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\begin{document}

\title{Vitamin D Supplementation Could Potentially Reduce Risk of COVID-19
Infections and Deaths}



\author[1]{Jing Qin Tay}%
\author[2]{Ajay L Mahajan}%
\author[2]{M Julie Thornton}%
\affil[1]{Bradford Teaching Hospitals NHS Foundation Trust}%
\affil[2]{University of Bradford}%


\vspace{-1em}



  
  \date{June 05, 2024}


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\selectlanguage{english}
\begin{abstract}
Vitamin D has long been known to be a major regulator for both the
endocrine and the immune system. With the advent of COVID-19 pandemic,
there has been a growing interest in looking at the feasibility of using
vitamin D as a preventative and therapeutic option in the management of
the disease. A low serum level of vitamin D is linked to higher
incidence of respiratory tract infection and disease progression.
Vitamin D supplementation has proven to be effective in enhancing the
immune system, strengthen lung epithelial barrier, and prevention of
unchecked inflammatory response. Previous studies on the roles of
vitamin D in managing influenza and other enveloped virus infection
could shed light on the possible roles of vitamin D in the current
pandemic. More randomised controlled trials are needed to explore the
effects of vitamin D supplementation on COVID-19 infection.%
\end{abstract}%



\sloppy


\section*{Review Criteria:}

{\label{abstract}}

Papers published in the MEDLINE and EMBASE databases were reviewed for
evidence relating viral and respiratory tract infections to vitamin D
deficiency; the effects of vitamin D supplementation on the immune and
inflammatory responses; and ongoing trials on the use of vitamin D in
managing COVID-19 illness. The findings were discussed and dose
recommendation for vitamin D supplements summarised.

\section*{Message for the Clinic:}

{\label{message-for-the-clinic}}

Vitamin D could be a readily accessible and cost-effective adjuvant
therapy for COVID-19 that deserves further research.

\section*{Introduction}

{\label{introduction}}

The outbreak of COVID-19 started at Wuhan City of China in December
2019. It has spread at a remarkable speed to countries all around the
world. There is now a race to find an effective vaccine and therapy.
COVID-19 is an enveloped, single-stranded, positive-sense RNA virus,
which belongs to the coronavirus family. The crown-like appearance of
COVID-19 is due to the presence of spike glycoproteins on the surface
envelope(1). It is the seventh member of the coronavirus family that is
able to infect humans(2). This virus is phylogenetically related to
previously known severe acute respiratory syndrome coronavirus
(SARS-CoV) and the Middle East respiratory syndrome coronavirus
(MERS-CoV)(3). Symptoms associated with COVID-19 are fever, persistent
dry cough, breathlessness and lethargy; with a minority of patients
suffering from headache, haemoptysis, diarrhoea, erythematous rash and
urticaria(4-6). Severe cases of COVID-19 may progress to pneumonia,
acute respiratory distress syndrome (ARDS) and multi organ failure(4).
In terms of mortality rate, COVID-19 ranked the third in the family of
coronavirus related death, compared to MERS-CoV with a reported
mortality rate of 37\% and SARS-CoV of 10\%(5). To date, there are over
four millions confirmed cases of COVID-19, with a fatality rate of just
over 300,000(7). At present, there is no definitive therapy for
COVID-19. Most of the therapeutic options come from previous experience
in managing SARS and MERS epidemics. Different regimes have been
proposed, including the use of type 1 interferon (IFN-I),
hydroxychloroquine, Ritonavir/lopinavir, Remdesivir, and neutralising
antibodies (Nabs)(8).While waiting for the development of an effective
vaccine, there has been ongoing research looking at alternatives that
may help in the management of COVID-19 patients. Vitamin C, vitamin D,
and Zinc have all been investigated as potential adjuvant therapies(9,
10).

