MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001
Posted Online 2020-03-24 Open Access
Vitamin D deficiency: a factor in COVID-19, progression,
severity and mortality? – An urgent call for research
Brown R*, Sarkar A
Members of McCarrison Society, U.K.
*Address for correspondence: Robert Brown, PhD. E-mail: RAB5155@gmail.com
© 2020 Brown et al. This is an Open Access extended abstract (not peer-reviewed)
distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the
original authors and source are credited. © remains with the authors, who have
granted MitoFit an Open Access preprint license in perpetuity.
Editor MitoFit Preprint Archives: Iglesias-Gonzalez J
COVID-19, Vitamin D deficiency, 25 hydroxy D, Vitamin D Receptor, VDR Receptor, Obesity, Influenza,
ACE, Angiotensin, Tight Junctions
The COVID-19 virus emerged in 2019. Mortality rates as at 20th March 2020 are much higher
in southern than northern Europe. The elderly, and those with pre-existing conditions, are at
greatest risk. It is hypothesised, vitamin D deficiency may significantly compromise, respiratory
immune response function, thus greatly increasing risk of COVID-19 hospitalisation, severity and
mortality. Winter vitamin D levels: based on; limited data, including; historical measured
regional vitamin D deficiency rates (<25nmol/L), intakes, and plasma vitamin D levels;
fortification and supplementation policies; and public vitamin D awareness: appear to be
significantly lower in southern, than northern Europe. In respiratory system conditions, such as
influenza, vitamin D has wide-ranging and fundamental roles, including through: gene
transcription via COVID-19 relevant VDR (Vitamin D Receptor) pathways; ACE1 and ACE2
pathways; wider immune function; airway epithelial cell tight-junction function and integrity;
and mitochondrial related, energetics, apoptosis and inflammation, management. Studies
suggest vitamin D supplementation may be protective against respiratory conditions, in ‘D’
deficient persons. Would vitamin D supplementation of the deficient, mitigate the severity of the
current COVID-19 outbreak; and reduce future, likely upcoming, seasonal amplification effects?
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It is hypothesised, herein and suggested by others (Watkins, 2020), and in a paper by Grant and
Lahore, (Grant et al., 2020) that vitamin D insufficiency may significantly compromise, respiratory
immune response function, greatly increasing risk of COVID-19 severity and mortality.
This hypothesis focuses primarily on the contention vitamin D deficiency is the most critical factor
in determining the extent, and severity, of COVID-19 infection, progression and outcomes. Further, it is
not discussed in depth, but a matter of importance, that obesity reduces vitamin D in plasma, increasing
risk of deficiency, and raising supplementation dosage requirements for correction of deficiency in the
obese. “Serum 25OHD is inversely correlated with body weight, BMI and fat mass” and “about 20% lower
in obese people than normal weight”. (Walsh, et al., 2017) Obesity and related comorbidities increase
risk of poor outcomes in influenzas, thus likely the risk of COVID-19.
In respiratory system conditions, such as influenza, vitamin D has wide-ranging and fundamental
roles, including through: gene transcription via COVID-19 relevant VDR (Vitamin D Receptor) pathways;
wider immune function; and airway epithelial cell tight-junction function and integrity. Further, studies
suggest vitamin D supplementation may be protective in respiratory conditions, the effect being highly
significant in ‘D’ deficient persons.
The elderly, and those with pre-existing conditions, are at greatest risk. The article ‘US studies offer
clues to COVID-19 swift spread, severity’ notes, “The first description of outcomes in 4,226 US COVID-19
cases reported to the CDC from Feb 12 to Mar 16 shows that 31% of cases, 45% of hospitalizations, 53% of
intensive care unit (ICU) admissions, and 80% of deaths occurred in people 65 years or older.
Fatality rates for people 85 years and older ranged from 10% to 27%. Of those aged 65 to 84 years, 3%
to 11% died. Death rates fell to 1% to 3% among those 55 to 64, less than 1% in those 20 to 54, and 0% in
those 19 and younger.”
“Of the 2,449 infected patients whose age was known, 6% were 85 years or older, 26% were 65 to 84,
18% were 45 to 54, 17% were 55 to 64, and 20% were 20 to 44. Only 5% of infections occurred in people
19 years and younger.”(Van Beusekom, 2020) (Begley, 2020; Dong et al., 2020)
Mortality rates for COVID-19 differ significantly between countries, ranging from 8.3 % in Italy (20th
March 2020) to between 0.27 and 1.0 % in northern European countries. The annual average 2011-
2017 percentage mortality to infection rate of influenza in the USA is around 0.14 %.(Disease Burden of
Influenza) The COVID-19 percentage mortality to infections rate is likely overstated, due to non-
reporting of asymptomatic COVID-19. However, irrespective of the variation in mortality rate, COVID-
19 is a new virus, with a capacity to spread rapidly.
Clearly it is important that the reasons for these differentials in mortality are better understood.
Answers may provide ways to better manage the COVID-19 pandemic. Improved immune function,
through better nutrition, is likely a factor. Nutrients such as vitamin D, and iodine, have important roles
in cellular, including immune function. Less is known about iodine than vitamin D.
Of course, a range of nutrients, not just vitamin D are likely involved. Vitamin D co-factors include
vitamin K2, vitamin A, magnesium and zinc. Interactions are complex. Insufficiencies of many nutrients,
including vitamin D and iodine, are common place. Northern European diets are probably more nutrient
dense than some, including due to consumption of whole grain minimally processed breads. Due to their
culture and more northerly latitude, they tend to include greater amounts of vitamin D rich foods, and
have greater focus on supplementation.
What constitutes vitamin D deficiency in adults is debated, but for the purposes of this hypothesis, is
taken to be plasma levels < (less than) 25nmol/L (10ng/ml). This hypothesis focuses on vitamin D
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deficiency, as a likely key factor, but by no means only factor, in COVID-19 progression and outcome.
Plasma vitamin D levels are inversely related to the amount of vitamin D ingested in food, and made in
‘summer sun’ months, following exposure to sun. Levels are reduced by obesity.
Vitamin D related immune pathways, have been demonstrated to be active in the progression of
COVID-19, in a patient. Wider research suggests, vitamin D is protective against respiratory conditions.
Population studies suggest that those with vitamin D deficiencies are more susceptible to respiratory
illnesses, including influenzas.
COVID-19 clinical manifestation and time progression
The paper ‘The outbreak of COVID-19’ provides an overview of the COVID-19 virus clinical
manifestation, and time progression; “COVID-19 has a mean incubation period of 5.2 days (95%
confidence interval, 4.1–7.0). The infection is acute without any carrier status. Symptoms usually begin
with nonspecific syndromes, including fever, dry cough, and fatigue. Multiple systems may be involved,
including respiratory (cough, short of breath, sore throat, rhinorrhea, hemoptysis, and chest pain),
gastrointestinal (diarrhea, nausea, and vomiting), musculoskeletal (muscle ache), and neurologic
(headache or confusion). More common signs and symptoms are fever (83%–98%), cough (76%–82%), and
short of breath (31%–55%). There were about 15% with fever, cough, and short of breath. Conjunctival
injection was not reported in the early series and cases with age under 18 were few. After onset of illness,
the symptoms are somehow mild and the median time to first hospital admission is 7.0 days (4.0–8.0). But
the disease progresses to short of breath (~8 days), acute respiratory distress syndrome (ARDS) (~9 days),
and to mechanical ventilation (~10.5 days) in about 39% patients. Patients with fatal disease develop ARDS
and worsened in a short period of time and died of multiple organ failure. The mortality rate in the early
series of hospitalized patients was 11%–15%, but the later statistics was 2%–3%.”(Wu et al., 2020)
Uncertainty as to extent of COVID-19 infection
The level of COVID-19 infection in populations is uncertain, due to; very mild even asymptomatic
manifestation in some; inherent lags in availability of testing facilities; compounded by, social stigma
attached to earlier infected persons, personal economic and social consequences; all magnified by
historical lack of testing capacity in many countries. Additionally, a number of testing mechanism are
being used, and until they are directly compared, there is no certainty measurements are equivalent.
