Vitamin-D an Immune Shield Against nCOVID-19

Abstract

Presently the world is battling a deadly pandemic without any effective licenced drugs or biologics to vanquish SARS-CoV-2. The experience of managing the past viral aetiological outbreaks has been extrapolated to nCOVID-19, yet its effectiveness is uncertain. This connotation invokes a potential insight to focus upon those elements and etiquettes which are an integral part of our life and expound for nCOVID-19 treatment. This further impels us to consider our food as a time-tested medicine. In a study, a decrease in Vitamin-D levels accounted for the bovine coronavirus infection in calves. Interestingly it paves the way for exploring the role of Vitamin-D as an accessible ‘magic bullet’ against nCOVID-19. Currently, its metabolism and immunomodulatory characterization are well-established. In fact, the studies have described an inverse relationship between Vitamin-D level and respiratory infections. This further substantiates for understanding its shielding effect against nCOVID-19. Few researchers have recommended dosage of Vitamin-D intake among adult and high-risk individuals including front-liners. However, the enforcement of this potent nutritional ergogenic calls for dose rationalisation with due effectivity and safety based on large randomized controlled trials.

Full text

IJCRR
Section: Healthcare
Sci. Journal Impact
Factor: 6.1 (2018)
ICV: 90.90(2018)
Review Article
Vitamin-D: An Immune Shield
Against nCOVID-19
Madhan Jeyaraman1, Arun Gulati2, Talagavadi Channaiah Anudeep3,
Dharma U Shetty4, Latha S5, Ajay SS6, Rashmi Jain7, Madhurya Santosh8
1
Senior
Resident,
Department
of
Orthopedics,
School
of
Medical
Sciences
and
Research,
Sharda
University,
Greater
Noida,
Uttar
Pradesh,
India;
2
Senior
Resident,
Department
of
Orthopedics,
Kalpana
Chawla
Government
Medical
College
&
Hospital,
Karnal,
Haryana,
India;
3
Senior
Resident,
Department
of
Plastic
Surgery,
Topiwala
National
Medical
College
and
BYL
Nair
Ch.
Hospital,
Mumbai,
Maharas
htr
a,
India;
4
Senior
Resident,
Department
of
Pulmonary
Medicine,
St.
John's
Medical
College,
Bengaluru,
Karnataka,
India;
5
Senior
Resident,
Department
of
Pharmacology,
Hassan
Institute
of
Medical
Sciences,
Hassan,
Karnataka,
India;
6
Junior
Resident,
Department
of
Orthopedics,
JJM
Medical
College,
Davangere,
Karnataka,
India;
7
Resident,
School
of
Medical
Sciences
and
Research,
Sharda
University,
Greater
Noida,
Uttar
Pradesh,
India;
8
Junior
Resident,
Department
of
Dermatology,
Rajarajeswari
Medical
college
&
Hospital,
Bengaluru,
Karnataka,
India.
ABSTRACT
Presently the world is battling a deadly pandemic without any effective licenced drugs or biologics to vanquish SARS-CoV-2.
The experience of managing the past viral aetiological outbreaks has been extrapolated to nCOVID-19, yet its effectiveness is
uncertain. This connotation invokes a potential insight to focus upon those elements and etiquettes which are an integral part
of our life and expound for nCOVID-19 treatment. This further impels us to consider our food as a time-tested medicine. In a
study, a decrease in Vitamin-D levels accounted for the bovine coronavirus infection in calves. Interestingly it paves the way
for exploring the role of Vitamin-D as an accessible ‘magic bullet’ against nCOVID-19. Currently, its metabolism and
immunomodulatory characterization are well-established. In fact, the studies have described an inverse relationship between
Vitamin-D level and respiratory infections. This further substantiates for understanding its shielding effect against nCOVID-19.
Few researchers have recommended dosage of Vitamin-D intake among adult and high-risk individuals including front-liners.
However, the enforcement of this potent nutritional ergogenic calls for dose rationalisation with due effectivity and safety based
on large randomized controlled trials.
