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\begin{document}

\title{Association between Vitamin D and COVID-19: a systematic review and
meta-analysis}



\author[1]{PAULO BIGNARDI}%
\author[1]{Paula Castello}%
\author[1]{Bruno Aquino}%
\affil[1]{Pontifical Catholic University of Parana School of Medicine Londrina Campus}%


\vspace{-1em}



  
  \date{May 25, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aim. Assess the association of plasma vitamin D levels or vitamin D
supplementation in the outcomes of COVID- 19. Methods. PubMed, EMBASE,
and Cochrane Library databases were searched. Studies with COVID-19
patients that reported an association between plasma vitamin D levels or
vitamin D supplementation and mortality, need of hospitalization, ICU
admission, or ventilation requirement published until December 8, 2020,
were included. The risk ratio (RR) and confidence interval (CI) were
pooled using a fixed-effects model. Results. A total of 16 studies were
included in the meta-analysis, eleven cohorts, one case-control, one
randomized clinical trial, and two quasi-experimental studies. Low
plasma vitamin D levels in patients with COVID-19 were associated with
mortality (RR=1.42, 95\%CI 1.14 -- 1.71), need for ICU admission
(RR=1.76, 95\%CI 1.03-2.49), and need for ventilation (RR=3.58, 95\%CI
1.45-5.70). Regular supplementation showed a decreased risk of death,
and vitamin D supplementation in patients with COVID-19 showed a
decrease in the need for ICU admission. Conclusion. Sufficient vitamin D
level is associated with better outcomes in patients with COVID-19.
Vitamin D supplementation in patients with COVID-19 appears to reduce
the risk of ICU admission and regular supplementation reduces mortality.%
\end{abstract}%



\sloppy


\textbf{Association between Vitamin D and COVID-19: a systematic review
and meta-analysis}

Paulo R Bignardi, PhD\textsuperscript{a}, Paula de Andrade
Castello\textsuperscript{a}, Bruno de Matos Aquino\textsuperscript{a}

Affiliations:

\textsuperscript{a}School of Medicine, Pontif\selectlanguage{ngerman}ícia Universidade Católica
do Paraná, Londrina, Brazil

* Correspondence author: Prof. Paulo R. Bignardi. e-mail:
pbignardi@gmail.com, School of Medicine. Address: 485 Jockey Club ave --
Hípica -- Londrina -- Paraná -- Brazil, Zip code 86072-360

\textbf{Declaration of Conflicting Interests}

The authors declare that there is no conflict of interests.

\textbf{ABSTRACT}

\textbf{Aim} . Assess the association of plasma vitamin D levels or
vitamin D supplementation with the outcomes of COVID-
19.\textbf{Methods} . PubMed, EMBASE, and Cochrane Library databases
were searched. Studies with COVID-19 patients that reported an
association between plasma vitamin D levels or vitamin D supplementation
and mortality, need of hospitalization, ICU admission, or ventilation
requirement published until December 8, 2020, were included. The risk
ratio (RR) and confidence interval (CI) were pooled using a
fixed-effects model. \textbf{Results} . A total of 16 studies were
included in the meta-analysis, eleven cohorts, one case-control, one
randomized clinical trial, and two quasi-experimental studies. Low
plasma vitamin D levels in patients with COVID-19 were associated with
mortality (RR=1.42, 95\%CI 1.14 -- 1.71), need for ICU admission
(RR=1.76, 95\%CI 1.03-2.49), and need for ventilation (RR=3.58, 95\%CI
1.45-5.70). Regular vitamin D supplementation showed a decreased risk of
death, and vitamin D treatment in patients with COVID-19 showed a
decrease in the need for ICU admission. \textbf{Conclusion} . Sufficient
vitamin D level is associated with better outcomes in patients with
COVID-19. Vitamin D supplementation in patients with COVID-19 appears to
reduce the risk of ICU admission and regular supplementation reduces
mortality.

\textbf{Keywords} : 25-hydroxyvitamin D; Cholecalciferol;
Ergocalciferols; Meta-analysis. SARS-Cov2.

\subsection*{INTROducTion}

{\label{introduction}}

Since the first case registered in December 2019 in the city of Wuhan,
Hubei Province, China, COVID-19 has spread rapidly throughout the world
for presenting strong contagious and infectious
characteristics\textsuperscript{1--3}, which have caused 1,663,474
deaths until December 19th, 2020 in 198 countries\textsuperscript{4}.

