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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 deciency 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
briey 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 inuence
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 deciency is widely prevalent
during the winter months and aects mainly elderly people and mi-
grants. In Scandinavia only 5% of the population is aected 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 deciency 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 signicant (P= .046) inverse correlation with the mean
25(OH)D plasma concentration [9].
This raises the question whether insucient vitamin D supply has
an inuence on the course of COVID-19 disease? An analysis of the
distribution of Covid-19 infections showed a correlation between geo-
graphical location (3050° N+), mean temperature between 511 °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 eects
The skeletal and extra skeletal eects of vitamin D have recently
been described in an extensive review [14]. Vitamin D exerts a genomic
and non-genomic eect on gene expression. The genomic eect 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 eects 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-
inammatory cytokines and increases the production of anti-in-
ammatory 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 eects on the adaptive (inhibition) and innate (pro-
motion) immunsystem This correlates with an anti-inammatory 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 inammation
and stimulate Treg cells proliferation, by increasing IL-10 formation in
DC cells, and thus enhance their suppressive eect [27,28].
1.3. Food sources
There are only few dietary sources of vitamin D (cod liver oil, fat
sh) that could satisfy the recommended daily allowance (1520 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 signicantly improved by fortied foods, as was shown in
a meta-analysis [33].
1.4. Vitamin D deciency
Insucient 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 sh and fortied food (if available) are the major
reason for deciency 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 deciency is a worldwide problem, which is not only
observed in the northern countries, but increasingly also in the south.
While in Europe, for example, decits (< 30 nmol) are between 20 and
60% in all age groups, in Asia the gure for children is 61% (Pakistan,
India) and 86% (Iran) [37,38].
Particularly critical is the number of migrants from Southern
countries with insucient 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 anity 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 deciency.
1.5. Risk factors for severe courses of COVID-19
Older age and co-morbidities are linked to an insucient 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 dierence in individuals aged 6280 yrs. compared
with controls (2030 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 2.292.98
Male 1.38 1.1951.521
Smoking 1.734 1.1462.626
Any co-morbidity 2.635 2.0983.309
Chronic kidney disease 6.017 2.19216.514
COPD 5.323 2.61310.847
Cerebrovascular disease 3.219 1.4866.972
Independent prognostic factors for COVID-19 related death:
Risk factor Relative risk 95% CI
Old age > 60 9.45 8.0911.04
CVD 6.75 5.408.43
Hypertension 4.48 3.695.45
Diabetes 4.43 3.495.61
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 uid 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 dierent receptors AT1R or AT2R. Synthesis and secretion of renin
in the kidney, as rate limiting enzyme of RAS, is stimulated by uid
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 eect and stimulated with decreasing Ang II [44].
The stimulating eect 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-inammatory and pro-
oxidative eects 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 19, and Ang II to Ang 17. This degradation can
weaken the eect of Ang II at AT1R and thus counteract the patholo-
gical changes. While Ang 19 exerts a cardioprotective eect via AT2R
[49], Ang 17 acts via the Mas Oncogene receptor. This counter-
balances the eect of ANG II at AT1R and subsequently the over-
stimulationof 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 broblasts, vascular
smooth muscle and endothelial cells. It can counteract the eects of
RAS, such as inammation, vasoconstriction, hypertrophy and brosis,
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 17/Mas axis which attenuates the proinammatory 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,
proinammatory 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 17/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 deciency
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 deciency
the expression and secretion of renin is increased at an early stage
[59,60]. This results in increased uid 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
signicant 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 eects 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 Ang19 via ACE2 or AT2R activation or Ang II to Ang17 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 eect 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 deciency 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 eects 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 eect of vitamin D is conceivable under physiological conditions
and in particular in participants with a compensated vitamin D de-
ciency. The plasma level of renin and 1,25(OH)2D show a signicant
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 ow, both eects 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 aected
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 ndings have been conrmed by the Framingham and
NHANES data [81,82]. As for the positive eects on respiratory diseases
shown by vitamin D supplementation, also for cardiovascular disease
positive eect was reported only if there was a vitamin D-decit 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 inammatory 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 proinammatory 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 inammatory stimuli results in an increasing and less controlled inammatory reaction.
Beside its eect on renin expression vitamin D can eectively inhibit NFκB activation [195]. This is especially ecient 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 signicant 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
decient (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 proinammatory 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
veried [89]. Obesity is therefore another risk factor for an insucient
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 eect of Vitamin D on
metabolic indicators [96]. Vitamin D deciency 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 suciently 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 eects, 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 deciency 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 conrmed that obesity is a risk factor
for severe course of disease. In a cohort of 383 patients with COVID-19,
overweight patients (BMI 2427.9) 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-inammatory 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 inltration 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 eect on T lymphocytes as well as on T regulatory cells further promotes a pro-
inammatory state. A number of other proinammatory processes are triggered by AT1R and favor the development of inammation, 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 deciency [108].
