Vitamin D: A cheap yet effective bullet against coronavirus disease-19 - Are we convinced yet?

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DOI: 10.5455/njppp.2020.10.05132202024052020
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Abstract
Novel corona virus disease (COVID-19) pandemic has seriously affected the entire world; moreover, infection and case fatality rate is quite high in countries located in North Hemisphere, where a large proportion of the population is living with Vitamin D (Vit D) deficiency. Vit D is a secosteroid hormone, which plays an important role in calcium and phosphorous homeostasis, and hence bone strength and also has a significant role in the immune health of an individual. It induces the expression of antimicrobial peptides that can decrease viral replication and also reduces the level of pro-inflammatory cytokines while enhancing the level of anti-inflammatory cytokines. Vit D supplementation in daily single doses (300–2000 IU/day) for 8–12 weeks had more protective effect for viral infections than large doses given at fixed intervals (100,000 or 200,000 IU per month or every 3 months). This evidence based review emphasizes the role of Vit D in the immune response to viral infections and proposes the immense value of Vit D supplementation, for the prevention and treatment of COVID-19.
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1 National Journal of Physiology, Pharmacy and Pharmacology 2020 | Vol 10 | Issue 07 (Online First)
REVIEW ARTICLE
Vitamin D: A cheap yet effective bullet against coronavirus
disease-19 – Are we convinced yet?
Suresh K Sharma1, Shiv Kumar Mudgal1, Venkatesh S Pai2, Jitender Chaturvedi3, Rakhi Gaur1
1College of Nursing, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India, 2Department of General Medicine, All India
Institute of Medical Sciences, Rishikesh, Uttarakhand, India, 3Department of Neurosurgery, All India Institute of Medical Sciences,
Rishikesh, Uttarakhand, India
Correspondence to: Suresh K Sharma, E-mail: suresh.nur@aiimsrishikesh.edu.in
Received: May 14, 2020; Accepted: May 24, 2020
ABSTRACT
Novel corona virus disease (COVID-19) pandemic has seriously affected the entire world; moreover, infection and case
fatality rate is quite high in countries located in North Hemisphere, where a large proportion of the population is living with
Vitamin D (Vit D) deficiency. Vit D is a secosteroid hormone, which plays an important role in calcium and phosphorous
homeostasis, and hence bone strength and also has a significant role in the immune health of an individual. It induces the
expression of antimicrobial peptides that can decrease viral replication and also reduces the level of pro-inflammatory
cytokines while enhancing the level of anti-inflammatory cytokines. Vit D supplementation in daily single doses (300–2000
IU/day) for 8–12 weeks had more protective effect for viral infections than large doses given at fixed intervals (100,000 or
200,000 IU per month or every 3 months). This evidence based review emphasizes the role of Vit D in the immune response
to viral infections and proposes the immense value of Vit D supplementation, for the prevention and treatment of COVID-19.
KEY WORDS: Coronavirus Disease-19; Cytokine Storm; Immune Response; Influenza; Severe Acute Respiratory
Syndrome-Coronavirus-2; Vitamin D
INTRODUCTION
As the world is in the grip of the Coronavirus (CoV) disease
(COVID-19) pandemic, we are in the quest for measures to
reduce the morbidity and mortality associated with this highly
contagious viral infection, which emerged in Wuhan city of
China. Winter season, with the least sun exposure, was the
time of origin of this infection in China. Lesser sun exposure
during winter is associated with lesser Vitamin D (Vit D)
levels, evident in several studies.[1,2] Further, COVID-19
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pandemic has a high mortality in countries such as United
States of America (USA), Italy, Spain, United Kingdom(UK),
Switzerland, Germany, Iran, France, and Turkey, where a
significant portion of their populations live with lower level
of Vit D level.[3] USA is the most severely affected country
with COVID-19, where, according to the US National Center
for Health Statistics, an estimated 70% of individuals may
be considered Vit D deficient.[4] This signifies that Vit D
deficiency may be one of the predisposing factors in the severe
acute respiratory syndrome (SARS)-(CoV)-2 infection and
case fatality rate (CFR). CFRs rise with age and with disease
comorbidities, which are both associated with lower Vit D
levels. Air pollution is also one of the factors that affect the
ultraviolet light B (UVB) level on ground and thereby results
in Vit D deficiency,[5] which could be one of the factors that
people living in metros are more affected by COVID-19 as
compared to rural areas and poor people.