Worldwide data from the pandemic demonstrate a mortality rate of 0.9\%
in patients without comorbidities, which increases progressively based
on the number of comorbidities and the age of the
patients\textsuperscript{5}. The existence of studies relating vitamin D
levels to Acute respiratory infections\textsuperscript{6}, led to the
carrying out an ecological study wich showed that countries, where the
plasma mean vitamin D population is low, had higher rates of infection
and mortality from SARS-CoV2\textsuperscript{7}.

Isaia et al\textsuperscript{8} found a correlation between regions with
higher levels of solar ultraviolet (UV) radiation and lower rates of
morbidity and mortality related to COVID-19, the hypothesis discussed by
the authors is that it may be related to vitamin D levels. Exposure to
UV radiation determines the photo-conversion of the pro-vitamin D3
(7-dehydrocholesterol) in the skin to pre-vitamin D3\textsuperscript{9}.

In addition, many observational studies relating vitamin D level to
COVID-19 outcomes have emerged with divergent
results\textsuperscript{10--14} and in the absence of randomized
clinical trials, we proposed conducting a systematic review to assess
the association of plasma vitamin D levels or vitamin D supplementation
in the mortality, and severity of COVID- 19.

\subsection*{METHODS}

{\label{methods}}

\subsubsection*{}

{\label{section}}

\subsubsection*{Data Search}

{\label{data-search}}

Two investigators searched MEDLINE, EMBASE, and Cochrane Library.
Studies published until December 8, 2020 were included. The following
search strategy was used: (coronavirus OR ``coronavirus infections'' OR
COVID-19 OR ``severe acute respiratory syndrome coronavirus 2'') AND
(``vitamin D'' OR ``ergocalciferol'' OR ``cholecalciferol'' OR ``vitamin
D deficiency'' OR calcitriol OR calcifediol OR alfacalcidol OR
paricalcitol OR doxercalciferol). The language of the searches was
limited to English, Spanish and Portuguese.

\subsubsection*{}

{\label{section-1}}

\subsubsection*{Study selection}

{\label{study-selection}}

The studies were screened by two independent authors. Disagreements were
resolved through discussion among all authors. Summaries of retrieved
articles were reviewed to exclude irrelevant studies, followed by
reading full text for screening.

Studies were included if they met the following inclusion criteria: (1)
enrolled COVID-19 patients with plasma vitamin D level
(25-hydroxyvitamin D) or COVID-19 patients in vitamin D or analogs use.
All studies used throat swab SARS-CoV-2 real-time reverse
transcription-polymerase chain reaction (RT-PCR) nucleic acid to confirm
COVID-19; (2) examined the association between vitamin D use or plasma
vitamin D level with mortality or disease severity (death,
hospitalization, intensive care unit - ICU admission and ventilation
requirement); (3) observational or interventional studies. Ecological,
cross-sectional, and studies that plasma vitamin D level was measured
more than a year ago were excluded.

\textbf{Data Extraction}

Eligible studies included assessment of death or disease severity in
individuals with plasma vitamin D or vitamin D non-use. They should
provide odds ratio (OR), risk ratio (RR), or hazard ratio (HR) with 95\%
confidence intervals (CI). Inclusion was not restricted by study size.

Data extraction was performed by two independent investigators. Data
extracted included authors, study design, country of origin, demographic
characteristics (age, sex, and sample size), COVID-19 diagnosis,
outcomes relevant studies on the study question. Disagreements were
resolved through discussion among all authors.

\subsubsection*{Results evaluation}

{\label{results-evaluation}}

The primary analysis focused on the outcomes: Mortality in patients with
COVID-19 in the low plasma vitamin D levels group compared with plasma
sufficient vitamin D levels group or supplement vitamin D group compared
with non-supplement vitamin D group. The secondary analysis focused on
need for hospitalization, ICU admission, and need for mechanical
ventilation.

We performed a stratified analysis by plasma vitamin D level and
hospitalized patients. Besides, a sensitivity analysis was performed
when necessary omitting each study to detect the influence on the
estimate of the overall effect.

\subsubsection*{Quality assessment and statistical
analysis}

{\label{quality-assessment-and-statistical-analysis}}

This systematic review was conducted in accordance with the Preferred
Items guidelines for Reporting for Systematic Reviews and Meta-Analysis
(PRISMA), and this study has not been registered.

The New-Castle-Ottawa quality scale\textsuperscript{15} was used to
evaluate the quality of the observational studies. The Cochrane risk of
bias tool was used for randomized controlled trials\textsuperscript{16}.
In the case of non-randomized interventional studies, the ROBINS - I
tool was used\textsuperscript{17}.

Studies included in the meta-analysis reported OR, HR, or RR. For
studies that did not report these measures of effects, the RR
calculation was based on the Cochrane Handbook for Systematic
Reviews\textsuperscript{18}.

