Cheng-Yao Li·Zhang Liu

Abstract Introduction The efficacy of inhaled budesonide for managing moderate-to-severe acute exacerbations in children is not clear.Therefore,this study aimed to evaluate hospital admission rates,need for use of systemic corticosteroids,length of hospital stay and adverse events when inhaled budesonide is added to standard pediatric emergency department management of moderate-to-severe acute exacerbations of asthma.Methods A systematic search was conducted in PubMed,Scopus,CENTRAL (Cochrane Central Register of Controlled Trials) and Google scholar databases.Randomized controlled trials that evaluated the effect of nebulized budesonide in moderate-to-severe acute exacerbations of asthma in pediatric patients were included for this meta-analysis.Statistical analysis was done using STATA version 13.0.Results A total of 16 RCTs were included.Children receiving nebulized budesonide had 43% lower risk of being hospitalized (RR 0.57;95% CI,0.39;0.85) and 66% lower risk of requiring systemic corticosteroids (RR 0.34;95 % CI,0.21;0.55)compared with those receiving placebo.There were no differences in the length of hospital stay (Hedges’s g standardized mean difference-1.53;95% CI,-3.64;0.58) and risk of adverse events (RR 0.87,95% CI;0.65;1.17) between the two groups.There was no evidence of publication bias for any of the outcomes considered.Conclusion The findings of this meta-analysis support the use of inhaled budesonide in reducing risk of hospitalization and the need for systemic corticosteroids among children with acute moderate-to-severe asthma exacerbation.

Keywords Acute asthma·Budesonide·Corticosteroids·Hospital admission·Pediatric emergency

Introduction

One frequently encountered condition in the pediatric emergency department is acute asthma [1].This illness is not only associated with high morbidity rates but also can lead to mortality [1,2].Data suggest that 10-20% of children with moderate or severe exacerbation require hospitalization [2].Such high incidence of hospitalization can lead to a substantial burden on hospital resources and also may increase healthcare costs for the patients.Considering the serious nature of the disease,clinicians should manage acute exacerbation of asthma promptly in the emergency department.Efficient management will reduce the incidence of hospitalizations and associated morbidities.

According to existing treatment guidelines,the first-line treatment for moderate or severe asthmatic exacerbation is inhaled or nebulized beta-agonists along with ipratropium bromide [3].In case of severe exacerbation,systemic corticosteroids can significantly reduce hospitalization rates and to improve pulmonary functions [4].However,systemic corticosteroids usually take effects 3-4 h to have an effect and have associated side-effects as well [5].Consequently,there is an ongoing effort to identify alternative effective therapies with acceptable safety profiles for use in acute asthmatic exacerbations,particularly in children.One such promising alternative is inhaled corticosteroids.Among the inhaled corticosteroids,budesonide is particularly interesting to be explored because it has substantial topical anti-inflammatory effects with minimal systemic action [6].Its high hepatic clearance and consequent short half-life reduces the risk of side-effects as well [6,7].

Currently,inhaled corticosteroids are used for long-term control of persistent symptoms [7].Evidence from studies evaluating the role of inhaled corticosteroids in the management of acute exacerbations of asthma in children is conflicting.This may be due to the fact that trials are conducted in different geographical areas amongst populations with diverse socioeconomic backgrounds and in different hospital settings varying in their medical infrastructure.Thus,a pooling of outcomes of different studies can provide highquality,level-1 evidence for clinicians in managing pediatric asthma.In this context,a recent meta-analysis has suggested that high doses of inhaled corticosteroids in conjunction with systemic corticosteroids can reduce the risk of hospitalization with modest improvement in clinical scores and vital signs of patients with acute exacerbation of asthma[8].However,this analysis focused on all types of inhaled steroids and not on budesonide in particular.To date,no review has summarized existing evidence on the effects of inhaled budesonide for managing moderate-to-severe acute exacerbations in children.Thus,the aim of this meta-analysis was to provide synthesized evidence on this subject.Our review assessed the hospital admission rates,the need for use of systemic corticosteroids,length of hospital stay,and adverse events when inhaled budesonide was added to standard pediatric emergency department management of moderate-to-severe acute exacerbations of asthma.

