Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study

Giannini et al., Nutrients, doi:10.3390/nu13010219

Jan 2021

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Retrospective 91 hospitalized patients, 36 treated with high-dose cholecalciferol, showing lower combined death/ICU admission with treatment.

Authors also analyze the relationship with comorbidity burden, finding that the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden.

Cholecalciferol was used in this study. Meta analysis shows that late stage treatment with calcitriol / calcifediol (or paricalcitol, alfacalcidol, etc.) is more effective than cholecalciferol: 65% [41‑79%] lower risk vs. 38% [25‑49%] lower risk. Cholecalciferol requires two hydroxylation steps to become activated - first in the liver to calcifediol, then in the kidney to calcitriol. Calcitriol, paricalcitol, and alfacalcidol are active vitamin D analogs that do not require conversion. This allows them to have more rapid onset of action compared to cholecalciferol. The time delay for cholecalciferol to increase serum calcifediol levels can be 2-3 days, and the delay for converting calcifediol to active calcitriol can be up to 7 days.

This is the 17th of 116 COVID-19 controlled studies for vitamin D, which collectively show efficacy with p<0.0000000001 (1 in 38 sextillion). 28 studies are RCTs, which show efficacy with p=0.0000081.

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risk of death/ICU, 36.6% lower, RR 0.63, p = 0.13, treatment 14 of 36 (38.9%), control 29 of 55 (52.7%), NNT 7.2, odds ratio converted to relative risk.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

Giannini et al., 14 Jan 2021, retrospective, Italy, peer-reviewed, 21 authors, dosage 200,000IU days 1-2.

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Effectiveness of In-Hospital Cholecalciferol Use on Clinical Outcomes in Comorbid COVID-19 Patients: A Hypothesis-Generating Study

Sandro Giannini, Giovanni Passeri, Giovanni Tripepi, Stefania Sella, Maria Fusaro, Gaetano Arcidiacono, Marco Onofrio Torres, Alberto Michielin, Tancredi Prandini, Valeria Baffa, Andrea Aghi, Colin Gerard Egan, Martina Brigo, Martina Zaninotto, Mario Plebani, Roberto Vettor, Paola Fioretto, Maurizio Rossini, Alessandro Vignali, Fabrizio Fabris, Francesco Bertoldo

Nutrients, doi:10.3390/nu13010219

Little information is available on the beneficial effects of cholecalciferol treatment in comorbid patients hospitalized for COVID-19. The aim of this study was to retrospectively examine the clinical outcome of patients receiving in-hospital high-dose bolus cholecalciferol. Patients with a positive diagnosis of SARS-CoV-2 and overt COVID-19, hospitalized from 15 March to 20 April 2020, were considered. Based on clinical characteristics, they were supplemented (or not) with 400,000 IU bolus oral cholecalciferol (200,000 IU administered in two consecutive days) and the composite outcome (transfer to intensive care unit; ICU and/or death) was recorded. Ninety-one patients (aged 74 ± 13 years) with COVID-19 were included in this retrospective study. Fifty (54.9%) patients presented with two or more comorbid diseases. Based on the decision of the referring physician, 36 (39.6%) patients were treated with vitamin D. Receiver operating characteristic curve analysis revealed a significant predictive power of the four variables: (a) low (<50 nmol/L) 25(OH) vitamin D levels, (b) current cigarette smoking, (c) elevated D-dimer levels (d) and the presence of comorbid diseases, to explain the decision to administer vitamin D (area under the curve = 0.77, 95% CI: 0.67-0.87, p < 0.0001). Over the follow-up period (14 ± 10 days), 27 (29.7%) patients were transferred to the ICU and 22 (24.2%) died (16 prior to ICU and six in ICU). Overall, 43 (47.3%) patients experienced the combined endpoint of transfer to ICU and/or death. Logistic regression analyses revealed that the comorbidity burden significantly modified the effect of vitamin D treatment on the study outcome, both in crude (p = 0.033) and propensity score-adjusted analyses (p = 0.039), so the positive effect of high-dose cholecalciferol on the combined endpoint was significantly amplified with increasing comorbidity burden. This hypothesis-generating study warrants the formal evaluation (i.e., clinical trial) of the potential benefit that cholecalciferol can offer in these comorbid COVID-19 patients.

Supplementary Materials: The following are available online at https://www.mdpi.com/2072-6 643/13/1/219/s1, Figure S1 : Kaplan-Meier survival curve of in-hospital mortality in vitamin Dtreated and untreated patients, Figure S2 : Kaplan-Meier survival curves of the effect modification by comorbidity burden on the effectiveness of vitamin D treatment for the combined endpoint (death/ICU transfer). Author Contributions: All authors contributed to data analysis, drafting and revising the article. All authors have read and agreed to the published version of the manuscript.

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