greater risk-taking were all statistically significantly related to testing Covid-19 positive.78 Rather than conducting a multivariate analysis on all potential influencers of Covid-19 positivity, Raisi-Estabragh, et al., grouped exposures, testing each group against sex, age, and ethnicity, finding no significant association between these three factors, seasonally and ethnically adjusted 25(OH)D levels, and positive Covid-19 status.78 The researchers found that 25(OH)D and Covid-19 status are confounded by ethnicity and BMI.78 Mean 25(OH)D levels for both Covid-19 negative (14.18ng/ml) and Covid-19 positive (13.55ng/ml) primarily hospitalized patients were extremely low.78
Rapid systematic review and meta-analysis with an ecological approach
Ghasemian, et al., conducted a formal systematic review of nine studies, with six studies entering into a meta-analyses, and added their own evaluation of the correlation between global vitamin D status and Covid-19 recovery and mortality.68 The meta-analysis revealed that 46.5% of Covid-
paitents were vitamin D deficient and an additional 43.3% were vitamin D insufficient.68 Although their basic evaluation of 51 countries did not find a significant correlation between population vitamin D status and recovery or mortality rates, when latitude was factored in, both mortality rates and recovery rates weakly supported the vitamin D hypothesis.68 The researchers recommended large randomized clinical trials of vitamin D during the “Age of Covid-19.”68

Covid-19-Specific Recommendations of Experts

Although a few recommended only sunshine or 400IU/day, none of the authors strongly opposed vitamin D supplements during the pandemic. At the extremes, some researchers recommend large bolus doses of vitamin D, or correction of deficiency, primarily for patients who are diagnosed with Covid-19, and others recommended only the dose of vitamin D needed to maintain bone health (200-400IU/day).28,29,71,89,106,158,167,221—228 Additional authors recommend vitamin D supplements to boost the immune systems of patients diagnosed with Covid- 19.2,48,67,69,72,73,ii6,ii8,i23,229-232 However, most authors recommend widespread daily vitamin D supplementation (most often with 1000 - 5000IU per day) to prevent and decrease the severity of Covid-19, at least until the pandemic
abates 1,9,26,38,45,47,49,62,63,105,107,111,112,114,119,122,125,163,169,170,176,188,190,195,196,208,212,217,220,233—247
Although vitamin D toxicity is extremely rare,considering the recent spate of chloroquine overdoses due to panic from Covid-19, recommendations include cautioning the public that excessive artificial supplementation can lead to serious harm.92,223,248,249 Suresh noted that in India, vitamin D deficiency is due in large part to calcium deficiency, which must therefore also be addressed.233
Serum response to vitamin D supplementation is highly variable between individuals, leading to recommendations of higher doses than the US RDA.38,41 The NIH states that vitamin D supplements of up to 5000IU/day have not produced toxicity, leading to a maximum recommended intake for persons 9 years and older of 4000IU (100mcg)/day. , Although the USRDA for vitamin D is 600-800IU/day, the Endocrine Society and many other experts recommend 1000 - 2000IU/day (widely available dosages). , , , A comprehensive article on optimizing nutrition to protect against Covid-19 specifically suggests adults take 2000IU/day of supplemental vitamin D, in keeping with the recommendations of the US National Academy of Medicine.49,250 The consensus of the authors reviewed here seems to be 2000IU/day for the entire adolescent and adult population.

Discussion

Prior to modern times, individuals living in high latitudes had a much larger food supply from April - October, leading to weight gain.251 Excess vitamin D from sunshine was stored in accumulated fat.21,204 Weight loss during relatively dark, food-scarce winters, released this excess vitamin D, preserving immune function.21,204 Now, food is plentiful year-round, leading to weight gain from decreased activity in winter.251 Without weight-loss related vitamin D release, dangerously low 25(OH)D can develop by spring, and the obese, the elderly, those with naturally melanin-rich skin living outside the tropics, and anyone not spending time in the sun are at risk
year-round.204
Sunscreen with a rating of only 15 SPF decreases vitamin D production in the skin by 99%.204 Studies show that non-burning sun exposure increases vitamin D levels and may be melanoma- protective.50 In tropical areas with wealthier populations, sun exposure may decrease in the summer due to a preference for air conditioning.252 Encouraging uninfected people, including the homeless, to stay indoors could cause an increase in Covid-19 fatalities by increasing vitamin D deficiency rates. In contrast, encouraging weight loss through increased activity and structured programs can serve to improve vitamin D levels.204 Studies show that exercise increases serum vitamin D levels, even when indoors, perhaps by triggering release of vitamin D stored in fat.253

