Optimal methods of vitamin D supplementation to prevent acute respiratory infections: a systematic review, dose-response and pairwise meta-analysis of randomized controlled trials

Abstract

Background: Vitamin D supplementation may prevent acute respiratory infections (ARIs). This study aimed to identify the optimal methods of vitamin D supplementation.

Methods: PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and the ClinicalTrials.gov registry were searched from database inception through July 13, 2023. Randomized-controlled trials (RCTs) were included. Data were pooled using random-effects model. The primary outcome was the proportion of participants with one or more ARIs.

Results: The analysis included 43 RCTs with 49320 participants. Forty RCTs were considered to be at low risk for bias. The main pairwise meta-analysis indicated there were no significant preventive effects of vitamin D supplementation against ARIs (risk ratio [RR]: 0.99, 95% confidence interval [CI]: 0.97 to 1.01, I² = 49.6%). The subgroup dose-response meta-analysis indicated that the optimal vitamin D supplementation doses ranged between 400-1200 IU/day for both summer-sparing and winter-dominant subgroups. The subgroup pairwise meta-analysis also revealed significant preventive effects of vitamin D supplementation in subgroups of daily dosing (RR: 0.92, 95% CI: 0.85 to 0.99, I² = 55.7%, number needed to treat [NNT]: 36), trials duration < 4 months (RR: 0.81, 95% CI: 0.67 to 0.97, I² = 48.8%, NNT: 16), summer-sparing seasons (RR: 0.85, 95% CI: 0.74 to 0.98, I² = 55.8%, NNT: 26), and winter-dominant seasons (RR: 0.79, 95% CI: 0.71 to 0.89, I² = 9.7%, NNT: 10).

Conclusion: Vitamin D supplementation may slightly prevent ARIs when taken daily at doses between 400 and 1200 IU/d during spring, autumn, or winter, which should be further examined in future clinical trials.

Keywords: Acute respiratory infection; Dosage; Dose–response analysis; Meta-analysis; Seasonal effects; Vitamin D.

Fig. 1

Literature search and selection flow diagram. ARI: acute respiratory infection

Fig. 2

Model comparison of main dose–response meta-analysis. The solid black line indicates the linear model (a), the quadratic model (b), and the restricted cubic spline model (c). Dashed black lines are 95% point-wise confidence intervals estimated by the respective 1-stage random-effects model. The Akaike Information Criterion values for each model are (a) -3.21, (b) 36.56 and (c) 15.81

Fig. 3

Main pairwise meta-analysis including all eligible studies based on random-effects model. Forest plot of the summary risk ratios comparing proportions of participants with one or more ARIs between intervention and control groups. In the comparison of vitamin D higher doses vs placebo, there were two or more levels of vitamin D doses in each included study; only the group with highest vitamin D dose and the placebo in each study were selected for pooling. In the comparison of vitamin D higher vs lower doses, there were no placebo control group in included studies; the two groups with different vitamin D doses in each study were selected for pooling. CI: confidence interval; DL: DerSimonian and Laird random effects model; n: number of participants with one or more ARI; N:total number of participants in the study group

Fig. 4

Funnel plot for assessment of overall small-study effects. Each dot represents an included study, located according to the logarithm of RR (X axis) and SE of logarithm of RR (Y axis). The dash black lines indicate the triangular region within which 95% of studies are expected to lie in the absence of biases. The plot asymmetry analysis was performed by Egger’s test, which suggests presence of small-study effects (p = 0.003). RR: relative risk; SE: standard error