Group: Vitamin D

Member:

1. Syfa Salmanita Pramesti (2008010043)

2. Keisya Haelal Muna (2008010053)

3. Puspita Indah Noor Rabbani (2008010054)

Role of vitamin D in preventing of COVID-19

Abstract

Background and aims: COVID-19 and low levels of vitamin D appear to disproportionately affect
black and minority ethnic individuals. We aimed to establish whether blood 25-hydroxyvitamin D
(25(OH)D) concentration was associated with COVID-19 risk, and whether it explained the higher
incidence ofCOVID-19 in black and South Asian people.

Methods: UK Biobank recruited 502,624 participants aged 37e73 years between 2006 and 2010.
Baseline exposure data, including 25(OH)D concentration and ethnicity, were linked to COVID-
19 test results. Univariable and multivariable logistic regression analyses were performed for the
association between25(OH)D and confirmed COVID-19, and the association between ethnicity
and both 25(OH)D and COVID-19.

Results: Complete data were available for 348,598 UK Biobank participants. Of these, 449 had
confirmedCOVID-19 infection. Vitamin D was associated with COVID-19 infection univariably
(OR¼0.99; 95% CI0.99e0.999; p¼0.013), but not after adjustment for confounders (OR¼1.00; 95%
CI¼0.998e1.01; p¼0.208). Ethnicity was associated with COVID-19 infection univariably (blacks
versus whitesOR¼5.32, 95% CI¼3.68e7.70, p-value<0.001; South Asians versus whites OR¼2.65,
95% CI¼1.65e4.25, p-value<0.001). Adjustment for 25(OH)D concentration made little
difference to the magnitude of the association.

