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1
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, 1822) 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.1,5–7
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.11–13
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.23,25–27 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, for at least 28 days.40,41
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
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
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
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.45–47 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
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
6
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)
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
7
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.63–65 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.46,74–76 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,
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
8
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.77,81–83 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,
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
9
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
relationship between vitamin D levels and Covid-19 can be found with a quick PubMed search.
Only a few examples are detailed here.
10
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
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
11
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: 1.08–1.95, 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. 0.983–0.986; 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
be infected with SARS-CoV-2 as those without this diagnosis (OR=5.155) 95% CI 3.974-6.688,
P<0.001).115
12
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=1.00–2.05).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=1.47–2.71) and 13 addressing mortality (RR 2.45; 95% CL=1.24–4.84).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=0.099–0.708, 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
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
13
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
individual supplementation response is influenced by genetics, obesity, diabetes, etc., trials must
be guided by participant 25(OH)D levels.16,125,126
14
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.36,37,40,74,122,127
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
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
15
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 However, the initial differences
between the supplemented and the control group were so dramatic that the inflammatory markers
remained higher than those of the control group even post supplementation.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.137–139 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.138–140 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.138–140 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.36,37,40 Despite this
concern, none of the treatment groups fared worse than the controls.137–140 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.144–147 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=0.32–0.99] 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(0.20–1.22), p = 0.13
If comorbities are seen as effect modifiers:
3+: ORadj 0.18, 95%CI0.04–0.83), 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 0.12–0.49), p < 0.001)
MV(ORadj 0.13, 95% CI 0.05–0.35, 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, 0.45–0.97; 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
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