Original Research Article
European Journal of Inﬂammation
Volume 19: 1–10
© The Author(s) 2021
Article reuse guidelines:
Association of vitamin D deﬁciency with
clinical presentation of COVID-19
, Abdullah Turjoman
, Ahmad El-Askary
, Alaa Shaﬁe
, Muhannad Alenazi
, Mustafa Halawi
and Amal F. Gharib
Background: The coronavirus disease 2019 (COVID-19) is a respiratory virus, the spread of which has caused a global
pandemic with catastrophic consequences. The current study aimed to investigate the association between vitamin D
deﬁciency and the clinical presentation of COVID-19.
Patients and methods: The current study included 166 COVID-19 patients recruited from Prince Mohammad Bin
Abdulaziz Hospital in Riyadh, Saudi Arabia. The study was conducted from October 2020 to January 2021. Patients were
diagnosed by positive polymerase chain reaction (PCR) results. History and clinical data were collected for all subjects. In
addition, laboratory analysis was done to estimate blood levels of 25 hydroxyvitamin D (25(OH)D), C-reactive protein
(CRP), ferritin, parathyroid hormone (PTH), alanine aminotransferase (ALT), D-dimer, calcium, and relative lymphocytic
count. COVID-19 patients were divided into three subgroups according to their vitamin D status. Patients were considered
sufﬁcient when their vitamin D level was above 30 ng/mL. Patients with vitamin D levels below 20 ng/mL were considered
deﬁcient. Patients with vitamin D levels ranging from 20 ng/mL to 30 ng/mL were considered insufﬁcient.
Results: Our results showed that 81 patients (49%) were deﬁcient in vitamin D, and 48 patients (29%) were insufﬁcient in
vitamin D. Only 37 patients (22%) had normal vitamin D levels. Moreover, a signiﬁcant difference was found regarding the
inﬂammatory markers of COVID-19 severity. Also, vitamin D levels were inversely correlated with the markers used for
monitoring the condition of COVID-19 patients: ferritin, CRP, and D-dimer.
Conclusion: Our results showed that vitamin D deﬁciency was associated with increased levels of inﬂammatory markers
of COVID-19 infection.
COVID-19, vitamin D, clinical presentation, inﬂammatory markers
Date received: 26 March 2021; accepted: 15 July 2021
The coronavirus infection has spread all over the world.
The outbreak started in Wuhan, Hubei, China, late in 2019
and was ofﬁcially named COVID-19 by the World Health
Organization (WHO) on 11 February 2020.
fection is associated with severe acute respiratory syn-
drome coronavirus-2 (SARS-CoV-2) and threatens the
There is variation in the clinical features of
COVID-19, as 17.9% of COVID-19 infections are mild,
while 15.7% of the patients developed severe illness after
Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons
Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use,
reproduction and distribution of the work without further permission provided the original work is attributed as speciﬁed on the
SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
Department of Clinical Laboratory Sciences, College of Applied Medical
Sciences, Taif University, Taif, Saudi Arabia
Prince Mohammed Bin Abdulaziz Hospital, Riyadh, Saudi arabia
Department of Medical Laboratory Technology, College of Applied
Medical Sciences, Jazan University, Jazan, Saudi Arabia, Jazan, SA
Mazen Almehmadi, Department of Clinical Laboratory Sciences, College
of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif
21944, Saudi Arabia.
being admitted to the hospital. On initial presentation, no
radiologic anomalies were found in 2.9% of patients with
COVID-19 shows its effect as initial immune suppres-
sion, followed by exaggerated immune system response,
resulting in a cytokine storm. COVID-19 can have severe
consequences, such as the development of acute respiratory
distress syndrome (ARDS) and systemic inﬂammatory re-
sponse syndrome (SIRS).
Vitamin D deﬁciency represents an important health
problem; more than one billion people are estimated to
have vitamin D deﬁciency worldwide.
In Saudi Arabia,
the prevalence of vitamin D deﬁciency is around 60%. Its
occurrence has been reported in different ages and both
Vitamin D exerts signiﬁcant antiviral and anti-inﬂammatory
effects via its immunoregulatory actions as vitamin D receptors
have been recognized in many immunological cells, and certain
cells of the immune system can synthesize the active form of
Vitamin D can reduce the risk of infection through several
effects: ﬁrst, it plays an antiviral role by enhancing antimi-
crobial peptides cathelicidin and B-defensin that diminish the
viral replication; second, enhancement of anti-inﬂammatory
and diminishment of pro-inﬂammatory cytokines (IL-6,
TNF-α,andIFN-γ) that cause pneumonia and lung insult.
