An update on the efficacy of oral corticosteroids in the treatment of wheezing episodes in preschool children

Abstract

Traditionally, oral corticosteroids (OCSs) have been the mainstay of treatment for acute wheezing episodes among preschool children with history of recurrent wheezing. Although there is substantial evidence for the efficacy of OCSs as a treatment for asthma exacerbations in school-aged children and adolescents, recent clinical studies questioned the benefits of OCSs as a treatment for acute wheezing in preschool children. This review summarizes the current evidence on the efficacy of OCSs as a treatment for acute wheezing episodes among preschool age children with episodic wheezing focusing on studies performed in three different settings: OCSs treatment initiated by the parents in the outpatient setting, OCSs initiated in the Emergency Department (ED), and OCSs treatment among hospitalized preschool children. The results of most studies reviewed in this paper do not support the efficacy of OCS treatment among preschool children with recurrent wheezing. The heterogeneity of early childhood wheezing and asthma might be part of the explanation for lack of efficacy of this intervention noted in multiple studies.

Introduction

International and national asthma guidelines recommend Oral Corticosteroids (OCSs) as a treatment for acute exacerbations that are not responsive to bronchodilators[National Asthma Education and Prevention Program, 2007, Prevention, 2011]. There is substantial evidence for the efficacy of OCSs as a treatment for asthma exacerbations in school-aged children and adolescents, especially in the acute care setting where OCSs treatment is associated with lower risk of relapse, fewer hospitalizations, and less need for β2-agonist treatments[Rowe et al., 2007]. Traditionally, wheezing episodes among preschool children have been treated with OCSs based on OCSs established efficacy among school-aged children and adolescents with asthma. However, many of the preschool children have a disease phenotype that is different than the one seen among older children with established asthma, as many of these young children experience significant morbidity during acute episodes of wheezing, but have minimal respiratory symptoms consistent with persistent asthma between these episodes (i.e., the “severe intermittent wheezing” phenotype)[Bacharier et al., 2007]. Recently, the results of clinical studies questioned the benefits of OCSs for acute wheezing in preschool children; and numerous editorials that have followed these studies have suggested that the role of OCSs treatment among preschool children should be reevaluated due to concerns of lack of efficacy and its potential side effects[Bush, 2009, Grigg, 2010, Gergen, 2013]. The purpose of this review is to present the current evidence for the efficacy of OCSs in preschool age children with recurrent wheezing.

Selection of studies in this review

This review focuses on the efficacy of OCSs in preschool age children with recurrent wheezing. Therefore, we have not reviewed the evidence from studies in which most/all patients presented in their first wheezing episode[Jartti et al., 2006], [Lehtinen et al., 2007], [Lukkarinen et al., 2013]. A summary of the management of this distinct clinical scenario has been reviewed elsewhere[Beigelman et al., 2014].

This review focuses on the evidence originating from randomized double-blinded and placebo-controlled trials (RDBPCT) and from observational trials that took specific measures to minimize selection and measurement biases. Thus, it does not include the result of a small (n=32) nonrandomized and nonblinded trial by Brunette et al.[Brunette et al., 1988], as well as a prospective observational trial by Najada et al.[Najada et al., 2001] that investigated the efficacy of OCSs to prevent urgent visits while using a historical cohort as the control group. Since the recurrent wheezing phenotype in preschool children is the focus of this review, it does not include studies that reported outcomes for wide age ranges of children without specific subgroup analysis for preschool age children[Harris et al., 1987, Storr et al., 1987, Gleeson et al., 1990, Scarfone et al., 1993, Jartti et al., 2007].

Studies investigating the efficacy of OCSs in preschool age children with episodic wheezing are very heterogeneous in their study designs, wheezing phenotypes, settings (e.g., parents initiated treatment at home vs. inpatient study), and dosing regimens. Therefore, we grouped the studies based on their primary outcome, which is related to the setting of the intervention. The main goals of studies performed in the outpatient setting are to prevent urgent visits and to relieve respiratory symptoms by OCSs provided by the parents. Studies performed in emergency departments (ED) predominantly aim to prevent hospitalization, while studies in the inpatient setting aim toward shortening the duration of hospitalization.

