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THE INFLUENCE OF VITAMIN D ON COVID-19 OUTCOMES Chapter 4 of Covid-19 and Nutraceuticals: A Guidebook Bohr Publishers and New Century Health Publishers, LLC

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  • Independent Researcher for Remote and Conflict Areas of Tropical Developing Countries , and Ferris Mfg. Corp.
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Abstract and Figures

NOTE: Although this document is a preprint, it has been peer-reviewed - twice. I solicited an open peer review from vitamin D experts and incorporated their edit suggestions, and the publishers simultaneously submitted it to anonymous peer review. The chapter has been accepted for publication in Covid-19 and Nutraceuticals. It is a follow-up to the 2020 Basic Review in Frontiers in Public Health. https://www.frontiersin.org/articles/10.3389/fpubh.2020.00513/full Abstract: Most of the world’s population has vitamin D levels which are suboptimal for healthy immune system function. Recent recommended goals are far higher than legacy guidelines, which are based entirely upon promoting bone health, rather than on supporting all the many other functions of vitamin D. Vitamin D strengthens the innate immune response, decreasing the likelihood of infection from SARS-CoV-2 exposure. Vitamin D also regulates the adaptive immune system and inflammation. Thus, with appropriate levels, infected persons have a reduced likelihood of developing hyperinflammatory (severe) Covid-19 (the cytokine or bradykinin “storm”). Many experts have noted that vitamin D plays a role in preventing every one of the disorders associated with severe Covid-19. In addition, the risk factors for getting severe Covid-19 are identical to the risk factors for becoming vitamin D deficient. Evidence of a link between low vitamin D levels and poor Covid-19 outcomes is robust, including numerous population and individual correlational studies, causal modeling, prospective cohort intervention studies, and randomized controlled trials.
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THE INFLUENCE OF VITAMIN D ON COVID-19 OUTCOMES
Chapter 4 of Covid-19 and Nutraceuticals: A Guidebook
Bohr Publishers and New Century Health Publishers, LLC,
Chandan Prasad, PhD and Güler Öztürk, PhD, Editors
Linda LL Benskin, PhD, RN, SRN (Ghana)
Independent researcher for improving health in rural areas of tropical developing countries, and
Ferris Mfg. Corp., Ft Worth, TX, USA
E-mail: LindaBenskin@utexas.edu
Light is sweet and it pleases the eyes to see the sun.”
Solomon
Hebrew King and Philosopher
ABSTRACT
Most of the world’s population has vitamin D levels which are suboptimal for healthy
immune system function. Recent recommended goals are far higher than legacy guidelines,
which are based entirely upon promoting bone health, rather than on supporting all the many
other functions of vitamin D. Vitamin D strengthens the innate immune response, decreasing the
likelihood of infection from SARS-CoV-2 exposure. Vitamin D also regulates the adaptive
immune system and inflammation. Thus, with appropriate levels, infected persons have a
reduced likelihood of developing hyperinflammatory (severe) Covid-19 (the cytokine or
bradykinin “storm”). Many experts have noted that vitamin D plays a role in preventing every
one of the disorders associated with severe Covid-19. In addition, the risk factors for getting
severe Covid-19 are identical to the risk factors for becoming vitamin D deficient. Evidence of a
link between low vitamin D levels and poor Covid-19 outcomes is robust, including numerous
population and individual correlational studies, causal modeling, prospective cohort intervention
studies, and randomized controlled trials.
I. Background
The industrial revolution led physicians such as Sniadecki (in Poland, 1840) to notice
that sunlight is protective for human health.1 He noticed that children living in the crowded,
polluted city of Warsaw developed rickets, while children living in the nearby countryside
remained rickets-free.1 The hypothesis that sunlight on skin could influence the deep tissues and
bones was initially met with skepticism, but the evidence became undeniable: in 1900 over 90%
of European urban children and 80% in Boston suffered from rickets.1 Though cod-liver oil had
been used to treat and prevent rickets for years, in the early 1900s, UV-irradiated fat (“vitamin
D”) was identified as another cure.1,2 In 1928, Adolf Windaus was awarded the Nobel Prize for
discovering “vitamin D.2,3 In 1936 it was discovered that UV light from sunshine produced D3
in the skin, which is then converted by the body to biologically active 25(OH)D, which means
that “vitamin” D is, in fact, a steroid.2
2
In 1979, a team led by Stumpf discovered Vitamin D receptors throughout the body,
revealing that vitamin D is important for more than just skeletal calcium maintenance.1 Evidence
gradually emerged that vitamin D is among the most powerful of the micronutrients, with
receptors in virtually every body system.4 Through its local actions (autocrine and paracrine
signaling), vitamin D helps regulate processes as varied as insulin production, apoptosis, and
innate and adaptive immunity, thus affecting infectious disease vulnerability and most
inflammation-related conditions, including hypertension, diabetes, cancer, arthritis,
cardiovascular disease, and autoimmune diseases.1,57
Prior to the industrial revolution, virtually all of humankind hunted, gathered, farmed,
and fished while the days were long, gaining body-weight and storing vitamin D in their fat and
muscle tissue.8 When the dark winter came, opportunities to obtain food diminished. As people
lost weight, vitamin D was released, promoting continued good health.9 The industrial revolution
led to a more indoor, often sedentary lifestyle, and more wealth for the masses, so that people
with chronically low vitamin D levels gain weight not only during the harvest, but also
throughout the winter, without exerting their muscles as much. Their blood vitamin D levels
drop precipitously, reaching critically low levels by the time the next summer arrives. For
example, vitamin D insufficiency is >85% in the winter and spring among pregnant women in
Southern England, dropping to 30% in the summer.10 In Ireland, 24% of the population is
vitamin D insufficient (calcifediol <20ng/ml) in summer, more than doubling to 49% in winter
11. Rare optimal calcifediol levels (>40ng/ml) were found primarily in older women (1-7%), who
would be most likely to take supplements year-round for bone health.1113
Because the UVB rays required to produce vitamin D in skin are obstructed by air
pollution, clouds, window glass and even ozone when the sun is low (below a 45 degree angle, as
is the case in winter, in areas far from the equator, and in the early mornings and late afternoons),
and the only significant dietary sources of vitamin D are wild-caught fatty fish (which feed on
sunbaked plankton), vitamin D deficiency has traditionally been addressed with food
supplementation.1,14,15 However, supplementation (except in Nordic countries) has decreased
over the years, consumption of foods traditionally fortified in some countries, such as cow’s
milk, is declining, and humans worldwide are adopting an affluent (obese), indoor lifestyle.16
Individuals with naturally melanin-rich skin who live outside the tropics are rarely able to obtain
sufficient vitamin D from the sun.17 As a person ages, the ability of their skin to produce
cholecalciferol decreases.18 All of these factors led to an alarming vitamin D deficiency
pandemic long before Covid-19 appeared on the scene.16,19,20
Covid-19 is caused by a novel coronavirus, but the symptoms of severe Covid-19 are not
at all without precedent. Respiratory viral illnesses of the past: the Spanish flu of 1918, SARS,
and MERS, are quite similar, and even dengue fever has the same basic history of illness.16,21,22
In each case, the initial viral illness is mild or asymptomatic for most people, with some sufferers
developing symptoms more like influenza. However, as they appear to be recovering (and their
viral load is dropping), a few people suddenly take a turn for the worse, because their immune
system over-reacts.23,24 This immune system overreaction, not the virus itself, causes life-
threatening hyper-inflammation.22,23 In the case of Covid-19, macrophages, cytokines, and
fibroblasts fill the lungs, which leads to difficulty breathing.23,2527 The increased inflammation
can also lead to blood clots and organ damage.23,26 We know the virus itself is not the proximate
cause of this organ damage because researchers do not find viable virus in the blood of Covid-19
sufferers, even when they have severe Covid-19.26,28,29 The rare exceptions seem to be when the
virus is forced into the blood stream from the lungs by high pressure ventilator treatment.
3
It is well known that vitamin D helps prevent chaotic immune responses such as those
characteristic of severe Covid-19 (the cytokine or bradykinin “storm”).30 Therefore, it should be
expected that many Covid-19 sufferers will have low levels of vitamin D. Already by March,
2020, dozens of published studies demonstrated that low vitamin D levels lead to poor Covid-19
outcomes.16 As of June 2021, a link between low vitamin D levels and poor Covid-19 outcomes
was asserted in ~3000 published studies and biological plausibility discussions in MEDLINE
indexed journal articles, including hundreds of population and case correlational studies, causal
modeling, RCTs, and prospective cohort intervention studies. At this point, multiple meta-
analysis author groups have concluded that there is a significant relationship between 25(OH)D
serum levels and Covid-19 infection, severity and/or mortality.4,31,32
II. Classification of vitamin D levels and why low levels are common
A. Defining Vitamin D
Confusion about vitamin D complicates the design and obscures the interpretation of research
studies.33 Four different molecules are commonly called vitamin D. (See Figure 1, page 4)
a) Cholecalciferol, or vitamin D3, is produced when UVB light (primarily 295-300nm) acts on
7-dehydrocholesterol in the skin to break the ring between carbon 9 and 10. Wild caught salmon
and other fatty fish whose food-chain begins with sun-exposed plankton are rich in D3; far lesser
amounts are found in free-range eggs and cheese.30 However, without added UVB skin synthesis
or supplements, only an almost exclusively wild fish diet will provide adequate vitamin D.
Cholecalciferol is the most common vitamin D supplement, easily extracted from sheep lanolin.
Before this process was discovered, Ergocalciferol, or vitamin D2, supplements were common.
Ergocalciferol, which is one third as potent as cholecalciferol, is formed in modest amounts
when mushrooms or yeast are irradiated with UVB light.34 Fruits and vegetables do not contain
significant vitamin D. In some countries, foods are fortified with vitamin D2 or D3, but often at
only modest levels. Because cholecalciferol, which stabilizes the endothelium and is in itself
anti-inflammatory, and has a half-life of only 24-50 hours, sunshine and/or D3 supplement intake
should ideally be daily, rather than at less frequent intervals.3,6,35
b) Calcifediol, 25(OH)D, 25hydroxyvitaminD, and calcidiol are all names for the form of
vitamin D that is produced when the enzymes CYP2R1, CYP27A1, etc. in the liver replace the H
with an OH group at the 25 position of cholecalciferol.36,37 Ergocalciferol is converted to
calcifediol as well, but the process is less efficient. Because calcifediol has a half-life of about
two weeks, appropriately increased weekly vitamin D intake provides almost as many benefits as
daily.38
c) Calcitriol, also called 1,25OHD or 1,25(OH)2D, is produced when CYP27B1 replaces the H
at the 1 position in calcifediol with another OH. This tightly regulated process takes place in the
kidneys for circulating calcitriol used in calcium transport, but it also takes place in other organs,
monocytes, and macrophages (see diagram).39 The vitamin D receptors found throughout the
body are activated only by calcitriol and its analogs.37
The ubiquitous enzyme CYP24A1, induced by high calcitriol levels, adds an OH to the 24
position of calcifediol and calcitriol. This irreversible process leads to the formation of calcitroic
4
acid, which aids in callus formation for fracture healing, but appears to be otherwise inactive and
is rapidly excreted, protecting against toxic vitamin D levels.37,40 A single bolus dose of
cholecalciferol can lead to increased calcitroic acid production for at least 28 days.41
Figure 1: Forms of vitamin D
The photochemistry of vitamin D biosynthesis in animal and fungi: UVB light breaks the ring between C 9 & 10
Note: In general, plants do not contain the cholesterol needed to synthesize vitamin D. Vitamin D2 (fungi) is one-third the potency of vitamin D3.
Liver hydroxylation of cholecalciferol (D3) to calcifediol, which is 25(OH)D: H at position 25 is replaced with OH
Kidney hydroxylation of calcifediol to calcitriol, which is 1,25(OH)2D: H at position 1 is replaced by OH
(Calcitriol is also formed, in lesser quantities, in the monocytes & macrophages, and in the many tissues with vitamin D receptors)
Circulating CYP24A1 adds an OH to the 24 position of calcifediol and calcitriol in response to high calcitriol levels to form calcitroic acid,
which is excreted, helping protect against toxicity. Calcitroic acid can be mistaken for calcifediol by many tests for 25(OH)D.
Molecular diagrams By: Hbf878 Own work CC0, modified by Robin Whittle, used with permission, all other images CC with no attribution required
Differences in units used to report blood levels of vitamin D and to discuss supplement
dosages can also be confusing. Serum 25(OH)D is reported in either ng/ml or nmol/L. To
convert ng/ml to nmol/L, multiply by 2.5 (20ng/ml = 50nmol/L). For vitamin D3 taken by mouth,
the conversion factor from mcg to IU is 40 (50mcg = 2000IU).
Although cholecalciferol and calcifediol both circulate in the blood, cholecalciferol is
more easily absorbed into muscle and fatty tissue.8,36 Serum vitamin D tests measure total
calcifediol, but most are cross-reactive with calcitroic acid that has not yet been excreted, which
can mislead researchers.36 Calcifediol, rather than cholecalciferol, supplements are appropriate
25(OH)D hydroxylated
by the kidney is used for:
Calcium homeostasis
Muscle & bone health
Regulate blood pressure
Cardiovascular health
Neurodevelopment
Immunomodulation
Unknown additional
benefits
25(OH)D
hydroxylated by the
monocytes and
macrophages:
Strengthens innate
immune system
Regulates acquired
immune system
Prevents autoimmune
diseases
Lowers inflammation
25(OH)D hydroxylated
by > 36 other tissues,
including the prostate
gland, breast, placenta,
colon, lung, parathyroid
gland, keratinocytes,
brain, pancreas β cells,
cardiac muscle, thymus,
and cancer cells:
Regulates differentiation
and cell growth in those
organs, cell signaling.
