Association of Vitamin D Status with SARS-CoV-2 Infection or COVID-19 Severity- A Systematic Review and Meta-analysis

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REVIEW
Association of Vitamin D Status with SARS-CoV-2
Infection or COVID-19 Severity: A Systematic
Review and Meta-analysis
Asma Kazemi,1 Vida Mohammadi,2 Sahar Keshtkar Aghababaee,3 Mahdieh Golzarand,4 Cain CT Clark,5 and Siavash Babajafari1
1Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran; 2Department of Nutrition, Sepidan
Bagherololoom Health Higher Education College, Shiraz University of Medical Sciences, Shiraz, Iran; 3Department of Nursing, College of Medical Sciences,
Qazvin Branch, Islamic Azad University, Qazvin, Iran; 4Nutrition and Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti
University of Medical Sciences, Tehran, Iran; and 5Centre for Intelligent Healthcare, Coventry University, Coventry, United Kingdom
ABSTRACT
This systematic review was conducted to summarize and clarify the evidence on the association between 25-hydroxyvitamin-D [25(OH)D]
concentrations and coronavirus disease 2019 (COVID-19) risk and outcomes. PubMed, Scopus, and Web of Science databases and Google Scholar
were searched up to 26 November 2020. All retrospective and prospective cohort, cross-sectional, case-control, and randomized controlled trial
studies that investigated the relation between 25(OH)D and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19
severity were included. Thirty-nine studies were included in the current systematic review. In studies that were adjusted (OR: 1.77; 95% CI: 1.24, 2.53;
I2: 44.2%) and nonadjusted for confounders (OR: 1.75; 95% CI: 1.44, 2.13; I2: 33.0%) there was a higher risk of SARS-CoV-2 infection in the vitamin D
deficiency (VDD) group. Fifteen studies evaluated associations between VDD and composite severity. In the studies that were adjusted (OR: 2.57;
95% CI: 1.65, 4.01; I2 = 0.0%) and nonadjusted for confounders (OR: 10.61; 95% CI: 2.07, 54.23; I2 = 90.8%) there was a higher severity in the VDD
group. Analysis of studies with crude OR (OR: 2.62; 95% CI: 1.13, 6.05; I2: 47.9%), and adjusted studies that used the Cox survival method (HR: 2.35; 95%
CI: 1.22, 4.52; I2: 84%) indicated a significant association of VDD with mortality, while in adjusted studies that used logistic regression, no relation
was observed (OR: 1.05; 95% CI: 0.63, 1.75; I2: 76.6%). The results of studies that examined relations between VDD and intensive care unit (ICU)
admission, pulmonary complications, hospitalization, and inflammation were inconsistent. In conclusion, although studies were heterogeneous
in methodological and statistical approach, most of them indicated a significant relation between 25(OH)D and SARS-CoV-2 infection, COVID-19
composite severity, and mortality. With regard to infection, caution should be taken in interpreting the results, due to inherent study limitations.
For ICU admission, inflammation, hospitalization, and pulmonary involvement, the evidence is currently inconsistent and insufficient. Adv Nutr
2021;00:1–23.
Keywords: COVID-19, vitamin D, severity, infection, SARS-CoV-2
Introduction
Vitamin D deficiency (VDD) and insufficiency in adults
and children, as a global problem, is associated with several
disorders, including metabolic disorders, autoimmune dis-
eases, cardiovascular disease, diabetes, and infections, and
has been widely considered by researchers and clinicians
(1). In particular, several studies have investigated the
link between the risk of respiratory tract infections and
VDD (2). For instance, Mamani et al. (3) reported an
association between incidence of community-acquired pneu-
monia and low serum concentrations of 25-hydroxyvitamin
D [25(OH)D], and adverse outcomes were observed in
acute respiratory distress syndrome (ARDS) patients with
VDD (4).
Vitamin D is a fat-soluble vitamin that plays an impor-
tant role in several physiological processes, such as bone
metabolism, calcium and phosphorus absorption, and im-
mune system function (5). It may reduce the risk of microbial
infections through stimulating innate cellular immunity,
inhibiting the cytokine storm, decreasing proinflammatory
cytokine production, and modulating the adaptive immune
response (6). Vitamin D3 and vitamin D2 are 2 primary
metabolites of vitamin D (7). Unstable 7-dehydrocholesterol
in the skin is transformed to pre-vitamin D3 and stable
vitamin D3, respectively, when exposed to UV-B radiation
(8). Vitamin D3, or cholecalciferol, can also be found in
foods, such as dairy products, eggs, and fish (9). Vitamin
D3 is subsequently converted to 25-hydroxyvitamin D3
C© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Adv
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(25(OH)D3) through 25-hydroxylase enzyme activity during
the hydroxylation process in the liver. The 25(OH)D3
form then transfers to the kidney and converts to 1α,25-
dihydroxyvitamin D3 via 1α-hydroxylase, otherwise known
as calcitriol, the active form of vitamin D (8, 10).
Currently, the global community is involved in a novel
pandemic named coronavirus disease 19 (COVID-19), a res-
piratory tract infection caused by the severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) (11). The WHO
reported the total global cases of SARS-CoV-2 infection
and death as >61.8 and 1.4 million, respectively (weekly
epidemiological update, 1 December 2020) (12). This novel
coronavirus (SARS-CoV-2), like the other viruses of the β-
coronavirus family, is extremely contagious, and COVID-
19 symptoms vary from initially mild symptoms such as
dry cough, fever, fatigue, and gastrointestinal symptoms, to
severe situations requiring admission to an intensive care
unit (ICU) or death in severe cases (13, 14). In some
cases, inflammation can increase following both local and
systemic immune responses generated by this virus and an
increased number of leukocyte and concentrations of plasma
proinflammatory cytokines have been reported in patients
infected with SARS-CoV-2 (15).
Several studies have investigated the association of
25(OH)D3 concentrations and supplementation with the risk
and severity of respiratory virus infections (16, 17). Indeed,
Martineau et al. (18) conducted a meta-analysis that included
25 placebo-controlled clinical trials (total of 10,933 people)
and concluded that vitamin D supplementation reduces the
risk of acute respiratory infections, especially in people with
the lowest 25(OH)D concentrations.
Recently, a growing body of evidence has emerged re-
garding potential factors affecting the incidence and severity
of COVID-19 (19–21). Recent reports highlight that certain
factors may be effective in controlling this pandemic or
reducing the damage caused by it. Indeed, based on the
global prevalence of VDD (22), it has attracted considerable
attention as a potential factor associated with the risk or
severity of COVID-19, and several studies have reported
on this possible association (6, 23–25). However, results
currently preclude a clear consensus. Thus, we conducted
this systematic review to summarize and clarify the evidence
on the association between 25(OH)D concentrations and
COVID-19 risk and outcomes.
This study was supported by Vice Chancellor of Research, Shiraz University of Medical Sciences
(grant number 22491).
Author disclosures: The authors report no conflicts of interest.
Supplemental Tables 1–15 and Supplemental Figures 1–4 are available from the
“Supplementary data” link in the online posting of the article and from the same link in the
online table of contents at https://academic.oup.com/advances/.
Address correspondence to AK (e-mail: kazemiasma66@gmail.com) or VM (e-mail:mohammadi_vida@yahoo.com).
Abbreviations used: ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease
2019; CRP, C-reactive protein; ICU, intensive care unit; RCT, randomized controlled trial;
SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TGF-β , transforming growth
factor β ; Th, T-helper; VDD, vitamin D deficiency; VDR, vitamin D receptor; WMD, weighted
mean difference; 25(OH)D, 25-hydroxyvitamin-D.
Methods
The protocol of this study has been registered in PROS-
PERO International Prospective Register of Systematic
Reviews (www.crd.york.ac.uk/prospero/index.asp, identifier
CRD42020203903). The Preferred Reporting Items for Sys-
tematic Reviews and Meta-Analyses (PRISMA) statement
was used in developing and conducting this systematic
review (26).
Search strategy and study selection
PubMed, Scopus, and Web of Science databases and the
first 500 Google Scholar search results were searched up to
26 November 2020, with no restriction in language. Refer-
ence lists of included studies and relevant review articles were
also scanned for additional relevant studies. The following
search strategy was used for our search: (Coronavirus or
COVID-19 or SARS-CoV-2) AND (vitamin D or 25-OH-D
or cholecalciferol or 25-hydroxycholecalciferol or calcitriol
or 25-hydroxyvitamin D or hydroxycholecalciferols or 25-
hydroxyvitamin D3).
Two reviewers independently assessed the eligibility of
studies. Studies that met the following criteria were included:
1) study design as retrospective, prospective, or cross-
sectional, or case-control studies reporting serum/plasma
concentrations of 25(OH)D; 2) participants as patients
diagnosed with COVID-19 with no restriction on age; 3)
exposure/intervention as serum/plasma concentrations of
vitamin D either reported as a continuous or categorical
variable (deficiency vs. sufficiency); and 4) outcome as SARS-
CoV-2 infection or COVID-19 severity, with severity defined
as at least 1 of the following outcomes—ARDS and/or
mechanical ventilation, ICU admission, length of hospital-
ization, and death. The exclusion criteria were as follows:
1) case reports, abstracts, and summaries of discussion; 2)
insufficient data on vitamin D measurement or COVID-19
outcomes; 3) preprint studies without peer review; and 4)
studies that were not individual based (compared countries
or regions).
Data extraction and quality assessment
The following data were extracted independently by 2 re-
viewers: first author, study design, start and completion
date, geographical location, age and gender composition of
patients, objective of the study [if the aim of the study was
to assess association of 25(OH)D status with risk of SARS-
CoV-2 infection or to assess the association with severity of
disease], definition of VDD, time of serum 25(OH)D mea-
surement, prevalence of VDD and insufficiency, definition
of disease severity, the number of events and nonevents in
the case and control groups, relative risk and 95% CIs for
SARS-CoV-2 infection and disease severity, and adjustment
factors.
Quality assessment of observational studies was assessed
using the Newcastle–Ottawa Scale, which included 3 items:
selection, comparability, and outcome (27). Studies with a
score of ≥7 were defined as high quality. The Cochrane
risk-of-bias tool was used to evaluate quality assessment
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mailto:kazemiasma66@gmail.com
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Google Scholar and other
FIGURE 1 Summary of the process for selecting studies that investigated the association of vitamin D status with SARS-CoV-2 infection
and COVID-19 severity. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; 25(OH)D,
25-hydroxyvitamin-D.
of randomized trials. This tool included selection bias,
performance and detection bias, attrition bias, reporting bias,
and the other biases (28).
Statistical analysis
Wherever it was probable, we pooled data and conducted
meta-analysis (SARS-CoV-2 infection, disease severity, ICU
admission, and mortality). We used ORs to estimate the
association between VDD and SARS-CoV-2 infection and
COVID-19 severity. ORs with 95% CIs were obtained using
a random-effects model. In studies that did not report
relative risk, the OR was calculated by the number of
events and nonevents in the case and control groups;
these studies together with studies with crude ORs were
analyzed separately from the studies that reported adjusted
relative risk. To compare concentrations of 25(OH)D3
between groups, we used the weighted mean difference
(WMD) and its 95% CI. Heterogeneity was evaluated using
Cochran’s Q test, deriving its magnitude from the I2. If
at least 10 studies were available, we explored potential
small-study effects, such as publication bias, using visual
examination of the funnel plot and Egger’s test (29). All
analyses were conducted using Stata version 13 software
(StataCorp).
Results
Characteristics of the study population
As described in Figure 1, 1518 records were obtained by the
literature search. Of these, 57 articles met the inclusion crite-
ria; however, 3 studies were excluded because they used old
25(OH)D data, and 15 papers were preprints (Supplemental
Table 1). Finally, 39 studies were included, with different
geographical locations and ethnic backgrounds, including
Europe (n = 17 studies), North America (United States)
(n = 2), South America (n = 2), West Asia (n = 9), South
Asia (n = 4), East Asia (n = 4), and Africa (n = 1). Ten
studies were of a case-control design, 19 cross-sectional, 2
retrospective cohorts, 2 randomized controlled trials (RCTs),
2 quasi-experimental design, and 4 studies were only descrip-
tive. All studies were conducted in adults, except for 1 study
in children and 1 study in pregnant women. All studies,
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except for 2, included both male and female participants; in 1
study, participants were only male (30), and in another, only
females were included (31). Nine studies were not included
in the analysis because 4 of them were only descriptive [only
reported concentration of 25(OH)D in patients; Supplemen-
tal Table 2] (31–34), 1 study was in children (35), and 4
were different in design from other studies [they assessed
the effect of 25(OH)D3 supplementation instead of 25(OH)D
measurement] (14, 36–38).
Twenty-one studies examined the association of 25(OH)D
concentrations with the severity, 14 studies with SARS-
CoV-2 infection, whereas 10 of them assessed severity as a
secondary outcome. Characteristics of studies that examined
the association of vitamin D with SARS-CoV-2 infection are
summarized in Table 1, and those examining COVID-19
severity are summarized in Table 2.