Conclusion

The 141 articles [Table 3] presenting primarily biological plausibility evidence overwhelmingly support the assertions that vitamin D sufficiency increases resistance to viral infections and helps prevent every symptom of severe Covid-19 that results in fatalities. They show that vitamin D deficiency can also explain every major risk factor, including the mystery of why children seem relatively protected and why males, the elderly, and people with naturally melanin-rich skin are especially vulnerable.
The 47 studies Table 2 summarized here demonstrate that vitamin D deficiency explains the geographical differences in Covid-19 case and fatality rates. They provide overwhelming correlational evidence for the hypothesis, and causal evidence as well. Covid-19 mortality was predicted by vitamin D in sixteen studies 11,21,37,46,61,120,125,144,148,180,195,204,207—209,217 and vitamin D levels or sunlight predicted contracting Covid-19 in seventeen. 45,120,122,148,195,196,198,199,202,203,205— 207,209,214,219,220. Both causal modeling studies and eight chart reviews demonstrated that lower 25(OH)D was linearly associated with more severe Covid-19 outcomes.40,46,47,61,155,209,213,215,217,2
None of the four objections to recommending universal vitamin D supplements are supported by the evidence. The exhaustive literature search found no vitamin D proponent who suggested that Covid-19 could be completely eliminated with supplementation. Rather than overstating the case, they present compelling evidence that vitamin D deficiency is one factor which increases risk for Covid-19 infection and progression. Although overdoses are theoretically possible, they are highly improbable. The recommended dose by consensus, 2000IU/day for adults, is 1/20th the amount that must be taken for many months to risk toxicity.38,86,89,90 The evidence strongly
suggests that vitamin D deficiency is an easily modifiable risk factor and correcting it is potentially life-saving. Suppressing this evidence out of fear that the public might believe supplements will make them “immune” to Covid-19 is not only elitist, but it is inconsistent with existing public policy approaches. Many mitigation strategies are publicized. None are seen as conferring immunity.
This succinct but comprehensive review of the evidence found that despite almost complete absence of official government guidelines favoring vitamin D supplements to potentially decrease Covid-19 risk and severity, support among clinicians and other researchers for correcting and preventing vitamin D deficiency with modest daily vitamin D supplementation during the Covid-19 pandemic is very strong, worldwide. The evidence supports recommending 2000IU (50 mcg) vitamin D daily for at-risk teens and adults, which is well within safe limits and might dramatically reduce Covid-19 fatalities.

Limitations

Many of the articles and studies included in this review were preprints, or were published in haste. The study descriptions were often too brief for a critical appraisal of the designs. Many researchers did not make their data public, although some emailed corrections or clarifications. Although the author is familiar with inflammation and cytokines from her work with chronic wounds, and she is familiar with epidemiology from her health education work in developing countries, she is not an endocrinologist or an epidemiologist. Single authorship could also be considered a limitation.

Afterward

Conflict of Interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Author Contributions
This article is the sole work of the author, Linda L Benskin.
Funding
No special funding was provided for the writing of this article.
Acknowledgments
The author wishes to thank her research associate, Richard Benskin, who provided invaluable editing help, John Newton whose encouragement led to this review, and her employer, Ferris Mfg. Corp., makers of PolyMem, who generously provided her with the time, as their charity liaison, to conduct the literature search and write this review.
Author Brief Biography
Linda Benskin is an independent nurse researcher working to improve the evidence base for village health workers in remote and conflict areas of tropical developing countries, where health care professionals are absent. Her research into how pain and inflammation impact wound healing has provided her with a basic familiarity with cytokine pathophysiology. Dr. Benskin’s improvised wound dressings clinical research study has been sidelined by the travel restrictions of Covid-19. Dr. Benskin is also the Clinical Research, Education, & Charity Liaison for Ferris Mfg. Corp. (makers of PolyMem dressings).