ACE2 exerts a counter-regulation of the harmful eect of ACE.
Ultimately, it would then be the balance between ACE and ACE2 that
explains the reaction of the RAS. The ACE2 eect 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 ow 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 signicantly attenuates the
lung damage caused by LPS. LPS exposure leads to a signicant increase
in the pulmonary expression of renin and ANGII. This promotes the pro-
inammatory eects 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 signicantly
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/Ang17 activity by vitamin D through its inuence
on renin synthesis.
Increased ACE and ANGII expression and reduced ACE2/Ang17
expression in lung tissue favors lung damage induced by ischemia re-
perfusion in mice [114]. The ACE/Ang17 expression and the amount
of circulating Ang 17 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/Ang17
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 signicant reduction in
clinical symptoms of ALI. Calcitriol treatment led to a signicant 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-inammatory eects [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-inammatory 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-inammatory eects of the
activated immune system. Vitamin D increases the expression of Treg
cells and supplementation of healthy volunteers results in a signicant
increase in Tregs [123]. Vitamin D causes a reduction in pro-in-
ammatory cytokines by inhibiting B- and T-cell proliferation
[124,125]. Inammatory 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-inammatory eect [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
inuence on angiotensin II [131]; since SARS-CoV-2 induces shedding,
it is assumed that sACE2 is directly related to the virus- induced in-
ammatory 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 inammation and vascular permeability. In-
ammatory 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 dierent 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 signicant
eects 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 (4.216.6 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 aecting
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 inamed 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 aected by respiratory diseases with HCoV: New
Haven coronavirus [149]. The authors concluded that there was a
signicant association between KD and HCoV-NH infection.
Just like current evidence suggest that vitamin D-deciency 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 signicantly 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 1020% need additional anti-inammatory
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-
ciency 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 deciency.
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
decit, 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 fortied
foods are not available, the importance of an adequate supply should be
emphasized. A sucient 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 signicant 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
signicantly reduced in the treated group. Those with an initial vitamin
Ddecit showed the greatest benet of the supplementation. With re-
spect to COVID-19 a recommendation for primary prevention of vi-
tamin D deciency 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 insuciency
(< 50 nmol/L) or deciency (< 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 calcication. 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 deciency is de-
tected. Nevertheless, it should be borne in mind that high doses of
Table 1
Risk factors for deciency (NHS) [163].
Inadequate skin synthesis Poor oral supply Co-Morbidities
Air pollution Vegetarian or sh 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 deciency ranges (25(OH)D).
Severe < 12.5 nmol/L < 5 ng/ml
Moderate 12.529 nmol/L 511.6 ng/ml
Mild 30.049 nmol/L 1219.6 ng/ml
Sucient > 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 eect on immune function (Ref:
Mangin M, Sinha R, Fincher K. Inammation and vitamin D: the in-
fection connection. Inkamm Res 2014; 63: 803-811)
The importance of a vitamin D deciency 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
deciency or insuciency 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 eect of imbalanced immune
response and have suppressant eects on the RAS. Since VDRA have
been observed to contribute to a signicant reduction of inammatory
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 amplied
neuroinammation in Coronavirus (JHMV) induced neurologic infec-
tion [175]. CXCL10 is also considered a critical factor in ARDS. H5N1
inuenza infection in mice resulted in increased CXCL10 secretion with
a consequent inamed neutrophils massive chemotaxis and a sub-
sequent pulmonary inammation [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 brosis [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 signicant albuminuria
reduction as well as a decrease in blood pressure despite increased salt
intake, as a sign of decreased RAS activity [180]; eect 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
17/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 inuence macrophages development
into pro-inammatory or anti-inammatory 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 eect 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 specic 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 inuence of COVID-19 on vitamin D status are missing.
Furthermore, it should not be overlooked that many of the eects of
vitamin D on genexpression in the immune system occur together with
vitamin A. The eect of vitamin A deciency in COVID-19 has not yet
been investigated. However, vitamin A deciency or combined de-
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 eects. 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 deciency, 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 deciency
more likely. Specic dietary advice, moderate supplementation or for-
tied foods can help prevent this deciency. 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 eect of sup-
plementing vitamin D in dierent 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 dierent dosages has an inuence 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 nancial
interests or personal relationships that could have appeared to inu-
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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... A recently published complete and exhaustive review , of the relationships between Vitamin D, COVID-19 and associated comorbidities, demonstrated unequivocally, the protective role of Vitamin D in controlling the hyper inflammatory state caused by SARS-CoV-2 (cytokine storm), as the «Vitamin D inhibits the production of proinflammatory cytokines and increases the production of anti-inflammatory cytokines» [143]. «Vitamin D exerts opposite effects on the adaptive (inhibition) and innate (promotion) immune system. ...
