Clinical Nutrition 42 (2023) 2198e2206

Contents lists available at ScienceDirect

Clinical Nutrition
journal homepage: http://www.elsevier.com/locate/clnu

Meta-analyses

The role of vitamin D in the prevention and treatment of SARS-CoV-2

infection: A meta-analysis of randomized controlled trials
Jiahao Meng a, Xi Li a, Weijie Liu a, Yifan Xiao a, Hang Tang a, Yumei Wu a, Yilin Xiong a,
Shuguang Gao a, b, c, d, *
a
Department of Orthopaedics, Xiangya Hospital, Central South University, #87 Xiangya Road, Changsha, 410008, Hunan, China
b
Hunan Key Laboratory of Joint Degeneration and Injury, Changsha, Hunan, China
c
Hunan Engineering Research Center of Osteoarthritis, Changsha, Hunan, China
d
National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China

a r t i c l e i n f o s u m m a r y

Article history: Background: Vitamin D (VitD) has been shown to be important for the immune response of the respi-
Received 10 July 2023 ratory system, but the preventive and therapeutic effects of vitamin D supplementation on SARS-CoV-2
Accepted 6 September 2023 infection are controversial. This study aimed to determine the role of vitamin D supplementation in the
prevention and treatment of SARS-CoV-2 infection through a meta-analysis of randomized controlled
Keywords: trials.
COVID-19
Methods: The databases of PubMed, Cochrane Library, Embase, Web of Science and Google Scholar were
SARS-CoV-2 infection
searched systematically from inception to April 17,2023 to identify trials involving a randomized com-
Prevention
Prognosis
parison of vitamin D supplementation versus non-vitamin D supplementation for SARS-CoV-2 infection
Vitamin D deficiency prevention or treatment.
Vitamin D supplement Results: We retrieved 25 eligible trials, including 8128 participants. Four trials compared the preventive
effects of vitamin D supplementation on SARS-CoV-2 infection, and the results (RR 0.31; 95%CI 0.07 to
1.32) were inconclusive. Regarding the treatment of SARS-CoV-2 infection with vitamin D supplemen-
tation, it was found that vitamin D supplementation could significantly reduce the rates of ICU admission
(RR 0.63; 95%CI 0.44 to 0.89) and mechanical ventilation (RR 0.58; 95%CI 0.39 to 0.84), but had no
statistically significant effect on mortality. However, in subgroup analyses based on the patients' specific
conditions, vitamin D supplementation significantly reduced the mortality in patients with vitamin D
deficiency (RR 0.76; 95%CI 0.58 to 0.98).
Conclusion: Vitamin D supplementation may have some beneficial impact on the severity of illness
caused by SARS-CoV-2, particularly in VitD deficient patients, but further studies are still needed.
© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction Vitamin D is a cholesterol-derived steroid hormone that impacts

SARS-CoV-2 infection causes a primarily respiratory disease,
COVID-19, that spreads rapidly with a high transmission rate. Se-
vere cases of SARS-CoV-2 infection can even be life-threatening,
posing a significant economic burden to the society and an enor-
mous threat to human health [1,2].
Abbreviations: RR, risk ratio; RCT, randomized controlled trial; PRISMA,
Preferred Reporting Items for Systematic Reviews and Meta-analysis; VitD, vitamin
D.
* Corresponding author. Department of Orthopaedics, Xiangya Hospital, Central
South University, 87 Xiangya Road, Changsha, 410008, Hunan, China.
E-mail address: gaoshuguang0341@qq.com (S. Gao).
the expression of numerous genes, including those within immune
cells [3,4]. It is controversial regarding whether vitamin D supple-
mentation is helpful in treating SARS-CoV-2 infection. Experi-
mental evidence from animal models suggests that vitamin D
deficiency can exacerbate the severity of lung damage in response
to inflammatory stimuli [5]. Studies have shown that Vitamin D
deficiency can impair the immune response to respiratory viruses
[6]. It has also been found that low circulating concentrations of 25-
hydroxyvitamin D [7,8] are associated with an increased risk of
acute respiratory infections and low levels of vitamin D are also
associated with long duration of SARS-CoV-2 infection syndrome in
SARS-CoV-2 infection survivors [9]. A systematic review indicates
that supplementing with vitamin D can effectively reduce the

