Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data

Adrian R Martineau, David A Jolliffe, Richard L Hooper, Lauren Greenberg, John F Aloia, Peter Bergman, Gal Dubnov-Raz, Susanna Esposito, Davaasambuu Ganmaa, Adit A Ginde, Emma C Goodall, Cameron C Grant, Christopher J Griffiths, Wim Janssens, Ilkka Laaksi, Semira Manaseki-Holland, David Mauger, David R Murdoch, Rachel Neale, Judy R Rees, Steve Simpson Jr, Iwona Stelmach, Geeta Trilok Kumar, Mitsuyoshi Urashima, Carlos A Camargo Jr, Adrian R Martineau, David A Jolliffe, Richard L Hooper, Lauren Greenberg, John F Aloia, Peter Bergman, Gal Dubnov-Raz, Susanna Esposito, Davaasambuu Ganmaa, Adit A Ginde, Emma C Goodall, Cameron C Grant, Christopher J Griffiths, Wim Janssens, Ilkka Laaksi, Semira Manaseki-Holland, David Mauger, David R Murdoch, Rachel Neale, Judy R Rees, Steve Simpson Jr, Iwona Stelmach, Geeta Trilok Kumar, Mitsuyoshi Urashima, Carlos A Camargo Jr

Abstract

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare financial support for this work from the National Institute for Health Research under its Health Technology Assessment programme. No author has had any financial relationship with any organisations that might have an interest in the submitted work in the previous three years. No author has had any other relationship, or undertaken any activity, that could appear to have influenced the submitted work.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5310969/bin/mara034434.f1_default.jpg
Fig 1 Flow of study selection. IPD=individual participant data
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/5310969/bin/mara034434.f2_default.jpg
Fig 2 Two step individual participant data meta-analysis: proportion of participants experiencing at least one acute respiratory tract infection (ARTI). Data from trial by Simpson et al were not included in this two step meta-analysis, as an estimate for the effect of the intervention in the study could not be obtained in the regression model owing to small sample size

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