Low COVID-19 death rate in Germany - hospital situation as at 20th March 2020
Germany as at 20th March 2020, has a comparatively low COVID-19 percentage death rate to
infections; 0.34 % representing 68 mortalities, out of 19,848 reported infections. The German
Government is nonetheless taking a reasonable and prudent position, in the face of uncertainty, and
absence of adequate information as to the characteristic of COVID-19.
Consistent with the comparatively low death rate to date, a media source ‘Speigel International’ (Ker,
2020) reported quotes from Medical Professionals, suggest hospitals are not yet seeing a large influx of
COVID-19 patients. Germany has significantly more acute bed capacity than Italy, but nonetheless, there
are no media reports as of 19th March 2020, of significant pressures on hospitals
This suggests that data for Germany on mortality, and anecdotal suggestions of a lower impact of
COVID-19 in Germany, are reasonable. Indeed, media asked why the death rate in Germany is
low(Monella & Priese, 2020). Speigel International quotes include:
“But how quickly are hospitals responding to Spahn’s (German Minister of Health) "urgent appeal"?
Are procedures really being cancelled; are intensive care unit beds being freed up? "We had to cancel all
operations on Monday because I had been in a risk area myself and hadn’t been tested yet," a chief physician
at one northern German hospital told DER SPIEGEL. "Apart from that, we haven’t postponed any specific
procedures yet, because there are no corona-infected patients in our hospital."(Ker, 2020)
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“An anesthesiologist at a municipal children's hospital reported the situation is similar where he works.
"Some parents have cancelled operations as a precaution," says the doctor, "a hernia or a gastroscopy
usually doesn’t have to take place immediately." He said things were pretty much business as usual at the
hospital on Monday and that they were still performing outpatient operations. "Otherwise, we wouldn't
have anything to do at the children's hospital right now," said the anesthetist.”(Ker, 2020)
“In terms of coronavirus patients, things are still quiet in many hospitals in Germany, and by no means
will all facilities have to be hectically converted into emergency facilities. When contacted by DER SPIEGEL,
the Schön-Kliniken, a company that operates 26 hospitals in Germany, said that clinics that don’t have
intensive care facilities are operating just as they have until now.”(Ker, 2020)
These reports do not suggest large number of patients in Germany are requiring intensive hospital
treatment. Thus, the lower mortality effects are likely real, and not just reporting differences.
Similarly, Swedish COVID-19 data below, media reporting, and detail on the Wikipedia page,
(Wikipedia contributors, 2020d) do not as yet, at 20th March 2020, suggest high levels of pressure on
medical facilities, or ‘large’ number of seriously ill patients, albeit shortages of protective equipment
were reported on 13th March 2020. Albeit there is less information on line, the situation appears broadly
similar in other Nordic Countries.
COVID-19 progression and outcome by age group - CDC data
Recent data from the USA suggests adults in their mid-years account for a significant portion of
infections, of which some are hospitalised. In the middle age group, the level of case severity of those
hospitalised is not clear, but progressions to ICU of younger people is likely low. Current figures suggest
risk of mortality in healthy persons in this age group is low.
The CDC report dated 18th March 2020 (Bialek et al., 2020), based on 2,249 patients, includes the
table below (See Table 1).
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Table 1. CDC COVID-19 data-table
“* Lower bound of range = number of persons hospitalized, admitted to ICU, or who died among total in
age group; upper bound of range = number of persons hospitalized, admitted to ICU, or who died among
total in age group with known hospitalization status, ICU admission status, or death.” Copies from the CDC
web site with many and grateful thanks to the Authors.(Bialek et al., 2020)
COVID-19 data – vitamin D – infection and mortality rates
Whilst infection data is incomplete, there is clear mortality data; as well as observable more diffuse
impact trends, including; hospital data, wider medical resource utilisation, and public pressure / media
reporting trends, which together, likely broadly reflect the actual number of patients under treatment
in each country.
As seen in table 2 below (See Table 2), there are striking differences between COVID-19 impacts in
countries such as, China, Italy and France; and the northern European countries. Despite having a
significant number of cases, and in some instances very similar reported infection progression profiles
(as seen in France and Germany), the northern European countries currently consistently suffer much
lower mortality to infection percentage rates (Figure 2).
Further, based on available limited data; a paucity of media suggestions that COVID-19, was at 20th
March, causing actual significant consequential requirements for extra hospital facilities; general media
coverage of public information announcements, and population responses; it appears the pandemic in
northern European countries, is currently less impactful, than in southern European countries, notably
Italy and Spain.
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Lower vitamin D deficiency in northern Europe?
Whilst as noted, limited recent European data is available, the paper “Current vitamin D status in
European and Middle East countries and strategies to prevent vitamin D deficiency: a position statement
of the European Calcified Tissue Society”, observes, “Vitamin D deficiency (serum 25-hydroxyvitamin D
(25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the
population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and up to 80% in
Middle East countries.”(Lips et al., 2019)
A lower level of vitamin D deficiency in northern Europe, would be consistent with their National
public health policies as to fortification, as well as promotion of the need for supplementation,
particularly in the elderly, and understanding by a public; and again particularly the elderly, acquainted
with issues of bone degradation; yearly faced with long dark nights, in northern latitudes; of the need
for vitamin D supplementation.
Greater vitamin D deficiency in southern Europe
In contrast, to northern Europe, vitamin D levels in southern and eastern Europe may be both lower,
and continuing to fall. The 2018 review, ‘Vitamin D status among Mediterranean regions’ observes
“Southern European countries are at greater deficiency risk than Northern ones.” “A recent systematic
review confirmed the high prevalence of low vitamin D concentration in countries of Southern Europe and
Eastern Mediterranean regions. Whereas food fortification with vitamin D and vitamin D supplementation
were common practice in northern Europe, in the Mediterranean regions were highly underestimated.
Additionally, further research showed that sun-seeking behavior is rather avoided in southern countries,
both due to heat avoidance or melanoma prevention guidelines.”(Kasapidou et al., 2018)
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Figure 1. Plot of the total number and time-lines of COVID-19 infections and deaths in; Italy, France
and Germany. The data was taken from a mixture of, WHO ‘Situation reports’, (WHO Coronavirus disease
(COVID-2019) situation reports), Worldometer (“Coronavirus Update (Live): 274,171 Cases and 11,354
Deaths from COVID-19 Virus Outbreak - Worldometer,” n.d.), and Wikipedia (Wikipedia contributors,
2020b, 2020a, 2020c). (For German data, there appears to be a one-day difference between the data on
the Wikipedia page and WHO figures, and those on Worldometer, hence the difference in German
figures, between those in Fig.1, and Figs.2 and 3.)
“Another aspect could be the urbanization that is observed in all Southern European regions. Studies
have shown that there is a higher prevalence rate of vitamin D insufficiency in urban populations due to
the modern lifestyle and office jobs that entail to less time outdoors. Fortification policies and the overall
capacity of the diet to supply enough vitamin D to maintain healthy serum 25-hydroxyvitamin D
concentration (S-25(OH)D) failed to be as effective as expected.”(Kasapidou et al., 2018) .
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Table 2#. COVID-19 infection cases, total death, serious/critical patients, vitamin D levels and
percentage population with <25 nmol/L vitamin D levels, in different countries on 18th March 2020.
