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Effect of a Single High-Dose Vitamin D3 on the Length of Hospital Stay of Severely 25-Hydroxyvitamin D-Deficient Patients with COVID-19

Abstract

OBJECTIVES:

In this ancillary analysis of a multicenter, double-blinded, randomized, placebo-controlled trial, we investigated the effect of a single high dose of vitamin D3 on the length of hospital stay of patients with severe 25-hydroxyvitamin D deficiency and COVID-19.

METHODS:

The primary outcome was length of hospital stay, defined as the total number of days that patients remained hospitalized from the date of randomization until the date of hospital discharge. Secondary outcomes included serum levels of 25-hydroxyvitamin D, mortality during hospitalization, number of patients admitted to the intensive care unit, and number of patients who required mechanical ventilation. ClinicalTrials.gov: NCT04449718.

RESULTS:

Thirty-two patients were included in the study. The mean (SD) age was 58.5 (15.6) years, body mass index was 30.8 (8.6) kg/m2, and 25-hydroxyvitamin D level was 7.8 (1.6) ng/mL. No significant difference was observed in the median interquartile range of length of hospital stay between the vitamin D3 group (6.0 [4.0-18.0] days) versus placebo (9.5 [6.3-15.5] days) (log-rank p=0.74; hazard ratio, 1.13 [95% confidence interval (CI), 0.53-2.40]; p=0.76). Vitamin D3 significantly increased serum 25-hydroxyvitamin D levels in the vitamin D3 group compared with that in the placebo group (between-group difference, 23.9 ng/mL [95% CI, 17.7-30.1]; p<0.001).

CONCLUSIONS:

A dose of 200.000 IU of vitamin D3 did not significantly reduce the length of hospital stay of patients with severe 25-hydroxyvitamin D deficiency and COVID-19.

SARS-CoV-2; Immune System; Pneumonia; Acute Respiratory Disease


INTRODUCTION

Vitamin D has potent antimicrobial effects, which may modulate the immune system (11. Bilezikian JP, Bikle D, Hewison M, Lazaretti-Castro M, Formenti AM, Gupta A, et al. MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19. Eur J Endocrinol. 2020;183(5):R133-R147. https://doi.org/10.1530/EJE-20-0665
https://doi.org/10.1530/EJE-20-0665...
) and protect against respiratory diseases (22. Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. https://doi.org/10.1136/bmj.i6583
https://doi.org/10.1136/bmj.i6583...
). Hospitalized patients with COVID-19 may present with low levels of 25-hydroxyvitamin D [25(OH)D] (33. Carpagnano GE, Di Lecce V, Quaranta VN, Zito A, Buonamico E, Capozza E, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. 2021;44(4):765-71. https://doi.org/10.1007/s40618-020-01370-x
https://doi.org/10.1007/s40618-020-01370...
,44. Hernández JL, Nan D, Fernandez-Ayala M, García-Unzueta M, Hernández-Hernández MA, López-Hoyos M, et al. Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection. J Clin Endocrinol Metab. 2021;106(3):e1343-e1353. https://doi.org/10.1210/clinem/dgaa733
https://doi.org/10.1210/clinem/dgaa733...
). However, the role of vitamin D in the management of COVID-19 remains controversial (33. Carpagnano GE, Di Lecce V, Quaranta VN, Zito A, Buonamico E, Capozza E, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. 2021;44(4):765-71. https://doi.org/10.1007/s40618-020-01370-x
https://doi.org/10.1007/s40618-020-01370...
,55. Jevalikar G, Mithal A, Singh A, Sharma R, Farooqui KJ, Mahendru S, et al. Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19. Sci Rep. 2021;11(1):6258. https://doi.org/10.1038/s41598-021-85809-y
https://doi.org/10.1038/s41598-021-85809...
,66. Bassatne A, Basbous M, Chakhtoura M, El Zein O, Rahme M, El-Hajj Fuleihan G. The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis. Metabolism. 2021;119:154753. https://doi.org/10.1016/j.metabol.2021.154753
https://doi.org/10.1016/j.metabol.2021.1...
). We recently showed that a single high dose of vitamin D3 versus placebo did not significantly reduce the length of hospital stay among hospitalized patients with moderate to severe COVID-19 and either normal (>30 ng/mL) or reduced levels of 25(OH)D (<20 ng/mL) (77. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CSC, et al. 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. JAMA. 2021;325(11):1053-60. https://doi.org/10.1001/jama.2020.26848
https://doi.org/10.1001/jama.2020.26848...
). However, in a subsequent cohort study, we observed that COVID-19 patients with 25(OH)D levels <10 ng/mL showed a trend (p=0.057) of longer length of hospital stay than those with 25(OH)D levels ≥10 ng/mL (95% confidence interval [CI]: 6.4-11.6 days versus 6.6-7.4 days) (88. Reis BZ, Fernandes AL, Sales LP, Santos MD, Dos Santos CC, Pinto AJ, et al. Influence of vitamin D status on hospital length of stay and prognosis in hospitalized patients with moderate to severe COVID-19: a multicenter prospective cohort study. Am J Clin Nutr. 2021;114(2):598-604. https://doi.org/10.1093/ajcn/nqab151
https://doi.org/10.1093/ajcn/nqab151...
).