Conclusions: Our findings do not support a potential link between vitamin D concentrations and
risk ofCOVID-19 infection, nor that vitamin D concentration may explain ethnic differences in
COVID-19infection
Introduction the correlation of vitamin D levels with
COVID-19severity and mortality [14–22].
Vitamin D is a steroid hormone, produced
The outbreak and fast spreading of SARS-
endogenously with the effect of ultraviolet
CoV-2 are a global health threat with an
radiation on the skin or available from
unstable outcome worldwide. A recent data
exogenous food sources or dietary
reported the antiviral effects of vitamin D,
supplements. Vitamin D insufficiency is a
which can hinder viral replication directly,
public health problem affecting over a billion
and also be effective in an anti-inflammatory
people across all life stages worldwide [1]. In
and immunomodulatory way [23]. It seems
the past decade, several studies demonstrated
that SARS-CoV-2 primarily uses the immune
a potential link between vitamin D deficiency
evasion process during infection, which is
and various diseases, including systemic
followed by hyper reaction and cytokine
infection [2–4]. Vitamin D insufficiency
storm in some patients [24], as a known
affects the immune functions as vitamin D
pathogenic process of acute respiratory
exerts an immunomodulation role [5],
disease syndrome (ARDS) development [25].
increasing innate immunity by secretion of
SARS-CoV-2 uses angiotensin-converting
antiviral peptides [6,7], which improves
enzyme 2 as the host receptor to enter into
mucosal defenses. In clinical studies, low
alveolar and intestinal epithelial cells [26].
levels of serum vitamin D were associated
Subsequent dysregulation of the renin–
with acute respiratory tract infections
angiotensin system may lead to excess
including epidemic influenza [8–10]. A
cytokine production resulting in prospective
recent meta-analysis incorporating data from
fatal ARDS [25]. Considering the differences
eight observational studies reported that
in the severity and fatality of COVID-19 in
subjects with a serum vitamin D
the globe, it is important to understand the
concentration <50 nmol/l (i.e. <20 ng/ml) had
reasons behind it. Improvement of immunity
a 64% increased risk of community-acquired
through better nutrition might be a
pneumonia [11]. Some recent reviews
considerable factor. The nutrient such as
hypothesized that vitamin D insufficiency
vitamin D shows significant roles in immune
may compromise respiratory immune
function. However, little is known about the
function, increasing the risk of COVID-19
role of vitamin D in preventing COVID-19
severity and mortality [12,13]. There are also
infection and fatality. This study evaluated
some retrospective studies that determined
the correlation of vitamin D concentrations
with COVID-19 cases and deaths per one
million of the population in 20 European
countries using data from the COVID-19
pandemic data portal [27] for 20 May 2020
(most countries after peak). This review also
discussed the possible preventing role of
vitamin D in acute respiratory tract infections.
Furthermore, the available studies that
determined the role of vitamin D in COVID-
19 severity and mortality have been
discussed. PubMed, Google Scholar, Web of
Science, Scopus, Cochrane Central Register
of Controlled Trials, and medRXiv were
searched for relevant literature about the role
of vitamin D inCOVID-19 infections,
severity, and mortality.
Some recent reviews demonstrated some
pathways by which vitamin D decreases the
risk of microbial infections [28–31]. Vita-
min D follows different mechanisms in
reducing the risk of viral infection and
mortality. To reduce the risk of common cold,
vitamin D uses three pathways: physical
barrier, cellular natural immunity, and
adaptive immunity [32]. A recent review also
supported the possible role of vitamin D in
decreasing the risk of COVID-19 infections
and mortality [12]. These comprise
maintaining of cell junctions, and gap
junctions, increasing cellular immunity by
decreasing the cytokine storm with influence
on interferon and tumor necrosis factor [12]
and regulating adaptive immunity through
inhibiting T helper cell type 1 responses and
stimulating of T cells induction [33]. Vitamin
D supplementation was also found to
enhance CD4+ T cell count in HIV infection
[34]. One of the major manifestations of
severe SARS-CoV-2 infection is
lymphopenia [35]. In both the mouse models
and in human cell lines, vitamin D exerted
activity in lung tissue and played protective
effects on experimental interstitial
pneumonitis [36]. Several in vitro studies
demonstrated that vitamin D plays a
significant role in local “respiratory
homeostasis” either by stimulating the
exhibition of antimicrobial peptides or by
directly interfering with the replication of
respiratory viruses [37]. Vitamin D
insufficiency can, therefore, be involved in
ARDS and heart failure [12] and these are the
manifestations of severely ill COVID-19
subjects. There-fore, vitamin D deficiency
promotes the renin-angiotensin system(RAS),
which may lead to chronic cardiovascular
disease (CVD)and reduced lung function [38].
People with such comorbidities account for a
higher percentage of severe ill cases in
COVID-19 [35]. Although, many studies
supported the immunomodulatory
characteristics of vitamin D and its
significant role in the maintenance of
immune homeostasis; well-designed
randomized controlled trials are required to
elucidate the plausible role of vitamin D in
protective immune responses against
respiratory microbes and in preventing
various types of acute respiratory tract
infections. The relevance of vitamin D to
COVID-19Yet, it is important to fully
elucidate the virulence mechanisms of
COVID-19, several cellular mechanisms
including Papain-likeprotease (PLpro)-
mediated replication, dipeptidyl peptidase-
4receptor (DPP-4/CD26) binding, disruption
of M-protein mediated type-1 IFN induction
and MDA5 and RIG-I host-recognition
evasion have been recognized in the closely-
related COVID-MERS virus [39,40]. Of the
above processal, human DPP-4/CD26 has
been exhibited to connect with the S1 domain
of the COVID-19 spike glycoprotein,
suggesting that it could also be a salient
virulence factor in Covid-19 infection [41].
The expression of the DPP-4/CD26 receptor
is reduced significantly in vivo upon the
correctness of vitamin D insufficiency [42].
There is also an indication that maintaining
of vitamin D may reduce some of the
unfavorable downstream immunological
sequelae thought to extract poorer clinical
out-come in Covid-19 infection, such as
interleukin 6 elevation, delayed interferon-
gamma response [37], and, a negative
prognostic marker in subject
Subjects
UK Biobank recruited 502,624 participants
aged 37e73 years across England, Scotland
and Wales between 2006 and 2010. Its aim
was to identify the causes of disease and
death in middle and old age by following up
participants over time. At baseline, bio-
logical measurements were recorded and
touch-screen questionnaires administered
according to a standardized protocol [12,13].
The study received ethical approval from the
