Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials
Authors: Jolliffe David A , Camargo Carlos A , Sluyter John D , Aglipay Mary , Aloia John F , Ganmaa Davaasambuu , Bergman Peter , Borzutzky Arturo , Damsgaard Camilla T , Dubnov-Raz Gal , Esposito Susanna , 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 , Mauger David T , Manaseki-Holland Semira , 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 , Kumar Geeta Trilok , Urashima Mitsuyoshi , Martineau Adrian R 
Published: July 2020

Background

A 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory infections revealed a protective effect of the intervention. Since then, 20 new RCTs have been completed.

Methods

Systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified 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 or dosing regimen. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from inception to 1st May 2020. Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were 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, were obtained from study authors. The study was registered with PROSPERO (no. CRD42020190633).

Findings

We identified 45 eligible RCTs (total 73,384 participants). Data were obtained for 46,331 (98.0%) of 47,262 participants in 42 studies, aged 0 to 95 years. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.91, 95% CI 0.84 to 0.99; P for heterogeneity 0.01). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of ≤12 months (OR 0.82, 95% CI 0.72 to 0.93). No significant interaction was seen between allocation to vitamin D vs. placebo and dose frequency, dose size, or study duration. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI 0.86 to 1.09). Risk of bias within individual studies was assessed as being low for all but three trials. A funnel plot showed left-sided asymmetry (P=0.008, Egger’s test).

Interpretation

Vitamin D supplementation was safe and reduced risk of ARI, despite evidence of significant heterogeneity across trials. Protection was associated with administration of daily doses of 400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not known and requires investigation.

Funding

None