Herein, we report on an ancillary analysis of our randomized clinical trial (77. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CSC, et al. 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. JAMA. 2021;325(11):1053-60. https://doi.org/10.1001/jama.2020.26848
https://doi.org/10.1001/jama.2020.26848...
) to investigate whether, in a subset of severely 25(OH)D-deficient patients with moderate to severe COVID-19, a single high dose of vitamin D3 could reduce the length of hospital stay and improve other clinical outcomes.

MATERIAL AND METHODS

In this ancillary analysis of a multicenter, double-blinded, randomized, placebo-controlled trial of a single dose of 200.000 IU of vitamin D3 versus placebo (ClinicalTrials.gov Identifier: NCT04449718), we assessed a subset of hospitalized patients with moderate to severe COVID-19 presenting with severe 25(OH)D deficiency [<10 ng/mL (99. Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Köstenberger M, Tmava Berisha A, et al. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr. 2020;74(11):1498-513. https://doi.org/10.1038/s41430-020-0558-y
https://doi.org/10.1038/s41430-020-0558-...
) at baseline]. Participants were enrolled from the Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo (a quaternary referral teaching hospital) and from the Ibirapuera Field Hospital, both located in São Paulo, Brazil. All patients were diagnosed with COVID-19 via polymerase chain reaction testing at the time of enrollment or using a serological assay (ELISA) to detect IgG against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary outcome was length of hospital stay, defined as the total number of days that patients remained hospitalized from the date of randomization until the date of hospital discharge. Secondary outcomes included serum levels of 25(OH)D, mortality during hospitalization, number of patients admitted to the intensive care unit, and number of patients who required mechanical ventilation.

The protocol followed the Declaration of Helsinki and local regulations and was approved by the National and Institutional Ethical Committee of the Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil. Written informed consent was obtained from each participant prior to enrollment. This manuscript has been reported according to the CONSORT guidelines. Further details on patient recruitment, supplementation protocol and blindness, procedures, and outcomes can be found elsewhere (77. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CSC, et al. 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. JAMA. 2021;325(11):1053-60. https://doi.org/10.1001/jama.2020.26848
https://doi.org/10.1001/jama.2020.26848...
).

The log-rank test was used to compare the Kaplan-Meier estimate curves for length of hospital stay, with deaths being right-censored in the analysis. A Cox regression model was used to estimate the hazard ratio (HR) with corresponding two-sided 95% CIs. Generalized estimating equations for repeated measures were used to test possible differences in 25(OH)D levels. Statistical analyses were performed using the IBM-SPSS software, version 20.0. The significance level was set at two-sided α=0.05.