Studies performed in the outpatient setting

Outpatient RDBPCT

Three clinical trials have investigated the efficacy of OCSs for recurrent wheezing among preschool children in the outpatient setting. A RDBPCT by Oommen et al.[Oommen et al., 2003] enrolled children 1 to 5 years old with a history of hospital admissions for viral-induced wheeze. Children were randomized to parent-initiated prednisolone 20 mg/day for 5 days, or placebo at the next episode of viral-wheeze, defined as wheeze occurring within two days of the onset of coryzal upper respiratory tract symptoms. The primary outcome was the parent reported seven days respiratory symptom scores that assessed daytime and nighttime cough, wheeze, and respiratory difficulties as well as daytime play limitations. Additional stratification was performed based on the child’s level of eosinophilic priming defined by serum levels of eosinophilic cationic protein and eosinophilic protein X. The purpose of this stratification was to evaluate OCS response among those children at greater risk for developing persistent atopic asthma. Outcome data was available for 120 children. Grant et al.[Grant et al., 1995] conducted a crossover RDBPCT (6 months in each block) of children 2 to 14 years old (n=86) with at least two previous urgent asthma visits in the preceding 12 months. Children were randomized to a single 2 mg/kg (up to 60 mg) dose of parent-initiated prednisone, or placebo, given if children did not respond to treatment with 3 hours of their regular asthma rescue medications. The primary outcome was the number of outpatient clinic or ED visits for acute asthma. Secondary outcomes included the number of episodes resulting in hospital admissions. This review will present the results of the subgroup analysis that included only the subpopulation of 2 to 5 year old children.

Webb et al.[Webb et al., 1986] conducted a small double blinded, partial crossover trial of children (n=38) less than 18 months of age with at least 2 previous wheezing episodes. Children were randomized to either receive parent-initiated prednisolone 1 mg/kg BID for 5 days, or placebo, for an acute wheezing episode. Crossover analysis was done if patients did not improve within 8 days of initiating treatment or if they had a second attack. Outcomes were reported for the entire study population and for age-stratified groups: 0 to 6 months, 6 to 12 months, and 12–18 months of age. The primary outcome was the difference in parent-recorded symptom scores over eight days.

Results of the RDBPCT outpatient studies

Effect on prevention of clinic visits, ED visits, and hospitalization

The results from the studies by Oommen[Oommen et al., 2003] and Grant[Grant et al., 1995] found that OCSs treatment initiated at home by the parents did not prevent unscheduled clinic visits, ED visits, or hospital admissions. Grant and colleagues reported outcomes for those attacks in which the study medication was given (more than 60% of the episodes) and surprisingly revealed that in the subgroup of 2 to 5 year olds, prednisone administration compared to placebo was associated with a greater proportion of episodes that resulted in unscheduled clinic or ED visits: 35% vs.14%, P=.04). Oommen[Oommen et al., 2003] revealed a similar trend toward less favorable outcomes associated with parent initiated OCSs at home by reporting a numerically, but not statistically significant, higher proportion of episodes that resulted in hospitalization in the prednisolone group (12% vs. 3% p= .06).

Effect on symptoms and reduction rescue albuterol use

Oommen[Oommen et al., 2003] and Webb[Webb et al., 1986] found no significant improvement in symptom scores between treatment and placebo groups. Moreover, Oommen found no difference in symptom scores in children with either high or low eosinophilic priming suggesting that OCSs are not beneficial during an acute wheezing episode even in those at greater risk of persistent wheeze. Finally, early parent OCSs treatment at home compared to placebo was not associated with a reduced number of rescue albuterol treatments[Oommen et al., 2003].