The pro-inﬂammatory cytokines are recognized as predictors
for bad outcomes in COVID-19 infection.
Previous research has reported that vitamin D deﬁciency
may enhance the possibility of respiratory infections, in-
cluding respiratory syncytial virus, tuberculosis, and ﬂu. In
addition, it is considered a risk factor for ARDS.
The COVID-19 virus principally involves the pulmo-
nary type-II alveolar pneumocytes by binding to the in-
creased angiotensin-converting enzyme 2 receptors
(ACE2) of the infected person,
production, and increasing surface tension, which results
from alveolar type-II pneumocytes dysfunction.
D metabolites can stimulate surfactant synthesis by mod-
ulating the renin-angiotensin system in alveolar type-II
cells protecting against acute lung injury.
Ddeﬁciency can be a pathogenic element in COVID-19.
Before the emergence of COVID-19 vaccines, vitamin D
supplementation and exposure to sunlight were included in
treatment protocols. In the current study, we aimed to deﬁne
the prevalence and clinical signiﬁcance of vitamin D de-
ﬁciency in hospitalized patients diagnosed with COVID-19.
Subjects and methods
Study design and participants
We planned a retrospective case control study including
166 patients with COVID-19, aged 23–88 years, who were
admitted to the Prince Mohammad Bin Abdulaziz Hospital
in Riyadh, Saudi Arabia, between October 2020 and
January 2021. They were diagnosed by RT-PCR and
further assessment was done by computed tomography
(CT) scans of the chest.
Patients were further classiﬁed into three subgroups
according to their vitamin D status: a vitamin D sufﬁcient
group (vitamin D > 30 ng/mL), a vitamin D–deﬁcient group
(vitamin D < 20 ng/mL) and a vitamin D–insufﬁcient group
(vitamin D from 20–30 ng/mL).
Speciﬁc criteria were
used to determine the number of cases to be recruited in the
study according Miaoulis and Michener.
of the minimum sample size, the formula of Cochran
used, with conﬁdence value 95% at a signiﬁcant concen-
tration of 5%.
We have excluded patients with malabsorption diseases,
liver cirrhosis, and serum creatinine levels of > 2 mg/dL.
Patients who obtained oral vitamin D supplements or
previous anticonvulsant treatment were also excluded from
Demographic and clinical data were collected from hospital
records of COVID-19 patients, stored in an electronic
database, and independently examined by two researchers.
Procedures were performed after prior approval by the
research ethics committee of Taif University (42-0010).
The outcome variable for COVID-19 severity was de-
ﬁned as the combination of intensive care unit (ICU) ad-
mission, mechanical ventilation prerequisite, or in-hospital
mortality. Generally, the ICU admittance criteria were set
by following the rules by the American Thoracic Society
and the Infectious Diseases Society of America.
Fasting venous blood samples were collected from
COVID-19 patients and allocated into two portions. The
sera were separated from the plain tubes for the estimation
of vitamin D, calcium, and the inﬂammatory markers.
The whole blood from ethylenediaminetetraacetic acid
(EDTA)–containing tubes were used for complete blood
count (CBC) tests. Serum 25(OH)D levels were determined
by using an Abcam human vitamin D enzyme-linked
immunosorbent assay (ELISA) kit, USA (Cat No.
ab213966), following the manufacturer’s protocol. The
range of detection was 0.5–1010 ng/mL, and the sensitivity
of the assay was 1.98 ng/mL. Serum vitamin D levels of
less than 20 ng/mL were considered deﬁcient. The PTH
serum levels were estimated by the Abcam Human PTH
ELISA kit, USA (Cat No. ab230931), based on the
company guidelines, with a detection range of 4.69–
300 pg/mL and a sensitivity of 0.761 pg/mL.
2European Journal of Inﬂammation
CRP was evaluated by using the immunoturbidimetric
method (CRP II Latex X2, Denka Seiken Co. Ltd., Tokyo,
Japan), utilizing an autoanalyzer (Toshiba, Tokyo, Japan).