RESULTS

Of the 237 patients who participated in the randomized controlled trial (77. Murai IH, Fernandes AL, Sales LP, Pinto AJ, Goessler KF, Duran CSC, et al. 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. JAMA. 2021;325(11):1053-60. https://doi.org/10.1001/jama.2020.26848
https://doi.org/10.1001/jama.2020.26848...
), 32 had severe 25(OH)D deficiency (16 in each arm). The mean (SD) age was 58.5 (15.6) years, body mass index was 30.8 (8.6) kg/m2, and 25(OH)D level was 7.8 (1.6) ng/mL (Table 1).

Table 1
Baseline demographic and clinical characteristics.

There was no significant difference in the median (interquartile range [IQR]) length of hospital stay between the vitamin D3 group (6.0 [4.0-18.0] days) versus placebo (9.5 [6.3-15.5] days) (log-rank p=0.74; HR for hospital discharge, 1.13 [95% CI, 0.53-2.40]; p=0.76) (Figure 1). Importantly, the number of patients with a length of hospital stay <7 [the median time observed in the entire cohort of patients (7)] was eight in the vitamin D3 group and four in the placebo group (Fischer’s exact test: p=0.273).

Figure 1
Hospital discharge and serum 25-hydroxyvitamin D levels. A, Vertical bars represent single censored events. The median (interquartile range [IQR]) observation time was not significantly different between the vitamin D3 group (6.0 [4.0-18.0] days) and the placebo group (9.5 [6.3-15.5] days) (log-rank p=0.74; HR for hospital discharge, 1.13 (95% confidence interval [CI], 0.53-2.40; p=0.76). B, 25-hydroxyvitamin D levels measured on the day of randomization (baseline) and on hospital discharge (post-intervention). A single high dose of vitamin D3 significantly increased 25-hydroxyvitamin D levels compared with the placebo (difference, 23.9 ng/mL [95% CI, 17.7-30.1]; p<0.001). The median IQR observation time of the post-intervention period was 6.0 (4.0-18.0) days for the vitamin D3 group and 9.5 (6.3-15.5) days for the placebo group. Intention-to-treat analysis was used.

A single high dose of vitamin D3 significantly increased the mean [SD] serum 25(OH)D levels in the vitamin D3 group (baseline: 7.7 [1.6] ng/mL; post: 31.7 [12.3] ng/mL) versus placebo (baseline: 7.9 [1.6] ng/mL; post: 7.8 [1.7] ng/mL) (between-group difference at post-intervention, 23.9 ng/mL [95% CI, 17.7-30.1]; p<0.001) (Figure 1).

Two patients in the vitamin D3 group (12.5%) and four patients in the placebo group (25.0%) were admitted to the intensive care unit during follow-up (between-group difference, -12.5% [95% CI, -39.2-14.2%]; p=0.65). None of the patients in the vitamin D3 group required mechanical ventilation versus one patient (6.3%) in the placebo group (p>0.99). There was no in-hospital mortality in the vitamin D3 group versus one death (6.3%) in the placebo group (p>0.99).