North West Multi-Centre Research Ethics
Committee (REC reference: 16/NW/0274),
and was conducted in accord with the
principles of the Declaration of Helsinki. All
participants gave written informed consent
for data collection, analysis, and record
linkage.
Materials and methods
Baseline data from UK Biobank were linked
to COVID-19 test results provided by Public
Health England [14], including the specimen
date, origin (whether the person was an
inpatient or not) and result (positive or
negative). Confirmed COVID-19 infection
was defined as at least one positive test result.
Data were available for the period 16th
March 2020 to 14th April 2020.Exposures
were measured at the baseline assessment
visits conducted between 2006 and 2010.
Blood collection sampling procedures for the
study have previously been described and
validated [15]. Biochemical assays, including
25(OH)D, a measure of vitamin D status,
were performed at a central laboratory on
around480,000 samples. Further details of
these measurements can be found in the UK
Biobank Data Showcase and Protocol [16].
Vitamin D was imputed with the minimum
detectable value (10 nmol/L) if it was below
the limit of detection, and the maximum
detectable value (375 nmol/L) if too high for
detection. Ethnicity was self-reported, and
categorized as white, black, South Asian, or
other. Smoking status was self-reported and
categorized as current or non (ex/former)
smoker. Blood pressure was measured at the
baseline visit using an automated
measurement, and the average of available
measures used. Height was measured using a
Seca 202 height measure. Weight was
measured to the nearest 0.1 kg using the
Tanita BC-418 MA body composition
analyser. Body mass index(BMI) was
derived from weight (kg)/height(m) [2]. It
was categorized into underweight
(BMI<18.5 kg/m2), normal weight
(BMI18.5e24.9 kg/m2), overweight
(BMI25e29.9 kg/m2) and obese (BMI30
kg/m2). Area-level socioeconomic
deprivation was assessed by the Townsend
score (incorporating measures of un-
employment, non-car ownership, non-home
ownership and household overcrowding)
[17]. Higher scores on the Town send score
represent greater socioeconomic deprivation;
scores were categorized into quintiles.
Diabetes at baseline was defined as self-
reported physician-diagnosed type 1 or type
2 diabetes, a primary care or hospital record
of diabetes at or before recruitment (defined
as ICD-10 codes E10-E14.9), or diabetes
medication. Household income was self-
reported and categorized
into:<£18,000;£18,000-£30,999;£31,000-
£51,999;£52,000-£100,000;
or>£100,000.Health was self-rated as
excellent, good, fair, or poor. Long-standing
illness, disability or infirmity was self-
reported as yes or no. Univariable logistic
regression analysis was performed of the
association between 25(OH)D concentration
(as a continuous variable) and confirmed
COVID-19 infection. The model was then
adjusted for sex, month of assessment,
Townsend deprivation quintile, household
income, self-reported health rating, smoking
status, BMI quintile, ethnicity, age at study participants by presence or absence of
assessment, diabetes, systolic blood pressure positive COVID-19 test result. Median
(SBP), diastolic blood pressure (DBP), and 25(OH)D concentration measured at
long-standing illness, disability or infirmity. recruitment was lower in patients who
As sensitivity analyses these models were subsequently had confirmed COVID-19
repeated with participants categorized as infection (28.7 (IQR 10.0e43.8) nmol/L) than
vitamin D deficient (defined as<25 nmol/L) other participants (32.7 (IQR 10.0e47.2)
or not deficient [18]and then categorized as nmol/L). It predictedCOVID-19 infection
vitamin D insufficient (defined as<50 nmol/L) univariably (Table 2; OR¼0.99, 95%
or sufficient. Next, univariable logistic CI0.99e0.999, p¼0.013), but not after
regression was performed of the association adjustment for covariates (OR¼1.00; 95%
between ethnicity and confirmed COVID-19 CI¼0.998e1.01; p¼0.208). Exposures that
infection. The model was first adjusted for did predict COVID-19 status in the
25(OH)D, then sex, month of assessment, multivariable logistic regression were male
Townsend deprivation quintile, household sex (OR¼1.41; 95% CI¼1.16e1.71;p-
income, self-reported health rating, smoking value¼0.001),higher socioeconomic
status, BMI quintile, age at assessment, deprivation (highest vs lowest Town send
diabetes, SBP, DBP, and long-standing quintile OR¼1.89; 95% CI¼1.37e2.60;p-
illness, disability or infirmity. Finally, value<0.001), poorer self-reported health
multivariable analysis was performed status (poor health vs excellent health
including anethnicity*vitamin D deficiency OR¼2.32;95% CI¼1.45e3.72;p-
interaction term. All analyses were value<0.001), age at assessment
undertaken using Stata v14.4. (OR¼1.02;95% CI¼1.00e1.03;p-
value¼0.016), being overweight
Results
(OR¼1.34;95% CI¼1.04e1.72;p-
Results were available for 2724 COVID-19 value¼0.024) or obese (OR¼1.62;
tests conducted on1474 individuals. 95%CI¼1.23e2.14;p-value¼0.001), and
Complete data on (25(OH)D) concentration non-white ethnicity (blacksOR¼4.30, 95%
and covariates were available for 348,598 CI¼2.92e6.31,p-value<0.001; South
UK Biobank participants. Of these, 449 had a AsiansOR¼2.42, 95% CI¼1.50e3.93,p-
positive COVID-19 test. Table 1presents value<0.001) (Fig. 1).
Discussion socioeconomic and lifestyle differences in
white and black and minority ethnic
Our findings are consistent with previous
participants; the risk of COVID-19 remained
studies [7,19] in demonstrating a higher risk
around 4-fold in black participants and more
of confirmed COVID-19 infection in ethnic
than 2-fold in South Asians. Further studies
minority groups. Vitamin D has been
are required to determine the mechanisms
suggested as possibly protective of COVID-
underlying ethnic variations in risk
19 infection [20e22] and, if so, could
ofCOVID-19 infection and its severity. It
plausibly play a role in ethnic variations in
may be that pathways related to cardio
COVID-19 infection. However, we found no
metabolic conditions or differences in cardio
association between 25(OH)D and COVID-
respiratory reserve, or potentially other social
19 infection after adjusting for potential
factors, are more relevant, as we have
confounders. Therefore, despite 25(OH)D
recently discussed [23]
concentration being lower in black and
minority ethnic participants, there was no Conclusion
evidence that it might play a role in their
Our analyses of UK Biobank data provided
higher risk of COVID-19 infection. It has
no evidence to sup-port a potential role for
been suggested in some media outlets that
(25 (OH)D) concentration to explain
language barriers may contribute to ethnic
susceptibility to COVID-19 infection either
differences in COVID-19 risk. This is
overall or in explaining differences between
unlikely to contribute to the risk we observed
ethnic groups.
in UK Biobank because all participants spoke
English (albeit with the possibility of fluency
variation). The association with ethnicity was
only slightly attenuated after adjustment for
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