• Anne Williamson, Adrian R Martineau, Aziz Sheikh, David Jolliffe, and Chris J Griffiths.
• Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
• Cochrane Db Syst Rev. 2023 Feb 6; 2 (2): CD011511CD011511.

BackgroundSince the previous Cochrane Review on this topic in 2016, debate has continued surrounding a potential role for vitamin D in reducing risk of asthma exacerbation and improving asthma control. We therefore conducted an updated meta-analysis to include data from new trials completed since this date.ObjectivesTo evaluate the effectiveness and safety of administration of vitamin D or its hydroxylated metabolites in reducing the risk of severe asthma exacerbations (defined as those requiring treatment with systemic corticosteroids) and improving asthma symptom control.Search MethodsWe searched the Cochrane Airways Group Trial Register and reference lists of articles. We contacted the authors of studies in order to identify additional trials. Date of last search: 8 September 2022.Selection CriteriaWe included double-blind, randomised, placebo-controlled trials of vitamin D in children and adults with asthma evaluating exacerbation risk or asthma symptom control, or both.Data Collection And AnalysisFour review authors independently applied study inclusion criteria, extracted the data, and assessed risk of bias. We obtained missing data from the authors where possible. We reported results with 95% confidence intervals (CIs). The primary outcome was the incidence of severe asthma exacerbations requiring treatment with systemic corticosteroids. Secondary outcomes included the incidence of asthma exacerbations precipitating an emergency department visit or requiring hospital admission, or both, end-study childhood Asthma Control Test (cACT) or Asthma Control Test (ACT) scores, and end-study % predicted forced expiratory volume in one second (FEV1). We performed subgroup analyses to determine whether the effect of vitamin D on risk of asthma exacerbation was modified by baseline vitamin D status, vitamin D dose, frequency of dosing regimen, form of vitamin D given, and age of participants.Main ResultsWe included 20 studies in this review; 15 trials involving a total of 1155 children and five trials involving a total of 1070 adults contributed data to analyses. Participant ages ranged from 1 to 84 years, with two trials providing data specific to participants under five years (n = 69) and eight trials providing data specific to participants aged 5 to 16 (n = 766). Across the trials, 1245 participants were male and 1229 were female, with two studies not reporting sex distribution. Fifteen trials contributed to the primary outcome analysis of exacerbations requiring systemic corticosteroids. The duration of trials ranged from three to 40 months; all but two investigated effects of administering cholecalciferol (vitamin D3). As in the previous Cochrane Review, the majority of participants had mild to moderate asthma, and profound vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25 nmol/L) at baseline was rare. Administration of vitamin D or its hydroxylated metabolites did not reduce or increase the proportion of participants experiencing one or more asthma exacerbations treated with systemic corticosteroids (odds ratio (OR) 1.04, 95% CI 0.81 to 1.34; I2 = 0%; 14 studies, 1778 participants; high-quality evidence). This equates to an absolute risk of 226 per 1000 (95% CI 185 to 273) in the pooled vitamin D group, compared to a baseline risk of 219 participants per 1000 in the pooled placebo group. We also found no effect of vitamin D supplementation on the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.86, 95% CI 0.62 to 1.19; I2 = 60%; 10 studies, 1599 participants; high-quality evidence), or the time to first exacerbation (hazard ratio 0.82, 95% CI 0.59 to 1.15; I2 = 22%; 3 studies, 850 participants; high-quality evidence). Subgroup analysis did not reveal any evidence of effect modification by baseline vitamin D status, vitamin D dose, frequency of dosing regimen, or age. A single trial investigating administration of calcidiol reported a benefit of the intervention for the primary outcome of asthma control. Vitamin D supplementation did not influence any secondary efficacy outcome meta-analysed, which were all based on moderate- or high-quality evidence. We observed no effect on the incidence of serious adverse events (OR 0.89, 95% CI 0.56 to 1.41; I2 = 0%; 12 studies, 1556 participants; high-quality evidence). The effect of vitamin D on fatal asthma exacerbations was not estimable, as no such events occurred in any trial. Six studies reported adverse reactions potentially attributable to vitamin D. These occurred across treatment and control arms and included hypercalciuria, hypervitaminosis D, kidney stones, gastrointestinal symptoms and mild itch. In one trial, we could not ascertain the total number of participants with hypercalciuria from the trial report. We assessed three trials as being at high risk of bias in at least one domain; none of these contributed data to the analysis of the outcomes reported above. Sensitivity analyses that excluded these trials from each outcome to which they contributed did not change the null findings.Authors' ConclusionsIn contrast to findings of our previous Cochrane Review on this topic, this updated review does not find evidence to support a role for vitamin D supplementation or its hydroxylated metabolites to reduce risk of asthma exacerbations or improve asthma control. Participants with severe asthma and those with baseline 25(OH)D concentrations < 25 nmol/L were poorly represented, so further research is warranted here. A single study investigating effects of calcidiol yielded positive results, so further studies investigating effects of this metabolite are needed.Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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