Vitamin D (nmol/L)
Population with <25
nmol/L of Vitamin D (%)
% Death to Infection
Vitamin D intake mcg
Vitamin D intake mcg
Iceland 57.0 4.2 409 0 1 - - -
Norway 65.4 0.29 1959 7 27 0.36 15.0 12.9
Sweden 72.9 0.8 1639 16 21 0.98 7.1 6.1
Finland 67.7 0.2 450 0 2 - 9.0 6.5
Denmark 65.0 0 1255 9 37 0.72 3.9 3.1
UK 47.4 15.4 3983 177 20 4.44 - -
Ireland 56.4 11.1 683 3 6 0.44 3.5 2.2
Netherlands 60.8 4.3 2994 106 210 3.54 4.8 3.6
Belgium 49.3 7.3 2257 37 164 1.64 - -
Germany 50.1 4.2 19848 68 2 0.34 4.4 3.4
France 60.0 6.3 12612 450 1297 3.58 - -
Italy 45.0 54.5 47021 4032 2655 8.58 - -
Switzerland 42.6 15.2 5615 56 141 1.00 2.5 2.4
Poland 32.5 25.0 425 5 3 1.18 - -
Iran 36.3 30.4 19644 1433 - 7.29 - -
Russia 33 40.1 253 1 - 0.39 - -
Spain 42.9e 47e,f, 21571 1093 939 5.07 0.7 0.7
China NA 70.3c 80967 3248 2136 4.01 - -
South Korea NA 70.2d 8652 94 59 1.09 - -
USA NA 30.6c 19383 256 64 1.32 - -
a The values of Vitamin D, and population numbers with <25 nmol/L of Vitamin D (%) (except for China,
Spain, South Korea and USA) have been taken from reference (Lips et al., 2019)
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b The values of total cases of COVID-19; infection; death; serious and critical patients; have been taken
from reference (Coronavirus Update (Live): (“Coronavirus Update (Live): 274,171 Cases and 11,354
Deaths from COVID-19 Virus Outbreak - Worldometer, n.d.) on 20 March 2020. Figures vary sligthly
between sources; for example between the WHO and Worldometer, thus figures are offered as
indicational only – but in general direction terms, are consistent.
c The values of population with <25 nmol/L of Vitamin D (%) for China and USA have been taken from reference
(Wei et al., 2019)
d The value of population with <25 nmol/L of Vitamin D (%) for South Korea has been taken from reference
(Park et al., 2018)
e Spain was included in the (Lips et al. study), but no data was included on the Spain data line. Many of the
studies in Europe used in (Lips et al. study) were 2015 and 2016, hence the selection of this study and the data it
used for this group. The authors of this hypothesis, have also found difficulty in finding relevant data for Spain.
(Spiro, 2014) data for an elderly group has been used for nmol/L. The other data was not used as two genders
f A Spanish study (Peláez V, 2017) indicates higher mortality in patients with low vitamin D under 12.48
nmol/L. 74 institutionalised patients had a mean level of 18.40 ± 7.58 nmol/L. The study makes reference to
(Portela, 2009), a very small which found 47 % of institutionalised women from Llieda, age was over 65, were
<25nmol/L. The 47 % figure is used as indicational only. Inclusion of the (Peláez V, 2017) nursing home data would
have substantially raised the % <25nmol/L.
# Adult population was considered for all values of vitamin D levels and percentage population with <25 nmol/L
of Vitamin D with age of >17 years (except UK). Due to unavailability of corresponding data the values for age
group 1.5 to 91 years have been considered.
z Male and female elderly group vitamin D intake; data from table 2, from reference (Spiro & Buttriss)
‘Residential’ institutions – high vitamin D deficiency risk environments
The extent of vitamin D insufficiency is magnified in those residing in institutions; with low access to
sunshine; often subject to nutritionally limited diets; and likely generally not having the benefits of
organised supplementation regimes; such as; prisons,(Nwosu et al., 2014; Prisoners have very low
vitamin D and get TB, influenza, and depression. n.d.) retirement homes (including those in
Sweden),(Arnljots et al., 2017) mental institutions,(Cuomo et al., 2019) long stay hospitals, and
submarines. Numerous studies confirm those in institutions are at risk of low Vitamin D levels.
Very sadly the greater susceptibility of those in residential care has been illustrated by events. In
respect of COVID-19, the CIDRAP commentary article observes “The report on the coronavirus outbreak
in a King County, Washington, nursing facility, which sickened 129 people (81 of about 130 residents, 34 of
170 workers, and 14 visitors) and killed 23 from Feb 27 to Mar 9, underscores the ability of the novel
coronavirus to spread quickly in such settings.”(Van Beusekom, 2020)
The article continues “Of those infected, the median age was 81 years (range, 54 to 100) in residents,
42.5 years in staff members (range, 22 to 79), and 62.5 years (range, 52 to 88) for visitors. Eighty-four
(65.1%) were women. (Van Beusekom, 2020)
Hospitalization rates were 56.8% for residents, 35.7% for visitors, and 5.9% of staff members. Death
rates were 27.2% for residents and 7.1% for visitors; no staff members died. The most common underlying
diseases in residents were high blood pressure (69.1%), heart disease (56.8%), kidney disease (43.2%),
diabetes (37%), obesity (33.3%), and lung disease (32.1%). The only underlying condition in six residents
and one visitor was high blood pressure.” (Van Beusekom, 2020)
If such high hospitalisation rates and mortality are common in residential institutions, ensuring
COVID-19 protective factors are optimised, including resolution of vitamin D deficiency, if determined
by studies to be relevant, could yield significant health and resource dividends.
Vitamin D deficiency: a factor in COVID-19?
Whilst currently there is insufficient data, and evidence, to come to any conclusion as to; the impact
of vitamin D on; COVID-19, infection, hospitalisation or mortality rate; consideration from a wide
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perspective, including: known COVID-19 immunity pathways; immune pathways; vitamin D physiology;
population studies on vitamin D levels and related respiratory condition outcomes; vitamin D clinical
studies; and wider information; suggests vitamin D deficiency is likely to prove to be, a significant factor
in COVID-19 progression and risks.
Interestingly, in figure 2, below, the total COVID-19 infection rates in different countries, are seen to
correlated, to an extent, with: the percentage of vitamin D deficiency in the population - those
with less than 25 nmol/L Vitamin D level,
and inversely correlated, to an extent, with: both;
o higher plasma vitamin D levels,
o and, higher dietary vitamin D intakes.
It is noticeable, that, the level of COVID-19; infections, serious/critical cases, and mortality rates; are
significantly lower; vitamin D intake higher; plasma vitamin D nmol/L higher; and vitamin D deficiency
<25nmol/L lower; in Nordic and northern European countries.
Vitamin D data Caveat - graphical indications of National vitamin D status
As discussed, there is a paucity of recent population data on vitamin D. Much of it is old. Dietary habits
(avoidance of dairy, specialist diets, movements towards vegetarian and vegan diets, reduction of intake
of offal, etc.); time spent indoors; avoidance of sun; greater use of sunscreens; all factors impacting
vitamin D status; have changed considerably in recent years.
Dietary data, is in any event, inherently difficult to quantify as set out in (Lips et al., 2019) and (Spiro,
2014), which were the two primary data sources used. The review, (Lips et al., 2019), in respect of
several European countries helpfully cites comparatively ‘recent’ data from 2013-2017, but which is still
some years old, a reflection of the lack of recent data. Changes in attitudes to supplementation since then
could help account for differentials.
Thus, data graphed below, should only be taken as indicational of intakes in northern, and southern
Europe, and more widely. There is a consensus in these two reviews, that vitamin D intakes, and blood
parameters, are indeed higher, in northern than southern Europe, but for exact quantification, including
consideration of relevance to COVID-19, data from new sepcific studies is requried.
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Figure 2. Graphical representation of; total COVID-19 deaths, and serious / critical cases at 20th
March, 2020, plotted against: vitamin serum 25OHD3 levels (nmol/L); % number of persons deficient
in vitamin D <25 nmol/L Vitamin 25OHD; across a range of countries; based on data sources and studies
as listed in table 1.
Physiological importance of vitamin D in respiratory and wider conditions
In modern human biology, vitamin D along with vitamin A, and oxidised lipids of Omega 3 and 6, are
signalling factors within a “superfamily of transacting transcriptional regulatory factors”,(Sertznig et al.,
2009) which includes the vitamin D receptor (VDR).
