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Effect of a Single High Dose of
Vitamin D3 on Hospital Length of
Stay in Patients With Moderate to
Severe COVID-19 A Randomized
Clinical Trial
Key Points
Question What is the effect of a single high dose of vitamin D3 on
hospital length of stay among hospitalized patients with moderate to
severe coronavirus disease 2019 (COVID-19)?
Findings In this randomized clinical trial that involved 240 hospitalized
patients with moderate to severe COVID-19, a single dose of 200 000
IU of vitamin D3, compared with placebo, did not significantly reduce
hospital length of stay (median of 7.0 vs 7.0 days; unadjusted hazard
ratio for hospital discharge, 1.07).
Meaning The study does not support the use of a high dose of vitamin
D3 for treatment of moderate to severe COVID-19 in hospitalized
patients.
Abstract
Importance The efficacy of vitamin D3 supplementation in coronavirus
disease 2019 (COVID-19) remains unclear.
Objective To investigate the effect of a single high dose of vitamin D3
on hospital length of stay in patients with COVID-19.
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Design, Setting, and Participants This was a multicenter, double-
blind, randomized, placebo-controlled trial conducted in 2 sites in Sao
Paulo, Brazil. The study included 240 hospitalized patients with COVID-
19 who were moderately to severely ill at the time of enrollment from
June 2, 2020, to August 27, 2020. The final follow-up was on October 7,
2020.
Interventions Patients were randomly assigned to receive a single oral
dose of 200 000 IU of vitamin D3 (n = 120) or placebo (n = 120).
Main Outcomes and Measures The primary outcome was length of
stay, defined as the time from the date of randomization to hospital
discharge. Prespecified secondary outcomes included mortality during
hospitalization; the number of patients admitted to the intensive care
unit; the number of patients who required mechanical ventilation and
the duration of mechanical ventilation; and serum levels of 25-
hydroxyvitamin D, total calcium, creatinine, and C-reactive protein.
Results Of 240 randomized patients, 237 were included in the primary
analysis (mean >SD@ age, 56.2 >14.4@ years; 104 >43.9%@ women; mean
>SD@ baseline 25-hydroxyvitamin D level, 20.9 >9.2@ ng/mL). Median
(interquartile range) length of stay was not significantly different
between the vitamin D3 (7.0 >4.0-10.0@ days) and placebo groups (7.0
>5.0-13.0@ days) (log-rank P = .59; unadjusted hazard ratio for hospital
discharge, 1.07 >95% CI, 0.82-1.39@; P = .62). The difference between
the vitamin D3 group and the placebo group was not significant for in-
hospital mortality (7.6% vs 5.1%; difference, 2.5% >95% CI, –4.1% to
9.2%@; P = .43), admission to the intensive care unit (16.0% vs 21.2%;
difference, –5.2% >95% CI, –15.1% to 4.7%@; P = .30), or need for
mechanical ventilation (7.6% vs 14.4%; difference, –6.8% >95% CI, –
15.1% to 1.2%@; P = .09). Mean serum levels of 25-hydroxyvitamin D
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significantly increased after a single dose of vitamin D3 vs placebo
(44.4 ng/mL vs 19.8 ng/mL; difference, 24.1 ng/mL >95% CI, 19.5-28.7@;
P < .001). There were no adverse events, but an episode of vomiting
was associated with the intervention.
Conclusions and Relevance Among hospitalized patients with
COVID-19, a single high dose of vitamin D3, compared with placebo,
did not significantly reduce hospital length of stay. The findings do not
support the use of a high dose of vitamin D3 for treatment of moderate
to severe COVID-19.