The measurement range of this assay was 0.01–32 mg/dL.
Serum ferritin levels were evaluated using an ELISA kit
(RCD012R, BioVendor) with an intra-assay CV of 7.3%
and an inter-assay CV of 4.5%. Serum D-dimer was mea-
sured by a human Abcam ELISA kit (Cat No. ab260076),
with a sensitivity of 2.36 ng/mL, intra-assay of 4.4%, and
inter-assay of 4.3%.
Serum calcium was estimated by a calcium colorimetric
assay kit, Abcam, USA (Cat No. ab102505), with a de-
tection range 0.4–100 mg/dL, according to the manufac-
Statistical Package for Social Sciences (SPSS) for Win-
dows version 20.0 (IBM SPSS Statistics, IBM Corporation,
Armonk, NY, USA) was used for data analysis. Data were
presented as mean ± standard deviation (SD) and one-way
analysis of variance (ANOVA), followed by Tukey’s
honestly signiﬁcant difference (HSD). Post-hoc analyses
were used for multiple comparisons between groups. The
) test of signiﬁcance was applied to compare
proportions, and the Pearson correlation coefﬁcient was
used to assess the association between vitamin D and the
studied parameters. pvalues were considered statistically
signiﬁcant at < 0.05.
For all COVID-19 patients, the mean age was (56 ± 16),
and sex distribution and laboratory characteristics are
shown in Table 1.
COVID-19 patients were divided into three subgroups
according to vitamin D levels. A signiﬁcant proportion
(49%) of COVID-19 patients (81 of 166) were deﬁcient in
vitamin D. About 48 patients (29%) were insufﬁcient in
vitamin D. Only 37 patients (22%) had sufﬁcient vitamin D
levels. Demographic data of the subgroups showed no
signiﬁcant difference regarding mean age of the vitamin D–
deﬁcient group in comparison to the insufﬁciency and
sufﬁciency groups (61 ± 15 vs 56 ± 15 and 54 ± 16, re-
spectively). Regarding sex distribution, there was no statis-
tically signiﬁcant difference between three patient subgroups
We reported a statistically high difference (pvalue <
0.001) when we compared the vitamin D deﬁciency group
and both the insufﬁciency and sufﬁciency groups regarding
laboratory parameters: serum ferritin (890 ± 170 in the
deﬁciency group versus 782 ± 188 in the insufﬁciency
group and 678 ± 154 in the sufﬁciency group), CRP (9 ± 4
in the deﬁciency group versus 7 ± 3 in the insufﬁciency
group and 6 ± 3 in the sufﬁciency group), D-dimer (2.3 ±
1.1 in the deﬁciency group versus 1.7 ± 0.8 in the insuf-
ﬁciency group and 1.4 ± 0.4 in the sufﬁciency group), PTH
(42 ± 7 in the deﬁciency group versus 39 ± 8 in the in-
sufﬁciency group and 36 ± 7 in the sufﬁciency group),
calcium (7.9 ± 1.2 in the deﬁciency group versus 8.2 ± 1.4
in the insufﬁciency group versus 9.5 ± 0.8 in the sufﬁciency
group), and vitamin D (14 ± 4 in the deﬁciency group
versus 24 ± 2 in the insufﬁciency group and 45 ± 15 in the
sufﬁciency group). ALT and relative lymphocytic counts
showed no signiﬁcant difference between the three sub-
groups (Table 3).
The clinical features for each subgroup are represented
in Table 4. Only fever and fatigue showed signiﬁcant
differences between the three subgroups of patients (p
values were 0.01 and 0.003, respectively). The other pa-
rameters showed no statistically signiﬁcant differences
between the three subgroups (Table 4).
In the current study, we investigated the correlation
between vitamin D levels in COVID-19 patients and other
parameters of the patients included in the study. There was
a statistically signiﬁcant negative correlation between vi-
tamin D levels and ferritin, PTH, CRP, and D-dimer (p
values = 0.01, < 0.001, < 0.001, and 0.03, respectively) and
a signiﬁcant positive correlation with calcium (pvalues =
0.007). However, ALT, relative lymphocytic count, and age
showed no signiﬁcant correlation (Table 5). In addition, the
scatter plot curves for each signiﬁcant parameter correlated
with vitamin D levels were demonstrated in Figures 1–5.