Vitamin D, as well as factoring, including through gene transcription, in reproductive biology,(Keane
et al., 2017) brain development; bone formation; and cancer; has roles in immune and inflammatory
systems;(Kawahito, 2003) and of particular relevance to COVID-19, has significant roles in respiratory
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Figure 3. Graphical representation of total infections, and total deaths at 20th March 2020; plotted
against: vitmain D intake in mcg/day in elderly males and females; and the percentage of a wider
population deficient in vitamin D; <25 nmol/L 25OHD; across a range of countries; based on data
sources and studies as listed in table 1. Daily vitamin D intake is inversely related to; vitamin D
deficiency, and % of blood levels of less than <25nmol/L. Data was taken from the British Nutrition
Foundation (Spiro 2014) Table 10. The elderly data was selected as representing a group particularly at
risk. The Spiro review sets out relevant caveats in the paragraph accompanying table 10. Whilst it is
clear the Nordic countries have higher vitamin D intake; it is inherent in population dietary data that it
can only be viewed as indicative.
The paper ‘Genomic Determinants of Vitamin D-Regulated Gene Expression’ observed, “From a genome
wide perspective” “between 2000 and 8000 VDR-binding sites are detected following activation by
1,25(OH)2D3”.(Pike et al., 2016) The paper ‘Vitamin D Effects on Lung Immunity and Respiratory
Diseases,’ observed “Vitamin D insufficiency has been linked to increased risk of infections, in particular
viral respiratory tract infections”. ‘Vitamin D and respiratory health’(Hughes & Norton, 2009) notes,
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“Vitamin D regulates more than 200 genes including genes for cellular proliferation differentiation and
More specifically, a study mapping gene expression changes in a SARS-CoV model, noted “The
transcription factors identified in these studies (vitamin D receptor [VDR], cyclic AMP receptor binding
protein 1 [CREB1], Oct3/4, hypoxia-inducible factor α2 [HIFα2]-Epas, p53, and SMAD4) play important
roles in the regulation of a variety of cellular processes, including transforming growth factor beta
induction, maintenance of normal lung cell functions, prevention of lung disease phenotypes, and proper
immune cell functions”.(Sims et al., 2013)
The paper ‘Epidemic influenza and vitamin D’ lists other mechanisms by which vitamin D modulates
immune response; “vitamin D, 1,25(OH)2D, a steroid hormone, has profound effects on human immunity.
1,25(OH)2D acts as an immune system modulator, preventing excessive expression of inflammatory
cytokines and increasing the ‘oxidative burst’ potential of macrophages. Perhaps most importantly, it
dramatically stimulates the expression of potent anti-microbial peptides, which exist in neutrophils,
monocytes, natural killer cells, and in epithelial cells lining the respiratory tract where they play a major
role in protecting the lung from infection.”(Cannell et al., 2006)
More widely, and thought provokingly, low vitamin D among 339 older adults with acute medical
conditions, was associated with a higher risk of mortality in a hospital in France, in the winter season,
January to October 2009.(Annweiler et al., 2010)
Pathways are further considered in the papers, ‘Vitamin D and Influenza—Prevention or
Therapy?’(Gruber-Bzura, 2018), ‘An update on vitamin D and human immunity’,(Hewison, 2012) and
‘Role of Fat-Soluble Vitamins A and D in the Pathogenesis of Influenza: A New Perspective’.(Mawson, 2013).
Airway and lung function
The paper ‘Vitamin D Effects on Lung Immunity and Respiratory Diseases’(Hansdottir & Monick, 2011)
comments, “epidemiological studies have consistently found an association between low vitamin D levels
and increased susceptibility to respiratory infections” and further notes, “localized synthesis of 1,25D
rather than systemic production is responsible for many of the immune effects of vitamin D.”; it takes place
in the airways (See Table 1 of Paper).
The paper ‘Vitamin D and respiratory health’,(Hughes & Norton, 2009) observes, “a recent large cross-
sectional study of the US population reported that vitamin D status is associated inversely with recent URTI
(Upper Respiratory Tract Infections)”. Vitamin D is active in a wide range of immune systems; cytokines,
lymphocytes, macrophages T cells, T helper cells; and related pathways IL-1, -2, -4, -5, -10, -12; Th1, -17,
There are a large number of studies suggesting vitamin D plays important roles in, and may be
protective against; asthma,(Martineau et al., 2016) acute respiratory infections including Influenza,
(meta-analysis 10,000+ patients - those who were vit D deficient - below 25nmol/l – with improvement
of vitamin D status, experienced a 70 % benefit – many globally are deficient – if this level of
improvement in deficient patients was relevant to COVID-19, it would be highly significant)(Campbell,
2020; Martineau et al., 2017) COPD,(Jolliffe et al., 2019) bronchitis(Martineau et al., 2017) and
Importantly, as set out in the review ‘Treating the host response to emerging virus diseases: lessons
learned from sepsis, pneumonia, influenza and Ebola’, “There is growing recognition that endothelial
dysfunction and the loss of endothelial barrier integrity are central to the pathophysiology of bacterial
sepsis and acute lung injury”, ”Many systemic virus diseases, including influenza, dengue and Hantavirus
pulmonary syndrome, are also characterized by endothelial dysfunction.” “The disruption of tight junctions
between endothelial cells leads to a loss of barrier integrity, followed by the leak of fluid from the blood
into interstitial tissues and beyond (e.g., the alveoli in pneumonia).” (Fedson D, 2016)
MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001 14
Crucially, vitamin D is essential to tight cell junction function, in the epithelial cells that line the lungs,
and other such tissues including the gut. Interestingly, iodine and selenium, “alone, or in combination
are able to strengthen the function of TJ’s in human endothelial cells”.(Martin et al., 2005, 2007) The tight
junctions help control passage of substances across the tissue barriers,(Zhang et al., 2013) between the
external and internal space, including of fluids. Further, and of likely significance, ‘Vitamin D Receptor
Deletion Leads to the Destruction of Tight and Adherens Junctions in Lungs’(Chen et al., 2018).
An assayed immune pathway response in a COVID-19 patient
A report mapping a COVID-19 patient’s immune response to COVID-19, in Nature Medicine, titled
‘Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-
19’, notes, “Since co-expression of CD38 and HLA-DR is the key phenotype of the activation of CD8+ T cells
in response to viral infections, we analyzed co-expression of CD38 and HLA-DR. As per reports for Ebola
and influenza, co-expression of CD38 and HLA-DR on CD8+ T cells (assessed as the frequency of CD38+HLA-
DR+ CD8+ T cells) rapidly increased in this patient from day 7 (3.57%) to day 8 (5.32%) and day 9 (11.8%),
then decreased at day 20 (7.05%).”(Galey & Hood, 2020)(Thevarajan et al., 2020)
Whilst research is diffuse, it is clear from other immune research, the CD38, HLA-DR, CD8, CD4
pathways have links to the VDR receptor, and thus are likely impacted by vitamin D deficiency. CD38 is
a glycoprotein expressed on immune cells, which has significant roles in the innate and programmed
immune function. Interestingly, the paper ‘Relevance of Vitamin D Receptor Target Genes for Monitoring
the Vitamin D Responsiveness of Primary Human Cells Of 12 target genes’(Vukić et al., 2015) notes, “in
PBMCs (Peripheral Blood Mononuclear Cell – “a diverse mixture of highly specialized immune cells”(Muir,
n.d.)) only the expression of the genes CD38 and TMEM37 kept a positive correlation with changes in
VDR is linked to CD38. VDR agonist inecalcitol in melanoma cells, resulted in “5-fold increase in CD38
antigen density at the surface of the cells”.(Hybrigenics presented at the ASH Annual Meeting the potency
of inecalcitol to induce CD38 on Multiple Myeloma cell lines, 2017) VDRs also have roles in control of
CD4 and CD8 (surface glycoproteins). (Chen et al., 2014) “When guinea pigs were supplemented with
1,25(OH)2D3, the percentage of CD4+ and CD8+ T lymphocyte were significantly elevated and
simultaneously, CD4+/CD8+ was reduced”.(Wang et al., 2017) HLA-DR surface receptor polymorphisms
have also been associated in various studies with VDR.
