Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant dataBMJ 2017; 356 doi: https://doi.org/10.1136/bmj.i6583 (Published 15 February 2017) Cite this as: BMJ 2017;356:i6583
- Adrian R Martineau, professor of respiratory infection and immunity1 2,
- David A Jolliffe, postdoctoral research fellow1,
- Richard L Hooper, reader in medical statistics1,
- Lauren Greenberg, medical statistician1,
- John F Aloia, professor of medicine3,
- Peter Bergman, associate professor4,
- Gal Dubnov-Raz, consultant paediatrician5,
- Susanna Esposito, professor of paediatrics6,
- Davaasambuu Ganmaa, assistant professor7,
- Adit A Ginde, professor of emergency medicine8,
- Emma C Goodall, assistant professor9,
- Cameron C Grant, associate professor10,
- Christopher J Griffiths, professor of primary care1 2 11,
- Wim Janssens, professor of pneumonology12,
- Ilkka Laaksi, chief administrative medical officer13,
- Semira Manaseki-Holland, senior clinical lecturer14,
- David Mauger, professor of public health sciences and statistics15,
- David R Murdoch, professor of pathology16,
- Rachel Neale, associate professor17,
- Judy R Rees, assistant professor18,
- Steve Simpson Jr, postdoctoral research fellow19,
- Iwona Stelmach, professor of paediatric allergy20,
- Geeta Trilok Kumar, associate professor21,
- Mitsuyoshi Urashima, professor of molecular epidemiology22,
- Carlos A Camargo Jr, professor of emergency medicine, medicine, and epidemiology23
- 1Centre for Primary Care and Public Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AB, UK
- 2Asthma UK Centre for Applied Research, Blizard Institute, Queen Mary University of London, London, UK
- 3Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA
- 4Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- 5Department of Exercise, Lifestyle and Nutrition Clinic, Edmond and Lily Safra Children’s Hospital, Tel Hashomer, Israel
- 6Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
- 7Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
- 8Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA
- 9Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
- 10Department of Paediatrics: Child & Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- 11MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Blizard Institute, Queen Mary University of London, London, UK
- 12Universitair ziekenhuis Leuven, Leuven, Belgium
- 13Tampere School of Public Health, University of Tampere, Tampere, Finland
- 14Department of Public Health, Epidemiology and Biostatistics, Institute of Applied Health Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- 15Department of Statistics, The Pennsylvania State University, Hershey, PA, USA
- 16Department of Pathology, University of Otago, Christchurch, New Zealand
- 17QIMR Berghofer Medical Research Institute, Queensland, Australia
- 18Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
- 19Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
- 20Department of Pediatrics and Allergy, Medical University of Lodz, Lodz, Poland
- 21Institute of Home Economics, University of Delhi, New Delhi, India
- 22Division of Molecular Epidemiology, Jikei University School of Medicine, Tokyo, Japan
- 23Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
- Correspondence to: A R Martineau
- Accepted 1 December 2016
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.
We thank the participants in the primary randomised controlled trials; the teams who conducted the trials; our patient and public involvement representatives Charanjit Patel and Jane Gallagher for comments on study design and drafts of this manuscript; and Khalid S Khan, Queen Mary University of London, for valuable advice and helpful discussions.
Contributors: ARM led the funding application, with input from RLH, CJG, and CAC who were co-applicants. ARM, DAJ, and CAC assessed eligibility of studies for inclusion. ARM, JFA, PB, GD-R, SE, DG, AAG, ECG, CCG, WJ, IL, SM-H, DM, DRM, RN, JRR, SS, IS, GTK, MU, and CAC were all directly involved in the acquisition of data for the work. RLH, LG, ARM, and DAJ designed the statistical analyses in consultation with authors contributing individual patient data. Statistical analyses were done by LG, RLH, and DAJ. ARM wrote the first draft of the report. He is the guarantor. All authors revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved.
Funding: This study was supported by a grant from the National Institute for Health Research (NIHR) under its Health Technology Assessment programme (reference No 13/03/25, to ARM). The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health. See the supplementary material for details of sources of support for individual investigators and trials. The NIHR was not involved in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
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.
Ethical approval: Not required.
Data sharing: A partial dataset, incorporating patient level data from trials for which the relevant permissions for data sharing have been obtained, is available from the corresponding author at email@example.com.
Transparency: The manuscript’s guarantor (ARM) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported and that no important aspects of the study have been omitted. All analyses were prespecified in the study protocol, other than those presented in tables 3 and 5, which were conducted in response to a reviewer’s request.
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