Association of 25(OH)D status with SARS-CoV-2
infection
Nine studies evaluated the relation between VDD and SARS-
CoV-2 infection. Studies that were adjusted (n = 3) (39–
41) (OR: 1.77; 95% CI: 1.24, 2.53; I2: 44.2%; Figure 2A)
and nonadjusted for confounders (n = 5) (42–45, 46) (OR:
1.75; 95% CI: 1.44, 2.13; I2: 33%; Figure 2B) indicated higher
risk of infection in the VDD group (Figure 2). The Blanch-
Rubió et al. (37) study was not included in analysis, because
of a different design. This study was a cross-sectional study
including 2102 patients with noninflammatory rheumatic
conditions and found that no association between intake of
vitamin D supplement and COVID-19 (risk ratio: 0.91; 95%
CI: 0.62, 1.34).
Twelve studies compared 25(OH)D concentration be-
tween COVID-19 patients and healthy subjects. The pooled
analysis of 10 studies (41–49) revealed a lower concentration
of 25(OH)D in cases compared with controls (WMD =
−7.0 ng/mL; 95%CI: −9.49, −4.50; I2 = 92.4%; cases,
n = 1899; controls, n = 11,122; Supplemental Figure 1).
Subgroup analysis indicated a greater difference in the studies
that measured 25(OH)D after a SARS-CoV-2 test (WMD =
−10.28 ng/mL; 95% CI: −14.41, −6.16; I2 = 90.1%; n = 6
studies) compared with studies that used 25(OH)D data
collected before a SARS-CoV-2 test (WMD = −3.0 ng/mL;
95% CI: −5.15, −0.86, I2 = 80.3%; n = 4 studies). Two
studies were not included in the analysis (35, 50); both studies
indicated that 25(OH)D concentrations were significantly
lower in cases compared with controls. In 1 study, the
participants were children (35); the other study only reported
that COVID-19 patients had a significantly lower 25(OH)D
concentration compared with healthy counterparts; however,
the mean ± SD values of 25(OH)D were not provided (50).
Results of studies are summarized in Supplemental Table 3.
Association of vitamin D status with COVID-19 severity
Twenty-one studies assessed the association of VDD with
severity (composite severity or 1 feature of severity)
as a primary outcome, and 10 studies as a secondary
outcome.
Composite severity
Fifteen studies evaluated the association between VDD and
composite severity. Studies that were adjusted (38, 41, 44, 46,
51, 52) (OR: 2.57; 95% CI: 1.65, 4.01; I2 = 0.0%; Figure 3A)
and nonadjusted for confounders (42, 45, 53–55) (OR: 10.61;
95% CI: 2.07, 54.23, I2 = 90.8%; Figure 3B) revealed a higher
severity in the VDD group. Four studies were not included in
the analysis; one of these studies was conducted in children
and found a negative correlation between fever symptom
and 25(OH)D concentration (P = 0.02), while no significant
correlations were found between other clinical parameters
and 25(OH)D concentration (35). The other study had a
quasi-experimental design and indicated that vitamin D3
supplementation was inversely associated with Ordinal Scale
for Clinical Improvement (OSCI) score for COVID-19 (β =
−3.84; 95% CI: −6.07, −1.62; P = 0.001) (56). The third
study, which assessed vitamin D supplementation in patients
with a past history of COVID-19, found that it reduces the
risk of exacerbation and worsening of the disease (OR: 0.29;
95% CI: 0.10, 0.083; P = 0.02) (57). The last study did not
provide sufficient data, and only reported that VDD was
significantly associated with severity; however, no data were
available to indicate this (58). Results of studies have been
summarized in Supplemental Table 4.
ICU admission or stay
Four studies examined the relation between VDD and ICU
admission and 1 study between VDD and ICU stay duration.
Pooled analysis of 3 studies (38, 44, 59) with unadjusted
ORs indicated no significant relation between VDD and ICU
admission (OR: 1.17; 95% CI: 0.67, 2.03; I2 = 69.3%), while
an RCT that was not pooled with these studies revealed
a lower risk of ICU admission in the intervention group
compared with the control group (OR: 0.03; 95% CI: 0.003,
0.25; P = < 0.001) (36). Carpagnano et al. (59) verified
the association of VDD with ICU stay, highlighting that
10 patients with severe VDD had a median ICU stay of 8 d
with the interquartile range (IQR) of 6 to 11.25., while 32
patients without VDD had a median stay of 12.5 d (IQ25 8,
IQ75 20.5) (Supplemental Table 5).
Pulmonary complications
Eight studies investigated the association of VDD with one
of the pulmonary complication indicators. In Abrishami et
al. (60), an increase in 25(OH)D concentrations yielded a re-
duction in the development of severe lung involvement (OR:
0.96; 95% CI: 0.93, 0.98; P = 0.04). Pizzini et al. (61) found
no significant difference between 25(OH)D concentrations
in patients with or without computed tomographic (CT)
abnormalities (22 vs. 21.6 ng/mL; P = 0.83). Three studies
assessed the relation between 25(OH)D concentration and
progression to ARDS. In a prospective study in 33 hospi-
talized patients, the patients who progressed to ARDS had
a lower serum 25(OH)D concentration on presentation to
the hospital compared with non-ARDS patients [mean (SD):
10.8 (4.8) ng/mL in ARDS and 16.4 (7.6) ng/mL in non-
ARDS patients; P = 0.03] (30), while there was no difference
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—
D
e
Sm
et
(4
2)
M
ar
ch
16
to
A
pr
il
16
,2
02
0
G
en
er
al
ho
sp
ita
li
n
Be
lg
iu
m
Re
tr
os
pe
ct
iv
e
ob
se
rv
a-
tio
na
l
st
ud
y
18
6
SA
RS
-C
oV
-2
+
ho
sp
ita
liz
ed
pa
tie
nt
s
an
d
27
17
di
se
as
ed
co
nt
ro
ls
Pa
tie
nt
s:
m
ed
ia
n
ag
e,
(IQ
R)
:6
9
(5
2–
80
);
m
al
e:
58
.6
%
;
co
nt
ro
ls
:6
8
(4
9–
82
);
m
al
e:
36
.8
%
Se
ru
m
25
(O
H
)D
<
20
ng
/m
L
M
ea
su
re
d
af
te
r
SA
RS
-C
oV
-2
te
st
A
re
lo
w
er
25
(O
H
)D
co
nc
en
tr
at
io
ns
co
rr
el
at
ed
w
ith
CO
VI
D
-1
9?
—
Fe
rr
ar
i(
43
)
Fe
br
ua
ry
to
A
pr
il,
20
20
Th
e
Sa
n
Ra
ffa
el
e
H
os
pi
ta
l,
M
ila
n,
Ita
ly
Re
tr
os
pe
ct
iv
e
co
ho
rt
12
8
SA
RS
-C
oV
-2
+,
21
9
SA
RS
-C
oV
-2
–
Pa
tie
nt
s:
64
.8
%
m
al
es
;
m
al
e
ag
e:
62
.7
;
fe
m
al
e
ag
e:
69
.3
;
he
al
th
y:
48
.8
5%
m
al
es
;m
al
e
ag
e:
62
.8
,f
em
al
e
ag
e:
54
.3
Se
ru
m
25
(O
H
)D
≤3
0
ng
/m
L
Th
e
av
er
ag
e
tim
e
in
te
rv
al
be
tw
ee
n
SA
RS
-C
oV
-2
te
st
an
d
th
ei
r
co
rr
es
po
nd
in
g
25
(O
H
)D
m
ea
su
re
m
en
ts
fo
rt
he
po
si
tive
gr
ou
p
w
as
33
.9
an
d
fo
rt
he
ne
ga
tiv
e
gr
ou
p
w
as
33
.3
3
d
—
— (
Co
nt
in
ue
d)
Vitamin D and COVID-19 5
D
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nloaded from
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ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
1
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
nt
ry
,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
D
efi
n
it
io
n
of
V
it
D
d
efi
ci
en
cy
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
A
d
ju
st
in
g
fa
ct
or
s
H
er
ná
nd
ez
(4
4)
M
ar
ch
10
to
M
ar
ch
31
,2
02
0
U
ni
ve
rs
ity
H
os
pi
ta
l,
Sp
ai
n
Re
tr
os
pe
ct
iv
e
ca
se
-c
on
tr
ol
st
ud
y
21
6
SA
RS
-C
oV
-2
+
an
d
19
7
po
pu
la
tio
n-
ba
se
d
co
nt
ro
ls
;i
n
CO
VI
D
-1
9
pa
tie
nt
s:
nu
m
be
ro
fV
D
D
:
35
;n
um
be
ro
f
no
n-
VD
D
:1
62
C
as
es
:a
ge
,m
ed
ia
n
(IQ
R)
:6
1.
0
(4
7.
5–
70
.0
);
co
nt
ro
ls
:6
1.
0
(5
6.
0–
66
.0
);
m
al
e:
62
.4
%
in
bo
th
gr
ou
ps
Se
ru
m
25
(O
H
)D
<
20
ng
/m
L
A
ta
dm
is
si
on
To
as
se
ss
se
ru
m
25
(O
H
)D
co
nc
en
tr
at
io
ns
in
ho
sp
ita
liz
ed
pa
tie
nt
s
w
ith
CO
VI
D
-1
9
an
d
to
an
al
yz
e
th
e
po
ss
ib
le
in
flu
en
ce
of
vi
ta
m
in
D
st
at
us
on
di
se
as
e
se
ve
rit
y
—
Im
(4
5)
Fe
br
ua
ry
to
Ju
ne
,
20
20
In
ha
U
ni
ve
rs
ity
H
os
pi
ta
l,
So
ut
h
Ko
re
a
C
as
e-
co
nt
ro
l
50
pa
tie
nt
s
w
ith
SA
RS
-C
oV
-2
+
an
d
15
0
co
nt
ro
ls
M
ea
n
ag
e:
57
.5
in
ca
se
an
d
52
.2
in
co
nt
ro
lg
ro
up
s;
m
al
e:
58
%
Se
ru
m
25
(O
H
)D
3
<
20
ng
/m
L
W
ith
in
7
d
of
ad
m
is
?s
io
n
Pr
ev
al
en
ce
of
VD
D
am
on
g
CO
VI
D
-1
9
pa
tie
nt
s,
co
m
pa
rin
g
vi
ta
m
in
D
st
at
us
be
tw
ee
n
CO
VI
D
-1
9
pa
tie
nt
s
an
d
he
al
th
y
in
di
vi
du
al
s
Co
nt
ro
lg
ro
up
w
as
m
at
ch
ed
fo
ra
ge
an
d
se
x
w
ith
th
e
CO
VI
D
-1
9
gr
ou
p
Ke
rg
et
(5
0)
M
ar
ch
24
,t
o
M
ay
15
,2
02
0
U
ni
ve
rs
ity
H
os
pi
ta
li
n
Tu
rk
ey
C
as
e-
co
nt
ro
l
88
SA
RS
-C
oV
-2
+,
20
SA
RS
-C
oV
-2
–
M
ea
n
ag
e:
ca
se
s:
49
.1
;
m
al
e:
60
%
;c
on
tr
ol
s:
35
.2
;m
al
e:
40
%
—
Fi
ft
h
da
y
of
ad
m
is
si
on
to
ho
sp
ita
l
To
de
te
rm
in
e
th
e
re
la
tio
n
of
se
ru
m
vi
ta
m
in
D
co
nc
en
tr
at
io
n
be
tw
ee
n
pa
tie
nt
s
an
d
he
al
th
y
co
nt
ro
ls
—
Lu
o
(4
6)
Fe
br
ua
ry
27
to
M
ar
ch
21
,2
02
0
H
os
pi
ta
li
n
C
hi
na
C
ro
ss
-s
ec
tio
na
l
33
5
CO
VI
D
-1
9
pa
tie
nt
s,
ag
e-
an
d
se
x-
m
at
ch
ed
po
pu
la
tio
n
of
56
0
in
di
vi
du
al
s
Pa
tie
nt
s:
m
ed
ia
n
(IQ
R)
ag
e:
56
(4
3–
64
);
m
al
e:
44
.2
%
;c
on
tr
ol
s:
ag
e:
55
(4
9.