Vitamin D in particular, has been in the spotlight recently. The
prevalence of vitamin D deficiency is increasing, with some studies
labelling it as a pandemic(11, 12). There is now an abundance of
evidence in the literature highlighting the consequences of vitamin D
deficiency, and its association with a variety of acute and chronic
illnesses including autoimmune disease, cardiovascular disease, cancers,
diabetes mellitus and neurological disorders(13, 14). Traditionally,
vitamin D is known as the ``sunshine vitamin'', sunlight being the main
source. 7-dehydrocholesterol in the skin is converted to
cholecalciferol. It then undergoes further hydroxylation in the liver
and kidney before becoming the biological active form,
1,25-dihydroxyvitaminD (1,25(OH)\textsubscript{2}D), also known as
calcitriol(15). 1,25(OH)\textsubscript{2}D activates the vitamin D
receptor (VDR), which is a nuclear receptor, to exert its functions. It
is now known that VDR is highly expressed in most cell types, suggesting
the myriad of regulatory roles vitamin D plays in maintaining healthy
functioning of our body(16) (Figure 1). In particular, there is strong
evidence supporting the role of vitamin D in regulating the immune
system(17).

Unfortunately, sunlight alone is a not a reliable source of vitamin D,
especially among those living at high latitudes, ethnicity with darker
skin colour and the institutionalised population(18). In high human
density habitations, a lack of open spaces and high pollution has led to
a decrease in direct sunlight exposure(18). To counteract this problem,
vitamin D supplementation has been recommended. Research studies have
shown that vitamin D supplement is effective in raising serum level of
vitamin D(19, 20). Vitamin D supplement helps to strengthen the immune
response and plays a vital role in respiratory illness prevention, among
its many other health benefits(17, 21). This paper discusses the roles
of vitamin D in reducing the risk of viral infections and mitigating the
severity of disease progression. More importantly this paper
investigates the feasibility of using vitamin D as an adjuvant therapy
in alleviating some of the symptoms associated with pneumonia and acute
respiratory distress syndrome (ARDS) that lead to a poorer outcome among
COVID-19 patients. This paper also discusses whether vitamin D could
play any role in reversing disease progression and the prevention of
COVID-19 in the general population.

\section*{Methods}

{\label{methods}}

We conducted a review of the evidence relating viral and respiratory
tract infections to vitamin D deficiency. We searched for papers
investigating the effects of vitamin D supplementation on the immune and
inflammatory responses. Finally, we reviewed all articles related to
COVID-19 and registered trials on the use of vitamin D in managing
COVID-19 illness. All relevant entries on MEDLINE and EMBASE databases
up to May 2020 were included in the discussion.

\section*{Vitamin D Reduces Risks of Viral Infection by Enhancing The
Immune Response and Maintaining Integrity of Epithelial
Barriers}

{\label{vitamin-d-reduces-risks-of-viral-infection-by-enhancing-the-immune-response-and-maintaining-integrity-of-epithelial-barriers}}

Vitamin D is a fat-soluble steroid hormone(22). Vitamin D modulates both
the innate and adaptive immune response(23-26). In the context of
disease prevention, vitamin D enhances macrophage activation, phagocytic
response and production of antimicrobial peptides to stimulate the
innate immune response(17, 27). It is known that vitamin D can suppress
the infectiveness of a variety of enveloped virus such as the Ebola,
Epstein-Barr and Hepatitis C viruses(28).Vitamin D's anti-viral
mechanism is mainly attributable to its effects in the upregulation of
anti-microbial peptides such as cathelicidins (LL37) and human beta
defensins 2(28). Cathelicidins and defensins act by perturbing the cell
envelope of the virus, binding lipopolysaccharide residues of commensal
bacteria, and inhibiting viral adhesion and entry(29-33). Lymphocytes,
macrophages and dendritic cells all express the necessary enzymes that
can metabolise vitamin D to its biological active form(34, 35). They are
also important target cells for vitamin D as VDR is highly expressed in
these cell types(35, 36). By regulating both T and B cells maturation
and proliferation, it plays a pivotal role in mounting an immune
response against viruses(34). Vitamin D also protects the integrity of
epithelial cells lining the respiratory tract and stimulates epithelial
repair, thereby alleviating lung injury associated with pneumonia that
commonly complicates COVID-19 infection(37-39).

