Vitamin D deficiency and co-morbidities in COVID-19 patients – A fatal relationship?

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NFS Journal
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Vitamin D deficiency and co-morbidities in COVID-19 patients –A fatal
relationship?
Hans K. Biesalski
Institute of Nutritional Sciences, University Hohenheim, D 70599 Stuttgart, Germany
1. Introduction
Infections of the respiratory tract are more frequent in the winter
months and especially in the northern latitudes than they are in summer
[1]. This obviously also applies to the COVID-19 infectious disease that
briefly spread all over the world in the winter months and became a
pandemic [2,3]. A common feature of the winter months and the in-
habitants of all countries north of the 42nd parallel is a hypovitaminosis
D that frequently occurs during this period [4]. In addition during cold
temperature the virus will be more easily transmitted. This raises the
question of whether an inadequate vitamin D supply has an influence
on the progression and severity of COVID-19 disease.
A low vitamin D status, measured as the plasma level of the trans-
port form of vitamin D, 25(OH)D,is widespread worldwide and is
mainly found in regions of northern latitudes, but also in southern
countries [5]. In Europe, vitamin D deficiency is widely prevalent
during the winter months and affects mainly elderly people and mi-
grants. In Scandinavia only 5% of the population is affected by a low
vitamin D status, in Germany, France and Italy more than 25%, parti-
cularly older people e.g. in Austria up to 90% of senior citizens [6,7]. In
Scandinavian countries, the low incidence of vitamin D deficiency may
be due to the traditional consumption of cod liver oil rich in vitamin D
and A or to genetic factors resulting in higher synthesis of vitamin D in
the epidermal layer [8]. Taken together, low vitamin D status is
common in Europe with the exception of the Scandinavian countries.
The calculated COVID-19 mortality rate from 12 European countries
shows a significant (P= .046) inverse correlation with the mean
25(OH)D plasma concentration [9].
This raises the question whether insufficient vitamin D supply has
an influence on the course of COVID-19 disease? An analysis of the
distribution of Covid-19 infections showed a correlation between geo-
graphical location (30–50° N+), mean temperature between 5–11 °C
and low humidity [10]. In a retrospective cohort study (1382 hospita-
lized patients) 326 died, Among them 70.6% were black patients.
However, black race was not independently associated with higher
mortality [11]. An excess mortality (2 to sixfold have been described in
African-Americans with average latitudes of their state of residence in
higher latitudes (> 40) [12]. The mortality of COVID-19 (cases/ mil-
lion population) shows a clear dependence on latitude. Below latitude
35, mortality decreases markedly [13]. Indeed, there are exceptions e.g.
Brazil (tenfold higher than all other latin American countries –except
mexico), however, the management of the pandemic may increase in-
fection risk.
1.1. Vitamin D effects
The skeletal and extra skeletal effects of vitamin D have recently
been described in an extensive review [14]. Vitamin D exerts a genomic
and non-genomic effect on gene expression. The genomic effect is
mediated by the nuclear vitamin D receptor (VDR), which acts as a
ligand activated transcription factor. The active form 1,25(OH)
2
D binds
to the VDR and in most cases heterodimerizes with the retinoid X re-
ceptor (RXR), whose ligand is one of the active metabolites of vitamin
A, 9-cis retinoic acid. The interaction of this complex with the vitamin
D responsive element can regulate the expression of target genes either
positively or negatively [15]. The non-genomic effects involve the ac-
tivation of a variety of signaling molecules that interact with Vitamin D
responsive element (VDRE) in the promoter regions of vitamin D de-
pendent genes [16]. Vitamins A and D are also of particlular importance
for the barrier function of mucous membranes in the respiratory tract
[17,18].
1.2. Vitamin D and immune system
Vitamin D plays an essential role in the immune system [19]. Vi-
tamin D interferes with the majority of the immune systems cells such
as macrophages, B and T lymphocytes, neutrophils and dendritic cells,
which express VDR (for details [20] and Fig. 3). Cathelicidin, a peptide
formed by vitamin D stimulated expression, has shown antimicrobial
activity against bacteria, fungi and enveloped viruses, such as corona
viruses [21,22]. Furthermore Vitamin D inhibits the production of pro-
inflammatory cytokines and increases the production of anti-in-
flammatory cytokines [23].
The active metabolite of vitamin D in macrophages and dendritic
cells, derived from the precursor 25(OH)D, leads to the activation of
VDR, which, after RXR heterodimerization, results in the expression of
various proteins of the innate and adaptive immune system (Treg cells,
cytokines, defensins, pattern recognition receptors etc.) [24]. Vitamin D
https://doi.org/10.1016/j.nfs.2020.06.001
Received 21 May 2020; Received in revised form 2 June 2020; Accepted 2 June 2020
E-mail addresses: biesal@t-online.de,biesal@uni-hohenheim.de.
NFS Journal 20 (2020) 10–21
Available online 07 June 2020
2352-3646/ © 2020 The Author. Published by Elsevier GmbH on behalf of Society of Nutrition and Food Science e.V. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

exerts opposite effects on the adaptive (inhibition) and innate (pro-
motion) immunsystem This correlates with an anti-inflammatory re-
sponse and balances the immune response [25].
The active metabolite of vitamin D, 1,25(OH)2D3 can be formed in
T and B lymphocytes and inhibits T cell proliferation and activation
[26]. This way, vitamin D may suppress T-cell mediated inflammation
and stimulate Treg cells proliferation, by increasing IL-10 formation in
DC cells, and thus enhance their suppressive effect [27,28].
1.3. Food sources
There are only few dietary sources of vitamin D (cod liver oil, fat
fish) that could satisfy the recommended daily allowance (15–20 μg/
day for adults). To reach such amount besides availability of dietary
sources, vitamin D skin synthesis, which contributes to 80% in healthy
individuals up to the age of 65, is important.