Key Words: Coronavirus, nCOVID-19, Vitamin D, Magic Bullet, Immunomodulator
INTRODUCTION
The world is witnessing the tight grip of the deadly pandemic
caused by the newly identified strain of Coronavirus (SARS-
CoV-2/nCOVID-19).1 Currently, no specific drugs or
biologics are available against nCOVID-19. However, the
evidence from past viral outbreaks (SARS-CoV-1, MERS-
CoV, EBOV and Influenza) have been extrapolated to
combat SARS-CoV-2; yet the efficacy remains uncertain.2 It
was found that a decrease in vitamin D in calves accounted
as the prime cause of bovine coronavirus infection
previously. This leads to plausible insight for exploring and
understanding the role of vitamin D against SARS-CoV-2 in
order to optimize it as a potent nutritional ergogenic for the
same. Vitamin D is a steroid hormone (also called sunshine
-hormone) synthesized endogenously from UV-B radiation to
the skin or as exogenous supplements from an animal source or
fortified food. The complex synthesis and its metabolism is well
established. It confers essential benefits in bone and muscle
health, helps in immune functioning by defying inflammation
and prevents respiratory infection.1 Various studies and
researches provide us with evidence of immunogenic and anti-
microbial properties of Vitamin-D.3,4 Vitamin D deficiency is
seen in those who get limited exposure to sunlight or inadequate
intake of vitamin D. The high-risk group also includes
individuals with chronic lung disease, obesity and those who are
physically inactive. Studies have shown an inverse relationship
between Vitamin D level and respiratory infection. This article
provides an insight into how Vitamin D can act as an
Int J Cur Res Rev | Vol 12 • Issue 09 • May 2020
19
Corresponding Author:
Dr. Arun Gulati, Senior Resident, Department of Orthopedics, Kalpana Chawla Government Medical College & Hospital, Karnal,
Haryana, India. Ph: +91 93817 28903; E-mail: gulati_arun123@yahoo.com
ISSN: 2231-2196 (Print) ISSN: 0975-5241 (Online)
Received: 27.04.2020 Revised: 01.05.2020 Accepted: 03.05.2020
International Journal of Current Research and Review
DOI: http://dx.doi.org/10.31782/IJCRR.2020.12095

Jeyaraman et.al: Vitamin-D an immune shield against nCOVID-19
immune shield in respiratory infections like nCOVID-19 and
substantiate for supplementary benefits for the front line
warriors, high-risk population and general adult population.
Vitamin D – Metabolism and Absorption
Vitamin D was first characterized as a vitamin in the 20th
century and now it is recognized as a prohormone. The two
important forms of vitamin D are vitamin D2 (ergocalciferol)
and vitamin D3 (cholecalciferol) respectively.1
Sources: Vitamin D3 is synthesized endogenously in the skin by
epidermis and dermis containing 7- dehydrocholesterol (DHC).
Then UV-B radiation (280–310 nm) passes through these skin
layers, 7- dehydrocholesterol absorbs UV-B photons and gets
converted to pre-vitamin D3 (precalciferol). This
photoisomerization is followed by thermal-dependent
isomerization of the pre vitamin D3, leading to the formation of
the vitamin D3 molecule, also known as cholecalciferol. Once
formed, vitamin D3 is bound preferentially to the vitamin D
binding protein (DBP), which allows its translocation into the
general circulation.5 The exogenous source of vitamin D
includes dietary supplementation through animal-based food
(mainly fish oils contain vitamin D3) or fortified food. On the
other hand, plant derivatives contain vitamin D2. Moreover,
fungi and mushrooms irradiated with UV-B also contain
vitamin D2.6
Metabolism: The complex process of Vitamin-D synthesis,
mechanism of action and absorption is explicably depicted in
Figure 1. The ‘hydroxylation reaction’ is the key biochemical
process involved in conversion into active form; calcitriol (1,25-
dihydroxycholecalciferol). This hydroxylation is mediated via
cytochrome P450 mixed-function oxidases (CYPs) located
either in the endoplasmic reticulum (ER) (e.g. CYP2R1) or in
the mitochondria (e.g. CYP27A1, CYP27B1 and CYP24A1).7
Figure 1: Metabolism and effects of Vitamin D in target organs.
