Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of stratified aggregate data
Authors: Jolliffe David A , Camargo Carlos A , Sluyter John D , Aglipay Mary , Aloia John F , Bergman Peter , Bischoff-Ferrari Heike A. , Borzutzky Arturo , Bubes Vadim Y , Damsgaard Camilla T , Ducharme Francine , Dubnov-Raz Gal , Esposito Susanna , Ganmaa Davaasambuu , Gilham Clare , Ginde Adit A , Golan-Tripto Inbal , Goodall Emma C , Grant Cameron C , Griffiths Christopher J , Hibbs Anna Maria , Janssens Wim , Khadilkar Anuradha Vaman , Laaksi Ilkka , Lee Margaret T , Loeb Mark , Maguire Jonathon L , Majak Paweł , Manaseki-Holland Semira , Manson JoAnn E , Mauger David T , Murdoch David R , Nakashima Akio , Neale Rachel E , Pham Hai , Rake Christine , Rees Judy R , Rosendahl Jenni , Scragg Robert , Shah Dheeraj , Shimizu Yoshiki , Simpson-Yap Steve , Trilok Kumar Geeta , Urashima Mitsuyoshi , Martineau Adrian R 
Published: September 2024

ABSTRACTBackgroundA 2021 meta-analysis of 37 randomised controlled trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARI) revealed a statistically significant protective effect of the intervention (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.86 to 0.99). Since then, 6 eligible RCTs have completed, including one large trial (n=15,804).MethodsUpdated systematic review and meta-analysis of data from RCTs of vitamin D for ARI prevention using a random effects model. Sub-group 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 were searched between May 2020 (previous search) and April 2024. No language restrictions were imposed. Double-blind RCTs supplementing vitamin D for any duration, with placebo or low-dose vitamin D control, were eligible if approved by 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).FindingsWe identified 6 new RCTs (19,337 participants). Data were obtained for 16,086 (83.2%) participants in 3 new RCTs and combined with data from 48,488 participants in 43 previously identified RCTs. For the primary comparison of any vitamin D vs. placebo, the intervention did not significantly affect overall ARI risk (OR 0.94, 95% CI 0.88 to 1.00, P=0.057; 40 studies; I226.4%). Pre-specified subgroup analysis did not reveal evidence of effect modification by age, baseline vitamin D status, or dosing regimen. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.96, 95% CI 0.90 to 1.04; 38 studies; I20.0%). A funnel plot showed left-sided asymmetry (P=0.002, Egger’s test).InterpretationThis 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 spans 1.00, indicating no statistically significant protection.FundingNoneResearch in contextEvidence before this studyWe searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from 1stMay 2020 (date of our previous search) to 30thApril 2024 for randomised Controlled Trials and meta-analyses of randomised Controlled Trials evaluating effectiveness of vitamin D supplementation for the prevention of acute respiratory infections. Our previous meta-analysis of 43 randomised Controlled Trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARI) conducted in 2021 revealed a statistically significant protective effect of the intervention (OR 0.92, 95% CI 0.86 to 0.99). A further 6 eligible RCTs, contributing data from 19,337 participants have now completed, including one large trial (n=15,804).Added value of this studyOur meta-analysis of aggregate data from 64,086 participants in 46 randomised controlled trials, stratified by baseline 25(OH)D concentration and age, provides an updated estimate of the protective effects of vitamin D against acute respiratory infection overall (OR 0.94, 95% CI 0.88 to 1.00), and in sub-groups defined by baseline vitamin D status, age, and dosing frequency, amount and duration.Implications of all the available evidenceUpdated meta-analysis including the latest available RCT data shows no statistically significant protective effect of vitamin D supplementation against ARI, either overall or in sub-group analyses.