https://doi.org/10.1016/j.clnu.2023.09.008
0261-5614/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
J. Meng, X. Li, W. Liu et al.
severity of SARS-CoV-2 infection, recommending vitamin D as an
adjunctive treatment for COVID-19 [10]. However, a meta-analysis
[11] enrolling 8 randomized controlled trials (RCTs) conducted in
2021 indicated that vitamin D supplementation did not improve
the clinical outcomes in SARS-CoV-2 infection patients. Prevention
is an important aspect for the control of infectious diseases. To date,
no meta-analysis focusing on the preventive effects of vitamin D on
SARS-CoV-2 infection has been reported. It is hypothesized that
vitamin D supplementation can potentially aid in preventing SARS-
CoV-2 infection and enhance the clinical outcomes for those who
have contracted the virus.
Recently, several RCTs investigating the preventive and thera-
peutic effects of vitamin D supplementation on SARS-CoV-2
infection have been published since the previous meta-analysis
[11]. Therefore, we aimed to conduct a meta-analysis to examine
whether vitamin D supplementation was helpful in preventing and
treating SARS-CoV-2 infection.
2. Methods and materials
This meta-analysis of RCTs was performed following the
guidelines outlined in the Preferred Reporting Items for Systematic
Reviews and Meta-analysis (PRISMA) checklist [12]. The study
protocol was registered on PROSPERO (CRD42023417371).
2.1. Search strategy and selection criteria
We conducted a comprehensive literature search on April 17,
2023 across several databases including PubMed, Cochrane Li-
brary, Embase, and Web of Science using predetermined search
terms such as “Vitamin D00 and “SARS-CoV-2 infection”. We also
conducted supplementary searches on Google Scholar. The
detailed search strategy can be found in the supplementation.
After removing duplicate articles, two reviewers independently
screened the preliminarily retrieved literature based on the in-
clusion and exclusion criteria as follow. Inclusion criteria: studies
focusing on SARS-CoV-2 infection that compared the efficacy of
vitamin D supplementation versus non-vitamin D supplemen-
tation, while reporting the intended outcomes. Exclusion
criteria: non-RCTs; studies on patients receiving treatment for
reasons other than SARS-CoV-2 infection; studies for which the
full text was unavailable. In cases of disagreement on study in-
clusion, a senior author (SGG) was consulted to make the final
decision.
2.2. Data extraction
Four reviewers, divided into two independent pairs, were
responsible for extracting data from the studies that met the in-
clusion and exclusion criteria for the meta-analysis. The extracted
data included the NCT number, first author, publication year, region,
number of participants, demographic characteristics of partici-
pants, treatment methods, rates of ICU admission and mechanical
ventilation, mortality during follow-up, lengths of hospital stay and
ICU stay, and follow-up times. Moreover, for studies that specif-
ically investigated the preventive effect of vitamin D, we also
collected data on the rate of SARS-CoV-2 infection.
2.3. Quality assessment
The same four reviewers, divided into two independent pairs,
evaluated the risk of bias in the included studies using the
Cochrane Collaboration's risk of Bias Tool [13], which is based on
seven potential domains of bias (random sequence generation,
allocation concealment, blinding of participants and personnel,
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Clinical Nutrition 42 (2023) 2198e2206
blinding of outcome assessment, incomplete outcome data, se-
lective reporting, and other forms of bias). Each domain was
classified as of a low, unclear, or high risk of bias, as deemed
appropriate. In cases of discrepancies, the reviewers would try to
arrive at a consensus by discussion or consult a senior author
(Gao) for decision making.
2.4. Primary and secondary outcomes
The primary outcomes were the rates of ICU admission and
mechanical ventilation, as well as mortality during follow-up. The
secondary outcomes were the lengths of hospital stay and ICU stay.
In addition, for studies on the preventive effects of vitamin D on
SARS-CoV-2 infection, the primary outcome was the rate of SARS-
CoV-2 infection.
2.5. Statistically analysis
Continuous variables were presented as mean and standard
deviation, while binary variables were presented as event number
and total number. The Inverse Variance method was used to
combine continuous and dichotomous variables, and the results
were reported as mean difference and risk ratio with 95% confi-
dence interval, respectively. Due to the variation in dosage, we
utilized a random-effects model for all analyses. Subgroup ana-
lyses were conducted to investigate the response to vitamin D in
different types of participants, as well as the effects of different
dosages and administration routes on the participants. Sensitivity
analysis was performed to explore heterogeneity, and funnel
plots, Egger's test, and Begg's test were used to evaluate publi-
cation bias. All statistical analyses were performed using R
Version 4.2.1.
3. Results
3.1. Study selection
Figure 1 illustrates the literature search and selection process,