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DOI: 10.5455/njppp.2020.10.05132202024052020
Sharma et al. Vitamin D supplementation for the prevention and treatment of COVID-19
National Journal of Physiology, Pharmacy and Pharmacology 2
2020 | Vol 10 | Issue 07 (Online First)
Vit D is a steroid hormone, which plays an important role
in calcium and phosphorous homeostasis, and hence bone
strength,[6,7] and also has a significant role in the immune
health of an individual.[4] Human skin can produce Vit D
naturally, when exposed to UVB rays of sunlight. This
evidence based review emphasizes the role of Vit D in immune
response to viral infections and proposes the immense value
of Vit D supplementation, for the prevention and treatment
of COVID-19.
VIT D AND IMMUNITY
Vit D is a hormone that has critical functions for regulating
calcium-phosphate homeostasis. Apart from its conventional
role, recent evidences support its crucial role in cell
proliferation and immunomodulation.[8] Vit D is critical
for immune function. A deficiency of this nutrient may
compromise immune response and increase the risk of
infection and disease. Although there is a dearth of evidence
about the role of Vit D supplements in decreasing the risk
SARS-CoV-2 infection, having adequate serum level of Vit
D can promote immunity.[9] In addition, Vit D supplements
show protective mechanism against respiratory infections.
Studies suggested various mechanisms by which Vit D
decreases the risk of viral infection and death. It is reported
that the incidence and CFR of COVID-19 infection increased
in patients with comorbidities such as diabetes, hypertension,
chronic obstructive pulmonary disease (COPD), and areas
with higher levels of air pollution and Vit D levels are inversely
correlated with many of these factors.[7,9] A review discussed
the action of Vit D in decreasing the viral infection (common
cold) summarized the action of Vit D into three main groups:
Physical barriers, innate immunity, and adaptive immunity.[10]
Physical Barriers
Physical barriers through tight junctions, gap junctions, and
adherens junctions are the first line defense against microbes.
The proteins encoding these structures occur through
gene regulation, where Vit D has a crucial role through
1α-hydroxyls.[11-13] Vit D also promotes the production and
expression of cathelicidin and defensins which enhance
immune response.[14]
Innate Immunity
Vit D modulates innate immune response by enhancing
expression of antimicrobial peptides, cathelicidin (LL-37),
and defensins. Figure 1 explains the role of Vit D on immune
response. Cathelicidins show its antimicrobial actions against
different microorganisms, including bacteria (Gram-positive
and Gram-negative), viruses (enveloped and non-enveloped)
and fungi.[15] These peptides destroy the invading infectious
agents by damaging the cell membranes and also neutralize
the effects of endotoxins released by them.[16]
Vit D stimulates monocyte maturation to macrophage and
thus promotes immunoglobulin and complement-mediated
phagocytosis. Furthermore, it supports to maintain self-
tolerance by diminishing an overactive adaptive immune
system.[17] Studies have shown that Vit D decreases the
replication of viruses including that of influenza A,[18]
rotavirus,[19] and dengue.[20] Vit D is also effective in decreasing
the cytokine storm that is caused by innate immune response,
against viral and other microbial infection, as seen in SARS-
CoV-2 patients.[21]
Adaptive Immunity
It is evident from human studies that Vit D modulates adaptive
immune responses. Vit D plays a key role in decreasing
production of pro-inflammatory T-helper cells type 1 (Th1)
cytokines, including tumor necrotic factor, interleukin-2
(IL-2), granulocyte-macrophage colony-stimulating factor,
and interferon, thus diminishing Th1 mediated autoimmunity.
Furthermore, 1,25 (OH)2 D3 enhance the synthesis of Th2
cells, and their anti-inflammatory Th2 cytokines, IL-4, IL-5,
and IL-10.[22] In addition, Vit D increases the production of
regulatory T cells, decreases production of IgG, and inhibits
dendritic cell differentiation.[10,23,24]
Cathelicidins
Damage microbial cell membranes (ex. Bacteria)
Decrease viral replication
Decrease production of pro-inflammatory cytokines
Vitamin D
Cathelicidins Defensins
Vit. D
TLRs
Microbial cell wall
Antimicrobial Peptide
Figure 1: Association of Vitamin D with viral infections
Sharma et al. Vitamin D supplementation for the prevention and treatment of COVID-19
3 National Journal of Physiology, Pharmacy and Pharmacology 2020 | Vol 10 | Issue 07 (Online First)
Mortality of the COVID-19 patient is attributed to an
overzealous immune response causing an inflammatory
maelstrom, a cytokine storm, which seriously damages the
lungs resulting in an acute respiratory distress syndrome
(ARDS). Vit D has shown a crucial role not only in enhancing
innate immune response but also applies brakes to a racing
immune response. This suggests that having adequate serum
levels of Vit D could protect patients against the most sinister
complications and death from SARS-CoV-2.[25]
Vit D also increases expression of genes associated with anti-
oxidation (glutathione reeducates and glutamate–cysteine ligase
modifier subunit).[26] The enhanced production of glutathione
allows the utilization of ascorbic acid that has antimicrobial
actions and has been suggested to protect the patients with
COVID-19.[27-29] Moreover, Dr. Tom Frieden, a former director
of CDC, suggested the use of Vit D supplementation to fight
against the SARS-CoV-2 pandemic on March 23, 2020.[9]
Apart from its role in modulating immune responses, evidence
exists to uncover the crucial role of Vit D in mediating the
immune response to viral infections. Several experimental and
observational studies report that populations with decreased
serum levels of Vit D have a significantly increased risk of
respiratory tract infection and influenza. Insufficiency of Vit
D is seen commonly in patients with HIV infection. Recent
evidences from cell culture studies have demonstrated the
effect of Vit D against viruses, especially the enveloped ones.