(Pic courtesy: Michael F. Holick. Resurrection of vitamin D
deficiency and rickets. J Clin Invest. 2006;116(8):2062-20728)
Calcitriol acts through the vitamin D receptor (VDR),
belonging to the nuclear receptor superfamily.7 The
absorption of dietary Vitamin-D2 or D3 usually occurs in
the small intestine with other dietary fats wherein the
following subsets of processes for packaging exogenous
Vitamin-D into chylomicrons occurs, and thereafter they
are transported to the liver. A fraction of the vitamin D
contained in the chylomicron can be taken up by the
adipose tissue and skeletal muscle and the remaining
chylomicrons reach the liver via specific carrier protein i.e.
vitamin D binding protein (DBP) which in turn also
facilitates their transport to different tissues as per
requirement.6 Calcitriol is mainly involved in the regulation
of plasma calcium and phosphate levels along with PTH by
acting on three major organs i.e. intestine, kidney and bone
(as shown in figure 1).6,7,8
Vitamin D – An Immune Shield
Vitamin D prevents respiratory infection by strengthening
and regularizing physical barrier, cellular innate immunity
and adaptive immunity (as shown in Figure 2).
Figure 2: Vitamin D as Immune Shield.
(Pic courtesy: MirentxuIruretagoyena, Daniela Hirigoyen,
Rodrigo Naves and Paula Isabel Burgos. Immune response
modulation by vitamin D: role in systemic lupus
erythematosus. Frontiers in Immunology. 2015;6:5139)
Physical barrier: Vitamin D acts as a physical barrier by
maintaining the integrity of the skin epithelium. It
upregulates genes via the 1α-hydroxylase enzyme, which
helps in the maintenance of tight junctions (occludins), gap
junctions (connexion-43), and adherens junctions (E-
cadherin) (as shown in Figure 3).
Viral infections resulting in subsequent bacterial
superinfections is well documented. The molecules
upregulated by the viral pathogen may serve as receptors for
bacteria and may result in this superinfection. Influenza
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Jeyaraman et.al: Vitamin-D an immune shield against nCOVID-19
Figure 3: Immunological functions of Vitamin D.
and parainfluenza viruses possess neuraminidase (NA)
activity, which appears to increase bacterial adherence after
viral preincubation.10 Tight junctions and adherens junctions
also prevent viruses from crossing the epithelial barrier.
However, viruses have adopted multiple strategies wherein
they utilize components of cell–cell adhesion structures as
receptors thus blazing their path through the epithelium.
Viruses take advantage of the apical junction complex to
spread. Whereas some viruses quickly disrupt epithelial
integrity, others carefully preserve it and use cell adhesion
proteins and their cytoskeletal connections to rapidly spread
laterally. This is exemplified by the hidden transmission of
enveloped viruses that use nectins as receptors (as shown in
Figure 4).11
Figure 4: Viruses use junctional proteins as receptors.
(Pic courtesy: Mateo M, Generous A, Sinn PL, Cattaneo R.
Connections matter− how viruses use cell–cell adhesion
components. Journal of cell science. 2015;128(3):431-911)
Cellular immunity: Vitamin D potentiates cellular innate
immunity through the induction of antimicrobial peptides,
including human cathelicidin LL-37 and β defensin, which
exist in neutrophils, monocytes, natural killer (NK) cells and
epithelial cells lining the respiratory tract.12 Cathelicidins
possess direct antimicrobial activities against a spectrum of
microbes, (gram-positive & negative bacteria, mycobacteria,
enveloped & non-enveloped viruses, protozoa and fungi) which
percolate cell membrane. They also neutralize the activity of
microbial endotoxins (as shown in Figure 5).13–15 Jeng et al.
demonstrated that systemic LL-37 levels may be regulated by
vitamin D status in acutely ill patients.16 Vitamin D enhances
chemotaxis and phagocytic ability of innate immune regulatory
cells.17
Figure 5: Antimicrobial effect of Vitamin D.
(Pic courtesy: Hewison, M. Antibacterial effects of vitamin
D. Nat Rev Endocrinol. 2011;7:337–34515)
Vitamin D mediates antioxidant property by enhancing
the upregulation of glutathione reductase genes and
glutamate–cysteine ligase modifier subunit genes which
prevent the microbial infection.18 Jain et al. reported that
glutathione upregulates vitamin D regulatory genes and
lowers oxidative stress & inflammation.19 Vitamin D
enhances the innate cellular immunity by reducing the
cytokine storm wherein it decreases the expression of pro-
inflammatory cytokines and increases the expression of anti-
inflammatory cytokines mediated by macrophages.20
Adaptive immunity: Vitamin D acts as a “Magic Bullet” in
modulating the adaptive immunity.21 Vitamin D3 (a)
suppresses T helper type 1 (Th1) cell-mediated responses by
primarily repressing production of IL-2 and INF-γ, (b)
upregulates T helper type 2 (Th2) cells, which indirectly
suppresses Th1 cells and (c) promotes induction of the T
regulatory cells, thereby inhibiting the inflammatory
process.21 The immunomodulatory activities of vitamin D are
depicted in Figure 6.