which eventually yielded 26 articles, including 25 unique studies.
Among them, 4 studies [14e17] investigated the preventive ef-
fects of vitamin D supplementation on SARS-CoV-2 infection,
while 21 studies [17e39] investigated the therapeutic effects of
vitamin D supplementation on SARS-CoV-2 infection patients.
One study [17] was primarily designed to study preventive effects
on infection but also reported data on outcomes of subsequent
COVID-19 illness.
3.2. Study characteristics
Regarding the preventive effects of vitamin D, a total of 1949
participants received vitamin D supplementation, with daily dos-
ages ranging from 800IU to 5000IU and administration frequencies
of daily or weekly. As controls, 3703 participants received placebo.
Regarding the therapeutic effects of vitamin D, a total of 1270
participants received vitamin D supplementation, with adminis-
tration methods including single dosing, continuous dosing, and
varying dosing. There were 1206 participants who did not receive
vitamin D supplementation or received low dosage of vitamin D as
part of the standard care. Participants in 8 studies were in a vitamin
D deficiency state, while participants in 3 studies were in a severe
SARS-CoV-2 infection state. Table 1 summarizes the characteristics
of the included RCTs.
J. Meng, X. Li, W. Liu et al.
3.3. Quality assessment
Nine studies involved a high risk of bias, which was mainly due
to the fact that most of these studies were open-labeled and did not
implement blindness. Eight studies had a low risk of bias. The
detailed distribution of bias is shown in eFigure 1 in supplement.
Fig. 1. Flow chart of literature retrieval.
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Clinical Nutrition 42 (2023) 2198e2206
3.4. Primary outcomes
Four studies reported on the preventive effects of vitamin D on
SARS-CoV-2 infection, and the pooled results showed that there
was no statistically difference between the vitamin D group and
control group (RR 0.31; 95%CI 0.07 to 1.32) (Fig. 2).
Twenty-one studies reported on the mortality during follow-up,
and the pooled results also showed that there was no statistically
difference between the vitamin D group and control group (RR
0.81; 95%CI 0.62 to 1.07) (Fig. 3).
Ten studies reported on the ICU admission rate, and the pooled
results showed that vitamin D supplementation was associated
with a statistically lower ICU admission rate compared to the
control group (RR 0.63; 95%CI 0.44 to 0.89) (Fig. 4).
Nine studies reported on the rate of receiving mechanical
ventilation, and the pooled results showed that vitamin D supple-
mentation was associated with a significantly lower rate of me-
chanical ventilation compared to the control group (RR 0.58; 95%CI
0.39 to 0.84) (Fig. 5).
3.5. Secondary outcomes
Twelve studies reported on the effects of vitamin D supple-
mentation on the length of hospital stay, and the pooled results
showed no statistically significant difference between the vitamin
D supplementation group and control group (MD -0.63; 95%CI -1.77
to 0.51) (eFig. 2 in supplement). In addition, 5 studies reported on
the length of ICU stay, and the pooled results also showed no sta-
tistically significant difference between the two groups (MD -0.42;
95%CI -4.74 to 3.89) (eFig. 3 in supplement).
3.6. Subgroup analysis
Limited by insufficient data, subgroup analysis was only possible
for some of the outcomes (Figure 6). More specifically, in view of
the varying conditions of the patients, we conducted subgroup
analysis on patients with vitamin D deficiency and those in severe
conditions and mild-to-moderate conditions of SARS-CoV-2 infec-
tion. Serum levels of 25(OH)D < 30 ng/ml, <20 ng/ml or <10 ng/ml
were varying used to define vitamin D deficiency, with Murai et al.
using <10 ng/ml to define severe vitamin D deficiency [36]. Severe
SARS-CoV-2 infection refers to patients who received treatment in
an intensive care unit (ICU) before undergoing trials, while mild to
moderate cases primarily refer to patients who did not receive
treatment in an intensive care unit before participating in trials. In
the vitamin D deficiency group, vitamin D supplementation
showed a statistically-significantly lower ICU admission rate and
mortality compared with the control group. Similarly, in the severe
SARS-CoV-2 infection group, vitamin D supplementation also
showed a statistically-significantly lower mortality compared with
the control group. It is important to note that the severe subgroup
only included 3 studies so this result should be treated with
caution. In the mild-to-moderate SARS-CoV-2 infection group,
vitamin D supplementation showed a statistically-significantly
lower mechanical ventilation rate and ICU admission compared
with the control group. Moreover, considering the different modes
of administration across the included studies, we conducted sub-
group analysis on the single-dose and multiple-dose administra-
tion. In the single-dose group, vitamin D supplementation showed
a statistically-significantly lower mechanical ventilation rate
compared with the control group, whereas in the multiple-dose
J. Meng, X. Li, W. Liu et al. Clinical Nutrition 42 (2023) 2198e2206