These anti-viral effects are also mediated by upregulation of
cathelicidin and defensins.[15,22,30]
Macrophages, monocytes, epithelial, and polymorphonuclear
cells play a central role in the innate immune response.
These cells have Toll-like receptors (TLRs), which have
the ability to identify specific molecular patterns which are
conserved in infectious agents (e.g., TLR2 identifies bacterial
lipopolysaccharides) including viral proteins and nucleic
acids.[31-33] On detection of pathogens, stimulated TLRs
induce release of cytokines which in turn triggers the release
of cathelicidin, antimicrobial peptide (LL-37), defensins,
and possibly supports expression of reactive oxygen species.
Some human antimicrobial peptides related to TLRs have
shown anti-viral properties and their production and release
are directly correlated with serum level of Vit D.[34]
Human antimicrobial peptide, LL-37, has shown antibacterial,
antifungal properties, and abilities to destroy bacteria/fungi
by disrupting the integrity of cell membrane and proton
gradient.[35] A mouse-model study shows that LL-37 has
ability to kill viruses with lipid envelopes, by compromising
the viral membrane integrity and defensins block the viral
binding by generating a protecting barrier of immobilized
surface proteins.[36,37] Cathelicidin has anti-viral properties
and ability to inhibit the replication of herpes simplex virus
type one, vaccinia virus, retrovirus, and of some serotypes of
adenovirus at specific LL-37 concentrations.[36,38,39]
These evidences explain a positive effect of Vit D on immune
system and support the belief that anti-viral properties of
cathelicidin and defensins may disrupt the cell membrane
integrity of enveloped viruses, hence protecting against viral
infections.
Mounting evidence suggests that Vit D has an important
role against viral respiratory infections. Epithelial cells of
lung tissues release more CYP27B1 and less CYP24A1,
supporting the transformation of Vit D to 1,25-dihydroxy
Vit D3 (active form).[40] In airway epithelium, this active form
of Vit D triggers IκBα, a NF-κB inhibitor which reduces
respiratory syncytial virus (RSV) initiation of NF-κB
stimulated genes like interferon-β. When a patient is treated
with Vit D supplementation, immune cells enhance the level
of cathelicidin and TLR coreceptor CD-14 and this leads to
reduction of viral stimulation of inflammatory genes.[41]
A recent study reported that SARS-CoV-2 enter into alveolar
and intestinal cells using angiotensin converting enzyme-2 as
viral receptor.[42] Subsequent alteration in the rennin-angiotensin
mechanism may cause production and release of inflammatory
cytokines which may lead to the development of ARDS.[43] As
Vit D has a central role in immune response modulation that
include reduction of pro-inflammatory cytokines, a mice-model
study, demonstrated its ability to reduce lung injury by inhibiting
the angiopoietin–2-Tie-2 signaling and the renin-angiotensin
mechanism.[44] Another experiment in mice and humans showed
that Vit D is locally activated in epithelial cells of lung tissues and
has an ability to prevent intestinal pneumonitis.[45] The results
of these studies support the notion that Vit D has protective
effect against SARS-CoV-2 because of its properties to reduce
cytokine response and decreased risk and severity of ARDS.[43]
Table 1 presents findings from meta-analyses that Vit D is
protective against acute respiratory tract infection, particularly
in patients with Vit D deficiency. These findings could be
utilized during the prevention and treatment of SARS-CoV-2
infection.