21
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Jeyaraman et.al: Vitamin-D an immune shield against nCOVID-19
Disease Vitamin D effects
Table 1: Effects of vitamin D
concentration
among viral agents
Dengue Inverse association between 25(OH)D3 concen-
tration and progression of the disease state.27
Vitamin D supplementation trials with 1000
and 4000 IU/day were started.
Figure 6: Immunomodulation effects of Vitamin D.
Dendritic cells (DCs) are the chief antigen-presenting cells
(APCs). They help in maintaining peripheral tolerance by
preventing self-reactive T cells from causing autoimmune
damage through an adaptive immune response. That’s how
DCs play a critical role against infectious agents and
tumours. DCs have a role in peripheral T cell tolerance, by
inducing T cell anergy or unresponsiveness to self-antigens.
Differentiation of tolerogenic dendritic cells is induced by
Vit-D.22 Due to the central tolerogenic activity of DCs, when
there is low serum Vitamin-D concentration, there is a risk of
development of autoimmune diseases.23
H9N2 Influ-
enza
Respiratory
Syncytial
Virus
4000 IU/day resulted in higher resistance to
DENV-2 infection.
Monocyte-derived dendritic cells (MDDCs)
from those supplemented with 4000 IU/day
showed decreased mRNA expression of TLR3,
7, and 9; downregulation of IL-12/IL-8
production; and increased IL-10 secretion in
response to DENV-2 infection.28
In a lung epithelial cell study, calcitriol treat-
ment prior to and post infection with H9N2
influenza significantly decreased expression of
the influenza M gene, IL-6, and IFN-β in A549
cells, but did not affect virus replication.29
T-allele of the vitamin D receptor has a lower
prevalence in African populations and runs
parallel to the lower incidence of RSV-
associated severe ALRI in African children.30
Relationship between vitamin D and viral
diseases
Seasonal influenza, which peaks in the winter, has a high
health impact on the population and poses a public health
problem. According to GLaMOR Project (2019), 389,000
(uncertainty range 294,000–518,000) respiratory deaths were
associated with influenza during the period 2002–2011.24
Cannell et al. hypothesized that the winter peak of infection
was due to the seasonal changes as the solar UV-B doses are
less in the winter leading to lesser vitamin D concentration,
in most mid and high latitude countries.25 Gruber-Bzura BM
(2018) suggested that vitamin D should reduce the risk of
influenza, but more studies are required to evaluate this
plausibility.26
An observational study conducted in Connecticut on 198
healthy adults concluded that concentrations of 38 ng/mL or
more were associated with a significant (p < 0.0001) two-
fold reduction in the risk of developing ARTIs and with a
marked reduction in the percentage of days ill.27 Evidence
from the effects of vitamin D concentration among viral
agents were shown in the following Table 1.
Postmenopausal women residing in Long Island, NY with
mean baseline 25(OH)D concentration 19±8 ng/mL were
included in a clinical trial wherein it was reported that
supplementation with 2000 IU/day accounted for lesser
number of cases of upper respiratory tract infections,
including influenza, than a placebo or supplementation with
800 IU/day.32
Martineau AR et al. reported that 25(OH)D3 concentrations
of 20–30 ng/mL reduced the risk of ARTIs.3 Sabetta JR et al.
conducted an observational study wherein they found 38
ng/mL as the appropriate concentration for reducing the risk
of Community Acquired Pneumonia.27 Vitamin D
supplementation for raising serum 25(OH)D3 concentrations
can help in the reduction of hospital-associated infections
(HAIs).33
Although the level of protection generally spikes with the
spiking of 25(OH)D3 concentration, the optimal range
appears to be 40–60 ng/mL (100–150 nmol/l) for the same.