Table 1
Characteristic of included studies.

NCT Study Location Patient Characteristics Treatment Follow-up

Intervention Control

04,883,203 Abroug2023 Tunisia NA 200,000 IU/1 ml cholecalciferol 1 ml for Placebo 1 year

[32] 3 months
04,551,911 Bishop2022 USA Mild to moderate 300 mcg calcifediol on days 1e3 and 60 Placebo 2 weeks
[18] COVID-19 mcg on days 4e27
04,552,951 Cannata- Spain, Argentina, Moderate to severe a single oral bolus of 100,000 IU of No supplement NA
Andía2022 [34] Guatemala COVID-19 cholecalciferol
and Chile
04,366,908 Entrenas Spain NA the first day calcifediol 0.532 mg， Standard care Patients were followed-
Castillo 2020 calcifediol (0.266 mg) on day 3 and 7) up until admission to
[23] and then weekly until discharge or ICU ICU, hospital discharge
admission or death.
NA Elamir2021 Mount Sinai NA calcitriol 0.5 mg daily for 14 days or No supplement NA
[22] hospital discharge
04596657 Helmond2022 USA NA 5000 IU of vitamin D3 per day，nine NA 9 months
[15] months
04483635 Hosseini2022 Canada NA 100,000 IU oral bolus at randomization placebo 16 weeks
[14] followed by a weekly dose of 10,000 IU
of vitamin D3
04579640 Jolliffe2022 UK NA lower dose vitamin D (800 IU/day) or No supplement 6 months
[17] higher dose vitamin D (3200 IU/day)
05166005 Karonova2022 Russia NA 50,000 IU of cholecalciferol on the 1st No supplement 9 days
[24] and the 8th day of hospitalization, with
the total dose being 100,000 IU
04411446 Mariani2022 Argentina Mild to moderate a single oral dose of 500,000 IU of Placebo Patients were followed-
[35] COVID-19 vitamin D3 soft gel capsules up until hospital
discharge
04449718 Murai2021 [37] Brazil Moderate to severe a single oral dose of 200,000 IU of Placebo 4 months
COVID-19, VD vitamin D3
deficiency (<10 ng/L)
Sabico2021 Saudi Arabia Mild to moderate 5000IU vitamin D3 for 14days Standard care including 30 days after discharge
[31] COVID-19 1000IU vitamin D3 and/or the last vitamin
dose
04981743 Said2022 [27] Egypt Mild to moderate 1000-IU of vitamin D3 tablets once Standard therapy 14 days
COVID-19 daily
NA Sanchez2021 Mexico NA 10000 IU daily of vitamin D3 for 14 days No supplement 14 days
[28]
04738760 Sarhan2022 Egypt Moderate to severe single high-dose vitamin D Standard care including NA
[38] COVID-19 cholecalciferol (200,000 IU) IM 1 mg/day of vitamin D
NA Soliman2022 Egypt Moderate to severe 200.000 units intramuscularly once as a placebo 6 weeks
[39] COVID-19 single dose
NA Villasis- Mexico NA 4000 IU VitD daily for 30 d Placebo 1 month
Keever2022
[16]
04502667 Zurita- Mexico Moderate COVID-19 1000 (children 1 year) or 2000 IU/day No supplement 30 days
Cruz2022 [29] (from 1 to 17 years)
Studies aimed at patients with VitD deficiency
05384574 Bugarin2023 Croatia Severe COVID-19, VitD 10,000 IU of cholecalciferol daily No supplement 2e3 months
[21] deficiency (<20 ng/L),
ICU
05092698 Bychinin2022 Russia Severe COVID-19 and cholecalciferol at a dose of 60,000 IU Placebo 7 days
[19] VitD deficiency once per seven days followed by daily
(<20 ng/L), ICU maintenance doses of 5000 IU.
01052020 Cervero2022 Spain VitD deficiency 10,000 IU of cholecalciferol once daily Standard care including 7.14.28 day
[30] (<30 ng/L) for 14 days 2000 IU of
cholecalciferol
NA Maghbooli2021 Iran VitD deficiency 25(OH)D3 was 25 mg administered Placebo 2 months
[25] (<30 ng/L) orally once daily
04449718 Murai2021 [36] Brazil Moderate to severe a single oral dose of 200,000 IU of Placebo 4 months
COVID-19, VD vitamin D3
deficiency (<10 ng/L)
04636086 Niet2022 [20] Belgium VitD deficiency 25,000 IU per day over 4 consecutive placebo 9 weeks
(<20 ng/L) days, followed by 25,000 IU per week
up to 6 weeks
04459247 Rastogi2022 India VitD deficiency daily 60000 IU of cholecalciferol for 7 Placebo 3 weeks
[26] (<20 ng/L) days， and a weekly supplementation
of 60000IU provided to those with
25(OH)D > 50 ng/ml or else continued
on daily vitamin D 60,000 IU
supplementation for another 7 days up
until day-14