Trial Registration ClinicalTrials.gov Identifier: NCT04449718
Introduction
Vitamin D may enhance innate1-3 and adaptive immunity.4,5 Because
antigen-presenting cells have the ability to synthesize 1,25-
dihydroxyvitamin D from 25-hydroxyvitamin D, it has been postulated
that vitamin D3 supplementation could improve the function of
macrophages and dendritic cells, thereby ameliorating overall immune
response.6 Vitamin D insufficiency is a potential risk factor for
noncommunicable7 and acute respiratory tract diseases,8,9 including
viral infections.10
It has been suggested that optimal serum levels of 25-hydroxyvitamin
D may have immunomodulatory and anti-inflammatory properties, and
could possibly benefit patients with coronavirus disease 2019 (COVID-
19).11,12 However, the benefits of supplementary vitamin D3 to patients
with COVID-19 remain speculative and only partially supported by
observational studies and 1 small-scale nonrandomized trial.13-15
The objective of this randomized clinical trial was to investigate the
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effect of vitamin D3 administration on hospital length of stay and other
relevant clinical outcomes and adverse events in hospitalized patients
with moderate to severe COVID-19. The main hypothesis was that a
single dose of 200 000 IU of vitamin D3 would increase 25-
hydroxyvitamin D levels and shorten hospital length of stay.
Methods
This was a multicenter, double-blind, parallel-group, randomized,
placebo-controlled trial. The study was approved by the ethics
committee of the Clinical Hospital of the School of Medicine of the
University of Sao Paulo and by the ethics committee of the Ibirapuera
field hospital. Patients provided written informed consent before
participation. The trial protocol and statistical analysis plan are included
in Supplement 1.
Participants
Patients were recruited from the Clinical Hospital of the School of
Medicine of the University of Sao Paulo (a quaternary referral teaching
hospital) and from the Ibirapuera field hospital, both located in Sao
Paulo, Brazil. Patients were enrolled from June 2, 2020, to August 27,
2020. The final follow-up was on October 7, 2020. To provide a
comprehensive demographic characterization, self-reported
race/ethnicity data were also collected based on the following fixed
categories: White, Black, Asian, and Pardo (the latter refers to people of
mixed ethnicities). All patients had COVID-19 diagnosis confirmed by
polymerase chain reaction (PCR) testing at the time of enrollment or by
serology assay (ELISA) to detect IgG against severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) throughout the study.
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Inclusion Criteria
Inclusion criteria were age 18 years or older; diagnosis of COVID-19 via
PCR testing for SARS-CoV-2 from nasopharyngeal swabs or computed
tomography scan findings compatible with the disease (bilateral
multifocal ground-glass opacities ≥50%); and diagnosis of flu
syndrome with institutional criteria for hospitalization on hospital
admission, presenting respiratory rate greater than 24/min, saturation
less than 93% while breathing room air, or risk factors for complications
(eg, heart disease, diabetes, systemic arterial hypertension,
neoplasms, immunosuppression, pulmonary tuberculosis, obesity)
followed by COVID-19 confirmation. Patients who met these criteria
were considered to have moderate to severe COVID-19.
Exclusion Criteria
Patients were excluded if they were unable to read and sign the written
informed consent form, were already admitted and receiving invasive
mechanical ventilation, received previous vitamin D3 supplementation
(>1000 IU/d), had kidney failure requiring dialysis or creatinine of at
least 2.0 mg/dL, had hypercalcemia (total calcium >10.5 mg/dL), were
pregnant or lactating, or had expected hospital discharge in less than
24 hours.
Randomization and Study Interventions
Patients were assigned in a 1:1 ratio to the vitamin D3 group or the
placebo group. The randomization list was created using a computer-
generated code with block sizes of 20. A staff member who had no role
in the study managed the randomization. Outcomes were assessed at
baseline and on hospital discharge.
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The vitamin D3 group received a single, oral dose of 200 000 IU of
vitamin D3 dissolved in a 10-mL peanut oil solution. This selected dose
is in the recommended range for effectively treating patients with 25-
hydroxyvitamin D deficiency.16 Patients from the placebo group
received 10 mL of a peanut oil solution. The solutions were identical in
color, taste, smell, consistency, and container. They were prepared by
the pharmacy unit of the Clinical Hospital and labeled by a staff
member who did not participate in the study. Patients and investigators
remained blinded to randomization until the final analysis.
Outcome Measures
The primary outcome was hospital length of stay, defined as the total
number of days that patients remained hospitalized from the date of
randomization until the date of hospital discharge. The criteria used for
patient discharge were no need for supplemental oxygen in the past 48
hours, no fever in the past 72 hours, and oxygen saturation greater than
93% without supplemental oxygen and without respiratory distress.