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Aspects of each study and 1-10 support of Vitamin D NOW

Table 2: Brief Summaries of Original Research (in vitro research is included in Table 3) (47 entries)
1st Author /LocationTitle (Truncated) . . . . . . . . . Number of Participant s/Type*/ #pagesSupporting Information **Results/ Recommendation Regarding Covid-19Support for
Sup. Now
Ahmed/ UKFirst Covid-19 maternal mortality ...thrombotic complications1861/CS 4 pagesTThrombosis kills/ Vigilance is needed5
Alipio/ PhilippinesVitamin D ... possibly improve clinical outcomes of patients infected with ... (Covid- 2019)40212/R 6 pagesR,CSig. D-outcome link /D suppl. could improve outcomes8
Alipio/ PhilippinesDo latitude and ozone concentration predict Covid-2019 cases in 34 countries?20534 countries /A 9 pagesR,Sig Covid-19- UV (D) link, no latitude link /D suppl. indicated7
Annweiler/France & ChinaPoint of view: Should COVID-19 patients be supplemented with vitamin D?2096 of 7 causal criteria/C 25 pagesG,P,R,F,C,J,SStrong biological plausibility case - supplement D9
Asyary/ IndonesiaSunlight exposure increased Covid-19 recovery rates: A study in … Indonesia2169 hospitals /R 4 pagesG,I,R,F,Patient exposure to sunshine helped Encourage it7
Backer/ USA (see note)Why COVID-19 May Be Disproportionately Killing African Americans...Irradian ce... Income118 locations in the USA/ A 6 pagesG,IIrradiation for disinfection, sun for protection6
Backer/ USA (see note)Slower COVID-19 morbidity and mortality growth at higher solar

159 locations/ A 59 21 pages

G,I,Encourage people to go where the sun is overhead6

  


 
irradiance and elevation148
 

 

 

 
ann/ USA (see note)

Non-black Hispanic/Latinos Spend More Time Outdoors ... Lower …Morbidity Than Non-Hispanic.202

All of Georgia /A 7 pagesG,I,PUrgently test sunlight exposure, especially for African Americans6
Backer/ USADouble COVID-19 … Fatality Rate in Countries with High Elderly Female Vitamin D Deficiency Prevalence18032 countries /A 11 pagesG,I,P,C,STest Vitamin D for prevention and treatment6
Bossoni/ ItalySevere hypocalcemia in a thyroidectomized woman with Covid- 19 infection2111/CS 2 pagesRWarn thyroid patients due to home confinement8
Braiman/ USALatitude …COVID- 19 mortality rate—a possible relationship to vitamin D deficiency?144all nations (WHO data) P/14 pagesG

Test for link by supplementing and looking for changes

7
Cunat/ SpainVitamin D deficiency in critically ill patients .COVID-19. Are we doing enough? ...226 patients.218226 patients (subset: 17)/R/7 pagesP,R,C,SShould assess D more often - all 17 were deficient8
Daneshkhah/USAThe Possible Role of Vitamin D in Suppressing Cytokine Storm and ... Mortality in COVID-19 Patients17210 countries /A/ 23 pagesCStudy if Vitamin D deficiency speeds mortality6
Darling /UKVitamin D status, body mass index, ethnicity and COVID-19:…UK Biobank COVID-19580 Covid+ vs 580 negative /R 3 pagesNone mentionedAll identified risk factors are uncontrollable - No recommendati

 


 
…(n 580)…negative controls (n 723)74
 

 
ons
 

Davies/UK Switzerland

Evidence Supports a Causal Model for Vitamin D in COVID- 19 Outcomes61 (two studies)