Vitamin D deficiency is common among acquired immune deficiency syndrome
(AIDS) patients(40). Research study on a group of AIDS patients showed
an increased mortality rate in patients who are vitamin D deficient(41,
42). The HIV virus mainly targets cluster of differentiation 4 (CD4)
found on the surface of immune cells such as T helper cells, monocytes,
macrophages and dendritic cells(43). The HIV virus damages and destroys
these infected cells, causing a gradual depletion in CD4 positive cells,
leading to immunological failure(43). There are studies which showed
that vitamin D has a positive impact on improving the CD4 count in HIV
patients(44). A longitudinal study in 2018 concluded that a high serum
level of 25(OH)D is associated with increased CD4 count and reduces
infection severity in HIV patients(45). This suggests that vitamin D
supplements can enhance the recovery of human immune system. Even in
AIDS patients, vitamin D supplementation has been shown to increase the
level of circulating vitamin D and therefore lower the risks of bone
disease and inflammation(40, 46). The use of vitamin D supplementation
in HIV patients have been reported to increase the immune response
against pathogens, improve immunologic recovery during combination
antiretroviral therapy and reduce levels of inflammation(47, 48).
Furthermore, vitamin D supplementation has been shown to reduce HIV and
Hepatitis C susceptibility by inhibiting viral entry into human
cells(49-52). With regards to COVID-19, vitamin D supplementation has
been shown to reduce human dipeptidyl peptidase-4 receptor (DPP-4/CD26)
expression(53). As DDP-4/CD26 is a receptor that interacts with the S1
domain of the COVID-19 spike glycoprotein for cell entry, vitamin D
supplementation could potentially reduce the virulence of COVID-19 in
humans(54, 55).

\section*{Vitamin D Reduces Risk of Respiratory Tract
Infection}

{\label{vitamin-d-reduces-risk-of-respiratory-tract-infection}}

COVID-19 infection shows similar properties to the Severe Acute
Respiratory Syndrome (SARS) and Middle Eastern Respiratory Syndrome
(MERS)(2). However, from an epidemiology perspective, COVID-19 is far
more contagious than SARS-CoV and MERS-CoV, with confirmed cases far
exceeding the latter two combined(2, 56). COVID-19 involves respiratory
tract illness ranging from mild, moderate to severe forms(57).

Research has shown that vitamin D deficiency is a predisposing factor in
respiratory tract infection (RTI)(58). RTI affect the majority of the
world population. It is also the one of the main causes for hospital
admission as it can progress into moderate to severe pneumonia(59, 60).
One of the main predisposing factors for developing RTI is partial or
full impairment of the immune system. Vitamin D is recognised to
regulate innate and adaptive immune system by stimulating the production
of antimicrobial peptides in the event of viral or bacterial
infections(28). Several studies have concluded a positive correlation
between low serum level of vitamin D with a higher incidence and
severity of lower respiratory infection in both adults and
children(61-65). There are also studies which showed that vitamin D
supplement helps to lower the rate of development of lower respiratory
tract infection, especially in winter when there is a scarcity of
sunlight(66, 67). However, there are some studies which showed no
beneficial effects of short-term bolus doses of vitamin D supplement on
the incidence and resolution of pneumonia(68-70). The mixed findings may
be explained by different ages at study enrolment and severity of
pneumonia, with children at the younger extreme of age having not fully
developed immune system associated with poorer outcomes(61). A large
European study has also shown that correcting serum level of 25(OH)D has
beneficial effects on prevention of RTI and reducing disease severity in
adults(71). A randomised controlled trial in Japan looking at the
effects of vitamin D supplement on prevention of seasonal influenza A
showed that taking 1200 international units (IU) of vitamin D per day
has a 58\% relative risk reduction of influenza A incidence in school
children compared to the placebo group(72).

Epidemiological and observational studies have linked vitamin D
deficiency with the spread of RTI and other infectious diseases(63,
73-76). It has been seen that vitamin D deficiency is common among
children below the age of five, which coincides with the prevalence of
lower respiratory tract infection (LRTI), respiratory syncytial virus
(RSV), and related human metapneumovirus (hMPV) infections(77). Reviews
of serum vitamin D levels among the paediatric population in America
shows a correlation between low serum vitamin D with LRTI and RSV
severity(78). Another large scale study of the paediatric population in
Middle Eastern countries further showed that children who have a low
serum level of vitamin D are usually tested positive for RSV
infection(79). There are studies which suggested that vitamin D
deficiency is an important predisposing factor for developing
community-acquired pneumonia and stroke-associated pneumonia (SAP)(80).
A low serum level of vitamin D is associated with poorer disease
progression in all types of acquired pneumonia including viral
pneumonia, streptococcal pneumonia, and Legionella pneumonia(81).
Granulomatosis with polyangiitis is an autoimmune disease characterised
by vasculitis that primarily affects the respiratory tract and the
kidneys. Vitamin D deficiency has been shown to be an important risk
factor for RTI in this group of patients(82). The effects of vitamin D
on lung immunity and respiratory diseases are well established(83).