The prespecified secondary outcomes were mortality, defined as the
number of patients who died during hospitalization; the number of
patients admitted to the intensive care unit; the number of patients who
needed mechanical ventilation and the duration of mechanical
ventilation; and serum levels of 25-hydroxyvitamin D (assessed by a
chemiluminescent immunoassay), total calcium (assessed by a 5-nitro-
5′-methyl->1,2-bis>o-aminophenoxy@ethan-N,N,N’,N’-tetraacetic acid
method), creatinine (assessed by a colorimetric assay based on the
kinetic Jaffe reaction), and C-reactive protein (assessed by an
immunoturbidimetric assay). In addition, a set of exploratory health-
related laboratory markers (eTable 1 and eTable 2 in Supplement 2)
were assessed. All of the laboratory assessments were analyzed in an
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accredited laboratory from the Clinical Hospital and were performed on
the day of randomization and on hospital discharge. Thus, follow-up
blood samples were not collected for patients who died during the trial.
Serum D-dimer was included as an outcome post hoc because the
investigators believed that this outcome would provide further
exploratory data on the effects of the intervention. Cytokines analysis
was originally planned, but sufficient financial resources were not
available. Physical activity was assessed for a separate prospective
cohort study nested in this clinical trial; therefore, those results are not
presented in this article.
Statistical Analysis
The number of participants was chosen on the basis of feasibility,
based on resources, capacity of research staff and facility, and
available patients, in line with current recommendations.17,18
Approximately 200 patients were expected to be enrolled, with the
expectation of 16 to 17 eligible patients per week in both centers.
Although the actual enrollment was approximately 20 patients per
week, the planned date for ending enrollment was not changed to
increase the study power, resulting in a larger final sample size than
originally anticipated. The minimal clinically important difference
between groups for length of stay among patients with COVID-19 is
unknown.
The log-rank test was used to compare the Kaplan-Meier estimate
curves for length of stay, with deaths being right-censored in the
analysis. Post hoc adjusted analyses for the primary outcome of length
of stay were performed using Cox regression models to estimate
hazard ratios (HRs) with corresponding 2-sided 95% CIs, considering
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potential confounders that were not fully balanced by randomization,
prespecified as P < .20 for baseline comparisons between groups.
These confounders were joint pain, sore throat, hypertension, diabetes,
parathyroid hormone, and creatinine. The proportionality assumption
for Cox regression models was confirmed by assessing Schoenfeld
residuals.
Generalized estimating equations for repeated measures were used for
testing possible differences in laboratory parameters and duration of
mechanical ventilation (using death as a covariate for the latter),
assuming group and time (when applicable) as fixed factors, with
marginal distribution, and a first-order autoregressive correlation matrix
to test the main and interaction effects. Bonferroni adjustment was
performed for generalized estimating equation analyses to maintain a
family-wise 2-sided significance threshold of .05, considering 6
pairwise comparisons for all secondary end points. Percentages were
compared between groups using χ2 and Fisher exact tests for mortality,
admission to the intensive care unit, and mechanical ventilation
requirement.
Post hoc analyses that included patients with 25-hydroxyvitamin D
deficiency (ie, <20 ng/mL) were performed for the primary outcome
and some secondary outcomes, using the same statistical procedures
aforementioned. Post hoc analyses were also performed to examine the
potential site effect on the primary outcome, by including site as strata
and using the same procedures previously described, and to test
whether deaths were noninformative for lengths of stay as initially
assumed. To that end, the 90th-percentile hospital length of stay for
each group for those who died were imputed and data were then
reanalyzed.
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All analyses were performed according to patient randomization group,
with retention of all patients in the analyses except for those who
withdrew consent before receiving the intervention. There was no
imputation for missing data. For laboratory parameters, missingness
was handled by generalized estimating equation models, assuming that
missingness was at random based on the nonsignificant differences
between groups for the proportion of missing data. Statistical analyses
were performed with IBM-SPSS software, version 20.0. The
significance level was set at 2-sided α = .05.
Results
Patients
Of 1240 patients assessed for eligibility, 240 were eligible and
randomized to either the vitamin D3 group or the placebo group.