... This correlates with an antiinflammatory response and balances the immune response». «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» [143]. This article explains in detail the biochemical and immunological dysregulation mechanisms by which SARS-CoV-2 acts and how it worsens other co-morbidities (hypertension, cardiovascular disease, diabetes, obesity and acute respiratory distress syndrome -ARDS) that condition the severity of disease, and how Vitamin D has an antagonistic effect on these mechanisms [143]. ...
... «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» [143]. This article explains in detail the biochemical and immunological dysregulation mechanisms by which SARS-CoV-2 acts and how it worsens other co-morbidities (hypertension, cardiovascular disease, diabetes, obesity and acute respiratory distress syndrome -ARDS) that condition the severity of disease, and how Vitamin D has an antagonistic effect on these mechanisms [143]. The author of this work states that «Vitamin D plasma level is an independent predictor of mortality» [143]. ...
Article
Introduction: When the first report appeared of a protective effect of universal BCG vaccination on COVID- 19 morbidity and case fatality rates, as well as referring to previous papers on the nonspecific protective effects of BCG, our interest was raised, because Mozambique was in an unusual position in relation to BCG vaccination. Based on our knowledge of the history of global public health, we constructed a table with the number of cases of COVID-19 per 100,000 inhabitants and the case fatality rate of the countries that had carried out universal BCG vaccination for a long period (India, Japan and the ex-USSR countries), compared to countries without a universal BCG vaccination programme. We found that countries that had carried out universal BCG vaccination for a long period had much lower case/population ratios and case fatality rates than those without a universal BCG vaccination programme. This exercise was repeated three times, during the month of April, with consistent results. These results made us take the decision to undertake a study of possible confounding factors Mozambique became independent in June 1975, and immediately after carried out a mass vaccination campaign with the six antigens of the recently created EPI. Smallpox vaccine was added, in order to consolidate smallpox eradication. WHO, at that time, was against vaccination campaigns, but an exceptional agreement was obtained. The campaign took place from the north to the south of the country, from February 1976 to January 1978. Every province started a routine EPI programme as soon as the campaign finished. In the campaign, all children 15 years old or younger received BCG vaccine. The coverage rate in the campaign was 97%, with 99% in the capital city of Maputo. Subsequently, the coverage rate of BCG vaccination at birth in the EPI has been always remarkably high in urban areas. In rural areas, coverage has been irregular, but has been at least 80% in the past 25 years. Therefore, most of the urban population aged 58 or less has received BCG, and so has an important part of the rural population. Such a high coverage of BCG is exceedingly rare in the world.
... In critically ill patients, 25-OH-cholecalciferol levels are inversely linked with the incidence of abrupt respiratory failure. In addition, Biesalski et al. (2020) emphasized that there is a deadly association between vitamin D deficiency and comorbidities in COVID-19 patients [26]. In addition, another study indicated that optimizing the vitamin D status certainly has benefits in COVID-19 patients [27]. ...
... In addition, Biesalski et al. (2020) emphasized that there is a deadly association between vitamin D deficiency and comorbidities in COVID-19 patients [26]. In addition, another study indicated that optimizing the vitamin D status certainly has benefits in COVID-19 patients [27]. This study revealed that the incidence of mechanical ventilation, ICU hospitalization, death, sepsis, and atrial fibrillation in the high-dosage vitamin D group was considerably reduced compared to the low-dosage vitamin D group. ...
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Background and Objectives: Vitamin D supplementation plays a key effect in lowering cytokine storms among COVID-19 patients by influencing the activity of the renin-angiotensin system and the production of the angiotensin-2 converting enzyme. The study was conducted to explore the effect of high-dose intramuscular vitamin D in hospitalized adults infected with moderate-to-severe SARS-CoV-2 in comparison with the standard of care in the COVID-19 protocol. Materials and Methods: Two groups of patients were compared in this prospective randomized controlled trial as the vitamin D was administered orally to group 1 (alfacalcidol 1 mcg/day) and intramuscularly to group 2 (cholecalciferol 200,000 IU). One hundred and sixteen participants were recruited in total, with fifty-eight patients in each group. Following the Egyptian Ministry of Health’s policy for COVID-19 management, all patients received the same treatment for a minimum of five days. Results: A significant difference was recorded in the length of hospital stay (8.6 versus 6.8 days), need for high oxygen or non-invasive mechanical ventilator (67% versus 33%), need for a mechanical ventilator (25% versus 75%), clinical improvement (45% versus 55%), the occurrence of sepsis (35% versus 65%), and in the monitored laboratory parameters in favor of high-dose vitamin D. Moreover, clinical improvement was significantly associated with the need for low/high oxygen, an invasive/non-invasive mechanical ventilator (MV/NIMV), and diabetes, while mortality was associated with the need for MV, ICU admission, atrial fibrillation, chronic obstructive pulmonary disease, asthma, and the occurrence of secondary infection. Conclusions: Our study showed that high-dose vitamin D was considered a promising treatment in the suppression of cytokine storms among COVID-19 patients and was associated with better clinical improvement and fewer adverse outcomes compared to low-dose vitamin D.