0–
60
.0
);
m
al
e:
45
.9
%
Se
ru
m
25
(O
H
)D
<
30
ng
/m
L
In
co
nt
ro
l,
se
ru
m
25
(O
H
)D
co
nc
en
tr
at
io
ns
w
er
e
m
ea
su
re
d
du
rin
g
th
e
sa
m
e
pe
rio
d
fro
m
20
18
–2
01
9;
in
pa
tie
nt
s,
se
ru
m
25
(O
H
)D
co
nc
en
tr
at
io
ns
w
er
e
m
ea
su
re
d
on
ad
m
is
si
on
To
in
ve
st
ig
at
e
w
he
th
er
VD
D
is
as
so
ci
at
ed
w
ith
CO
VI
D
-1
9
in
ci
de
nc
e
A
ge
,s
ex
,
co
m
or
bi
di
tie
s,
sm
ok
in
g
st
at
us
,
an
d
BM
I
M
ar
da
ni
(4
9)
M
ar
ch
,2
02
0
A
ge
ne
ra
lc
lin
ic
,
Ira
n
C
as
e-
co
nt
ro
l
63
SA
RS
-C
oV
-2
+,
60
SA
RS
-C
oV
-2
–
M
ed
ia
n
ag
e
of
39
;
m
al
e:
52
%
D
efi
ci
en
t
[2
5(
O
H
)D
<
10
ng
/m
L]
,
in
su
ffi
ci
en
t
[2
5(
O
H
)D
:
10
–3
0
ng
/m
L]
A
tb
as
el
in
e
of
th
e
st
ud
y
Re
la
tio
n
be
tw
ee
n
VD
D
an
d
SA
RS
-C
oV
-2
in
fe
ct
io
n
N
ot
ad
ju
st
ed (C
on
tin
ue
d)
6 Kazemi et al.
D
ow
nloaded from
 https://academ
ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
1
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
nt
ry
,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
D
efi
n
it
io
n
of
V
it
D
d
efi
ci
en
cy
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
A
d
ju
st
in
g
fa
ct
or
s
M
el
tz
er
(3
9)
M
ar
ch
3
to
A
pr
il
10
,2
02
0
A
ca
de
m
ic
ho
sp
ita
li
n
U
SA
Re
tr
os
pe
ct
iv
e
co
ho
rt
st
ud
y
63
SA
RS
-C
oV
-2
+,
36
5
SA
RS
-C
oV
-2
–
M
ea
n
ag
e:
45
.7
;m
al
e:
25
.2
%
VD
D
w
as
de
fin
ed
by
th
e
m
os
t
re
ce
nt
25
(O
H
)D
<
20
ng
/m
L
or
1,
25
(O
H
)D
<
18
pg
/m
L
W
ith
in
1
y
be
fo
re
SA
RS
-C
oV
-2
te
st
(s
ub
je
ct
s
re
ce
iv
ed
tr
ea
tm
en
ti
n
th
is
du
ra
tio
n
w
er
e
ex
cl
ud
ed
)
Is
VD
D
as
so
ci
at
ed
w
ith
po
si
tiv
e
te
st
fo
rS
A
RS
-C
oV
-2
?
D
em
og
ra
ph
ic
an
d
co
m
or
bi
di
ty
M
er
zo
n
(4
0)
Fe
br
ua
ry
1
to
M
ar
ch
30
,2
02
0
H
ea
lth
Se
rv
ic
es
in
Is
ra
el
Re
tr
os
pe
ct
iv
e
co
ho
rt
st
ud
y
78
2
SA
RS
-C
oV
-2
+,
70
25
SA
RS
-C
oV
-2
–
SA
RS
-C
oV
-2
+:
m
ea
n
ag
e:
35
.6
;m
al
e:
49
.2
3%
;
SA
RS
-C
oV
-2
–:
m
ea
n
ag
e:
47
.4
;m
al
e:
40
.6
%
“S
ub
op
tim
al
”o
r
“lo
w
”:
pl
as
m
a
25
(O
H
)D
<
30
ng
/m
L
A
tl
ea
st
1
pr
ev
io
us
bl
oo
d
te
st
fo
r
pl
as
m
a
25
(O
H
)D
co
nc
en
tr
at
io
n
Is
VD
D
ris
k
fa
ct
or
fo
r
SA
RS
-C
oV
-2
in
fe
ct
io
n?
D
em
og
ra
ph
ic
va
ria
bl
es
,
ps
yc
hi
at
ric
an
d
so
m
at
ic
di
so
rd
er
s
Su
n
(3
4)
Fe
br
ua
ry
to
Fe
br
ua
ry
,2
02
0
H
os
pi
ta
l
U
ni
ve
rs
ity
in
W
uh
an
,
C
hi
na
D
es
cr
ip
tiv
e
24
1
pa
tie
nt
s
w
ith
co
nfi
rm
ed
CO
VI
D
-1
9
M
ed
ia
n
ag
e:
65
(IQ
R:
55
–7
2)
;m
al
e:
46
.4
%
—
W
ith
in
24
h
of
ad
m
is
si
on
25
(O
H
)D
co
nc
en
tr
at
io
n
in
SA
RS
-C
oV
-2
+
ad
ul
ts
—
Ye
(4
1)
Fe
br
ua
ry
to
M
ar
ch
,2
02
0
A
H
os
pi
ta
li
n
C
hi
na
C
as
e-
co
nt
ro
l
62
SA
RS
-C
oV
-2
+,
80
he
al
th
y
co
nt
ro
ls
Co
nt
ro
ls
:m
ed
ia
n
ag
e
(IQ
R)
:4
2
(3
1–
52
);
m
al
e:
40
%
;
pa
tie
nt
s:
ag
e:
43
(3
2–
59
);
m
al
e:
37
%
25
(O
H
)D
<
20
ng
/m
L
A
ta
dm
is
si
on
To
ex
am
in
e
th
e
re
la
tio
n
be
tw
ee
n
se
ru
m
25
(O
H
)D
co
nc
en
tr
at
io
n
an
d
SA
RS
-C
oV
-2
in
fe
ct
io
n
D
em
og
ra
ph
ic
s
an
d
co
m
or
bi
di
tie
s
Yı
lm
az
(3
5)
M
ar
ch
to
M
ay
,
20
20
U
ni
ve
rs
ity
H
os
pi
ta
li
n
Tu
rk
ey
C
as
e-
co
nt
ro
l
85
ch
ild
re
n
(4
0
SA
RS
-C
oV
-2
+
an
d
ho
sp
ita
liz
ed
,4
5
he
al
th
y
ch
ild
re
n
in
co
nt
ro
lg
ro
up
)
CO
VI
D
-1
9
pa
tie
nt
s:
10
1.
76
m
o;
m
al
e:
47
.5
%
;c
on
tr
ol
s:
75
.6
8
m
o;
m
al
e:
60
%
25
(O
H
)D
<
12
ng
/m
L
Fr
om
re
tr
os
pe
ct
iv
e
fil
e
re
co
rd
s
Is
VD
D
a
ris
k
fa
ct
or
fo
r
CO
VI
D
-1
9
in
ch
ild
re
n?
N
on
e
1
CO
VI
D
-1
9,
co
ro
na
vi
ru
s
di
se
as
e
20
19
;P
C
R,
po
ly
m
er
as
e
ch
ai
n
re
ac
tio
n;
re
f,
re
fe
re
nc
e;
SA
RS
-C
oV
-2
,s
ev
er
e
ac
ut
e
re
sp
ira
to
ry
sy
nd
ro
m
e
co
ro
na
vi
ru
s
2;
VD
D
,v
ita
m
in
D
de
fic
ie
nc
y;
Vi
tD
,v
ita
m
in
D
;2
5(
O
H
)D
,2
5-
hy
dr
ox
yv
ita
m
in
D
;2
5(
O
H
)D
3,
25
-h
yd
ro
xy
vi
ta
m
in
D
3;
1,
25
(O
H
)D
,1
,2
5-
hy
dr
ox
yv
ita
m
in
D
.
Vitamin D and COVID-19 7
D
ow
nloaded from
 https://academ
ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
Ch
ar
ac
te
ris
tic
s
of
st
ud
ie
s
in
ve
st
ig
at
ed
as
so
ci
at
io
n
of
vi
ta
m
in
D
st
at
us
w
ith
CO
VI
D
-1
9
se
ve
rit
y1
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
ency
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
A
br
is
ha
m
i(
60
)
Fe
br
ua
ry
to
A
pr
il,
20
20
A
ca
de
m
ic
ho
sp
ita
l
in
Ira
n
Re
tr
os
pe
ct
iv
e
st
ud
y
73
SA
RS
-C
oV
-2
–
po
si
tiv
e
(+
)
pa
tie
nt
s
M
ea
n
ag
e:
55
.1
8;
m
al
e:
46
.4
%
To
ev
al
ua
te
th
e
pr
og
no
st
ic
ro
le
of
se
ru
m
25
(O
H
)D
3
on
th
e
ex
te
nt
of
lu
ng
in
vo
lv
em
en
t
an
d
fin
al
ou
tc
om
e
in
pa
tie
nt
s
w
ith
CO
VI
D
-1
9
Lu
ng
in
vo
lv
em
en
ta
nd
m
or
ta
lit
y;
se
ru
m
25
(O
H
)D
<
25
ng
/m
L
A
ta
dm
is
si
on
Fo
rm
or
ta
lit
y,
m
ul
tiv
ar
ia
te
lin
ea
r
re
gr
es
si
on
an
al
ys
is
ad
ju
st
ed
fo
r
po
te
nt
ia
l
co
nf
ou
nd
er
s
in
cl
ud
in
g
se
x,
ag
e,
an
d
co
m
or
bi
di
ty
A
nj
um
(6
2)
M
ar
ch
to
Ju
ne
,
20
20
A
ho
sp
ita
li
n
Pa
ki
st
an
Pr
os
pe
ct
iv
e
14
0
SA
RS
-C
oV
-2
+
pa
tie
nt
s
M
ea
n
ag
e:
42
.4
6;
ag
e
ra
ng
e:
15
–7
5;
m
al
e:
58
.5
7%
To
de
te
rm
in
e
th
e
as
so
ci
at
io
n
be
tw
ee
n
se
ve
re
VD
D
an
d
m
or
ta
lit
y
in
pa
tie
nt
s
w
ith
CO
VI
D
-1
9
Se
ve
rit
y
w
as
de
fin
ed
as
m
or
ta
lit
y;
se
ve
re
VD
D
w
as
de
fin
ed
as
25
(O
H
)D
<
10
ng
/m
l
A
ta
dm
is
si
on
—
A
nn
w
ei
le
r(
56
)
M
ar
ch
to
A
pr
il,
20
20
N
ur
si
ng
ho
m
e
in
Fr
an
ce
Q
ua
si
-
ex
pe
rim
en
ta
l
st
ud
y
w
ith
m
ea
n
fo
llo
w
-u
p
of
36
d
66
fra
il
el
de
rly
nu
rs
in
g-
ho
m
e
re
si
de
nt
s:
in
te
rv
en
tio
n,
n
=
57
;
co
m
pa
ra
to
r,
n
=
9
Ex
pe
rim
en
t:
m
ea
n
ag
e:
87
.7
;m
al
e:
21
%
Co
m
pa
ra
to
r:
m
ea
n
ag
e:
87
.4
;m
al
e:
33
%
To
ev
al
ua
te
CO
VI
D
-1
9
se
ve
rit
y
an
d
th
e
us
e
of
CO
VI
D
-1
9
dr
ug
s;
th
e
pr
im
ar
y
an
d
se
co
nd
ar
y
ou
tc
om
es
w
er
e
CO
VI
D
-1
9
m
or
ta
lit
y
an
d
O
SC
Is
co
re
in
ac
ut
e
ph
as
e
O
SC
Is
co
re
Th
e
in
te
rv
en
tio
n
gr
ou
p
re
ce
iv
ed
Vi
tD
3
(s
in
gl
e
do
se
of
80
,0
00
IU
ev
er
y
2–
3
m
o)
du
rin
g
CO
VI
D
-1
9
or
in
th
e
pr
ec
ed
in
g
m
on
th
;t
he
co
m
pa
ra
to
r
gr
ou
p
co
rr
es
po
nd
ed
to
al
lo
th
er
pa
rt
ic
ip
an
ts
A
ge
,g
en
de
r,
dr
ug
s,
fu
nc
tio
na
l
ab
ili
tie
s,
al
bu
m
in
ur
ia
A
nn
w
ei
le
r(
51
)
M
ar
ch
to
M
ay
,
20
20
O
ne
ge
ria
tr
ic
ac
ut
e
ca
re
un
it
de
di
ca
te
d
to
CO
VI
D
-1
9
pa
tie
nt
s
in
Fr
an
ce
Q
ua
si
-
ex
pe
rim
en
ta
l
st
ud
y
G
ro
up
1
(n
=
29
),
gr
ou
p
2
(n
=
16
),
gr
ou
p
3
(n
=
32
)
M
ea
n
ag
e:
88
;
m
al
e:
51
%
14
-d
ay
m
or
ta
lit
y
an
d
hi
gh
es
t
(w
or
st
)s
co
re
on
th
e
O
SC
I
m
ea
su
re
d
du
rin
g
CO
VI
D
-1
9
ac
ut
e
ph
as
e
To
de
te
rm
in
e
w
he
th
er
vi
ta
m
in
D
3
su
pp
le
m
en
ta
tio
n
ta
ke
n
ei
th
er
re
gu
la
rly
ov
er
th
e
pr
ec
ed
in
g
ye
ar
or
af
te
rt
he
di
ag
no
si
s
of
CO
VI
D
-1
9
w
as
G
ro
up
1
(n
=
29
):
su
pp
le
m
en
te
d
re
gu
la
rly
w
ith
Vi
tD
ov
er
th
e
pr
ec
ed
in
g
ye
ar
G
ro
up
2
(n
=
16
):
su
pp
le
m
en
te
d
w
ith
Vi
tD
af
te
r
Po
te
nt
ia
l
co
nf
ou
nd
er
s
w
er
e
ag
e,
ge
nd
er
,
fu
nc
tio
na
l
ab
ili
tie
s,
un
-
de
rn
ut
rit
io
n,
ch
ro
ni
c
(C
on
tin
ue
d)