5
for individuals with chronic kidney disease, because their elevated parathyroid levels inhibit the
conversion process in the liver.42 Individuals with liver failure may also require calcifediol.36
Recently it has been learned that giving calcifediol rather than cholecalciferol also leads
to a much faster and a 3-6 times larger increase in available active vitamin D (calcitriol).42,43 This
has significant implications for remedying vitamin D deficiency in acutely ill patients, as it can
take up to 7 days for large doses of cholecalciferol to be converted to calcifediol naturally, and a
much higher percentage is lost to storage in the fatty tissue.42 However, raising calcifediol levels
too rapidly can cause rapid catabolism while dramatically increasing calcium levels.37 As was
mentioned earlier, this catabolism may mislead researchers who are unaware of the fact that most
25(OH)D tests do not distinguish between circulating calcifediol and unexcreted calcitroic acid
36. Therefore, extended release calcifediol or multiple moderately high doses should be used.37
Research into the reasons intensive care patients often require 10 100 times the normal dose of
cholecalciferol to raise their 25(OH)D levels above 20ng/ml is ongoing, but it appears related to
decreased CYP2R1 activity induced by fasting, diabetes, obesity, exposure to high-dose
glucocorticoids, illness, and other factors.39
B. Recommended serum levels and intake goals from organizations and governments
Most legacy public health guidelines for target serum vitamin D levels, based entirely
upon supporting bone health, define <10-12ng/ml 25(OH)D as “vitamin D deficient” and
<20ng/ml as “vitamin D insufficient.16 However, clinical practice guidelines that take into
account the many other functions of vitamin D widely recognize that levels below 30ng/ml are
insufficient.10,37,44 Most researchers define 25(OH)D levels below 20ng/ml as deficient.16,44
Parathyroid levels are elevated for all races, which would logically indicate that a deficiency
exists, when 25(OH)D is below 32ng/ml.4547 When living a traditional lifestyle in the tropics,
the Hadzabe and Maasai of East Africa have mean 25(OH)D levels of close to 50ng/ml, as do
lifeguards 48,49. Both surgical and hospital-acquired infection rates plateau at very low levels
when 25(OH)D levels reach 50ng/ml.12 Researchers evaluating 191,779 PCR test results from a
laboratory database found that Covid-19 positivity rates also plateau at very low levels when
25(OH)D reach 50ng/ml.50 (See Figures 2 and 3, page 6)
The National Academy of Medicine, the UK’s NICE and most other public health policy
organizations recommend age-dependent daily intakes of vitamin D3 in the range of 100
800IU, with a goal of reaching serum 25(OH)D levels of 20 50ng/ml.51,52 However, two
groups of researchers have evaluated the data and concluded that the statistical calculations used
to determine these recommended intakes contain an error.51,53 A third group agreed, finding that
the recommended vitamin D3 intake for adults to reach only the minimal 20ng/ml serum levels
needed for bone health could be over 7000IU/day.54,55 Because circulating levels of 30ng/ml or
greater are required for the immune cells to convert calcifediol to calcitriol, 40-60ng/ml is
recommended.7,56
The Endocrine Society recommends 2000IU of vitamin D3 daily for most adult patients
to reach their minimum target 25(OH)D level of 30ng/ml, but acknowledges 4000 6000IU/day
may be required for obese and malabsorptive patients, and that up to 10,000IU/day is safe.7,51
Recent research exploring the role of vitamin D in maintaining immune health, regulating
inflammation, and helping prevent autoimmune diseases, cancers, allergic disorders, infections,
skin diseases, neuropsychiatric disorders, and cardiovascular disease has led to further support
for higher supplementation recommendations.57 Serum 25(OH)D levels of 40-60ng/ml are now
considered optimal for immune health, and even higher levels are recommended for treating
6
autoimmune and many other serious health conditions.7,45,46,58,59 Vitamin D’s critical autocrine
signaling requires 25(OH)D concentrations of 40-60ng/ml to function properly.7
Figure 2: Relationship between circulating 25(OH)D level and COVID-19 positivity rate50
(from Kaufman, et al., PLOS ONE, 2020, an open source publication)
Figure 3: Relationship between circulating 25-hydroxyvitamin D levels and risk of infection12
(Data from Quraishi, et al., JAMA 2014. Image from https://vitamindstopscovid.info/02-autocrine/#04-quraishi by Robin Whittle, with permission)
7
The vitamin D deficiency pandemic began long before Covid-19 appeared on the
scene.16,52,60 In the USA, in Minnesota (44°N), 60% of the immigrant and refugee population
suffer from vitamin D insufficiency, as do 40% of all Canadians and 56% in the UK.61 Not
surprisingly, the highest risk groups for vitamin D deficiency mirror the those of severe Covid-
19: people who are elderly (particularly those living in care homes), obese, hypertensive,
diabetic, male, have naturally melanin-rich skin and live outside the tropics, or those who live in
areas with high levels of air pollution.16,17,22,62
Despite this, many public health officials continue to discount vitamin D supplementation
during Covid-19, with the WHO recommending 200-600IU, depending upon age, for individuals
who are not able to take in sunlight due to lockdowns, and the NHS and British Dietetic
Association continuing to suggest 400IUs for sun-starved adults.6365 As of 5 Sept 2021, the US
NIH had no official stance on vitamin D for the prevention or treatment of Covid-19, noting that
deficiency is the most common in groups that are hardest hit by Covid-19 and biological
plausibility is strong, but there is a theoretical risk for toxicity with high doses; the only study
cited is one in which the authors of the page themselves note that vitamin D3 was given to
patients very late in their illness.62
A hypothetical concern for toxicity (serum 25(OH)D>150ng/ml), often mentioned while
stating that vitamin D is a fat soluble vitamin (harkening to vitamin A) is the main reason given
for not recommending population-wide vitamin D supplements.66 However, vitamin D toxicity is
far more rare than vitamin A toxicity, in part because of the built in fail-safe described earlier.37
What is called vitamin D toxicity is, in fact, calcium toxicity, and it occurs only in extreme
situations: when calcium intake is far too high; when the person has serious calcium-altering
diseases (e.g., primary hyperparathyroidism, tuberculosis, lymphoma, sarcoidosis, or other
granulomatous disorders); or when the person ingests doses of vitamin D in excess of 20 times
the upper recommended dose of 10,000IU for prolonged periods of time, which has happened
historically primarily as a result of errors in manufacturing, labelling, or prescribing.66,67
Even when hypervitaminosis D occurs, treatment is simple and permanent damage is
rare.68,69 A large ecological study of high vitamin D supplementation took place by accident
when in 1990-1992 a dairy in the Boston area accidentally fortified milk with 230,000IU/quart
instead of 400IU/quart: 575 times the intended amount.70 The overage remained undiscovered
for two years, as despite taking in this high dose day after day most customers did not become
ill; but eventually Boston area emergency departments linked the resultant approximately 19
cases of vitamin D toxicity to the dairy.70,71 The only sufferer who did not recover died of
pneumonia due to immune compromise from the prednisone given her as treatment, rather than
from effects of hypercalcemia.70,72 The jury found that the dairy’s dramatic error did not cause
the decedent’s death.72
Virtually all experts agree that up to 10,000IU/day of D3 is safe, long-term.66,67,73 Studies
of vitamin D supplementation consistently find no differences in adverse events between controls
and treatment groups, despite up to 50,000IU/day being given, long-term.46,7476 Patients
receiving short-term high dose (60,000IU/day) vitamin D3 therapy for Covid-19 raised their
25(OH)D levels to 39-113ng/ml without a significant increase in their calcium levels.77,78
III. Biological Plausibility: How vitamin D’s known mechanisms of action relate to Covid-19
Multiple vitamin D functions are relevant to Covid-19 outcomes. At the most basic level,
vitamin D reinforces natural barriers against respiratory tract invaders, preserving the tight, gap,
8
and adherin junctions between epithelial cells.52,79,80 Vitamin D strengthens the innate immune
response, significantly decreasing the likelihood of exposed individuals becoming ill with a
respiratory virus at all, with modest daily doses being far superior to larger monthly doses.74,76,81
Vitamin D also controls the adaptive immune response, providing a robust response to the viral
threat while calming excess inflammation, which should help prevent the acute respiratory
distress syndrome (ARDS) that is responsible for ~70% of Covid-19 fatalities.77,8183 Through its
regulation of the renin-angiotensin system (RAS), vitamin D directly limits the initial severe
Covid-19 complication, ARDS.22 Vitamin D also protects against thrombolytic events, which
affect 28% of ICU patients with Covid-19.22,82,84 Therefore, one should expect individuals with
higher vitamin D levels to be less likely to test positive for Covid-19, to be hospitalized due to
Covid-19, to require ICU or ventilator care, and to die of Covid-19. The evidence, reviewed later
in this chapter, supports this expectation.16
Optimal 25(OH)D levels can more than halve the incidence and significantly reduce the
duration of acute respiratory infections by enhancing the innate immune response, including
increasing vitamin D dependent antimicrobial peptides, such as cathelicidins and defensins.81,85,86
Cathelicidin LL-37 is antiviral, and it also helps regulate inflammation during illness.31,87
Supplementation with 4000IU/day of vitamin D decreased dengue virus infection.88
The adaptive immune response to SARS-CoV-2 relies upon memory and regulatory T
cells, which are heavily dependent upon adequate vitamin D levels.81,89 People who have had
asymptomatic or mild Covid-19 have robust memory T cell immunity which persists post
infection.90 In contrast, patients who died of severe Covid-19 had impaired T cell responses,
which would permit auto-immune responses while allowing the SARS-CoV-2 virus to reproduce
unchecked.25,90 Vitamin D regulates the adaptive immune response, recruiting neutrophils,
macrophages, and dendritic cells early in the infection while limiting maturation of dendritic
cells to prevent excessive inflammation.91 Vitamin D suppresses excess T helper type 2 cell
responses and induces T regulatory cells to inhibit inflammation, improving adaptive immune
system functioning.57
Vitamin D increases anti-inflammatory cytokines such as IL10 and decreases pro-
inflammatory cytokines such as IL1, IL6 and TNFα.16,32,91 Vitamin D deficient Covid-19 patients
had significantly higher serum IL-6, TNFα, and ferritin levels than did patients with higher
25(OH)D.92 Prospective trials of high-dose daily vitamin D treatment for Covid-19 have also
found significant decreases in inflammatory markers (CRP, IL6, LDH, fibrinogen, and ferritin)
when compared with pretreatment levels and controls.77,78 Vitamin D also inhibits MMP-9,
bradykinin, and CRP.83,93 Therefore, one would expect vitamin D to help prevent Covid-19’s
infamous cytokine or bradykinin “storm”.30,80
ACE2 receptors, to which SARS-CoV-2 binds in the lungs, are highly expressed on
surfactant-producing type 2 pneumocytes.83 By disrupting these pneumocytes, the virus
decreases surfactant production, causing the alveoli to collapse.83 Calcitriol increases ACE2
expression, which could prevent this complication.83 ACE2 helps protect the lungs against
ARDS.32 Vitamin D deficiency, which is more common in older males than females in many
areas, is associated with increased X-chromosome-linked RAS activity.22,94 For this reason,
males are far more susceptible to ACE2 receptor dysregulation and the resultant hyper-
inflammation that is the hallmark of severe Covid-19.94 This role of vitamin D alone strongly
suggests a protective role against severe Covid-19.22
Thromboembolism affects 28-50% of Covid-19 patients in the ICU, resulting in
significant morbidity and mortality.22,95 These appear to be cases of anti-phospholipid syndrome,
9
which is often directly related to low vitamin D.22 Microcirculatory dysfunction in patients with
severe Covid-19 appears to be related to endotheliopathy.96 Endothelium destabilization by
inflammatory cytokines, found in hypertension, diabetes mellitus, chronic renal failure,
atherosclerosis, and many other inflammatory diseases, causes dysregulated clotting.6,91 All of
these conditions are associated with low levels of vitamin D, which is known to stabilize the
endothelium.6,16 Vitamin D supplementation has successfully corrected high levels of
inflammatory cytokines, including TNF-α, IL-6, and CRP.83,91 Vitamin D’s induction of LL37
would lead to decreased expression of inflammatory IL17, which is abnormally high in Covid-19
and can lead to thrombosis and ARDS.32 Low vitamin D is also implicated in higher levels of
cellular adhesion molecules.91 Vitamin D supplementation has been shown to decrease thrombus
formation directly in high risk patients.91
A recent study demonstrated that inadequate vitamin D levels can result in a poor
immune response to vaccines in elderly individuals, which has clear implications for
recommendations during the Covid-19 pandemic.97
IV. Correlational evidence regarding serum vitamin D levels and Covid-19 outcomes
As early as February, 2020, experts were presenting evidence to support the hypothesis
that low vitamin D has a dramatic influence on Covid-19 outcomes.98 It was clear that the
populations with the worst Covid-19 outcomes are the exact same populations who tend to have
the lowest vitamin D levels: the elderly, males, people with metabolic syndrome-related illnesses
like diabetes, obesity, hypertension, and kidney failure, people whose area had just experienced
winter, and people with melanin-rich skin who do get not consistent exposure to the tropical
sun.16
Dramatically, of the first 10 physicians in the UK to die of Covid-19, all had naturally
melanin-rich skin, and by the time 119 NHS staff had succumbed, the fact that people with
melanin-rich skin living outside the tropics are at much higher risk was undeniable in the USA,
as well.99,100 On 29 April 2020 a communication went out to all “BAME” working doctors in
England and Wales, warning them that they could be at high risk for Covid-19 due to vitamin D
deficiency, and urging supplementation, including a high loading dose: three days later, the
deaths in this group came to an abrupt end.101 Meanwhile, despite poverty and poor health
infrastructure, Africans living in the tropics have still not succumbed in large numbers.102
Ockham’s Razor, “Do not multiply entities without necessity” (The simplest explanation is likely
to be true) would appear to apply.103
For some vitamin D experts, a devastating viral pandemic had been anticipated; they had
long been watching the immune systems of populations around the world become increasingly
dysregulated due to lower vitamin D levels, particularly in winter.60,104,105 Eerily, every symptom
of severe Covid-19 could be explained by inadequate vitamin D.16 Their strong response (there
were already 181 scholarly works on the topic by mid-June, 2020) was to document what
appeared to be a clear relationship between lower vitamin D levels and worse Covid-19
outcomes in order to persuade public health authorities to support widespread supplementation
16. This early documentation came primarily in the form of biological plausibility presentations,
population (geographical) evidence analyses, prospective correlational studies, and retrospective
chart reviews (see links at www.vitaminDforAll.org).16,106 (Figure 4, page 10)
These forms of evidence have increased daily. Today, in addition to the earlier evidence
types, some intervention studies and dozens of meta-analyses and systematic reviews on the
10
relationship between vitamin D levels and Covid-19 can be found with a quick PubMed search.
Only a few examples are detailed here.
Figure 4: Early study demonstrating a dramatic correlation between lower vitamin D levels and
worse Covid-19 outcomes.92 (Figure: original work of Richard Benskin. Data from Jain, et al., Scientific Reports. 2020)
A. Evidence based population data (geographical, ecological)
Pugach and Pugach evaluated recent reliable data on the country-wide prevalence of
vitamin D deficiency in 10 European countries, finding a statistically significant and linear
relationship between prevalence of vitamin D deficiency and deaths/million from Covid-19.107
Adjusting for the countries’ age structure and health expenditures, each 1% increase In severe
vitamin D deficiency increased deaths from Covid-19 by 55/million.107
Walrand challenged the widely held belief that Covid-19 cases increase in winter due to
cooler temperatures.108 Using automatic fitting software to compare case data for 18 countries
against temperature and UV radiation (adjusted for latitude and time of year) 2 weeks prior, he
determined that the autumn 2020 “surge” in Covid-19 cases in Europe was completely unrelated
to temperatures but was significantly related to decreased sunshine, and predicted that the crisis
would continue until spring (which it did).108,109
A group of Italian researchers led by Isaia and Diémoz noted that despite uniform
exposure prevention measures throughout the country, the Covid-19 pandemic hit northern Italy
much harder than it hit southern Italy.110 A literature search for potential environmental causes
yielded UVB for its ability to increase population vitamin D levels.110 Taking into account air
quality, they calculated the UVB exposure for residents in each of the 20 regions from June-Dec
2019: the time leading up to the pandemic.110 They also compared air temperature, relative
humidity, population age, percentage in nursing homes, and potentially relevant comorbidities.110
Univariate regression found that 74.2% of the variation in Covid-19 fatalities between districts
and 41.4% of the variation in cases between districts was explained by vitamin D producing UV
light in the preceding months, far more than any other parameter.110
A group led by Jayawardena compared population vitamin D deficiency prevalence from
the past 10 years (mostly in the past 5 years) with Covid-19 cases and fatalities per million in 24
countries in Asia, an area with dramatically divergent Covid-19 outcomes, as of Dec 31, 2020.111
Vitamin D deficiency, defined as 25(OH)D<20ng/ml affected over 50% of the adults in three-
fourths of these countries, in part due to customs which limit sunlight exposure.111 Covid-19
cases/million population and fatalities/million were positively correlated with the prevalence of
11
vitamin D deficiency (cases: r=0.55, p=0.01; fatalities: r=0.50, p=0.01).111 The variation of total
cases and total fatalities can be attributed to vitamin D deficiency at proportions of 33% for cases
and 25% for fatalities.111
B. Evidence based on individual data (chart reviews)
Early chart reviews demonstrating that lower vitamin D levels were correlated with worse
Covid-19 outcomes were criticized because it is known that illness can cause vitamin D levels to
decline.4,112 Although this decline would not explain the dramatic differences some of these
studies found,112 more recent studies often use vitamin D levels taken weeks or months prior to
infection to eliminate this confounder. The four such studies summarized here all corroborate the
conclusions of earlier researchers.