ICU, intensive care unit; VitD, vitamin D; NA, not addressed.

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J. Meng, X. Li, W. Liu et al. Clinical Nutrition 42 (2023) 2198e2206

Fig. 2. Effect of Vitamin D supplement in preventing SARS-CoV-2 infection.

Fig. 3. Effect of Vitamin D supplement on mortality rate.

Fig. 4. Effect of Vitamin D supplement on ICU admission rate.

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J. Meng, X. Li, W. Liu et al. Clinical Nutrition 42 (2023) 2198e2206

Fig. 5. Effect of Vitamin D supplement on mechanical ventilation rate.

Fig. 6. Subgroup analysis of effect of Vitamin D supplement according to different administration and participants' state (Serum levels of 25(OH)D < 30 ng/ml, <20 ng/ml or <10 ng/
ml were varyingly used to define vitamin D deficiency; Severe SARS-CoV-2 infection refers to patients who received treatment in the ICU before the start of the trial; Mild-to-
moderate SARS-CoV-2 infection refers to patients who did not receive treatment in the ICU before the start of the trial).

group, vitamin D supplementation showed a statistically- concern (eFig. 6 in supplement). Furthermore, statistical tests
significantly lower ICU admission rate and mortality compared including Egger's test and Begg's test did not reveal any significant
with the control group. evidence of publication bias either (p > 0.05 for all tests).

