Vitamin D supplementation to prevent acute respiratory infections: 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, 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:10.1101/2020.07.14.20152728
Background: A 2017 meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for the prevention of acute respiratory infections revealed a protective effect of the intervention. Since then, 20 new RCTs have been completed.
Methods : Systematic review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for ARI prevention using a random effects model. Pre-specified 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 or dosing regimen. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the ClinicalTrials.gov registry from inception to 1st May 2020. Double-blind RCTs of supplementation with vitamin D or calcidiol, of any duration, were eligible if they were 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, were obtained from study authors. The study was registered with PROSPERO (no. CRD42020190633).
Findings: We identified 45 eligible RCTs (total 73,384 participants). Data were obtained for 46,331 (98.0%) of 47,262 participants in 42 studies, aged 0 to 95 years. For the primary comparison of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds Ratio [OR] 0.91, 95% CI 0.84 to 0.99; P for heterogeneity 0.01). No statistically significant effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D concentration. However, protective effects were seen for trials in which vitamin D was given using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of 400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of ≤12 months (OR 0.82, 95% CI 0.72 to 0.93). No significant interaction was seen between allocation to vitamin D vs. placebo and dose frequency, dose size, or study duration. Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI 0.86 to 1.09). Risk of bias within individual studies was assessed as being low for all but three trials. A funnel plot showed left-sided asymmetry (P=0.008, Egger's test).
Author Contributions DAJ and ARM wrote the study protocol and designed statistical analyses. DAJ, CAC and ARM assessed eligibility of studies for inclusion and performed risk of bias assessments. Statistical analyses were done by DAJ; results were checked and verified by JDS. DAJ and ARM wrote the first draft of the report. 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.
Competing Interests All authors have completed the ICMJE uniform disclosure form. 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.
Transparency Declaration DAJ and ARM are the manuscript's guarantors and they affirm that this 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 pre-specified in the study protocol, other than the exploratory analyses whose results are presented in Table 2 (sub-group analyses by age and presence of asthma/COPD, requested by reviewers), Table S5 and Figure S7 . Data Sharing: the study..
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>A 2017 '
'meta-analysis of data from 25 randomised controlled trials of vitamin D supplementation for '
'the prevention of acute respiratory infections revealed a protective effect of the '
'intervention. Since then, 20 new RCTs have been '
'completed.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Systematic '
'review and meta-analysis of data from randomised controlled trials (RCTs) of vitamin D for '
'ARI prevention using a random effects model. Pre-specified 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 or dosing regimen. We searched MEDLINE, EMBASE, '
'the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and the '
'ClinicalTrials.gov registry from inception to 1st May 2020. Double-blind RCTs of '
'supplementation with vitamin D or calcidiol, of any duration, were eligible if they were '
'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, were obtained from study authors. The study was registered with PROSPERO (no. '
'CRD42020190633).</jats:p></jats:sec><jats:sec><jats:title>Findings</jats:title><jats:p>We '
'identified 45 eligible RCTs (total 73,384 participants). Data were obtained for 46,331 '
'(98.0%) of 47,262 participants in 42 studies, aged 0 to 95 years. For the primary comparison '
'of vitamin D supplementation vs. placebo, the intervention reduced risk of ARI overall (Odds '
'Ratio [OR] 0.91, 95% CI 0.84 to 0.99; P for heterogeneity 0.01). No statistically significant '
'effect of vitamin D was seen for any of the sub-groups defined by baseline 25(OH)D '
'concentration. However, protective effects were seen for trials in which vitamin D was given '
'using a daily dosing regimen (OR 0.75, 95% CI 0.61 to 0.93); at daily dose equivalents of '
'400-1000 IU (OR 0.70, 95% CI 0.55 to 0.89); and for a duration of ≤12 months (OR 0.82, 95% CI '
'0.72 to 0.93). No significant interaction was seen between allocation to vitamin D vs. '
'placebo and dose frequency, dose size, or study duration. Vitamin D did not influence the '
'proportion of participants experiencing at least one serious adverse event (OR 0.97, 95% CI '
'0.86 to 1.09). Risk of bias within individual studies was assessed as being low for all but '
'three trials. A funnel plot showed left-sided asymmetry (P=0.008, Egger’s '
'test).</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>Vitamin D '
'supplementation was safe and reduced risk of ARI, despite evidence of significant '
'heterogeneity across trials. Protection was associated with administration of daily doses of '
'400-1000 IU vitamin D for up to 12 months. The relevance of these findings to COVID-19 is not '
'known and requires '
'investigation.</jats:p></jats:sec><jats:sec><jats:title>Funding</jats:title><jats:p>None</jats:p></jats:sec>',
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