With the exception of mushrooms there are no plant sources of vi-
tamin D. In particular wild mushrooms, which are grown in light. Sun-
dried but not fresh mushrooms can contain between 7 and 25 μg/100 g
of vitamin D2 [29], which is an important source [30] with a good shelf
life [31] and comparable bioavailability to vitamin D3 [32]. Vitamin D
status can be significantly improved by fortified foods, as was shown in
a meta-analysis [33].
1.4. Vitamin D deficiency
Insufficient levels of vitamin D are caused by two main physiolo-
gical causes: Low UVB exposure, especially in northern regions during
the winter season [34] and in case of strong pigmentation, as well as
decreased vitamin synthesis in the skin with aging [35]. In addition a
poor diet, low in fish and fortified food (if available) are the major
reason for deficiency in old age and people living in poverty. Major risk
groups [36], besides pregnant women and children under 5, include
elderly, over 65 years, those with little or no sun exposure (full body
coverage, little contact with the outside world) as well as people with
dark skin, especially in Europe and the USA.
The vitamin D deficiency is a worldwide problem, which is not only
observed in the northern countries, but increasingly also in the south.
While in Europe, for example, deficits (< 30 nmol) are between 20 and
60% in all age groups, in Asia the figure for children is 61% (Pakistan,
India) and 86% (Iran) [37,38].
Particularly critical is the number of migrants from Southern
countries with insufficient vitamin D status (< 25 nmol/L) [39]: e.g.
Netherlands 51%, Germany 44% (in summer), UK 31% (end of
summer) and 34% (autumn). In India, the number of adults with va-
lues < 25 nmol/L ranges from 20% to 96% depending on the region.
The half-life of 25(OH)D
3
is about 15 days and that of 25(OH)D
2
is
between 13 and 15 days, due to the weaker affinity to the vitamin D
binding protein [40]. Consequently, longer periods of time indoor, e.g.
in care homes or longer time in quarantine, pose risk for developing
vitamin D deficiency.
1.5. Risk factors for severe courses of COVID-19
Older age and co-morbidities are linked to an insufficient vitamin D
supply. Over 60 years of age, a reduction in the synthesis of vitamin D
in the skin becomes apparent, which further increases getting older
[41]. The precursor of vitamin D, 7-dehydrocholesterol in the skin
declines about 50% from age 20 to 80 [42], and the elevation of cho-
lecalciferol levels in serum following UVB radiation of the skin shows
more than a 4-fold difference in individuals aged 62–80 yrs. compared
with controls (20–30 yrs) [43]. This explains the high number of older
individuals with an inadequate vitamin D status.
Based on a meta-analysis including 30 studies with 53.000 COVID-
19 patients, co-morbidities are risk factors for disease severity:
Risk factor Odds ratio 95% CI
Old age > 50yrs 2.61 2.29–2.98
Male 1.38 1.195–1.521
Smoking 1.734 1.146–2.626
Any co-morbidity 2.635 2.098–3.309
Chronic kidney disease 6.017 2.192–16.514
COPD 5.323 2.613–10.847
Cerebrovascular disease 3.219 1.486–6.972
Independent prognostic factors for COVID-19 related death:
Risk factor Relative risk 95% CI
Old age > 60 9.45 8.09–11.04
CVD 6.75 5.40–8.43
Hypertension 4.48 3.69–5.45
Diabetes 4.43 3.49–5.61
Co-morbidities and old age show a relationship with Renin-
Angiotensin-Aldosteron-System (RAS), vitamin D status and COVID-19
infection.
1.6. The renin-angiotensin-system (RAS)
RAS plays an important role in maintaining vascular resistance and
extracellular fluid homoeostasis. Fig. 1 summarizes the essential steps
of this system.
Mainly in the juxtaglomerular apparatus of the kidney, but also in
other tissues and cells, renin is formed, which cleaves the angiotensi-
nogen secreted from the liver very selectively to the inactive form an-
giotensin I (Ang I). This decapeptide is then cleaved by a further pro-
tease the angiotensin-converting-enzyme (ACE) on the surface of the
endothelial cells to the active angiotensin II (Ang II), which can bind to
two different receptors AT1R or AT2R. Synthesis and secretion of renin
in the kidney, as rate limiting enzyme of RAS, is stimulated by fluid
volume, reduction of the perfusion pressure or salt concentration and
by the sympathetic nervous system activity.
Renin synthesis and secretion is inhibited with increasing Ang II via
an AT1R mediated effect and stimulated with decreasing Ang II [44].
The stimulating effect on renin synthesis and secretion due to either low
levels of Ang II or Ang II converting inhibitors (ACEI) or Ang II receptor
blockers (ARB) is mediated through ligands that activate cAMP/PKA
(Protein Kinase A) pathways (e.g. catecholamines, prostaglandins and
nitric oxide) [45,46].
Ang II leads to the release of catecholamines and vasoconstriction.
Via AT1R, Ang II increases aldosterone release and sodium reabsorp-
tion. Furthermore, binding to AT1R has pro-inflammatory and pro-
oxidative effects and inhibits the action of insulin in endothelial and
muscle cells. The latter can lead to a decrease in NO production in
endothelial cells and thus will further increase vasoconstriction [47].
