Effects of Vitamin D Supplementation on COVID-19 Related Outcomes: A Systematic Review and Meta-Analysis

May 2022
Citations:73
Influential Citations:1
Systematic Reviews / Meta-Analyses
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Methods
Systematic review and meta-analysis. Included nine randomized controlled trials and fourteen non-randomized intervention studies in adults (≥18 years; one study included participants over 15). Primary prevention (uninfected individuals), secondary prevention (asymptomatic/mild COVID-19 outpatients), and tertiary prevention (hospitalized COVID-19 patients) contexts. Total participants: 1,548 in RCTs (873 intervention, 675 control) and 5,868,641 in NRISs (9,764 intervention, 5,858,877 control). Countries across multiple regions.
Intervention
Vitamin D supplementation regimens included oral vitamin D3 (cholecalciferol) and active vitamin D forms (calcitriol, calcifediol), delivered as bolus, daily, or monthly dosing across primary, secondary, and tertiary prevention contexts. Examples: bolus 100,000 IU followed by 10,000 IU/week; daily regimens up to 10,000 IU/day for 7–14 days; bolus doses ranging 50,000–300,000 IU; single bolus 80,000 IU; monthly 50,000 IU; complex schedules such as 21,620 IU on day 1 and 10,810 IU on day 3 with additional doses on days 7, 15 and 30; 21,280 IU/day on days 1, 3 and 7 with weekly continuation; intramuscular 300,000 IU; durations from 2 weeks to 1 month; some studies used calcifediol or calcitriol.
Results
Primary prevention: Vitamin D supplementation did not significantly reduce risk of SARS-CoV-2 infection (RR 0.91; 95% CI 0.81–1.02; I2=0). Secondary prevention: insufficient data for hospitalization outcomes; one NRIS reported no significant effect on hospital admission (adjusted OR 1.30; 95% CI 0.51–3.32). Tertiary prevention (hospitalized patients): mortality reduced (RR 0.52; 95% CI 0.36–0.75; I2=54%) and ICU admission reduced (RR 0.35; 95% CI 0.20–0.62; I2=75%). Overall, mortality benefit (RR 0.52; 95% CI 0.36–0.75) was observed in tertiary prevention with some heterogeneity. Subgroup analyses suggested greater benefits with non-bolus regimens for mortality (RR 0.37) vs bolus (RR 0.69; p=0.04) and for ICU (non-bolus RR 0.22 vs bolus RR 0.71; p<0.001). Benefits were more evident when baseline 25(OH)D ≥25 nmol/L. Safety signals were minimal; no major vitamin D toxicity reported. Authors conclude vitamin D may improve outcomes in hospitalized COVID-19 but provide insufficient evidence for infection prevention or mild disease prevention; more high-quality trials needed.
Limitations
High heterogeneity across studies (e.g., ICU mortality I2 up to 82%); reliance on non-randomized studies with risk of bias; wide variation in dosing regimens and populations; incomplete reporting for some outcomes; potential publication bias suggested by funnel plots; results not generalizable to children or younger adolescents; limited randomized evidence to define optimal dosing or regimen.

Abstract

The COVID-19 outbreak has rapidly expanded to a global pandemic; however, our knowledge is limited with regards to the protective factors against this infection. The aim of this systematic literature review and meta-analysis was to evaluate the impac...