Overall, these RDBPCTs revealed no benefit of parent-initiated OCSs at home with regard to prevention of urgent asthma visits or improvement of clinical symptoms. The suboptimal study adherence in Dr Oommen’s study reduces its external validly and precludes drawing a firm conclusion about lack of efficacy of OCSs treatment for outpatient wheezing, as approximately 70% of parents were not fully adherent to study protocol. However, Dr. Grant’s study had a higher study adherence and showed an unexpected result: OCSs treatment was associated with an increased number and proportion of episodes that resulted in ED visits. The exact cause of this unexpected finding could not be determined.

Outpatient post-hoc analysis

Challenges such as low adherence to study procedures and intervention make it difficult to investigate the efficacy of OCSs in the outpatient setting by a prospective randomized trial. Therefore, we recently took a different approach to investigate OCSs efficacy in the outpatient setting[Beigelman et al., 2013]. The study included post-hoc and replication analyses in two outpatient cohorts of children aged 1–5 years with recurrent wheezing participating in 2 clinical trials of The Childhood Asthma Research and Education (CARE) Network: the Acute Management Intervention Strategies (AIMS) [Bacharier et al., 2008], and the Maintenance and Intermittent Inhaled Corticosteroids in Wheezing Toddlers (MIST) clinical trials[Zeiger et al., 2011]. In both studies, prednisolone (once daily dose at 2 mg/kg/day for 2 days, followed by 1 mg/kg/day for an additional 2 days) was a rescue treatment prescribed for significant lower respiratory tract illnesses (LRTI), based on specific predefined protocol criteria. Symptom scores during LRTIs (more than 700 episodes in each cohort) were compared between episodes that were and were not treated with OCSs after adjusting for differences in disease and episode severity covariates that could result in a selection bias (i.e., the more severe episodes are more likely to be treated with OCSs), while using a propensity score adjustment [Beigelman et al., 2013]. The results in the initial cohort (AIMS[Bacharier et al., 2008]) showed that the addition of OCSs treatment during significant LRTI did not reduce symptoms severity, measured by symptoms scores, and it did not hasten clinical recovery measured by the time to resolution of symptoms. The results were confirmed in the validation cohort (MIST[Zeiger et al., 2011]), which includes only preschool children who have higher risk for future asthma based on a positive modified asthma predictability index (mAPI) status, suggesting that in this study OCSs treatment did not reduce symptoms severity even among these preschool children with recurrent wheezing who have personal history of atopy and/or family history of asthma. Although the methodological approach of this study was very sound, an unknown residual bias could not be excluded based on the post-hoc nature of this study. Therefore, this study should be viewed as hypothesis generating, and should be followed by outpatient prospective trials.

Studies performed in ED setting

RDBPCTs in the ED

Two RDBPCT trials investigated OCSs efficacy in the ED setting. Tal et al. [Tal et al., 1990], conducted an age-matched RDBPCT of children (n=76) 7 to 54 months old with history of at least three previous wheezing episodes seen in the ED with acute asthma symptoms. Children were randomized to a single dose of 4 mg/kg of IM methylprednisolone, or placebo, given within 30 minutes of ED arrival, as well as inhaled open label salbutamol. Patients were admitted or discharged after 3 hours based on clinical criteria. The primary outcome was the rate of hospital admission. Subgroups analysis for children 7 to 24 months old and for children 25 to 54 months old was reported.

A RDBPCT by Csonka et al. [Csonka et al., 2003] studied the effect of oral prednisolone (2 mg/kg once then 2 mg/kg/day BID for 3 days) given in the ED on hospital admission rates among 123 children 6 to 35 months old with not more than one previous physician diagnosed wheezing episodes. Forty-four percent of the placebo group and 37% of the prednisolone group had never been treated for wheezing before.