Merzon’s group in Israel found that over half (7807) of the 14,022 patients in their health
maintenance organization’s database who were tested for Covid-19 in Feb-April of 2020 had a
previous 25(OH)D level on file.113 The proportion who tested positive was the same for those
with and those without recorded vitamin D levels.113 After controlling for demographic,
psychiatric, and somatic variables, multivariate analysis demonstrated a significant and
independent association between 25(OH)D below 30ng/ml and positive PCR results [1.45 (95%
CI: 1.081.95, p<0.001)].113 Plasma 25(OH)D under 20mg/ml almost doubled the risk of
hospitalization due to Covid-19.113
Researchers accessed a de-identified laboratory database with 191,779 patients from all
50 US states who had both PCR tests for Covid-19 and 25(OH)D levels from the preceding 12
months, using zip code data to determine race/ethnicity proportions and latitude.50 Patients with
seasonally adjusted 25(OH)D levels below 20ng/ml were significantly more likely to test
positive for Covid-1950 and those with levels ≥55ng/ml were the least likely to test positive.50 A
multivariate logistic model demonstrated that the relationship is robust, remaining significant
(ORadj 0.984 per ng/mL increment, 95% C.I. 0.9830.986; p<0.001) when adjusted across
latitudes, race/ethnicity, sex, and age ranges.50
A large Chicago-based medical center database was mined for a relationship between
vitamin D levels within the previous year and positive Covid-19 test results as of Dec 30,
2020.114 Treatment for deficiency was factored into the results to provide an estimate of
concurrent vitamin D levels.114 A total of 4638 individuals were included in the study, of whom
48% were black.114 Black patients had significantly lower vitamin D levels than did white
patients.114 Of the 333 patients with Covid-19 positive tests, over two-thirds were black.114
Multivariate analysis found that a negative Covid-19 test was associated with vitamin D level
>30ng/ml (IRR 0.97 (95% CL=0.94-0.99; P=0.008) per 1-ng/ml increase in vitamin D) with an
even greater effect in black patients.114 The authors found that 40ng/ml, rather than 30ng/ml, was
the level at which vitamin D became significantly protective against Covid-19, leading them to
recommend supplementation with 10,000IU of vitamin D3/day.114
Using a 987,849 patient database in Florida, Katz, Yue, and Xue searched ICD 10 codes
for Covid-19 patients for vitamin D deficiency, diabetes, obesity, malabsorption, and dental
diseases diagnosed in the previous 5 years.115 The researchers found that 887 had a Covid-19
diagnosis, 31950 had vitamin D deficiency, and 87 had both.115 Those with both were more
likely to be male, and only 12% were white.115 Vitamin D deficient patients were 4.6 times more
likely to test Covid-19 positive than patients without this diagnosis.115 The association remained
highly significant (p<0.001) even after controlling for all comorbidities.115 After adjusting for
age, it was determined that patients diagnosed as vitamin D deficient were 5 times more likely to
12
be infected with SARS-CoV-2 as those without this diagnosis (OR=5.155) 95% CI 3.974-6.688,
P<0.001).115
C. Evidence based on meta-analyses and systematic reviews
At least 26 systematic and basic review and meta-analysis papers on the topic of the
relationship between Covid-19 outcomes and vitamin D levels have been published to date (see
Table 1, pages 18-19).
An early meta-analysis of 10 case control studies found, in the pooled analysis, that
vitamin D deficiency or insufficiency, defined as 25(OH)D < 30ng/ml, significantly increased
the odds of contracting Covid-19 (OR=1.43,95%, CI=1.002.05).116 In addition, the average
vitamin D level of Covid-19 positive groups was significantly lower than that of negative groups
(SMD=-0.37,95% CI=-0.52 to -0.21, I2=89.6%).116
Oscanoa’s group evaluated the 23 observational studies published by the end of 2020 to
determine the relationship between Covid-19 severity and mortality and vitamin D levels.4
Pooled results demonstrated that vitamin D deficiency is associated with significantly increased
risks of poor Covid-19 outcomes, with 17 studies addressing severe Covid-19 (RR 2.00; 95%
CL=1.472.71) and 13 addressing mortality (RR 2.45; 95% CL=1.244.84).4
The first meta-analysis to include only intervention studies which all had a very low risk
of bias found that vitamin D supplementation clearly decreases Covid-19 mortality (pooled
OR=0.264, 95% CI=0.0990.708, p=0.008) and two studies demonstrated a significant
(p=0.001) decrease in OSCI severity scores.117 The four studies included in this analysis will be
further discussed in the next section.
A large rigorous meta-analysis of studies examined 39 cohort, randomized controlled
trials, and cross-sectional studies as of 26 Nov 2020, excluding all preprints.31 ORs and CIs were
reported for each outcome by pooling studies based upon the statistical adjustments used by the
authors.31 Kazemi, et al., found that vitamin D was strongly associated with Covid-19 mortality
and severity, and is also likely a factor in infection rates, although those study designs were less
strong.31 The evidence for decreasing inflammatory markers and hospital, ICU, and ventilator
utilization was less clear.31 In one study, the probability of a fatal outcome was ten times higher
if 25(OH)D was less than 10ng/ml than if it was more than 10ng/ml.31,118
Authors of a June 2021 meta-analysis of 13 vitamin D intervention studies that reported
ICU admissions, severity and/or fatality rates for Covid-19 patients found that cholecalciferol
(11 studies) or calcifediol (2 studies) supplementation significantly reduced risk of ICU
admissions/mortality (pooled OR 0.41, 95% CL=0.20, 0.81, p=0.01, I2=66%, random-effects
model) and adverse outcomes (pooled OR 0.27, 95% CL= 0.08, 0.91, p=0.03, 2I=80%, random-
effects model).32
A meta-analysis in July 2021 found 13 RCTs, quasi-RCTs and observational studies
meeting the authors’ quality criteria which included individual vitamin D levels upon testing for
infection. The researchers determined that low 25(OH)D is statistically significantly associated
with risk of Covid-19 infection, recommending supplementation for high risk and deficient
groups.119 Another meta-analysis published in June evaluated 23 studies both qualitatively and
quantitatively, finding that Covid-19 patients all had low mean 25(OH)D levels, and D
deficiency was associated with a 3x higher risk of infection and 5x higher risk of severe Covid-
19.120
The clear consensus of these meta-analysis authors is that there is a strong relationship
between vitamin D levels and Covid-19 outcomes. The studies reviewed demonstrated that
13
vitamin D supplementation and/or higher vitamin D levels are associated with decreased chances
of developing Covid-19 infection; decreased chance of developing severe Covid-19; decreased
chance of requiring oxygen, hospitalization, ICU care, or mechanical ventilation; and decreased
chance of death due to Covid-19 (see Table 1, pages 18-19). Vitamin D supplementation is also
associated with a decrease in fibrinogen, an inflammatory marker.78
Despite this powerful evidence, public health officials continued to call for randomized
controlled trials. The question of causation had to be addressed, particularly for those unfamiliar
with the biological plausibility of the relationship.
IV. Evidence that vitamin D is a causal factor in poor Covid-19 outcomes
Calls for randomized controlled trials to prove a causal relationship cannot, however, be
heeded by most vitamin D experts. Vitamin D is not a novel drug which may or may not be
beneficial, but rather, it is known to be essential to human health. A scientist who believes that
low vitamin D levels are responsible for high mortality rates cannot ethically withhold this life-
saving substance from the placebo group.121,122
A. Early causal modeling studies
This ethical dilemma was solved in 1965 by Sir Bradford Hill, who developed a causal
model to demonstrate that smoking is a cause of lung cancer. Hill’s criteria were used to
demonstrate that low vitamin D is a cause of severe Covid-19 in a MEDLINE indexed article in
May of 2020.123 Vitamin D met all but one of Hill’s criteria, specificity, which it failed only
because vitamin D deficiency is ubiquitous.123 Later authors concurred that the evidence to date
satisfied Hill’s criteria (strength of association, consistency, temporality, biological gradient,
plausibility, and coherence), clearly demonstrating causality.83
The idea that robust vitamin D levels are merely a marker for good health (a “bystander”)
has persisted in part because sick people are less likely to spend time outdoors, and because
vitamin D is consumed in slightly higher quantities during illness. Davies, Garami, & Byers
noticed a strong relationship between early Covid-19 fatalities and latitude.124 This observation
led them to create a causal inference framework specific to testing the vitamin D hypothesis.124
The model produced strong evidence that Vitamin D was a cause of Covid-19 fatalities, and
moderate evidence for vitamin D causing cases, with causation fitting the data for 16
predictions.124 The bystander model for vitamin D was strongly contradicted by the data for 14
predictions.124
B. Intervention studies
Calls for RCTs continued, and several have been conducted. However, the study designs
often reveal a lack of insight into how vitamin D is utilized by the body. Giving oral
cholecalciferol to patients who already have severe Covid-19 is clearly unlikely to be effective
(see section IIA, pages 3-4, Defining vitamin D). In addition, the response curve for vitamin D is
S-shaped, not linear.121,125 Therefore, providing vitamin D to individuals whose levels are
already replete will not demonstrate a benefit, and giving inadequate doses to people who are
severely deficient may not bring their levels up high enough to provide immune benefits.121,125
Because either of these common scenarios can make an intervention that could be life-saving for
people whose vitamin D levels are in between these extremes appear ineffective, and because
14
individual supplementation response is influenced by genetics, obesity, diabetes, etc., trials must
be guided by participant 25(OH)D levels.16,125,126
Vitamin D requirements for immune health are far higher than those for bone health.16,58
Virtually any medication can be “proven” ineffective by a study in which only 1/10 the required
dose is given. Dosing intervals are also of critical importance in vitamin D trials; studies have
shown that large infrequent boluses can prevent the formation of new calcifediol for at least 28
days, and are instead broken down by the body relatively quickly, with the by product, calcitroic
acid, being indistinguishable from active calcifediol to most 25(OH)D tests.36,37,41,74,122,127
Finally, in recent Covid-19 trials, some large-seeming studies had relatively few participants who
were actually exposed to SARS-CoV-2 during the study period.128
Beginning in late 2020, an increasing number of innovative intervention studies were
published demonstrating a clear causal relationship between low vitamin D levels and worse
Covid-19 outcomes. (See Table 2, pages 20-21, for summaries of these studies as of June 2021,
along with odds ratios, hazard ratios, confidence intervals, and other statistical findings.)
Several researchers evaluated Covid-19 outcomes for individuals who were already
supplementing with vitamin D. Annweiler published two quasi-experimental studies which
found that if frail elderly people in long term care or in a hospital geriatric ward had been given a
cholecalciferol bolus (50,000-80,000IU) more recently, their subsequent cases of Covid-19 were
statistically significantly less likely to be as severe when compared with their counterparts who
had not had the supplemental D3 as recently.79,129 Both studies also found that the recently
supplemented frail elderly patients were over three times less likely to die than those who did not
receive supplements recently.79,129 Cangiano’s team found that, when compared with no vitamin
D supplements, routine vitamin D3 supplements of any kind also decreased the risk of Covid-19
mortality in nursing home residents to less than a third that of the unsupplemented group.130
In a study in which only 19 hospitalized patients had a history of any vitamin D
supplementation (usually monthly) and 82% of the patients had very low 25(OH)D levels on
admission (mean 13.8ng/ml), Hernandez, et al., found that vitamin D seemed to improve several
indicators of Covid-19 severity, but none reached statistical significance.131
Oristrell compared the electronic health records (EHR) of 6252 patients who were on
calcitriol for severe kidney disease or hypoparathyroidism with matched controls, finding a
significant (p=0.002) and progressive decline in risk of severe Covid-19 with increasing doses of
calcitriol.132 End stage renal disease patients were also significantly less likely to have become
infected with Covid-19 (p=0.010).132 The likelihood of fatal Covid-19 was decreased (p=0.031)
for all patients taking calcitriol.132
During the height of the Covid-19 pandemic, Fasano’s group conducted telephone
interviews of 1486 Parkinson’s patients who had attended their practice, finding that the 329 who
regularly took cholecalciferol supplements were about half as likely to have tested positive for
Covid-19.133
Two groups of researchers mined large EHR databases to explore the relationship
between vitamin D supplement prescriptions and testing positive for Covid-19.134,135 Ma, et al.,
looked at 8207 records from over 10 years prior to the pandemic, while Israel looked at 2794
records from within 4 months of testing.134,135 Ma, et al., found that “habitual” vitamin D
supplementation was associated with a 34% decrease in Covid-19 cases, while Israel et al., found
that recent supplementation with vitamin D3 drops decreased Covid-19 cases, but not with
tablets, perhaps because the tablets were so costly that they were likely to be prescribed only to
patients with severe vitamin D deficiency.134,135
15
Loucera, et al., mined a database with 16401 hospitalized Covid-19 patients to see if the
1203 who were prescribed vitamin D supplements in the 15 or 30 days prior to their
hospitalization were more likely to survive than those who were not prescribed D.136 They found
a significant reduction in mortality, which was larger if the form of vitamin D was calcifediol or
the prescription was only 15 days prior to hospitalization p=0.003).136
Two research groups in India each gave 60,000IU/day of cholecalciferol to outpatients
who tested positive for Covid-19 and compared their inflammatory marker levels with
controls.77,78 Lakkireddy, et al., found that vitamin D3 decreased CRP, LDH, IL-6, Ferritin, and
the N/L ratio with a significance of p=0.0004 or better, while in the control group several of
these markers increased and only CRP levels improved.77 Rastogi, et al., found that in the D3
supplemented group fibrinogen decreased more quickly (p=0.007) and that three times as many
in the treatment group achieved Covid-19 PCR test negativity by day 21 (62.5% vs 20.8%,
p=0.018).78 The more rapid viral clearance was expected to result in less chance of spreading
Covid-19 and a more rapid return to work.78
Patients were given a one-time large dose of cholecalciferol after hospitalization for
Covid-19 in three studies.137139 In two of these intervention studies plus a third in which lesser
doses of cholecalciferol were given at regular intervals, patients with 25(OH)D levels less than
20ng/ml were more likely to receive supplementation.138140 It is quite possible that many of
these patients subsequently enjoyed higher 25(OH)D levels than some of the initially "vitamin D
sufficient" patients.138140 In a fourth study, the one-time large dose of cholecalciferol was given
an average of 10.3 days after symptom onset.137 It is likely that much of the cholecalciferol given
to seriously ill patients in these four studies was immediately broken down into calcitroic acid
and that calcifediol levels were actually depressed as a result of the boluses.36,37,41 Despite this
concern, none of the treatment groups fared worse than the controls.137140 The researchers who
gave lesser doses of cholecalciferol at regular intervals found that this treatment led to
significantly (p=0.001) fewer mortalities when compared with unsupplemented patients.139
Two research groups compared D3 supplementation at 1000IU/day with a higher daily
dose in hospitalized Covid-19 patients to evaluate the differences in severity of symptoms.141,142
In a case series with four patients, Ohaebulam, et al., found that 50,000IU/day led to shorter
lengths of stay, lower oxygen requirements, decreased CRP and LDH, and a dramatic drop in IL-
6 compared with patients who received 1000IU/day, whose 25(OH)D levels did not increase.141
The second study was a 69 patient randomized controlled trial in which, again, 25(OH)D levels
did not increase for the 1000IU/day group.142 These researchers found that 5000IU/day for two
weeks led to significantly quicker resolution of cough (p=0.039) and loss of taste (p=0.035).142
A historical cohort study compared previously treated hospital patients with the next 17
patients, who were managed with the same treatment protocols, but with the addition of 1000IU
D3 + 500mcg B12 + 150mg magnesium (DBM) daily, assessing for new need for oxygen or ICU
care.143 New oxygen need decreased from 61.5% to 17.6% (multivariate-adjusted p=0.006), and
the need for ICU care decreased from 30.8% to 5.9%.143 The authors called for a randomized
controlled trial of their DBM treatment protocol.143
In an anecdotal published report, physicians at the Iranian Hospital in Dubai, UAE
described their Covid-19 vitamin D supplementation protocol, which is individualized according
to the patient’s weight and 25(OH)D level.59 Asserting that typical endocrine societies guidelines
suggest that 40-60ng/ml is the ideal 25(OH)D level, they routinely aggressively supplement with
70-100IU of D3 per kg per day in their neuro-ophthalmology department without any cases of
toxicity.59 Finding that, despite their high risk, none of their patients who contracted Covid-19
16
had a severe case, they recommended this dosage plus an initial bolus of 300,000IU IM for all
Covid-19 admissions, which they report resulted in the ICU being completely cleared of Covid-
19 patients.59
Researchers for three studies conducted in several hospitals in Spain addressed the
problem of slow metabolism of cholecalciferol by giving patients moderately high doses of
calcifediol early in their hospitalization and at regular intervals.144147 This protocol consistently
resulted in a dramatic decline in ICU admissions and mortality rates. In the pilot study, the ICU
admission rate for the treated patients was 2% with no fatalities, compared with a 50% ICU
admission and 7.7% fatality rate for the untreated patients.144 A second trial of the same
calcifediol protocol resulted in a decrease in fatalities from 20% for the control group to only 5%
in the treatment group.145 The third study resulted in 4.5% of the vitamin D supplementation
group being admitted to ICU, compared with 21% in the control group.146 In 53 cases, physicians
believed that an ICU patient in the control group might be rescued by giving them calcifediol.146
Mortality for the original study groups was 4.7% for the treatment group and 15.9% for the
control group.146 If the 53 control group patients who received calcifediol only after being
admitted to the ICU are added to the treatment group, the mortality for the treatment group
increases to 7.2% and mortality for the control group decreases to 13.9% (p=0.001).146 The
researchers noted that the patients who died had lower baseline 25(OH)D levels (9ng/ml) than
the ones who survived (13ng/ml).146
These intervention studies all strongly support the hypothesis that low serum calcifediol
levels are a significant causal factor in poor Covid-19 outcomes.
