Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of stratified aggregate data

David A Jolliffe; Carlos A Camargo Jr; John D Sluyter; Mary Aglipay; John F Aloia; Peter Bergman; Heike A Bischoff-Ferrari; Arturo Borzutzky; Vadim Y Bubes; Camilla T Damsgaard; Francine M Ducharme; Gal Dubnov-Raz; Susanna Esposito; Davaasambuu Ganmaa; 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; Semira Manaseki-Holland; JoAnn E Manson; David T Mauger; 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(24)00348-6

Vitamin D supplementation to prevent acute respiratory infections: systematic review and meta-analysis of stratified aggregate data

Lancet Diabetes Endocrinol. 2025 Apr;13(4):307-320. doi: 10.1016/S2213-8587(24)00348-6. Epub 2025 Feb 21.

Authors

David A Jolliffe¹, Carlos A Camargo Jr², John D Sluyter³, Mary Aglipay⁴, John F Aloia⁵, Peter Bergman⁶, Heike A Bischoff-Ferrari⁷, Arturo Borzutzky⁸, Vadim Y Bubes⁹, Camilla T Damsgaard¹⁰, Francine M Ducharme¹¹, Gal Dubnov-Raz¹², Susanna Esposito¹³, Davaasambuu Ganmaa¹⁴, Clare Gilham¹⁵, Adit A Ginde¹⁶, Inbal Golan-Tripto¹⁷, Emma C Goodall¹⁸, Cameron C Grant¹⁹, Christopher J Griffiths²⁰, Anna Maria Hibbs²¹, Wim Janssens²², Anuradha Vaman Khadilkar²³, Ilkka Laaksi²⁴, Margaret T Lee²⁵, Mark Loeb²⁶, Jonathon L Maguire⁴, Paweł Majak²⁷, Semira Manaseki-Holland²⁸, JoAnn E Manson⁹, David T Mauger²⁹, David R Murdoch³⁰, Akio Nakashima³¹, Rachel E Neale³², Hai Pham³³, Christine Rake¹⁵, Judy R Rees³⁴, Jenni Rosendahl³⁵, Robert Scragg³, Dheeraj Shah³⁶, Yoshiki Shimizu³⁷, Steve Simpson-Yap³⁸, Geeta Trilok Kumar³², Mitsuyoshi Urashima³¹, Adrian R Martineau³⁹

Affiliations

¹ Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK; Centre for Applied Respiratory Research Innovation and Implementation, Wolfson Institute of Population Health, 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 Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
⁷ Department of Aging Medicine and Aging Research, University of Zurich, Zurich, Switzerland.
⁸ Department of Pediatric Infectious Diseases and Immunology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
⁹ Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg, Denmark.
¹¹ Departments of Paediatrics and of Social and Preventive Medicine, University of Montréal, Canada.
¹² Exercise, Lifestyle and Nutrition Clinic, Edmond and Lily Safra Children's Hospital, Tel Hashomer, Israel.
¹³ Paediatric Clinic, Department of Medicine and Surgery, University of Parma, Parma, Italy.
¹⁴ Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
¹⁵ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
¹⁶ Department of Emergency Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
¹⁷ Saban Pediatric Medical Center, Soroka University Medical Center, Faculty of Health Sciences, Ben-Gurion University, Beer Sheva, Israel.
¹⁸ Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.
¹⁹ Department of Paediatrics: Child & Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
²⁰ Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK; Centre for Applied Respiratory Research Innovation and Implementation, Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
²¹ Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USA; University Hospitals Rainbow Babies and Children's Hospital, Cleveland, OH, USA.
²² Universitair ziekenhuis Leuven, Leuven, Belgium.
²³ Hirabai Cowasji Jehangir Medical Research Institute, Maharashtra, India.
²⁴ Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland; The Centre For Military Medicine, Finland.
²⁵ Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York, NY, USA.
²⁶ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
²⁷ Department of Pediatric Pulmonology, Medical University of Lodz, Korczak Pediatric Center, Lodz, Poland.
²⁸ Department of Public Health, Epidemiology and Biostatistics, Institute of Applied Health Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
²⁹ Department of Statistics, The Pennsylvania State University, Hershey, PA, USA.
³⁰ Department of Pathology, University of Otago, Christchurch, New Zealand.
³¹ Jikei University School of Medicine, Tokyo, Japan.
³² Trivedi School of Biosciences, Ashoka University, Sonepat, Haryana, India.
³³ Population Health Department, QIMR Berghofer Medical Research Institute, Queensland, Australia.
³⁴ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
³⁵ Children's Hospital, Pediatric Research Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
³⁶ Department of Paediatrics, University College of Medical Sciences, Delhi, India.
³⁷ FANCL Research Institute, FANCL Corporation, Yokohama, Japan.
³⁸ Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia; Neuroepidemiology Unit, Melbourne School of Population & Global Health, The University of Melbourne, Carlton, VIC, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
³⁹ Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK; Centre for Applied Respiratory Research Innovation and Implementation, Wolfson Institute of Population Health, Queen Mary University of London, London, UK. Electronic address: a.martineau@qmul.ac.uk.