Patients were not eligible for inclusion due to the following reasons:
284 were in the intensive care unit, 263 had hospital discharge within
24 hours, 217 did not have COVID-19, 95 had kidney dysfunction, 37
had dementia or severe mental confusion precluding them from
providing consent for participation, 32 refused to participate, 30 were
pregnant or lactating women, 14 had hypercalcemia, 11 were receiving
vitamin D3 (≥1000 IU/d), 9 were younger than 18 years, 6 could not
read/write to provide consent, and 2 died before randomization.
Of the 240 patients eligible for participation, 122 were recruited at the
Clinical Hospital of the School of Medicine of the University of Sao
Paulo and 118 were recruited at the Ibirapuera field hospital. Of the 120
patients who were randomized to the vitamin D3 group, 3 did not
receive the intervention (1 withdrew the consent before receiving the
intervention, 1 vomited immediately after ingesting the supplement, and
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1 was admitted to the intensive care unit before receiving the
intervention). During the follow-up period, 1 patient received an extra
dose of vitamin D3 as part of a fracture treatment. Of the 120 patients
who were randomized to the placebo group, 2 did not receive the
intervention because they withdrew consent. Of the 240 patients, only
3 who withdrew consent were excluded from the analysis,
corresponding to 1.25% of missing data (Figure 1).
Overall, 125 of 210 patients (59.5%) had computed tomography scan
findings suggestive of COVID-19 and 147 of 237 (62.0%) had a PCR
test result positive for SARS-CoV-2 at the time of enrollment. All
remaining patients had the diagnosis confirmed by serology assay to
detect IgG against SARS-CoV-2 at some point during the hospital stay.
The mean (SD) time from the onset of symptoms to randomization was
10.3 (4.3) days and from hospitalization to randomization was 1.4 (0.9)
days. The mean (SD) age of the patients was 56.2 (14.4) years, the
mean (SD) body mass index was 31.7 (7.1), 104 patients (43.9%) were
women, and 212 (89.5%) required supplemental oxygen at baseline
(181 were receiving oxygen therapy and 31 were receiving noninvasive
ventilation). Baseline characteristics of both groups are shown in Table
1.
Primary Outcome
The median (interquartile range >IQR@) hospital length of stay was not
significantly different between the vitamin D3 group (7.0 >4.0-10.0@
days) and the placebo group (7.0 >5.0-13.0@ days) (log-rank P = .59;
unadjusted HR for hospital discharge, 1.07 >95% CI, 0.82-1.39@; P = .62;
adjusted HR, 0.99 >95% CI, 0.71-1.37@; P = .94) (Figure 2).
Secondary Outcomes
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There were no significant differences between the vitamin D3 and
placebo groups for in-hospital mortality (7.6% vs 5.1%; difference,
2.5% >95% CI, –4.1% to 9.2%@; P = .43), admission to the intensive care
unit (16.0% vs 21.2%; difference, –5.2% >95% CI, –15.1% to 4.7%@; P
= .30), or need for mechanical ventilation (7.6% vs 14.4%; difference, –
6.8% >95% CI, –15.1% to 1.2%@; P = .09) (Table 2). The mean duration of
mechanical ventilation was not significantly different between the
vitamin D3 and the placebo group (15.0 vs 12.8 days; difference, 2.2
>95% CI, –8.4 to 12.8@; P = .69).
Mean (SD) 25-hydroxyvitamin D was significantly increased from
baseline after a single high dose of vitamin D3 (from 21.2 >10.1@ ng/mL
to 44.4 >15.0@ ng/mL) vs placebo (from 20.6 >8.1@ ng/mL to 19.8 >10.5@
ng/mL ) (between-group postintervention difference, 24.1 ng/mL >95%
CI, 19.5-28.7@; P < .001) (Figure 3). After receiving the intervention, 91 of
105 patients (86.7%) in the vitamin D3 group had 25-hydroxyvitamin D
levels above 30 ng/mL (compared with 11 of 101 >10.9%@ in the placebo
group) and only 7 patients (6.7%) in the vitamin D3 group had 25-
hydroxyvitamin D deficiency (compared with 52 >51.5%@ in the placebo
group).