Table 1. Demographic and laboratory characteristics of all
patients included in the study.
Parameter Patients (n= 166)
(Mean ± SD) 56 ± 16
Female (n, %) 58 (35%)
Male (n, %) 108 (65%)
(Mean ± SD) 790 ± 670
(Mean ± SD) 140 ± 106
(Mean ± SD) 38 ± 10
Lymphocytes (%) 8.0 ± 2.0
(Mean ± SD) 8.0 ± 1.0
(Mean ± SD) 7.0 ± 6.0
(Mean ± SD) 2.0 ± 3.0
Vitamin D (ng/mL)
(Mean ± SD) 23 ± 15
Data are presented as mean ± SD, number, and (%).
Almehmadi et al. 3
The current study was conducted to evaluate the vitamin D
status among COVID-19 patients and to study the asso-
ciation of vitamin D deﬁciency with clinical data and in-
ﬂammatory biomarkers in COVID-19 patients.
Although little is known about the effects of vitamin D
deﬁciency on the clinical presentation and the outcome of
several studies have demonstrated
the relationship between other respiratory infections and
vitamin D. Vitamin D has been reported to protect against
Table 2. Comparison between subgroups of COVID-19 patients according to demographic data.
Parameter Deﬁciency (n= 81) Insufﬁciency (n= 48) Sufﬁciency (n= 37) p-value
Mean ± SD 61 ± 15 56 ± 15 54 ± 16 0.06
Female 24 (30%) 15 (31%) 19 (51%) —
Male 57 (70%) 33 (69%) 18 (49%) 0.06
Data are presented as mean using F-one-way analysis of variance.
Data are presented as number and (%) using the chi-square test.
**p-value < 0.001 HS; *p-value < 0.05 S.
Table 3. Comparison between COVID-19 patients subgroups according to laboratory data.
Laboratory data Deﬁciency (n = 81) Insufﬁciency (n = 48) Sufﬁciency (n = 37) p-value
Ferritin (ng/ml) 890 ± 170 782 ± 188a 678 ± 154ab < 0.001**
ALT (U/L) 132 ± 95 139 ± 108 160 ± 124 0.38
PTH (pg/mL) 42 ± 7 39 ± 8a 36 ± 7ab < 0.001**
Relative lymphocytes (%) 7 ± 3 8 ± 2 8 ± 2 0.08
Calcium (mg/dL) 7.9 ± 1.2 8.2 ± 1.4a 9.5 ± 0.8ab < 0.001**
CRP (mg/L) 9 ± 4 7 ± 3a 6 ± 3ab < 0.001**
D-dimer (ng/mL) 2.3 ± 1.1 1.7 ± 0.8a 1.4 ± 0.4ab < 0.001**
Vitamin D 14 ± 4 24 ± 2a 45 ± 15ab < 0.001**
Using: F-one-way analysis of variance.
Post-hoc test, LSD: a: statistically signiﬁcant difference with the deﬁciency group; b: statistically signiﬁcant difference with insufﬁciency group.
p-value > 0.05 NS; *p-value < 0.05 S; **p-value < 0.001 HS.
Table 4. Clinical characteristics of COVID-19 patients in the three subgroups.
Deﬁciency (n= 81) Insufﬁciency (n= 48) Sufﬁciency (n= 37) p-value
Fever 73 38 25 0.01*
Cough 45 28 22 0.91
Headache 29 19 16 0.73
Fatigue 61 36 17 0.003*
Anosmia 45 35 27 0.06
Loss of taste 44 33 25 0.18
Diarrhea 32 21 16 0.86
Diabetes mellitus 19 13 5 0.31
Hypertension 17 11 4 0.32
ICU admission 7 3 1 0.48
CPAP 5 2 1 0.69
Mechanical ventilation 2 1 0 0.64
Mortality 2 1 0 0.64
Data are presented as number using the chi-square test.
Abbreviation: CPAP: continuous positive airway pressure.
*p-value < 0.05 S; p-value > 0.05 NS.