... Vitamin Daffects gene expressions -bothgenomic and non-genomic. 11 The genomic impact of Vitamin D includesligand activated transcription factors known as VDR vitamin D receptor, calcitriol binds to VDR and heterodimerizes are form in some cases with active metabolites of vitamin A retinoid X receptor RXXR. This interaction regulates the gene expression positively or negatively. ...
... This interaction regulates the gene expression positively or negatively. 11 Non genomics effect includes the interaction of dependent genes in promoter region of vitamin D with responsive element VDRE. 12 Besides, these also play major role in neuro muscular function, cellular growth, immune function includes antiinflammatory action, its insufficiency associated with overexpression of TH1 cytokines, and inhibit the expression of inflammatory cytokines e.g tumor necrosis factor TNF alpha, IL-1B, ILK6, IL-1D. ...
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Article
The novel corona virus disease (COVID-19) outbreak imposed the catastrophic impact on the communities worldwide. Recentevidence suggests that vitamin D is one of the important factors that affects the COVID-19 disease severity and the mortality increased in the vitamin D deficient COVID-19 patients. Since C- reactive protein (CRP)is an indicator of inflammation, an increase in levels of Vitamin D hence leads to the decrease in cytokines which ultimately affects the degree of C reactive proteins in the patients. In this review, we have focusedhere on the association between vitamin D and surrogate marker C- reactive protein (CRP)in cytokine storms in COVID-19 patients.International Journal of Human and Health Sciences Vol. 06 No. 04 Oct’22 Page: 355-361
... Vitamin D plays an important role by interfering with most of the macrophages, B and T lymphocytes, neutrophils, and dendritic cells in the immune system [23]. Additionally, vitamin D deficiency been found to be involved in various diseases such as diabetes, changes in regulation of immune system, cardiovascular diseases, cancer, inflammation, hypertension, cognitive changes, and osteoporosis [22]. ...
... It is recommended that individuals consume vitamin D-fortified foods if they have access to them. It is emphasized that the vitamin D level of COVID-19 patients staying in hospital must be measured and supplemented with supplements if low [23]. ...
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Article
Coronavirus 2019 (COVID-19) is an infectious disease that has brought life to a standstill around the world. Until a vaccine was found to combat COVID-19, the world conducted research and made recommendations for nutritional natural foods. Considering the risks incurred by contracting the disease, even though the production of various vaccines and vaccination of healthy people has started in some countries, individuals need useful foods to be ready for the COVID-19 pandemic. Recently, nutrient contents such as antioxidant compounds, vitamins, minerals, and probiotics that contribute to the immune system have been investigated. This paper attempts to determine the role of these dietary supplements in reducing the risk of COVID-19 and/or changing the course of the disease in COVID-19 patients and their effects on mortality. Supplements used and recommended for the COVID-19 pandemic life were investigated. In conclusion, more research is needed to determine the effectiveness of nutrients, vitamins, minerals, probiotics, prebiotics, and antioxidants used during the COVID-19 pandemic to inhibit the effect of SARS-CoV-2. In order to overcome the new global crisis, nutritional cures and treatments should be upgraded. However, additional research on the subject is needed.
... Deficiencies in total 25(OH)D have been correlated with risk for other infections including influenza and tuberculosis [29]. Emerging evidence exists in the UK and Portugal for potential causal relationships between Vitamin D status and COVID-19 disease risk [3,5,30]. ...