Results of the RDBPCT ED studies

Prevention of hospital admissions and reduction in length of stay

The ED trials yielded conflicting results. Tal et al.[Tal et al., 1990] reported that systemic corticosteroids treatment was associated with a significantly smaller proportion of participants requiring admission (20% vs. 43%, p< .05). The treatment effect was significant among children 7 to 24 months old but not among children 25 to 54 months old. However, Csonka et al.[Csonka et al., 2003] found no significant difference in the percentage of those admitted from the prednisolone compared to the placebo group (54% vs. 53%; p= .88); OCS treatment, among the children who were eventually hospitalized, was associated with numerically shorter, but not statistically significant, duration of hospital stay (2 vs 3 days, P = 0.06).

Improvement in respiratory symptoms

Tal et al. reported a significant improvement in symptom scores (p < .01), and Csonka et al. reported a reduced median duration of symptoms in hospitalized children from 2.0 days in the placebo group to 1.0 day in the prednisolone group (p < .001). Csonka et al. found no significant difference in asthma-revisits within 14 days after ED discharge in the prednisolone vs. placebo group (25% vs. 28.8%; p=.67).

Overall, these 2 studies, which investigated the efficacy of systemic steroids in the ED setting, yielded conflicting results regarding the effect of systemic corticosteroids on hospitalization prevention; however, the intervention was beneficial for improvement in respiratory symptoms. There were important differences between study populations as approximately 40% of the children in Csonka’s trial never wheezed before, compared to Tal’s study population that included only children with at least three previous wheezing episodes

Studies performed in the inpatient setting

Until recently, only one relatively small study has investigated the efficacy of OCSs in a cohort of hospitalized preschool children: Fox et al.[Fox et al., 1996] conducted a RDBPCT enrolling children (n=62) 3 to 15 months of age with at least one previous episode of wheeze hospitalized due to acute wheezing. Children were randomized to one of three groups: group A received oral salbutamol and prednisolone 2 mg/kg/day for 5 days, group B received oral salbutamol and placebo, and group C received placebo and placebo. The investigators reported on a reduction in number of treatment failure, defined as readmission to the hospital and/or the presence of wheeze on day 14, with oral salbutamol compared to placebo. However, adding oral prednisolone did not reduce the risk of treatment failure, anddid not improve symptom scores.

The main evidence on the efficacy of OCSs treatment for hospitalized children with viral wheeze has originated from a multi-center RDBPCT by Panickar et al.[Panickar et al., 2009]. The study population included children between 10 and 60 months of age (n=687) with acute wheezing preceded by viral URI symptoms. 68% of the placebo group and 63.6% of the prednisolone group had at least one previous wheezing episode, and 124 (18%) children had a positive API. Children were randomized to receive prednisolone: 10 mg/day for 5 days for children 24 months old and younger, or 20 mg/day for 5 days for children older than 24 months; or placebo. There was no significant difference in the primary outcome: the median time until actual discharge between the prednisolone and placebo groups (13.9 vs. 11.0 hours, p= 0.18), or in the median time until signoff for discharge (12.0 vs. 10.1, p=.16). There was no significant difference between the groups in all secondary outcomes including: clinical symptoms measured by the study team using the Preschool Respiratory Assessment Measure (PRAM) scale scores over the first day of admission, the mean 7-day symptom score assessed by the parents, the mean number of albuterol treatments given at home over 7-day period, the time required for the child to be “back to normal”, and the number of hospital readmissions for wheezing within a month after discharge. No positive treatment effect was noted among patients with higher risk for future asthma as there was no difference in the duration of hospital stay among patients with a positive API. Stratification by baseline PRAM score did not reveal any significant differences in the time to actual discharge, suggesting that OCSs response was not dependent on the initial severity of the episode.