Abstract

Background: A 2021 meta-analysis of 37 randomised controlled trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARIs) revealed a statistically significant protective effect of the intervention (odds ratio [OR] 0·92 [95% CI 0·86 to 0·99]). Since then, six eligible RCTs have been completed, including one large trial (n=15 804). We aimed to re-examine the link between vitamin D supplementation and prevention of ARIs.

Methods: Updated systematic review and meta-analysis of data from RCTs of vitamin D for ARI prevention using a random effects model. Subgroup analyses were done to determine whether effects of vitamin D on risk of ARI varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, dosing regimen, or age. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov between May 1, 2020 (end-date of search of our previous meta-analysis) and April 30, 2024. No language restrictions were imposed. Double-blind RCTs supplementing vitamin D for any duration, with placebo or lower-dose vitamin D control, were eligible if approved by a Research Ethics Committee and if ARI incidence was collected prospectively and pre-specified as an efficacy outcome. Aggregate data, stratified by baseline 25(OH)D concentration and age, were obtained from study authors. The study was registered with PROSPERO (no. CRD42024527191).

Findings: We identified six new RCTs (19 337 participants). Data were obtained for 16 085 (83·2%) participants in three new RCTs and combined with data from 48 488 participants in 43 RCTs identified in our previous meta-analysis. For the primary comparison of any vitamin D versus placebo, the intervention did not statistically significantly affect overall ARI risk (OR 0·94 [95% CI 0·88-1·00], p=0·057; 40 studies; 61 589 participants; I²=26·4%). Pre-specified subgroup analysis did not reveal evidence of effect modification by age, baseline vitamin D status, dosing frequency, or dose size. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0·96 [95% CI 0·90-1·04]; 38 studies; I²=0·0%). A funnel plot showed left-sided asymmetry (p=0·0020, Egger's test).

Interpretation: This updated meta-analysis yielded a similar point estimate for the overall effect of vitamin D supplementation on ARI risk to that obtained previously, but the 95% CI for this effect estimate now includes 1·00, indicating no statistically significant protection.

Funding: None.

Publication types

Systematic Review
Meta-Analysis

MeSH terms

Acute Disease
Dietary Supplements*
Humans
Randomized Controlled Trials as Topic
Respiratory Tract Infections* / epidemiology
Respiratory Tract Infections* / prevention & control
Vitamin D* / administration & dosage
Vitamin D* / analogs & derivatives
Vitamin D* / therapeutic use
Vitamins* / therapeutic use

Substances

Vitamin D
Vitamins
25-hydroxyvitamin D

Grants and funding

R01 AT011729/AT/NCCIH NIH HHS/United States