Thus, vitamin D may well impact immune response to COVID-19 through: CD38, HLA-DR, CD8 and
CD4; pathways identified in a patient, as highly relevant to COVID-19, infection progression, and
Mitochondria, immune function, and vitamin D
Mitochondria are truly central to cellular function. Vitamin D plays important roles in mitochondrial
regulation and function, including in “redox homeostasis and protection against oxidative stress,”.(Santos
et al. 2017) Thus, “Vitamin D is one of the key controllers of systemic inflammation, oxidative stress and
mitochondrial respiratory function,”(Wimalawansa, 2019).
Mitochondrial energetics, and management of inflammatory oxidative stress, including apoptosis,
(Vringer et al, 2019) are key determinants of outcomes in severe clinical conditions, including of tissue
health. The paper ‘Vitamin D Receptor Is Necessary for Mitochondrial Function and Cell Health’ notes “Our
data reveal that VDR plays a central role in protecting cells from excessive respiration and production of
ROS that leads to cell damage.”, “ we conclude that VDR is essential for the health of human tissues.”(Ricca
et al. 2018)
The review ‘The Role of Vitamin D in the Immune System as a Pro-survival Molecule’ observes, “The
ability of vitamin D to check and mediate the biology of calcium as a signal molecule, however, relates its
function to energetics (a task particularly associated with mitochondria and ER) and to the
MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001 15
inflammasome(and immunity), just at the cellular level.” . . . “The overall amount of evidence reporting the
anti-inflammatory and immunoregulatory action of vitamin D, in its active vitamin D3 forms, suggests a
function that might be generally called “stress-quenching activity.” The ability of vitamin D to inhibit
metabolic stress and energetic expenditure in a cell microenvironment and in contexts such as
mitochondria or brown adipose tissue is intriguing. This ability suggests the existence of a wider task
beyond its immune-tolerant or immune/anti-inflammatory role”.(Chirumbolo, 2017)
The ACE2 pathway may factor in regulation of mitochondria, including related endoplasmic reticular
stress (Cao Xi).
Interaction of vitamin D receptor pathways with ACE, ACE2
ACE, ACE2, and related pathways, have been suggested to be implicated in COVID-19, an influenza
like disease, which, when severe, results in lung damage evidenced by very fast shallow breathing,
ending in terminal loss of lung function. A doctor described a COVID-19 patient “gasping for breath with
every ounce of life that he could muster” “I could see the terror in his eyes. He knew.” (A Frontline Doctor
for the Mail on Sunday, 2020)
A BMJ ‘Preventing a COVID-19 pandemic’ thread on COVID-19, contains the observation “SARS-CoV-2
uses ACE2 for target cell entry by fixing on it via its viral spike glycoprotein”, “SARS-CoV-2 downregulates
ACE2”; it is postulated therein that upregulation of ACE2 may mitigate effects of COVID-19 (BMJ
Preventing a COVID-19 pandemic - Responses. (Michely D.)
These pathways have been recognised as being of significant importance for the treatment of
emerging viral diseases, as set out in the paper “Treating the host response to emerging virus diseases:
lessons learned from sepsis, pneumonia, influenza and Ebola” which observes inter alia “Studies published
more than a decade ago showed that ACE2 is the functional receptor for SARS coronavirus. Soon thereafter,
ACE2 was shown to protect mice from acute lung injury (ALI) associated with experimental sepsis. This
study suggested a broad role for ACE2 signaling in the pathogenesis of sepsis, acute lung injury and other
forms of acute critical illness.”(Fedson D, 2017)
The paper ‘VDR attenuates acute lung injury by blocking Ang-2-Tie-2 pathway and renin-angiotensin
system.’ observes “Taken together, these observations provide evidence that the vitamin D-VDR signaling
prevents lung injury by blocking the Ang-2-Tie-2-MLC kinase cascade and the renin-angiotensin system.”
(Kong J, 2013))
Acute lung injury ALI was induced in Wisestar rats using lipopolysaccharide, and calcitriol, a vitamin
D3 ‘active form’ analogue, was administered, “To observe the effect of vitamin D on angiotensin converting
enzyme 2 ( ACE2 ) and vitamin D receptor ( VDR ) expression”. “The clinical manifestations (rapid shallow
breathing; listlessness; the oral and nose hemorrhage) in LPS group were obvious, and the clinical
manifestations and pathological changes of lung tissues in the LPS + calcitriol groups were significantly
milder than those in LPS group.” The paper concluded “Calcitriol can increase the expressions of VDR
mRNA and ACE2 mRNA and protein levels of VDR and ACE2 in rat models of LPS-induced ALI, thus
suggesting the increased expressions of ACE2 mRNA and VDR mRNA playing a role in protection against
the development of ALI.” (Yang et al. 2016)
A later study titled ‘Vitamin D alleviates lipopolysaccharide
induced acute lung injury via regulation
of the renin
angiotensin system’ observed “Results from reverse transcription
chain reaction, western blotting and ELISA analysis demonstrated that calcitriol also modulated the
expression of members of the renin
angiotensin system (RAS), including angiotensin (Ang) I
enzymes (ACE and ACE2), renin and Ang II, which indicates that calcitriol may exert protective effects on
induced lung injury, at least partially, by regulating the balance between the expression of members
of the RAS.” (Xu J 2017)
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Thus, vitamin D deficiency may figure in the determination of the severity of COVID-19, and
consequently, vitamin D; and or the active form, or an analogue such as ‘calcitriol’, in severe urgent
cases; potentially, may be capable of being used in the clinical setting, for treatment purposes, in those
with COVID-19 related respiratory conditions, to, as in the rodents above “improve clinical
manifestations”. Arguably the necessary population and clinical studies should be undertaken as a
matter of urgency, to determine these questions.
Global vitamin D deficiency
Multiple studies, from numerous countries, over the years, indicate that vitamin D deficiency and
insufficiency, is a global issue.(Edwards et al., 2020; Roth et al., 2018) Reasons for rising plasma vitamin
D deficiency, are multiple, and include; lifestyle changes resulting in less time outdoors, increased use
of UVB blockers, desire for paler tone wrinkle free skin, smog blocking UV, fear of skin cancers, obesity,
and often a lack of understanding of the wider importance of vitamin D by, Governments, many Doctors,
Dentists, and the Public.
In consequence, population vitamin D levels are often falling, as seen in southern Europe, and even
in more southerly latitudes; for example, it was reported in 2018, in Korea, “vitamin D status in South
Koreans is still deteriorating” (Park, 2018)
Vitamin D levels vary between populations, which logically will have public specific, regional, health-
effects. Providing a comprehensive 2020 global overview of vitamin D levels is not possible, as the data
simply does not exist. Data examples are included in table 2.
Table 3. Variation of vitamin D levels in different populations
Location <10 or 12 ng
Iran and Jordan 50 % 90 % Arabi et al (2010)
China ~ 37 % ~ 72 % Zhang et al (2013)
African continent 18 % 34 % Mogire et al (2019)
USA 5 % 18 % Herrick et al (2019)
Data with thanks from table in ‘Comment’ ‘Vitamin D status in Africa is worse than in other
(To convert ng/ml to nmol/L multiply the ng/mL by 2.5 :- 10 ng/ml is equivalent to 25 nmol/L.)
Lack of current extensive data
Significant, meaningful, comprehensive, regular, population based public vitamin D data, will not
exist until the importance of vitamin D to health is more widely recognised. There is no mechanism for
global collection and reporting of anonymised individual medical vitamin D test data. In so far as testing
takes place, vitamin D testing, even in vulnerable groups, in many countries, is not a priority.
This hypothesis calls for change, in vitamin D testing frequency, and national public health data
collection, including wider recognition of the likely role of vitamin D in COVID-19, and wider health
MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001 17
Influenza Seasonal Trends – vitamin D a key factor?