With the discovery of ACE2, a novel homologue of ACE, a trans-
membrane metallopeptidase with an extracellular ectodomain, the
understanding of RAS manifold regulatory function was deepened
(Review [48]). ACE2, a monocarboxypeptidase has been shown to
cleave Ang I to Ang 1–9, and Ang II to Ang 1–7. This degradation can
weaken the effect of Ang II at AT1R and thus counteract the patholo-
gical changes. While Ang 1–9 exerts a cardioprotective effect via AT2R
[49], Ang 1–7 acts via the Mas Oncogene receptor. This counter-
balances the effect of ANG II at AT1R and subsequently the “over-
stimulation”of the RAS and its pathological consequences [50]. ACE2 is
expressed in many organs, especially kidney and lung, and in the car-
diovascular system in cardiomyocytes, cardiac fibroblasts, vascular
smooth muscle and endothelial cells. It can counteract the effects of
RAS, such as inflammation, vasoconstriction, hypertrophy and fibrosis,
H.K. Biesalski NFS Journal 20 (2020) 10–21
11

by degrading Ang I and Ang II, thus making them less available for the
ACE/AngII/AT1 axis. At the same time ACE2 can strengthen the ACE2/
Ang 1–7/Mas axis which attenuates the proinflammatory RAS activa-
tion.
1.7. RAS and SARS-CoV-2
Infection with SARS-CoV-2 causes the virus spike protein to come
into contact with ACE2 on the cell surface and thus to be transported
into the cell. This endocytosis causes upregulation of a metallopepti-
dase (ADAM17), which releases ACE2 from the membrane, resulting in
a loss of the counter regulatory activity to RAS [51]. As a result,
proinflammatory cytokines are released extensively into the circulation.
This leads to a series of vascular changes, especially in the case of
preexisting lesions, which can promote further progression of cardio-
vascular pathologies.
SARS-CoV-2 not only reduces the ACE2 expression, but also leads to
further limitation of the ACE2/Ang 1–7/Mas axis via ADAM17 activa-
tion, which in turn promotes the absorption of the virus. This results in
an increase in Ang II, which further upregulates ADAM 17. Thus a vi-
cious circle is established turning into a constantly self-generating and
progressive process. This process may contribute not only to lung da-
mage (Acute respiratory distress syndrome - ARDS), but also to heart
injury and vessels damage, observed in COVID-19 patients. Thus, pre-
vious lesions of the cardiovascular system represent a risk factor, since
coexisting pathologies can progress as a result of the virus infection
[52,53].
1.8. RAS and vitamin D deficiency
Several studies have shown increased plasma renin activity, higher
Ang II concentrations and higher RAS activity as a consequence of low
vitamin D status [54,55]. The same applies to the decreasing Renin
activity with increasing vitamin D levels [56]. There is an inverse re-
lationship between circulating 25(OH)D and renin, which is explained
by the fact that vitamin D is a negative regulator of renin expression
and reduces renin expression by suppressing transcriptional activity in
the renin gene promoter, thus acting as a negative RAS regulator to
prevent overreaction In VDR knock out mice [57,58]. The 1,25(OH)2D
induced repression of the renin gene expression is independent from
Ang II feedback regulation.
Permanent increase of the renin levels with an increased Ang II
formation has been described, suggesting that in vitamin D deficiency
the expression and secretion of renin is increased at an early stage
[59,60]. This results in increased fluid and salt intake and rise in blood
pressure, that has been explained by an increase in renin and con-
secutive upregulation of the RAS in the brain [61].
Fig. 2 gives a short description of the impact of vitamin D on RAS.
In a small (open-label, blinded endpoint) study with 101 partici-
pants who received 2000 IU vitamin D3 or placebo over 6 weeks, a
significant decrease in plasma renin activity and concentration was
described [62].
Fig. 1. In the classical RAS pathway Renin, expressed from the renin gene induces cleavage of Angiotensinogen to Angiotensin I which is converted to Angiotensin II
via Angiotensin converting enzyme (ACE). Ang II activates the Angiotensin 1 receptor which results in an increase of blood pressure and further effects on the
vascular system. In addition, Ang II suppresses renin synthesis via AT1R. To keep the system in balance a counter regulatory pathway exists. This pathway is activated
through cleavage of Ang I to Ang1–9 via ACE2 or AT2R activation or Ang II to Ang1–7 which counter regulates via Mas receptor. This helps the system to stay within
a homoeostatic balance, as long as the RAS activity is controlled.
H.K. Biesalski NFS Journal 20 (2020) 10–21
12

The EVITA study examined the effect of vitamin D supplementation
(4000 IU/day) over 36 months [63]. No relationship was found be-
tween blood levels of 1,25(OH)2D and various parameters of the RAS
(renin, aldosterone) and vitamin D plasma levels increase. Rather, vi-
tamin D supplementation led to an increase in renin in a subgroup that
initially had a mild deficiency of vitamin D. The 25(OH)D value in these
subgroups increased from 20.4 nmol/L to 83.7nmol/L after 36months.
Renin from 859 mIU/L to 1656mIU/L. It cannot be excluded that these
were rather toxic effects of a dose in the upper level range. However,
the fact that blood levels increase naturally reduced the renin con-
centration become clear when looking at the placebo group with initial
hypovitaminosis D (21.3 nmol/L) with a strong increase after
36 months (45.6 nmol/L). Renin decreases from the initial value of 507
to 430mIU/L after 36 months. According to this, a moderate suppres-
sive effect of vitamin D is conceivable under physiological conditions
and in particular in participants with a compensated vitamin D defi-
ciency. The plasma level of renin and 1,25(OH)2D show a significant
inverse correlation in hypertensive individuals [64]. In a study on 184
normotensive participants, higher circulating Ang II levels were asso-
ciated with decreasing 25(OH)D blood levels. After infusion of Ang II
there was a blunted renal blood flow, both effects were considered RAS
activation in the setting of lower plasma 25(OH)D [65].
1.9. Vitamin D, blood pressure, and COVID-19 mortality
Vitamin D supplementation leads to a reduction in blood pressure in
patients with essential hypertension [66,67], and to a reduction in
blood pressure, plasma renin activity and angiotensin II levels in pa-
tients with hyperparathyroidism [68,69]. Low vitamin D status may
contribute to increased activity of the RAS and subsequent higher blood
pressure. An inverse relationship between the concentration of the
active metabolite 1,25(OH)2D3 and blood pressure has been described
in hypertensive as well as normotensive individuals [70,71]. In a study
using the mendelian randomization approach in 35 trials (146,581
participants) with four SNPs (Single Nucleotid Polymorphism), a causal
relationship was shown between increasing 25(OH)D levels and de-
creased risk of hypertension in individuals with genetic variants leading
to low Vitamin D plasma levels [72].