There were no significant differences between the vitamin D3 group
and the placebo group in total calcium (0.02 mg/dL >95% CI, –0.17 to
0.22@; P > .99), creatinine (0.06 mg/dL >95% CI, –0.17 to 0.29@; P > .99),
C-reactive protein (–0.66 mg/L >95% CI, –5.34 to 4.00@; P = .99), and
D-dimer (a post hoc outcome; 30.4 ng/mL >95% CI, –255.4 to 316.2@; P
>.99) (eTable 2 in Supplement 2).
Post Hoc Analyses
In a post hoc analysis imputing the 90th-percentile hospital length of
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stay for those who died, the median (IQR) hospital length of stay was
not significantly different between the vitamin D3 group (7.0 >4.0-10.0@
days) and the placebo group (7.0 >5.0-13.0@ days) (log-rank P = .33;
unadjusted HR for hospital discharge, 1.13 >95% CI, 0.87-1.45@; P = .36;
adjusted HR, 1.03 >95% CI, 0.75-1.41@; P = .88). The median (IQR) time
to death did not significantly differ between the vitamin D3 (26.0 >13.5-
48.5@ days) and placebo group (26.5 >17.0-32.2@ days) (P = .69 for
Mann-Whitney test).
In a post hoc analysis involving patients with 25-hydroxyvitamin D
deficiency at baseline (n = 115), a single high dose of vitamin D3
significantly increased mean (SD) 25-hydroxyvitamin D levels from
baseline (from 12.8 >3.9@ ng/mL to 35.7 >11.1@ ng/mL) vs placebo (from
13.9 >4.7@ ng/mL to 13.0 >4.4@ ng/mL) (between-group postintervention
difference, 22.7 ng/mL >95% CI, 19.3-26.1@; P < .001) (Figure 3; eTable 3
in Supplement 2). Among the patients with 25-hydroxyvitamin D
deficiency at baseline, no significant differences were observed in the
median (IQR) hospital length of stay between the vitamin D3 (8.0 >4.0-
11.5@ days) and placebo group (7.0 >6.0-13.3@ days) (log-rank P = .59;
unadjusted HR for hospital discharge, 0.91 >95% CI, 0.62-1.32@; P = .61;
adjusted HR, 0.77 >95% CI, 0.46-1.27@; P = .30) (Figure 2). In addition,
there were no significant differences between the vitamin D3 group and
the placebo group for in-hospital mortality (7.0% vs 1.7%; difference,
5.3% >95% CI, –3.3% to 15.1%@; P = .21), admission to the intensive care
unit (19.3% vs 15.5%; difference, 3.8% >95% CI, –10.3% to 17.8%@; P
= .59), or need for mechanical ventilation (7.0% vs 8.6%; difference, –
1.6% >95% CI, –12.5% to 9.2%@; P > .99) (Table 2). The mean duration
of mechanical ventilation was not significantly different between the
vitamin D3 and placebo group (12.2 vs 16.0 days; difference –3.8 >95%
CI, –19.0 to 11.4@; P = .63).
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A post hoc analysis showed no site effect in the median length of stay
between the vitamin D3 and the placebo group (log-rank P = .51;
unadjusted HR for hospital discharge, 1.09 >95% CI, 0.83-1.42@; P = .54;
adjusted HR, 1.00 >95% CI, 0.72-1.38@; P = .97).
Adverse Events
A single high dose of vitamin D3 was well tolerated and no severe
adverse events were reported throughout the trial, with the exception
of 1 patient who vomited after vitamin D3 administration. There were no
significant between-group differences in any health-related laboratory
markers after the intervention (eTable 2 in Supplement 2).
Discussion
In this randomized, double-blind, placebo-controlled clinical trial, a
single high dose of vitamin D3 did not significantly reduce hospital
length of stay or improve any other clinically relevant outcomes among
hospitalized patients with moderate to severe COVID-19. To our
knowledge, this is the first randomized clinical trial to demonstrate
these findings.
