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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 Correction of Vitamin D Deficiency in Critically Ill Patients (VITdAL-ICU) study was a multicenter randomized clinical trial that tested the effect of vitamin D3 administration (540 000 IU) vs placebo in 475 critically ill patients with vitamin D deficiency, defined as 25-hydroxyvitamin D (25[OH]D) less than or equal to 20 ng/mL. The primary end point, hospital length of stay, was similar between the groups, although hospital mortality (a secondary end point) was lower in patients who received vitamin D3 vs placebo among those with severe vitamin D deficiency (defined as 25[OH]D ≤12 ng/mL).5 The Vitamin D to Improve Outcomes by Leveraging Early Treatment (VIOLET) trial sought to examine the effect of the same dose of vitamin D3 (540 000 IU) vs placebo on 90-day mortality in 3000 critically ill patients with vitamin D deficiency, but was stopped early for futility after enrollment of 1360 patients demonstrated very low likelihood for benefit.6 Randomized clinical trials testing vitamin D3 administration as a therapeutic strategy for disease prevention in other settings have yielded similarly null results.7-9
Leaf DE, Ginde AA. Vitamin D3 to Treat COVID-19: Different Disease, Same Answer. JAMA. 2021;325(11):1047–1048. doi:10.1001/jama.2020.26850
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