Depending on the study, the number of COVID-19 patients affected
with hypertension was between 20 and 30% and the proportion of
diabetics between 15 and 22% [73]. Data from 5 studies in Wuhan
(n:1458) reported 55.3% and 30.6% cases respectively of hypertension
and of diabetes [74]. 49% of the 1591 patients in ICUs in Italy (Lom-
bardy), 1287 of whom needed respirators, had hypertension and were
older than the normotensive ones [75].,
Hypertension, followed by diabetes (16.2%), was the most frequent
concomitant morbidity in patients with severe course disease
[76,77,78].
1.10. Vitamin D and cardiovascular diseases
Vitamin D has multiple functions in the cardiovascular system and
thus represents an important protective factor of endothelial, vascular
muscle, and cardiac muscle cells [79]. In a meta-analysis of 65,994
participants an inverse relationship between 25(OH)D vitamin D
plasma levels (below 60 nmol/L) and cardiovascular events was shown
[80]. These findings have been confirmed by the Framingham and
NHANES data [81,82]. As for the positive effects on respiratory diseases
shown by vitamin D supplementation, also for cardiovascular disease
positive effect was reported only if there was a vitamin D-deficit before
supplementation.
In a large cohort of patients (n= 3296) referred to coronary
Fig. 2. If the system is dysbalanced this may result in a rising formation of Ang II and a higher renin synthesis which at least increases inflammatory responses. This is
important in cases of a poor vitamin D status because vitamin D (1,25(OH)
2
D) can counteract the disbalance via negative expression of the renin gen which results in
lower renin synthesis independent from Ang II. An increase of aldosterone will block the activities of the ACE2 and as a consequence attenuate the counter regulatory
balance. If the counter regulatory circle is disrupted via ACE2 dysfunction due to SARS-CoV2 infection an uncontrolled classical pathway will run out of control and
increase proinflammatory reactions and blood pressure and contribute to a couple of problems (e.g. cardiovascular, ARDS, Kawasaki disease). Ang II activates NFκB
through AT1 receptors [194]. This and further interactions of the RAS with inflammatory stimuli results in an increasing and less controlled inflammatory reaction.
Beside its effect on renin expression vitamin D can effectively inhibit NFκB activation [195]. This is especially efficient when the VDR is upregulated, which also plays
an important role in other processes in the immune system through vitamin D activity.
H.K. Biesalski NFS Journal 20 (2020) 10–21
13

angiography, a significant increase in plasma renin and angiotensin II
was observed with decreased 25(OH)D and 1,25(OH)2D levels, but not
with circulating aldosterone levels [83]. Vitamin D plasma levels are an
independent risk factor for CVD mortality. 92% of 1801 patients with
metabolic syndrome, had a low vitamin D status (22.2% were severely
deficient (25(OH)D < 25 nmol). CVD mortality and total mortality
were reduced respectively by 69% and 75% in those with highest
25(OH)D levels (> 75 nmol/L) [84].
CVD is considered an independent risk factor for fatal outcome in
COVID-19 patients. The proportion of survivors with CVD was 10.8%,
among non-survivors 20% [85]. Disturbed coagulation, endothelial
dysfunction and proinflammatory stimuli described as a result of a viral
infection are considered to be among the major causes [86].
1.11. Vitamin D, obesity and type II diabetes
Obesity (BMI > 30 kg/m2) is often associated with low 25(OH)D
plasma level [87,88]. Using a bi-directional genetic approach, 26 stu-
dies (42,024 participants - Caucasians from Northern Europe and
America), including 12 SNPs, showed that higher BMI (Body Mass
Index) leads to lower 25(OH)D plasma levels. The repeatedly discussed
hypothesis that low 25(OH)D level leads to increased BMI could not be
verified [89]. Obesity is therefore another risk factor for an insufficient
vitamin D status independent from age [90].
Low 25(OH)D plasma values are also found in diabetes II [91,92].
This is often associated with an increased risk of metabolic syndrome,
hypertension and cardiovascular diseases [93,94]. One of the main
causes could be insulin resistance, often found in connection with low
vitamin D levels [95]. This is well documented by the evaluation of
observational and intervention studies using metabolic indicators. 10
out of 14 intervention studies showed a positive effect of Vitamin D on
metabolic indicators [96]. Vitamin D deficiency is therefore also con-
sidered to be a potential link between obesity and diabetes type II [97].
Via a short-loop feedback Ang II inhibits the further release of renin
via AT1R.
If the renin secretion is not sufficiently inhibited, an overreaction of
the RAS can lead to a further increase in blood pressure, increased
sodium reabsorption, increased aldosterone secretion and thus in-
creased insulin resistance [98]. This overreaction is considered to be a
major cause of the development of hypertension, diabetes and cardio-
vascular disease, especially in people with high BMI, since adipose
tissue contributes to an overreaction of the RAS [99]. Adiponectin
synthesis in adipocytes counteracts most of these effects, however cir-
culating levels are inversely related to BMI [100,101]. Vitamin D can
regulate the formation and release of adiponectin [102,103]. Obese
people often have low adiponectin and vitamin D levels and an inverse
relationship between fat mass and vitamin D levels has been described
[104]. Therefore, vitamin D deficiency might explain RAS overreaction
and following consequences [105].