3.7. Sensitivity analysis 4. Discussion

We conducted sensitivity analysis using the one-at-a-time
removal method on the primary outcomes. For the preventive ef-
fects, after excluding the study by Jolliffe et al., vitamin D supple-
mentation was found to significantly lower the incidence of SARS-
CoV-2 infection (eFig. 4 in supplement). No changes in the rates of
ICU admission and mechanical ventilation were observed. For the
mortality, after excluding the study by Cannata-Andia et al., vitamin
D supplementation significantly reduced the mortality of the pa-
tients (eFig. 5 in supplement).
3.8. Publication bias
Funnel plots showed a symmetric distribution of the included
studies, suggesting that publication bias might not be a significant
2203
In our meta-analysis, we found that vitamin D supplementation
could reduce the rates of SARS-CoV-2 infection patients requiring
ICU admission and mechanical ventilation, but had no significant
effect on the mortality during follow-up and the lengths of hospital
stay and ICU stay. Therefore, we believe that vitamin D supple-
mentation plays a beneficial role in the treatment of SARS-CoV-2
infection.
The studies included in our analysis mainly administrated a
single-dose, high-dosage vitamin D supplementation therapy for
severe SARS-CoV-2 infection patients. Single-dose supplementa-
tion was found to reduce the rate of mechanical ventilation, while
the multiple-dose therapy was found to reduce the rate of ICU
admission and mortality. The results appear to provide more sup-
port for the use of multiple doses of vitamin D supplementation.
J. Meng, X. Li, W. Liu et al.
Two reviews concluded that for SARS-CoV-2 infection, daily
maintenance doses of vitamin D supplementation are more bene-
ficial for patient outcomes, whereas single doses of vitamin D
supplementation may be ineffective for patients [40,41]. This is
consistent with our findings, but it's important to note that we did
not directly compare single doses and multiple doses. More
research is needed to further establish the benefits of vitamin D
supplementation through multiple doses for indications including
SARS-CoV-2 infection.
Research reports that administering vitamin D supplementa-
tion, such as at the time of first symptoms, can result in better
survival rates for patients [42]. A review discusses the importance
of early nutrition interventions, including Vitamin D, in combating
coronaviruses and related viral infections, enhancing immune
function, and reducing inflammation [43]. It is recommended to
initiate adequate supplementation promptly in high-risk areas and/
or suspected cases of SARS-CoV-2 infection [43]. IL-37, as an anti-
inflammatory cytokine, has been suggested to be associated with
the progression of SARS-CoV-2 infection [44]. Research has shown
that IL-37 and vitamin D levels are significantly decreased in pa-
tients, and there is a notable correlation between IL-37 and vitamin
D levels [45]. Therefore, providing Vitamin D in the early stage may
be an effective approach. Meanwhile, a large-scale cohort study
also found that Cholecalciferol, as a Vitamin D supplement, could
yield better clinical outcomes for patients compared to Calcifediol
[46]. However, further research is needed in the future to explore
appropriate choices.
The definition of vitamin D deficiency primarily involves levels
of 25(OH)D in serum being <30 ng/ml or <20 ng/ml
[19e21,25,26,30]. If the levels of 25(OH)D in serum are <10 ng/ml, it
is defined as severe vitamin D deficiency [36]. Vitamin D deficiency
is prevalent all over the world. For example, 40% of Europeans were
reported to be deficient in vitamin D [47]. Sutherland et al.'s
Mendelian randomization study found a causal relationship be-
tween vitamin D deficiency and mortality and evidence for an as-
sociation was also observed in analyses of mortality from cancer,
cardiovascular disease, and respiratory diseases [48]. In our study,
we investigated the impact of vitamin D supplementation on SARS-
CoV-2 infected patients with vitamin D deficiency. Our findings
suggest a potential reduction in ICU admission and mortality rates
within this subgroup. However, it is important to note that our
study did not yield statistically significant evidence for an effect on
the rate of mechanical ventilation requirement. In the future, more
research is required to investigate whether vitamin D supplemen-
tation offers greater advantages for patients with vitamin D defi-
ciency compared to those with normal vitamin D levels.
Severe SARS-CoV-2 infection is a life-threatening condition, and
our study showed that vitamin D supplementation could reduce
the mortality in severe SARS-CoV-2 infection patients. However, it
is important to note that the severe subgroup only included 3
studies so this result should be treated with caution. For mild-to-
moderate SARS-CoV-2 infection patients, vitamin D supplementa-
tion could reduce the rates of ICU admission and mechanical
ventilation, but had no significant effect on mortality. Overall,
regardless of whether a single-dose or multiple-dose therapy was
administrated, and whether for severe or mild-to-moderate pa-
tients, or for those who are vitamin D deficient, vitamin D sup-
plementation can help reduce the rates of ICU admission,
mechanical ventilation, or mortality, especially for severe SARS-
CoV-2 infection patients and those who are vitamin D deficient.
In a large retrospective cohort study, it was found that vitamin D
