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

  1. David A Jolliffe
  2. Carlos A Camargo
  3. John D Sluyter
  4. Mary Aglipay
  5. John F Aloia
  6. Peter Bergman
  7. Heike A. Bischoff-Ferrari
  8. Arturo Borzutzky
  9. Vadim Y Bubes
  10. Camilla T Damsgaard
  11. Francine Ducharme
  12. Gal Dubnov-Raz
  13. Susanna Esposito
  14. Davaasambuu Ganmaa
  15. Clare Gilham
  16. Adit A Ginde
  17. Inbal Golan-Tripto
  18. Emma C Goodall
  19. Cameron C Grant
  20. Christopher J Griffiths
  21. Anna Maria Hibbs
  22. Wim Janssens
  23. Anuradha Vaman Khadilkar
  24. Ilkka Laaksi
  25. Margaret T Lee
  26. Mark Loeb
  27. Jonathon L Maguire
  28. Paweł Majak
  29. Semira Manaseki-Holland
  30. JoAnn E Manson
  31. David T Mauger
  32. David R Murdoch
  33. Akio Nakashima
  34. Rachel E Neale
  35. Hai Pham
  36. Christine Rake
  37. Judy R Rees
  38. Jenni Rosendahl
  39. Robert Scragg
  40. Dheeraj Shah
  41. Yoshiki Shimizu
  42. Steve Simpson-Yap
  43. Geeta Trilok Kumar
  44. Mitsuyoshi Urashima
  45. Adrian R Martineau
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Abstract

Background

A 2021 meta-analysis of 37 randomised controlled trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARI) revealed a statistically significant protective effect of the intervention (odds ratio [OR] 0.92, 95% confidence interval [CI] 0.86 to 0.99). Since then, 6 eligible RCTs have completed, including one large trial (n=15,804).

Methods

Updated systematic review and meta-analysis of data from RCTs of vitamin D for ARI prevention using a random effects model. Sub-group 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 were searched between May 2020 (previous search) and April 2024. No language restrictions were imposed. Double-blind RCTs supplementing vitamin D for any duration, with placebo or low-dose vitamin D control, were eligible if approved by 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 6 new RCTs (19,337 participants). Data were obtained for 16,086 (83.2%) participants in 3 new RCTs and combined with data from 48,488 participants in 43 previously identified RCTs. For the primary comparison of any vitamin D vs. placebo, the intervention did not significantly affect overall ARI risk (OR 0.94, 95% CI 0.88 to 1.00, P=0.057; 40 studies; I 2 26.4%). Pre-specified subgroup analysis did not reveal evidence of effect modification by age, baseline vitamin D status, or dosing regimen. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.96, 95% CI 0.90 to 1.04; 38 studies; I 2 0.0%). A funnel plot showed left-sided asymmetry (P=0.002, 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 spans 1.00, indicating no statistically significant protection.

Funding

None

Research in context

Evidence before this study

We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from 1 st May 2020 (date of our previous search) to 30 th April 2024 for randomised Controlled Trials and meta-analyses of randomised Controlled Trials evaluating effectiveness of vitamin D supplementation for the prevention of acute respiratory infections. Our previous meta-analysis of 43 randomised Controlled Trials (RCTs) of vitamin D supplementation for prevention of acute respiratory infections (ARI) conducted in 2021 revealed a statistically significant protective effect of the intervention (OR 0.92, 95% CI 0.86 to 0.99). A further 6 eligible RCTs, contributing data from 19,337 participants have now completed, including one large trial (n=15,804).

Added value of this study

Our meta-analysis of aggregate data from 64,086 participants in 46 randomised controlled trials, stratified by baseline 25(OH)D concentration and age, provides an updated estimate of the protective effects of vitamin D against acute respiratory infection overall (OR 0.94, 95% CI 0.88 to 1.00), and in sub-groups defined by baseline vitamin D status, age, and dosing frequency, amount and duration.

Implications of all the available evidence

Updated meta-analysis including the latest available RCT data shows no statistically significant protective effect of vitamin D supplementation against ARI, either overall or in sub-group analyses.

Article activity feed

  1. Version published to 10.1101/2024.09.18.24313866v1 on medRxiv