In order to achieve those levels, a study reported that it calls
for administering approximately half of the population with
at least 2000–5000 IU/day of vitamin D3 respectively.34
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Jeyaraman et.al: Vitamin-D an immune shield against nCOVID-19
Relationship between Vitamin D and nCOVID-19
The world distribution of nCOVID-19 fatalities appears to
overlap with that of the vitamin D lacking population.35
Epidemiological studies have shown that people with low
vitamin D levels have a higher risk of acute respiratory tract
infection and community-acquired pneumonia.3
Grant WB et al. recommended that people at risk of influenza
and/or nCOVID-19 should consider taking 10,000 IU/day of
vitamin D3 for a few weeks to rapidly raise 25(OH)D3
concentrations, followed by 5000 IU/day. “The goal should
be to raise 25(OH)D3 concentrations above 40–60 ng/mL
(100–150 nmol/L),” the team adds. “For treatment of people
who become infected with nCOVID-19, higher vitamin D3
doses might be useful”.4
The correction of vitamin D deficiency is thought to suppress
CD26, a putative adhesion molecule for nCOVID-19 host
cell invasion. Vitamin D may also attenuate interferon
gamma (IFN-γ) and interleukin-6 (IL-6) inflammatory
responses, both potent predictors of poorer outcome in
critically-ill ventilated patients including those with
nCOVID-19.36-38
In the expanding face of the nCOVID-19 pandemic, and
in the absence of a vaccine or any effective anti-viral drug
therapy to treat those infected, these findings call for the
prioritized supplementation of all hospital in patients,
nursing home residents and community-dwelling older adults
with vitamin D at a minimum daily dose of 20 micrograms
per day. It is further recommended that supplementation be
targeted at other vulnerable constituencies (e.g. those with
diabetes mellitus or compromised immune function, those
with darker skin, vegetarians and vegans, those who are
overweight or obese, smokers and healthcare workers), and
ultimately extended to rest of the population in order to
mitigate the grave public health risks associated with
nCOVID-19 infection.39
DISCUSSION
Our life has come to a standstill due to the rampant spread of
the novel coronavirus. The ever-pacing life of each and every
individual has now been turned up-side- down. What is more
saddening is that till date we haven’t been able to direct our
specific medical armours (drugs & biologics) effectively
and also we are striving hard to address the efficacy and
safety concerns rationalised for curbing this contagion. This
gives us an opportunity to expand our insight to focus upon
those elements and etiquettes which are an integral part of our
life and expound for nCOVID-19 treatment. We, the authors
of this article staunchly agree with this famous quotation “Let
your food be your medicine” by Hippocrates, the father of
Medicine. The food we eat contributes a substantial
amount to our body’s healthy functioning. The food rich in
all the nutrients, what we call as balanced diet adjuncts for
being an ever-green medicine. And this framework made us
inquire into how the most deficit reported vitamin i.e.
Vitamin-D can boost our fight against nCOVID-19. Can this
act as an easily accessible “magic bullet”? If it has any role in
conferring immunity? Is there any specific role of Vitamin D
in combating respiratory infections? To add, if we can
extrapolate this as a prophylaxis or treatment against
nCOVID-19. And finally, if it will be beneficial for any
specific population, and if it is, to tabulate the optimum dose.
These are some potential questions which we have explicably
addressed in this review article.
Vitamin-D, also known as the sunshine vitamin is readily
accessible from 10-15 minutes of exposure to sunlight,
whereby upon absorption it undergoes a complex metabolic
procedure relayed at liver and kidney for making it available
in the active form (Calcitriol; 1,25-dihydroxycholecalciferol).
It can also be exogenously supplemented from an animal
source or fortified food. This vitamin is further known to
regulate calcium metabolism and plays an important role in
strengthening the skeletal system. Some research analysis also
accounts that its deficiency during pregnancy can result in
preterm delivery.
The individuals who are deficient in Vitamin-D are
susceptible to infections and it has been proved that it is more
so in the elderly in whom this deficiency is more common.
Recent research has highlighted that it may have an important
role in regulating the immune system. The immune response
with advancing age swiftly inclines towards pro-
inflammatory state accentuating chronic low-level
inflammation with the progression of the disease. This age-
associated state is regarded as ‘inflammaging’. Notably, this
also plays a crucial role in preventing respiratory infections as
per recent research. The mechanism recognised involves the
interplay of physical barrier, innate cellular immunity and
adaptive immunity respectively. In conjunction, these
function to downregulate the inflammatory factors and
further attenuate the cytokine storm phenomenon. This
storming phenomenon of cytokines accounts for morbidity
and mortality in the underlying infective condition which has
been discussed in detail in this review.
