Vitamin D3 to Treat COVID-19 – Different Disease, Same Answer

Biological activity of vitamin D and its metabolites include, among other properties, potent antimicrobial and anti-inflammatory effects in vitro.1 In animal models, administration of vitamin D metabolites attenuates a variety of acute organ dysfunction, including acute lung injury.2 Observational data from patient cohorts support the potential therapeutic application of these findings.3 Specifically, lower circulating levels of vitamin D metabolites are independently associated with worse outcomes in patients with acute illness, including patients with coronavirus disease 2019 (COVID-19).4

These multiple lines of evidence in support of a potential therapeutic role for vitamin D generated enthusiasm over the past decade for testing whether administration of large doses of vitamin D might improve outcomes in various groups of patients, including those with critical illness.

The COVID-19 pandemic has spurred renewed interest in vitamin D to address viral replication and hyperinflammation that have a major role in the pathogenesis of severe COVID-19. In addition to known antimicrobial and anti-inflammatory effects, vitamin D metabolites also have direct action on angiotensin-converting enzyme 2 (ACE2), which serves as the cell surface entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 

In this issue of JAMA, Murai et al12 examine the therapeutic efficacy of vitamin D3 administration in patients with COVID-19. The authors enrolled 240 hospitalized patients with moderate to severe COVID-19 admitted to 2 hospitals in Brazil and randomly assigned them to receive a single dose of vitamin D3 (200 000 IU) or placebo

Administration of a high dose of vitamin D3 also did not appear to improve outcomes in the subgroup of 115 patients with vitamin D deficiency (25[OH]D <20 ng/mL) at randomization.

When this clinical trial is taken is isolation, the findings may appear ambiguous; that is, the findings do not exclude clinically important benefit (or harm) from high-dose vitamin D3 administration in hospitalized patients with moderate to severe COVID-19. In addition, this study did not address the use of vitamin D for patients with mild (outpatient) COVID-19 who are early in their symptom course or for use as prophylaxis against COVID-19.

Given the lack of highly effective therapies against COVID-19, except perhaps for corticosteroids, it is important to remain open-minded to emerging results from rigorously conducted studies of vitamin D (despite smaller sample sizes and important limitations of some studies). However, taken together with existing randomized clinical trials of vitamin D administration in hospitalized patients with respiratory infection and critical illness, the results reported by Murai et al12 do not support routine administration of vitamin D in hospitalized patients with moderate to severe COVID-19.

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.


Interventions  Patients were randomly assigned to receive a single oral dose of 200 000 IU of vitamin D3 (n = 120) or placebo (n = 120).

Results The difference between the vitamin Dgroup 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.

 

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.

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Ut elit tellus, luctus nec ullamcorper mattis, pulvinar dapibus leo.