DISCUSSION

In this ancillary analysis including a subset of patients with moderate to severe COVID-19 and severe 25(OH)D deficiency, we showed that a single high dose of 200.000 IU of vitamin D3 resulted in an approximate four-fold increase in 25(OH)D levels but did not significantly reduce length of hospital stay, mortality, admission to intensive care unit, mechanical ventilation requirement, or other clinical outcomes. Despite the well-recognized role of vitamin D in the immune system (11. Bilezikian JP, Bikle D, Hewison M, Lazaretti-Castro M, Formenti AM, Gupta A, et al. MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19. Eur J Endocrinol. 2020;183(5):R133-R147. https://doi.org/10.1530/EJE-20-0665
https://doi.org/10.1530/EJE-20-0665...
), findings from observational studies are controversial concerning the association between vitamin D deficiency and COVID-19 severity (33. Carpagnano GE, Di Lecce V, Quaranta VN, Zito A, Buonamico E, Capozza E, et al. Vitamin D deficiency as a predictor of poor prognosis in patients with acute respiratory failure due to COVID-19. J Endocrinol Invest. 2021;44(4):765-71. https://doi.org/10.1007/s40618-020-01370-x
https://doi.org/10.1007/s40618-020-01370...
,55. Jevalikar G, Mithal A, Singh A, Sharma R, Farooqui KJ, Mahendru S, et al. Lack of association of baseline 25-hydroxyvitamin D levels with disease severity and mortality in Indian patients hospitalized for COVID-19. Sci Rep. 2021;11(1):6258. https://doi.org/10.1038/s41598-021-85809-y
https://doi.org/10.1038/s41598-021-85809...
). In addition, a recent systematic review including randomized controlled trials did not collate sufficient evidence to conclude that vitamin D supplementation benefits COVID-19 patients (1010. Stroehlein JK, Wallqvist J, Iannizzi C, Mikolajewska A, Metzendorf MI, Benstoem C, et al. Vitamin D supplementation for the treatment of COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021;5(5):CD015043. https://doi.org/10.1002/14651858.CD015043
https://doi.org/10.1002/14651858.CD01504...
). In the current study, the wide CIs for HR regarding length of hospital stay suggest that some patients may have benefited from the intervention, a hypothesis that needs to be tested by larger clinical trials involving severely 25(OH)D-deficient patients.

The strengths of this study include its randomized, controlled, double-blinded design, confirmation of the ability of the supplementation protocol to raise 25(OH)D levels, and assessment of patients before vaccination, which could be an important confounder affecting the clinical outcomes.

The limitations of this study were the small sample size, considering that this trial was not planned to evaluate severely 25(OH)D-deficient patients only, and the long time that elapsed from symptom onset to vitamin D3 administration (i.e., 8.6 days), which could mask potential early benefits evoked by this intervention.

CONCLUSION

A dose of 200.000 IU of vitamin D3 did not significantly reduce the length of hospital stay of hospitalized patients with COVID-19 presenting with severe 25(OH)D deficiency, although there was great heterogeneity in the responses likely associated with the low sample size. Further trials are warranted to test the efficacy of vitamin D3 supplementation, particularly as a pre- or post-exposure prophylaxis strategy, in patients with COVID-19 and severe 25(OH)D deficiency.

ACKNOWLEDGMENTS

The authors are thankful to Lucas P. Sales, MSc; Ana J. Pinto, BSc; Karla F. Goessler, PhD; Camila S. C. Duran, MD; Carla B. R. Silva, MD; André S. Franco, MD; Marina B. Macedo, MD. MSc; Henrique H. H. Dalmolin, MD; Janaina Baggio, MD; Guilherme G. M. Balbi, MD; Bruna Z. Reis, PhD; Valeria F. Caparbo, PhD, from the University of Sao Paulo; Monica Pinheiro, MD, MSc and Roberta Costa, MSc, both from Ibirapuera Field Hospital, for the assistance with the study; Cleuber Esteves Chaves, BSc, from pharmacy unit of the Clinical Hospital, for the vitamin D3 and placebo solution preparation; Rogério Ruscitto do Prado, PhD, from Albert Einstein Hospital for conducting the statistical analyses; all the staff members from both centers; and all the patients who participated in this study. None of the individuals described in this section received compensation for their participation in the study. Funding/Support: This study was supported by the Sao Paulo Research Foundation (FAPESP) (grants 20/05752-4; 19/24782-4; 20/11102-2) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (88887.507119/2020-00).

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    » https://doi.org/10.1038/s41430-020-0558-y
  • 10
    Stroehlein JK, Wallqvist J, Iannizzi C, Mikolajewska A, Metzendorf MI, Benstoem C, et al. Vitamin D supplementation for the treatment of COVID-19: a living systematic review. Cochrane Database Syst Rev. 2021;5(5):CD015043. https://doi.org/10.1002/14651858.CD015043
    » https://doi.org/10.1002/14651858.CD015043

Publication Dates

  • Publication in this collection
    26 Nov 2021
  • Date of issue
    2021

History

  • Received
    30 Sept 2021
  • Accepted
    20 Oct 2021
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