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Vitamin D deficiency is common in the United States and leads to altered immune function, including T cell and macrophage activity that may impact responses to SARS-CoV-2 infection. This study investigated 131 adults with a history of a positive SARS-CoV-2 nasopharyngeal PCR and 18 adults with no COVID-19 diagnosis that were recruited from the community or hospital into the Northern Colorado Coronavirus Biorepository (NoCo-COBIO). Participants consented to enrollment for a period of 6 months and provided biospecimens at multiple visits for longitudinal analysis. Plasma 25-hydroxyvitamin D levels were quantified by LC-MS/MS at the initial visit (n = 149) and after 4 months (n = 89). Adults were classified as deficient (<30 nM or <12 ng/mL), insufficient (<30–50 nM or 12–20 ng/mL), or optimal (50–75 nM or >20 ng/mL) for 25-hydroxyvitamin D status. Fisher’s exact test demonstrated an association between disease severity, gender, and body mass index (BMI) at baseline. Mixed model analyses with Tukey-Kramer were used for longitudinal analysis according to BMI. Sixty-nine percent (n = 103) of the entire cohort had optimal levels of total 25(OH)D, 22% (n = 32) had insufficient levels, and 9% (n = 14) had deficent levels. Participants with severe disease (n = 37) had significantly lower 25-hydroxyvitamin D (total 25(OH)D) when compared to adults with mild disease (p = 0.006) or no COVID-19 diagnosis (p = 0.007). There was 44% of the cohort with post-acute sequalae of COVID-19 (PASC) as defined by experiencing at least one of the following symptoms after 60 days’ post-infection: fatigue, dyspnea, joint pain, chest pain, forgetfulness or absent-mindedness, confusion, or difficulty breathing. While significant differences were detected in 25-hydroxyvitamin D status by sex and BMI, there were no correlations between 25-hydroxyvitamin D for those without and without PASC. This longitudinal study of COVID-19 survivors demonstrates an important association between sex, BMI, and disease severity for 25-hydroxyvitamin D deficiency during acute stages of infection, yet it is not clear whether supplementation efforts would influence long term outcomes such as developing PASC.
... Recent research has shown that vitamin D has an anti-inflammatory effect, and the stronger the inflammatory process in the disease, the greater the need for vitamin D (10,11). The etiology of this association may be related to the immune modulatory role of vitamin D, and the accepted pathophysiology of MIS-C, which is an exaggerated immune response (12). ...
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Article
Objective - To assess 25(OH)D status in children with Multisystem Inflammatory Syndrome (MIS-C) associated with SARSCoV-2 infection, and the association between serum levels of 25(OH)D and inflammatory marker values.Patients and methods - This retrospective study was conducted at the Clinic for Children’s Diseases, University Clinical Center, Tuzla in the period from November 2020 to November 2021.Results - The study included 23 children with MIS-C with a median age of 6.9 years, and 22 children with acute SARS-CoV-2 infection, with a median age of 1.1 years. Both groups of children had low serum levels of 25(OH)D in the range of deficiency; median levels of 25(OH)D in MIS-C children were lower (median 44.60 nmol/L) than in children with acute SARS-CoV-2 infection - median 52.45 nmol/L. There was no statistically significant difference in 25(OH) D levels between the two groups of children included in the study (P=0.33). The same number of children in both groups had adequate serum levels of 25(OH)D. The children in both groups had elevated markers of inflammation, but we did not find a significant correlation between the values of 25(OH)D and the inflammatory marker values.Conclusion - Deficiency of 25(OH) D could be one of the precipitating factors that lead to the development of both MIS-C - related SARS-CoV-2 and more severe forms of acute infection. 25(OH)D enriched food, as well as supplementation with 25(OH)D, should be considered a long-term strategy in all high-risk children and adolescents.
... Nonetheless, several studies revealed a link between vulnerability to infection and worse prognosis in COVID-19 patients with deficiencies in one or more of these fat-soluble vitamins [14]. Various new therapeutic interventions have acquired FDA approval or are under clinical trials, including repurposed drugs, antivirals, anti-inflammatory, and immuno-modulatory agents. ...
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Article
COVID-19 is a recent pandemic that mandated the scientific society to provide effective evidence-based therapeutic approaches for the prevention and treatment for such a global threat, especially to those patients who hold a higher risk of infection and complications, such as patients with autoimmune diseases and cancer. Recent research has examined the role of various fat-soluble vitamins (vitamins A, D, E, and K) in reducing the severity of COVID-19 infection. Studies showed that deficiency in fat-soluble vitamins abrogates the immune system, thus rendering individuals more susceptible to COVID-19 infection. Moreover, another line of evidence showed that supplementation of fat-soluble vitamins during the course of infection enhances the viral clearance episode by promoting an adequate immune response. However, more thorough research is needed to define the adequate use of vitamin supplements in cancer and autoimmune patients infected with COVID-19. Moreover, it is crucial to highlight the vitamin–drug interactions of the COVID-19 therapeutic modalities and fatsoluble vitamins. With an emphasis on cancer and autoimmune patients, the current review aims to clarify the role of fat-soluble vitamins in SARS-CoV-2 infection and to estimate the risk-to-benefit ratio of a fat-soluble supplement administered to patients taking FDA-approved COVID-19 medications such as antivirals, anti-inflammatory, receptor blockers, and monoclonal antibodies.