Effect estimates with the greatest degree of adjustment for potential
confounding factors were extracted. HR was considered comparable to RR.
For studies that reported OR, a corrected RR was computed as already
described\textsuperscript{19}. Pooled RR and 95\% confidence interval
(CI) were calculated using a fixed or random-effects model according to
the homogeneity of the studies. The Cochran Q test and the
I\textsuperscript{2} statistic were used to evaluate the statistical
significance and degree of heterogeneity between the studies,
respectively. The statistic I\textsuperscript{2}\selectlanguage{english}[?]50\% reveals
substantial heterogeneity. Finally, the publication bias was examined by
the Egger test. All analyses were performed with Stata/SE v.14.1
software (StataCorpLP, USA).

\subsection*{RESULTS}

{\label{results}}

\textbf{Characteristics of the selection studies}

Four-hundred and six (406) studies were identified through database
research. Of these, 353 studies are duplicate articles or were excluded
based on predetermined eligibility criteria during title/abstract
review. Excluded criteria were ecological studies, case reports,
cross-sectional, not human, not on vitamin D level or not vitamin D
supplementation at COVID-19. We identified 17
studies\textsuperscript{13,20,29--35,21--28} (total 3,108 participants)
that were eligible for this review (Figure 1), of which 16 were involved
in the meta-analysis. Eleven of them was
cohort\textsuperscript{20,21,35,24,26,28--31,33,34}, one
case-control\textsuperscript{27}, one randomized clinical
trial\textsuperscript{25}, and two quasi-experimental
studies\textsuperscript{22,23}. It was not possible to extract data from
Pizzini et al\textsuperscript{32} for analysis. The characteristics of
selected studies and participants are summarized in Table 1.

\textbf{Plasma vitamin D level and mortality in patients with COVID-19}

The mortality outcome was extracted from 10 studies, but the adjusted
analysis used 9. As shown in figure 2, the mortality in patients with
deficient plasma vitamin D levels was significantly high when compared
to patients with sufficient plasma vitamin D levels (Adjusted analysis,
removing Carpagnano et al, RR=1.41, 95\%CI 1.13 -- 1.69,
I\textsuperscript{2}=0.0\%). The analysis included Carpagnano et
al\textsuperscript{13} showed no has significant statically (RR=7.41,
95\%CI -2.27 -- 17.09) with high heterogeneity
(I\textsuperscript{2}=99.9\%).

In subgroup analysis, hospitalized patients with deficient plasma
vitamin D levels also have an increased risk of mortality (RR=1.42,
95\%CI 1.14 -- 1.71, I\textsuperscript{2}=0.0\%). The plasma vitamin D
levels adopted in studies was \textless{}10 ng / ml by one study,
\textless{}12 ng / ml in four studies, \textless{}20 ng / ml in five
studies and \textless{}25 ng / ml in one study.

\textbf{Vitamin D supplementation and risk of deaths in patients with
COVID-19}

The pooled RR of deaths in COVID-19 patients in vitamin D
supplementation versus non-vitamin D supplementation was 0.10 (95\%CI
0.07 -- 0.28), without significant heterogeneity
(I\textsuperscript{2}=0.0\%) (Figure 3). Subgroup analysis showed RR =
0.10 (95\% CI 0.08 - 0.28) for regular vitamin D supplementation.