Global data /A and C/ 30 pages

G,P,RD deficiency is a cause of Covid-19 Give up to 4000IU9
D'Avolio/ Switzerland, Italy25-Hydroxyvitamin D ..Are Lower in Patients with Positive PCR for SARS-CoV-2122

107 Covid+ vs 1377 /R/ 7 pages

RD correlated to + Supplements urged as per Grant, et al.9
De Smet/ BelgiumVitamin D deficiency as risk factor for severe 1 COVID-19: a convergence of two pandemics219

186 Covid+ vs 2717 /R/ 23 pages

D,P,R,C,Deficiency seems to cause severe, supplements urged9
Fasano/ Italy, CanadaCOVID-19 in Parkinson's Disease Patients Living in … Italy214

105 Covid+ vs 1381/S/ 12 pages

G,CParkinson's doesn't matter; D does. Conduct D studies7
Faul/ IrelandVitamin D Deficiency and ARDS after SARS- CoV-2 Infection213

33 Covid+ S/ 2 pages

D,CWorse outcomes in men with lower D7
Fox/ USANo Association ...Between Vitamin D Deficiency and COVID-19 Infection, Hospitalization, or Mortality83

28,185 patients 3 pages

None mentionedNo difference with deficiency, but authors call for better studies
Ghasemian/ Iran, Australia, Russia,The Role of Vitamin D in The Age of COVID-19: A Systematic Review and Meta-Analysis Along with an Ecological Approach68

9 studies (subset:6) 51 countries 20 pages

G,P,R,C,Patients with Covid-19 lacked D, slight country link Need RCTs6
Glicio/ IndiaVitamin D Level of Mild and Severe Elderly Cases of

176 Covid+ 18 pages

p,R,c,Link is suggested Supplement6

 


 
COVID-19…47
 

 
elderly
 
Hastie/ UKVitamin D concentrations and COVID-19 infection in UK Biobank10449 Covid+ vs 348,149 R/5 pagesG,P,Link attributed to confounds - D has no role in Covid-19
Horowitz/ USAEfficacy of glutathione ..dyspnea …COVID- 19 pneumonia …2 210 cases2 (1 D) 8 pagesNone mentionedOne patient had D deficiency5
Ilie/UKThe role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality25420 countries /P/ 4 pagesD,G,P,R,C,SRecommend study comparing D levels & Covid- 19 severity6
Kara/Italy,Turkey, Taiwan‘Scientific Strabismus' or Two Related Pandemics COVID-19 & Vitamin D Deficiency25540 countries /P/ 6 pagesD,G,P,R,SGoal 40- 60ng/ml 10,000旧/day x1mo then 5000IU/day10
Kohlmeier/ USAAvoidance of vitamin D deficiency to slow the COVID- 19 pandemic20422 states/A/ 7 pagesD,G,P,R,CPrecision nutrition RDA - <4000旧/Day8
Kumar/ IndiaSpurious Correlation? A review of the relationship ... Vitamin D and Covid-19 infection & mortality19720 countries /P/ 7 pagesNone mentionedIlie is wrong - no role for vitamin D Overdose is likely
Laird/ UK, IrelandVitamin D and Inflammation: Potential Implications for Severity of Covid- 193712 countries /P/ 7 pagesD,P,G,R,C,SCorrelation exists Publicize D recommendations6
Lau/USAVitamin D insufficiency is prevalent in severe COVID-1915520 Covid+ R/14 pagesG,P,R,C,TWorse with low D Study D further6
Li/ China, USAIdentifying novel factors ... COVID-19A (machine)Not discussedD is independent7