Several articles report that SARS-CoV-2 is more prevalent
and fatal among the elderly and the possible reasons for
this could be more comorbidities such as diabetes mellitus,
hypertension, COPD, and Vit D deficiency associated with
aging. Participants with chronic illnesses have low serum
level of Vit D than healthy controls.[9] Male and female
participants with COPD had mean Vit D level of 16 ng/mL
and 13 ng/mL, respectively, in an Italian study.[49] A South
Korean study reported mean serum level of Vit D of 14 ±
8 ng/mL at the time of admission, among patients with
community acquired pneumonia.[50] Many viral infections
like influenza, SARS-CoV2 are prevalent in winter, as poor
exposure to sunlight is associated with low Vit D levels. A
study found correlation between lower levels of Vit D across
20 European countries and more morbidity and mortality
of SARS-CoV-2.[51] Substantial indirect evidences suggest
Sharma et al. Vitamin D supplementation for the prevention and treatment of COVID-19
National Journal of Physiology, Pharmacy and Pharmacology 4
2020 | Vol 10 | Issue 07 (Online First)
the protective effect of Vit D against SARS-CoV-2. Table 2
displays the results of individual studies regarding the effect
of Vit D on enveloped viruses.
With these strong evidences, it makes us in believe
that Vit D supplementation may result in decreased incidence
of cases, reduced severity of disease and mortality caused by
SARS-CoV-2.
PROPOSED THERAPEUTIC VIT D
SUPPLEMENTATION IN COVID-19
The reviewed studies provide evidence to support the
hypothesis that higher serum level of Vit D is associated
with a low risk of microbial infections and deaths from
acute RTIs caused by pneumonia, CoV, and influenza.
Further, the normal serum Vit D levels may be effective
against the SARS-CoV-2 infection and decrease the
severity and mortality associated.[9] Unfortunately, there is
a lack of standard guidelines about the dose and desirable
concentration of Vit D required to protect the people from
RTIs during winter season.
A recent article reports that Vit D level >20 ng/mL is desired
and many countries follow this recommendation.[59] Another
study recommends a similar level for RTIs and suggests
levels >30 ng/mL as beneficial in decreasing risk of cancer,
unfavorable pregnancy and birth outcomes, and type 2
diabetes mellitus.[60] It is recommended from another study
that desirable level of Vit D should be 40–60 ng/mL for
prevention of breast and colorectal cancer.[61]
Initial data from the Philippines on 212 confirmed COVID-19
patients showed that Vit D levels strongly correlated with
Table 1: Meta-analyses on efficacy of vitamin D on respiratory tract infections
Study characteristics Participants Results
Bergman et al.[46] Eleven randomized
placebo-controlled trials
5660 participants (age ranging
from 6 months to 75 years)
Supplementation with Vitamin D significantly decreased the risk of
RTI (OR: 0.64; 95% CI: 0.49, 0.84; P=0.0014)
Charan et al.[47] Five clinical trials 1868 participants (aged 1–83
years)
The reduction of episodes of RTI was significantly lower in Vitamin D
supplementation group compared to the control group (OR=0.58; 95%
CI: 0.42, 0.81; P=0.001)
Martineau et al[48] Twenty five
randomized controlled trials
10,933 participants (aged 0–95
years) from 14 different countries
Overall results showed that Vitamin D supplementation has protective
effective in decreasing the risk of suffering at least one acute RTI
(OR 0.88; 95% CI: 0.81, 0.96; P=0.003)
OR: Odds ratio, RTI: Respiratory tract infection, CI: Confidence interval
Table 2: Empirical evidences on association of Vitamin D and virus infections
Study characteristics Virus Results
Martínez-Moreno et al.[20]
Randomized controlled trial. 20
participants
Dengue virus (DENV)
infection
Study reported that participants who were treated with 4000 IU/day of Vitamin D
showed low susceptibility to DENV-2 infection than those participants who were treated
with 1000 IU/day of Vitamin D. Study support the evidence that Vitamin D has possible
role in modulating the innate immune response and protective effect against DENV
Villamor et al.[52] Case-control
study. 345 participants
Dengue Study reported negative correlation between Vitamin D concentration and
progression of dengue fever to dengue hemorrhagic fever/dengue shock syndrome
Brice et al.[53] Laboratory study Kaposi’s sarcoma-associated
herpes virus (KSHV)
Study proposed that LL-37 inhibits KSHV infection in oral epithelial cells by
disrupting KSHV envelope
Currie et al.[54] Laboratory study Respiratory syncytial virus
(RSV)
Study reported that LL-37 inhibited cell death due to viral infection, significantly
reduced the expression of new infectious particles and reduced the spread of