\textbf{Plasma vitamin D level and hospitalization in patients with
COVID-19}The data were extracted from two studies\textsuperscript{30,31}
that showed that there was no increase in the risk of hospitalization in
patients with COVID-19 when the serum vitamin D is low (OR=1.80, 95\%CI
0.97-2.64, I\textsuperscript{2}=0.0\%) (Figure 4). Mendy et
al\textsuperscript{30} analyzed patients with plasma vitamin D levels
lass 12 ng/ml and Merzon et al\textsuperscript{31} analyzed levels lass
30 ng/ml.\textbf{Plasma vitamin D level, vitamin D supplementation and
ICU admission in patients with COVID-19}The data was extracted from
three studies\textsuperscript{21,27,30}(Figure 5), two cohorts, and one
case-control. The analysis showed that patients with low vitamin D level
have was increased risk of ICU admission (RR=1.76, 95\%CI 1.03-2.49,
I\textsuperscript{2}=0.0\%). In the analysis of vitamin D
supplementation, the data was extracted from two studies, one randomized
clinical trial\textsuperscript{25} with calcifediol treatment and one
cohort\textsuperscript{35} that analyzed at the use of cholecalciferol
(Figure S1). The analysis showed that the treatment group has was a
decreased risk of ICU admission (RR=0.04, CI95\% 0.07-0.16,
I\textsuperscript{2}=0.0\%).\textbf{Plasma vitamin D level and
ventilation requirement in patients with COVID-19}The data was extracted
and pooled from three cohorts (Figure 6). Alguwaihes et
al\textsuperscript{21} analyzed patients with plasma vitamin D level
lass 5 ng/ml, Baktash et al\textsuperscript{24} analyze level lass 12
ng/ml, and Radujkovic et al\textsuperscript{33} analyzed patients with
plasma vitamin D level lass 12 ng/ml and lass 20 mg/ml separately.
Comparing the deficient plasma vitamin D level with the control group,
the results suggested that there is an increased risk of ventilation
requirement (RR=3.58, 95\%CI 1.45-5.70,
I\textsuperscript{2}=0.0\%).\textbf{Plasma vitamin D level and COVID-19
severity} The data COVID-19 severity (Outcomes combined analysis: Death,
ICU, and Mechanical Ventilation) was extracted and pooled from three
cohort\textsuperscript{21,29,30} and one
case-control\textsuperscript{27}. The analysis showed that patients with
low vitamin D level have was increased risk of deaths, ICU admission, or
mechanical ventilation (RR=1.77, 95\%CI 1.13-2.42,
I\textsuperscript{2}=0.0\%) (Figure 7).\textbf{Sensitivity analyses,
assessment of heterogeneity}

For sensitivity analyses were performed by excluding one study at a time
for the mortality outcome. The inclusion of Carpagnano et
al\textsuperscript{13} in any scenario raised the
I\textsuperscript{2}from 0.0\% to 99.9\%, which led us to carry out the
adjusted analysis (Figure 2). Carpagnano et al\textsuperscript{13},
despite showing an effect measure for mortality with low vitamin D level
(\textless{}10 ng / ml), had only 3 deaths in their study (two in the
group with vitamin D deficiency). As the others analysis did not show
heterogeneity (I\textsuperscript{2}=0.0\% to
I\textsuperscript{2}=6.2\%), a sensitivity analysis was not performed.

\textbf{Risk of bias of the included studies in the meta-analysis}

The Cochrane risk of bias tool for RCTs for evaluation of the risk of
bias in Castillo et al\textsuperscript{25}. Data showed in Figure S2.
The risk of bias assessment of the two non-randomized interventional
studies is shown in Table S1. The risk of bias in observational studies
is detailed in Table S2.

Results of the estimated bias coefficient were from 0.014 to 0.141,
giving a P-value \textgreater{} 0.05 for all analyses. Therefore, the
tests provide weak evidence for the presence of publication bias.

\subsection*{DISCUSSION}

{\label{discussion}}

This is the first systematic review with meta-analysis to show an
association between low plasma vitamin D level and increased risk of
death in inpatients with COVID-19 (1.41-fold). The results of this study
also show an association between low plasma vitamin D levels in COVID-19
patients and increase ICU admission risk (1.76-fold) and ventilation
requirement (3.50-fold).

Vitamin D deficiency is associated with an increased risk of developing
viral and bacterial infections\textsuperscript{36}. Several studies have
linked the reduction of plasma vitamin D levels with increase
respiratory infections\textsuperscript{37,38}, as influenza infection,
and vitamin D supplementation with the decrease of risk of these
infections\textsuperscript{39--41}. Others studies revealed a higher
risk of ICU admission, sepsis, and death in hospitalized patients who
had low levels of vitamin D in pre-admission\textsuperscript{42,43}.

Vitamin D has a role in regulating mineral metabolism, an important role
in the modulation of the immune response, and control the exacerbation
of the cellular immune response\textsuperscript{36,44,45}. Studies
report that critically ill patients with COVID-19 have elevated in
inflammatory cytokines such as IL-1 and IL-6, and chemokines associated
with a Th1 response, corroborating the hypothesis of a cytokine storm in
this disease\textsuperscript{46,47}.Vitamin D regulates feedback control
pathways that serve to decrease potential inflammatory damage from
disproportionate activation of the immune response\textsuperscript{48}

Others authors question the role of the cytokine storm in COVID-19, and
that severity of the disease occurs due to direct viral injury,
endovasculitis, and or viral-induced
immunosuppression\textsuperscript{49}. There is some evidence to support
this question. The less pronounced cytokine elevations in COVID-19 could
reflect a regulated, or inadequate, inflammatory response to infection
from SARS-Cov2. In addition, non-cytokine biomarkers, such D-dimer,
C-reactive protein, and ferritin, are elevated to a similar in patients
with COVID-19 when comparing with patients of another
disorders\textsuperscript{49,50}.