 


 
using …machine learning20332 pages
 
risk factor for cases
 
Li/USAMultivariate Analysis of Factors Affecting COVID-19 ...U.S. Counties: …Black Race and Temperature195661 & 217 counties A/21 pagesD,P,R,CD is a likely factor Conducting studies Supplement all7
Li/USA, ChinaSunlight and vitamin D in ... (COVID-19) infection and mortality …20749 states A/ 15 pagesD,G,P,R,C,Appears related Need more studies6
Marik/ USADoes vitamin D status impact mortality from SARS-CoV-2 …?20850 states A/ 2 pagesG,P,R,CAppears related Standard dosages6
Meltzer/ USAAssociation of Vitamin D Deficiency ... Treatment with COVID-19 …220499 patients R/22 pagesD,G,P,R,CD decreases risk 4000- 5000IU/day10
Moozhipurath/ GermanyEvidence of Protective Role of Ultraviolet-B (UVB) Radiation in Reducing COVID-19 Deaths21152 affected countries/ A/ 42 pagesR,C,FD decreases deaths Encourage time in sun for deficient6
Notari/ Spain, BrazilCOVID-19 transmission risk factors199126 countries, 24 factors A/ 42 pagesRIndependent risk: Type 1 diabetes, BCG vaccination, and vitamin D7
Panarese/ ItalyLetter: Covid-19, and vitamin D (response to Tian, et al. Gastro)196108countri es A/3 pagesG,P,R,C,SImmune control 2000IU/day8
Pinzon/ IndonesiaVitamin D Deficiency . Patients with COVID-19 : Case Series and Recent Literature Review21210 patients CS 9 pagesD,G,P,R,CImmune benefits They give all patients 2000IU8
Raharusuna/Patterns of COVID-780R,CD is strongly8

 

Indonesia19 Mortality and Vitamin D: An Indonesian Study46patients R 14 pages
 
associated with death - do RCTs
 
Raisi-Estabragh/ UKGreater risk of severe COVID-19 in non-White ethnicities is not explained by …vitamin D status: study of 1,326 …UK Biobank78Hospitalize d 1326 + 3184 - R/21 pagesNot discussedRuled out cardio- metabolic, social, behavior, and D - leaving genetic?
Rhodes/ UKEditorial: low population mortality …south of latitude 35 degrees North supports vitamin D …256120 countries A/ 4 pagesD,P,C,Could protect from cytokine storm 1000IU/day7
Singh/ IndiaRevisiting the role of vitamin D ... prevention and mortality in European ...post peak19820 countries 2 dates A/ 8 pagesR,C,SD influenced cases more than deaths study ? of giving D3
Skutsch/Netherla nds, Mexico, GermanyThe association of UV with rates of COVID-19 transmission and deaths in Mexico: the possible mediating role of vitamin D20645 cities in Mexico A/ 29 pagesD,P,R,C,Further study of link between UV (vitamin D) and transmission rates6
Sun/ ChinaSerum calcium as a biomarker of clinical severity and prognosis…217241 patients P/18 pagesnot discussedDeficiency suggests larger studies7
Tan/ SingaporeA cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-1943 patients 26 controls 17 supplement R/ 6 pagesR,CGive combination earlier to all cases and to high risk contacts9

 


 

patients215


 

 

 

 
Yao/ China

No Association of COVID-19 transmission with temperature or UV radiation in Chinese cities193

224 cities in China/ G/ 9 pagesG,RUV (therefore D) not related to transmission
 

*Type of Study

  • A = Analyses of population data or latitude data (geographic)
  • C = Causal inference modeling report, Hill's methodology for exploring causality, etc.
  • P = Prospective correlational study
  • R = Retrospective chart (or data) review
  • CS = Single or Multiple Case Study

** Supporting Information provided by these authors:

  • G = geographical observations (not research) of relationship between low vitamin D and high Covid-19
  • I = Irradiance in the geographic area influences vitamin D deficiency

Biological plausibility:

  • R = vitamin D enhances resistance to respiratory viruses, decreasing incidence of infection
  • F = vitamin D decreases overall fatalities from respiratory viruses
  • C = vitamin D suppresses cytokines that are implicated in severe Covid-19
  • J = vitamin D tightens junctions, helping prevent viral infections from progressing to pneumonia
  • T = vitamin D decreases the risk of thrombosis
  • S = vitamin D suppresses the ‘Renin-Angiotensin' System activity, which is more of a problem for males


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