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 | Complementary and Alternative Medicine | JAMA | JAMA Network
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Figure 1.  Flow of Patients in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019 (COVID-19)
Flow of Patients in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019 (COVID-19)

All analyses were completed according to the patients’ randomization group. There was no imputation for missing data, except for laboratory parameters, in which missingness appeared to be at random and was modeled using generalized estimating equations. 25(OH)D indicates 25-hydroxyvitamin D.

Figure 2.  Hospital Discharge in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019
Hospital Discharge in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019

Vertical bars represent single censored events. A, The median (interquartile range) observation time was not significantly different between the vitamin D3 group (7.0 [4.0-10.0] d) and the placebo group (7.0 [5.0-13.0] d). B, Among the patients with 25-hydroxyvitamin D deficiency, there was no significant difference observed in the median (interquartile range) observation time between the vitamin D3 group (8.0 [4.0-11.5] d) and the placebo group (7.0 [6.0-13.3] d).

Figure 3.  Serum 25-Hydroxyvitamin D Levels in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019
Serum 25-Hydroxyvitamin D Levels in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019

Serum 25-hydroxyvitamin D levels were measured on the day of randomization (baseline) and on hospital discharge (postintervention). A, For all patients, a single high dose of vitamin D3 significantly increased 25-hydroxyvitamin D levels compared with placebo (difference, 24.1 ng/mL [95% CI, 19.5-28.7]; P < .001). Median (interquartile range) observation time of the postintervention period was 7.0 (4.0-10.0) days for the vitamin D3 group and 7.0 (5.0-13.0) days for the placebo group. B, For patients with 25-hydroxyvitamin D deficiency, a single high dose of vitamin D3 significantly increased 25-hydroxyvitamin D levels compared with placebo (difference, 22.7 ng/mL [95% CI, 19.3-26.1]; P < .001). Median (interquartile range) observation time of the postintervention period was 8.0 (4.0-11.5) days for the vitamin D3 group and 7.0 (6.0-13.3) days for the placebo group. Boxes represent median and interquartile range and whiskers extend to the highest and lowest values within 1.5 times the interquartile range of the 25th and 75th percentiles. Circles represent outliers.

Table 1.  Baseline Characteristics in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019 (COVID-19)
Baseline Characteristics in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019 (COVID-19)
Table 2.  Secondary Outcomes in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019
Secondary Outcomes in a Study of the Effect of a High Dose of Vitamin D3 on Patients With Moderate to Severe Coronavirus Disease 2019
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.2017.8708PubMedGoogle 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 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 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.2020.19722PubMedGoogle 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:10.1186/1741-7015-8-17PubMedGoogle 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 Metab. 2020;dgaa733. doi:10.1210/clinem/dgaa733PubMedGoogle Scholar
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    10 Comments for this article
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    In Line With What We Know About Vitamin D
    Talat Islam, MBBS, PhD | University of Southern California
    The immunomodulatory effect of vitamin D3 is possibly a result of its long-term rather than short-term actions. Although epidemiological evidence from multiple sclerosis shows a potential protective effect of high serum vitamin D3 levels, it has never been substantiated in acute treatment or randomized trials.

     It would be informative if the authors reported whether the clinical outcome of the patients (summing up both groups) differed by baseline levels (quartile or quintile) of vitamin D3.
    CONFLICT OF INTEREST: None Reported
    Unhelpful Trial
    Sam Mansour, M.Sc., MD | George Washington University
    While a legitimate case can be made for chronic supplementary use of Vitamin D3 as possibly preventive for some viral upper respiratory tract diseases, there is no serious basis for a single high dose infusion of Vitamin D3 possibly altering the course of moderate to severe COVID-19 disease. The analogy would be showing up to a 4th alarm house fire with a bucket of water!
    CONFLICT OF INTEREST: None Reported
    Primary Prevention
    Christopher Foley, MD ABIM | Private Practice Internal medicine
    There is observational evidence that vitamin D levels above 20 ng/dL are associated with a reduction in risk of death from coronavirus and levels above 36 ng/dL are associated with a reduction in risk of severe disease. These numbers are a combination of both serum AND intracellular vitamin D3 levels that translate much more efficiently into hepatic 25 hydroxylation then giving a massive bolus that takes days, perhaps weeks, to actually undergo first pass metabolism and intracellular absorption. For physicians trained and who are familiar with nutraceutical science the approach taken in this trial would make no sense.