C. Future Research Opportunities
Several of the research studies described above show enough promise that expanding
upon them is likely to be beneficial. In addition, much more needs to be learned about the
relationship between supplementation and calcifediol levels.
Research priorities during the Covid-19 pandemic are:
A rigorous, multi-center study of the calcifediol supplementation protocol used in the
three highly successful Spanish studies for hospitalized Covid-19 patients
A longitudinal study comparing individuals who take daily D3 supplements at various
doses to determine the optimal usual dose based upon percent body fat
A large EHR study of individuals with 25(OH)D levels taken within the past year,
comparing Covid-19 infection, hospitalization, ICU admission, and fatality rates between
those with levels over 50ng/ml and those the levels that are 20-30ng/ml.
V. Specific recommendations for Vitamin D supplementation to improve Covid-19
outcomes
Several groups of experts have called for widespread vitamin D supplementation to help
prevent poor Covid-19 outcomes. The largest group is VitaminDforAll.org, a coalition
representing 220 professors, medical doctors, and PhD vitamin D experts from 33 countries.106
Every signatory recommends universal supplementation with 4000IU/day of vitamin D3 (or at
least 2000IU/day) in the absence of testing, with the goal of raising 25(OH)D levels to at least
30ng/ml.106 Those at especially high risk for deficiency (due to weight, frailty, dark skin) are
encouraged to consider doubling that dose.106 Individuals who have not previously taken vitamin
D supplements should take D3 10,000IU/day for 2-3 weeks initially, or until serum 25(OH)D
17
levels can be drawn, then drop to the above amounts.106
The Italian Academy of Medicine of Turin letter, signed by a group of 152 Italian
professors and physicians, also calls for universal supplementation with D3 4000IU/day, but with
a goal of acquiring 25(OH)D levels of 40ng/ml.148 The French La Revue du Praticien, signed by
73 French authors with the support of 6 national scientific societies, calls for prophylaxis with D3
of 1200IU/day, or double that amount for obesity, noting that 4000IU/day is safe.149 The Health
Committee of the Legislature of Ireland (Oireachtas) recommends daily vitamin D
supplementation of 800-1000IU for the entire adult population, with higher doses for vulnerable
groups, along with public education and encouragement, including reducing the cost and making
supplementation an opt-out.150,151
The vitaminDforAll.org coalition and Italian Academy of Medicine of Turin letter both
recommend that all hospitalized Covid-19 patients have 25(OH)D levels drawn upon admission
and be treated with calcifediol or D3, using a protocol for calcifediol such as the one the three
Spanish trials used so successfully or the cholecalciferol 60,000IU/day used successfully by
Rastogi, et al.106,148 The French La Revue du Praticien recommends D3 100,000IU upon
diagnosis, to be repeated 7 days later.149
Based upon the totality of the evidence, the vitaminDforAll.org recommendation:
4000IU per day as maintenance for all adults without medical contraindications
10,000IU/day for 2-3 weeks initially for those not previously supplemented
adjusted to meet a goal serum 25(OH)D of at minimum 30ng/ml
should be safe (all studies support this), and is the most likely to be effective.
CONFLICT OF INTEREST DISCLOSURE
Linda Benskin is the sole author of this chapter, with no conflicts of interest to declare.
ACKNOWLEDGEMENTS
The author wishes to thank the vitaminDforAll group; Robin Whittle, Barbara Boucher, Peter
Cobbold, William B Grant, and Scott Reid; John Newton, and most especially Richard Benskin,
for their invaluable advice, edit suggestions, and encouragement.
ABBREVIATIONS
ARDS acute respiratory distress syndrome
RAS renin-angiotension system
EHR electronic health record
18
Table 1 - Summary of Systematic and Basic Reviews and Meta-analyses Specific to Covid-19 and Vitamin D
Reference
Search
end date
Number and
types of evidence
Specific studies included (first author)
D related conclusions
Akbar et al,
2021152
9Dec20
14 observational
cutoff of 20-30ng/ml
Abrishami, Backtash, Cereda, Hastie,
Hernandez, Im, Jain, Katz, Luo, Maghbooli,
Meltzer, Merzon, Radujkovic, De Smet
Low D sig assoc with infection,
severity, & fatality
Artusi et al,
2021153
10Jan21
16 Parkinson’s
observational studies
Only one study in this meta-analysis included
vitamin D: (Fasano, Lombardy, Italy)
22.9% vs 12.4% case rate with D
supplementation
Bassatne et
al, 2021154
20Jan21
31 observational D
3 intervention trials
Removed Maghbooli dt expression of concern
Removed studies that used higher cutoffs for low
D than authors required, etc.
No significant findings. Maybe
calcifediol in ICU.
Benskin
202016
16Jun20
47 human research
studies of any type
Basic review summaries of each study
See list early studies none interventional
D assoc with high mortality:16
studies, cases: 17, higher severity:
10
Chamberg
o-Michilot
et al,
2021155
1Apr21
4 case controlled
2 cross-sectional
Fasano & Sainz-Amo included D in reports
Both found that D supplementation lowers risk
for Covid-19 cases, not stat sig in Sainz-Amo
Low D significantly increases risk
of Covid-19 infection
Chen et al,
2020156
1Oct20
6 with multivariate
analysis
Chang, Hastie, Meltzer, Mendy, Merzon,
Radujkovic,
Low D assoc. with incr. infection:
47%, hospital: 83%, poss. death,
no dose response
Damayanthi
et al,
2021157
2020
3 related to D specif.
Tan, Annweiler, Annweiler
Each study result
Das et al,
2020158
3Nov20
11 studies, cohort,
cross-sectional, case-
control, no RCTs.
Abishami, Maghbooli, Radujkovic, Hastie, Otros,
Merzon, Meltzer, Ye, Kaufman, D’Avolio,
Baktash
(authors are doing major revision)
5.84x >chance die 2.2x >chance
severe, also > chance infection
Drame et
al, 2021159
15Mar21
11 age 60+ only
4 supplement or no
7 deficient or no
Annweiler, Annweiler, Giannini, Tan (age 60+
data extracted), Baktash, Carpagnano, Cereda,
Hars, Macaya, Radujkovic, Sulli
Overall, studies support D for O2 &
vent needs, severity, & death
Ghasemian
et al,
2021120
18Dec20
23 for quantitative
and qualitative
analysis
Meltzer, Merzon, Nicola, Faul, Carpagnano,
Macaya, Hamza, Karahan, Abdollahi, Arvinte,
Cereda, Panagiotou, Radujkovic, Hernandez,
Jain, Im, Baktash, Vassiliou, Ye, Maghbooli,
Ling, Luo, Karonova,
Covid-19 patients all had low
mean 25(OH)D levels. D
deficiency was associated with a
3x higher risk of infection and 5x
higher risk of severe Covid-19.
Grove et al,
2021160
10Jun20
SARS, MERS, Covid-
19 yielded only 4
quant, 12 qualitative
Quant: only D’Avolio, Hastie, Ilie, Fasano:
search should have found more. Qual: not listed
because they had not yet passed the peer-
review process at time of publication
It is speculative to even consider
that vitamin D could have a role.
Kazemi et
al, 202131
26Nov20
39 cohort, RCT, case-
control or cross-
sectional -no
preprint
Very rigorous review
Bahat, Baktash, Blanch-Rubio, D’Avolio, De
Smet, Ferrari, Hernandez, Im, Kerget, Jain,
Mardani, Meltzer, Merzon, Sun, Ye, Yilmaz,
Abrishami, Anjum, Annweiler, Luo, Annweiler,
Arvinte, Bagheri, Castillo, Cereda, Haraj, Faul,
Goncalves, Hamza, Karahan, Saronova,
Macaya, Maghbooli, Panagiotou, Pizzini, Perez,
Radujkovic, Rastogi, Carpagnano
D assoc with severity: definitely
mortality: yes
infection: yes
ICU admit, vent, hosp, & inflam:
results inconsistent
Liu et al,
2021116
25Sep20
10 observational
(case control) studies
Baktash, Avolio, Hastie, Raisi-Estabragh,
Chodick, Im, Mardani, Merzon, Ye, Meltzer
(Hastie eliminated due to age of data)
Low D assoc with increased risk
lower D → PCR+
Mercola et
al, 202083
15Oct20
14 observational
3 large population
Hastie, D’Avolio, Panagiotou, Carpagnano, Im,
Karonova, Tort, Baktash, Hastie, Radujkovic,
Pizzini, Macaya, Ye,
Large population: Merzon, Meltzer, Kaufman
Evidence is strong for D assoc
with incidence and severity
Munshi et
al, 2020161
8Jun20
6 including MedRxiv
and case series
Lau, D’Avolio, Tian, Faul, De Smet, Prinzon all
from April and May 2020
Pooled results show D influences
prognosis (signif)
Nikniaz et
al, 2021117
16Dec20
D supplementation
4 RCT & quasi
Annweiler, Annweiler, Castillo, Rastogi all very
low risk of bias according to JBI
2: lower mortality
Improved severity
1: ICU, fibrinogen
19
Oscanoa et
al, 20214
Dec20
23 studies all
observational
Carpagnano, Panagiotou, Alipio, De Smet, Lau,
Radujkovic, Baktash, Mardani, Pepkowitz,
Macaya, Hars, Ye, Yilmaz, Im, Hernandez,
Campi, Abrishami, Walk, Karonova, Luo,
Cereda, Jain, Karahan
Deficiency assoc with higher risks
of severe & mortality
Pal et al,
202132
8 Jun21
13: ICU & death only
3RCTs;10observation
Annweiler, Annweiler, Ling, Giannini,
Hernandez, Jevalikar, Cereda, Alcala-Diaz,
Lohia, Cangiano, Castillo, Murai, Lakkireddy
D supplem assoc with reduced
ICU, severity, mortality
Pereira et
al, 2021162
9Oct20
27 observational
Alipio, Baktash, Carpagnano, Cunat, D’Avolio,
Darling, Lau, Faniyi, Faul, Hastie, Karonova,
Macaya, Maghbooli, Mardani, Meltzer, Smet,
Mendy, Merzon, Panagiotou, Pinzon, Pizzini,
Radujkovic, Raharusun, Raisi, Sun, Im, Glicio
D deficiency assoc w severe,
hosp, & mortality, but not infection
dt Hastie & Darling
Petrelli et
al, 2020163
31Jan21
35 Observational
only
8 supplement effect
Abdollahi, Abrishami, Alguwaihes, Annweiler,
Annweiler, Baktash, Barassi, Bennouar, Blanch-
Rubio, Cangiano, Carpagnano, Cereda, Chang,
De Smet, Demir, Castillo, Ferrari, Giannini,
Hastie, Hernandez, Jain, Karahan, Katz,
Kaufman, Li, Ling, Lohia, Luo, Ma, Macaya,
Maghbooli, Mardani, Meltzer, Mendy, Merzon,
Pal, Panagiotou, Radujkovic, Raisi-Estabragh,
Szeto, Tan, Vessiliou, Ye
D deficiency associated with
infection, severity, & fatality rates
Rothenberg
et al,
2021164
13 Jan 21
All types, only elderly
Benskin, Castillo, Kaufman, Radujkovic, Pizzini
all of which were discounted by the authors.
Omitted at least 3 intervention studies on elderly,
D and Covid-19 found using their exact search
terms & dates (Annweiler, Annweiler, and Tan)
Narrative review inconclusive
Szarpak et
al, 2021119
10May21
RCTs, quasi-RCTs,
and observational
with 25(OH)D levels
Abdollahi, Aguwalhes, Al-Daghri, Baktash,
D’Avolio, Hernandez, Im, Livingston, Mardani,
Merzon, Raisi-Estabragh, Sulli, Ye
Low 25(OH)D is statistically
significantly associated with risk of
Covid-19 infection. Supplements of
vitamin D are indicated, especially
for high-risk and deficient groups.
Shah et al,
2021165
17Dec20
3 RCTs only
Murai, Hernandez, Castillo
Insufficient studies
Stroehlein
et al,
2021166
1Mar21
3 RCTs only
Murai, Hernandez, Castillo
May decrease ventilator need
Teshome et
al, 2021167
20Dec 20
14 qual,
of these, 8 quant*
Meltzer,* Raharusun, Merzon,* Hastie, De
Smet,* D’Avolio, Abdollahi,* Ye,* Hernandez,*
Kaufman,* Yilmaz,* Maghbooli, Panagiotou,
Alguwaihes,
D deficiency was signif assoc with
infection risk (80% more likely)
Wang et al,
2021168
3Dec20
17 observational
De Smet, Carpagnano, Jain, Hars, Cereda, Luo,
Hernandez, Abrishami, Ye, Baktash, Mendy, Im,
Mardani, Macaya, Pizzini, , Radujkovic, Anjum
D deficiency signif assoc with
hosp, mortality, stays,
not ICU admission
Yadav et al,
2021169
5Jun20
3 chart reviews
Ilie, Hastie, D’Avolio
Only circumstantial evidence
Yisak et al,
2021170
Sept20
9 observational
(each study is
described)
Mendy, Hastie, Raisi-Estabragh, Ali, Merzon,
Daneshkhah, Carpagnano, Entrenas Castillo,
Fasano
7 with recent D: assoc infection,
severity, & death
20
Table 2 Summary of Intervention Studies
Study
Setting
Study Type:
Intervention
N/
total
Outcomes
Measured
Results
Recommendation
Hospital
Retrospective cohort:
Calcifediol 0.266mg x2 at
admit + day 3,7,14,21,28
79/
537
Mortality
5% vs 20%
OR=0.22, 95% CI=0.08 - 0.61, p<0.01
MVA: OR=0.16, 95% CI=0.03 - 0.80 sig
Conducting large RCT
of this calcifediol
treatment
Alcala-
Diaz et al,
2021145
Nursing
home
Quasi-experimental:
80,000IU D3 <-1-4wks
prior to Covid vs >4wks
57/
66
Mortality
OSCI score
Mortality: 17.5% vs 55.6% p=0.023
HRadj =0.11, 95% CI:0.03 - 0.48, p=0.003
Recent D: 7.8% vs 33.7% p=0.023
OSCI: β=-3.84 95%CI= -6.07- -1.62, p=0.001
RCTs underway
(population is extremely
frail elderly)
Annweiler
et al,
2020a79
Hospital
geriatric
s
Quasi-experimental:
1: D3 50,000IU/mo or
80,000IU-100,000IU/2-3
mo; 2: 80,000IU D3 stat;
3: no supplements
29/
16/
32/
77
tot
Mortality
OSCI score
No sig. differences between groups 2 and 3
Mortality: 6.9% vs 18.8% vs 31.3% p=0.02
Group 1 (vs 3) HR = 0.07, p = 0.017
OSCI group 1 vs 3: ≥5 OR=0.08, p = 0.03
Regular
supplementation
monthly with moderate
dose boluses, but not a
last-minute bolus, is
beneficial. Should test
higher one-time dose.