Vitamin D has other roles in regulating the immune system. LL37 peptide,
a component of the innate immune system that acts in the lungs against
SARS-CoV-2, requires sufficient levels of vitamin D to be effective,
which could indicate the preventive effect of vitamin D levels for the
development of respiratory viruses\textsuperscript{51}.

T lymphocytes are directly susceptible to SARS-CoV-2 infection and are
depleted in clinical COVID-19\textsuperscript{52}. Vitamin D modulates
the function of immune cells, such as T and B cells, monocytes, and
dendritic cells, in an interaction between the innate and adaptive
immune systems\textsuperscript{53}. Lachmann et
al\textsuperscript{54}conducted an RCT that showed that vitamin D
deficiency is associated with an absolute lower CD4\textsuperscript{+} T
cell count in HIV patients, however, that vitamin D supplementation
increased the absolute recovery of CD4\textsuperscript{+} T cell count
in these patients.

It has also been previously shown that vitamin D affects on blood
coagulation parameters\textsuperscript{55}. Hejazi et
al\textsuperscript{56} where the treatment of the deficiency of vitamin
D in patients with thromboembolism resulted in control of events with
the lowest doses of warfarin. Although COVID-19 is a respiratory
disease, many data have pointed to coagulopathy as a marker of mortality
from this disease\textsuperscript{57}. Thus, anticoagulant therapy seems
to be associated with a better prognosis in critically ill patients with
COVID-19 \textsuperscript{57}. Therefore, it is possible to assume that
the sufficient levels of vitamin D may be useful in the anticoagulant
treatment of critically ill patients with COVID-19 or may prevent mild
cases from becoming severe.

SARS- CoV-2 uses the angiotensin-converting enzyme receptor 2 to enter
alveolar epithelial cells, which would lead to the deregulation of the
Renin-Angiotensin System (RAS), accumulating the toxic product
angiotensin II in alveolar cells and causing an acute lung
injury\textsuperscript{58,59}. Vitamin D regulates the balance between
the expression of members of the RAS and their deficiency pointed to
excessive activation of this system\textsuperscript{60}. Therefore,
vitamin D deficiency may exacerbate pulmonary RAS dysregulation induced
by SARS-CoV-2 infection.

This study also showed that regular vitamin D supplementation was
associated with a lower risk of death and vitamin D treatment of
patients with COVID-19 was associated with a lower risk of ICU
admission. Castilho et al and Tan et al showed that administration of
calcifediol and cholecalciferol, respectively, reduced the need for ICU
admission of patients with COVID-19 that requiring hospitalization.
However, treatment with vitamin D in patients already diagnosed with
COVID-19 needs to be further studied.

This study has several strengths. To our knowledge, this is the first
meta-analysis using interventional studies associating vitamin D with
COVID-19 patients, and that included analyzing the risk of mortality in
hospitalized patients. This study informs physicians and patients
regarding the importance of monitoring vitamin D levels. Some
limitations of our study were the small number of interventional
studies, the analysis that used different treatments for vitamin D
supplementation, different cut-off plasma vitamin D levels,
observational design of the selected studies, and sample size.

\textbf{CONCLUSION}

These results suggest that COVID-19 patients with sufficient plasma
vitamin D levels is decreased risks of death, ICU admission, and
ventilation requirement. However, randomized clinical trials are needed
to confirm the benefits of vitamin D treatment in patients with
COVID-19.

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retrospective study. \emph{Cardiovasc Diabetol} . 2020;19(1):1-12.
doi:10.1186/s12933-020-01184-4

22. Annweiler C, Hanotte B, Grandin de l'Eprevier C, Sabatier JM, Lafaie
L, Célarier T. Vitamin D and survival in COVID-19 patients: A
quasi-experimental study. \emph{J Steroid Biochem Mol Biol} .
2020;204(October):1-6. doi:10.1016/j.jsbmb.2020.105771

23. Annweiler G, Corvaisier M, Gautier J, et al. Vitamin d
supplementation associated to better survival in hospitalized frail
elderly covid-19 patients: The geria-covid quasi-experimental
study.\emph{Nutrients} . 2020;12(11):1-12. doi:10.3390/nu12113377

24. Baktash V, Hosack T, Patel N, et al. Vitamin D status and outcomes
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2020;2:1-6. doi:10.1136/postgradmedj-2020-138712

25. Castillo ME, Costa LME, Vaquero Barrios JM, et al. ``Effect of
calcifediol treatment and best available therapy versus best available
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26. Cereda E, Bogliolo L, Klersy C, et al. Vitamin D 25OH deficiency in
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27. Hernández JL, Nan D, Fernandez-Ayala M, et al. Vitamin D Status in
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28. Jain A, Chaurasia R, Sengar NS, Singh M, Mahor S, Narain S. Analysis
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29. Macaya F, Espejo C, Valls A, et al. Interaction between age and
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30. Mendy A, Apewokin S, Wells AA, Morrow AL. Diverse Population of
COVID-19 Patients. 2020:1-24.