8 Kazemi et al.
D
ow
nloaded from
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ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
en
cy
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
eff
ec
tiv
e
in
im
pr
ov
in
g
su
rv
iv
al
am
on
g
ho
sp
ita
liz
ed
fra
il
el
de
rly
CO
VI
D
-1
9
pa
tie
nt
s;
se
ve
re
CO
VI
D
-1
9
de
fin
ed
as
an
O
SC
I
sc
or
e
≥5
CO
VI
D
-1
9
di
ag
no
si
s
G
ro
up
3
(n
=
32
):
co
m
pa
ra
to
r
re
ce
iv
ed
no
Vi
tD
di
se
as
e,
dr
ug
s;
th
e
3
gr
ou
ps
w
er
e
si
m
ila
ri
n
th
e
tr
ea
tm
en
ts
us
ed
fo
r
CO
VI
D
-1
9
A
rv
in
te
(6
3)
M
ay
,2
02
0
IC
U
of
m
ed
ic
al
ce
nt
er
in
Co
lo
ra
do
,U
SA
C
ro
ss
-s
ec
tio
na
l,
de
sc
rip
tiv
e
21
cr
iti
ca
lly
ill
CO
VI
D
-1
9
pa
tie
nt
s
ho
sp
ita
liz
ed
;1
1
su
rv
iv
ed
,1
0
di
ed
M
ed
ia
n
ag
e
61
;
ag
e
ra
ng
e:
20
–9
4;
m
al
e:
71
.4
%
To
m
ea
su
re
se
ru
m
25
(O
H
)D
2,
3
in
pa
tie
nt
s
w
ith
cr
iti
ca
l
CO
VI
D
-1
9
ill
ne
ss
an
d
to
as
se
ss
if
VD
D
co
rr
el
at
ed
w
ith
ot
he
r
ill
ne
ss
ris
k
fa
ct
or
s
Se
ve
rit
y
w
as
de
fin
ed
as
m
or
ta
lit
y
A
tI
C
U
ad
m
is
si
on
—
Ba
kt
as
h
(4
7)
M
ar
ch
to
A
pr
il,
20
20
G
en
er
al
ho
sp
ita
li
n
th
e
U
K
Pr
os
pe
ct
iv
e
co
ho
rt
st
ud
y
70
el
de
rly
SA
RS
-C
oV
-2
+
in
di
vi
du
al
s
(a
ge
d
≥6
5
y)
;
VD
D
pa
tie
nt
s:
(n
=
39
);
no
n-
VD
D
pa
tie
nt
s:
(n
=
31
)
M
ea
n
ag
e:
81
.2
8;
M
al
e:
60
%
in
CO
VI
D
-1
9
pa
tie
nt
s
an
d
40
%
in
no
n–
CO
VI
D
-1
9
pa
tie
nt
s
Vi
ta
m
in
D
st
at
us
an
d
ou
tc
om
es
fo
rh
os
pi
ta
liz
ed
ol
de
rp
at
ie
nt
s
w
ith
CO
VI
D
-1
9
N
on
in
va
si
ve
ve
nt
ila
tio
n
an
d
hi
gh
-d
ep
en
de
nc
y
un
it;
cl
in
ic
al
m
ar
ke
rs
of
di
se
as
e
se
ve
rit
y;
25
(O
H
)D
≤1
2
ng
/m
L
Co
nc
ur
re
nt
w
ith
SA
RS
-C
oV
-2
te
st
N
ot
ad
ju
st
ed
fo
r
co
nf
ou
nd
er
s;
an
ot
he
r
lim
ita
tio
n
is
th
e
su
pp
le
-
m
en
ta
tio
n
of
Vi
tD
af
te
rt
he
ac
ut
e
ph
as
e
of
ill
ne
ss
Ba
gh
er
i(
57
)
M
ar
ch
to
M
ay
20
20
U
ni
ve
rs
ity
ho
sp
ita
l
in
Ira
n
C
ro
ss
-s
ec
tio
na
l
10
3
ou
tp
at
ie
nt
s
an
d
28
ho
sp
ita
liz
ed
pa
tie
nt
s
M
ea
n
ag
e:
43
.7
4
in
ou
tp
at
ie
nt
s
an
d
58
.7
7
in
in
pa
tie
nt
s
Th
e
vi
ta
m
in
D
su
pp
le
m
en
ta
-
tio
n
pa
tt
er
n
in
pa
st
hi
st
or
y
of
pa
tie
nt
s
w
ith
CO
VI
D
-1
9
in
a
cr
os
s-
se
ct
io
na
l
in
qu
iry
Se
ve
rit
y
w
as
co
ns
id
er
ed
as
ho
sp
ita
liz
at
io
n
Su
pp
le
m
en
te
d
or
no
t
su
pp
le
m
en
te
d
w
ith
vi
ta
m
in
D
A
dj
us
te
d
fo
rt
he
fa
ct
or
s
aff
ec
tin
g
th
e
se
ve
rit
y
of
th
is
di
se
as
e
C
ar
pa
gn
an
o
(6
4)
M
ar
ch
11
to
A
pr
il
30
,
20
20
Ita
ly
,h
os
pi
ta
l
po
lic
lin
ic
Re
tr
os
pe
ct
iv
e,
ob
se
rv
a-
tio
na
l
st
ud
y
42
pa
tie
nt
s
w
ith
A
RF
du
e
to
CO
VI
D
-1
9,
tr
ea
te
d
in
re
sp
ira
to
ry
in
te
rm
ed
ia
te
ca
re
un
it,
an
d
no
ne
ed
of
in
tu
ba
tio
n
or
in
va
si
ve
ve
nt
ila
tio
n
M
ea
n
ag
e:
65
;
m
al
e:
71
%
A
ss
es
si
ng
an
y
co
rr
el
at
io
ns
w
ith
di
se
as
e
se
ve
rit
y
an
d
pr
og
no
si
s
Tr
an
sf
er
to
IC
U
,d
ea
th
;
vi
ta
m
in
D
in
su
ffi
ci
en
cy
,
m
od
er
at
e
de
fic
ie
nc
y,
an
d
se
ve
re
de
fic
ie
nc
y
w
er
e
de
fin
ed
as
25
(O
H
)D
co
nc
en
tr
at
io
ns
of
20
–2
9,
10
–1
9,
an
d
<
10
ng
/m
L,
re
sp
ec
tiv
el
y
M
ea
su
re
d
af
te
r
SA
RS
-C
oV
-2
te
st
—
(C
on
tin
ue
d)
Vitamin D and COVID-19 9
D
ow
nloaded from
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ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
en
cy
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
En
tr
en
as
C
as
til
lo
(3
6)
M
ay
,2
02
0
U
ni
ve
rs
ity
ho
sp
ita
l,
Sp
ai
n
RC
T
76
pa
tie
nt
s
ho
sp
ita
liz
ed
w
ith
SA
RS-C
oV
-2
in
fe
ct
io
n
(5
0
in
th
e
in
te
rv
en
tio
n
an
d
26
in
th
e
co
nt
ro
l)
M
ea
n
ag
e:
53
;
m
al
e:
59
%
Eff
ec
to
fc
al
ci
fe
di
ol
tr
ea
tm
en
to
n
IC
U
ad
m
is
si
on
an
d
m
or
ta
lit
y
ra
te
am
on
g
pa
tie
nt
s
ho
sp
ita
liz
ed
fo
r
CO
VI
D
-1
9
A
dm
is
si
on
to
IC
U
,
(0
.5
3
m
g
Vi
tD
at
ad
m
is
si
on
,0
.2
6
m
g
at
da
y
3
an
d
7,
an
d
th
en
w
ee
kl
y
un
til
di
sc
ha
rg
e
or
IC
U
ad
m
is
si
on
)
N
ot
m
ea
su
re
d
A
dj
us
te
d
fo
r
va
ria
bl
es
th
at
w
er
e
di
ffe
re
nt
be
tw
ee
n
gr
ou
ps
at
ba
se
lin
e
(H
TN
,
D
M
);
M
LR
an
al
ys
is
fo
r
pr
ob
ab
ili
ty
of
th
e
IC
U
ad
m
is
si
on
C
er
ed
a
(6
5)
M
ar
ch
to
A
pr
il,
20
20
Ita
lia
n
te
rt
ia
ry
re
fe
rr
al
ho
sp
ita
l
Si
ng
le
-c
en
te
r
co
ho
rt
st
ud
y
12
9
CO
VI
D
-1
9
pa
tie
nt
s:
VD
D
gr
ou
p,
n
=
99
;
no
n-
VD
D
,
n
=
30
M
ed
ia
n
ag
e:
77
(IQ
R,
65
.0
,8
5.
0)
;
m
al
e:
54
.3
%
To
de
te
rm
in
e
th
e
pr
ev
al
en
ce
of
VD
D
in
CO
VI
D
-1
9
pa
tie
nt
s
an
d
ex
pl
or
e
its
as
so
ci
at
io
n
w
ith
cl
in
ic
al
ou
tc
om
es
of
di
se
as
e
se
ve
rit
y
C
lin
ic
al
ou
tc
om
es
(s
ev
er
e
pn
eu
m
on
ia
,
ad
m
is
si
on
to
IC
U
an
d
in
-h
os
pi
ta
l
m
or
ta
lit
y)
an
d
bi
oc
he
m
ic
al
m
ar
ke
rs
of
di
se
as
e
se
ve
rit
y
25
(O
H
)D
<
20
ng
/m
L
W
ith
in
48
h
si
nc
e
ho
sp
ita
l
ad
m
is
si
on
A
ge
,s
ex
,C
RP
,
IH
D
,a
nd
se
ve
re
pn
eu
m
on
ia
D
e
Sm
et
(4
2)
M
ar
ch
1
to
A
pr
il
7,
20
20
Be
lg
iu
m
,g
en
er
al
ho
sp
ita
l
Re
tr
os
pe
ct
iv
e
ob
se
rv
a-
tio
na
l
st
ud
y
18
6
ho
sp
ita
liz
ed
SA
RS
-C
oV
-2
–
in
fe
ct
ed
pa
tie
nt
s
A
ge
68
.5
;m
al
e:
58
.6
%
A
re
lo
w
er
25
(O
H
)D
co
nc
en
tr
at
io
ns
co
rr
el
at
ed
w
ith
CO
VI
D
-1
9
se
ve
rit
y?
Pa
tie
nt
s
w
er
e
cl
as
si
fie
d
ba
se
d
on
th
e
ra
di
ol
og
ic
al
le
si
on
as
ea
rly
st
ag
e
1
(g
ro
un
d-
gl
as
s
op
ac
iti
es
),
pr
og
re
ss
iv
e
st
ag
e
2
(c
ra
zy
pa
vi
ng
pa
tt
er
n)
,o
rp
ea
k
st
ag
e
3
(c
on
so
lid
at
io
n)
,
25
(O
H
)D
<
20
ng
/m
L
M
ea
su
re
d
af
te
r
SA
RS
-C
oV
-2
te
st
N
on
e
H
ar
aj
(3
3)
A
pr
il
17
to
M
ay
26
,2
02
0
En
do
cr
in
ol
og
y
se
rv
ic
e
in
M
or
oc
co
D
es
cr
ip
tiv
e
ob
-
se
rv
at
io
na
l
st
ud
y
41
pa
tie
nt
s
ad
m
itt
ed
to
th
e
en
do
cr
in
ol
og
y
se
rv
ic
e
fo
r
ad
di
tio
na
lc
ar
e
af
te
ra
st
ay
in
IC
U
M
ea
n
ag
e:
55
<
45
ye
ar
s
(2
6.
8%
),
45
–7
0
ye
ar
s
(4
8.
8%
),
>
70
(2
4.