4European Journal of Inﬂammation
In our current research, we found that 49% of COVID-
19 patients enrolled in the study were deﬁcient in vitamin
D, while 29% were insufﬁcient in vitamin D, resulting in a
total of 78% with deﬁciency or insufﬁciency in vitamin D.
Also, we found that the vitamin D deﬁciency group in-
cluded elderly patients.
In accordance with our ﬁndings, Zhou et al.
that patients with a serum vitamin D level of less than
20 ng/mL had a 64% higher chance of getting community-
acquired pneumonia. Ricci et al.
reported that 80% of
their COVID-19 patients had vitamin D deﬁciency and
6.5% had vitamin D insufﬁciency. Paiz et al.
vitamin D has recently become more prominent in studies
due to its possible effect on the incidence of COVID-19
infection. Moreover, Ilie et al.
found that the oldest
portion of the population, which is the most susceptible to
COVID-19 infection, is also the group with the lowest
vitamin D levels. On the other hand, Ali,
there is insufﬁcient evidence to link vitamin D levels with
COVID-19 severity and mortality.
The current study evaluated the effect of vitamin D
deﬁciency on the inﬂammatory markers that are used to
assess the clinical conditions of patients, such as serum
ferritin, CRP, ALT, and D-dimer. We observed higher
concentrations of inﬂammatory markers in the vitamin
Ddeﬁciency group when compared to the other two
Our ﬁndings agree with a previous study by Yilmaz and
which found that vitamin D may reduce the incidence
of inﬂammatory markers, which are effective predictors of
worse outcomes in children with COVID-19 infection. The
pathology of COVID-19 includes a complex interaction
between the virus and the host immune system. COVID-19
triggers the release of pro-inﬂammatory cytokines. Vitamin
D has been reported as a modulator of the immune re-
sponse of macrophages, preventing them from releasing
several inﬂammatory cytokines and chemokines.
Table 5. Correlation between vitamin D with all parameters in
COVID-19 patients group.
Age (years) 0.13 0.09
Ferritin (ng/ml) 0.44 0.01*
ALT (U/L) 0.07 0.34
PTH (pg/mL) 0.60 < 0.001**
Lymphocytes (%) 0.14 0.07
Calcium (mg/mL) 0.5 0.007*
CRP (mg/L) 0.6 < 0.001**
D-dimer (ng/mL) 0.36 0.03*
Using r-Pearson correlation coefﬁcient.
p-value > 0.05 NS; *p-value < 0.05 S; **p-value < 0.001 HS.
Figure 1. Scatter plot between Vitamin D with ferritin in patients group. r = 0.44; p= 0.01.
Almehmadi et al. 5
Figure 2. Scatter plot between Vitamin D with PTH in patients group. r = 0.60; p< 0.001.
Figure 3. Scatter plot between Vitamin D with D-dimer in patients group. r = 0.36, p= 0.03.
6European Journal of Inﬂammation
Figure 4. Scatter plot between Vitamin D with CRP in patients group. r = 0.6, p< 0.001.
Figure 5. Scatter plot between Vitamin D with calcium in patients group. r = 0.5, p= 0.007.
Almehmadi et al. 7
In our current research, we studied the correlation be-
tween vitamin D and inﬂammatory markers used in clinical
practice to assess the severity of COVID-19. Signiﬁcant
negative correlations were reported between lower vitamin
D levels and higher inﬂammatory markers CRP, ferritin,
and D-dimer. In accordance with our ﬁndings, Daneshkhah
observed that high CRP was inversely correlated
with vitamin D levels. Our results suggest a possible role
for vitamin D in the reduction of complications caused by
the cytokine storm, considering C-reactive protein as an
important marker for the severity of COVID-19 inﬂam-
mation and the cytokine storm. Moreover, Ricci et al.
found a signiﬁcant relation between high levels of D-dimer
and low levels of vitamin D.
The relationship between vitamin D and inﬂammatory
diseases has triggered a lot of debate because the mech-
anism of the link between low vitamin D concentrations
and increased inﬂammatory cytokines levels has not been
completely explored. A recent meta-analysis conducted by
Kazemi et al.
discovered that in COVID-19, the associ-
ation between vitamin D deﬁciency and lung inﬂammation
was contradictory and the relationship between vitamin D
deﬁciency and mortality was ambiguous. Vitamin D deﬁ-
ciency is prevalent in hospitalized patients with severe
illnesses, especially in those who are critically ill.