infection
Zhao et al.[19] Laboratory study Respiratory syncytial virus
(RSV)
Study demonstrated the mechanism how Vitamin D decreased the risk of RSV
Gui et al.[55] Mice-model study H9N2 influenza virus The results suggest that calcitriol treatment reduced the production of the influenza
M gene, IL-6, and IFN-β in A549 cells in mice with H9N2 influenza
Bucak et al.[56] 137 participants Rotavirus Study reported that 25(OH)D(3) was significantly different 14.6±8.7ng/mL versus
29.06±6.51ng/mL in patient with rota viral diarrhea versus in the health controls
respectively and concluded that Vitamin D is inversely associated with rotavirus diarrhea
Hu et al.[57] Systematic review
and meta-analysis (7 studies
included)
Hepatitis B virus Study revealed that decreased level of Vitamin D in chronic hepatitis B patients
than that of healthy participants [pooled r -2.03ng/mL (−2.60, −1.46)] and inversely
associated with HBV viral loads [pooled r −0.41(−0.54, −0.27)]
Alvarez et al.[58] extensive
review of 29 clinical studies
HIV Results showed that Vitamin D supplementation led to normal Vitamin D level and
its effect on decrease inflammation, increase in CD4+ T cell count and antibacterial
response
Sharma et al. Vitamin D supplementation for the prevention and treatment of COVID-19
5 National Journal of Physiology, Pharmacy and Pharmacology 2020 | Vol 10 | Issue 07 (Online First)
severity of COVID-19 reporting 85.5% of patients with
sufficient (>30 ng/mL) level of Vit D having mild disease
while 72.8% of patients with Vit D deficiency (<20 ng/mL)
having severe or critical disease.[62] A larger study in Indonesia
investigated Vit D level in 780 confirmed COVID-19 cases.
According to their report, compared to COVID-19 patients
with sufficient levels of Vit D, the patients with Vit D levels
in the categories, 20-30 ng/mL and <20 ng/mL, were 12.55
times and 19.12 times more likely to die from COVID-19,
respectively. The key finding is that, even after controlling
for age, gender, and having comorbidities, deaths were 10.12
times more likely in Vit D deficient patients than patients
with normal Vit D level.[63]
Moreover, it is observed that the degree of protection
usually increases as Vit D concentration reaches to
its optimum range of 40–60 ng/mL. To achieve this
level, an individual should take 2000–5000 IU/day
of Vit-D3.[64] In 2011, the U.S. Institute of Medicine
suggested Vit D supplementation of 600 IU/d and 800 IU/d
for people younger than 70 years and older than 70 years,
respectively, and a serum Vit-D level of 20 ng/mL or more,
for skeletal health.[65] Moreover, the Endocrine Society
issued guidelines recommending Vit-D supplementation of
1000–4000 IU/d and Vit D level of 30 ng/mL or more for
patients, including anyone with chronic disease.[66] Table 3
summarizes the findings of some studies which suggest
various doses of Vit D to achieve normal concentration of
this vitamin.
Therefore, from reviewed literature, it seems fairly appropriate
to suggest taking Vit-D at 10,000 IU/day as an adequate
dose to enhance circulatory concentration of Vit-D into the
optimal range of 40–60 ng/mL; after 1 month the dose can
be reduced to 5000 IU/day to maintain serum levels.[71,72] A
recent article proposed the loading doses of 200,000–300,000
IU to achieve the optimal serum range to decrease the risk
and severity of COVID-19.[29]
A multicenter randomized control study, CoVit trial, which is
in its recruitment phase at Angers, France, to compare high
dose versus standard dose Vit-D3 in high risk COVID-19
patients, may give us further answers to this question.[73]
CONCLUSION
Evidences for the protective effects of Vit-D against bacterial,
viral and fungal infections are immense. It has properties
to enhance innate immunity, modulate adaptive immunity,
and also increases the expression of anti-oxidation-related
genes. Therefore, we suggest daily low dose (1000–2000 IU)
Vit-D supplementation to maintain optimum serum levels for
prevention and treatment of COVID-19.
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Study characteristics Doses of Vitamin D Results
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National Journal of Physiology, Pharmacy and Pharmacology 6
2020 | Vol 10 | Issue 07 (Online First)
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How to cite this article: Sharma SK, Mudgal SK, Pai VS,
Chaturvedi J, Gaur R. Vitamin D: A cheap yet effective bullet
against coronavirus disease-19 – Are we convinced yet?. Natl J
Physiol Pharm Pharmacol 2020;10 (Online First). DOI: 10.5455/
njppp.2020.10.05132202024052020
Source of Support: Nil, Conflicts of Interest: None declared.
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