Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of aggregate data from randomised controlled trials

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

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.