There are several conﬂicting results at this point.
Yousefzadeh et al.
reported that vitamin D levels mea-
sured during an acute disease may be an inaccurate
biomarker of vitamin D status, and the changes in vitamin
D–binding protein (DBP) levels should be noted as con-
founding factors when interpreting 25(OH)D concentra-
tions in blood. Another explanation by Quraishi and
is that lower 25(OH)D levels can be caused by
lower levels of DBP due to interstitial leakage caused by
increased vascular permeability during inﬂammatory dis-
eases. Amrein et al.
revealed that vitamin D levels as-
sessed at the beginning of an acute inﬂammatory injury can
represent the acute phase of the illness rather than true
vitamin D levels. Moreover, Waldron et al.
serum 25(OH)D is a negative acute phase reactant, and
after an acute inﬂammatory injury, serum 25(OH)D is an
ineffective biomarker of vitamin D status.
On the other hand, vitamin D regulates immune reac-
tions induced by macrophages and dendritic cells, which
are the ﬁrst line of host defense, preventing them from the
production of excessive inﬂammatory cytokine and che-
The value of vitamin D sufﬁciency in serious
disease is strongly supported by the study of Braun et al.,
in which 25(OH)D was measured at the start of critical
treatment. Mata-Granados et al.
observed that large doses
of oral 25(OH)D can correct vitamin D deﬁciency and
could lead to improvement in general health and most
likely, a decrease in the overall mortality rate of critically ill
Regarding the clinical presentations of the COVID-19
patients we studied, the clinical features of COVID-19
infection were more prominent among the vitamin D–
deﬁcient group in comparison to other groups. Patients
who were deﬁcient in vitamin D had a higher frequency of
fever and fatigue in comparison to the other groups, and the
difference was statistically signiﬁcant. In consistency with
our results, Mardani et al.
observed that adequate vitamin
D may have a controlling effect on the symptoms of
COVID-19 infection by interfering with the rennin-
angiotensin-aldosterone system (RAAS) and immune sys-
tem functions through the vitamin D receptor (VDR), which
is a ligand-activated transcription factor. Pereira et al.
observed a positive association between vitamin D deﬁ-
ciency and the severity of the disease. Moreover, Ilie et al.
found a signiﬁcant relation between vitamin D levels and the
number of COVID-19 cases in different European countries,
with increased mortality.
Considering the causes of clinical diversity in the course
and mortality rates of COVID-19 cases, it is necessary to
point out that vitamin D deﬁciency may also underlie the
comorbidity of patients.
This study has limitations. The retrospective design of
the study may possibly involve incomplete or incorrect
data, and the number of patients in the study may be small,
but it may provide guidance which helps researchers
perform larger studies to explore the effects of vitamin D
deﬁciency on COVID-19 infected patients. The study was
underpowered to examine severity due to the small
numbers of mortality and ICU-admitted patients. In ad-
dition, vitamin D levels before the start of COVID-19
infection were not reported for included patients. So, vi-
tamin D levels should be measured before and at the onset
of acute diseases in future research, with adjustment for all
possible affecting factors such as age, sex, BMI, diet,
medication, vitamin D supplementation, and socioeco-
We evaluated vitamin D status and its relationship with
clinical features in hospitalized patients with COVID-19.
Our results suggested that vitamin D deﬁciency was as-
sociated with increased levels of inﬂammatory markers of
The authors would like to thank Taif University, Taif, Saudi Arabia,
for their support (Taif University Researchers Supporting Project
number: TURSP-2020/80), Taif University, Taif, Saudi Arabia.