Vitamin D appears to regulate both innate and adaptative immune
responses.6,19 Observational studies have shown that higher 25-
hydroxyvitamin D levels are associated with better clinical outcomes in
respiratory diseases.20 Positive associations between low 25-
hydroxyvitamin D levels and poor prognosis among patients with
COVID-19 have also been observed.21 Furthermore, a small
nonrandomized trial demonstrated that administration of regular
boluses of vitamin D3 before the infection was associated with better
survival and less severe disease among older frail patients with COVID-
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19.22 However, in the current trial, a single dose of 200 000 IU of
vitamin D3 did not result in any clinically relevant effects among
hospitalized patients with moderate to severe COVID-19, contesting
the use of supplementary vitamin D3 as a treatment for patients with
this disease.
The lack of clinical benefits seen in this study was independent of the
ability of vitamin D3 to increase serum 25-hydroxyvitamin D levels.
After the intervention, 86.7% of the patients in the vitamin D3 group
achieved 25-hydroxyvitamin D sufficiency (≥30 ng/mL) vs 10.9% in the
placebo group. In a post hoc analysis confined to the patients
exhibiting 25-hydroxyvitamin D deficiency, a single high dose of vitamin
D3 remained effective in increasing 25-hydroxyvitamin D levels
compared with placebo, yet no clinical improvements were noted.
These analyses indicate that a single oral dose of 200 000 IU of vitamin
D3 can rapidly increase 25-hydroxyvitamin levels, so the present null
findings cannot be attributed to the failure of increasing serum 25-
hydroxyvitamin D levels.
The strengths of this study include the randomized, double-blind,
placebo-controlled, experimental design; the very low attrition rate
(1.25%); the concomitant assessment of 25-hydroxyvitamin D levels
along with clinical outcomes; and the assessment of hospitalized
patients with moderate to severe COVID-19.
Limitations
This trial has several limitations. First, the minimal clinically important
difference in hospital length of stay among patient with COVID-19
remains to be determined. Although the HR for the primary outcome
indicates that the intervention was ineffective, the relatively low sample
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size in this trial could have had inadequate power to exclude small, but
clinically meaningful, differences between the groups. Second,
because the patients had several coexisting diseases and were
subjected to a diverse medication regimen, the results could have been
affected by the heterogeneity of the sample and its treatment. Third,
the percentage of patients with 25-hydroxyvitamin D deficiency
enrolled in this study was considerably lower than those reported in
other cohorts,23 possibly as a consequence of differences in
geographic locations. Therefore, caution should be exercised in
generalizing these findings to patients from other geographical regions.
Fourth, the patients were given a dose of vitamin D3 after a relatively
long time from symptom onset to randomization (ie, mean of 10.3
days). Further studies should determine whether preventive or early
vitamin D3 supplementation could be useful in the treatment of patients
with COVID-19, especially those with mild or moderate disease.
Conclusions
Among hospitalized patients with COVID-19, a single high dose of
vitamin D3, compared with placebo, did not significantly reduce
hospital length of stay. The findings do not support the use of vitamin
D3 for treatment of moderate to severe COVID-19.
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Article Information
Corresponding Author: Rosa Maria Rodrigues Pereira, MD, PhD,
Rheumatology Division, Faculdade de Medicina FMUSP, 3° andar,
Universidade de Sao Paulo, Sao Paulo, SP, BR. Av. Dr. Arnaldo, 455,
Pacaembu, Sao Paulo, SP, Brazil, 01246-903
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(rosamariarp@yahoo.com).
Accepted for Publication: February 3, 2021.
Published Online: February 17, 2021. doi:10.1001/jama.2020.26848
Author Contributions: Dr Pereira had full access to all of the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis. Drs Murai and Fernandes contributed
equally.
Concept and design: Murai, Fernandes, Pinto, Macedo, Gualano,
Pereira.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Murai, Fernandes, Franco, Macedo,
Gualano, Pereira.
Critical revision of the manuscript for important intellectual content: All
authors.
Statistical analysis: Murai, Fernandes, Reis, Pereira.
Obtained funding: Gualano, Pereira.
Administrative, technical, or material support: Sales, Pinto, Duran, Silva,
Franco, Dalmolin, Baggio, Balbi, Antonangelo, Caparbo.
Supervision: Gualano, Pereira.