Historically, between 1964 and 1975, before the advent of modern sun-creams, mass electronics, and
fear of moderate sun exposure, there was a strong seasonal trend to increased winter influenza
occurrence.(Cannell et al., 2006) This may logically have been associated with the seasonally changing,
UVB related, vitamin D status of populations.
In more northern latitudes, the UV element of light is only sufficiently strong, to make vitamin D in
exposed skin, during the summer months; the exact time frame is dependent on the latitude of the
Interestingly the paper ‘Epidemic influenza and vitamin D’ observes, “Volunteers inoculated with live
attenuated influenza virus are more likely to develop fever and serological evidence of an immune response
in the winter.”(Cannell et al., 2006)
The paper further notes, “Ultraviolet radiation (either from artificial sources or from sunlight) reduces
the incidence of viral respiratory infections, as does cod liver oil (which contains vitamin D).” Vitamin D
deficiency predisposes children to respiratory infections.”(Cannell et al., 2006)
It is also possible, increased ultraviolet light, and raised surface temperature due to light absorption
heating effects, reduces life-span of the virus on clothes, and other surfaces, exposed to sun-light. In
more recent times, use of UVB blocking sun-creams, and lifestyles that are focused to a greater extent
on indoor activities, by reducing vitamin D status, may reduce the historical seasonality effect.
Possibility of seasonal re-emergence – warnings from history
Of possible relevance to COVID-19, concerningly, the history of Hong Kong flu, suggests seasonal
effects may also be applicable to new flu variants. The paper ‘Epidemic influenza and vitamin D’ observes
“For example, Miller et al. reported that the Hong Kong virus was first isolated in Britain in August 1968
but it did not cause significant summertime illness despite being a new antigenic variant in a non-immune
population. However, clinical case rates increased in intensity as the sun became progressively lower in the
sky each day (autumn), waiting until the winter solstice of 1968 before the first community outbreaks
appeared. Influenza case rates peaked for several months but waned as the sun rose higher in the sky each
day (spring). Predictably, influenza virtually ceased following the summer solstice. Clinical case rates for
Hong Kong influenza (again) increased from September 1969, only to explode again in the days preceding
the winter solstice, even though a much higher proportion of the British population had virus-specific
antibodies at the beginning of the lethal second wave than they did at the beginning of its less lethal first
wave.”(Cannell et al., 2006)
The then new, Hong Kong virus, did not manifest in summer, despite then access of the then new
virus to a population with no immunity; given the historical seasonal trend of many influenzas, will
COVID-19 follow this pattern? Further, and thought provokingly, the virus remerged more strongly the
following winter; weekly influenza related consultations for diagnosed illness rates per 100,000,
increased from 400 in February March 1969, to 1200 in December January 1970. See (Fig. 2 of cited
study).(Cannell et al., 2006)
Clearly development and administration of a successful vaccine, may moderate the impact of any
future reoccurrence of COVID-19 in 2021, but the elderly will remain particularly at risk. IF reduction of
vitamin D deficiency, is shown to be protective against COVID-19, public policy to ensure populations
were vitamin D sufficient, may help inhibit likely mid-year increase of COVID-19 in the Southern
Hemisphere, or return to the Northern Hemisphere in winter 2021.
Vitamin D and (25 hydroxy D)
Professor Holick, an acknowledged leader in the vitamin D field, provides an overview, in ‘Vitamin D
deficiency: a worldwide problem with health consequences’.(Holick & Chen, 2008) Humans in a
MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001 18
preindustrial setting, mainly acquired vitamin D through the oxidation in the skin, by UVB, (but not UVA
or longer light) of a cholesterol derivative to cholecalciferol, and to a lesser extent from dietary sources.
Vitamin D is stored long term in adipose tissue, and supplied for more current use, by serum to cells.
Within cells, vitamin D is converted as needed to 25-hydroxyvitaminD3, also called D 25(OH)D3. This is
further converted to the 1,25-D3 form (‘calcitriol’ is an analogue) (a VDR receptor agonist), and other
The action of vitamin and its metabolites, is more complex than generally appreciated, impacting a
range of genes.(Hassan-Smith et al., 2017) Conversion of vitamin D to metabolites happens mainly in
the liver, but many cells possess conversion capacity, including as part of their immune function
Importance – of vitamin D - a quasi-hormone - an evolutionary perspective
The wide biological importance of vitamin D, beyond its role in bone health, is often
underappreciated, including in the Medical and Dental professions. Cholesterol like substances, were
likely early evolutionary membrane building blocks, that helped facilitate light initiated oxidative stress
messaging systems, and have been genetically conserved as integral factors in many biological
structures, processes, and pathways.
The capacity of cholesterol, and other ring based organic molecules, to react with UV, and particularly
UVB, gave them early relevance. In an early low atmospheric oxygen world; life forms needed
mechanisms to protect their light exposed membranes from UV oxidation, and to provide them, with
mechanisms to sense and respond to damaging UV light.(Brown, 2016b)
Further, on an evolutionary basis, cholesterol oxidised derivatives, exposed to both UV and solutions
containing high levels of calcium, may have interacted with calcium ions in solution,(Marfey et al., 1975)
leading to accumulation; helping provide mechanisms for calcification at surfaces. Interestingly,
oxidised lipids and cholesterol are associated with calcium accretion in vascular systems.(Parhami et
al., 1997; Tintut et al., 2018)
The likely early role of oxidised cholesterol like molecules, in external membranes, may explain the
ongoing importance of an oxidised derivative of cholesterol, in regulation of tight cell junction function,
and protection of barrier tissues from external threat, thus in immune systems. Similarly, the UVB
oxidised products of linoleic acid retain central roles in immune biology, including as pain
Oxidised cholesterol remains relevant to external membrane function; indeed, a cholesterol
derivative is oxidised to vitamin D on exposure to UVB, in the external and surface layers of the skin. As
part of that process it retains a role in signalling external conditions, protecting against oxidative stress,
and moderating behaviour to optimise function in relation to external UV stimulus.
Capacity to make Vitamin D
Possibly 90 %, of the vitamin D in plasma, of those with adequate vitamin D levels - who do not
supplement; or eat fish, offal, eggs, dairy products, or sun exposed mushrooms; and do not eat processed
vitamin D supplemented foods - is derived from the oxidative action of UVB, in summer strength
sunlight, on a cholesterol derivative delivered to the skin. If they do not have sufficient UVB-skin-
product-blocker-free, summer sun, exposure; they will be vitamin D deficient – it is almost impossible
for them to be otherwise.
A light skinned Caucasian, who has not been exposed to the sun for a while, can make in the order of
20000IU of vitamin D. Dietary sources do not supply the same quantities, providing in comparison,
limited amounts of vitamin D, as discussed below. Capacity of individuals to make vitamin D on exposure
to sunlight is governed by a number of factors, including:
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Exposure to UVB
o dose and time dependent;
o determining factors include - latitude, time of day and year, altitude, albedo reflection
from water or snow, UV blocking product use, clothing type, shade, atmospheric
pollution levels (UVB can be significantly reduced by city atmospheric pollution);
exposure time, and skin type;
o changing life styles mean people are spending less time outdoors, thus are at greater risk
of low vitamin D, which may help account for falling levels;
o propensity to skin oxidation, thus burning on exposure to UVB, may be moderated by
dietary factors, including Omega 3:6 balance, iodine, and potentially, wider dietary
antioxidant capacity derived from plant products for example phenols.(Saric & Sivamani,
2016) Research in these fields is extremely limited, and arguably more is required, to
facilitate safer sun exposure.
