Wang M, Liu M, Wang C, et al. Association between vitamin D status and asthma control: A meta-analysis of randomized trials. Respir Med. 2019;150:85-94. doi:10.1016/j.rmed.2019.02.016

Abstract:
Background: There is a controversy in terms of the efficacy of vitamin D supplementation in improving asthma symptom control. Moreover, whether there is a difference in the treatment effect with respect to baseline vitamin D status remains unknown. This meta-analysis was to assess the correlations of vitamin D status with asthma-related respiratory outcomes.

Methods: PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials of vitamin D supplementation in patients with asthma. Primary outcomes were the rate of asthma exacerbation and predicted percentage of forced expiratory volume in first second (FEV₁%). Secondary outcomes were asthma control test (ACT) scores, fractional exhaled nitric oxide (FeNO), interleukin-10 (IL-10) and adverse events.

Results: A total of 14 randomized controlled trials (1421 participants) fulfilled the inclusion. Vitamin D supplementation was associated with a significant reduction in the rate of asthma exacerbation by 27% (RR: 0.73 95%Cl (0.58-0.92)). In subgroup analysis, the protective effect of exacerbation was restricted in patients with vitamin D insufficiency (vitamin D < 30 ng/ml) (RR: 0.76 95%Cl (0.61-0.95)). An improvement of FEV₁% was demonstrated in patients with vitamin D insufficiency and air limitation (FEV₁% < 80%) (MD: 8.3 95%Cl (5.95-10.64). No significant difference was observed in ACT scores, FeNO, IL-10 and adverse events.

Conclusions: Vitamin D supplementation reduced the rate of asthma exacerbation, especially in patients with vitamin D insufficiency. Additionally, the benefit of vitamin D had a positive effect on pulmonary function in patients with air limitation and vitamin D insufficiency.

Jolliffe DA, Greenberg L, Hooper RL, et al. Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data [published correction appears in Lancet Respir Med. 2018 Jun;6(6):e27]. Lancet Respir Med. 2017;5(11):881-890. doi:10.1016/S2213-2600(17)30306-5

Abstract:
Background
A previous aggregate data meta-analysis of randomised controlled trials showed that vitamin D supplementation reduces the rate of asthma exacerbations requiring treatment with systemic corticosteroids. Whether this effect is restricted to patients with low baseline vitamin D status is unknown.

Methods
For this systematic review and one-step and two-step meta-analysis of individual participant data, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Web of Science for double-blind, placebo-controlled, randomised controlled trials of vitamin D3 or vitamin D2 supplementation in people with asthma that reported incidence of asthma exacerbation, published between database inception and Oct 26, 2016. We analysed individual participant data requested from the principal investigator for each eligible trial, adjusting for age and sex, and clustering by study. The primary outcome was the incidence of asthma exacerbation requiring treatment with systemic corticosteroids. Mixed-effects regression models were used to obtain the pooled intervention effect with a 95% CI. Subgroup analyses were done to determine whether effects of vitamin D on risk of asthma exacerbation varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration, age, ethnic or racial origin, body-mass index, vitamin D dosing regimen, use of inhaled corticosteroids, or end-study 25(OH)D levels; post-hoc subgroup analyses were done according to sex and study duration. This study was registered with PROSPERO, number CRD42014013953.

Findings
Our search identified 483 unique studies, eight of which were eligible randomised controlled trials (total 1078 participants). We sought individual participant data for each and obtained it for seven studies (955 participants). Vitamin D supplementation reduced the rate of asthma exacerbation requiring treatment with systemic corticosteroids among all participants (adjusted incidence rate ratio [aIRR] 0·74, 95% CI 0·56–0·97; p=0·03; 955 participants in seven studies; high-quality evidence). There were no significant differences between vitamin D and placebo in the proportion of participants with at least one exacerbation or time to first exacerbation. Subgroup analyses of the rate of asthma exacerbations treated with systemic corticosteroids revealed that protective effects were seen in participants with baseline 25(OH)D of less than 25 nmol/L (aIRR 0·33, 0·11–0·98; p=0·046; 92 participants in three studies; moderate-quality evidence) but not in participants with higher baseline 25(OH)D levels (aIRR 0·77, 0·58–1·03; p=0·08; 764 participants in six studies; moderate-quality evidence; pinteraction=0·25). p values for interaction for all other subgroup analyses were also higher than 0·05; therefore, we did not show that the effects of this intervention are stronger in any one subgroup than in another. Six studies were assessed as being at low risk of bias, and one was assessed as being at unclear risk of bias. The two-step meta-analysis did not reveal evidence of heterogeneity of effect (I2=0·0, p=0·56).

Interpretation
Vitamin D supplementation reduced the rate of asthma exacerbations requiring treatment with systemic corticosteroids overall. We did not find definitive evidence that effects of this intervention differed across subgroups of patients.

Martineau  AR, Cates  CJ, Urashima  M, Jensen  M, Griffiths  AP, Nurmatov  U, Sheikh  A, Griffiths  CJ. Vitamin D for the management of asthma. Cochrane Database of Systematic Reviews 2016, Issue 9. Art. No.: CD011511. DOI: 10.1002/14651858.CD011511.pub2.