Panickar et al. concluded that the most likely explanation for lack of OCSs efficacy in their trial, in contrast to the beneficial effects reported by Tal et al.[Tal et al., 1990] in the ED setting, is related to disease phenotype, as the majority of children in their trial did not have “the classic atopic asthma phenotype”. However, even stratification by API status did not detect any beneficial effects of OCSs therapy suggesting lack of OCS effect even in patients with atopic characterizations. We suggest that the negative results of this study could also be related to the relatively mild disease severity of these patients, as the mean duration of hospitalization in the placebo group was 13.9 hours, making it hard to detect additional reduction in duration of hospitalization. It should not be excluded that potential OCSs benefits might be detected among a cohort with more severe episodes and/or longer duration of hospitalization. Although we highlighted this potential limitation of this study, we still believe that the negative results of this large and well-designed trial are likely an accurate reflection of the lack of efficacy of OCSs for viral-induced wheeze.

Although most current evidence suggests that OCSs are not an effective treatment for viral-induce wheeze, it may be that OCSs response is virus related. This was recently suggested by Jartti et al.[Jartti et al., 2007] who conducted a post-hoc analysis of a RDBPCT that investigated the effect of 4 days of prednisolone vs. placebo on the duration of hospitalization among children 3 months to 7 years old (mean age of 2.1 vs. 2.9 years in the prednisolone vs. placebo groups) who had at least 2 previous wheezing episodes. Among the entire study population there was no difference in time until ready for discharge between the prednisone and placebo groups. However, there was a significant reduction in the time until ready for discharge in children treated with prednisone among the sub group of children with positive viral PCR studies for rhinovirus or enterovirus. This is the first study to demonstrate a potential virus-specific effect of OCSs treatment. As these findings originated from a post hoc analysis, confirmation by a future prospective trial is warranted.

Summary of evidence and discussion

The available data suggest that there is little high quality evidence to support the efficacy of oral corticosteroids in preschool children with recurrent wheeze (i.e., the severe intermittent wheezing phenotype), as only one RDBPCT clearly showed benefit for this intervention when provided in the ED[Tal et al., 1990] (Table 1). The largest RDBPCT investigating the efficacy of OCSs for episodic wheeze among preschoolers was performed in the inpatient setting and did not detect any benefit for the intervention[Panickar et al., 2009]. RDBPCTs in the outpatient setting also failed to demonstrate clinical efficacy of OCSs given by the parents at home. However, the exact role of OCSs in the treatment of outpatient wheezing episodes could not be definitely determined, as the largest outpatient RDBPCT was complicated with low parents’ adherence to study procedures, which affects the external validity of its results. A post-hoc analysis that was conducted to overcome this obstacle of low adherence in outpatient trials, revealed no benefit of OCSs treatment[Beigelman et al., 2013].

Table 1.

Summary of studies investigating the efficacy of oral corticosteroids in the treatment of wheezing episodes in preschool children

