Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of stratified aggregate data

Abstract

Background: A 2021 meta-analysis of 37 randomised controlled trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARIs) revealed a statistically significant protective effect of the intervention (odds ratio [OR] 0·92 [95% CI 0·86 to 0·99]). Since then, six eligible RCTs have been completed, including one large trial (n=15 804). We aimed to re-examine the link between vitamin D supplementation and prevention of ARIs.

Methods: Updated systematic review and meta-analysis of data from RCTs of vitamin D for ARI prevention using a random effects model. Subgroup analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, dosing regimen, or age. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov between May 1, 2020 (end-date of search of our previous meta-analysis) and April 30, 2024. No language restrictions were imposed. Double-blind RCTs supplementing vitamin D for any duration, with placebo or lower-dose vitamin D control, were eligible if approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. The study was registered with PROSPERO (no. CRD42024527191).

Findings: We identified six new RCTs (19 337 participants). Data were obtained for 16 085 (83·2%) participants in three new RCTs and combined with data from 48 488 participants in 43 RCTs identified in our previous meta-analysis. For the primary comparison of any vitamin D versus placebo, the intervention did not statistically significantly affect overall ARI risk (OR 0·94 [95% CI 0·88-1·00], p=0·057; 40 studies; 61 589 participants; I²=26·4%). Pre-specified subgroup analysis did not reveal evidence of effect modification by age, baseline vitamin D status, dosing frequency, or dose size. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0·96 [95% CI 0·90-1·04]; 38 studies; I²=0·0%). A funnel plot showed left-sided asymmetry (p=0·0020, Egger's test).

Interpretation: This updated meta-analysis yielded a similar point estimate for the overall effect of vitamin D supplementation on ARI risk to that obtained previously, but the 95% CI for this effect estimate now includes 1·00, indicating no statistically significant protection.

Funding: None.

Figure 1:. Study selection.

ARI=acute respiratory infection.

Figure 2:. Forest plot of placebo-controlled RCTs reporting proportion of participants experiencing one or more acute respiratory infection

Weights are from random effects analysis. The numerator is the number of participants who reported an ARI on at least one survey. The ARI outcomes for participants who completed fewer than five surveys and who did not report an ARI (N=2239; 14%) were estimated based on the percent affected among those who completed all five surveys (N=12 152; 76%). ARI=acute respiratory infection. RCT=randomised controlled trial. *Proportions for this trial were corrected for cluster randomisation using the calculated design effect of 3·49. †This analysis includes data from the subset of ViDiFlu trial participants who were randomised to vitamin D versus placebo control; correction for cluster randomisation was not possible due to the lack of power. ‡For this trial, participants were asked to report the occurrence of ARI during the one month prior to completing each annual survey (max surveys=5).