    The
    object should be to keep people out of the hospital. We should try to prevent aortic aneurysms, chronic renal failure requiring dialysis, gunshot wounds requiring emergency surgery, and acute bowel obstructions from advanced neoplasms. Trying to cure stage 4 adenocarcinoma of the colon with a supranormal dose of fruits and vegetables upon hospitalization is similar to the intent here.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Vitamin D Source and Levels of 1,25-dihydroxycholecalciferol.
    Gary Ordog, MD, DABEM, DABMT | County of Los Angeles, Department of Health Services, (retired)
    Thank you for your study on Vitamin D in COVID-19, moderate to severe disease. One of the variables I always ask about in these types of studies: "What was your source of Vitamin D?" I have to assume you used the usual hospital source which is a semisynthetic derivative of lanolin. This unfortunately, is chemically derived and includes mainly competitive enantiomers. I don't believe that it has any of the actual 1,25-dihydroxycholecalciferol that is required. This is especially important in these patients who probably cannot metabolize your supplement to the active form, either by competition by analogue enantiomers and by factor 23 which may be in high levels in these ill patients. I do note that it may be more prudent to use the natural cod liver oil that is already sufficient in the active Vitamin D, 1,25-dihydroxycholecalciferol, when conducting experiments of this type. Again thank you. Gary Joseph Ordog, MD.
    CONFLICT OF INTEREST: None Reported
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    Differences Between Groups
    Wendy McLean, B.Sc. Mathematics | None
    There are considerable differences between the control and treatment groups in a number of variables known to be highly relevant to covid severity and hence length of stay. The treatment group had more people with diabetes who are more likely to die from covid. You used an adjusted length of stay for deaths. The treatment group also had more males, more people with high BMI, more hypertension. There were racial differences. I note that a fixed block size, not different block sizes, was used for randomisation.

    I would expect to see considerably more discussion of the
    differences between groups - and an analysis of the effect of excluding diabetic participants before reaching the conclusion that intervention was ineffective.

    Admission to ICU and breathing support were less common in the treated group but it had more deaths. This may be caused by the disproportionate number of people with diabetes in the treatment group dying rapidly but again it needs explanation.

    I have noted the concerns about the formulation used but this did raise vitamin D levels.
    CONFLICT OF INTEREST: None Reported
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    High Dose Suppresses 1-Alpha-Hydroxyase.Activation
    Jonathan Rhodes, MD FRCP FMedSci | University of Liverpool, UK
    This study adds to evidence that single high dose bolus vitamin D is ineffective for various endpoints including rickets, tuberculosis and acute respiratory infections. With colleagues we have reviewed this in a perspective (1) and point out that there is a plausible biological explanation – large bolus dosing has been shown to cause long-term induction of the inactivating 24-hydroxylase plus induction of fibroblast growth factor 23 (FGF23) that suppresses the 1-alpha-hydroxylase enzyme required for vitamin D activation. Regular daily vitamin D supplementation aiming for sufficiency rather than excess looks a much better bet and should be more widely recommended, particularly during the pandemic when healthy immune function is likely to be critical.

    Reference

    1. https://doi.org/10.7861/clinmed.2021-0035 
    CONFLICT OF INTEREST: None Reported
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    A bolus, loading dose requires followup, maintenance doses
    Reinhold Vieth, PhD | Department of Nutritional Sciences, University of Toronto
    Aside from raising the serum 25-hydroxyvitamin D (25(OH)D) level, bolus doses of vitamin D do not work (1–3). The classic example of this is the failed fracture-prevention clinical trial of Sanders et al who treated with annual, 500,000 IU doses of vitamin D, only to find increased risk of falls and fractures in the treatment arm (1).
    I appreciate the limited time-frame for studying COVID-19, but the expectations for vitamin D are beyond what one should expect for any nutrient. Nutrition is a long-term undertaking. Still, the clinical trial of Murai et al.
    needed to be done. Despite the lack of benefit, the vitamin D did no harm. But this was only a bolus, or loading, dose. That dose requires followup with an ongoing maintenance intake. Based on the typical 60-day biological half-life for vitamin D in adults, the serum 25(OH)D level achieved with the single, 200,000 IU dose given by Murai et al, should be followed up with ongoing intakes of 3,000 IU vitamin D3 per day (4)

    1. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822. doi:10.1001/jama.2010.594
    2. Sanders KM, Nicholson GC, Ebeling PR. Is high dose vitamin D harmful? Calcif Tissue Int. 2013;92(2):191-206. doi:10.1007/s00223-012-9679-1
    3. Vieth R, Holick MF. Chapter 57B - The IOM—Endocrine Society Controversy on Recommended Vitamin D Targets: In Support of the Endocrine Society Position. In: Feldman D, ed. Vitamin D (Fourth Edition). Academic Press; 2018:1091-1107. doi:10.1016/B978-0-12-809965-0.00059-8
    4. Vieth R. Chapter 57 - The Pharmacology of Vitamin D. In: Feldman D, Pike JW, Adams JS, eds. Vitamin D (Third Edition). Academic Press; 2011:1041-1066. doi:10.1016/B978-0-12-381978-9.10057-5
    CONFLICT OF INTEREST: Receive patent royalty from Ddrops(R), an infant vitamin D supplement
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    Reanalysis Suggests Vitamin D Decreased Intensive Care and Mechanical Ventilation Use
    David Meltzer, MD, PhD | The University of Chicago
    Murai and colleagues’ important study found that one 200,000 IU dose of vitamin D3 substantially increased serum vitamin D levels but did not affect hospital length of stay for patients with moderate-to-severe COVID-19. They also found only non-statistically significant reductions in secondary outcomes of transfer to intensive care (p=0.3) and use of mechanical ventilation (p=0.09) among patients receiving vitamin D versus placebo. A post-hoc analysis of patients with baseline vitamin D <20 ng/ml found attenuated or opposing differences in use of intensive care or mechanical ventilation for patients receiving vitamin D versus placebo. These patterns among patients with baseline vitamin D < 20ng/ml compared to the full sample led us to use data in Table 2 to calculate rates of these outcomes among persons with vitamin D ≥ 20 ng/ml. The rates for the vitamin D and placebo groups were 8/62 (13%) vs 16/60(27%,), RR=0.48, p(chi-square) = 0.055 for intensive care and 5/62 (8%) vs. 12/60 (20%), RR=0.40, p(chi-square) = 0.057 for mechanical ventilation, consistent with large protective effects of the vitamin D supplementation in this subgroup.

