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Health Technol Assess. 2019 Jan;23(2):1-44. doi: 10.3310/hta23020.

Vitamin D supplementation to prevent acute respiratory infections: individual participant data meta-analysis.

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Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Asthma UK Centre for Applied Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA.
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Deptartment of Exercise, Lifestyle and Nutrition Clinic, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel.
Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada.
Department of Paediatrics: Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Universitaire ziekenhuizen Leuven, Leuven, Belgium.
Centre for Asthma and Respiratory Diseases, University of Newcastle, Newcastle, NSW, Australia.
Dublin City University, Dublin, Ireland.
Centre for Military Medicine, Finnish Defense Forces, University of Tampere, Tampere, Finland.
Department of Public Health, Epidemiology and Biostatistics, Institute of Applied Health Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Department of Statistics, The Pennsylvania State University, Hershey, PA, USA.
Department of Pathology, University of Otago, Christchurch, New Zealand.
Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
Department of Pediatrics and Allergy, Medical University of Łódź, Łódź, Poland.
Institute of Home Economics, University of Delhi, New Delhi, India.
Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan.
Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Medical Research Council and Asthma UK Centre in Allergic Mechanisms of Asthma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.



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.


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


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


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 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.


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.


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


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.


This study is registered as PROSPERO CRD42014013953.


The National Institute for Health Research Health Technology Assessment programme.

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Conflict of interest statement

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.

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