Ethnicity and skin colour
o Capacity to make vitamin D for any given UVB exposure is significantly impacted by skin
tone. Dark skin provides very high UVB absorbance equivalent, depending on shade,
equivalent to strong UV skin protection products. Those with dark skins require much
greater sun exposure, to make equivalent amounts of vitamin D, to those produced by
Caucasians following limited sun exposure. Burning and reddening in Caucasians,
following sun exposure, is due to exhaustion of ‘antioxidants’, including the vitamin D
cholesterol derivative precursor, by UVB in sunlight.
o A wide range of polymorphisms exist that will impact many facets of vitamin D creation
and metabolism, acquired because they provided greater capacity for survival and
reproduction, in given environments.
o Studies suggest that age may diminish capacity to make and store vitamin D. Certainly
levels in the elderly tend to be lower.
o Women generally have higher capacity to make UVB, including due to naturally lighter
skins than males. The impact of skin lightening on vitamin D production is unknown.
o One of the roles of adipose cells, is to store fat-soluble nutrients, as a reservoir, in a
seasonal, weather and food environment. In consequence, logically a portion of available
vitamin D is partitioned into the fat compartment. This may account in the obese, for
reduced vitamin D plasma availability in comparable populations with the same intake.
A study suggests plasma 25OHD3 are closely linked to body fat mass in healthy fasted
individuals (interestingly 58 % of the cohort were vitamin D deficient).(Edwards et al.,
2020) Obesity / excess weight increases the amount of vitamin D required to maintain
adequate vitamin D plasma concentrations. The study, ‘The Importance of Body Weight
for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-
Hydroxyvitamin D in Healthy Volunteers’ comments, “We recommend vitamin D
supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for
overweight subjects relative to normal weight subjects”.(Ekwaru et al., 2014) Further the
review ‘Impact of Obesity on Influenza A Virus Pathogenesis, Immune Response, and
Evolution’ notes, “Obese hosts exhibit delayed and blunted antiviral responses to influenza
virus infection, and they experience poor recovery from the disease.”(Honce & Schultz-
Cherry, 2019) Those with weight issues are also more at risk of diabetes, a risk factor for
Regular use soaps etc.
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o Showering after sun exposure with soap may reduce Vitamin D by washing it off the skin,
however much of the vitamin D is produced by oxidation within the skin and does not
appear to be affected by washing.
As noted by the National Institute of Health in the USA, natural food sources of vitamin D are very
limited, and the amounts contained generally small.(Vitamin D — Health Professional Fact Sheet, n.d.)
Fortified foods are the next best source of vitamin D. The range of foods fortified varies by countries,
and level of fortification in individual foods is limited, including by government recommendation.
The USA NIH web advisory observes “Very few foods in nature contain vitamin D. The flesh of fatty fish
(such as salmon, tuna, and mackerel) and fish liver oils are among the best sources. Small amounts of
vitamin D are found in beef liver, cheese, and egg yolks. Vitamin D in these foods is primarily in the form of
vitamin D3 and its metabolite 25(OH)D3. Some mushrooms provide vitamin D2 in variable amounts.
Mushrooms with enhanced levels of vitamin D2 from being exposed to ultraviolet light under controlled
conditions are also available.”(Vitamin D — Health Professional Fact Sheet, n.d.)
Many do not have access to oily fish, or do not eat it for fear of contaminants. Significant numbers
have diets, which may exclude eggs meat and or dairy. (A serving of salmon contains between 400-800IU
depending if it is wild or farmed - other fish contain much less – a bowl of fortified cereals may contain
more). Without access to fortification, and or suitable sun exposure, people are likely to be deficient.
For the reasons discussed above, fortification, and or supplementation, is essential for the avoidance
of vitamin D deficiency, in many population groups. The NIH continues, “Fortified foods provide most of
the vitamin D in the American diet. For example, almost all of the U.S. milk supply is voluntarily fortified
with 100 IU/cup. (In Canada, milk is fortified by law with 35–40 IU/100 mL, as is margarine at ≥530 IU/100
g.) In the 1930s, a milk fortification program was implemented in the United States to combat rickets, then
a major public health problem. Other dairy products made from milk, such as cheese and ice cream, are
generally not fortified. Ready-to-eat breakfast cereals often contain added vitamin D, as do some brands of
orange juice, yogurt, margarine and other food products. Plant milk alternatives (such as beverages made
from soy, almond, or oats) are often fortified with vitamin D to the amount found in fortified cow’s milk
(about 100 IU/cup); the Nutrition Facts label will list the actual amount.(Vitamin D — Health Professional
Fact Sheet, n.d.)
Both the United States and Canada mandate the fortification of infant formula with vitamin D: 40–100
IU/100 kcal in the United States and 40–80 IU/100 kcal in Canada.”(Vitamin D — Health Professional Fact
Countries with vitamin D fortification including of dairy
Countries that fortify fluid milk include, Finland, Canada, United States; some dairy products are
fortified in Sweden, and Norway.(Itkonen et al., 2018) (See table 1 of referenced paper) Fortification in
these countries is due to a mix of Federal, and State or Regional mandatory requirement, or
United Kingdom, Ireland, Spain, and Australia have some non-systemic fortification; lack of clear
labelling, and understanding of vitamin D, may contribute to lower vitamin D levels on a population
Low COVID-19 in children
Whilst vitamin D levels in children are often low, feed ‘formula’ is generally always supplemented,
thus providing some protection to the very young.(WHO | Vitamin D supplementation and respiratory
MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001 21
infections in children, 2019) Toddlers and younger children, probably also on average, get a little more
exposure to sunshine that their older peers.
Suggestions for Future
Whilst some of the data above, and below, public policy, and population attitudes and knowledge,
may provide limited indicative information as to vitamin D deficiency status, ultimately the hypothesis
that vitamin D deficiency factors negatively in COVID-19, can only be determined by appropriate testing.
Further, global deficiencies of vitamin D can only be addressed by: encouraging testing, particularly
of those in at risk groups, including those in residential institutions; reporting and collation of test result
data at national level; maintenance of a rolling annual global database of results; and implementation of
National polices for fortification and or supplementation, that appropriately, increase, or decrease,
vitamin D intake, based on data, thus minimising risks of population vitamin D deficiencies.
Basal human vitamin D levels
Whilst governments issue advisories, as to optimal vitamin D intakes and blood levels; and there is
debate as to optimal intakes and plasma levels; there is only very limited research, in groups with non-
westernised lifestyles, to determine natural endogenous human vitamin D levels.
Interestingly, studies in East Africa(Krzyścin et al., 2016; Luxwolda et al., 2012) reported vitamin D
levels in non-westernised groups (Av: Masai 119nmol/L; Hadzabe 109nmol/L), were higher than those
prescribed by many national advisories.
Caucasian beach guards, in times before significant application of UVB blocking sun creams, have
similar levels. Interestingly cattle(Nelson et al., 2016) and swine(Larson-Meyer et al., 2017) raised in
the open also have levels in the 40-100ng/l (100–240 nmol/L)(Nelson et al., 2016) range.
Thus endogenous ‘natural’ levels of vitamin D in humans, livestock and pets, may be significantly
higher than those used for national health advisory recommendations. More studies as to human basal
endogenous vitamin D levels in non-westernised groups, whilst they still exist, are urgently required; to
both to secure better public health; and more objectively define intake guideline requirements.
Policies encouraging supplementation and awareness
Nordic, and other northern European countries, appear to have higher vitamin D levels, despite their
more northerly latitude, possibly due to stronger polices on fortification, and encouragement of Vitamin
D supplementation in winter. Recent data is scarce, and commercial sales data for vitamin D
supplements difficult to find; however food supplementation polices, and attitudes to vitamin D
supplementation, as well as limited data; would suggest that vitamin D profiles in northern European
countries are likely to be higher, and crucially deficiency less prevalent, in the critical winter season,
than in their more southerly neighbours.
