Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials

David A Jolliffe; Carlos A Camargo Jr; John D Sluyter; Mary Aglipay; John F Aloia; Davaasambuu Ganmaa; Peter Bergman; Heike A Bischoff-Ferrari; Arturo Borzutzky; Camilla T Damsgaard; Gal Dubnov-Raz; Susanna Esposito; Clare Gilham; Adit A Ginde; Inbal Golan-Tripto; Emma C Goodall; Cameron C Grant; Christopher J Griffiths; Anna Maria Hibbs; Wim Janssens; Anuradha Vaman Khadilkar; Ilkka Laaksi; Margaret T Lee; Mark Loeb; Jonathon L Maguire; Paweł Majak; David T Mauger; Semira Manaseki-Holland; David R Murdoch; Akio Nakashima; Rachel E Neale; Hai Pham; Christine Rake; Judy R Rees; Jenni Rosendahl; Robert Scragg; Dheeraj Shah; Yoshiki Shimizu; Steve Simpson-Yap; Geeta Trilok-Kumar; Mitsuyoshi Urashima; Adrian R Martineau

doi:10.1016/S2213-8587(21)00051-6

Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials

Lancet Diabetes Endocrinol. 2021 May;9(5):276-292. doi: 10.1016/S2213-8587(21)00051-6. Epub 2021 Mar 30.

Authors

David A Jolliffe¹, Carlos A Camargo Jr², John D Sluyter³, Mary Aglipay⁴, John F Aloia⁵, Davaasambuu Ganmaa⁶, Peter Bergman⁷, Heike A Bischoff-Ferrari⁸, Arturo Borzutzky⁹, Camilla T Damsgaard¹⁰, Gal Dubnov-Raz¹¹, Susanna Esposito¹², Clare Gilham¹³, Adit A Ginde¹⁴, Inbal Golan-Tripto¹⁵, Emma C Goodall¹⁶, Cameron C Grant¹⁷, Christopher J Griffiths¹⁸, Anna Maria Hibbs¹⁹, Wim Janssens²⁰, Anuradha Vaman Khadilkar²¹, Ilkka Laaksi²², Margaret T Lee²³, Mark Loeb²⁴, Jonathon L Maguire⁴, Paweł Majak²⁵, David T Mauger²⁶, Semira Manaseki-Holland²⁷, David R Murdoch²⁸, Akio Nakashima²⁹, Rachel E Neale³⁰, Hai Pham³⁰, Christine Rake¹³, Judy R Rees³¹, Jenni Rosendahl³², Robert Scragg³, Dheeraj Shah³³, Yoshiki Shimizu³⁴, Steve Simpson-Yap³⁵, Geeta Trilok-Kumar³⁶, Mitsuyoshi Urashima²⁹, Adrian R Martineau³⁷

Affiliations

¹ Barts and The London School of Medicine and Dentistry, and Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK. Electronic address: d.a.jolliffe@qmul.ac.uk.
² Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ School of Population Health, University of Auckland, Auckland, New Zealand.
⁴ Department of Pediatrics, St Michael's Hospital, Toronto, ON, Canada.
⁵ Bone Mineral Research Center, Winthrop University Hospital, Mineola, NY, USA.
⁶ Department of Nutrition, Harvard TH Chan Shool of Public Health, Boston, MA, USA.
⁷ Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
⁸ Department of Geriatric Medicine and Aging Research, University Hospital Zurich, Zurich, Switzerland.
⁹ Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
¹⁰ Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg, Denmark.
¹¹ Exercise, Lifestyle and Nutrition Clinic, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel.
¹² Paediatric Clinic, Department of Medicine and Surgery, University of Parma, Parma, Italy.
¹³ Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK.
¹⁴ Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁵ Saban Pediatric Medical Center, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.
¹⁶ Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.
¹⁷ Department of Paediatrics: Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
¹⁸ Barts and The London School of Medicine and Dentistry, and Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK.
¹⁹ Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
²⁰ Universitair Ziekenhuis Leuven, Leuven, Belgium.
²¹ Hirabai Cowasji Jehangir Medical Research Institute, Maharashtra, India.
²² Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland; Centre for Military Medicine, Helsinki, Finland.
²³ Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University Medical Center, New York, NY USA.
²⁴ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
²⁵ Department of Pediatric Pulmonology, Medical University of Lodz, Lodz, Poland.
²⁶ Department of Statistics, The Pennsylvania State University, Hershey, PA, USA.
²⁷ Department of Public Health, Epidemiology and Biostatistics, Institute of Applied Health Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
²⁸ Department of Pathology, University of Otago, Christchurch, New Zealand.
²⁹ Jikei University School of Medicine, Tokyo, Japan.
³⁰ Population Health Department, QIMR Berghofer Medical Research Institute, QLD, Australia.
³¹ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
³² Children's Hospital, Pediatric Research Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³³ Department of Paediatrics, University College of Medical Sciences, Delhi, India.
³⁴ FANCL Research Institute, FANCL Corporation, Yokohama, Japan.
³⁵ Neuroepidemiology Unit, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
³⁶ Institute of Home Economics, University of Delhi, New Delhi, India.
³⁷ Barts and The London School of Medicine and Dentistry, and Asthma UK Centre for Applied Research, Queen Mary University of London, London, UK. Electronic address: a.martineau@qmul.ac.uk.