\section*{Vitamin D Prevents the Maladaptive Cycle of Local Inflammation
and Secondary Injury that Leads to Poorer
Outcomes}

{\label{vitamin-d-prevents-the-maladaptive-cycle-of-local-inflammation-and-secondary-injury-that-leads-to-poorer-outcomes}}

A recent large-scale epidemiological study suggested a possible link
between vitamin D deficiency and the severity of COVID-19 cases among
patients in the USA, France and the United Kingdom(84). This study
correlated the low serum level of vitamin D with a higher C-reactive
protein (CRP) level in COVID-19 patients based on previous findings(85,
86). In fact, multiple observational and intervention studies have
suggested the beneficial effects of vitamin D on reducing circulating
CRP and pro-inflammatory cytokines(86-90). This has a beneficial impact
in lowering a heightened inflammation state that is associated with
poorer outcomes(91-93). Vitamin D also modulates the renin-angiotensin
cascade(94). A high expression of angiotensin converting enzyme (ACE)
and angiotensin II, coupled with reduced expression of angiotensin
converting enzyme 2 (ACE2) are common features in a pro-inflammatory
state in acute respiratory distress syndrome (ARDS). Vitamin D reduces
the susceptibility to acute lung injury (ALI) by inhibiting renin
thereby angiotensin II biosynthesis(95-98). This may have a protective
effect in preventing a ``cytokine storm'' that is often implicated in
severe COVID-19 cases(84, 99).

Vitamin D also enhances the production of interleukin-10 (IL-10), a
cytokine with potent anti-inflammatory properties(100). Increasing IL-10
favours the proliferation and differentiation of T helper cell 2 (Th2)
and T regulator (T reg) cells over T helper cell 1 (Th1) and T helper
cell 17 (Th 17) (101, 102). This could have an effect in promoting
tolerance and controlling an exacerbated immune response(41).
Furthermore, vitamin D supplementation reduces the expression of
pro-inflammatory cytokines and increases the expression of
anti-inflammatory cytokines by macrophages, by enhancing expression of
MAPK phosphatase-1 and suppressing p38 activation(103-105). A persistent
immune activation leads to an increased mortality in HIV patient.
Vitamin D protects against the development of immune reconstitution
inflammatory syndrome events in HIV patients, likely through
downregulating CD38 expression on the surface of memory
CD8\textsuperscript{+} T cells(106, 107). Vitamin D also decreases the
expression of major histocompatibility complex (MHC) class II and their
co-stimulatory molecules such as CD80, thereby decreasing T cell
activation with persistent antigen presentation(108). It could be
posited that these anti-inflammatory properties of vitamin D could have
beneficial impacts on patients suffering from severe form of COVID-19.

In animal studies, it has been shown that vitamin D can reduce the
severity of coronavirus illness such as the enteropathogenic porcine
epidemic diarrhoea virus (PEDV)(109). Adding 155.5\selectlanguage{greek}µ\selectlanguage{english}g/kg diet 25(OH)D to
the feed given to weaned pigs can have a protective effect on
PEDV-induced inflammation and alleviate damage to the intestinal
tracts(109). This is achieved by regulating autophagy, enhancing
cathelicidins production and inhibiting jejuna mucosa interleukin-6
(IL-6) and interleukin-8 (IL-8) mRNA expression, hence lessening the
severity of damage(109-111). The VDR-knockout mice model has
demonstrated that vitamin D has protective effects on the integrity of
epithelial cells lining the respiratory tract, by reducing
lipopolysaccharides-induced acute lung injury(112). These animal studies
suggest that active vitamin D could be effective in reducing the
severity of acute lung injury and suppress a heightened inflammatory
state in COVID-19 patients.