Abstract:
Background
Several clinical trials of vitamin D to prevent asthma exacerbation and improve asthma control have been conducted in children and adults, but a meta‐analysis restricted to double‐blind, randomised, placebo‐controlled trials of this intervention is lacking.

Objectives
To evaluate the efficacy of administration of vitamin D and 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 methods
We 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: January 2016.

Selection criteria
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 analysis
Two 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).

Main results
We included seven trials involving a total of 435 children and two trials involving a total of 658 adults in the primary analysis. Of these, one trial involving 22 children and two trials involving 658 adults contributed to the analysis of the rate of exacerbations requiring systemic corticosteroids. Duration of trials ranged from four to 12 months, and the majority of participants had mild to moderate asthma. Administration of vitamin D reduced the rate of exacerbations requiring systemic corticosteroids (rate ratio 0.64, 95% CI 0.46 to 0.90; 680 participants; 3 studies; high‐quality evidence), and decreased the risk of having at least one exacerbation requiring an emergency department visit or hospitalisation or both (odds ratio (OR) 0.39, 95% CI 0.19 to 0.78; number needed to treat for an additional beneficial outcome, 27; 963 participants; 7 studies; high‐quality evidence). There was no effect of vitamin D on % predicted forced expiratory volume in one second (mean difference (MD) 0.48, 95% CI ‐0.93 to 1.89; 387 participants; 4 studies; high‐quality evidence) or Asthma Control Test scores (MD ‐0.08, 95% CI ‐0.70 to 0.54; 713 participants; 3 studies; high‐quality evidence). Administration of vitamin D did not influence the risk of serious adverse events (OR 1.01, 95% CI 0.54 to 1.89; 879 participants; 5 studies; moderate‐quality evidence). One trial comparing low‐dose versus high‐dose vitamin D reported two episodes of hypercalciuria, one in each study arm. No other study reported any adverse event potentially attributable to administration of vitamin D. No participant in any included trial suffered a fatal asthma exacerbation. We did not perform a subgroup analysis to determine whether the effect of vitamin D on risk of severe exacerbation was modified by baseline vitamin D status, due to unavailability of suitably disaggregated data. We assessed two trials as being at high risk of bias in at least one domain; neither trial contributed data to the analysis of the outcomes reported above.

Authors’ conclusions
Whilst we are confident that Vitamin D reduced the risk of asthma exacerbation in these trials (high quality GRADE assessment), we recognise that there is uncertainty about how these findings might be applied in practice. More research is needed to clarify whether there is a difference in effect between adults and children and with respect to asthma severity, baseline vitamin D status and doses.

Effects of vitamin D on acute exacerbation, lung function, and fraction of exhaled nitric oxide (FeNO) in patients with asthma are controversial. We aim to further evaluate the roles of vitamin D supplementation in addition to asthma controllers in asthmatics. From 1946 to July 2015, we searched the PubMed, Embase, Medline, Cochrane Central Register of Controlled Trials, and ISI Web of Science using “Vitamin D,” “Vit D,” or “VitD” and “asthma,” and manually reviewed the references listed in the identified articles. Randomized controlled trials which reported rate of asthma exacerbations and adverse events, forced expiratory volume in 1 s (FEV1, % of predicted value), FeNO, asthma control test (ACT), and serum 25-hydroxyvitamin D levels were eligible. We conducted the heterogeneities test and sensitivity analysis of the enrolled studies, and random-effects or fixed-effects model was applied to calculate risk ratio (RR) and mean difference for dichotomous and continuous data, respectively. Cochrane systematic review software Review Manager (RevMan) was used to test the hypothesis by Mann-Whitney U test, which were displayed in Forest plots. Seven trials with a total of 903 patients with asthma were pooled in our final studies. Except for asthma exacerbations (I2 = 81%, χ2 = 10.28, P = 0.006), we did not find statistical heterogeneity in outcome measures. The pooled RR of asthma exacerbation was 0.66 (95% confidence interval: 0.32-1.37), but without significant difference (z = 1.12, P = 0.26), neither was in FEV1 (z = 0.30, P = 0.77), FeNO (z = 0.28, P = 0.78), or ACT (z = 0.92, P = 0.36), although serum 25-hydroxyvitamin D was significantly increased (z = 6.16, P < 0.001). Vitamin D supplementation in addition to asthma controllers cannot decrease asthma exacerbation and FeNO, nor improve lung function and asthma symptoms, although it can be safely applied to increase serum 25-hydroxyvitamin D levels.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058899/

Riverin BD, Maguire JL, Li P. Vitamin D Supplementation for Childhood Asthma: A Systematic Review and Meta-Analysis. PLoS One. 2015 Aug 31;10(8):e0136841. doi: 10.1371/journal.pone.0136841. PMID: 26322509; PMCID: PMC4556456.

Importance: There is growing evidence that vitamin D plays a role in the pathogenesis of asthma but it is unclear whether supplementation during childhood may improve asthma outcomes.