Study	Population	Intervention	Outcomes	Results
Outpatient studies
Oommen et al, 2003 RDBPCT	1–5 y/o (n=120) with history of hospitalization for wheeze, stratified by eosinophilic priming status	Early parent-initiated prednisolone 20 mg/day x 5 days, or placebo	Parent reported symptom scores Admission rates, frequency of rescue medication use, and ED visits	No significant difference in symptom scores (independent of eosinophilic priming status) No significant difference in hospitalization or ED visits rate
Grant et al, 1995 RDBPCT, crossover design	2–14 y/o (n=86) with history of 2 acute visits for asthma in past 12 months. Specific subgroup analysis of the 2–5 y/o	Parent-initiated prednisone 2 mg/kg x 1 (max 60 mg), or placebo, if no response to rescue asthma medication within 3 hours from the initiation of exacerbation	Unscheduled outpatient and ED visits Admission rates	Results for the 2–5 y/o group: Higher number and a greater proportion of episodes that resulted in unscheduled outpatient visits or ED visits once the children were treated with prednisone
Webb et al, 1986 Double blinded partial-crossover trial	< 18 m/o (n=38) with ≥ 2 previous wheezing episodes	Parent-initiated prednisolone 1 mg/kg BID x 5 days, or placebo	Difference in symptom scores over 8 days	No significant improvement in symptom scores on days 1, 3, 5, or 8 between the treatment groups
Beigelman et al, 2013 Post hoc analyses of 2 RDBPCTs	1–5 y/o with episodic wheeze (at least 2 previous episodes) participating in 2 clinical trials (more than 700 episodes in each cohort)	Prednisolone 2 mg/kg/day x 2 days, then 1 mg/kg/day x 2 days, prescribed as a rescue treatment based on pre-defined protocol criteria	Difference in symptom scores Time until resolution of symptoms	Prednisolone treatment was not associated with a reduction in symptoms severity or in a shorter time until symptom resolution
Emergency department studies
Tal et al, 1990 Age-matched RDBPCT	7–54 m/o (n=76) with ≥ 3 previous wheezing episodes, 7–24 m/o and 25–54 m/o subgroup analysis	Single dose of IM methylprednisolone 4 mg/kg, or placebo within 30 minutes of ED arrival	Admission rate symptoms score	Significant reduction in admission rate (significant in 7–24 month olds, but not in the 25–54 month olds) Significant improvement in symptoms score
Csonka et al, 2003 RDBPCT	6–35 month olds (n=123) with ≤ 1 previous wheezing episodes (35%-45% in each group with no history of previous wheezing episodes)	Prednisolone 2 mg/kg once then 2 mg/kg/day x 3 days, or placebo	Admission rate Length of hospital stay, duration of symptoms, revisits within 14 days of ED discharge, revisits after hospitalization	No significant difference in admission rate Significant reduction in symptom duration No significant difference in length of hospital stay, revisits after initial ED visit, or after the hospitalization
Inpatient studies
Fox et al, 1996 RDBPCT	3–15 months old (n=62) with ≥ 1 previous wheezing episode	Group A: oral salbutamol + prednisolone (2 mg/kg/day x 5 days) Group B: oral salbutamol + placebo Group C: placebo + placebo	Clinical symptom scores on days 3, 5, 7, 10, and 14 Time in the hospital, salbutamol use, treatment failures	Reduction of treatment failures with the addition of salbutamol, but not with the addition of prednisolone No significant decrease in symptom scores
Panickar et al, 2009 RDBPCT	10–60 months old (n=687) with acute wheeze preceded by URI symptoms Two third of participants with history of previous wheeze Subgroup analysis based on API positivity status and additional stratification based on initial symptoms score	Prednisolone 10 mg/day x 5 days (≤ 24 months old), Prednisolone 20 mg/day x 5 days (≥ 24 months old); or placebo	Duration of hospitalization symptoms score over the first 24 hours, mean 7 day symptom score, albuterol use	No significant difference in duration of hospitalization, 24 hours symptom score, mean 7 day symptom score, or albuterol use (independent of API status, or initial symptom score)
Jartti et al, 2007 Post hoc analysis of RDBPCT	3 months – 7 y/o (median age 2.1 - 2.9 yrs.) with ≥ 2 previous wheezing episodes	Prednisolone 2 mg/kg once then 2 mg/kg/day divided TID x 3 days, or placebo	Time until ready for discharge	No significant difference in the primary outcome for the entire study population Significant reduction in the time until ready for discharge among patients with evidence for rhinovirus or enterovirus respiratory infection

API: asthma predictability index; ED: emergency department; LRTI: lower respiratory tract illnesses; URI: upper respiratory tract infection; RDBPCT: randomized double-blinded and placebo-controlled trial