31. Merzon E, Tworowski D, Gorohovski A, et al. Low plasma 25(OH)
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32. Pizzini A, Aichner M, Sahanic S, et al. Impact of vitamin d
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33. Radujkovic A, Hippchen T, Tiwari-Heckler S, Dreher S, Boxberger M,
Merle U. Vitamin D deficiency and outcome of COVID-19
patients.\emph{Nutrients} . 2020;12(9):1-13. doi:10.3390/nu12092757

34. Smet D De, Smet K De, Herroelen P, Gryspeerdt S. OUP accepted
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doi:10.1093/ajcp/aqaa252

35. Tan CW, Ho LP, Kalimuddin S, et al. Cohort study to evaluate effect
of vitamin D, magnesium, and vitamin B12 in combination on severe
outcome progression in older patients with coronavirus
(COVID-19).\emph{Nutrition} . 2020;79-80:111017.
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36. Van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin
D3: Basic concepts. In: \emph{Journal of Steroid Biochemistry and
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37. Li W, Cheng X, Guo L, et al. Association between serum
25-hydroxyvitamin D concentration and pulmonary infection in
children.\emph{Med (United States)} . 2018;97(1).
doi:10.1097/MD.0000000000009060

38. Juusela M, Pallasaho P, Sarna S, Piirilä P, Lundbäck B, Sovijärvi A.
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Decreased FEV1, the main determinant. \emph{Clin Respir J} .
2013;7(1):34-44. doi:10.1111/j.1752-699X.2012.00279.x

39. Jung HC, Seo MW, Lee S, Kim SW, Song JK. Vitamin D3 supplementation
reduces the symptoms of upper respiratory tract infection during winter
training in vitamin D-insufficient taekwondo athletes: A randomized
controlled trial. \emph{Int J Environ Res Public Health} . 2018;15(9).
doi:10.3390/ijerph15092003

40. 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.\emph{BMJ} . 2017;356. doi:10.1136/bmj.i6583

41. Arihiro S, Nakashima A, Matsuoka M, et al. Randomized Trial of
Vitamin D Supplementation to Prevent Seasonal Influenza and Upper
Respiratory Infection in Patients With Inflammatory Bowel
Disease.\selectlanguage{english}\emph{Inflamm Bowel Dis *} . 2019;25(6). doi:10.1093/ibd/izy346

42. Moromizato T, Litonjua AA, Braun AB, Gibbons FK, Giovannucci E,
Christopher KB. Association of low serum 25-hydroxyvitamin D levels and
sepsis in the critically ill. \emph{Crit Care Med} . 2014;42(1):97-107.
doi:10.1097/CCM.0b013e31829eb7af

43. Braun A, Chang D, Mahadevappa K, et al. Association of low serum
25-hydroxyvitamin D levels and mortality in the critically
ill.\emph{Crit Care Med} . 2011;39(4):671-677.
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44. Looman KIM, Jansen MAE, Voortman T, et al. The role of vitamin D on
circulating memory T cells in children: The Generation R
study.\emph{Pediatr Allergy Immunol} . 2017;28(6):579-587.
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45. Wang T-T, Nestel FP, Bourdeau V, et al. Cutting Edge:
1,25-Dihydroxyvitamin D 3 Is a Direct Inducer of Antimicrobial Peptide
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46. Yang Y, Shen C, Li J, et al. Plasma IP-10 and MCP-3 levels are
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47. England JT, Abdulla A, Biggs CM, et al. Weathering the COVID-19
storm: Lessons from hematologic cytokine syndromes. \emph{Blood Rev} .
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48. Bikle DD. Vitamin D and immune function: Understanding common
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49. Leisman DE, Ronner L, Pinotti R, et al. Rapid Review Cytokine
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50. Mardani R, Alamdary A, Mousavi Nasab S, Gholami R, Ahmadi N, Gholami
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51. Benskin LL. A Basic Review of the Preliminary Evidence That COVID-19
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52. Wang X, Xu W, Hu G, et al. SARS-CoV-2 infects T lymphocytes through
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53. Greiller CL, Martineau AR. Modulation of the immune response to
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54. Lachmann R, Bevan MA, Kim S, et al. A comparative phase 1 clinical
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55. Liu G, Hong T, Yang J. A single large dose of vitamin d could be
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56. Hejazi ME, Modarresi-Ghazani F, Hamishehkar H, Mesgari-Abbasi M,
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59. Carter SJ, Baranauskas MN, Fly AD. Considerations for Obesity,
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doi:10.3892/mmr.2017.7546