4%
);
51
.2
%
m
al
e
To
as
se
ss
th
e
vi
ta
m
in
D
st
at
us
of
pa
tie
nt
s
w
ith
CO
VI
D
-1
9
af
te
r
a
st
ay
in
in
te
ns
iv
e
ca
re
—
A
tt
he
be
gi
nn
in
g
of
th
e
st
ud
y
—
(C
on
tin
ue
d)
10 Kazemi et al.
D
ow
nloaded from
 https://academ
ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
en
cy
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
Fa
ul
(3
0)
D
ur
in
g
M
ar
ch
,
20
20
Ire
la
nd
,C
on
no
lly
H
os
pi
ta
l
Bl
an
ch
ar
ds
to
w
n
Co
ho
rt
33
ho
sp
ita
liz
ed
fo
r
CO
VI
D
-1
9–
re
la
te
d
pn
eu
m
on
ia
;
ca
se
s:
pa
tie
nt
s
pr
og
re
ss
ed
to
A
RD
S
(n
=
12
);
co
nt
ro
ls
:t
ho
se
w
ho
di
d
no
t
pr
og
re
ss
to
A
RD
S
(n
=
21
)
M
ea
n
ag
e:
60
;
m
al
e:
10
0%
D
oe
s
lo
w
25
(O
H
)D
co
nt
rib
ut
e
to
se
ve
re
di
se
as
e
an
d
pr
og
re
ss
io
n
to
A
RD
S
in
so
m
e
pa
tie
nt
s
in
fe
ct
ed
w
ith
SA
RS
-C
oV
-2
?
Pr
og
re
ss
io
n
to
A
RD
S,
re
qu
ire
in
tu
ba
tio
n
an
d
m
ec
ha
ni
ca
l
ve
nt
ila
tio
n,
de
at
h
M
ea
su
re
d
af
te
r
ad
m
is
si
on
to
ho
sp
ita
l
—
Fe
rr
ar
i(
43
)
Fe
br
ua
ry
20
to
A
pr
il
7,
20
20
Sa
n
Ra
ffa
el
e
H
os
pi
ta
l,
M
ila
n,
Ita
ly
Re
tr
os
pe
ct
iv
e
co
ho
rt
12
8
SA
RS
-C
oV
-2
+
pa
tie
nt
s:
se
ve
re
di
se
as
e
(n
=
16
),
no
ns
ev
er
e
(n
=
11
2)
M
ea
n
ag
e:
62
.7
;
m
al
e:
64
.8
%
A
ss
oc
ia
tio
n
be
tw
ee
n
CO
VI
D
-1
9
se
ve
rit
y
an
d
Vi
tD
co
nc
en
tr
at
io
ns
Se
ve
rit
y
cl
as
si
fic
at
io
n
w
as
no
te
xp
la
in
ed
;
25
(O
H
)D
<
30
ng
/m
L
Vi
tD
co
nc
en
tr
at
io
n
m
ea
su
re
d,
at
le
as
to
nc
e,
be
tw
ee
n
th
e
1s
t
of
Ja
nu
ar
y
an
d
th
e
31
st
of
M
ay
,
20
20
;t
he
av
er
ag
e
tim
e
in
te
rv
al
be
tw
ee
n
SA
RS
-C
oV
-2
te
st
an
d
Vi
tD
m
ea
su
re
m
en
ts
w
as
33
.5
d
—
G
on
ça
lv
es
(3
2)
M
ar
ch
to
A
pr
il,
20
20
IC
U
in
Br
az
il
D
es
cr
ip
tiv
e
cr
os
s-
se
ct
io
na
l
st
ud
y
17
6
el
de
rly
(a
ge
d
≥6
0
y)
M
ea
n
ag
e:
72
.9
;
m
al
e:
54
%
Pr
ev
al
en
ce
of
VD
D
in
el
de
rly
pa
tie
nt
s
ad
m
itt
ed
to
th
e
IC
U
du
e
to
SA
RS
-C
oV
-2
—
In
th
e
fir
st
da
y
of
IC
U
ad
m
is
si
on
—
H
am
za
(5
8)
M
ar
ch
to
A
pr
il,
20
20
M
ed
ic
al
co
lle
ge
ho
sp
ita
li
n
Pa
ki
st
an
D
es
cr
ip
tiv
e
cr
os
s-
se
ct
io
na
l
st
ud
y
16
8
SA
RS
-C
oV
-2
+
pa
tie
nt
s
A
ge
ra
ng
ed
fro
m
30
to
80
;m
ea
n
ag
e:
42
.2
6;
m
al
e:
56
%
To
de
te
rm
in
e
th
e
VD
D
in
CO
VI
D
-1
9
pa
tie
nt
s
an
d
its
as
so
ci
at
io
n
w
ith
th
e
se
ve
rit
y
an
d
fa
ta
lit
y
of
CO
VI
D
-1
9
di
se
as
e
Th
e
CO
VI
D
-1
9
pa
tie
nt
s
w
er
e
ca
te
go
riz
ed
in
to
as
ym
pt
om
at
ic
an
d
sy
m
pt
om
at
ic
;
th
e
sy
m
pt
om
at
ic
pa
tie
nt
s
w
er
e
ca
te
go
riz
ed
in
to
m
ild
,m
od
er
at
e,
an
d
se
ve
re
di
se
as
e
ac
co
rd
in
g
to
qu
es
tio
na
irr
e
A
tt
he
be
gi
nn
in
g
of
th
e
st
ud
y
—
(C
on
tin
ue
d)
Vitamin D and COVID-19 11
D
ow
nloaded from
 https://academ
ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
en
cy
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
H
er
ná
nd
ez
(4
4)
M
ar
ch
10
to
M
ar
ch
31
,
20
20
U
ni
ve
rs
ity
ho
sp
ita
l
in
Sp
ai
n
Re
tr
os
pe
ct
iv
e
ca
se
-c
on
tr
ol
st
ud
y
19
7
CO
VI
D
-1
9
pa
tie
nt
s;
ca
se
s
w
er
e
th
e
pa
tie
nt
s
w
ith
VD
D
(n
=
35
);
co
nt
ro
lp
at
ie
nt
s
w
ith
no
n-
VD
D
(n
=
16
2)
A
ge
,m
ed
ia
n
(IQ
R)
:
61
.0
(4
7.
5–
70
.0
)
in
ca
se
s,
61
.0
(5
6.
0–
66
.0
)i
n
co
nt
ro
ls
;m
al
es
in
bo
th
gr
ou
p:
62
.4
%
To
as
se
ss
se
ru
m
25
(O
H
)D
3
in
ho
sp
ita
liz
ed
pa
tie
nt
s
w
ith
CO
VI
D
-1
9
an
d
to
an
al
yz
e
th
e
po
ss
ib
le
in
flu
en
ce
of
vi
ta
m
in
D
st
at
us
on
di
se
as
e
se
ve
rit
y
A
dm
is
si
on
to
IC
U
,
re
qu
ire
m
en
tf
or
m
ec
ha
ni
ca
l
ve
nt
ila
tio
n,
or
in
-h
os
pi
ta
lm
or
ta
lit
y;
25
(O
H
)D
<
20
ng
/m
L
A
ta
dm
is
si
on
A
ge
,s
m
ok
in
g,
ch
ro
ni
c
di
se
as
e,
im
m
un
os
up
-
pr
es
si
on
,B
M
I,
se
ru
m
-
co
rr
ec
te
d
ca
lc
iu
m
,G
FR
,
an
d
th
e
m
on
th
of
vi
ta
m
in
D
de
te
rm
in
at
io
n
Im
(4
5)
Fe
br
ua
ry
to
Ju
ne
,2
02
0
U
ni
ve
rs
ity
ho
sp
ita
l,
So
ut
h
Ko
re
a
C
as
e-
co
nt
ro
l
50
pa
tie
nt
s
w
ith
CO
VI
D
-1
9,
32
w
ith
pn
eu
m
on
ia
an
d
18
w
ith
ou
t
pn
eu
m
on
ia
M
ed
ia
n
ag
e:
57
.5
in
ca
se
s
an
d
52
.2
in
co
nt
ro
ls;
m
al
e:
58
%
A
ss
oc
ia
tio
n
of
25
(O
H
)D
3
w
ith
di
se
as
e
se
ve
rit
y
(d
efi
ne
d
by
pn
eu
m
on
ia
)
Pr
og
re
ss
io
n
to
pn
eu
m
on
ia
in
cl
ud
es
ca
se
s
w
ith
or
w
ith
ou
ta
n
ox
yg
en
su
pp
ly
,h
ig
h-
flo
w
na
sa
lc
an
nu
la
,
m
ec
ha
ni
ca
l
ve
nt
ila
to
r,
an
d
EC
M
O
/d
ea
th
w
as
co
ns
id
er
ed
as
se
ve
re
;2
5(
O
H
)D
3
≤2
0
ng
/d
L
W
ith
in
7
d
of
ad
m
is
si
on
—
Ja
in
(5
3)
Ju
ne
5
to
Ju
ly
20
,2
02
0
Te
rt
ia
ry
CO
VI
D
-1
9
ca
re
ce
nt
er
in
In
di
a
Pr
os
pe
ct
iv
e
ob
-
se
rv
at
io
na
l
St
ud
y
in
cl
ud
ed
bo
th
as
ym
pt
om
at
ic
CO
VI
D
–1
9
pa
tie
nt
s
(g
ro
up
A
,n
=
91
)a
nd
se
ve
re
ly
ill
pa
tie
nt
s
re
qu
iri
ng
IC
U
ad
m
is
si
on
(g
ro
up
B,
n
=
63
)
30
–6
0
y:
G
ro
up
A
:m
ea
n
ag
e:
42
.3
4;
m
al
e:
58
.2
%
G
ro
up
B:
m
ea
n
ag
e:
51
.4
1;
m
al
e:
66
.6
6%
A
na
ly
si
s
of
vi
ta
m
in
D
co
nc
en
tr
at
io
n
am
on
g
as
ym
pt
om
at
ic
an
d
cr
iti
ca
lly
ill
CO
VI
D
–1
9
pa
tie
nt
s
an
d
its
co
rr
el
at
io
n
w
ith
in
fla
m
m
at
or
y
m
ar
ke
rs
A
sy
m
pt
om
at
ic
vs
.I
C
U
pa
tie
nt
s;
25
(O
H
)D
<
20
ng
/d
L
A
tt
he
be
gi
nn
in
g
of
th
e
st
ud
y
N
ot
ad
ju
st
ed
(C
on
tin
ue
d)
12 Kazemi et al.
D
ow
nloaded from
 https://academ
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/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
en
cy
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
Ka
ra
ha
n
(5
4)
A
pr
il
1
to
M
ay
20
,2
02
0
Tr
ai
ni
ng
an
d
re
se
ar
ch
ho
sp
ita
l,
Tu
rk
ey
Re
tr
os
pe
ct
iv
e
ob
se
rv
a-
tio
na
l
st
ud
y
14
9
CO
VI
D
-1
9
pa
tie
nt
s;
m
od
er
at
e
(n
=
47
),
se
ve
re
–c
rit
ic
al
(n
=
10
2)
M
ea
n
ag
e:
63
.5
;
ag
e
ra
ng
e:
24
–9
0;
m
al
e:
54
.4
%
To
in
ve
st
ig
at
e
th
e
ro
le
of
se
ru
m
25
(O
H
)D
co
nc
en
tr
at
io
n
on
CO
VI
D
se
ve
rit
y
an
d
re
la
te
d
m
or
ta
lit
y
Th
e
se
ve
rit
y
of
CO
VI
D
w
as
cl
as
si
fie
d
ac
co
rd
in
g
to
th
e
C
hi
ne
se
C
lin
ic
al
G
ui
de
lin
e
fo
r
cl
as
si
fic
at
io
n
of
CO
VI
D
-1
9
se
ve
rit
y2
;
25
(O
H
)D
≤2
0
ng
/d
L
D
at
a
w
er
e
re
tr
ie
ve
d
fro
m
th
e
ho
sp
ita
l
el
ec
tr
on
ic
da
ta
ba
se
sy
st
em
Co
nf
ou
nd
in
g
fa
ct
or
s
no
t
m
en
tio
ne
d
Ša
ro
no
va
(5
5)
A
pr
il
1
to
M
ay
15
,2
02
0
H
os
pi
ta
li
n
Ru
ss
ia
C
ro
ss
-s
ec
tio
na
l
80
CO
VI
D
-1
9
pa
tie
nt
s;
se
ve
re
:
(n
=
25
),
m
od
er
at
e:
(n
=
55
)
A
ll
pa
tie
nt
s:
A
ge
ra
ng
e:
18
–9
4;
m
ea
n
ag
e:
53
.2
;
m
al
e:
53
.8
%
Se
ve
re
di
se
as
e:
m
ea
n
ag
e:
51
.8
;
m
al
e:
48
%
M
od
er
at
e
di
se
as
e:
m
ea
n
ag
e:
53
.7
;
m
al
e:
56
.4
%
A
ss
oc
ia
tio
n
of
25
(O
H
)D
co
nc
en
tr
at
io
n
in
pa
tie
nt
s
w
ith
CO
VI
D
-1
9
ho
sp
ita
liz
ed
w
ith
co
m
m
un
ity
-
ac
qu
ire
d
pn
eu
m
on
ia
an
d
co
m
pa
re
se
ru
m
25
(O
H
)D
w
ith
cl
in
ic
al
ou
tc
om
e
25
(O
H
)D
<
20
ng
/d
L
—
—
Ke
rg
et
(5
0)
M
ar
ch
24
to
M
ay
15
,2
02
0
Tw
o
ho
sp
ita
ls
in
Tu
rk
ey
C
as
e-
co
nt
ro
l
88
CO
VI
D
-1
9
pa
tie
nt
s;
20
pa
tie
nt
s
de
ve
lo
pe
d
M
A
S
an
d
35
de
ve
lo
pe
d
A
RD
S
an
d
8
di
ed
M
ea
n
ag
e:
M
A
S:
70
.1
;
no
n-
M
A
S:
43
.4
;
A
RD
S:
67
.9
;
no
n-
A
RD
S:
38
.3
To
de
te
rm
in
e
th
e
re
la
tio
n
of
se
ru
m
25
(O
H
)D
to
cl
in
ic
al
co
ur
se
an
d
pr
og
no
si
s
D
ev
el
op
in
g
M
A
S
an
d
A
RD
S,
an
d
de
at
h
Fi
ft
h
da
y
of
ad
m
is
si
on
to
ho
sp
ita
l
—
Lu
o
(4
6)
Fe
br
ua
ry
to
M
ar
ch
20
20
W
uh
an
To
ng
ji
H
os
pi
ta
l
C
ro
ss
-s
ec
tio
na
l
33
5
CO
VI
D
-1
9
pa
tie
nt
s;
74
se
ve
re
,2
61
no
ns
ev
er
e
Se
ve
re
:
M
ed
ia
n
ag
e:
62
.5
;
IQ
R:
51
.0
–7
5.