Annweiler
et al,
2020b129
Nursing
home
Observational:
Routine D3 supplements
vs no supplements
20/
98
Mortality
3/20 died in vitamin D group, vs 39/78
without
Mortality rate was 15% vs 50%
3/42 deceased vs 17/56 survived: p=0.005
Need RCTs, but with
common deficiency,
administration of D3 to
elderly seems prudent
Cangiano
et al,
2020130
Hospital
RCT:
Calcifediol 0.266mg x2 at
admit + day 3,7,14,21,28
50/
76
Mortality
ICU
admission
Mortality: 0% vs 7.69% deceased
ICU: 2% vs 50% p<0.001
MVRE OR=0.03 95 %CI 0.003-0.25
Expanded study
COVIDIOL will include
earlier Covid-19 stages
and more patients
Entrenas
Castillo et
al, 2020144
Commu
nity
Parkins
on’s
Observational: of patients
regularly taking D3, how
many became infected?
329/
148
6
Covid-19
infection
5.7% vs 7.9% (Cases: vit D vs no vit D)
12.4% vs 22.9% (Vit D: cases vs unaffected)
ORadj: 0.56, 95% CI=0.320.99] p=0.048
Vitamin D is possibly
protective, recommend
RCTs
Fasano et
al, 2020133
Hospital
Physicians chose yes/no:
D3 200,000IU/day x 2.
More likely if patient had
25(OH)D<20ng/ml, was a
smoker, had high D-dimer,
had comorbidities
39/
91
Mortality
ICU
admission
Never listed outcomes for D treated patients.
If comorbidities are seen as confounders:
ORadj 0.45 95% CI(0.201.22), p = 0.13
If comorbities are seen as effect modifiers:
3+: ORadj 0.18, 95%CI0.040.83), p=0.039
(see article for fewer comorbidities)
Authors hypothesize:
Two consecutive daily
doses of 200,000IU
cholecalciferol can
significantly improve the
outcome in Covid-10
patients with 3 or more
comorbidities.
Giannini
et al,
2021140
Hospital
Retrospective case-
control: 19 patients took
monthly D3 or calcifediol
19/
216
Many
dependent
variables
Supplement group: lower PaO2/FIO2
ratio<300 prevalence, serum ferritin levels,
severity index, ICU, length of stay. None sig.
All had low D.
Supplemented
21.1ng/ml,
unsupplemented
13.8ng/ml. Call for D
RCTs.
Hernande
z et al,
2021131
Populati
on
Population study (EHR):
obtained D supplements in
past 4 months
279
4
Covid-19
positive
test
D drops decreased risk, tablets sl increased
it.
Drops: OR=0.905 (95% CI 0.848-0.967)
Tablets: OR=1.248 (95% CI 1.152-1.352)
D supplements are also
OCT. Tablets are
costly, may be a
surrogate for D
deficiency
Israel et
al, 2020134
Hospital
Prospective nonrandom:
Physicians gave one time
~60,000IU D3 to some
with 25(OH)D<20ng/ml
128/
197
Inflammato
ry markers,
ICU,fatality,
severity
Deficient patients: 25(OH)D mean of
9.8ng/ml
Dramatically lower levels of inflammatory
markers, fatality of 0.8% vs 4.3%
None statistically significant.
Did not see any benefit
with vitamin D
Jevalikar
et al,
2021138
Outpati
ent
RCT: vitamin D deficient
Covid-19 patients given
44/
87
Inflammato
ry markers,
Decreases in CRP, LDH, IL6, Ferritin, and
N/L ratio all p=0.0004 or better for D group,
Ongoing study. Raised
25(OH)D to 80-
Lakkiredd
y et al,
21
60,000IU D3/day x 8 days
duration
increased or same for controls except CRP
100ng/ml with benefits
and no side effects.
202177
Hospital
Retrospective (EHR): had
D3 “booster” therapy if
known 25(OH)D<20ng/ml
151/
986
Mortality
Booster sig protective (main group’s stats):
(ORadj 0.25, 95% CI 0.120.49), p < 0.001)
MV(ORadj 0.13, 95% CI 0.050.35, p < 0.001)
Likely most hospitalized
with Covid-19 are poor
responders to vitamin
D, need extra.
Ling et al,
2020139
Hospital
Retrospective (EHR):
Calcifediol or D3 in
preceding 15-30 days
120
3/
164
01
Mortality
Survival sig more likely if D prior to Covid-19.
Survival prob if D up to 30 days prior
p=0.032
Survival prob if D up to 15 days prior
p=0.003
Calcifediol better than
D3 & 15 days better
than 30. Should test
long-term too, in RCTs
Loucera
et al,
2021136
Commu
nity
Retrospective (EHR): Any
D supplementation 10-15
years prior to Covid-19
363/
820
7
Covid-19
infection
Habitual D suppl. was associated with a 34%
decrease in Covid-19 cases (13.5% vs
16.8%)
ORadj, 0.66; 95% CI, 0.450.97; P = 0.034
Did not find evidence of
selection bias.
Supplement data was
very old. Need new.
Ma et al,
2021135
Hospital
RCT: Single oral dose of
200,000IU D3
117/
237
Hospital
length of
stay, etc.
No significant differences between groups for
any parameter except 25(OH)D levels, up
from 21.2 to 44.4ng/ml. ?Calcitroic acid?
No benefit, therefore
use of D3 is not
supported. D was given
10.3 days after illness
onset.
Murai et
al, 2020137
Hospital
Observational cohort
(randomized by ward):
Calcifediol 266ug x2 at
admit + day 3,7,15,30
*(retracted because it was
not randomized by patient)
447
+53/
838
Mortality
ICU
admission
Mortality: 4.7% vs 15.9% p=0.0001 ORadj
0.21 [95% CI 0.10; 0.43] add 53 ICU
“rescues” ORadj 0.52 [95% CI 0.27;0.99].
ICU: 4.5% vs 21% p=0.0001. ORadj 0.13
[95% CI 0.07;0.23]
ICU admission
requirements markedly
reduced, mortality
decreased by 50%.
Vitamin D deficiency is
easily modifiable.
Nogues et
al, 2021171
Hospital
4 patient case series: at
diagnosis, 1000IU/day or
50,000IU/day for 5 days
4
Lessening
severity of
ARDS
By day 5 high dose patients had lower O2
requirements. Had lower lengths of stay.
CRP & LDH decreased as 25(OH)D
increased. IL6 dropped dramatically. Not so
with low dose D.
Looks promising, but
the two with 1000IU had
diabetes and
hypertension
(confounders). RCTs
should be conducted.
Ohaegbul
am et al,
2020141
Hospital
&
Commu
nity
Retrospective (EHR):
Already on calcitriol due to
kidney failure or HPTH
625
2/
12,5
04
Infection
Severe
Fatal
Inf stage 4&5 only: HR 0.78 95%CI 0.64-
0.94, p=0.010 Severe 1.4% vs 1.9%, HR
0.68; 95%CL0.53-0.87, p=0.002 Fatal 1.2%
vs 1.7%: HR 0.75; 95%CI= 0.57-0.97;
p=0.031
A progressive decline in
risk of severe Covid-19
and mortality was seen
with increasing calcitriol
doses.
Oristrell et
al, 2021132
Commu
nity
RCT: D3 60,000IU/day x 7
days longer if still low
16/
40
Viral
clearance
62.5% vs 20.18% p<0.018 by day 21. Only
other change: Fibrinogen decreased p<0.007
D3 may help prevent
Covid-19 transmission
Rastogi et
al, 202078
Hospital
RCT: : D3 1000IU/day or
5000IU/day x 2 weeks
36/
69
Decreased
symptoms
Cough: adj6.2 ± 0.8 versus 9.1 ±0.8; p=0.039
Taste: adj11.4 ± 1.0 versus 16.9 ±1.7;
p=0.035
25(OH)D increased only
for 5000IU group.
Recommend.
Sabico et
al, 2021142
Hospital
Historical cohort:
150mg Mg + 500mcg B12
+ 1000IU D3 daily (DMB)
17/
43
New need
for O2 or
ICU
Needed oxygen: 17.6 vs 61.5%,
MVadjP=0.006
OR 0.13 95% CI= 0.03-0.59) Needed
ICU: 5.9% vs 30.8% OR 0.20 95% CI= 0.04-
0.93
Despite small sample
size, DMB seemed to
prevent deterioration.
Need RCT.
Tan et al,
2020143
22
REFERENCES
1. Norval M. A Short Circular History of Vitamin D from its Discovery to its Effects. Res Medica [Internet].
2005 [cited 2021 Jun 8];268(2). Available from: http://journals.ed.ac.uk/resmedica/article/view/1031
2. Wolf G. The Discovery of Vitamin D: The Contribution of Adolf Windaus. The Journal of Nutrition
[Internet]. 2004 Jun 1 [cited 2021 Jun 29];134(6):1299302. Available from:
https://doi.org/10.1093/jn/134.6.1299
3. Hollis BW, Wagner CL. The Role of the Parent Compound Vitamin D with Respect to Metabolism and
Function: Why Clinical Dose Intervals Can Affect Clinical Outcomes. J Clin Endocrinol Metab [Internet].
2013 Dec [cited 2021 Jun 25];98(12):461928. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849670/
4. Oscanoa TJ, Amado J, Vidal X, Laird E, Ghashut RA, Romero-Ortuno R. The relationship between the
severity and mortality of SARS-CoV-2 infection and 25-hydroxyvitamin D concentration a metaanalysis.
Advances in Respiratory Medicine [Internet]. 2021 [cited 2021 May 10];89(2):14557. Available from:
https://journals.viamedica.pl/advances_in_respiratory_medicine/article/view/ARM.a2021.0037
5. Mailhot G, White JH. Vitamin D and Immunity in Infants and Children. Nutrients [Internet]. 2020 Apr 27
[cited 2021 Jun 10];12(5). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282029/
6. Gibson CC, Davis CT, Zhu W, Bowman-Kirigin JA, Walker AE, Tai Z, et al. Dietary Vitamin D and Its
Metabolites Non-Genomically Stabilize the Endothelium. PLOS ONE [Internet]. 2015 Oct 15 [cited 2021
Jun 24];10(10):e0140370. Available from:
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140370
7. Charoenngam N, Holick MF. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients
[Internet]. 2020 Jul [cited 2021 Jun 12];12(7):2097. Available from: https://www.mdpi.com/2072-
6643/12/7/2097
8. Rybchyn MS, Abboud M, Puglisi DA, Gordon-Thomson C, Brennan-Speranza TC, Mason RS, et al.
Skeletal Muscle and the Maintenance of Vitamin D Status. Nutrients [Internet]. 2020 Nov [cited 2021 Aug
20];12(11):3270. Available from: https://www.mdpi.com/2072-6643/12/11/3270
9. Martinaityte I, Kamycheva E, Didriksen A, Jakobsen J, Jorde R. Vitamin D Stored in Fat Tissue During a 5-
Year Intervention Affects Serum 25-Hydroxyvitamin D Levels the Following Year. The Journal of Clinical
Endocrinology & Metabolism [Internet]. 2017 Oct 1 [cited 2021 Jun 25];102(10):37318. Available from:
https://doi.org/10.1210/jc.2017-01187
10. Hyppönen E, Boucher BJ. Avoidance of vitamin D deficiency in pregnancy in the United Kingdom: the case
for a unified approach in National policy. British Journal of Nutrition [Internet]. 2010 Aug [cited 2021 Jun
24];104(3):30914. Available from: https://www.cambridge.org/core/journals/british-journal-of-
nutrition/article/avoidance-of-vitamin-d-deficiency-in-pregnancy-in-the-united-kingdom-the-case-for-a-
unified-approach-in-national-policy/B13CC21188F1FF9C67486629518DA20F
11. Scully H, Laird E, Healy M, Walsh JB, Crowley V, McCarroll K. Geomapping Vitamin D Status in a Large
City and Surrounding PopulationExploring the Impact of Location and Demographics. Nutrients
[Internet]. 2020 Aug 31 [cited 2021 Jun 24];12(9):2663. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551618/
12. Quraishi SA, Bittner EA, Blum L, Hutter MM, Camargo CA. Association Between Preoperative 25-
Hydroxyvitamin D Level and Hospital-Acquired Infections Following Roux-en-Y Gastric Bypass Surgery.
23
JAMA Surg [Internet]. 2014 Feb 1 [cited 2021 Jun 1];149(2):112. Available from:
http://archsurg.jamanetwork.com/article.aspx?doi=10.1001/jamasurg.2013.3176
13. Grant WB, Baggerly CA, Lahore H. Reply: “Vitamin D Supplementation in Influenza and COVID-19
Infections. Comment on: Evidence That Vitamin D Supplementation Could Reduce Risk of Influenza and
COVID-19 Infections and Deaths Nutrients 2020, 12(4), 988.” Nutrients [Internet]. 2020 Jun [cited 2020 Jun
16];12(6):1620. Available from: http://www.mdpi.com/2072-6643/12/6/1620
14. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, et al. Preventing vitamin D deficiency
during the COVID-19 pandemic: UK definitions of vitamin D sufficiency and recommended supplement
dose are set too low. Clinical Medicine [Internet]. 2020 Nov 6 [cited 2020 Nov 6]; Available from:
https://www.rcpjournals.org/content/clinmedicine/early/2020/11/06/clinmed.2020-0858
15. Lu Z, Chen TC, Zhang A, Persons KS, Kohn N, Berkowitz R, et al. An Evaluation of the Vitamin D3
Content in Fish: Is the Vitamin D Content Adequate to Satisfy the Dietary Requirement for Vitamin D? J
Steroid Biochem Mol Biol [Internet]. 2007 Mar [cited 2021 Jun 9];103(35):6424. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2698592/
16. Benskin LL. A Basic Review of the Preliminary Evidence That COVID-19 Risk and Severity Is Increased in
Vitamin D Deficiency. Front Public Health [Internet]. 2020 Sep 10 [cited 2020 Sep 11];8:513. Available
from: https://www.frontiersin.org/article/10.3389/fpubh.2020.00513/full
17. Ames BN, Grant WB, Willett WC. Does the High Prevalence of Vitamin D Deficiency in African
Americans Contribute to Health Disparities? Nutrients [Internet]. 2021 Feb [cited 2021 Feb 3];13(2):499.
Available from: https://www.mdpi.com/2072-6643/13/2/499
18. Holick MichaelF, Matsuoka LoisY, Wortsman J. AGE, VITAMIN D, AND SOLAR ULTRAVIOLET. The
Lancet [Internet]. 1989 Nov 4 [cited 2020 Apr 23];334(8671):11045. Available from:
http://www.sciencedirect.com/science/article/pii/S0140673689911240
19. Kara M, Ekiz T, Ricci V, Kara Ö, Chang K-V, Özçakar L. “Scientific Strabismus” or two related pandemics:
coronavirus disease and vitamin D deficiency. Br J Nutr. 2020 Oct 14;124(7):73641.
20. Cashman KD, Dowling KG, Škrabáková Z, Gonzalez-Gross M, Valtueña J, De Henauw S, et al. Vitamin D
deficiency in Europe: pandemic? Am J Clin Nutr. 2016 Apr;103(4):103344.
21. Docea AO, Tsatsakis A, Albulescu D, Cristea O, Zlatian O, Vinceti M, et al. A new threat from an old
enemy: Re-emergence of coronavirus (Review). Int J Mol Med [Internet]. 2020 Jun [cited 2020 Jun
22];45(6):163143. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169834/
22. Rhodes JM, Subramanian S, Laird E, Griffin G, Kenny RA. Perspective: Vitamin D deficiency and COVID-
19 severity plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. Journal of
Internal Medicine [Internet]. 2021 [cited 2021 Jun 25];289(1):97115. Available from:
https://onlinelibrary.wiley.com/doi/abs/10.1111/joim.13149
23. Delorey TM, Ziegler CGK, Heimberg G, Normand R, Yang Y, Segerstolpe Å, et al. COVID-19 tissue
atlases reveal SARS-CoV-2 pathology and cellular targets. Nature. 2021 Apr 29;
24. Cevik M, Kuppalli K, Kindrachuk J, Peiris M. Virology, transmission, and pathogenesis of SARS-CoV-2.
BMJ [Internet]. 2020 Oct 23 [cited 2021 Jun 25];371:m3862. Available from:
https://www.bmj.com/content/371/bmj.m3862
25. Melms JC, Biermann J, Huang H, Wang Y, Nair A, Tagore S, et al. A molecular single-cell lung atlas of
lethal COVID-19. Nature. 2021 Apr 29;
24
26. Cevik M, Tate M, Lloyd O, Maraolo AE, Schafers J, Ho A. SARS-CoV-2, SARS-CoV, and MERS-CoV
viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis.