\textbf{Table 1.} Characteristics of studies selected.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Author}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Country}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Study Design}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Follow-up}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Population}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Age (years)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Outcomes}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Sample Size}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Exposure or Intervention (n/cut-off or dose)}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\textbf{Confounder adjusted}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Abrishami et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Iran\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
retrospective Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
February 28, 2020 and April 19, 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hospitalized patients with COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
55.18\selectlanguage{ngerman}±14.98\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Death and hospitalization\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
73\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Vitamin D [?]25ng/mL\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, sex, BMI, and comorbidities\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Alguwaihes et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Saudi Arabia\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
retrospective Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
May to July 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hospitalized adults with COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
55 (19--101)*\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Mortality, ICU admission and NVI\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
150\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
112 (Vitamin D [?]12ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, sex, BMI, smoking, comorbidities, serum vitamin D, use of
medications, HbA1c, Neutrophil count, Creatinine and ALT.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Annweiler, C et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
France\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Quasi-experimental study\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
March-April 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Frail elderly nursing-home residents with COVID-1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
87.7 \selectlanguage{ngerman}± 9.0\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Mortality of COVID-19 and clinical improvement\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
66\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
57 80,000 IU vitamin D3 either in the week following the suspicion or
diagnosis of COVID-19, or during the previous month\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, gender, number of drugs daily taken, functional abilities,
nutritional status, COVID-19 treatment with corticosteroids and/or
hydroxychloroquine and/or dedicated antibiotics, and hospitalization for
COVID-19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Annweiler, G et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
France\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Quasi-experimental study\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
March--May 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Patients hospitalized with COVID-19 in geriatric acute care unit\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
88 (85--92)*\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
14-Day COVID-19 Mortality and clinical improvement\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
77\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Group 1 (n=29): Regular Vitamin D Supplementation Group 2 (n=16):
Vitamin D Supplementation After COVID-19 Diagnosis\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, gender, functional abilities, severe undernutrition, history of
cancer, hypertension, cardiomyopathy, glycated hemoglobin, number of
acute health issues at admission, hospital use of antibiotics, use
systemic corticosteroids, and pharmacological treatments of respiratory
disorders\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Baktash et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
UK\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Prospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1 March to 30 April 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hospitalized patients aged [?]65 years with COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Mortality secondary to COVID-19; NIV support and admission to HDU,
COVID-19 radiographic changes on chest X-ray\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
70\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
39 (Vitamin D [?]12ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Vitamin D; CRP, D-dimer, ferritin, high sensitivity troponin T, LDH and
lymphocyte count. Age, weight, height, ethnicity, smoking status and
comorbidities\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Carpagnano et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Italy\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
retrospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11 March to 30 April, 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
COVID-19 hospitalized patients\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
65\selectlanguage{ngerman}±13\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Survival\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
42\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10 (Vitamin D [?] [?]10ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Demographic characteristics, medical history, underlined comorbidities,
symptoms, laboratory findings, respiratory parameters as fraction of
inspired oxygen (FiO2) and arterial partial pressure oxygen PaO2/FiO2
ratio, respiratory and pharmacological treatment.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Castillo et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Spain\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Parallel pilot randomized open label, double-masked clinical trial\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
calcifediol,\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hospitalized patients with COVID-19 i\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
53 \selectlanguage{ngerman}± 10\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
ICU admission and deaths\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
76\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
50 Treatment group 20000-IU in admission (10000-IU on days 3 and
7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, comorbidity, CRP, D-Dimer, LDH, Lymphocytes, Ferritin, IL-6\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Cereda et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Italy\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
March - April 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hospitalized patients with COVID-19 i\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
77 (65.0-85.0)*\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Mortality\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
129\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
99 (Vitamin D \textless{}20 ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, gender, BMI, comorbidities, severe pneumonia, serum level of
vitamin D, calcium, phosphorus, magnesium, D-Dimer, sodium, potassium,
ALT, AST, LDH, CK, CRP, lymphocytes and platelets.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hern\selectlanguage{ngerman}ández et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Spain\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
case-control\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
hospitalized patients aged [?]18 years with confirmed COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
61.0 (47.5-70.0)*\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