Methods

Search strategy

The study protocol was designed and conducted based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines.A systematic search was conducted in PubMed,Scopus,CENTRAL (Cochrane Central Register of Controlled Trials) and Google scholar databases for English as well as non-English language papers published until 31 November 2019.For non-English language papers,google translator was used for translation to English prior to extraction of relevant information.Free text words and medical subject heading (MeSH) terms were used.Details of the search strategy have been provided in supplemental document (Supplemental Table 1).Studies that reported relevant outcome measures of interest to this metaanalysis were potentially considered for inclusion.

Selection criteria and methods

Two authors (CL and ZL) reviewed citations and selected studies.After removing the duplicates,screening of titles and abstracts was performed as a first step.Thereafter,review of the full text of potential studies was done.Any discrepancies related to the inclusion of studies were resolved through detailed discussion among the study authors (CL and ZL).Only those studies that fulfilled the inclusion criteria were selected for the meta-analysis.The bibliographic list of the identified studies and relevant reviews on the subject were examined for additional possible studies.

Inclusion criteria

For a study to be included in the meta-analysis,it should have been a randomized controlled trial (RCT) conducted among children with acute moderate-to-severe asthma that attended the pediatric emergency department.The study should have compared the efficacy of budesonide against a placebo or control.Outcomes of the study should have been at least one of the following:hospitalization rate,need for systemic corticosteroids,length of hospital stays and any potential adverse events.

Exclusion criteria

Studies that were done in children with mild or persistent asthma were excluded.Studies on adults and non-randomized studies,such as case-reports,observational studies (case-control,cohort studies) or review articles,also were excluded.

Data extraction and quality assessment

Using a data extraction sheet,two authors (CL and ZL) independently extracted information from the included studies.The following data were extracted from all eligible studies:surname of first author,year in which the study was published,geographical location where the study was done,design of the study,characteristics of the study subjects,study groups and key findings of the study.The methodological assessment was done independently by two authors(CL and ZL) using the assessment tool by Cochrane [9].

Statistical analysis

RCTs that reported similar findings were pooled together to generate effect sizes.For the remaining outcomes not included in the meta-analysis,we performed a descriptive presentation of the salient findings.Statistical analysis was done using STATA version 13.0 (StataCorp.2013.Stata Statistical Software:Release13.College Station,TX:StataCorp LP).Effect sizes were reported as weighted mean differences (WMD) for continuous outcomes.For categorical outcomes,pooled relative risks (RR) were reported.All estimates were reported with 95% confidence intervals (CI).Heterogeneity of effects was assessed and quantified by theI2statistic.AnI2value greater than 50% was considered to represent substantial heterogeneity [10].In cases with substantial heterogeneity,random-effects modeling was used[10].Sub-group analysis was conducted based on the use of systemic corticosteroids in addition to budesonide in the study group.APvalue ＜ 0.05 was considered to be statistically significant.Publication bias was assessed using Egger’s test and visual inspection of funnel plots.

Results

Selection of articles,study characteristics and quality of included studies

A total of 1656 unique citations were obtained after running the systematic search (Fig.1).Among these,1458 records were excluded after screening of the title.In addition,173 citations were excluded after reading the abstract.The full texts of the remaining 25 articles were reviewed.Among these,nine articles were excluded upon full-text review.The final number of included articles in this meta-analysis was 16 [11-26].Table 1 presents the key characteristics of the included studies along with the study outcomes.All of the included studies were double-blinded,placebo-controlled RCTs.Two studies were conducted in China,four in Turkey and one each in India,Bangladesh,Canada,Brazil,Belgium,Canada,USA,France,Denmark and Saudi Arabia.Supplemental Table 2 presents the author’s judgement of the risk of bias in included studies.All the studies adopted random sequence generation;blinding of participants;blinding of study personnel,and blinding of outcome assessment.Allocation concealment was reported in 14 studies,and 11 studies did not have attrition bias.Overall,the quality of the included studies was judged to be good.In six studies,systemic corticosteroids were provided as a co-intervention in both the study as well as the control group (14,15,18,19,21,26).Most of the studies were conducted on children aged between 5 and 15 years (10/16;62.5%).The dose of budesonide used in the included studies ranged from 1 to 3 mg.