3
y;
m
al
e:
58
.1
%
N
on
se
ve
re
:
M
ed
ia
n
ag
e:
54
;
IQ
R:
40
–6
2
y;
m
al
e:
40
.2
%
To
in
ve
st
ig
at
e
w
he
th
er
VD
D
is
as
so
ci
at
ed
w
ith
CO
VI
D
-1
9
di
se
as
e
se
ve
rit
y
Se
ve
rit
y
of
CO
VI
D
-1
9
w
as
de
te
rm
in
ed
ba
se
d
on
th
e
le
ve
lo
f
re
sp
ira
to
ry
in
vo
lv
em
en
t;
ba
se
d
on
Co
m
m
is
si
on
an
d
St
at
e
A
dm
in
is
tr
at
io
n
of
Tr
ad
iti
on
al
C
hi
ne
se
M
ed
ic
in
e3
;
25
(O
H
)D
<
30
ng
/m
L
Fo
rt
he
co
nt
ro
l
gr
ou
p,
se
ru
m
25
(O
H
)D
da
ta
on
th
e
sa
m
e
pe
rio
d
fro
m
20
18
–2
01
9
w
er
e
us
ed
;f
or
th
e
CO
VI
D
-1
9
pa
tie
nt
s,
on
ad
m
is
si
on
to
ho
sp
ita
l
A
ge
,s
ex
,
co
m
or
bi
di
tie
s,
sm
ok
in
g
st
at
us
,a
nd
BM
I (C
on
tin
ue
d)
Vitamin D and COVID-19 13
D
ow
nloaded from
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ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
en
cy
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
M
ac
ay
a
(5
2)
—
Te
rt
ia
ry
ho
sp
ita
li
n
M
ad
rid
,S
pa
in
Re
tr
os
pe
ct
iv
e
80
CO
VI
D
-1
9
pa
tie
nt
s
(n
on
se
ve
re
,
n
=
49
;s
ev
er
e,
n
=
31
)
N
on
se
ve
re
:
M
ed
ia
n
ag
e:
63
;
IQ
R
(5
0–
72
);
m
al
e:
29
%
Se
ve
re
:
A
ge
:7
5
(6
6–
84
);
m
al
e:
21
%
Th
e
as
so
ci
at
io
n
of
VD
D
w
ith
a
co
m
po
si
te
of
ad
ve
rs
e
cl
in
ic
al
ou
tc
om
es
D
ea
th
,a
dm
is
si
on
to
th
e
IC
U
,a
nd
/o
rn
ee
d
fo
rh
ig
he
ro
xy
ge
n
flo
w
th
an
th
at
pr
ov
id
ed
by
a
na
sa
l
ca
nn
ul
a;
25
(O
H
)D
<
20
ng
/m
L
A
ta
dm
is
si
on
or
w
ith
in
th
e
3
pr
ev
io
us
m
on
th
s
O
be
si
ty
,c
ar
di
ac
di
se
as
e,
an
d
ag
e
M
ag
hb
oo
li
(3
8)
U
nt
il
M
ay
1,
20
20
A
ho
sp
ita
li
n
Te
hr
an
C
ro
ss
-s
ec
tio
na
l
23
5
CO
VI
D
-1
9
pa
tie
nt
s;
m
ild
–m
od
er
at
e
se
ve
rit
y:
n
=
64
;
se
ve
re
–c
rit
ic
al
se
ve
rit
y:
n
=
17
2
M
ea
n
ag
e
w
as
58
.7
;a
ge
ra
ng
e:
20
–9
0;
m
al
e:
61
.3
%
To
in
ve
st
ig
at
e
th
e
as
so
ci
at
io
n
be
tw
ee
n
se
ru
m
25
(O
H
)D
an
d
cl
in
ic
al
ou
tc
om
es
,
pa
ra
m
et
er
s
of
im
m
un
e
fu
nc
tio
n
an
d
m
or
ta
lit
y
C
D
C
cr
ite
ria
4
w
er
e
us
ed
fo
rt
he
di
se
as
e
se
ve
rit
y
an
d
pr
og
no
si
s;
25
(O
H
)D
<
30
ng
/m
L
A
ta
dm
is
si
on
to
th
e
ho
sp
ita
l
A
ge
,s
ex
,B
M
I,
sm
ok
in
g,
an
d
hi
st
or
y
of
a
ch
ro
ni
c
m
ed
ic
al
di
so
rd
er
M
er
zo
n
(4
0)
Fe
br
ua
ry
to
M
ar
ch
,2
02
0
Is
ra
el
,H
ea
lth
Se
rv
ic
es
Re
tr
os
pe
ct
iv
e
co
ho
rt
st
ud
y
78
2
SA
RS
-C
oV
-2
+
SA
RS
-C
oV
-2
+:
m
ea
n
ag
e:
35
.6
;
m
al
e:
49
.2
3%
SA
RS
-C
oV
-2
–
ne
ga
tiv
e
(–
):
ag
e:
47
.4
;m
al
e:
40
.6
%
Is
VD
D
a
ris
k
fa
ct
or
fo
rC
O
VI
D
-1
9
ho
sp
ita
liz
at
io
n?
H
os
pi
ta
liz
at
io
n
w
as
co
ns
id
er
ed
as
th
e
m
ar
ke
ro
fs
ev
er
ity
;
25
(O
H
)D
<
30
ng
/m
L
A
tl
ea
st
1
pr
ev
io
us
bl
oo
d
te
st
fo
r
pl
as
m
a
25
(O
H
)D
3
co
nc
en
tr
at
io
n
D
em
og
ra
ph
ic
va
ria
bl
es
,
ps
yc
hi
at
ric
an
d
so
m
at
ic
di
so
rd
er
s
Pa
na
gi
ot
ou
(5
9)
—
U
K,
lo
ca
lc
lin
ic
al
ca
re
pa
th
w
ay
Re
tr
os
pe
ct
iv
e
in
te
rim
au
di
t
13
4
SA
RS
-C
oV
-2
+
pa
tie
nt
s;
42
ad
m
itt
ed
to
IC
U
;
de
ce
as
ed
:1
6
M
ea
n
ag
e:
65
.9
;m
al
e:
48
.7
%
Th
e
pr
ev
al
en
ce
of
VD
D
am
on
g
CO
VI
D
-1
9
in
pa
tie
nt
s,
an
d
its
as
so
ci
at
io
ns
w
ith
di
se
as
e
se
ve
rit
y
Se
ve
re
CO
VI
D
-1
9
w
as
de
fin
ed
as
ad
m
is
si
on
to
IC
U
an
d
m
or
ta
lit
y;
25
(O
H
)D
<
20
ng
/m
L
M
ea
su
re
d
af
te
r
CO
VI
D
-1
9
te
st
in
g
A
ge
,g
en
de
r,
co
m
or
bi
di
tie
s,
an
d
C
RP
co
n-
ce
nt
ra
tio
ns
fo
r
m
or
ta
lit
y
Pi
zz
in
i(
61
)
Be
ga
n
on
A
pr
il
29
,2
02
0;
on
go
in
g
Se
ve
ra
lh
os
pi
ta
ls
an
d
ca
re
ce
nt
er
s
in
A
us
tr
ia
Pr
os
pe
ct
iv
e
m
ul
tic
en
te
r
ob
se
rv
a-
tio
na
l
st
ud
y
22
no
n-
ho
sp
ita
liz
ed
(m
ild
)a
nd
87
ho
sp
ita
liz
ed
pa
tie
nt
s
(m
od
er
at
e:
34
;
se
ve
re
:5
3)
;3
8%
w
ith
VD
D
M
ed
ia
n
ag
e:
58
;
m
al
e:
60
%
To
in
ve
st
ig
at
e
as
so
ci
at
io
ns
of
vi
ta
m
in
D
st
at
us
to
di
se
as
e
pr
es
en
ta
tio
n
D
is
ea
se
se
ve
rit
y
w
as
ca
te
go
riz
ed
as
m
ild
fo
rp
at
ie
nt
s
in
ou
tw
ar
d
tr
ea
tm
en
t;
m
od
er
at
e
fo
r
pa
tie
nt
s
in
in
w
ar
d
tr
ea
tm
en
t;
an
d
se
ve
re
fo
rp
at
ie
nt
s
re
qu
iri
ng
ox
yg
en
su
pp
ly
,r
es
pi
ra
to
ry
su
pp
or
t,
or
IC
U
;
25
(O
H
)D
<
12
ng
/m
L
Th
e
25
(O
H
)D
3
co
nc
en
tr
at
io
n
w
as
m
ea
su
re
d
2
tim
es
:t
he
fir
st
da
ys
of
ho
sp
ita
l
ad
m
is
si
on
an
d
8
w
k
af
te
rt
he
di
ag
no
si
s
—
(C
on
tin
ue
d)
14 Kazemi et al.
D
ow
nloaded from
 https://academ
ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
en
cy
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
Pé
re
z
(6
6)
—
H
os
pi
ta
lC
en
tr
al
M
ili
ta
ry
M
ex
ic
o
17
2
pa
tie
nt
s
w
ith
CO
VI
D
-1
9;
ca
se
s:
th
os
e
w
ho
di
ed
(n
=
35
);
co
nt
ro
ls
:t
ho
se
w
ho
su
rv
iv
ed
M
ea
n
ag
e:
51
.4
4;
m
al
e:
77
.3
%
D
et
er
m
in
e
th
e
as
so
ci
at
io
n
be
tw
ee
n
25
(O
H
)D
co
nc
en
tr
at
io
ns
an
d
m
or
ta
lit
y
in
ho
sp
ita
liz
ed
pa
tie
nt
s
w
ith
CO
VI
D
-1
9
M
or
ta
lit
y
w
as
co
ns
id
er
ed
as
se
ve
re
;2
5(
O
H
)D
<
20
ng
/d
L
—
—
Ra
du
jk
ov
ic
(1
3)
M
ar
ch
to
Ju
ne
,
20
20
M
ed
ic
al
un
iv
er
si
ty
ho
sp
ita
l,
H
ei
de
lb
er
g,
G
er
m
an
y
Co
ho
rt
18
5
pa
tie
nt
s;
pa
tie
nt
s
w
ith
VD
D
(n
=
41
);
no
n-
VD
D
(n
=
14
4)
;
ou
tp
at
ie
nt
s:
92
;
in
pa
tie
nt
s:
93
M
ed
ia
n
ag
e:
60
,
IQ
R
(4
9–
70
);
m
al
e:
51
%
To
ex
pl
or
e
po
ss
ib
le
as
so
ci
at
io
ns
of
vi
ta
m
in
D
st
at
us
w
ith
di
se
as
e
se
ve
rit
y
an
d
su
rv
iv
al
D
ec
is
io
n
fo
ri
np
at
ie
nt
vs
.o
ut
pa
tie
nt
ad
m
is
si
on
w
as
ba
se
d
on
sp
on
ta
ne
ou
s
ox
yg
en
sa
tu
ra
tio
n,
co
m
or
bi
di
tie
s,
an
d
th
e
ov
er
al
l
pe
rf
or
m
an
ce
st
at
us
;
ba
se
d
on
CO
VI
D
-1
9
se
ve
rit
y
cl
as
si
fic
at
io
ns
,a
ll
in
pa
tie
nt
s
ha
d
se
ve
re
di
se
as
e
(d
efi
ne
d
as
ta
ch
yp
ne
a,
ox
yg
en
sa
tu
ra
tio
n
<
93
%
at
re
st
,o
rI
C
U
re
qu
ire
m
en
t)
;
25
(O
H
)D
<
12
ng
/m
L
A
tt
he
tim
e
of
ad
m
is
si
on
A
dj
us
te
d
fo
ra
ge
,
ge
nd
er
,a
nd
co
m
or
bi
di
tie
s
Ra
st
og
i(
14
)
—
Te
rt
ia
ry
ca
re
ho
sp
ita
li
n
no
rt
h
In
di
a
RC
T
40
A
sy
m
pt
om
at
ic
or
m
ild
ly
sy
m
pt
om
at
ic
SA
RS
-C
oV
-2
+
w
ith
VD
D
[2
5(
O
H
)D
3
<
20
ng
/m
L]
M
ed
ia
n
ag
e
in
th
e
in
te
rv
en
tio
n
gr
ou
p:
50
.0
,I
Q
R
(3
6–
51
);
m
al
e:
37
.5
%
Co
nt
ro
l:
47
.5
(3
9.
