Vitamin D, acute respiratory infections, and Covid-19: the curse of small-size randomised trials. A critical review with meta-analysis of randomised trials
Philippe Autier, Giulia Doi, Patrick Mullie, Patrick Vankrunkelsven, Oriana D’ecclesiis, Sara Gandini
doi:10.1101/2024.04.26.24306354
Background: Randomised trials conducted before 2021 indicated that vitamin D supplementation (VDS) was able to prevent severe COVID-19 and acute respiratory infections (ARI). However, these health benefits were not confirmed by larger randomised trials published after 2021. Objective: To examine the characteristics of randomised trials on VDS to COVID-19 patients and admission to intensive care unit (ICU), and on VDS for the prevention of ARI. Method: A systematic search retrieved randomised trials on VDS to COVID-19 patients and admission to ICU. Data on VDS and ARI were extracted from the meta-analysis of Jolliffe et al., 2021. The associations between VDS vs no VDS, and admission to ICU were evaluated using random effect models. Meta-analyses were done for all trials and by groups trial size. Publication bias was assessed using the LFK index (no bias if index between -1 and +1) and the Trim and Fill method. Results: Nine trials on VDS for preventing admission to ICU were identified. The summary odds ratio (SOR) was 0.61 (95%CI: 0.39-0.95) for all trials, 0.34 (0.13-0.93) for trials including 50 to <106 patients and 0.88 (0.62-1.24) for trials including 106 to 548 patients (effect modification: p=0.04). The LFK index was -3.79, and after Trim and Fill, the SOR was 0.80 (0.40-1.61). The SOR for the 37 trials on VDS for ARI prevention was 0.92 (0.86-0.99) for all trials, 0.69 (0.57-0.83) for trials including 25 to <248 patients and 0.98 (0.94-1.03) for trials including 248 to 16,000 patients (effect modification p=0.0001). The LFK index was -3.11, and after Trim and Fill, the SOR was 0.96 (0.88-1.05). Conclusion: Strong publication bias affected randomised trials on VDS for the prevention of severe COVID-19 and of ARI. Systematic reviews should beware of smallsize randomised trials that generally exaggerate health benefits.
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'abstract': '<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Randomised '
'trials conducted before 2021 indicated that vitamin D supplementation (VDS) was able to '
'prevent severe COVID-19 and acute respiratory infections (ARI). However, these health '
'benefits were not confirmed by larger randomised trials published after '
'2021.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To examine the '
'characteristics of randomised trials on VDS to COVID-19 patients and admission to intensive '
'care unit (ICU), and on VDS for the prevention of '
'ARI.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>A systematic search '
'retrieved randomised trials on VDS to COVID-19 patients and admission to ICU. Data on VDS and '
'ARI were extracted from the meta-analysis of Jolliffe et al., 2021. The associations between '
'VDS vs no VDS, and admission to ICU were evaluated using random effect models. Meta-analyses '
'were done for all trials and by groups trial size. Publication bias was assessed using the '
'LFK index (no bias if index between -1 and +1) and the Trim and Fill '
'method.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Nine trials on '
'VDS for preventing admission to ICU were identified. The summary odds ratio (SOR) was 0.61 '
'(95%CI: 0.39-0.95) for all trials, 0.34 (0.13-0.93) for trials including 50 to <106 '
'patients and 0.88 (0.62-1.24) for trials including 106 to 548 patients (effect modification: '
'p=0.04). The LFK index was -3.79, and after Trim and Fill, the SOR was 0.80 (0.40-1.61). The '
'SOR for the 37 trials on VDS for ARI prevention was 0.92 (0.86-0.99) for all trials, 0.69 '
'(0.57-0.83) for trials including 25 to <248 patients and 0.98 (0.94-1.03) for trials '
'including 248 to 16,000 patients (effect modification p=0.0001). The LFK index was -3.11, and '
'after Trim and Fill, the SOR was 0.96 '
'(0.88-1.05).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Strong '
'publication bias affected randomised trials on VDS for the prevention of severe COVID-19 and '
'of ARI. Systematic reviews should beware of small-size randomised trials that generally '
'exaggerate health benefits.</jats:p></jats:sec>',
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