Conflict of Interest Disclosures: Dr Murai reported receiving grants
from the Sao Paulo Research Foundation (FAPESP; grant 19/24782-4)
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during the conduct of the study. Dr Fernandes reported receiving
grants from FAPESP during the conduct of the study. Dr Silva reported
receiving grants from FAPESP during the conduct of the study. Dr
Baggio reported receiving grants from FAPESP during the conduct of
the study. Dr Balbi reported receiving grants from FAPESP during the
conduct of the study. Dr Pereira reported receiving grants from FAPESP
(grant 20/05752-4) and grants from Conselho Nacional de
Desenvolvimento Científico e Tecnológico (grant 305556/2017-7)
during the conduct of the study. No other disclosures were reported.
Funding/Support: This study was supported by FAPESP (grants
20/05752-4; 19/24782-4; 20/11102-2; 16/00006-7; 17/13552-2;
15/26937-4; 19/18039-7) and Conselho Nacional de Desenvolvimento
Científico e Tecnológico (305556/2017-7).
Role of the Funder/Sponsor: The funders had no role in the design
and conduct of the study; collection, management, analysis, and
interpretation of the data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript for publication.
Data Sharing Statement: See Supplement 3.
Additional Contributions: The authors are thankful to Monica
Pinheiro, MD, MSc, and Roberta Costa, MSc (Ibirapuera field hospital),
for assistance with the study; Cleuber Esteves Chaves, BSc (pharmacy
unit of the clinical hospital), for the vitamin D3 and placebo solution
preparation; Rogério Ruscitto do Prado, PhD (Albert Einstein Hospital),
for conducting statistical analyses; Cibele Russo, PhD (University of
Sao Paulo), for statistical review; Mayara Diniz Santos, MS (School of
Medicine of University of Sao Paulo), for technical support; all of the
staff members from both centers; and all of the patients who
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participated in this study. None of these individuals received
compensation for their participation.
References
1.
Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin
D-mediated human antimicrobial response. Science.
2006;311(5768):1770-1773.
doi:10.1126/science.1123933PubMedGoogle ScholarCrossref
2.
Aglipay M, Birken CS, Parkin PC, et al; TARGet Kids! Collaboration.
Effect of high-dose vs standard-dose wintertime vitamin D
supplementation on viral upper respiratory tract infections in young
healthy children. JAMA. 2017;318(3):245-254.
doi:10.1001/jama.2017.8708
ArticlePubMedGoogle ScholarCrossref
3.
Campbell GR, Spector SA. Autophagy induction by vitamin D inhibits
both Mycobacterium tuberculosis and human immunodeficiency virus
type 1. Autophagy. 2012;8(10):1523-1525.
doi:10.4161/auto.21154PubMedGoogle ScholarCrossref
4.
van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin
D3: basic concepts. J Steroid Biochem Mol Biol. 2005;97(1-2):93-101.
doi:10.1016/j.jsbmb.2005.06.002PubMedGoogle ScholarCrossref
5.
Laplana M, Royo JL, Fibla J. Vitamin D receptor polymorphisms and
risk of enveloped virus infection: a meta-analysis. Gene.
2018;678:384-394. doi:10.1016/j.gene.2018.08.017PubMedGoogle
2021-02-19 下午7:17
⻚码：18/22
ScholarCrossref
6.
Bilezikian JP, Bikle D, Hewison M, et al. Mechanisms in
endocrinology: vitamin D and COVID-19. Eur J Endocrinol.
2020;183(5):R133-R147. doi:10.1530/EJE-20-0665PubMedGoogle
ScholarCrossref
7.
Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a
systematic review. Lancet Diabetes Endocrinol. 2014;2(1):76-89.
doi:10.1016/S2213-8587(13)70165-7PubMedGoogle ScholarCrossref
8.
Aibana O, Huang CC, Aboud S, et al. Vitamin D status and risk of
incident tuberculosis disease: a nested case-control study, systematic
review, and individual-participant data meta-analysis. PLoS Med.
2019;16(9):e1002907.
doi:10.1371/journal.pmed.1002907PubMedGoogle Scholar
9.