Pooled effect of nebulized budesonide on risk of hospitalization

The pooled RR suggested a significant effect of nebulized budesonide in reducing the hospitalization rates.Comparedto placebo,children receiving budesonide had 43% lower risk of being hospitalized (RR 0.57;95% CI,0.39-0.85,I 2=70.3%;p=0.01) (Fig.2).There was no evidence of publication bias (P=0.754).The funnel plot is presented as Supplemental Fig.1.In a sub-group analysis based on the use of systemic corticosteroids as a co-intervention,the beneficial effect of budesonide was noted both in studies that did not use systemic corticosteroids (RR 0.24;95% CI,0.09-0.63,I2=0.0%,p=0.82) and in those where systemic corticosteroids were used (RR 0.67;95% CI,0.46-0.98,I2=77.6%,p＜ 0.01) (Fig.2).

Fig.1 Selection process of the studies included in the review

Pooled effect of nebulized budesonide on need for using systemic corticosteroids

The pooled RR suggested that use of inhaled budesonide reduced the need for systemic corticosteroids,compared to placebo.Children receiving nebulized budesonide had lower need for systemic corticosteroids,compared to children receiving placebo (RR 0.34;95% CI,0.21-0.55,I2=0.0%,p＜ 0.01) (Fig.3).There was no evidence of publication bias (p=0.462).A funnel plot is presented as Supplemental Fig.2.

Pooled effect of nebulized budesonide on length of hospital stay

There were no differences in the length of hospital stay between children receiving budesonide and those that received placebo.The standardized mean difference (in hours) between the two groups was not significant (WMD-1.53;95%CI,-3.64;0.58,I2=99.2%,p=0.16) (Fig.4).There were no differences in the length of hospital stay when studies where systemic corticosteroids were used as co-intervention were pooled (WMD-1.86;95% CI,-4.72;0.99,I2=99.4%,p＜ 0.01).There was only one study where systemic corticosteroids were not used as a co-intervention,and the finding suggested a reduction in length of hospital stay (WMD-0.55;95%CI,-1.06;-0.05) (Fig.4).There was no evidence of publication bias (P=0.925).A funnel plot is presented as Supplemental Fig.3.

Pooled effect of nebulized budesonide on adverse events.

The use of nebulized budesonide was not associated with an increased risk of adverse events (RR 0.87,95%CI;0.65-1.17,I2=27.9%,p=0.37),(Fig.5).There was no evidence of publication bias (P=0.602).A funnel plot is presented as Supplemental Fig.4.

Fig.2 Effect of nebulized budesonide compared to placebo on risk of hospitalization in children with moderate-to-severe acute asthma exacerbation with sub-group analysis based on use of systemic corticosteroids

Descriptive findings for outcomes that could not be pooled

Several other outcomes were assessed by studies that demonstrated the beneficial effect of nebulized budesonide in additional to the variables considered in this meta-analysis.A meta-analysis was not conducted owing to differences in the methods of reporting and to the limited number of studies assessing these additional outcomes.

Fig.3 Effect of nebulized budesonide compared with placebo on need for use of systemic corticosteroids in children with moderate-to-severe acute asthma exacerbation

Fig.4 Effect of nebulized budesonide,compared to placebo on length of hospital stay (in hours) in children with moderate-to-severe acute asthma exacerbation with sub-group analysis based on use of systemic corticosteroids

Nuhoglu et al.showed that use of budesonide led to a significant increase in mean peak expiratory flow rate (PEFR)[21].Van Bever et al.documented a tendency of fewer wheezing episodes in patients receiving budesonide [22].Akhtaruzzaman et al.[26]in their study showed an improved PEFR,respiratory rate,pulse rate,oxygen saturation and asthma score in children receiving budesonide compared to the control group.Pedersen et al.[24]documented that budesonide markedly improved asthma symptoms and PEFR and reduced the need for use of beta-agonists.Similarly,De Blic et al.[23]found lower incidence of asthma exacerbation with use of budesonide,a shorter duration of oral steroid therapy,and a lower number of wheezing episodes.