... Clinical experience has indicated that these factors increase the risk of a severe COVID-19 illness course. Although multiple studies and investigations have revealed a link between vitamin D deficiency and COVID-19 illness and death intensity [16,17], no molecular/structural information is available concerning its direct involvement in the disease. ...
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Article
Vitamin D’s role in combating the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus causing COVID-19, has been established in unveiling viable inhibitors of COVID-19. The current study investigated the role of pre and pro-vitamin D bioactives from edible mushrooms against Mpro and PLpro proteases of SARS-CoV-2 by computational experiments. The bioactives of mushrooms, specifically ergosterol (provitamin D2), 7-dehydrocholesterol (provitamin-D3), 22,23-dihydroergocalciferol (provitamin-D4), cholecalciferol (vitamin-D3), and ergocalciferol (vitamin D2) were screened against Mpro and PLpro. Molecular docking analyses of the generated bioactive protease complexes unravelled the differential docking energies, which ranged from −7.5 kcal/mol to −4.5 kcal/mol. Ergosterol exhibited the lowest binding energy (−7.5 kcal/mol) against Mpro and PLpro (−5.9 kcal/mol). The Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) and MD simulation analyses indicated that the generated complexes were stable, thus affirming the putative binding of the bioactives to viral proteases. Considering the pivotal role of vitamin D bioactives, their direct interactions against SARS-CoV-2 proteases highlight the promising role of bioactives present in mushrooms as potent nutraceuticals against COVID-19.
... 34 It has been reported both elderly and comorbidities such as diabetes, coronary heart disease, hypertension, and also COVID-19 are linked to vitamin D insufficiency. 35 This suggests that comorbidities in combination with vitamin D deficiency might negatively affect the risk of severe COVID-19 progression. ...
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Article
Objective: There is no conclusive evidence to suggest vitamin D level can prevent or treat infection with the new coronavirus disease 2019. This study aimed to investigate the effects of serum level of vitamin D in patients with coronavirus disease 2019 on death, severity, and hospitalization duration. Materials and methods: Baseline characteristic of patients was extracted from the Isfahan coronavirus disease 2019 registry database (I-CORE). Blood samples were taken from all patients to measure the level of vitamin D (25-hydroxyvitamin D) and categorized. The effect of 25(OH) D on death, severity, and hospitalization duration was analyzed by logistic regression. Results: Among our study patients, 5.5% had a severe deficiency of vitamin D, 23.7% deficiency, and 24.8% insufficiency. Of the 107 patients who died, 7.5% were severely deficient in vitamin D. We found that vitamin D deficiency had no significant effect on death, disease severity, and hospitalization (P > .05). However, having at least one comorbidity increased the odds of death five times after adjusting age > 60 years and gender (P < .0001). The results showed that among all comorbidities, diabetes has the greatest impact on the outcomes as it raised the odds of death, disease severity, and length of hospital stay by 2.23,1.72, and 1.48, respectively, after controlling the age > 60 and gender (P = .0002, P=.08, P=.012). Conclusions: The mortality, disease severity, and hospitalization of coronavirus disease 2019 patients seem to be not affected by the low levels of 25(OH)D. However, the synergy between vitamin D levels and comorbidities, age, and gender could affect the outcome of coronavirus disease 2019 patients.
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Article
COVID-19 is a disease that has caused a high number of deaths in the world, and despite being controlled, it requires attention and the search for new quick and economical therapeutic strategies. In this sense, vitamin D stands out, an immunomodulator that has shown beneficial effects in decreasing the risk and severity of acute respiratory tract infections, including COVID-19. Therefore, this review presents a number of experimental, observational and clinical studies on the importance of vitamin D against viral infections with an emphasis on COVID-19, highlighting the relationship between vitamin D, Renin-Angiotensin System and cytokine storms with decreased inflammatory lesions in patients with COVID-19. In addition, aspects of pathophysiology, metabolism, risk factors, sources and recommendations of vitamin D are described. We conclude that vitamin D plays a protective role against inflammatory lesions and can decrease the risk of infections and the severity of COVID-19. Therefore, it is essential to maintain adequate levels of vitamin D to avoid complications related to its deficiency.