Lancet Microbe. 2021 Jan;2(1):e1322.
27. Gustine JN, Jones D. Immunopathology of Hyperinflammation in COVID-19. Am J Pathol [Internet]. 2021
Jan [cited 2021 Aug 20];191(1):417. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484812/
28. Andersson MI, Arancibia-Carcamo CV, Auckland K, Baillie JK, Barnes E, Beneke T, et al. SARS-CoV-2
RNA detected in blood products from patients with COVID-19 is not associated with infectious virus.
Wellcome Open Res [Internet]. 2020 Oct 12 [cited 2021 Jun 25];5:181. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689603/
29. Wölfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Müller MA, et al. Virological assessment of
hospitalized patients with COVID-2019. Nature [Internet]. 2020 May [cited 2021 Jun 25];581(7809):4659.
Available from: https://www.nature.com/articles/s41586-020-2196-x
30. Saponaro F, Saba A, Zucchi R. An Update on Vitamin D Metabolism. Int J Mol Sci. 2020 Sep 8;21(18).
31. Kazemi A, Mohammadi V, Aghababaee SK, Golzarand M, Clark CCT, Babajafari S. Association of Vitamin
D Status with SARS-CoV-2 Infection or COVID-19 Severity: A Systematic Review and Meta-analysis. Adv
Nutr. 2021 Mar 5;
32. Pal R, Banerjee M, Bhadada SK, Shetty AJ, Singh B, Vyas A. Vitamin D supplementation and clinical
outcomes in COVID-19: a systematic review and meta-analysis. J Endocrinol Invest [Internet]. 2021 Jun 24
[cited 2021 Jun 25]; Available from: https://doi.org/10.1007/s40618-021-01614-4
33. Uday S, Högler W. Nutritional Rickets and Osteomalacia in the Twenty-first Century: Revised Concepts,
Public Health, and Prevention Strategies. Curr Osteoporos Rep [Internet]. 2017 [cited 2021 Jun
12];15(4):293302. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5532418/
34. Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for
good health. The American Journal of Clinical Nutrition [Internet]. 2008 Aug 1 [cited 2021 Jun
24];88(2):491S-499S. Available from: https://doi.org/10.1093/ajcn/88.2.491S
35. The Body Needs All Forms of Vitamin D [Internet]. GrassrootsHealth. [cited 2021 Jun 25]. Available from:
https://myemail.constantcontact.com/The-Body-Needs-All-Forms-of-Vitamin-
D.html?soid=1102722411090&aid=emRzSamZebM
36. Sosa Henríquez M, Gómez de Tejada Romero MJ. Cholecalciferol or Calcifediol in the Management of
Vitamin D Deficiency. Nutrients [Internet]. 2020 May 31 [cited 2021 Jun 24];12(6):1617. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352679/
37. Petkovich M, Bishop CW. Chapter 91 - Extended-Release Calcifediol in Renal Disease. In: Feldman D,
editor. Vitamin D (Fourth Edition) [Internet]. Academic Press; 2018 [cited 2021 Jun 24]. p. 66778.
Available from: https://www.sciencedirect.com/science/article/pii/B9780128099636000912
38. Jones KS, Assar S, Harnpanich D, Bouillon R, Lambrechts D, Prentice A, et al. 25(OH)D2 Half-Life Is
Shorter Than 25(OH)D3 Half-Life and Is Influenced by DBP Concentration and Genotype. J Clin
Endocrinol Metab [Internet]. 2014 Sep [cited 2021 Sep 5];99(9):337381. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207933/
39. Bouillon R, Bikle D. Vitamin D Metabolism Revised: Fall of Dogmas. Journal of Bone and Mineral
Research [Internet]. 2019 [cited 2021 Feb 26];34(11):198592. Available from:
https://asbmr.onlinelibrary.wiley.com/doi/abs/10.1002/jbmr.3884
25
40. Demay MB. The good and the bad of vitamin D inactivation. J Clin Invest [Internet]. 2018 Aug 31 [cited
2021 Jun 23];128(9):37368. Available from: https://www.jci.org/articles/view/122046
41. Ketha H, Thacher TD, Oberhelman SS, Fischer PR, Singh RJ, Kumar R. Comparison of the effect of daily
versus bolus dose maternal vitamin D3 supplementation on the 24,25-dihydroxyvitamin D3 to 25-
hydroxyvitamin D3 ratio. Bone [Internet]. 2018 May 1 [cited 2021 Jun 29];110:3215. Available from:
https://www.sciencedirect.com/science/article/pii/S8756328218300838
42. Biondi P, Pepe J, Biamonte F, Occhiuto M, Parisi M, Demofonti C, et al. Oral calcidiol is a good form of
vitamin D supplementation. Clin Cases Miner Bone Metab [Internet]. 2017 [cited 2021 Jun 23];14(2):2078.
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726211/
43. Navarro-Valverde C, Sosa-Henríquez M, Alhambra-Expósito MR, Quesada-Gómez JM. Vitamin D3 and
calcidiol are not equipotent. The Journal of Steroid Biochemistry and Molecular Biology [Internet]. 2016
Nov 1 [cited 2021 Jun 23];164:2058. Available from:
https://www.sciencedirect.com/science/article/pii/S0960076016300140
44. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation,
Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. The
Journal of Clinical Endocrinology & Metabolism [Internet]. 2011 Jul 1 [cited 2021 Aug 20];96(7):191130.
Available from: https://doi.org/10.1210/jc.2011-0385
45. Marques CDL, Dantas AT, Fragoso TS, Duarte ÂLBP. The importance of vitamin D levels in autoimmune
diseases. Rev Bras Reumatol [Internet]. 2010 Feb [cited 2021 Jun 24];50:6780. Available from:
https://www.scielo.br/j/rbr/a/5BcvSsQGhJPXXD8Q9Pzff8H/?lang=en#
46. McCullough PJ, Lehrer DS, Amend J. Daily oral dosing of vitamin D3 using 5000 TO 50,000 international
units a day in long-term hospitalized patients: Insights from a seven year experience. The Journal of Steroid
Biochemistry and Molecular Biology [Internet]. 2019 May 1 [cited 2021 Jun 25];189:22839. Available
from: https://www.sciencedirect.com/science/article/pii/S0960076018306228
47. Kagotho E, Omuse G, Okinda N, Ojwang P. Vitamin D status in healthy black African adults at a tertiary
hospital in Nairobi, Kenya: a cross sectional study. BMC Endocr Disord [Internet]. 2018 Oct 11 [cited 2021
Jun 30];18:70. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180659/
48. Luxwolda MF, Kuipers RS, Kema IP, van der Veer E, Dijck-Brouwer DAJ, Muskiet FAJ. Vitamin D status
indicators in indigenous populations in East Africa. Eur J Nutr. 2013 Apr;52(3):111525.
49. Holick MF. VITAMIN D STATUS: MEASUREMENT, INTERPRETATION AND CLINICAL
APPLICATION. Ann Epidemiol [Internet]. 2009 Feb [cited 2020 May 23];19(2):738. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665033/
50. Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2 positivity rates associated with
circulating 25-hydroxyvitamin D levels. PLOS ONE [Internet]. 2020 Sep 17 [cited 2020 Dec
8];15(9):e0239252. Available from:
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239252
51. Christakos S, Li S, De La Cruz J, Bikle DD. New developments in our understanding of vitamin D
metabolism, action and treatment. Metabolism [Internet]. 2019 Sep 1 [cited 2020 Jun 5];98:11220.
Available from: http://www.sciencedirect.com/science/article/pii/S0026049519301192
52. Jovic TH, Ali SR, Ibrahim N, Jessop ZM, Tarassoli SP, Dobbs TD, et al. Could Vitamins Help in the Fight
Against COVID-19? Nutrients [Internet]. 2020 Sep [cited 2020 Dec 2];12(9):2550. Available from:
https://www.mdpi.com/2072-6643/12/9/2550
26
53. Veugelers P, Ekwaru J. A Statistical Error in the Estimation of the Recommended Dietary Allowance for
Vitamin D. Nutrients [Internet]. 2014 Oct 20 [cited 2020 Jun 17];6(10):44725. Available from:
http://www.mdpi.com/2072-6643/6/10/4472
54. Heaney R, Garland C, Baggerly C, French C, Gorham E. Letter to Veugelers, P.J. and Ekwaru, J.P., A
statistical error in the estimation of the recommended dietary allowance for vitamin D. Nutrients 2014, 6,
4472-4475; doi:10.3390/nu6104472. Nutrients. 2015 Mar 10;7(3):168890.
55. Grassroots Health. GrassrootsHealth Data supports much higher vitamin D RDA [Internet].
GrassrootsHealth. 2015 [cited 2021 Jun 28]. Available from:
https://www.grassrootshealth.net/blog/grassrootshealth-data-supports-much-higher-intake-of-vitamin-d-
than-the-current-rda/
56. Bleizgys A. Vitamin D and COVID-19: It is time to act. International Journal of Clinical Practice [Internet].
2021 [cited 2021 Jun 24];75(3):e13748. Available from:
https://onlinelibrary.wiley.com/doi/abs/10.1111/ijcp.13748
57. Grant WB, Lahore H, McDonnell SL, Baggerly CA, French CB, Aliano JL, et al. Evidence that Vitamin D
Supplementation Could Reduce Risk of Influenza and COVID-19 Infections and Deaths. Nutrients
[Internet]. 2020 Apr [cited 2020 Jun 22];12(4):988. Available from: https://www.mdpi.com/2072-
6643/12/4/988
58. Grant WB, McDonnell SL. Letter in response to the article: Vitamin D concentrations and COVID-19
infection in UK biobank (Hastie et al.). Diabetes & Metabolic Syndrome: Clinical Research & Reviews
[Internet]. 2020 Sep 1 [cited 2020 Jun 22];14(5):8934. Available from:
http://www.sciencedirect.com/science/article/pii/S1871402120301648
59. Afshar P, Ghaffaripour M, Sajjadi H. Suggested role of Vitamin D supplementation in COVID-19 severity.
Journal of Contemporary Medical Sciences [Internet]. 2020 Aug 26 [cited 2020 Dec 2];6(4). Available from:
http://www.jocms.org/index.php/jcms/article/view/822
60. Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev
Endocr Metab Disord. 2017;18(2):15365.
61. van Schoor N, Lips P. Global Overview of Vitamin D Status. Endocrinology and Metabolism Clinics of
North America [Internet]. 2017 Dec 1 [cited 2020 Dec 14];46(4):84570. Available from:
http://www.sciencedirect.com/science/article/pii/S0889852917300646
62. National Institutes of Health. Vitamin D [Internet]. COVID-19 Treatment Guidelines. [cited 2021 Jun 24].
Available from: https://www.covid19treatmentguidelines.nih.gov/therapies/supplements/vitamin-d/
63. Coronavirus disease - Answers [Internet]. [cited 2021 Jun 24]. Available from:
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/coronavirus-disease-answers
64. BDA. COVID-19 / Coronavirus - Advice for the General Public [Internet]. [cited 2021 Jun 24]. Available
from: https://www.bda.uk.com/resource/covid-19-corona-virus-advice-for-the-general-public.html
65. Vitamins and minerals - Vitamin D [Internet]. nhs.uk. 2017 [cited 2020 May 20]. Available from:
https://www.nhs.uk/conditions/vitamins-and-minerals/vitamin-d/
66. Marcinowska-Suchowierska E, Kupisz-Urbańska M, Łukaszkiewicz J, Płudowski P, Jones G. Vitamin D
ToxicityA Clinical Perspective. Front Endocrinol [Internet]. 2018 [cited 2020 Jun 23];9. Available from:
https://www.frontiersin.org/articles/10.3389/fendo.2018.00550/full
27
67. Taylor PN, Davies JS. A review of the growing risk of vitamin D toxicity from inappropriate practice. Br J
Clin Pharmacol [Internet]. 2018 Jun [cited 2021 Jun 26];84(6):11217. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980613/
68. Asif A, Farooq N. Vitamin D Toxicity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;
2021 [cited 2021 Jun 26]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK557876/
69. Araki T, Holick MF, Alfonso BD, Charlap E, Romero CM, Rizk D, et al. Vitamin D Intoxication with
Severe Hypercalcemia due to Manufacturing and Labeling Errors of Two Dietary Supplements Made in the
United States. The Journal of Clinical Endocrinology & Metabolism [Internet]. 2011 Dec 1 [cited 2021 Aug
20];96(12):36038. Available from: https://doi.org/10.1210/jc.2011-1443
70. Saul AW. Vitamin D: Deficiency, Diversity and Dosage. JOM [Internet]. 2003 [cited 2021 Jun 28];18(3
4):194204. Available from: https://isom.ca/jom-archives/vol18-no3-4-2003/
71. Stipp D. Vitamin D Level in Milk, Infant Formula Is Often Too High or Low, Survey Says. Wall Street
Journal. Eastern Edition. 1992 Apr 30;6.
72. Norfolk County Ct 380. TARPEY vs. CRESCENT RIDGE DAIRY, INC., 47 Mass. App. Ct. 380 [Internet].
1999 [cited 2021 Jun 28]. Available from: http://masscases.com/cases/app/47/47massappct380.html
73. Shirvani A, Kalajian TA, Song A, Holick MF. Disassociation of Vitamin D’s Calcemic Activity and Non-
calcemic Genomic Activity and Individual Responsiveness: A Randomized Controlled Double-Blind
Clinical Trial. Sci Rep [Internet]. 2019 Nov 27 [cited 2021 Aug 20];9(1):17685. Available from:
https://www.nature.com/articles/s41598-019-53864-1
74. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D
supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of
individual participant data. BMJ [Internet]. 2017 Feb 15 [cited 2020 May 8];356. Available from:
https://www.bmj.com/content/356/bmj.i6583
75. Kimball SM, Mirhosseini N, Holick MF. Evaluation of vitamin D3 intakes up to 15,000 international
units/day and serum 25-hydroxyvitamin D concentrations up to 300 nmol/L on calcium metabolism in a
community setting. Dermatoendocrinol [Internet]. 2017 Apr 13 [cited 2020 Jun 20];9(1). Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402701/
76. Jolliffe DA, Camargo CA, Sluyter JD, Aglipay M, Aloia JF, Ganmaa D, et al. Vitamin D supplementation to
prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from
randomised controlled trials. The Lancet Diabetes & Endocrinology [Internet]. 2021 May 1 [cited 2021 Apr
24];9(5):27692. Available from: https://www.thelancet.com/journals/landia/article/PIIS2213-
8587(21)00051-6/abstract
77. Lakkireddy M, Gadiga SG, Malathi RD, Karra ML, Raju ISSVPM, Ragini, et al. Impact of daily high dose
oral vitamin D therapy on the inflammatory markers in patients with COVID 19 disease. Scientific Reports
[Internet]. 2021 May 20 [cited 2021 May 21];11(1):10641. Available from:
https://www.nature.com/articles/s41598-021-90189-4
78. Rastogi A, Bhansali A, Khare N, Suri V, Yaddanapudi N, Sachdeva N, et al. Short term, high-dose vitamin
D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study).
Postgraduate Medical Journal [Internet]. 2020 Nov 12 [cited 2020 Dec 14]; Available from:
https://pmj.bmj.com/content/early/2020/11/12/postgradmedj-2020-139065
79. Annweiler C, Hanotte B, de l’Eprevier CG, Sabatier J-M, Lafaie L, Célarier T. Vitamin D and survival in
COVID-19 patients: A quasi-experimental study. The Journal of Steroid Biochemistry and Molecular
28
Biology [Internet]. 2020 Oct 13 [cited 2020 Oct 19];105771. Available from:
http://www.sciencedirect.com/science/article/pii/S096007602030296X
80. Srivastava A, Gupta RC, Doss RB, Lall R. Trace Minerals, Vitamins and Nutraceuticals in Prevention and
Treatment of COVID-19. Journal of Dietary Supplements [Internet]. 2021 [cited 2021 Apr 4];135.