For example “In Denmark of participants (n=4,479; 53% females) aged 18–75 years 60 % percent of
females and 51% of males were users of supplements”, “total intake of selected micronutrients among the
users of dietary supplements of vitamins E and D was increased fourfold and, for iron, selenium, and zinc
two- to threefold compared with non-users”(Tetens et al., 2011)
In Norway “According to figures from the Norwegian Prescription Database, the number of users of
prescription-only vitamin D3 supplements increased 85-fold in Norway over the six-year period from 2011
to 2017. In the same period, the sales of defined daily doses (20 µg) increased more than a hundredfold. In
2017, sales amounted to 39.5 million defined daily doses. In addition, sales of over-the-counter dietary
supplements are high. High-dosage supplements that contain up to 80 µg vitamin D3 per tablet are
currently available on the Norwegian market. In contrast, according to the Nordic nutrition
MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001 22
recommendations, the recommended daily intake of vitamin D for the general population amounts to 10
µg per day for children and adults and 20 µg per day for those 75 years and older”(Holvik et al., 2019)
In Sweden, vitamin D is a high-profile issue; indeed, a case was brought, in which the Swedish
Supreme Administrative Court overruled a local government decision, prohibiting sale of food
supplements, including vitamin D, in 2018.(Chu, 2018) A supplement market research agency reports
“Vitamin D continued to be the strongest performer with many consumers seeing this as a way to support
the development of healthy bones and teeth, particularly as the long dark Swedish winters result in a lack
of natural vitamin D from sunlight”.(Vitamins in Sweden | Market Research Report | Euromonitor, n.d.)
However, in common with many northern countries, vitamin D insufficiencies remain, more prevalent
in patients born outside Europe.(Wändell et al., 2018)
In Finland, vitamin D has long been a central public health issue; indeed, the national recommended
intake was at one time 4000IU, and some suggest that type 1 diabetes, and immune related condition,
rose in consequence of a subsequent reduction of that recommendation.(Papadimitriou, 2017)
According to social media apparently vitamin D is widely supplemented in Finland.(Does the average
Finn take vitamin D supplements? : Finland, n.d.)
In Germany and other countries, it may well be that populations are ahead of public policy, in that
they are more conscious of the need to supplement with vitamin D. Sadly study data is generally not
recent, sometimes 10-20 years old, and thus does not accurately reflect current vitamin D status in
There is clearly significant focus of the importance of vitamin D in Germany as helpfully set out in ‘A
Critical Appraisal of Strategies to Optimize Vitamin D Status in Germany, a Population with a Western
Diet’,(Saternus et al., 2019) but clearly also a need for new large-scale data.
German Medical Policy 2.04.135 includes a recommendation as to vitamin D which can be provided
free and is recommended for those over 65; “Benefit Application - Consistent with federal mandates,
vitamin D supplements are covered as preventive care for individuals age 65 and older(without cost
sharing) when the member’s contract is subject to those mandates. A written prescription is needed for
coverage. The USPSTF recommends exercise or physical therapy and vitamin D supplementation to prevent
falls in community-dwelling adults aged 65 years or older who are at increased risk for falls. (Grade B
recommendation)”(Testing Serum Vitamin D Level, 2020).
Implementation of national vitamin D recommendations
Most countries have existing health recommendations as to vitamin D intakes, yet significant
portions of populations are often deficient and or insufficient. Better data would allow fine tuning of
food and direct supplementation polices, to ensure national recommendations were met.
Other dietary factors in oxidative stress related conditions
Iodine, and Omega 3 and 6 lipids and their oxidised products, also have important roles in the
interaction of ‘body’ ‘external’ membranes, to stimuli, including in regulation of cell junction and
immune function, in the lungs, airways, digestive and reproductive organs. Imbalance contributes to
oxidative stress, and inflammation episodes including sepsis, and cachexia.(Brown, 2016a) Iodine in the
diet is often insufficient; omega 6 linoleic acid is consumed in excess; and Omega 3 linolenic acid is
present in diets in insufficient amounts. Other nutrients are also often imbalanced or insufficient,
including due to over processing of foods, and changing farming practices.
The paper ‘Potential interventions for novel coronavirus in China: A systematic review’, highlights the
relevance of nutrition to COVID-19 patient treatment, suggesting “the nutritional status of each infected
patient should be evaluated before the administration of general treatments” and usefully sets out
nutritional factors affecting particular immune pathways, and diseases, in table 1.(Zhang & Liu, 2020)
MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001 23
There is currently a significant apparent difference in the COVID-19 data for, mortality percentage,
and number of patients requiring intensive care, between northern European countries and southern
European countries, which it is postulated may be related in significant part to vitamin D status, and
Whilst it could be suggested that mortality in the northern European countries is yet to emerge, data
on infection rate history, and timing in Germany  and France(Wikipedia Contributors, 2020) are
similar, yet mortality is much higher in France. Time will indeed clarify these issues, but clearly
collection of data for studies on the pandemic, is only possible during the active phase of the pandemic,
and with the assistance and order of Governments.
Thus, the certainly feasible, and likely issue of vitamin D deficiency, through immune impairment,
impacting COVID-19 progression, and mortality, needs raising at Governmental level as a matter of
Prompt global investigation at depth, using standardised measuring parameters, is required to
determine if vitamin D deficiency at population level, factors in; and further, if vitamin D (or its oxidised
derivatives) administration alleviates; visible infection rate, severity, and mortality of COVID-19.(Grant
et al., 2020)
Given the wide ranging health impacts including in respiratory function, the global nature of vitamin
D deficiency, and importance in addressing it;(Roth et al., 2018) good current population data globally
on vitamin D status, would be of significant wider public health information value, irrespective of any
COVID-19 related outcomes.
Further, it is important for COVID-19 decision making, that mortality rates are; accurate, without
“selection bias”, and based on accurate infection rate data; as noted in the article ‘A fiasco in the making?
As the coronavirus pandemic takes hold, we are making decisions without reliable data.’(Ioannidis, 2020)
Any determination that vitamin D deficiency did moderate risk of; visible infection, progression, and
mortality, outcomes of COVID-19; and or that vitamin D derivatives, had clinical uses in reducing the
severity of respiratory consequences of COVID-19, as seen in related rodent studies; would have
significant policy implications, including for consideration of; seasonal ramifications; advice to remain
indoors; and potential benefits of mass vitamin D supplementation in accordance with existing National
Governmental Guidelines (with allowance for obesity); and for the reduction of the current
consequences of the COVID-19 pandemic, which is having widespread impact on; at risk individuals,
public health provision, individual, corporate and national finances, and the global economy.
What constitutes optimal vitamin D levels, including by reference to endogenous levels in non-
westernised groups, is an issue for future consideration, as it makes no difference to the need to ensure
populations are not at risk of being plain vitamin D deficient.
The COVID-19 mortality rate in northern European countries, once unaccounted-for COVID-19
infections are added, may prove to be not hugely different from average flu mortality in the
Vitamin D supplementation in the ‘D’ deficient increases resistance against influenza.
Vitamin D likely is a controlling factor in immune pathways, CD38, HLA-DR, CD8 and CD4,
already identified in a COVID-19 patient, as key to COVID-19 infection progression and
MitoFit Preprint Arch (2020) doi:10.26124/mitofit:200001 24
Vitamin D can improve ACE related respiratory function, including breathlessness, in animal
There is an urgent need for Governments to facilitate research into the impact of vitamin D in
COVID-19, to determine if vitamin D factors in COVID-19, and if vitamin D in its ‘passive’ or
‘active’ forms, can be used to treat those with COVID-19 in clinical settings.
There are no studies on vitamin D and COVID-19. Such studies could be conducted in parallel
with COVID-19 testing, and treatment. Costs in the scheme of things would be modest.
Rewards could be very significant at many levels.
If vitamin D deficiency is found to impact COVID-19 outcomes; public health information and
supplementation, could reduce COVID-19 severity and mortality, before seasonal effects, risk
repeated further COVID-19 pandemic spread, and reoccurrence.
Amrita Sarkar (PhD) was responsible for promotion of the need for, and inclusion of, the graphic
illustrations; and helped prepare data, references, content organisation, presentation, and more
generally generously contributed time, to preparation of this manuscript.
Conflicts of interests
The work is entirely self-funded with no assistance from any external agency or source. The authors
have no conflicts of interest.
RB and AS wrote the manuscript, organized and supervised the study. Both authors reviewed and
approved the manuscript for publication.
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