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Article
Vitamin D deficiency, which impedes good immune function, is common during winter and spring in regions of high latitude. There is good evidence that vitamin D deficiency contributes to the seasonal increase of virus infections of the respiratory tract, from the common cold to influenza, and now possibly also COVID-19. This communication explores key factors that make it more likely, particularly in combination, that individuals are vitamin D deficient. These factors include old age, obesity, dark skin tone and common genetic variants that impede vitamin D status. Precision nutrition is an approach that aims to consider known personal risk factors and health circumstances to provide more effective nutrition guidance in health and disease. In regard to avoiding vitamin D deficiency, people with excess body fat, a dark skin tone or older age usually need to use a moderately dosed daily vitamin D supplement, particularly those living in a high-latitude region, getting little ultraviolet B exposure due to air pollution or staying mostly indoors. Carriers of the GC (group-specific component) rs4588 AA genotype also are more likely to become deficient. Very high-dosed supplements with more than 4000 IU vitamin D are rarely needed or justified. A state-by-state Mendelian randomisation analysis of excess COVID-19 mortality of African-Americans in the USA shows a greater disparity in northern states than in southern states. It is conceivable that vitamin D adequacy denies the virus easy footholds and thereby slows spreading of the contagion. This finding should drive home the message that vitamin D supplementation is particularly important for individuals with dark skin tones. Vitamin D deficiency, even for a few months during the winter and spring season, must be rigorously remedied because of its many adverse health impacts that include decreased life expectancy and increased mortality. Slowing the spread of COVID-19 would be an added bonus.
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Background Vitamin D is a micronutrient which is essential to help maintain bone and musculoskeletal health 1. However, recent research has highlighted a crucial supportive role for vitamin D in immune cell function, particularly in modulating the inflammatory response to viral infection 2,3. At a cellular level, vitamin D modulates both the adaptive and innate immune system through cytokines and regulation of cell signalling pathways 4. Vitamin D receptor (VDR) is present on both T and B immune cells; Vitamin D modulates the proliferation, inhibition and differentiation of these cells 5. In experimental models of lipopolysaccharide-induced inflammation, vitamin D is associated with lower concentrations of the pro-inflammatory cytokine Interleukin-6 (IL-6) 6 , which plays a significant role in Covid-19 induced acute respiratory distress syndrome (ARDS) 7. Vitamin D also reduces lipolysaccharide-induced lung injury in mice by blocking Abstract Background Recent research has indicated that vitamin D may have immune supporting properties through modulation of both the adaptive and innate immune system through cytokines and regulation of cell signalling pathways. We hypothesize that vitamin D status may influence the severity of responses to Covid-19 and that the prevalence of vitamin D deficiency in Europe will be closely aligned to Covid-19 mortality.
Article
Background Many reports on coronavirus disease 2019 (Covid-19) have highlighted age- and sex-related differences in health outcomes. More information is needed about racial and ethnic differences in outcomes from Covid-19. Methods In this retrospective cohort study, we analyzed data from patients seen within an integrated-delivery health system (Ochsner Health) in Louisiana between March 1 and April 11, 2020, who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus that causes Covid-19) on qualitative polymerase-chain-reaction assay. The Ochsner Health population is 31% black non-Hispanic and 65% white non-Hispanic. The primary outcomes were hospitalization and in-hospital death. Results A total of 3626 patients tested positive, of whom 145 were excluded (84 had missing data on race or ethnic group, 9 were Hispanic, and 52 were Asian or of another race or ethnic group). Of the 3481 Covid-19–positive patients included in our analyses, 60.0% were female, 70.4% were black non-Hispanic, and 29.6% were white non-Hispanic. Black patients had higher prevalences of obesity, diabetes, hypertension, and chronic kidney disease than white patients. A total of 39.7% of Covid-19–positive patients (1382 patients) were hospitalized, 76.9% of whom were black. In multivariable analyses, black race, increasing age, a higher score on the Charlson Comorbidity Index (indicating a greater burden of illness), public insurance (Medicare or Medicaid), residence in a low-income area, and obesity were associated with increased odds of hospital admission. Among the 326 patients who died from Covid-19, 70.6% were black. In adjusted time-to-event analyses, variables that were associated with higher in-hospital mortality were increasing age and presentation with an elevated respiratory rate; elevated levels of venous lactate, creatinine, or procalcitonin; or low platelet or lymphocyte counts. However, black race was not independently associated with higher mortality (hazard ratio for death vs. white race, 0.89; 95% confidence interval, 0.68 to 1.17). Conclusions In a large cohort in Louisiana, 76.9% of the patients who were hospitalized with Covid-19 and 70.6% of those who died were black, whereas blacks comprise only 31% of the Ochsner Health population. Black race was not associated with higher in-hospital mortality than white race, after adjustment for differences in sociodemographic and clinical characteristics on admission.