SARS-CoV-2 emerged as ‘pneumonia of unknown
aetiology’; later mechanism of entry into the host cell
portrays it as respiratory virus primarily. Serum vitamin D
concentrations tend to decrease with age, which may be
important for nCOVID-19 as case-fatality rates (CFRs)
increase with age. By increasing the upregulation of
glutathione, vitamin D is being hypothesized to prevent and
treat nCOVID-19.
23
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Jeyaraman et.al: Vitamin-D an immune shield against nCOVID-19
In view of this, several clinical trials are afoot for optimising
Vitamin-D as a potential option. A recent study from Ireland
identified Vitamin-D as the potent immuno-modifier which
can be used in individuals who are above 70 years and
‘cocooning’ during this outbreak. The recommendations
include 10ug/day (400 IU) from the diet during winters. But
since the level in the diet is lower than this, 10ug/day
supplementation can be taken and for those who are
housebound due to quarantine, additional supplementation of
15-20 ug/ day (600-800 IU) is advised. Persons over 70 years
are recommended to take 20-25 ug/day (800-1000 IU)
respectively.4
In another study, a team from the US recommended taking
10,000 IU/d of vitamin D3 for a few weeks to raise 25(OH)
D3 concentrations rapidly followed by 5000 IU/d
respectively. They defined that the purpose should be to raise
25(OH)D3 concentrations to 40–60 ng/mL (100–150
nmol/L), and recommended higher doses for individuals
who are infected with COVID-19.40
With this background, considering all the evidence-based
literature reviewed above, we postulate that Vitamin-D may
be administered as chemoprophylaxis to all the front-liners
and can also be considered as an add-on supplement in
hospitalised nCOVID-19 patients after dose optimization.
CONCLUSION
The world is witnessing the tremendous contagiosity of
nCOVID-19 wherein the greatest challenge is being
confronted by the medical fraternity. Clinical evaluation and
trials are pacing globally to come-up with specific drugs or
biologics for nCOVID-19 treatment. Amidst all, it is
equivalently significant to understand and practice healthy
eating habits. The available literature beautifully enlightens
us with the imperative role of diet and how these biochemical
molecules boost up an individual’s immunity; further
rendering a shielding effect against infections. In this
connotation, Vitamin-D has been studied and further
extrapolated for nCOVID-19 treatment. The immuno-
modulatory property has been outlined with a positive
outlook for chemoprophylaxis and combination therapy. This
surely will be beneficial for high-risk candidates; however,
the dose optimization for the optimum benefits and efficacy
should be re-enforced based on large randomized controlled
trials. Some clinical trials are underway; in the interim, the
recommended daily allowance can be regarded as a safe play.
Clinicians should thus advocate wisely in relation to the
rapidly emerging views on nCOVID-19 treatment.
ACKNOWLEDGEMENTS
All the authors have equally contributed in framing and re-
viewing the manuscript. Authors acknowledge the immense
help received from the scholars whose articles are cited and
included in references of this manuscript. The authors are also
grateful to authors / editors / publishers of all those articles,
journals and books from where the literature for this article has
been reviewed and discussed. We thank Dr. Shirodkar Jaswandi
Dilip, Medical Officer, ESIS hospital (Worli), Mumbai,
Maharashtra, India, Dr. Naveen Jeyaraman, Junior Resident of
Orthopedics, Kasturba Medical College, Manipal, Karnataka,
India, and Dr. Prajwal GS, Junior Resident of Orthopedics, JJM
Medical College, Davangere, Karnataka, India for literature
search regarding nCOVID-19.
Conflicts of interest:Nil
Funding sources:Nil
Abbreviation: APC – Antigen Presenting Cells; DC –
Dendritic Cells; DHC – Dehydrocholesterol; DBP – vitamin
D-Binding Protein; EBOV – Ebola Virus; NK cells – Natural
Killer cells; NA – Neuraminidase; UV-B – Ultraviolet – B;
VDR – Vitamin D Receptor
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Int J Cur Res Rev | Vol 12 • Issue 09 • May 2020