In a small study on 124 IUC patients with SARS-CoV-2 it was found
that obesity (BMI > 35 kg/m
2
) occurred in 47.6% of the cases and
severe obesity (BMI > 35 kg/m
2
) in 28.2% [106]. In the latter case,
85.7% had to be mechanically ventilated invasively, 60 patients (50%)
had hypertension, 48 of these (80%) had to be ventilated invasively. A
study from Shenzhen, China also confirmed that obesity is a risk factor
for severe course of disease. In a cohort of 383 patients with COVID-19,
overweight patients (BMI 24–27.9) had 86% higher risk of developing
pneumonia and obese patients (BMI > 28) had 142% higher risk of
developing pneumonia compared to normal weight patients [107].
Fig. 3. Ang II leads to a series of pro-inflammatory stimuli in the immune system via the activation of AT1R. These include an increase in the expression of MCP-1 as
well as the chemokine receptor CCR2, which lead to a massive infiltration of the endothelium with macrophages. The same applies to the activation, migration and
maturation of dendritic cells (DC) and the antigen (Ag) presentation. The negative effect on T lymphocytes as well as on T regulatory cells further promotes a pro-
inflammatory state. A number of other proinflammatory processes are triggered by AT1R and favor the development of inflammation, hypertension and diabetes.
Vitamin D is considered to counteract this reaction by contributing to a normalization of immune function through a variety of processes. However, it should not be
overlooked that most processes in the immune system initiated by vitamin D occur together with vitamin A [196].
H.K. Biesalski NFS Journal 20 (2020) 10–21
14

1.12. Vitamin D and ARDS (adult respiratory distress syndrome)
The main cause of death in COVID-19 patients is ARDS. Patients
(without COVID-19) (mean age 62 Y) with ARDS (n:52) and those at
high risk of ARDS (n:57) (esophagectomy) had low (27.6 nmol/L) to
very low (13.7 nmol/L) 25(OH)D blood levels as a sign for severe vi-
tamin D deficiency [108].
ACE2 exerts a counter-regulation of the harmful effect of ACE.
Ultimately, it would then be the balance between ACE and ACE2 that
explains the reaction of the RAS. The ACE2 effect on the RAS is shown
in experimental studies in which ACE2 knock out mice developed se-
vere lung disease with increased vascular permeability and pulmonary
edema [109]. Over-expression or the use of recombinant ACE2 im-
proves blood flow and oxygenation and inhibits the development of
ARDS after LPS-induced lung damage [110,111].
The development of ARDS shows typical changes in membrane
permeability of the alveolar capillary, progressive edema, severe ar-
terial hypoxemia and pulmonary hypertension [112]. The same
changes can be achieved in animal experiments by injection of lipo-
polysaccharides (LPS) [113]. Vitamin D significantly attenuates the
lung damage caused by LPS. LPS exposure leads to a significant increase
in the pulmonary expression of renin and ANGII. This promotes the pro-
inflammatory effects of the conversion of AngII via AT1R and sup-
presses ACE2 expression. The administration of vitamin D was able to
reduce the increased renin and AngII expression and thus significantly
lower the lung damage. The authors conclude that this may have been
due to the reduction of the renin and ACE/AngII/AT1R cascade and the
promotion of ACE2/Ang1–7 activity by vitamin D through its influence
on renin synthesis.
Increased ACE and ANGII expression and reduced ACE2/Ang1–7
expression in lung tissue favors lung damage induced by ischemia re-
perfusion in mice [114]. The ACE/Ang1–7 expression and the amount
of circulating Ang 1–7 was increased at the onset of ischemia and then
decreased rapidly in contrast to the tissue concentration, while AngII
increased. This suggests a dysregulation of local and systemic RAS. The
application of recombinant ACE2 was able to correct the dysregulation
and attenuate the lung damage, while ACE2 knock out increased the
imbalance and was associated with more severe damage. Inhibition of
the ACE/AngII/AT1R pathway or activation of the ACE2/Ang1–7
pathway have therefore been proposed as therapeutic options.
In rats with LPS-induced acute lung injury (ALI), the administration
of vitamin D (calcitriol) was associated with a significant reduction in
clinical symptoms of ALI. Calcitriol treatment led to a significant in-
crease in the expression of VDR mRNA and ACE2 mRNA. VDR ex-
pression may have resulted in a reduction of angiotensin II, ACE2 ex-
pression in increased anti-inflammatory effects [115].
VDR is not only a negative regulator of renin, but also of NFkB
[116], leading both to an increase in Ang II formation [117], which in
turn promotes pro-inflammatory cascades. Furthermore SARS-CoV-2
infects T-lymphocytes [118] and the Covid-19 disease severity seems to
be related to lymphopenia [119], which occurs in 83,2% of COVID-19
patients at hospital admission [120]. Indeed, in a recent meta-analysis
on 53.000 COVID-19 patients decreased lymphocyte count and in-
creased CRP were highly associated with severity [121].
Regulatory T cells (Treg) play an important role in the development
of ARDS [122]. They can attenuate the pro-inflammatory effects of the
activated immune system. Vitamin D increases the expression of Treg
cells and supplementation of healthy volunteers results in a significant
increase in Tregs [123]. Vitamin D causes a reduction in pro-in-
flammatory cytokines by inhibiting B- and T-cell proliferation
[124,125]. Inflammatory processes also play an important role in the
development of hypertension and CVD [126,127]. Here, an interesting
but so far not proven connection between vitamin D and RAS is found.
T-cells have a RAS system, which contributes to the generation of re-
active oxygen species (ROS) and the development of high blood pres-
sure through the formation of Ang II [128]. To what extent vitamin D in
T cells is also a negative regulator of renin is not known, but could be
one of the reasons for the anti-inflammatory effect [129].