Martineau AR, Jolliffe DA, Hooper RL, et al. Vitamin D
supplementation to prevent acute respiratory tract infections:
systematic review and meta-analysis of individual participant data.
BMJ. 2017;356:i6583. doi:10.1136/bmj.i6583PubMedGoogle
ScholarCrossref
10.
Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry
ML. Serum 25-hydroxyvitamin d and the incidence of acute viral
respiratory tract infections in healthy adults. PLoS One.
2010;5(6):e11088. doi:10.1371/journal.pone.0011088PubMedGoogle
Scholar
11.
Mitchell F. Vitamin-D and COVID-19: do deficient risk a poorer
2021-02-19 下午7:17
⻚码：19/22
outcome? Lancet Diabetes Endocrinol. 2020;8(7):570.
doi:10.1016/S2213-8587(20)30183-2PubMedGoogle ScholarCrossref
12.
Martineau AR, Forouhi NG. Vitamin D for COVID-19: a case to
answer? Lancet Diabetes Endocrinol. 2020;8(9):735-736.
doi:10.1016/S2213-8587(20)30268-0PubMedGoogle ScholarCrossref
13.
Meltzer DO, Best TJ, Zhang H, Vokes T, Arora V, Solway J.
Association of vitamin D status and other clinical characteristics with
COVID-19 test results. JAMA Netw Open. 2020;3(9):e2019722.
doi:10.1001/jamanetworkopen.2020.19722
ArticlePubMedGoogle Scholar
14.
Kaufman HW, Niles JK, Kroll MH, Bi C, Holick MF. SARS-CoV-2
positivity rates associated with circulating 25-hydroxyvitamin D levels.
PLoS One. 2020;15(9):e0239252.
doi:10.1371/journal.pone.0239252PubMedGoogle Scholar
15.
Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention
of coronavirus disease 2019 infection and mortality. Aging Clin Exp
Res. 2020;32(7):1195-1198. doi:10.1007/s40520-020-01570-
8PubMedGoogle ScholarCrossref
16.
Kearns MD, Alvarez JA, Tangpricha V. Large, single-dose, oral vitamin
D supplementation in adult populations: a systematic review. Endocr
Pract. 2014;20(4):341-351. doi:10.4158/EP13265.RAPubMedGoogle
ScholarCrossref
17.
Bacchetti P. Current sample size conventions: flaws, harms, and
alternatives. BMC Med. 2010;8:17. doi:10.1186/1741-7015-8-
2021-02-19 下午7:17
⻚码：20/22
17PubMedGoogle ScholarCrossref
18.
Bacchetti P, McCulloch CE, Segal MR. Simple, defensible sample
sizes based on cost efficiency. Biometrics. 2008;64(2):577-585.
doi:10.1111/j.1541-0420.2008.01004_1.xPubMedGoogle
ScholarCrossref
19.
Franco AS, Freitas TQ, Bernardo WM, Pereira RMR. Vitamin D
supplementation and disease activity in patients with immune-
mediated rheumatic diseases: a systematic review and meta-analysis.
Medicine (Baltimore). 2017;96(23):e7024.
doi:10.1097/MD.0000000000007024PubMedGoogle Scholar
20.
Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin
D. Epidemiol Infect. 2006;134(6):1129-1140.
doi:10.1017/S0950268806007175PubMedGoogle ScholarCrossref
21.
Carpagnano GE, Di Lecce V, Quaranta VN, et al. Vitamin D deficiency
as a predictor of poor prognosis in patients with acute respiratory
failure due to COVID-19. J Endocrinol Invest. Published online August
9, 2020. doi:10.1007/s40618-020-01370-xPubMedGoogle Scholar
22.
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. Nutrients. 2020;12(11):e3377.
doi:10.3390/nu12113377PubMedGoogle Scholar
23.
Hernández JL, Nan D, Fernandez-Ayala M, et al. Vitamin D status in
hospitalized patients with SARS-CoV-2 infection. J Clin Endocrinol
2021-02-19 下午7:17
⻚码：21/22
Metab. 2020;dgaa733. doi:10.1210/clinem/dgaa733PubMedGoogle
Scholar
2021-02-19 下午7:17
⻚码：22/22