COVID-19 severity (death and ICU admission)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
197\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
162 (Vitamin D [?] [?]20ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, sex, BMI, smoking, comorbidities, CRP. GFR, death, ICU, 25OHD and
PTH\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Jain et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
India\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Prospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
6 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Patients with COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Serum IL-6, serum TNF-\selectlanguage{greek}α, \selectlanguage{english}serum ferritin and serum level of vitamin
D\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
154\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
90 (Vitamin D \textless{}20 ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, gender, comorbidity, BMI, mortality, asymptomatic patients and
critically patients\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Macaya et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Spain\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
retrospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
March 5 to March 31, 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
COVID-19 hospitalized patients\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Non-severe COVID-19: 63 (50-72)* Severe COVID-19: 75 (66-84)*\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
COVID-19 severity (death, admission to ICU, and/or NVI)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
80\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
45 (Vitamin D [?] [?]20ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, gender, obesity, cardiac disease, kidney disease, and vitamin
D\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Mendy et al (preprint)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
USA\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
retrospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
March 13, 2020 to May 31, 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Patients with COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
49.5 (35.2- 67.5)*\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hospitalization and disease severity (ICU and/or death)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
689\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
89 (Vitamin D \textless{}12 ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, sex, race/ethnicity, smoking, comorbidities\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Merzon et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Israel\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
retrospective Cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
February 1 to April 30, 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Patients tested for COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
COVID-19 group: 35.58 (34.49-36.67)** Non-COVID-19 group: 47.35
(46.87--47.85)**\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Risk of COVID-19 and hospitalization\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
782 COVID-19 group\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
703 (Vitamin D [?]30ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, sex, BMI, smoking and comorbidities\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Pizzini et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Austria\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Prospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
8 weeks\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
COVID-19 hospitalized patients and outpatients with persistent
symptoms\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
58 \selectlanguage{ngerman}± 14\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Severity and persistent cardio-pulmonary damage of COVID-19
patients\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
109\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
41 (Vitamin D \textless{}12 ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, gender, comorbidity, BMI, vitamin D supplementation e and serum
level of vitamin D, PTH, calcium, phosphate, creatinine, urea, CRP,
interleukin-6, serum ferritin, and D-dimer\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Radujkovic et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Germany\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Prospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
18 Marchto 18 June 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Inpatients and Outpatients diagnosed with COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
NVI and survival\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
185\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
41 (Vitamin D \textless{}12 ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, gender, comorbidity, vitamin D supplementation e and serum level of
vitamin D\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Smet et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Belgium\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
retrospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
March 1, 2020, to April 7, 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Hospitalized patients with COVID-19 i\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
COVID-19 severity (stage disease and death)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
186\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
109 (Vitamin D \textless{}20 ng/mL)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, sex, and comorbidities.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Tan et al\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
China\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
retrospective cohort\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
January 15 and April 15, 2020\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
hospitalized patients [?]50 y of age with COVID-19\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Treatmente group:58.4 \selectlanguage{ngerman}±7 Control group: 64.1 ±7.9\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Requiring oxygen therapy or ICU\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
43\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
17 1000-IU dose of vitamin D3 (cholecalciferol),\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age, sex, clinical features and comorbidities. Use of magnesium oxide,
and vitamin B12 (methylcobalamine).\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
25OHD: 25-hydroyvitamin D, ALT: alanine transaminase, AST: aspartate
aminotransferase, BMI: body-mass index, CK: creatine kinase, CRP: C
reactive protein, GFR: glomerular filtration rate, HDU: High dependency
unit, IL-6: interleukin-6; ICU: Intensive Care Unit, LDH: lactate
dehydrogenase, NVI: Non-invasive ventilation, PCT: procalcitonin, PTH:
parathyroid hormone. * Data represented as median (IQR). ** Data
represented as mean (CI 95\%)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Figure 1. Flow chart of study selection.

Figure 2. Association of plasma vitamin D level with mortality in
patients with COVID-19.

Figure 3. Effect of vitamin D supplementation on the risk of death in
patients with COVID-19.

Figure 4. Association of plasma vitamin D level with need for
hospitalization in patients with COVID-19.

Figure 5. Association of plasma vitamin D level with ICU admission in
patients with COVID-19.

Figure 6. Association of plasma vitamin D level with ventilation
requirement in patients with COVID-19.

Figure 7. Association of plasma vitamin D level with COVID-19 severity
(Death, ICU and need for ventilation).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4/Figure-4}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5/Figure-5}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-6/Figure-6}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-7/Figure-7}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-S1/Figure-S1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-S2/Figure-S2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