1.13. Cytokine storm: Vitamin D, SARS-CoV-2, and ACE2
In patients with a severe disease course (ARDS) a cytokine storm is
assumed to be the underlying cause [130]. SARS CoV-2 can lead to a
downregulation of ACE2 in the lungs and to a shedding of the ectodo-
main of ACE2. This soluble sACE2 shows enzymatic activity, but the
biological role is unclear. The soluble form is believed to exert systemic
influence on angiotensin II [131]; since SARS-CoV-2 induces shedding,
it is assumed that sACE2 is directly related to the virus- induced in-
flammatory response [132].
Downregulation of ACE2 expression by SARS-CoV infection is as-
sociated with acute lung damage (edema, increased vascular perme-
ability, reduced lung function) [ 133] and with RAS dysregulation
leading to increased inflammation and vascular permeability. In-
flammatory cytokines such as TACE (TNF-a-converting enzyme) induce
increase shedding [134], which in turn can be also caused by spike
protein of the virus, promoting virus uptake by ACE2 [135]. Com-
parative studies on mortality rates in different countries and analysis of
the relationship between vitamin D and CRP (as a marker of cytokine
storm) plasma levels, concluded that.
risk factors for severity of the clinical course, predicted by high CRP
and low vitamin D (< 25 nmol) levels, were reduced by by 15.6%
following vitamin D status normalization (> 75 nmol) [136]. It is in-
teresting to note that calmodulin kinase IV (CaMK IV) stimulates vi-
tamin D receptor (VDR) transcription and interaction with co-activator
SRC (steroid receptor coactivator) [ 137]. According to the authors, this
would explain the linkage of the genomic and non-genomic membrane
pathways of vitamin D. The calmodulin binding domain at ACE2 [138]
may explain why calmodulin inhibits the shedding of the ectodomain of
ACE2 [139]. It is also conceivable that vitamin D may show significant
effects either by stimulating VDR-mediated transcription, or by med-
iating 1,25(OH)D calcium-dependent activity through CaMK II and
phospholipase A [140].
1.14. Kawasaki syndrome
Children and adolescents rarely show severe disease courses. A
meta-analysis comprising 18 studies with 444 children under 10 years
of age and 553 between 10 and 19 years of age, reported only one case
of severe complication in a 13-year-old child. In North America, 48
cases of children (4.2–16.6 yrs) have been described with severe disease
course. Independently of this, COVID-19 children have a clinical picture
that has not been associated with usual acute clinical manifestations of
SARS-CoV-2 infection, showing an unusually high proportion of chil-
dren with gastrointestinal involvement, Kawasaki disease (KD) like
syndrome, until now [141].
KD is an acute vasculitis which can lead to aneurysms of the cor-
onary arteries and is considered the leading cause of acquired heart
disease in children [142]. A number of cases have been observed in
recent weeks suggesting a relationship between Kawasaki syndrome
and COVID-19 [143].
One reason probably relies upon ACE gene polymorphisms [144]. In
these polymorphisms there is a strong increase in ACE without affecting
AngII plasma levels [145]. There is a direct relationship between ACE
polymorphism (with high ACE plasma levels) and the occurrence of KD,
according to a recent meta-analysis [146].
Irrespective of this, the disease occurs seasonally during the winter
months in extratropical northern atmosphere and is often associated to
respiratory tract infections [147]. A KD associated Antigen was found in
proximal bronchial epithelium in 10 out of 13 patients with acute KD
and in a subset of macrophages of inflamed tissues [148]. That
strengthens the hypothesis that an infectious agent entering the re-
spiratory tract, might be the cause of KD. Indeed, it was reported that
H.K. Biesalski NFS Journal 20 (2020) 10–21
15

children with KD were affected by respiratory diseases with HCoV: New
Haven coronavirus [149]. The authors concluded that there was a
significant association between KD and HCoV-NH infection.
Just like current evidence suggest that vitamin D-deficiency is as-
sociated with increased risk of CVD, including hypertension, heart
failure, and ischemic heart disease, patients with KD also show very low
vitamin D levels. Children with KD (79) had significantly lower 25(OH)
D levels (9.17 vs 23.3 ng/ml) compared to healthy children of the same
age [150].
Intravenous immunoglobulin (IVIG) has become the standard
therapy for KD [151], with a good therapeutic response from young
patients, of which only 10–20% need additional anti-inflammatory
medication [152]. In a study on 91 KD children, 39 of them with very
low plasma vitamin D levels (< 20 ng/ml), showed immunoglobulin
resistance compared to the rest of the children (n= 52) children with
higher levels (> 20 ng/ml) [153]. Children with immunoglobulin re-
sistance also have a higher incidence of coronary artery complications
[154,155].
The relationship between ACE polymorphism and peripheral vas-
cular disease is observed in Asians but not in Caucasians [156,157].
Furthermore the prevalence of KD in Japan (240/100,000) is 10 times
higher than in North America (20/100,000) [158,159]. During Feb-
ruary and April 2020, 10 cases of COVID-19 and KD were reported in
Bergamo, Italy, corresponding to 30 times higher rate than the last
5 years incidence [160]. The higher incidence of KD in Asian children
(35.3 cases/100,000) as reported in California, may indeed indicate a
more frequent ACE polymorphism in Asian population, followed by
African-Americans (24.6/100,000) probably due to the fact that pig-
mentation reduces vitamin D production in the skin [161] compared to
white children (14.7/100.000). From 189 children hospitalized be-
tween 1991 and 1998 136 (72%) of the children were African-American
and 43 (23%) were white [162]. It is conceivable that Vitamin D de-
ficiency which activates the RAS, promotes the development and course
of KD.
1.15. Therapeutic aspects
1.15.1. Vitamin D status
The aim of a therapy with vitamin D should be a normalization of
the vitamin D status, preferably > 75 nmol/L. Basically, it can be as-
sumed that a vitamin in physiological doses can do little more than
remedy the symptoms or secondary manifestations of a deficiency.