The negative results of the outpatient studies may be related to the relativity mild severity of these episodes leaving little room for clinical improvement. However, the study by Panickar et al. [Panickar et al., 2009] that was performed in the inpatient setting, and theoretically should have included the most severe patients, failed to show benefits for OCSs treatment. Never the less, mild severity of exacerbation as a reason for negative results could not be completely ruled-out as even this inpatient study[Panickar et al., 2009] included not very severe patients, as evident by a relatively short duration of hospitalization. It was recently suggested that lack of OCSs efficacy in previous trials might be related to relatively low OCSs dosing, and that higher OCSs dosing could result in clinical improvement[Weinberger, 2014]. Although this could not be completely excluded, there is no solid evidence that higher OCSs dosing in children would provide additional benefits, as a randomized controlled study in children hospitalized for asthma exacerbation that compared the efficacy of 3 single doses of prednisolone (0.5, 1, or 2 mg/kg) showed no differential effects on the duration of hospitalization, improvement in pulmonary function, or clinical scores[Langton Hewer et al., 1998]. Timing of the intervention might affect the response to treatment: Early OCSs administration given very early at the course of exacerbation potentially could prevent the development of acute airway inflammation. However, the two outpatients studies that have investigated early parents administration of OCSs at home failed to show benefit of this intervention[Grant et al., 1995, Oommen et al., 2003]. Finally, lack of OCS response noted in the studies by Csonka [Csonka et al., 2003], and Panickar [Panickar et al., 2009] might be related to inclusion of first-time wheezers among study participants. This might dilute a potential effect of OCSs among populations of preschool children with viral-induced recurrent wheeze, as the lack of effect of systemic corticosteroids in first-time viral-induced wheeze (i.e., viral bronchiolitis) has been previously demonstrated [Corneli et al., 2007].

We do not suggest that response (or lack of response) to OCSs is solely age related, as we do not believe that there is a well defined age cutoff after which children start to respond to OCSs. Instead, we suggest that the age-dependent differential response to OCSs may be attributed to different phenotypes of early childhood wheezing and asthma. These phenotypes might be associated with different patterns of airway inflammation, which in-turn might result in a differential OCSs response. It could be that preschool children with recurrent wheezing have a greater extent of acute neutrophilic airway inflammation, which is more steroid resistant; while older school children with established asthma have more chronic eosinophilic airway inflammation, which is more corticosteroid responsive. Lack of chronic eosinophilic airway inflammation among young children with recurrent wheezing was confirmed in one study[Le Bourgeois et al., 2002], but not in another study[Saglani et al., 2007]. The exact type of airway inflammation among these young children, and its association with disease phenotype, are yet to be determined.

Conclusions and recommendations

The vast majority of studies that evaluated the efficacy of OCSs among preschoolers with episodic wheeze failed to show benefit for this intervention (Table 1). However, the exact role of OCSs remains uncertain as the current studies have limitations including relatively mild severity of exacerbations in the inpatient study, and low compliance in the largest outpatient study. Based on the current evidence we suggest that clinicians should continue treating these children with inhaled β-agonists, but may consider avoiding OCSs treatment in outpatient episodes provided adequate follow-up is assured. As the data regarding lack of efficacy of OCSs treatment is even more compelling among hospitalized toddlers, we suggest that clinicians may consider postponing OCSs treatment in many hospitalized recurrent wheezers, and reserve the treatment for patients with a current or an anticipated severe clinical course including: patients requiring intensive-care admission, patient who do not improve appropriately with β-agonist treatment, and patients who have indicators of severe disease (e.g., persistent hypoxemia) or other significant medial history (as chronic lung disease). Overall, the evidence base for the management of recurrent wheezing in preschool children is still incomplete, and additional RDBPCTs are required, mainly in the outpatient setting.

Abbreviations

API

asthma predictability index

ED

emergency department

ICS

inhaled corticosteroids

LRTI

lower respiratory tract illnesses

mAPI

modified asthma predictability index

OCSs

oral corticosteroids

PIS

pulmonary index score

PRAM

Preschool Respiratory Assessment Measure

RDBPCT

randomized double-blinded and placebo-controlled trial

URI

upper respiratory tract infection