\section*{Dose recommendation for vitamin D
supplements}

{\label{dose-recommendation-for-vitamin-d-supplements}}

Unfortunately, there is no consensus on the optimal dose of vitamin D
supplementation for managing viral diseases or RTI. A previous study has
reported that in children suffering from recurrent respiratory tract
infection, giving vitamin D supplements could reduce the number of
disease occurrences in a year, with no noticeable adverse side effects,
suggesting that vitamin D supplementation could be an effective adjuvant
therapy in managing RTI(113). Doses ranging from 800 IU to 100,000 IU
per day have been suggested(114). When using a bolus schedule, the
effects seems to be smaller(115-117). Vitamin D has been shown to be
beneficial in the prevention and treatment of influenza(118). Research
conducted in Japan has reported that taking 1200 IU per day of vitamin D
supplement could reduce the risk of contracting influenza by six
fold(72). In terms of recommending dosage of vitamin D as an adjuvant
therapy for influenza, it has been shown that there is a lower incidence
of influenza among patients whose serum level of vitamin D is above
40ng/mL(118, 119). Besides that, by giving 50,000IU of vitamin
D\textsubscript{3} supplement once daily or 10,000IU of vitamin D three
times a day, significantly reduced the severity of symptoms in patients
who suffer from influenza after a period of seventy-two hours(120).

Vitamin D supplementation should ideally be guided by serum levels of
vitamin D to avoid untoward effects. Recent trials challenged whether
serum vitamin D levels of [?]30 ng/mL promote human health(121). A study
by Quraishi et al (2013) found that people with vitamin D levels of less
than 30 ng/ml were 56\% more likely to develop community acquired
pneumonia than those with levels of 30 ng/ml or higher(80). A recent
paper by Grant \emph{et al} (2020) suggested taking 10,000 IU per day of
vitamin D\textsubscript{3} for a few weeks as a loading dose, followed
by 5000 IU per day as a maintenance dose, in order to raise serum
vitamin D level above 40--60 ng/mL(122). Indeed, a dose of up to 4000 IU
or 100 micrograms per day has been cited as a safe dose by several
studies(123, 124). Public Health England (PHE) has recently recommended
taking 10 micrograms of vitamin D per day as a supplement during the
lockdown period(125). More randomised controlled trials and large
population studies should be conducted to evaluate these
recommendations(122).

\section*{Conclusion}

{\label{conclusion}}

In conclusion, the impacts of COVID 19 and its strain on the healthcare
system are huge. The mortality rate is especially high in vulnerable
populations that are vitamin D deficient. The situation is likely to be
worse with the introduction of emergency lockdown measures that confines
the population indoors. Vitamin D deficiency is prevalent among the U.K.
population, with crude incidence rate increased from 0.29 per 1000
person-year in 2005 to 16.08 per 1000 person-year in 2015(126). It
affects one in five people in the U.K. according to a national
survey(127). In the northern hemisphere, Vitamin D deficiency is often
worse over the months from October to March when there is less sunlight
in the day, corresponding to a peak in the spread of COVID-19. To date
there are ongoing clinical trials in the U.S. and Spain involving
COVID-19 patients to establish whether taking vitamin D can help in
attenuating disease progression(9). The use of vitamin D as a readily
accessible and cost-effective strategy to reduce the incidence and
severity of disease in COVID-19 patients is an option that deserves
further consideration.

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\section*{Figure Legend}

{\label{figure-legend}}

Figure 1: The metabolic pathway of vitamin D synthesis and the tissue
specific cellular response it mediates that may reduce COVID-19
severity. CYP2R1, CYP27A1, and CYP27B1 are the cytochrome enzymes
involve in the hydroxylation processes of cholecalciferol to the active
form of vitamin D, 1,25(OH)\textsubscript{2}D.
1,25(OH)\textsubscript{2}D then binds to VDR which forms a heterodimer
with retinoid X receptor (RXR). Interaction of the heterodimer with the
vitamin D response element (VDRE) leads to downstream target gene
regulation.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-manuscript/Figure-1-manuscript}

\end{center}
\end{figure}

\selectlanguage{english}
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