Vitamin D is a prohormone. Therefore, the question of correcting the
status should be treated in the same way as for other hormones (e.g.
thyroid hormone). Before starting therapy, the plasma level should be
determined. This allows a dosage and therapy to be initiated that cor-
responds to the respective status. The analysis should be carried out
especially in risk groups (Table 1) in order to be able to react ade-
quately, especially in acute cases. The general recommendation to
supplement with a recommended daily dose (800 IU) may apply to
people who do not belong to a risk group, are healthy.
The vitamin D status is the basis for treatment with vitamin D. There
are indeed, risk groups were a poor status can be expected.
As it is known that the amount of 25(OH)D circulating in the blood
and less the active metabolite 1,25(OH)2D is a better indicator for a
deficit, threshold values have been set here (Table 2).
A vitamin D status below 20 ng/ml or < 50 nmol/L should be
treated to achieve a minimum level of 30 ng/ml (75 nmol/L). Values
around 75 nmol/L are considered optimal, with respect to the skeletal
activities [167]. Particularly in countries where vitamin D fortified
foods are not available, the importance of an adequate supply should be
emphasized. A sufficient vitamin D status can be achieved in the
healthy populations following the recommendations and the thresholds
of the plasma levels. In case of comorbidities related to the clinical
development of COVID-19 there might be a higher need and therefore it
is discussed to choose other recommendations for the adequate care of
persons with chronic diseases [168,169].
A recent meta analysis related to vitamin D and respiratory tract
infections showed that a daily or weekly Vitamin D dose between 20μg
and 50μg resulted in a significant reduction of infections [170]. An
isolated or added bolus with high doses (2.5 mg once or monthly) did
not reduce risk. One study supplemented adults with high risk for ARDS
with a 100μg/daily for one year [171]. The overall infection score was
significantly reduced in the treated group. Those with an initial vitamin
Ddeficit showed the greatest benefit of the supplementation. With re-
spect to COVID-19 a recommendation for primary prevention of vi-
tamin D deficiency seems meaningful. Whether this will be prevention
against COVID related diseases remains speculative. If a patient be-
longing to a risk group is delivered to the hospital, vitamin D status
should be immediately assessed and in case of insufficiency
(< 50 nmol/L) or deficiency (< 25 nmol/L) higher doses might be
needed as recommended by the NHS [172].
The recommendations of the National Health Service UK are based
on those of various professional associations. It should be noted that
vitamin D therapy is contraindicated for patients with hypercalcemia or
metastatic calcification. Suggested therapy should be used when low
plasma levels and the following symptoms are present:
- muscle pain
- Proximal muscle weakness
- Rib, hip, pelvis, thigh and foot pain (typical)
- Fractures.
So far, there is no experience on the use of vitamin D in COVID-19.
The observation that a normal vitamin D status is important for the
immune system as well as for the regulation of the RAS should, how-
ever, lead to a correction of the Vitamin D status if a deficiency is de-
tected. Nevertheless, it should be borne in mind that high doses of
Table 1
Risk factors for deficiency (NHS) [163].
Inadequate skin synthesis Poor oral supply Co-Morbidities
Air pollution Vegetarian or fish Reduced synthesis
Northern latitude/Winter Free diet Increased breakdown
Occlusive garments Malabsorption Drugs: rifampicin, HAART-
Pigmented skin Short bowel Therapy, ketoconazole
Habitual sunscreen use Cholestatic jaundice Anticonvulsants
Institutionalized/housebound and people with poor mobility Pancreatitis Glucocorticoids
Age > 65 Celiac disease CKD (eGFR < 60) [164]
Table 2
Threshold levels to calculate deficiency ranges (25(OH)D).
Severe < 12.5 nmol/L < 5 ng/ml
Moderate 12.5–29 nmol/L 5–11.6 ng/ml
Mild 30.0–49 nmol/L 12–19.6 ng/ml
Sufficient > 50 nmol/L > 20 ng/ml
165
> 75 nmol/L > 30 ng/ml
166
Toxicity > 250 nmol/L > 100 ng/ml
H.K. Biesalski NFS Journal 20 (2020) 10–21
16

vitamin D also carry risks, as they can contribute to changes in VDR
competence and thus have n inhibitory effect on immune function (Ref:
Mangin M, Sinha R, Fincher K. Inflammation and vitamin D: the in-
fection connection. Inflkamm Res 2014; 63: 803-811)
The importance of a vitamin D deficiency is shown by a recently
published analysis of the COVID-19 deaths of 780 COVID-19 patients in
Indonesia [173].
table 3 data of patients with COVID-19 related to vitamin D levels and disease
outcome
Vitamin D:
< 20 ng/ml
20-30 ng/ml > 30 ng/ml
Overall, N 179 213 388
Mean age 66.9 ± 13.8 62.9 ± 14.7 46.6 ± 12.6
Comorbidity, % 80.0 73.8 18.8
Death, % 98.9 87.8 4.1
Active, % 1.1 12.2 95.9
Odds ratio
Adjusted for age, sex and c-
omorbidity
10.12 (p < .001) 7.63
(p< .001)
The table illustrates thate old age, comorbidities and vitamin D
deficiency or insufficiency contributed to outcome of the disase. Based
on thes data Vitamin D plasma level is an independent precitor of
mortality.
1.15.2. VDR agonists (VDRA)
VDRA are discussed to counteract the effect of imbalanced immune
response and have suppressant effects on the RAS. Since VDRA have
been observed to contribute to a significant reduction of inflammatory
processes, they are increasingly used in immunosuppressive therapy to
control TH1-related overreactions via interaction of VDRA with the
chemokine CXCL10, a T cell chemoattractant chemokine [174]. The
induction of CXCL10 is an important step against bacterial and virus
infections. However, sustained CXCL10 induction leads to amplified
neuroinflammation in Coronavirus (JHMV) induced neurologic infec-
tion [175]. CXCL10 is also considered a critical factor in ARDS. H5N1
influenza infection in mice resulted in increased CXCL10 secretion with
a consequent inflamed neutrophils massive chemotaxis and a sub-
sequent pulmonary inflammation [176]. Following SARS-CoV-2 infec-
tion, CXCL10 and other chemo- and cytokines are upregulated [177].
