Background:

Randomised controlled trials (RCTs) exploring the potential of vitamin D to prevent acute respiratory infections have yielded mixed results. Individual participant data (IPD) meta-analysis has the potential to identify factors that may explain this heterogeneity.

Objectives:

To assess the overall effect of vitamin D supplementation on the risk of acute respiratory infections (ARIs) and to identify factors modifying this effect.

Data sources:

MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, ClinicalTrials.gov and the International Standard Randomised Controlled Trials Number (ISRCTN) registry.

Study selection:

Randomised, double-blind, placebo-controlled trials of supplementation with vitamin D₃ or vitamin D₂ of any duration having incidence of acute respiratory infection as a prespecified efficacy outcome were selected.

Study appraisal:

Study quality was assessed using the Cochrane Collaboration Risk of Bias tool to assess sequence generation, allocation concealment, blinding of participants, personnel and outcome assessors, completeness of outcome data, evidence of selective outcome reporting and other potential threats to validity.

Results:

We identified 25 eligible RCTs (a total of 11,321 participants, aged from 0 to 95 years). IPD were obtained for 10,933 out of 11,321 (96.6%) participants. Vitamin D supplementation reduced the risk of ARI among all participants [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.81 to 0.96; heterogeneity p < 0.001]. Subgroup analysis revealed that protective effects were seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI 0.72 to 0.91), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI 0.86 to 1.10; p = 0.05). Among those receiving daily or weekly vitamin D, protective effects of vitamin D were stronger in individuals with a baseline 25-hydroxyvitamin D [25(OH)D] concentration of < 25 nmol/l (aOR 0.30, 95% CI 0.17 to 0.53) than in those with a baseline 25(OH)D concentration of ≥ 25 nmol/l (aOR 0.75, 95% CI 0.60 to 0.95; p = 0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI 0.80 to 1.20; p = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.

Limitations:

Our study had limited power to detect the effects of vitamin D supplementation on the risk of upper versus lower respiratory infection, analysed separately.

Conclusions:

Vitamin D supplementation was safe, and it protected against ARIs overall. Very deficient individuals and those not receiving bolus doses experienced the benefit. Incorporation of additional IPD from ongoing trials in the field has the potential to increase statistical power for analyses of secondary outcomes.

Study registration:

This study is registered as PROSPERO CRD42014013953.

Funding:

The National Institute for Health Research Health Technology Assessment programme.

Article history

The research reported in this issue of the journal was funded by the HTA programme as project number 13/03/25. The contractual start date was in October 2014. The draft report began editorial review in January 2017 and was accepted for publication in October 2017. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Susanna Esposito reports grants and personal fees from GlaxoSmithKline (GSK) plc (GSK House, Middlesex, UK), grants and personal fees from Pfizer Inc. (New York, NY, USA), grants and personal fees from Sanofi Pasteur MSD [Sanofi Pasteur (Lyon France) and Merck Sharp & Dohme Corp. (MSD, Kenilworth, NJ, USA)], grants from DuPage Medical Group (DMG, Downers Grove, IL, USA), personal fees from Valeas S.p.A. (Milan, Italy), and grants and personal fees from Vifor Pharma (Bern, Switzerland), outside the submitted work. Emma Goodall reports personal fees from GSK outside the submitted work. Wim Janssens reports grants from Instituut voor Innovatie door Wetenschap en Technologie (IWT)–Vlaanderen and from Laboratoires SMB (Brussels, Belgium) during the conduct of the study. David Mauger reports funding from the National Heart, Lung, and Blood Institute, MA, USA. Rachel Neale reports grants from the National Institutes of Health and the Medical Research Council during the conduct of the study. Judy R Rees reports that a use patent is held by Dartmouth College and Dr John A Baron for calcium as a chemopreventive agent. Dr Baron is not an author on this paper but is the principal investigator of the parent study from which the study by Rees (Rees JR, Hendricks K, Barry EL, Peacock JL, Mott LA, Sandler RS, et al. Vitamin D₃ supplementation and upper respiratory tract infections in a randomized, controlled trial. Clin Infect Dis 2013;57:1384–92) was conducted. The patent was previously licensed by Pfizer (with royalties), but has not been licensed for about 5 years. Judy R Rees is not involved in the patent and the patent does not involve vitamin D.