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

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

Journal: BMJ (Clinical research ed.) 2017;356():i6583

PMID: 28202713

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Plain Language Summary

Acute respiratory tract infections are responsible for more than 2.5 million deaths worldwide. Previous studies report consistent associations between low vitamin D levels and an increased risk of acute respiratory tract infection. Vitamin D may protect against respiratory pathogens of viral and bacterial origin, due to antimicrobial and other mechanisms. This paper is a systematic review and meta-analysis of 25 randomised double-blind placebo controlled trials of vitamin D supplementation for the prevention of acute respiratory tract infection. The trials were conducted in 14 countries in 4 continents and included a total of 11,321 participants of both sexes, aged 0-95 years. The follow-up durations ranged from seven weeks to 1.5 years. All studies administered vitamin D3 orally, using either daily or weekly doses or bolus doses 1-3 months apart, or combined daily and bolus doses. Individual participant data were obtained from 96.6% of participants. The majority of studies that were included in the analyses were considered to be of a high quality, with a low risk of bias. The analyses showed that vitamin D supplementation reduced the risk of acute respiratory tract infections among all participants. The strongest positive effects were seen in those with baseline vitamin D levels less than 25 nmol/l, when compared to those with levels higher than 25 nmol/l, although benefits were also seen in the latter. Furthermore, daily or weekly vitamin D supplementation, without additional bolus doses were shown to protect against acute respiratory tract infections, while regimens with large bolus doses did not. The authors concluded that people who are very deficient in vitamin D are most likely to benefit from daily or weekly vitamin D supplementation, without additional bolus doses, in the prevention of acute respiratory tract infections. They call for the introduction of public health measures, such as food fortification, to improve vitamin D status, particularly in settings where vitamin D deficiency is common.

Abstract

To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect. Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials. 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. Randomised, double blind, placebo controlled trials of supplementation with vitamin D or vitamin D 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. 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. 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. PROSPERO CRD42014013953.

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Address: Centre 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 [email protected].; Asthma UK Centre for Applied Research, Blizard Institute, Queen Mary University of London, London, UK.; Centre 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.; Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA.; Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.; Department 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, Ontario, Canada.; Department of Paediatrics: Child & Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Blizard Institute, Queen Mary University of London, London, UK.; Universitair ziekenhuis Leuven, Leuven, Belgium.; Tampere School of Public Health, 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.; QIMR Berghofer Medical Research Institute, Queensland, Australia.; Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.; Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia.; Department of Pediatrics and Allergy, Medical University of Lodz, Lodz, 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.

DOI: 10.1136/bmj.i6583