Anti CXCL10 antibodies have shown ARDS improvement following LPS
induced lung injury with high CXCL10 levels [178].
Additionally evidence from animal models (diabetic nephropathy)
has shown that VDRA block TGFß system in the glomerulus and thus
abolish interstitial fibrosis [179]. It is assumed that VDRA modulates
increased RAS activity. Indeed, a clinical study on 281 patients (type II
diabetes with albuminuria) revealed that VDR activator paricalcitol
(19-nor-1,15-dihydroxyvitamin D
2
) led to a significant albuminuria
reduction as well as a decrease in blood pressure despite increased salt
intake, as a sign of decreased RAS activity [180]; effect that could not
be achieved with losartan (ANG II receptor antagonist) [181].
1.15.3. Morphine
Morphine medication is an essential part of treatment for COVID
patients with severe ARDS. it is used early for dyspnea or pain and for
shivers [182]. Morphine, at doses similar to those used in humans, can
lead to downregulation of VDR in human T cells and activation of RAS
with renin upregulation and a threefold increase in Ang II production,
resulting in increased reactive oxygen species (ROS) responsible for
DNA damage and T cells apoptosis .
VDR agonist (EB1089) inhibits VDR downregulation, leading to RAS
decreased activity, inhibition of morphine induced ANG II production,
reduced ROS formation and lower DNA damage, thus inhibiting T-cell
apoptosis [183]. In addition, if Jurkat cells were pretreated with EB
1089 and Losartan, an Angiotensin II receptor antagonist (ARB) before
incubation with morphine. The combination of the Vitamin D Receptor
agonist and Losartan attenuated the morphine-induced ROS formation.
Indeed, as an example ARB increase ACE2 expression [184] and Ang
1–7/Mas axis activation reduced ROS formation [185].
1.15.4. Autophagy, spermidine and vitamin D
Spermidine is a metabolite of polyamines which are delivered
through the diet and partially metabolized by colon bacteria from un-
digested proteins. Polyamines can influence macrophages development
into pro-inflammatory or anti-inflammatory type by altering cellular
metabolism and triggering mito- and autophagy [186]. The capacity of
spermidine to ensure proteostasis through the stimulation of the cyto-
protective autophagy is acknowledged as one of its main features.
Recently, the effect of spermidine on autophagy in SARS-CoV-2
infected cells which results in inhibition of autophagy has been de-
scribed [187]. Since spermidine promotes autophagy, spermidine and
other agents may be a therapeutic approach to SARS-CoV-2 infection.
With regard to the specific risk of elderly to develop severe course of
SARS-CoV-2 infection, it is interesting to note that spermidine con-
centrations in organs and cells decline with age and resulting in a de-
crease of autophagy [188]. Consumption of LKM512 yogurt increases
spermidine synthesis in the gut in elderly [189]. Whether that has any
impact on supply of spermidine to enterocytes or other tissues remains
to be elucidated. Spermin and spermidine but not putrescine another
polyamine metabolite can activate VDR in vitro within their physiolo-
gical intracellular concentrations [190]. Vitamin D and VDR play an
important role in autophagy. Vitamin D can induce autophagy similar
to spermidine by inhibiting mTORC1 complex activation [191] and by
increasing Beclin-1 expression, similar to spermidine [192].
2. Limitations
A major limitation of al studies dealing with low levels of vitamin D
and disease is the fact that there are only few studies, which show a
causal relationship. Most studies show associations and data regarding
the influence of COVID-19 on vitamin D status are missing.
Furthermore, it should not be overlooked that many of the effects of
vitamin D on genexpression in the immune system occur together with
vitamin A. The effect of vitamin A deficiency in COVID-19 has not yet
been investigated. However, vitamin A deficiency or combined defi-
ciencies with vitamin D or other micronutrients exists not only in low
income countries. .
3. Conclusion
An inadequate supply of vitamin D has a variety of skeletal and non-
skeletal effects. There is ample evidence that various non-communic-
able diseases (hypertension, diabetes, CVD, metabolic syndrome) are
associated with low vitamin D plasma levels. These comorbidities, to-
gether with the often concomitant vitamin D deficiency, increase the
risk of severe COVID-19 events. Much more attention should be paid to
the importance of vitamin D status for the development and course of
the disease. Particularly in the methods used to control the pandemic
(lockdown), the skin's natural vitamin D synthesis is reduced when
people have few opportunities to be exposed to the sun. The short half-
lives of the vitamin therefore make an increasing vitamin D deficiency
more likely. Specific dietary advice, moderate supplementation or for-
tified foods can help prevent this deficiency. In the event of hospitali-
sation, the status should be urgently reviewed and, if possible, im-
proved.
In the meantime, 8 studies have started to test the effect of sup-
plementing vitamin D in different dosages (up to 200,000 IU) on the
course of the COVID-19 disease. The aim is to clarify whether supple-
mentation with vitamin D in different dosages has an influence on the
course of the disease or, in particular, on the immune response, or
H.K. Biesalski NFS Journal 20 (2020) 10–21
17

whether it can prevent the development of ARDS or thromboses [193].
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgement
The author is grateful to the Society of Nutrition and Food Science
e.V. (www.snfs.org) for defraying the open access publication charges
for this article. My sincere thanks to Hellas Cena, University Pavia,
Italy, for the critical reading of my manuscript and the excellent hints
for strengthening the information contained therein. Ute Gola, Institute
for nutrition and prevention, Berlin, Germany for valuable suggestions
and advice.
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