Article
Background The Bergamo province, which is extensively affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, is a natural observatory of virus manifestations in the general population. In the past month we recorded an outbreak of Kawasaki disease; we aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic. Methods All patients diagnosed with a Kawasaki-like disease at our centre in the past 5 years were divided according to symptomatic presentation before (group 1) or after (group 2) the beginning of the SARS-CoV-2 epidemic. Kawasaki- like presentations were managed as Kawasaki disease according to the American Heart Association indications. Kawasaki disease shock syndrome (KDSS) was defined by presence of circulatory dysfunction, and macrophage activation syndrome (MAS) by the Paediatric Rheumatology International Trials Organisation criteria. Current or previous infection was sought by reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swabs, and by serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively. Findings Group 1 comprised 19 patients (seven boys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed between Jan 1, 2015, and Feb 17, 2020. Group 2 included ten patients (seven boys, three girls; aged 7·5 years [SD 3·5]) diagnosed between Feb 18 and April 20, 2020; eight of ten were positive for IgG or IgM, or both. The two groups differed in disease incidence (group 1 vs group 2, 0·3 vs ten per month), mean age (3·0 vs 7·5 years), cardiac involvement (two of 19 vs six of ten), KDSS (zero of 19 vs five of ten), MAS (zero of 19 vs five of ten), and need for adjunctive steroid treatment (three of 19 vs eight of ten; all p<0·01). Interpretation In the past month we found a 30-fold increased incidence of Kawasaki-like disease. Children diagnosed after the SARS-CoV-2 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS. The SARS-CoV-2 epidemic was associated with high incidence of a severe form of Kawasaki disease. A similar outbreak of Kawasaki-like disease is expected in countries involved in the SARS-CoV-2 epidemic. Funding None.
Article
In 2019-2020 a new coronavirus named SARS-CoV-2 was identified as the causative agent of a several acute respiratory infection named COVID-19, which is causing a worldwide pandemic. There are still many unresolved questions regarding the pathogenesis of this disease and especially the reasons underlying the extremely different clinical course, ranging from asymptomatic forms to severe manifestations, including the Acute Respiratory Distress Syndrome (ARDS). SARS-CoV-2 showed phylogenetic similarities to both SARS-CoV and MERS-CoV viruses, and some of the clinical features are shared between COVID-19 and previously identified beta-coronavirus infections. Available evidence indicate that the so called “cytokine storm” an uncontrolled over-production of soluble markers of inflammation which, in turn, sustain an aberrant systemic inflammatory response, is a major responsible for the occurrence of ARDS. Chemokines are low molecular weight proteins with powerful chemoattractant activity which play a role in the immune cell recruitment during inflammation. This review will be aimed at providing an overview of the current knowledge on the involvement of the chemokine/chemokine-receptor system in the cytokine storm related to SARS-CoV-2 infection. Basic and clinical evidences obtained from previous SARS and MERS epidemics and available data from COVID-19 will be taken into account.
Article
Background Coronavirus disease 2019 (Covid-19) may disproportionately affect people with cardiovascular disease. Concern has been aroused regarding a potential harmful effect of angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in this clinical context. Methods Using an observational database from 169 hospitals in Asia, Europe, and North America, we evaluated the relationship of cardiovascular disease and drug therapy with in-hospital death among hospitalized patients with Covid-19 who were admitted between December 20, 2019, and March 15, 2020, and were recorded in the Surgical Outcomes Collaborative registry as having either died in the hospital or survived to discharge as of March 28, 2020. Results Of the 8910 patients with Covid-19 for whom discharge status was available at the time of the analysis, a total of 515 died in the hospital (5.8%) and 8395 survived to discharge. The factors we found to be independently associated with an increased risk of in-hospital death were an age greater than 65 years (mortality of 10.0%, vs. 4.9% among those ≤65 years of age; odds ratio, 1.93; 95% confidence interval [CI], 1.60 to 2.41), coronary artery disease (10.2%, vs. 5.2% among those without disease; odds ratio, 2.70; 95% CI, 2.08 to 3.51), heart failure (15.3%, vs. 5.6% among those without heart failure; odds ratio, 2.48; 95% CI, 1.62 to 3.79), cardiac arrhythmia (11.5%, vs. 5.6% among those without arrhythmia; odds ratio, 1.95; 95% CI, 1.33 to 2.86), chronic obstructive pulmonary disease (14.2%, vs. 5.6% among those without disease; odds ratio, 2.96; 95% CI, 2.00 to 4.40), and current smoking (9.4%, vs. 5.6% among former smokers or nonsmokers; odds ratio, 1.79; 95% CI, 1.29 to 2.47). No increased risk of in-hospital death was found to be associated with the use of ACE inhibitors (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54) or the use of ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74). Conclusions Our study confirmed previous observations suggesting that underlying cardiovascular disease is associated with an increased risk of in-hospital death among patients hospitalized with Covid-19. Our results did not confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital death in this clinical context. (Funded by the William Harvey Distinguished Chair in Advanced Cardiovascular Medicine at Brigham and Women’s Hospital.)