3
to
49
.2
);
m
al
e:
58
.3
%
Eff
ec
to
f
hi
gh
-d
os
e
or
al
ch
ol
ec
al
ci
fe
ro
l
su
pp
le
m
en
ta
-
tio
n
on
SA
RS
-C
oV
-2
vi
ra
lc
le
ar
an
ce
—
A
tt
he
be
gi
nn
in
g
of
st
ud
y
—
Ye
(4
1)
Fe
br
ua
ry
to
M
ar
ch
,2
02
0
G
ua
ng
xi
Pe
op
le
’s
H
os
pi
ta
l,
C
hi
na
C
as
e-
co
nt
ro
l
80
he
al
th
y
co
nt
ro
ls
an
d
62
pa
tie
nt
s
di
ag
no
se
d
w
ith
CO
VI
D
-1
9
M
ed
ia
n
ag
e
in
co
nt
ro
ls
:4
2,
IQ
R
(3
1–
52
);
m
al
e:
40
%
A
ge
in
ca
se
s:
43
(3
2–
59
);
m
al
e:
37
%
To
ex
am
in
e
th
e
re
la
tio
n
be
tw
ee
n
se
ru
m
25
(O
H
)D
3
co
nc
en
tr
at
io
n
an
d
CO
VI
D
-1
9
se
ve
rit
y,
an
d
its
cl
in
ic
al
ca
se
ch
ar
ac
te
ris
tic
s
Se
ve
re
CO
VI
D
-1
9
ca
se
w
as
de
fin
ed
ac
co
rd
in
g
to
th
e
gu
id
el
in
es
of
th
e
N
at
io
na
lH
ea
lth
Co
m
m
is
si
on
of
C
hi
na
5
;2
5(
O
H
)D
<
20
ng
/d
L
A
ta
dm
is
si
on
D
em
og
ra
ph
ic
s
an
d
co
m
or
bi
di
tie
s
(C
on
tin
ue
d)
Vitamin D and COVID-19 15
D
ow
nloaded from
 https://academ
ic.oup.com
/advances/advance-article/doi/10.1093/advances/nm
ab012/6159489 by guest on 09 M
arch 2021
TA
BL
E
2
(C
on
tin
ue
d)
Fi
rs
ta
ut
h
or
(r
ef
)
St
ud
y
d
at
e
C
ou
n
tr
y,
se
tt
in
g
D
es
ig
n
Sa
m
p
le
si
ze
,n
A
g
e
(y
);
se
x
O
b
je
ct
iv
e/
st
ud
y
q
ue
st
io
n
Se
ve
ri
ty
d
efi
n
it
io
n
/v
it
am
in
d
efi
ci
en
cy
d
efi
n
it
io
n
Ti
m
e
of
V
it
D
as
ce
rt
ai
n
m
en
t
A
d
ju
st
in
g
fa
ct
or
s
Yı
lm
az
(3
5)
M
ar
ch
to
M
ay
20
20
Tu
rk
ey
,D
ic
le
U
ni
ve
rs
ity
Fa
cu
lty
of
M
ed
ic
in
e
C
as
e-
co
nt
ro
l
85
ch
ild
re
n
(4
0
pa
tie
nt
s
w
ho
w
er
e
di
ag
no
se
d
w
ith
CO
VI
D
-1
9
an
d
ho
sp
ita
liz
ed
,4
5
he
al
th
y
ch
ild
re
n
in
th
e
co
nt
ro
l
gr
ou
p)
CO
VI
D
-1
9
pa
tie
nt
s:
10
1.
76
±
27
.9
1
m
o;
m
al
e:
47
.5
%
Co
nt
ro
ls
:7
5.
68
±
27
.3
4
m
o;
m
al
e:
60
%
To
de
te
rm
in
e
th
e
pr
ev
al
en
ce
an
d
cl
in
ic
al
im
po
rt
an
ce
of
VD
D
in
ch
ild
re
n
an
d
ad
ol
es
ce
nt
pa
tie
nt
s
w
ho
w
er
e
ho
sp
ita
liz
ed
w
ith
th
e
di
ag
no
si
s
of
CO
VI
D
-1
9
M
ild
:c
as
es
w
ith
up
pe
r
re
sp
ira
to
ry
tr
ac
t
in
fe
ct
io
n
w
ith
no
rm
al
re
sp
ira
to
ry
sy
st
em
ex
am
in
at
io
n
M
od
er
at
e:
pn
eu
m
on
ia
w
ith
fe
ve
ra
nd
co
ug
h
bu
tw
ith
ou
t
sy
m
pt
om
s
of
dy
sp
ne
a
an
d
hy
po
xe
m
ia
or
ca
se
s
w
ith
fin
di
ng
s
of
CO
VI
D
-1
9
on
C
T
sc
an
w
ith
ou
ta
ny
sy
m
pt
om
s
Se
ve
re
:f
ev
er
an
d
co
ug
h
in
th
e
ea
rly
pe
rio
d
w
ho
de
ve
lo
p
dy
sp
ne
a
an
d
ce
nt
ra
l
cy
an
os
is
C
rit
ic
al
:d
ev
el
op
A
RD
S
or
RF
ra
pi
dl
y
25
(O
H
)D
<
20
ng
/m
L
Fr
om
re
tr
os
pe
ct
iv
e
fil
e
re
co
rd
s
N
on
e
1
A
RF
,a
cu
te
re
sp
ira
to
ry
fa
ilu
re
;A
RD
S,
ac
ut
e
re
sp
ira
to
ry
di
st
re
ss
sy
nd
ro
m
e;
CO
VI
D
-1
9,
co
ro
na
vi
ru
s
di
se
as
e
20
19
;C
RP
,C
-r
ea
ct
iv
e
pr
ot
ei
n;
C
T,
co
m
pu
te
d
to
m
og
ra
ph
y;
D
M
,d
ia
be
te
s
m
el
lit
us
;E
C
M
O
,e
xt
ra
co
rp
or
ea
lm
em
br
an
e
ox
yg
en
at
io
n;
Fi
O
2
,f
ra
ct
io
n
of
in
sp
ire
d
ox
yg
en
;G
FR
,g
lo
m
er
ul
ar
fil
tr
at
io
n
ra
te
;H
TN
,h
yp
er
te
ns
io
n;
IC
U
,i
nt
en
si
ve
ca
re
un
it;
IH
D
,i
sc
he
m
ic
he
ar
td
is
ea
se
;M
A
S,
m
ac
ro
ph
ag
e
ac
tiv
at
io
n
sy
nd
ro
m
e;
M
LR
,m
ul
tiv
ar
ia
te
lo
gi
st
ic
re
gr
es
si
on
;O
SC
I,
O
rd
in
al
Sc
al
e
fo
rC
lin
ic
al
Im
pr
ov
em
en
t;
Pa
O
2
,p
ar
tia
lo
xy
ge
n
pr
es
su
re
;R
C
T,
ra
nd
om
iz
ed
co
nt
ro
lle
d
tr
ia
l;
re
f,
re
fe
re
nc
e;
RF
,r
en
al
fa
ilu
re
;S
A
RS
-C
oV
-2
,s
ev
er
e
ac
ut
e
re
sp
ira
to
ry
sy
nd
ro
m
e
co
ro
na
vi
ru
s
2;
Sp
O
2
,o
xy
ge
n
sa
tu
ra
tio
n;
VD
D
,v
ita
m
in
D
de
fic
ie
nc
y;
Vi
tD
,v
ita
m
in
D
;2
5(
O
H
)D
,
25
-h
yd
ro
xy
vita
m
in
D
;2
5(
O
H
)D
3,
25
-h
yd
ro
xy
vi
ta
m
in
D
3;
1,
25
(O
H
)D
,1
,2
5-
hy
dr
ox
yv
ita
m
in
D
.
2
C
hi
ne
se
C
lin
ic
al
G
ui
de
lin
e
fo
rc
la
ss
ifi
ca
tio
n
of
CO
VI
D
-1
9
se
ve
rit
y.
M
od
er
at
e:
fe
ve
ra
nd
pu
lm
on
ar
y
sy
m
pt
om
s
al
on
g
w
ith
pn
eu
m
on
ia
on
ra
di
ol
og
ic
im
ag
in
g.
Se
ve
re
:t
he
pr
es
en
ce
of
an
y
of
th
e
fo
llo
w
in
g
cr
ite
ria
:1
)r
es
pi
ra
to
ry
di
st
re
ss
(≥
30
br
ea
th
s/
m
in
),
2)
ox
yg
en
sa
tu
ra
tio
n
≤9
3%
at
re
st
,3
)P
aO
2
/F
iO
2
≤3
00
m
m
H
g
or
ch
es
ti
m
ag
in
g
sh
ow
s
ob
vi
ou
s
le
si
on
pr
og
re
ss
io
n
>
50
%
w
ith
in
24
–4
8
h.
3
Co
m
m
is
si
on
an
d
St
at
e
A
dm
in
is
tr
at
io
n
of
Tr
ad
iti
on
al
C
hi
ne
se
M
ed
ic
in
e:
1)
m
ild
:m
ild
sy
m
pt
om
s
w
ith
no
si
gn
s
of
pn
eu
m
on
ia
on
im
ag
in
g;
2)
m
od
er
at
e:
fe
ve
r,
re
sp
ira
to
ry
sy
m
pt
om
s
w
ith
ra
di
ol
og
ic
al
ev
id
en
ce
of
pn
eu
m
on
ia
;3
)s
ev
er
e
[i.
e.
,m
ee
tin
g
an
y
of
th
e
fo
llo
w
in
g:
re
sp
ira
to
ry
di
st
re
ss
,r
es
pi
ra
to
ry
ra
te
≥3
0
br
ea
th
s/
m
in
,h
yp
ox
em
ia
,S
pO
2
≤9
3%
(a
tr
es
t)
,o
rl
un
g
in
fil
tr
at
es
of
>
50
%
w
ith
in
24
–4
8
h]
;a
nd
4)
cr
iti
ca
l(
i.e
.,
m
ee
tin
g
an
y
of
th
e
fo
llo
w
in
g
cr
ite
ria
:r
es
pi
ra
to
ry
fa
ilu
re
re
qu
iri
ng
m
ec
ha
ni
ca
lv
en
til
at
io
n,
sh
oc
k,
or
m
ul
tip
le
or
ga
n
dy
sf
un
ct
io
n
re
qu
iri
ng
IC
U
m
on
ito
rin
g
an
d
tr
ea
tm
en
t)
.
4
C
D
C
cr
ite
ria
w
er
e
us
ed
fo
rt
he
di
se
as
e
se
ve
rit
y
an
d
pr
og
no
si
s,
w
hi
ch
in
cl
ud
es
m
ild
–m
od
er
at
e
(m
ild
re
sp
ira
to
ry
sy
m
pt
om
s
an
d
fe
ve
ro
n
an
av
er
ag
e
of
5–
6
d
af
te
ri
nf
ec
tio
n)
,s
ev
er
e
di
se
as
e
(d
ys
pn
ea
,r
es
pi
ra
to
ry
fre
qu
en
cy
≥3
0
br
ea
th
s/
m
in
,b
lo
od
ox
yg
en
sa
tu
ra
tio
n
≤9
3%
,a
nd
/o
rl
un
g
in
fil
tr
at
es
>
50
%
of
th
e
lu
ng
fie
ld
w
ith
in
24
–4
8
h)
an
d
cr
iti
ca
l(
re
sp
ira
to
ry
fa
ilu
re
,s
ep
tic
sh
oc
k,
an
d/
or
m
ul
tip
le
-o
rg
an
dy
sf
un
ct
io
n/
fa
ilu
re
).
5
Pe
rG
ui
de
lin
es
of
th
e
N
at
io
na
lH
ea
lth
Co
m
m
is
si
on
of
C
hi
na
se
ve
re
ca
se
s
m
et
at
le
as
t1
of
th
e
fo
llo
w
in
g
cr
ite
ria
:1
)r
es
pi
ra
to
ry
ra
te
>
30
br
ea
th
s/
m
in
,2
)p
ul
se
ox
im
et
er
Sp
O
2
≤9
3%
w
he
n
br
ea
th
in
g
am
bi
en
ta
ir,
3)
ra
tio
of
Pa
O
2
to
Fi
O
2
≤3
00
m
m
H
g
(1
m
m
H
g
=
0.