Discussion

Budesonide is a 16 and 17-α glucocorticosteroid with potent anti-inflammatory effect [6].In asthmatic patients,budesonide promptly suppresses airway hyperperfusion and exerts an anti-inflammatory response [27].The advantages of budesonide are that it is well tolerated among the pediatric population,it has a short half-life,and it does not lead to systemic side-effects [6].The current meta-analysis was done to provide robust,synthesized estimates on the efficacy of nebulized budesonide in reducing the hospitalization rates,the need for use of systemic corticosteroids,and the length of hospital stay in children with acute moderate-to-severe asthma exacerbations attending the pediatric emergency department.We found that use of nebulized budesonide was beneficial in terms of reducing the hospitalization rates and the need for use of systemic corticosteroids.Furthermore,use of budesonide was not associated with increased occurrence of adverse events.These findings agree with previous published reviews of inhaled corticosteroids in acute asthmatic exacerbations.A Cochrane review,published in 2012,reported that inhaled corticosteroids,compared with placebo,substantially attenuate the risk of hospitalization(odds ratio=0.27) [28].A recent meta-analysis published in 2019 also suggested that use of inhaled corticosteroids,in conjunction with systemic corticosteroids,reduces the risk of hospital admissions and leads to improvements in clinical symptoms [8].A recent review [29]of 9 studies involving 1473 pediatric patients with acute asthma documented that a combination of nebulized corticosteroids with systemic corticosteroids,compared to systemic corticosteroids alone,did not affect the rate of hospitalization but did lead to a decrease in length of hospital stay by about one day and significantly improved the acute asthma severity score.In the current meta-analysis,we noted a significant beneficial effect of nebulized budesonide,with or without concurrent systemic corticosteroid,in reducing the risk of hospitalization.However,no such effect was noted on the length of hospital stay.

Fig.5 Effect of nebulized budesonide compared with placebo on rates of adverse events in children with moderate-to-severe acute asthma exacerbation with sub-group analysis based on use of systemic corticosteroids

There were a few limitations of this meta-analysis.First,in some of the studies,the sample size was small and this could have affected the overall pooled estimates and also could have reduced the statistical power of our analysis.Second,we could not calculate pooled effect sizes for all clinical outcomes reported by the included studies owing to limited data and non-coherent reporting.We presented the findings of these outcomes only in a narrative manner.Third,for few of the outcomes (risk of hospitalization and length of hospital stay),the degree of heterogeneity was high.The high inter-study heterogeneity may be attributed to the methodological differences between the included studies.Lastly,our review was restricted to moderate-tosevere asthma exacerbations,and the findings of the metaanalysis may not be applicable to children with mild and/or persistent asthma.

To conclude,the meta-analysis provides evidence to support the use of inhaled budesonide in reducing the risk of hospitalization and the need for systemic corticosteroids among children with acute moderate-to-severe asthma exacerbation.In addition,the use of budesonide is not associated with an increase in adverse events among children.These findings underscore the need to consider using nebulized budesonide in managing asthmatic children presenting with moderate-to-severe acute exacerbations in the pediatric emergency department.Future studies should aim to determine the frequency of re-exacerbations and hospital revisits in patients receiving nebulized budesonide and to assess the effect of inhaled budesonide in mild asthma exacerbations.High-quality RCTs shall strengthen current evidence.

Supplementary InformationThe online version contains supplementary material available at https:// doi.org/ 10.1007/ s12519-020-00403-y.

Author contributionsCL designed the project;CL and ZL were involved in data collection and data analysis;CL prepared the manuscript;ZL edited the manuscript;all authors read and approved the final manuscript.

FundingNo funding was received.

Compliance with ethical standards

Ethical approvalNot required for a systematic review.

Conflict of interestThere is no benefit has been received or will be received from any party related directly or indirectly to the subject of this article.