Available from: https://app.dimensions.ai/details/publication/pub.1136165220
81. Aranow C. Vitamin D and the Immune System. Journal of Investigative Medicine [Internet]. 2011 Aug 1
[cited 2020 May 4];59(6):8816. Available from: https://jim.bmj.com/content/59/6/881
82. Corrao S, Mallaci Bocchio R, Lo Monaco M, Natoli G, Cavezzi A, Troiani E, et al. Does Evidence Exist to
Blunt Inflammatory Response by Nutraceutical Supplementation during COVID-19 Pandemic? An
Overview of Systematic Reviews of Vitamin D, Vitamin C, Melatonin, and Zinc. Nutrients. 2021 Apr
12;13(4).
83. Mercola J, Grant WB, Wagner CL. Evidence Regarding Vitamin D and Risk of COVID-19 and Its Severity.
Nutrients [Internet]. 2020 Nov [cited 2020 Dec 24];12(11):3361. Available from:
https://www.mdpi.com/2072-6643/12/11/3361
84. Cavezzi A, Troiani E, Corrao S. COVID-19: Hemoglobin, Iron, and Hypoxia beyond Inflammation. A
Narrative Review. Clinics and Practice [Internet]. 2020 May [cited 2021 Jun 25];10(2):2430. Available
from: https://www.mdpi.com/2039-7283/10/2/1271
85. Boucher BJ. The Problems of Vitamin D Insufficiency in Older People. Aging Dis [Internet]. 2012 Jun 6
[cited 2020 Apr 23];3(4):31329. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501367/
86. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-Hydroxyvitamin D and
the Incidence of Acute Viral Respiratory Tract Infections in Healthy Adults. PLoS One [Internet]. 2010 Jun
14 [cited 2020 Apr 23];5(6). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885414/
87. Ahmed A, Siman-Tov G, Hall G, Bhalla N, Narayanan A. Human Antimicrobial Peptides as Therapeutics
for Viral Infections. Viruses [Internet]. 2019 Aug 1 [cited 2021 Jun 25];11(8):704. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722670/
88. Martínez-Moreno J, Hernandez JC, Urcuqui-Inchima S. Effect of high doses of vitamin D supplementation
on dengue virus replication, Toll-like receptor expression, and cytokine profiles on dendritic cells. Mol Cell
Biochem. 2020 Jan;464(12):16980.
89. King EM. T-cells really are the superstars in fighting COVID-19 - but why are some of us so poor at making
them? BMJ (British Medical Journal) [Internet]. 2021 Jun 14 [cited 2021 Jun 25];2020(370):m3563/rr-6.
Available from: https://www.bmj.com/content/370/bmj.m3563/rr-6
90. Sekine T, Perez-Potti A, Rivera-Ballesteros O, Strålin K, Gorin J-B, Olsson A, et al. Robust T Cell
Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19. Cell [Internet]. 2020 Oct 1
[cited 2020 Oct 30];183(1):158-168.e14. Available from:
http://www.sciencedirect.com/science/article/pii/S0092867420310084
91. Mohd S, Sharma S, Mishra A, Ashraf MZ. Vitamin D and Its Relationship with the Pathways Related to
Thrombosis and Various Diseases [Internet]. IntechOpen; 2021 [cited 2021 May 19]. Available from:
https://www.intechopen.com/online-first/vitamin-d-and-its-relationship-with-the-pathways-related-to-
thrombosis-and-various-diseases
92. Jain A, Chaurasia R, Sengar NS, Singh M, Mahor S, Narain S. Analysis of vitamin D level among
asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers. Sci Rep
29
[Internet]. 2020 Nov 19 [cited 2021 Jun 26];10(1):20191. Available from:
https://www.nature.com/articles/s41598-020-77093-z
93. Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D, et al. Circulating MMP9,
vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage
in chronic disorders? QJM. 2002 Dec;95(12):78796.
94. Rabaan AA, Al-Ahmed SH, Garout MA, Al-Qaaneh AM, Sule AA, Tirupathi R, et al. Diverse
Immunological Factors Influencing Pathogenesis in Patients with COVID-19: A Review on Viral
Dissemination, Immunotherapeutic Options to Counter Cytokine Storm and Inflammatory Responses.
Pathogens [Internet]. 2021 May [cited 2021 May 10];10(5):565. Available from:
https://www.mdpi.com/2076-0817/10/5/565
95. Price LC, McCabe C, Garfield B, Wort SJ. Thrombosis and COVID-19 pneumonia: the clot thickens!
European Respiratory Journal [Internet]. 2020 Jul 1 [cited 2021 Jun 26];56(1). Available from:
https://erj.ersjournals.com/content/56/1/2001608
96. Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood [Internet].
2020 Jun 4 [cited 2021 Jun 26];135(23):203340. Available from:
https://doi.org/10.1182/blood.2020006000
97. Chambers ES, Vukmanovic-Stejic M, Turner CT, Shih BB, Trahair H, Pollara G, et al. Vitamin D3
replacement enhances antigen-specific immunity in older adults. Immunotherapy Advances [Internet]. 2020
Nov 25 [cited 2020 Dec 21];(ltaa008). Available from: https://doi.org/10.1093/immadv/ltaa008
98. Brown RA, Sarkar A. Vitamin D deficiency: a factor in COVID-19, progression, severity and mortality?
An urgent call for research. MitoFit Preprint Arch [Internet]. 2020 Feb 29 [cited 2021 Jun 27]; Available
from: https://www.mitofit.org/index.php/Brown_2020_MitoFit_Preprint_Arch
99. BAPIO and BMA raise concerns over ethnic minority doctor deaths to Covid-19 [Internet]. Pulse Today.
2020 [cited 2021 Jun 27]. Available from: https://www.pulsetoday.co.uk/news/uncategorised/bapio-and-
bma-raise-concerns-over-ethnic-minority-doctor-deaths-to-covid-19/
100. Cook T, Kursumovic E, Lennane S. Exclusive: deaths of NHS staff from covid-19 analysed [Internet].
Health Service Journal. 2020 [cited 2020 Jun 24]. Available from: https://www.hsj.co.uk/exclusive-deaths-
of-nhs-staff-from-covid-19-analysed/7027471.article
101. Grimes DS. Covid-19 & Vitamin D : Deaths of doctors from Covid-19 [Internet]. Dr David Grimes,
Consultant physician and gastroenterologist. 2020 [cited 2021 Jun 27]. Available from:
http://www.drdavidgrimes.com/2020/11/covid-19-vitamin-d-deaths-of-doctors.html
102. Grimes DS. Covid-19 & Vitamin D: There is no African Paradox [Internet]. Dr David Grimes, Consultant
physician and gastroenterologist. 2021 [cited 2021 Jun 27]. Available from:
http://www.drdavidgrimes.com/2021/04/covid-19-vitamin-d-there-is-no-african.html
103. Grimes DS. Covid-19 & Vitamin D : The common link. Remember William of Ockham? [Internet]. Dr
David Grimes, Consultant physician and gastroenterologist. 2021 [cited 2021 Jun 27]. Available from:
http://www.drdavidgrimes.com/2021/02/covid-19-vitamin-d-disappearance-of.html
104. Cannell JJ, Vieth R, Umhau J, Holick MF, Grant WB, Madronich S, et al. Epidemic influenza and vitamin
D. Epidemiol Infect [Internet]. 2006 Dec [cited 2020 May 8];134(6):112940. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870528/
105. Roth DE, Abrams SA, Aloia J, Bergeron G, Bourassa MW, Brown KH, et al. Global prevalence and disease
burden of vitamin D deficiency: a roadmap for action in low- and middle-income countries. Ann N Y Acad
30
Sci [Internet]. 2018 Oct [cited 2021 Jun 10];1430(1):4479. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309365/
106. Pfleger K, Davies G, Boucher BJ, Umhau J, Kimball SM, Thakkar V, et al. Over 200 Scientists, Doctors, &
Leading Authorities Call For Increased Vitamin D Use To Combat COVID-19 [Internet]. Vitamin D For All
Collaboration; 2020. Available from: https://vitamindforall.org/letter.html
107. Pugach IZ, Pugach S. Strong correlation between prevalence of severe vitamin D deficiency and population
mortality rate from COVID-19 in Europe. Wien Klin Wochenschr [Internet]. 2021 Mar 15 [cited 2021 Jun
27];13. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957444/
108. Walrand S. Autumn COVID-19 surge dates in Europe correlated to latitudes, not to temperature-humidity,
pointing to vitamin D as contributing factor. Sci Rep [Internet]. 2021 Jan 21 [cited 2021 Jul 22];11(1):1981.
Available from: https://www.nature.com/articles/s41598-021-81419-w
109. Worldometer. Coronavirus Graphs: Worldwide Cases and Deaths - Worldometer [Internet]. covid-19
CORONAVIRUS. 2021 [cited 2021 Jun 27]. Available from:
https://www.worldometers.info/coronavirus/worldwide-graphs/#countries-cases
110. Isaia G, Diémoz H, Maluta F, Fountoulakis I, Ceccon D, di Sarra A, et al. Does solar ultraviolet radiation
play a role in COVID-19 infection and deaths? An environmental ecological study in Italy. Science of The
Total Environment [Internet]. 2021 Feb 25 [cited 2021 Jun 27];757:143757. Available from:
https://www.sciencedirect.com/science/article/pii/S0048969720372880
111. Jayawardena R, Jeyakumar DT, Francis TV, Misra A. Impact of the vitamin D deficiency on COVID-19
infection and mortality in Asian countries. Diabetes & Metabolic Syndrome: Clinical Research & Reviews
[Internet]. 2021 May [cited 2021 Apr 7];15(3):75764. Available from:
https://linkinghub.elsevier.com/retrieve/pii/S1871402121000746
112. Herrera-Quintana L, Gamarra-Morales Y, Vázquez-Lorente H, Molina-López J, Castaño-Pérez J, Machado-
Casas JF, et al. Bad Prognosis in Critical Ill Patients with COVID-19 during Short-Term ICU Stay regarding
Vitamin D Levels. Nutrients [Internet]. 2021 Jun [cited 2021 Jun 18];13(6):1988. Available from:
https://www.mdpi.com/2072-6643/13/6/1988
113. Merzon E, Tworowski D, Gorohovski A, Vinker S, Cohen AG, Green I, et al. Low plasma 25(OH) vitamin
D level is associated with increased risk of COVID-19 infection: an Israeli population-based study. The
FEBS Journal [Internet]. 2020 [cited 2020 Oct 25];287(17):3693702. Available from:
https://febs.onlinelibrary.wiley.com/doi/abs/10.1111/febs.15495
114. Meltzer DO, Best TJ, Zhang H, Vokes T, Arora VM, Solway J. Association of Vitamin D Levels,
Race/Ethnicity, and Clinical Characteristics With COVID-19 Test Results. JAMA Network Open [Internet].
2021 Mar 19 [cited 2021 Apr 4];4(3):e214117e214117. Available from:
https://doi.org/10.1001/jamanetworkopen.2021.4117
115. Katz J, Yue S, Xue W. Increased risk for COVID-19 in patients with vitamin D deficiency. Nutrition
[Internet]. 2021 Apr 1 [cited 2021 Jan 8];84:111106. Available from:
http://www.sciencedirect.com/science/article/pii/S0899900720303890
116. Liu N, Sun J, Wang X, Zhang T, Zhao M, Li H. Low vitamin D status is associated with coronavirus disease
2019 outcomes: a systematic review and meta-analysis. International Journal of Infectious Diseases
[Internet]. 2021 Mar 1 [cited 2021 Jun 28];104:5864. Available from:
https://www.ijidonline.com/article/S1201-9712(20)32600-X/abstract
117. Nikniaz L, Akbarzadeh MA, Hosseinifard H, Hosseini M-S. The impact of vitamin D supplementation on
mortality rate and clinical outcomes of COVID-19 patients: A systematic review and meta-analysis.
31
medRxiv [Internet]. 2021 Jan 5 [cited 2021 Jan 8];2021.01.04.21249219. Available from:
https://www.medrxiv.org/content/10.1101/2021.01.04.21249219v1
118. Carpagnano GE, Di Lecce V, Quaranta VN, Zito A, Buonamico E, Capozza E, et al. Vitamin D deficiency
as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol
Invest [Internet]. 2020 Aug 9 [cited 2020 Nov 24];17. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415009/
119. Szarpak L, Rafique Z, Gasecka A, Chirico F, Gawel W, Hernik J, et al. A systematic review and meta-
analysis of effect of vitamin D levels on the incidence of COVID-19. Cardiol J. 2021 Jul 26;
120. Ghasemian R, Shamshirian A, Heydari K, Malekan M, Alizadeh-Navaei R, Ebrahimzadeh MA, et al. The
role of vitamin D in the age of COVID-19: A systematic review and meta-analysis. International Journal of
Clinical Practice [Internet]. 2021 [cited 2021 Aug 20];n/a(n/a):e14675. Available from:
https://onlinelibrary.wiley.com/doi/abs/10.1111/ijcp.14675
121. Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail.
Dermatoendocrinol [Internet]. 2012 Apr 1 [cited 2021 Jun 29];4(2):95100. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427206/
122. Griffin G, Hewison M, Hopkin J, Kenny R, Quinton R, Rhodes J, et al. Vitamin D and COVID-19: evidence
and recommendations for supplementation. Royal Society Open Science [Internet]. 2020 [cited 2021 Jun
29];7(12):201912. Available from: https://royalsocietypublishing.org/doi/10.1098/rsos.201912
123. Annweiler C, Cao Z, Sabatier J-M. Point of view: Should COVID-19 patients be supplemented with vitamin
D? Maturitas [Internet]. 2020 Oct [cited 2020 Jun 18];140:246. Available from:
https://linkinghub.elsevier.com/retrieve/pii/S0378512220302929
124. Davies G, Garami AR, Byers JC. Evidence Supports a Causal Role for Vitamin D Status in COVID-19
Outcomes. medRxiv [Internet]. 2020 Jun 13 [cited 2020 Jun 16];2020.05.01.20087965. Available from:
https://www.medrxiv.org/content/10.1101/2020.05.01.20087965v3
125. Boucher BJ. Why do so many trials of vitamin D supplementation fail? Endocr Connect [Internet]. 2020
Aug 11 [cited 2021 Jun 29];9(9):R195206. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487184/
126. Grant WB, Boucher BJ, Bhattoa HP, Lahore H. Why vitamin D clinical trials should be based on 25-
hydroxyvitamin D concentrations. The Journal of Steroid Biochemistry and Molecular Biology [Internet].
2018 Mar 1 [cited 2021 Jun 29];177:2669. Available from:
https://www.sciencedirect.com/science/article/pii/S0960076017302236
127. Griffin G, Hewison M, Hopkin J, Kenny RA, Quinton R, Rhodes J, et al. Perspective: Vitamin D
supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as
intermittent bolus: implications for COVID-19. Clin Med (Lond) [Internet]. 2021 Mar [cited 2021 Jun
12];21(2):e1449. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002781/
128. Davies G, Mazess R, Benskin LL. Letter to the editor in response to the article: “Vitamin D concentrations
and COVID-19 infection in UK Biobank” (Hastie et al). Diabetes & Metabolic Syndrome: Clinical Research
& Reviews [Internet]. 2021 Feb 9 [cited 2021 Feb 10]; Available from:
https://www.sciencedirect.com/science/article/pii/S1871402121000394
129. Annweiler G, Corvaisier M, Gautier J, Dubée V, Legrand E, Sacco G, et al. Vitamin D Supplementation
Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-
Experimental Study. Nutrients [Internet]. 2020 Nov [cited 2021 Feb 2];12(11):3377. Available from:
https://www.mdpi.com/2072-6643/12/11/3377
32
130. Cangiano B, Fatti LM, Danesi L, Gazzano G, Croci M, Vitale G, et al. Mortality in an Italian nursing home
during COVID-19 pandemic: correlation with gender, age, ADL, vitamin D supplementation, and limitations
of the diagnostic tests. Aging (Albany NY). 2020 Dec 22;12(24):2452234.