13
3
ki
lo
pa
sc
al
),
an
d
4)
lu
ng
im
ag
in
g
sh
ow
in
g
si
gn
ifi
ca
nt
pr
og
re
ss
io
n
of
>
50
%
w
ith
in
24
to
48
h.
C
rit
ic
al
ca
se
s
w
er
e
de
fin
ed
as
ha
vi
ng
at
le
as
t1
of
th
e
fo
llo
w
in
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FIGURE 2 Relation between vitamin D deficiency and risk of SARS-CoV-2 infection in studies that adjusted for confounders (adjusted OR)
(A) and studies that did not adjust for confounders (crude OR) (B). ES, effect size; SARS-CoV-2, severe acute respiratory syndrome
coronavirus 2.
between concentrations of 25(OH)D in ARDS [mean (SD):
16.8 (10.5) ng/mL) and non-ARDS [21.8 (15.8)] patients
in Kerget et al. (50) (P = 0.10). Similarly, no significant
association between VDD and ARDS was observed in the
Maghbooli et al. (38) study (17.1% in VDD vs. 11.7% in
non-VDD that progressed to ARDS; P = 0.33); moreover,
bilateral lung involvement was observed in 33.3% in VDD
versus 31.7% in non-VDD (P = 0.86) in this study. Three
remaining studies evaluated the relation between VDD and
risk of ventilation requirement. In a prospective study, VDD
increased the risk of invasive mechanical ventilation and/or
death (HR: 6.12; 95% CI: 2.79, 13.42; P < 0.001) (13).
Consistently, another study indicated a significant relation
between VDD and ventilation requirement (OR: 4.15; 95%
CI: 1.05, 16.34; P = 0.042) (47), while one reported no
relation (22.8% in VDD vs. 17.14% in non-VDD; P = 0.58)
(44). Confounders were adjusted in the Radujkovic et al. (13)
and Abrishami et al. (60) studies, while not adjusted in the
Baktash et al. (47), Hernández et al. (44), Kerget et al. (50),
Faul et al. (30), Maghbooli et al. (38), Pizzini et al. (61),
and Im et al. (45) studies, respectively. Results of studies are
summarized in Supplemental Table 6.
Hospitalization
Three studies investigated the relation between 25(OH)D
and hospital admission and 2 with hospital stay. A significant
association between VDD and risk of hospitalization was
observed in Radujkovic et al. (13) (31% hospitalization in
VDD vs. 69% in non-VDD, P = 0.004) and a marginally
significant relation in Merzon et al. (40) (adjusted OR: 1.95;
95% CI: 0.98, 4.845; P = 0.06). The third study was a
cross-sectional study that compared history of vitamin D3
supplement intake between inpatients and outpatients (57),
where vitamin D3 intake was reported in 30% of outpatients
versus 16.5% of hospitalized patients (P = 0.001).
Hernández et al. (44) found a significant relation between
VDD and hospital stay [median (IQR) of 12.0 d (8.0–16.0) in
patients with VDD vs. 8.0 d (6.0–14.0) in non-VDD patients;
P = 0.01], while Luo et al. (46) failed to find a significant
relation between serum 25(OH)D concentrations and length
FIGURE 3 Relation between vitamin D deficiency and COVID-19 severity in studies that adjusted for confounders (adjusted OR) (A) and
studies that did not adjust for confounders (crude OR) (B). COVID-19, coronavirus disease 2019; ES, effect size.
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of hospital stay (B = −0.03, P = 0.64) (Supplemental
Table 7).
Concentration of 25(OH)D between severe and less
severe status of disease
Thirteen studies compared the serum concentration of
25(OH)D between patients with severe and nonsevere status
of COVID-19 (either composite or 1 feature of severity).
Analysis of 12 studies (13, 30, 41, 42, 43, 46, 50, 53–55, 59,
61), with 806 cases and 1024 controls, indicated that serum
concentrations of 25(OH)D in patients with severe status of
disease was lower (WMD = −7.17 ng/mL; 95% CI: −9.99,
−4.34; I2 = 87.6%) compared with less-severe counterparts
(Supplemental Figure 2). In all of the studies except for
one (43), 25(OH)D was measured after SARS-CoV-2 testing.
One study was not included in the analysis, since the sample
size according to hospitalization was not reported. Indeed,
in this retrospective study, mean concentrations of 25(OH)D
were 18.38 ng/mL (95% CI: 16.79, 19.96) in hospitalized
and 20.45 ng/mL (95% CI: 20.22, 20.68) in nonhospitalized
individuals (P < 0.001) (40) (Supplemental Table 8).
Inflammatory markers
We assessed the association of VDD with C-reactive protein
(CRP), IL-6, D-dimer, and ferritin in COVID-19 patients.
Nine studies examined the association of at least 1 of these
markers with VDD. In an RCT in 40 COVID-19 patients,
cholecalciferol supplementation did not significantly reduce
CRP and D-dimer (14). A retrospective study in 42 patients
with acute respiratory failure due to COVID-19 (64) revealed
no statistically significant differences in inflammation indices
among the 4 vitamin D groups (normal, insufficiency,
deficiency, severe deficiency).Another retrospective study in
197 COVID-19 patients revealed that only ferritin, but not
CRP, IL -6, and D-dimer, was significantly higher in VDD
compared with non-VDD (44). In a prospective multicenter
observational study in 109 patients, the correlation between
25(OH)D concentrations at follow-up and CRP, IL-6, ferritin,
and D-dimer was not significant. The same was true for
25(OH)D concentrations measured at disease onset and CRP
(r = 0.152, P = 0.45), IL-6 (r = 0.050, P = 0.80), and ferritin
(r = 0.070, P = 0.73). In contrast, D-dimer concentrations
were moderately associated with 25(OH)D concentrations
(r = 0.437, P < 0.05) (61). Karahan and Katkat (54) in
their retrospective study in 149 COVID-19 patients found
a significant negative relation between serum 25(OH)D
concentration and CRP (r = −0.253, P = 0.002). Kerget et al.
(50) found a significant negative correlation only with CRP (r
= −0.297, P = 0.01), but not IL-6, ferritin, and D-dimer. In
a prospective study in 70 elderly individuals, it was reported
that the VDD group demonstrated higher peak CRP, lactate
dehydrogenase (LDH), and ferritin concentrations (47).
Maghbooli et al. (38) in a cross-sectional study in 235
patients indicated that a relative risk of CRP >40 mg/L
(inpatient mortality serum concentrations) was significantly
higher in VDD. In Radujkovic et al. (13), IL-6 concentration
was significantly higher in VDD versus non-VDD [median
(IQR): 70.5 pg/mL (32.0–326.3) vs. 29.7 pg/mL (14.3–59.9);
P = 0.01]. Only Maghbooli et al. and Radujkovic et al.
adjusted for confounders, whereas the other studies did
not report any adjustment. Results of studies are listed in
Supplemental Table 9.
Mortality
Among 15 studies that assessed the relation between mor-
tality and VDD, 13 studies were included in the analysis.
Pooled analysis of 4 adjusted studies that used the Cox
survival method (13, 51, 56, 60) (HR: 2.35; 95% CI: 1.22,
4.52; I2: 84%; Figure 4A) and 5 studies (44, 47, 53, 55,
62) with crude OR (OR: 2.62; 95% CI: 1.13, 6.05; I2:
47.8%; Figure 4B) indicated a significant association of VDD
with mortality, while in adjusted studies that used logistic
regression (54, 59, 65), no relation was observed (OR: 1.05;
95% CI: 0.63, 1.75; I2: 76.6%). Two studies were not included
in the analysis since 1 study had an RCT design (36) and
another one used different statistical methods (64). In the
RCT, 2 deaths in the control group versus no deaths in
the intervention group were observed (36). In the other
study, which had a retrospective design, patients with serum
25(OH)D <10 ng/mL had a 50% probability of mortality,
while those with 25(OH)D ≥10 ng/mL had a 5% mortality
risk after 10 d of hospitalization (P = 0.02) (64).
Moreover, 6 studies compared serum concentrations of
25(OH)D between deceased patients and those who survived
(50, 54, 55, 60, 63, 66); pooled analysis of studies indicated
lower concentrations of 25(OH)D in patients who died
compared with those who survived (WMD: −9.05 ng/mL;
95% CI: −13.86, −4.23; I2: 87.8%; Supplemental Figure 3).
Results of studies are summarized in Supplemental Table 10.
Publication bias and quality assessment
Assessment of publication bias was conducted for 25(OH)D
concentration between SARS-CoV-2–positive and –negative
subjects as well as between severe and less-severe COVID-
19 groups. Based on Egger’s test, publication bias was
evident in comparison of SARS-CoV-2–positive with –
negative subjects (P = 0.002) and the funnel plot was
asymmetric (Supplemental Figure 4A). The probable reason
for publication bias may be that the studies with 25(OH)D
data collected before SARS-CoV-2 testing had larger sample
sizes and detected smaller differences compared with the
studies that measured 25(OH)D after SARS-CoV-2 testing.
There was no publication bias in the comparison of severe
and less-severe COVID-19 patients (P = 0.60); however,
a small deviation towards an WMD ∼ −5 and an SE ≈2
was observed in a funnel plot (Supplemental Figure 4B);
this implies that studies with a smaller SE (more precision)
indicate less difference in 25(OH)D concentration compared
with the pooled WMD. Therefore, it should be considered
that a small overestimation is probable. The quality of most
of the studies was classified as poor (Supplemental Tables
11–14). Moreover, the strength and limitations of studies are
summarized in Supplemental Table 15.
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FIGURE 4 Relation between vitamin D deficiency and risk of mortality from COVID-19 in studies that adjusted for confounders (adjusted
HR) (A) and studies that did not adjust for confounders (crude OR) (B). COVID-19, coronavirus disease 2019; ES, effect size; MLR, multiple
logistic regression.
Discussion
In this systematic review, we investigated the relation
between 25(OH)D concentrations and risk of SARS-
CoV-2 infection and COVID-19 severity. For this purpose,
we systematically reviewed and, where appropriate, meta-
analyzed the related retrospective, cohort, cross-sectional,
and clinical trial studies that assessed the association of
25(OH)D concentrations and the risk of SARS-CoV-2
infection, composite severity, or 1 feature of severity.
Higher risk of SARS-CoV-2 infection was observed in
VDD and serum concentrations of 25(OH)D were lower in
COVID-19 patients compared with healthy counterparts, as
indicated by pooled results of both adjusted and nonadjusted
studies. Among the 3 adjusted studies, 2 measured 25(OH)D
in the preceding year before SARS-CoV-2 infection (39, 40);
the sample sizes in one of these studies were sufficiently pow-
ered (case/control: 782/7025) (39). The nonadjusted studies
measured 25(OH)D at admission and the sample sizes were
sufficient in 4 studies (186/2700, 197/197, 128/219, 335/560)
(39, 43, 39, 39). Moreover, concentrations of 25(OH)D were
lower in COVID-19 patients compared with healthy subjects.
Based on the findings, VDD is associated with increased risk
of SARS-CoV-2 infection; however, caution should be made
in interpreting these results, since the studies have inherent
limitations.
All of the studies indicated a lower concentration of
25(OH)D with more severe status (composite severity) of
disease. Furthermore, VDD was associated with composite
severity in studies that were both adjusted and not adjusted
for confounders. The significant relation between VDD and
composite severity was evident in all of the primary studies,
except for the Hernández et al. (44) and De Smet et al. (42)
studies, where De Smet et al. revealed such a relation only in
males but not in females. Zero heterogeneity was estimated
for adjusted studies based on the I2 statistic. It should be
noted that the heterogeneity I2 statistic can be biased in small
meta-analyses and so an I2 of 0.0% does not necessarily reflect
perfect homogeneity (67).
Pooled results from the studies that were unadjusted
and adjusted studies using Cox survival analysis indicated
a higher risk of mortality in VDD; however, the adjusted
studies that used logistic regression failed to find a significant
relation. The Cox model estimates the instantaneous proba-
bility of death at a particular time, while logistic regression
estimates the cumulative probability; instantaneous risk
could be important as the cumulative probability can be
conditioned by a complex clinical outcome. Moreover, it is
noteworthy to mention that the Cox model tends to have
greater statistical power to detect a significant exposure effect
than logistic regression (68). Among the 4 adjusted studies
that used logistic regression, 1 study indicated higher risk
of mortality in VDD, 2 revealed no significant relation, and
1 study unexpectedly found a lower risk of mortality in VDD.
In this study, the prevalence of ≥2 comorbidities was higher
in the non-VDD (46.7%) versus the VDD group (30.3%).
Although this difference between groups was not statistically
significant, it