    Although persons with lower vitamin D levels might have been expected to benefit more from raising vitamin D levels, rates of some respiratory infections, including COVID-19, have been found to be lower with vitamin D supplementation (1) and when vitamin D levels are ≥20 ng/ml (2-4), suggesting optimal levels for immune function may be higher. Moreover, White patients typically have higher vitamin D levels than patients with darker skin and were likely overrepresented among participants with baseline vitamin D ≥ 20ng/ml in this racially heterogeneous population. White persons also more frequently have Gc1S and Gc2 vitamin D binding protein (VDBP) alleles that more easily release bound vitamin D than does the Gc1F allele, which is more common in populations of more recent African origin (5). Thus, the borderline statistically significant finding of association between vitamin D supplementation and reduced intensive care and mechanical ventilation in patients in this study with levels ≥ 20 ng/ml may reflect effects of VDBP polymorphisms in that subgroup and might explain why this single vitamin D dose did not improve outcomes in persons with baseline levels < 20ng/ml. Obesity might also reduce baseline levels and benefits in persons with lower levels.

    Given these and other findings suggesting vitamin D may be associated with COVID-19 outcomes (6), we encourage further subgroup and multivariable analysis by race in this sample, additional caution in interpreting the results of this study, and that future studies examine daily versus bolus vitamin D dosing in COVID-19 and the potential roles of VDBP polymorphisms, especially in non-White populations.

    David Meltzer MD, PhD, Tom Best, PhD, Andrew Schram MD, MBA, Julian Solway MD
    Department of Medicine, Section of Hospital Medicine, and Center for Health and the Social Sciences, the University of Chicago.

    References

    1. Martineau et al., BMJ, 2017
    2. Meltzer et al., JAMA Network Open, 2020
    3. Merzon et al., The FEBS Journal, 2020
    4. Kaufman et al., PLOS ONE, 2020
    5. Speeckaert et al, Clin Chim Acta, 2006
    6. Castillo et al., Biochem Mol Biol, 2020
    CONFLICT OF INTEREST: I have grant funding to study vitamin D and COVID-19 from NIH, Cures within Reach, the Ingalls Memorial Hospital Foundation, and a private philanthropist
    READ MORE
    A study that was designed to fail.
    Bruce Hollis, PhD | Medical University of South Carolina, Charleston, SC
    A single bolus dose of vitamin D for almost all clinical situations is of no value. This is especially true if given to critically sick individuals. First, bolus dosing basically turns off the normal physiological metabolism of vitamin D. The rise in the intermediate form of vitamin D, 25-hydroxyvitamin D would not rise to significant levels until days after dosing. I published a paper in 2013 that outlined the futility of administering vitamin D by bolus dosing (1). Subsequent clinical trials have demonstrated the failure of this technique several times now. 

    Reference

    1. J Clin Endocrinol Metab. 2013 Dec; 98(12):
    4619–4628.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Timing
    Morry Silberstein, MD | Curtin University, Australia
    I wonder if there might be a correlation between symptom onset time (when Vit D was administered) and clinical outcome, ie the earlier D was given, the shorter the hospital stay. 
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    February 17, 2021

    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

    Author Affiliations
    • 1Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
    • 2Applied Physiology & Nutrition Research Group, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
    • 3Clinical Pathology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
    • 4Food Research Center, Universidade de Sao Paulo, Sao Paulo, Brazil
    JAMA. Published online February 17, 2021. doi:10.1001/jama.2020.26848
    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.

    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 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 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.

    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.

    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 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 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.

    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 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

    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 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).

    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-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 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 (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) 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 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.2017.8708PubMedGoogle 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 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 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.2020.19722PubMedGoogle 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:10.1186/1741-7015-8-17PubMedGoogle 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 Metab. 2020;dgaa733. doi:10.1210/clinem/dgaa733PubMedGoogle Scholar
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