131. Hernández JL, Nan D, Fernandez-Ayala M, García-Unzueta M, Hernández-Hernández MA, López-Hoyos
M, et al. Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection. J Clin Endocrinol Metab.
2021 Mar 8;106(3):e134353.
132. Oristrell J, Oliva JC, Subirana I, Casado E, Dominguez D, Toloba A, et al. Association of Calcitriol
Supplementation with Reduced COVID-19 Mortality in Patients with Chronic Kidney Disease: A
Population-based Study. 2021 Apr 6 [cited 2021 Apr 12]; Available from:
https://www.preprints.org/manuscript/202104.0173/v1
133. Fasano A, Cereda E, Barichella M, Cassani E, Ferri V, Zecchinelli AL, et al. COVID-19 in Parkinson’s
Disease Patients Living in Lombardy, Italy. Mov Disord. 2020 Jul;35(7):108993.
134. Israel A, Cicurel AA, Feldhamer I, Dror Y, Giveon SM, Gillis D, et al. The link between vitamin D
deficiency and Covid-19 in a large population. medRxiv [Internet]. 2020 Sep 7 [cited 2020 Nov
24];2020.09.04.20188268. Available from:
https://www.medrxiv.org/content/10.1101/2020.09.04.20188268v1
135. Ma H, Zhou T, Heianza Y, Qi L. Habitual use of vitamin D supplements and risk of coronavirus disease
2019 (COVID-19) infection: a prospective study in UK Biobank. Am J Clin Nutr. 2021 May 8;113(5):1275
81.
136. Loucera C, Peña-Chilet M, Esteban-Medina M, Muñoyerro-Muñiz D, Villegas R, Lopez-Miranda J, et al.
Real world evidence of calcifediol use and mortality rate of COVID-19 hospitalized in a large cohort of
16,401 Andalusian patients. medRxiv [Internet]. 2021 Apr 29 [cited 2021 Jun 25];2021.04.27.21255937.
Available from: https://www.medrxiv.org/content/10.1101/2021.04.27.21255937v1
137. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CSC, et al. Effect of Vitamin D3
Supplementation vs Placebo on Hospital Length of Stay in Patients with Severe COVID-19: A Multicenter,
Double-blind, Randomized Controlled Trial. medRxiv [Internet]. 2020 Nov 17 [cited 2020 Nov
18];2020.11.16.20232397. Available from:
https://www.medrxiv.org/content/10.1101/2020.11.16.20232397v1
138. Jevalikar G, Mithal A, Singh A, Sharma R, Farooqui KJ, Mahendru S, et al. Lack of association of baseline
25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-
19. Scientific Reports [Internet]. 2021 Mar 18;11(1):6258. Available from: https://doi.org/10.1038/s41598-
021-85809-y
139. Ling SF, Broad E, Murphy R, Pappachan JM, Pardesi-Newton S, Kong M-F, et al. High-Dose
Cholecalciferol Booster Therapy is Associated with a Reduced Risk of Mortality in Patients with COVID-
19: A Cross-Sectional Multi-Centre Observational Study. Nutrients [Internet]. 2020 Dec [cited 2020 Dec
12];12(12):3799. Available from: https://www.mdpi.com/2072-6643/12/12/3799
140. Giannini S, Passeri G, Tripepi G, Sella S, Fusaro M, Arcidiacono G, et al. Effectiveness of In-Hospital
Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating
Study. Nutrients [Internet]. 2021 Jan [cited 2021 Jan 19];13(1):219. Available from:
https://www.mdpi.com/2072-6643/13/1/219
141. Ohaegbulam KC, Swalih M, Patel P, Smith MA, Perrin R. Vitamin D Supplementation in COVID-19
Patients: A Clinical Case Series. American Journal of Therapeutics [Internet]. 2020 Oct [cited 2020 Dec
3];27(5):e485. Available from:
33
https://journals.lww.com/americantherapeutics/Abstract/2020/10000/Vitamin_D_Supplementation_in_COV
ID_19_Patients__A.8.aspx
142. Sabico S, Enani MA, Sheshah E, Aljohani NJ, Aldisi DA, Alotaibi NH, et al. Effects of a 2-Week 5000 IU
versus 1000 IU Vitamin D3 Supplementation on Recovery of Symptoms in Patients with Mild to Moderate
Covid-19: A Randomized Clinical Trial. Nutrients [Internet]. 2021 Jul [cited 2021 Jun 28];13(7):2170.
Available from: https://www.mdpi.com/2072-6643/13/7/2170
143. Tan CW, Ho LP, Kalimuddin S, Cherng BPZ, Teh YE, Thien SY, et al. Cohort study to evaluate the effect
of vitamin D, magnesium, and vitamin B12 in combination on progression to severe outcomes in older
patients with coronavirus (COVID-19). Nutrition. 2020 Dec;7980:111017.
144. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon
R, et al. “Effect of calcifediol treatment and best available therapy versus best available therapy on intensive
care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical
study.” J Steroid Biochem Mol Biol [Internet]. 2020 Oct [cited 2020 Sep 22];203:105751. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456194/
145. Alcala-Diaz JF, Limia-Perez L, Gomez-Huelgas R, Martin-Escalante MD, Cortes-Rodriguez B, Zambrana-
Garcia JL, et al. Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study. Nutrients
[Internet]. 2021 Jun [cited 2021 Jun 2];13(6):1760. Available from: https://www.mdpi.com/2072-
6643/13/6/1760
146. Nogués X, Ovejero D, Quesada-Gomez JM, Bouillon R, Arenas D, Pascual J, et al. Calcifediol Treatment
and COVID-19-Related Outcomes [Internet]. Rochester, NY: Social Science Research Network; 2021 Jan
[cited 2021 Feb 12]. Report No.: ID 3771318. Available from: https://papers.ssrn.com/abstract=3771318
147. Quesada-Gomez JM, Bouillon R. Is calcifediol better than cholecalciferol for vitamin D supplementation?
Osteoporos Int. 2018 Aug;29(8):1697711.
148. Vitamina D nella prevenzione e nel trattamento del COVID-19: nuove evidenze (3 dicembre 2020)
[Internet]. [cited 2021 Sep 5]. Available from: https://www.accademiadimedicina.unito.it/attivita/altro/317-
vitamina-d-nella-prevenzione-e-nel-trattamento-del-covid-19-nuove-evidenze.html
149. Effet bénéfique de la vitamine D dans la Covid : quelles sont les données ? [Internet]. [cited 2021 Sep 5].
Available from: https://www.larevuedupraticien.fr/article/effet-benefique-de-la-vitamine-d-dans-la-covid-
quelles-sont-les-donnees
150. McCartney DM, O’Shea PM, Faul JL, Healy MJ, Byrne G, Griffin TP, et al. Vitamin D and SARS-CoV-2
infectionevolution of evidence supporting clinical practice and policy development. Ir J Med Sci
[Internet]. 2020 Nov 21 [cited 2020 Dec 2]; Available from: https://doi.org/10.1007/s11845-020-02427-9
151. Oireachtas H of the. Oireachtas Health Committee launches report on addressing Vitamin D deficiency in
Ireland 7 Apr 2021, 11.00 Houses of the Oireachtas [Internet]. 2021 [cited 2021 Sep 5]. Available from:
https://www.oireachtas.ie/en/press-centre/press-releases/20210407-oireachtas-health-committee-launches-
report-on-addressing-vitamin-d-deficiency-in-ireland
152. Akbar MR, Wibowo A, Pranata R, Setiabudiawan B. Low Serum 25-hydroxyvitamin D (Vitamin D) Level
Is Associated With Susceptibility to COVID-19, Severity, and Mortality: A Systematic Review and Meta-
Analysis. Front Nutr [Internet]. 2021 [cited 2021 Jun 26];8. Available from:
https://www.frontiersin.org/articles/10.3389/fnut.2021.660420/full
153. Artusi CA, Romagnolo A, Ledda C, Zibetti M, Rizzone MG, Montanaro E, et al. COVID-19 and
Parkinson’s Disease: What Do We Know So Far? J Parkinsons Dis [Internet]. 2021 [cited 2021 Jun
10];11(2):44554. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150504/
34
154. Bassatne A, Basbous M, Chakhtoura M, El Zein O, Rahme M, El-Hajj Fuleihan G. The link between
COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis. Metabolism [Internet]. 2021
Jun [cited 2021 Jul 1];119:154753. Available from:
https://linkinghub.elsevier.com/retrieve/pii/S0026049521000536
155. Chambergo-Michilot D, Barros-Sevillano S, Rivera-Torrejón O, De la Cruz-Ku GA, Custodio N. Factors
associated with COVID-19 in people with Parkinson’s disease: a systematic review and meta-analysis. Eur J
Neurol. 2021 May 13;
156. Chen J, Xie L, Yuan P, Ma J, Yu P, Zheng C, et al. Low serum vitamin D level and COVID-19 infection and
outcomes, a multivariate meta-analysi [Internet]. 2020 [cited 2021 Jun 26]. Available from:
https://europepmc.org/article/PPR/PPR230641
157. Damayanthi HDWT, Prabani KIP. Nutritional determinants and COVID-19 outcomes of older patients with
COVID-19: A systematic review. Arch Gerontol Geriatr. 2021 Aug;95:104411.
158. Das P, Samad N, Ahinkorah BO, Peprah P, Mohammed A, Seidu A-A. Effect of Vitamin D deficiency on
COVID-19 status: A systematic review. medRxiv [Internet]. 2020 Dec 3 [cited 2020 Dec
14];2020.12.01.20242313. Available from:
https://www.medrxiv.org/content/10.1101/2020.12.01.20242313v1
159. Dramé M, Cofais C, Hentzien M, Proye E, Coulibaly PS, Demoustier-Tampère D, et al. Relation between
Vitamin D and COVID-19 in Aged People: A Systematic Review. Nutrients [Internet]. 2021 Apr [cited 2021
May 18];13(4):1339. Available from: https://www.mdpi.com/2072-6643/13/4/1339
160. Grove A, Osokogu O, Al-Khudairy L, Mehrabian A, Zanganeh M, Brown A, et al. Association between
vitamin D supplementation or serum vitamin D level and susceptibility to SARS-CoV-2 infection or
COVID-19 including clinical course, morbidity and mortality outcomes? A systematic review. BMJ Open.
2021 May 28;11(5):e043737.
161. Munshi R, Hussein MH, Toraih EA, Elshazli RM, Jardak C, Sultana N, et al. Vitamin D insufficiency as a
potential culprit in critical COVID-19 patients. J Med Virol. 2020 Jul 27;93(2):73340.
162. Pereira M, Damascena AD, Azevedo LMG, Oliveira T de A, Santana J da M. Vitamin D deficiency
aggravates COVID-19: systematic review and meta-analysis. Critical Reviews in Food Science and
Nutrition [Internet]. 2020 Nov 4 [cited 2020 Nov 5];0(0):19. Available from:
https://doi.org/10.1080/10408398.2020.1841090
163. Petrelli F, Luciani A, Perego G, Dognini G, Colombelli PL, Ghidini A. Therapeutic and prognostic role of
vitamin D for COVID-19 infection: A systematic review and meta-analysis of 43 observational studies. J
Steroid Biochem Mol Biol [Internet]. 2021 Jul [cited 2021 Jun 10];211:105883. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997262/
164. Rothenberg E. Coronavirus Disease 19 from the Perspective of Ageing with Focus on Nutritional Status and
Nutrition ManagementA Narrative Review. Nutrients [Internet]. 2021 Apr [cited 2021 Apr
24];13(4):1294. Available from: https://www.mdpi.com/2072-6643/13/4/1294
165. Shah K, Saxena D, Mavalankar D. Vitamin D supplementation, COVID-19 and disease severity: a meta-
analysis. QJM. 2021 May 19;114(3):17581.
166. Stroehlein JK, Wallqvist J, Iannizzi C, Mikolajewska A, Metzendorf M-I, Benstoem C, et al. Vitamin D
supplementation for the treatment of COVID-19: a living systematic review. Cochrane Database Syst Rev.
2021 May 24;5:CD015043.
35
167. Teshome A, Adane A, Girma B, Mekonnen ZA. The Impact of Vitamin D Level on COVID-19 Infection:
Systematic Review and Meta-Analysis. Front Public Health [Internet]. 2021 Mar 5 [cited 2021 Jun 10];9.
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973108/
168. Wang Z, Joshi A, Leopold K, Jackson S, Christensen S, Nayfeh T, et al. Association of Vitamin D
Deficiency with COVID-19 Infection Severity: Systematic Review and Meta-analysis. Clin Endocrinol
(Oxf). 2021 Jun 23;
169. Yadav SK, Gaurav K, Johri G, Jaiswal SK, Jha CK, Yadav N. A systematic review of the role of
hypovitaminosis D in coronavirus disease-19 (COVID-19) infection and mortality: Is there a role of
recommending high dose vitamin D supplementation? Human Nutrition & Metabolism [Internet]. 2021 Mar
1 [cited 2021 Apr 30];23:200120. Available from:
https://www.sciencedirect.com/science/article/pii/S2666149721000025
170. Yisak H, Ewunetei A, Kefale B, Mamuye M, Teshome F, Ambaw B, et al. Effects of Vitamin D on COVID-
19 Infection and Prognosis: A Systematic Review. Risk Manag Healthc Policy. 2021;14:318.
171. Nogues X, Ovejero D, Pineda-Moncusí M, Bouillon R, Arenas D, Pascual J, et al. Calcifediol treatment and
COVID-19-related outcomes. J Clin Endocrinol Metab [Internet]. [cited 2021 Jun 9]; Available from:
https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgab405/6294179
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COVID 19 is known to cause immune dysregulation and vitamin D is a known immunomodulator. This study aims to objectively investigate the impact of Pulse D therapy in reducing the inflammatory markers of COVID-19. Consented COVID-19 patients with hypovitaminosis D were evaluated for inflammatory markers (N/L ratio, CRP, LDH, IL6, Ferritin) along with vitamin D on 0th day and 9th/11th day as per their respective BMI category. Subjects were randomised into VD and NVD groups. VD group received Pulse D therapy (targeted daily supplementation of 60,000 IUs of vitamin D for 8 or 10 days depending upon their BMI) in addition to the standard treatment. NVD group received standard treatment alone. Differences in the variables between the two groups were analysed for statistical significance. Eighty seven out of one hundred and thirty subjects have completed the study (VD:44, NVD:43). Vitamin D level has increased from 16 ± 6 ng/ml to 89 ± 32 ng/ml after Pulse D therapy in VD group and highly significant (p < 0.01) reduction of all the measured inflammatory markers was noted. Reduction of markers in NVD group was insignificant (p > 0.05). The difference in the reduction of markers between the groups (NVD vs VD) was highly significant (p < 0.01). Therapeutic improvement in vitamin D to 80–100 ng/ml has significantly reduced the inflammatory markers associated with COVID-19 without any side effects. Hence, adjunctive Pulse D therapy can be added safely to the existing treatment protocols of COVID-19 for improved outcomes.
Article
Background We sought to evaluate the association between vitamin D deficiency and severity of COVID-19 infection. Methods Multiple databases from January 1st, 2019 to December 3rd, 2020 were searched for observational studies evaluating the association between vitamin D deficiency and severity of COVID-19 infection. Independent reviewers selected studies and extracted data for the review. The main outcomes of interest were mortality, hospital admission, length of hospital stay and intensive care unit admission. Results 17 observational studies with 2,756 patients were included in the analyses. Vitamin D deficiency was associated with significantly higher mortality (OR: 2.47, 95% CI: 1.50 to 4.05; 12 studies; HR: 4.11, 95% CI: 2.40 to 7.04; 3 studies), higher rates of hospital admissions (OR: 2.18, 95% CI: 1.48 to 3.21; 3 studies); and longer hospital stays (0.52 days; 95% CI: 0.25 to 0.80; 2 studies) as compared to non-vitamin D deficient status. Subgroup analyses based on different cut offs for defining vitamin D deficiency, study geographic locations and latitude also showed similar trends. Conclusions Vitamin D deficiency is associated with greater severity of COVID-19 infection. Further studies are warranted to determine if vitamin D supplementation can decrease severity of COVID-19. This article is protected by copyright. All rights reserved.