PMID: 33798465
DOI: 10.1016/S2213-8587(21)00051-6

Abstract

Background: A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis.

Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry for studies listed from database inception to May 1, 2020. Double-blind RCTs of vitamin D₃, vitamin D₂, or 25-hydroxyvitamin D (25[OH]D) supplementation for any duration, with a placebo or low-dose vitamin D control, were eligible if they had been approved by a research ethics committee, and if ARI incidence was collected prospectively and prespecified as an efficacy outcome. Studies reporting results of long-term follow-up of primary RCTs were excluded. Aggregated study-level data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. Using the proportion of participants in each trial who had one or more ARIs, we did a random-effects meta-analysis to obtain pooled odds ratios (ORs) and 95% CIs to estimate the effect of vitamin D supplementation on the risk of having one or more ARIs (primary outcome) compared with placebo. Subgroup analyses were done to estimate whether the effects of vitamin D supplementation on the risk of ARI varied according to baseline 25(OH)D concentration (<25 nmol/L vs 25·0-49·9 nmol/L vs 50·0-74·9 nmol/L vs >75·0 nmol/L), vitamin D dose (daily equivalent of <400 international units [IU] vs 400-1000 IU vs 1001-2000 IU vs >2000 IU), dosing frequency (daily vs weekly vs once per month to once every 3 months), trial duration (≤12 months vs >12 months), age at enrolment (<1·00 years vs 1·00-15·99 years vs 16·00-64·99 years vs ≥65·00 years), and presence versus absence of airway disease (ie, asthma only, COPD only, or unrestricted). Risk of bias was assessed with the Cochrane Collaboration Risk of Bias Tool. The study was registered with PROSPERO, CRD42020190633.

Findings: We identified 1528 articles, of which 46 RCTs (75 541 participants) were eligible. Data for the primary outcome were obtained for 48 488 (98·1%) of 49 419 participants (aged 0-95 years) in 43 studies. A significantly lower proportion of participants in the vitamin D supplementation group had one or more ARIs (14 332 [61·3%] of 23 364 participants) than in the placebo group (14 217 [62·3%] of 22 802 participants), with an OR of 0·92 (95% CI 0·86-0·99; 37 studies; I²=35·6%, p_{heterogeneity}=0·018). No significant effect of vitamin D supplementation on the risk of having one or more ARIs was observed for any of the subgroups defined by baseline 25(OH)D concentration. However, protective effects of supplementation were observed in trials in which vitamin D was given in a daily dosing regimen (OR 0·78 [95% CI 0·65-0·94]; 19 studies; I²=53·5%, p_{heterogeneity}=0·003), at daily dose equivalents of 400-1000 IU (0·70 [0·55-0·89]; ten studies; I²=31·2%, p_{heterogeneity}=0·16), for a duration of 12 months or less (0·82 [0·72-0·93]; 29 studies; I²=38·1%, p_{heterogeneity}=0·021), and to participants aged 1·00-15·99 years at enrolment (0·71 [0·57-0·90]; 15 studies; I²=46·0%, p_{heterogeneity}=0·027). No significant interaction between allocation to the vitamin D supplementation group versus the placebo group and dose, dose frequency, study duration, or age was observed. In addition, no significant difference in the proportion of participants who had at least one serious adverse event in the vitamin supplementation group compared with the placebo group was observed (0·97 [0·86-1·07]; 36 studies; I²=0·0%, p_{heterogeneity}=0·99). Risk of bias within individual studies was assessed as being low for all but three trials.

Interpretation: Despite evidence of significant heterogeneity across trials, vitamin D supplementation was safe and overall reduced the risk of ARI compared with placebo, although the risk reduction was small. Protection was associated with administration of daily doses of 400-1000 IU for up to 12 months, and age at enrolment of 1·00-15·99 years. The relevance of these findings to COVID-19 is not known and requires further investigation.

Funding: None.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Dietary Supplements
Humans
Randomized Controlled Trials as Topic
Respiratory Tract Infections / diet therapy*
Respiratory Tract Infections / prevention & control*
Treatment Outcome
Vitamin D / administration & dosage*

Substances

Vitamin D