8European Journal of Inﬂammation
Declaration of conﬂicting interests
The author(s) declared no potential conﬂicts of interest with
respect to the research, authorship, and/or publication of this
The author(s) disclosed receipt of the following ﬁnancial support
for the research, authorship, and/or publication of this article: The
work was funded by Taif University, Taif, Saudi Arabia. (Taif
University Researchers Supporting Project number: TURSP-
Mazen Almehmadi https://orcid.org/0000-0002-7580-8667
1. Zhu N, Zhang D, Wang W, et al. A novel coronavirus from
patients with pneumonia in China, 2019. N Engl J Med 2020;
2. Grant WB, Lahore H, McDonnell SL, et al. Evidence that
vitamin D supplementation could reduce risk of inﬂuenza
and COVID-19 infections and deaths. Nutrients 2020;
3. Guo YR, Cao QD, Hong ZS, et al. The origin, transmission
and clinical therapies on coronavirus disease 2019 (COVID-
19) outbreak an update on the status. Mil Med Res 2020;
4. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of co-
ronavirus disease 2019 in China. N Engl J Med 2020; 382:
5. Teymoori-Rad M, Shokri F, Salimi V, et al The interplay
between vitamin D and viral infections. Rev Med Virol 2019;
6. Hong M, Xiong T, Huang J, et al., Association of vitamin D
supplementation with respiratory tract infection in infants.
Matern Child Nutr 2020; 16(3): e12987.
7. Palacios C and Gonzalez L. Is vitamin D deﬁciency a major
global public health problem? J Steroid Biochem Mol Biol
2014; 144: 138–145.
8. van Schoor NM and Lips P. Worldwide vitamin D status.
Best Pract Res Clin Endocrinol Metab 2011; 25(4):
9. Al-Daghri NM, Vitamin D in Saudi Arabia: prevalence,dis-
tribution and disease associations. J Steroid Biochem Mol
Biol 2018; 175:102–107.
10. Al-Alyani H, Al-Turki HA, Al-Essa ON, et al. Vitamin D
deﬁciency in Saudi Arabians: a reality or simply hype: a
meta-analysis (2008-2015). J Family Community Med 2018;
11. Prietl B, Treiber G, Pieber TR, et al. Vitamin D and immune
function. Nutrients 2013; 5(7):2502–2521.
12. McCartney DM and Byrne DG. Optimisation of Vitamin D
Status for Enhanced Immuno-protection Against Covid-19.
Ir Med J 2020; 113(4): 58.
13. Marik PE, Kory P and Varon J. Does vitamin D status impact
mortality from SARS-CoV-2 infection? Med Drug Discov
2020; 6: 100041.
14. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-
CoV-2 cell entry depends on ACE2 and TMPRSS2 and is
blocked by a clinically proven protease inhibitor. Cell 2020;
15. Bombardini T and Picano E. Angiotensin-converting enzyme
2 as the molecular bridge between epidemiologic and clinical
features of COVID-19. Can J Cardiol 2020; 36(5):
16. Rehan VK, Torday JS, Peleg S, et al. 1Alpha, 25-dihydroxy-
3-epi-vitamin D3, a natural metabolite of 1alpha,25-
dihydroxy vitamin D3: production and biological activity
studies in pulmonary alveolar type II cells. Mol Genet Metab
2020; 76(1): 46–56.
17. Shamsi U, Khan S, Azam I, et al. A multicenter case control
study of association of vitamin D with breast cancer among
women in Karachi, Pakistan. PLoS One 2020; 15(1):
18. Miaoulis G and Michener RD. An introduction to sampling,
Dubuque, Iowa: Kendall/Hunt Pub. Co, 1976.
19. Cochran WG. Sampling techniques, Wiley, New York, 1963.
20. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and
treatment of adults with community-acquired pneumonia.
An ofﬁcial clinical practice guideline of the American
thoracic society and infectious diseases society of America.
Am J Respir Crit Care Med 2019; 200(7): e45–e67.
21. Marik PE, Kory P and Varon J. Does vitamin D status impact
mortality from SARS-CoV-2 infection? Med Drug Discov
2020; 6: 100041.
22. Ilie PC, Stefanescu S and Smith L. The role of vitamin D in
the prevention of coronavirus disease 2019 infection and
mortality. Aging Clin Exp Res 2020; 32(7): 1195–1198.
23. Baqui AH, Black RE, Arifeen SE, et al. Causes of childhood
deaths in Bangladesh: results of a nationwide verbal autopsy
study. Bull World Health Organ 1998; 76(2): 161–171.
24. Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D
supplementation to prevent acute respiratory tract infections:
systematic review and meta-analysis of individual participant
data. BMJ 2017; 356: i6583.