supplementation can mitigate the severity of COVID-19's preva-
lence [49]. However, in a large RCT by Brunvoll et al. [50], it was
found that cod liver oil supplementation and low-dosage vitamin D
supplementation were not effective in reducing respiratory
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Clinical Nutrition 42 (2023) 2198e2206
infections, including SARS-CoV-2 infection. Similarly, our study did
not identify any significant evidence on the effect of vitamin D
supplementation in reducing the incidence of SARS-CoV-2 infec-
tion either. However, considering the wide confidence interval of
RR in our analysis, and the limited number of studies we included,
the effect of Vitamin D on preventing SARS-CoV-2 infection was
inconclusive.
A meta-analysis [11] of 9 RCTs conducted in 2021 concluded that
vitamin D supplementation did not improve the clinical outcomes
in SARS-CoV-2 infection patients. However, owing to recent pub-
lications, our study included 25 RCTs, allowing us to analyze the
preventive effects of vitamin D on SARS-CoV-2 infection based on a
larger sample. We found that, while vitamin D might not signifi-
cantly reduce the infection rate of SARS-CoV-2 infection, it seemed
to be able to improve the clinical outcomes in SARS-CoV-2 infection
patients. Some earlier published reviews and meta-analyses have
also indicated improvements in the clinical outcomes of SARS-CoV-
2 infection patients with regards to vitamin D from various per-
spectives [51e54].
Nevertheless, more research is needed in the future to investi-
gate the effects of vitamin D on respiratory infections, including
SARS-CoV-2 infection, particularly in terms of which patients and
which methods of administration are most effective.
In our sensitivity analyses, it was revealed that vitamin D sup-
plementation could significantly reduce the mortality of patients
during hospitalization after excluding the study by Cannata-Andia
et al. [34] This is possibly due to the fact that Cannata-Andia's
study [34] had a larger number of participants, giving it a greater
weight in the meta-analysis. In addition, after excluding the study
by Jolliffe et al. [17], vitamin D was found to significantly reduce the
incidence of SARS-CoV-2 infection, which may also be attributed to
the larger number of participants in Jolliffe's study [17]. At the same
time, the very high rate of vaccination that occurred in participants
during the study also introduced a certain bias [17]. Moreover,
Jolliffe's study [17] mainly focused on the general population, while
the other three studies in the subgroup analysis targeted at the
health care workers in hospitals, and the chance of infection may
vary among different study populations.
There are several limitations to our study. Firstly, we only
included 4 RCTs in our analysis regarding the preventive effects
of vitamin D on SARS-CoV-2 infection, and the resulting data had
a wide confidence interval. More research is needed in the future
to further explore the effects of vitamin D supplementation on
respiratory system infections. Secondly, the included studies
showed statistical heterogeneity, and the vitamin D dosage, pa-
tient type, and administration methods varied across different
studies. Nevertheless, we used a random-effects model to esti-
mate the true situation as far as possible. Thirdly, due to limited
data, some of the subgroup analyses only included a small
number of RCTs for the outcomes of specific types of patients or
different administration methods. Fourthly, also due to the
limited data, analysis of outcomes for specific patients receiving
specific methods of administration could not be performed.
Lastly, due to unique data constraints and study design, we were
unable to conduct interaction tests for subgroup analyses, such as
vitamin D deficiency and COVID-19 severity. Therefore, our
interpretation of the subgroup analysis results provides more of a
directional insight, and the interpretation of outcomes should be
approached cautiously. Future research is needed to further
explore these aspects.
5. Conclusion
Vitamin D supplementation may reduce the chances of patients
with SARS-CoV-2 infection requiring mechanical ventilation and
J. Meng, X. Li, W. Liu et al.
ICU admission. Further studies are needed to assess its possible
effects on risk of SARS-CoV-2 infection and associated mortality.
Funding
The National Clinical Research Center for Geriatric Disorders,
Xiangya Hospital, Central South University (2021KFJJ06) and Hunan
Provincial Natural Foundation of China (2021JJ30040).
Availability of data and analysis
All data generated or analyzed are included in this article and
supplementary files.
Author contributions
Dr Shuguang Gao had full access to all of the data in the study
and takes responsibility for the integrity of the data and the accu-
racy of the data analysis.
Concept and design: Gao, Meng.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Meng, Xiong.
Critical revision of the manuscript for important intellectual
content: All authors.
Statistical analysis: Xiao, Wu.
Administrative, technical, or material support: Tang, Wu.
Supervision: Gao.
Conflicts of interest
All authors declare no competing interests.
Acknowledgements
We gratefully acknowledge the help of the Epidemic Statistics
Unit Support Team from Hunan Key Laboratory of Joint Degenera-
tion and Injury.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.clnu.2023.09.008.
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