Objectives: The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of vitamin D supplementation as a treatment or adjunct treatment for asthma.

Data sources: We searched MEDLINE, Embase, CENTRAL, and CINAHL through July 2014.

Study selection: We included RCTs that evaluated vitamin D supplementation in children versus active control or placebo for asthma.

Data extraction and synthesis: One reviewer extracted data and one reviewer verified data accuracy. We qualitatively summarized the main results of efficacy and safety and meta-analyzed data on comparable outcomes across studies. We used GRADE for strength of evidence.

Main outcome measures: Main planned outcomes measures were ED visits and hospitalizations. As secondary outcomes, we examined measures of asthma control, including frequency of asthma exacerbations, asthma symptom scores, measures of lung function, β2-agonist use and daily steroid use, adverse events and 25-hydroxyvitamin D levels.

Results: Eight RCTs (one parallel, one crossover design) comprising 573 children aged 3 to 18 years were included. One study (moderate-quality, n = 100) reported significantly less ED visits for children treated with vitamin D. No other studies examined the primary outcome (ED visits and hospitalizations). There was a reduced risk of asthma exacerbations in children receiving vitamin D (low-quality; RR 0.41, 95% CI 0.27 to 0.63, 3 studies, n = 378). There was no significant effect for asthma symptom scores and lung function. The serum 25(OH)D level was higher in the vitamin D group at the end of the intervention (low-quality; MD 19.66 nmol/L, 95% CI 5.96 nmol/L to 33.37 nmol/L, 5 studies, n = 167).

Limitations: We identified a high degree of clinical diversity (interventions and outcomes) and methodological heterogeneity (sample size and risk of bias) in included trials.

Conclusions and relevance: Randomized controlled trials provide some low-quality evidence to support vitamin D supplementation for the reduction of asthma exacerbations. Evidence on the benefits of vitamin D supplementation for other asthma-related outcomes in children is either limited or inconclusive. We recommend that future trials focus on patient-relevant outcomes that are comparable across studies, including standardized definitions of asthma exacerbations.

(# of subjects/ studies, cohort definition etc. )

-Of the 14 studies, nine were solely adults and five were solely children.

-Eleven studies focused on those deficient in vitamin D and two focused on those that were within range at baseline.

-Four studies evaluated Vitamin D as a sole therapy, and the rest evaluated Vitamin D as adjunctive therapy.

-Secondary outcomes were “asthma control test (ACT) scores, fractional exhaled nitric oxide (FeNO), interleukin-10 (IL-10) and adverse events” (Wang et.a l).

-No significant difference was observed in asthma control test scores, fractional exhaled nitric oxide, or interleukin-10 levels.

-In a subgroup analysis, the findings suggested that only those who were already Vitamin D deficient benefitted from supplementation.

– The definition of “asthma exacerbation” varied between studies.

(# of subjects/ studies, cohort definition etc. )

– All the studies had to be double-blind, placebo-controlled RCTs. 

-A subgroup analysis evaluated the effects of Vitamin D supplementation based on baseline Vitamin D status, race/ethnicity, BMI, dosing regimen, ICS use, and Vitamin D levels at the end of the study (Joliffe et. al).

-However, Vitamin D did not decrease exacerbations as defined by the primary trials. Thus, it is suggested that Vitamin D supplementation may be effective only in more severe exacerbations.

-No significant difference was noted between groups in percentage with at least one exacerbation or time to first exacerbation.

-There was no increase in adverse effects, such as hypercalcemia or kidney stones, with Vitamin D supplementation.

-There was a non-significant finding that those with Vitamin D levels under 25 nmol/L benefitted from Vitamin D supplementation, while those above this level did not.

(# of subjects/ studies, cohort definition etc. )

-All articles were were double-blind, randomized, and placebo-controlled.

-The trials lasted between four and twelve months.

-Secondary outcomes included number of asthma exacerbations needing ED visits or inpatient treatment, asthma control test score, FEV1%, adverse effects, fatal exacerbations, eosinophils % in sputum/ bronchoalveolar lavage, peak expiratory flow rate, proportion of patients withdrawing from trial.

-Vitamin D supplementation had no noted effect on FEV1% or asthma control test scores.

-No increased adverse effects with Vitamin D supplementation.

-Being that the pediatric sample size was smaller, most of the results are reflective of the benefits in adults, whereas the benefits in the pediatric population are still inconclusive.

(# of subjects/ studies, cohort definition etc. )

-All studies included were randomized control trials.

-No increase in adverse effects was noted in either group.

– There was variation between studies in the dose, routine, and duration of treatment between trials.

(# of subjects/ studies, cohort definition etc. )

-Secondary outcomes were “frequency of asthma exacerbations, asthma symptom scores, measures of lung function, β2-agonist use and daily steroid use, adverse events and 25-hydroxyvitamin D levels” (Riverin et.al).

-There was also no improvement noted in symptoms or lung function.

-There was significant heterogeneity in terms of the interventions/ dosing and the results of the studies.

-Ethnicity/ race were not provided from the various trials thus the analysis could not assess if that affected outcomes.