25. Zhou YF, Luo BA and Qin LL. The association between
vitamin D deﬁciency and community-acquired pneumonia:
A meta-analysis of observational studies. Medicine 2019;
26. Ricci A, Pagliuca A, D’Ascanio M, et al. Circulating vitamin
D levels status and clinical prognostic indices in COVID-19
patients. Respir Res 2021; 22(1): 76.
27. Paiz N, Alonso P and Portillo AL, Vitamin D status: can it
affect the risk of infection and the severity of COVID-19
symptoms? Curr Trop Med Rep 2021; 1–8.
Almehmadi et al. 9
28. Ali N, Role of vitamin D in preventing of COVID-19 in-
fection, progression and severity. J Infect Public Health
2020; 13(10): 1373–1380.
29. Yılmaz K and S
¸en V. Is vitamin D deﬁciency a risk factor for
COVID-19 in children? Pediatr Pulmonol 2020; 55(12):
30. Zhou Y, Fu B, Zheng X, et al. Pathogenic T cells and
inﬂammatory monocytes incite inﬂammatory storm in
severe COVID-19 patients. Natl Sci Rev 2020; 7(6):
31. Daneshkhah A, Agrawal V, Eshein A, et al. Evidence for
possible association of vitamin D status with cytokine storm
and unregulated inﬂammation in COVID-19 patients. Aging
Clin Exp Res 2020; 32(10): 2141–2158.
32. Kazemi A, Mohammadi V, Aghababaee SK, et al. Associ-
ation of Vitamin D status with SARS-CoV-2 infection or
COVID-19 severity: a systematic review and meta analysis.
Adv Nutr 2021; nmab012.
33. Leaf DE, Croy HE, Abrahams SJ, et al. Cathelicidin anti-
microbial protein, vitamin D, and risk of death in critically ill
patients. Crit Care 2015; 19(1): 80.
34. Brook K, Camargo CA, Christopher KB, et al. Admission
vitamin D status is associated with discharge destination in
critically ill surgical patients. Ann Intensive Care 2015; 5(1):
35. Czarnik T, Czarnik A, Gawda R, et al. (2018) Vitamin D
kinetics in the acute phase of critical illness: a prospective
observational study. J Crit Care. 43:294–299.
36. Yousefzadeh P, Shapses SA and Wang X. Vitamin D binding
protein impact on 25-hydroxyvitamin D levels under dif-
ferent physiologic and pathologic conditions. Int J Endo-
crinol 2014; 2014: 981581.
37. Quraishi SA and Camargo CA. Vitamin D in acute stress and
critical illness. Curr Opin Clin Nutr Metab Care 2012; 15(6):
38. Amrein K, Papinutti A, Mathew E, et al. Vitamin D and
critical illness: what endocrinology can learn from intensive
care and vice versa. Endocr Connect 2018; 7(12):
39. Waldron JL, Ashby HL, Cornes MP, et al. Vitamin D: a
negative acute phase reactant. J Clin Pathol 2013; 66(7):
40. Aranow CJ. Vitamin D and the immune system. J Investig
Med 2011; 59(6): 881–886.
41. Braun AB, Gibbons FK, Litonjua AA, et al. Low serum 25-
hydroxyvitamin D at critical care initiation is associated with
increased mortality. Crit Care Med 2012; 40 (1): 63–72.
42. Mata-Granados JM, Vargas-Vasserot J, Ferreiro-Vera C, et al.
Evaluation of vitamin D endocrine system (VDES) status
and response to treatment of patients in intensive care units
(ICUs) using an on-line SPE-LC-MS/MS method. J Steroid
Biochem Mol Biol 2010; 121: 452–455.
43. Mardani R, Alamdary A, Mousavi Nasab SD, et al. Asso-
ciation of vitamin D with the modulation of the disease
severity in COVID-19 2020; Virus Res. 289: 198148.
44. Pereira M, Dantas Damascena A, Galvão Azevedo LM, et al.
Vitamin D deﬁciency aggravates COVID-19: systematic
review and meta-analysis. Crit Rev Food Sci Nutr 2020; 4:
45. Murdaca G, Pioggia G and Negrini S. Vitamin D and Covid-
19: an update on evidence and potential therapeutic impli-
cations. Clin Mol Allergy 2020; 18(1): 23.
10 European Journal of Inﬂammation