Efficacy of oral corticosteroids for preschool wheeze

Abstract

INTRODUCTION: Acute preschool wheeze is one of the most common respiratory conditions in children aged 1 to 6 years. Due to its high prevalence, it consumes substantial healthcare resources and creates economic burdens. Although oral corticosteroids (OCS) have been widely used to treat acute wheezing episodes in clinical practice, evidence has been contentious regarding the efficacy of OCS for preschool wheeze. This thesis aims to assess the OCS treatment in treating acute preschool wheeze by incorporating perspectives of health professionals (HPs) and patients into an individual participant data (IPD) analysis.

METHODS: This PhD project comprises four complementary phases. In Phase One, I conducted a global systematic review and meta-analysis of the literature published between 1994 and 2020 in eight databases. Summary estimates were obtained using a random-effects model, employing the Hartung-Knapp-Sidik-Jonkman (HKSJ) approach. In Phase Two, I invited two groups (1) HPs, including lead authors of OCS preschool wheeze trials, and (2) parents of children who had experience with OCS for acute wheeze in children aged 1-6 years. In the first stage, each group was asked to rank outcome measures based on their priority, and in the second stage, they were invited to a group meeting based on a nominal group technique to identify a consensus primary outcome measure.

In Phase Three, a meta-analysis was conducted using IPD from seven trials (no. of children=2172) for children aged 12-71 months (n=1823). The primary outcome was the change in wheeze severity score (WSS), and secondary outcomes were length of hospital stay (LOS), revisit to general practice (GP)/emergency department (ED) or hospital, and further use of asthma medications. I performed a two-stage meta-analysis for overall analyses and adopted a one-stage approach when very few cases were available. Subgroup analyses by risk factors were conducted to examine effect modification and treatment-covariate interaction.

In Phase Four, I undertook a Desirability Of Outcome Ranking (DOOR) analysis to assess overall clinical outcomes using data for change in WSS, repeat healthcare service utilisation (i.e. revisit to GP/ED and/or rehospitalisation), and adverse events (AEs). Ordinal DOOR outcomes were constructed by combining these single outcomes. Ranks 1 to 8 were assigned to the ordinal DOOR outcomes of individual patients in order of desirability, in which higher ranks were assigned to those with better DOOR outcomes. I then calculated the probability of those receiving OCS having a better DOOR outcome compared to those receiving a placebo.

RESULTS: In Phase One, of 11 studies satisfying the eligibility criteria, ten were included in the meta-analysis, and one study was excluded because the majority of the children were younger than 12 months. According to the meta-analyses, there was no sufficient evidence showing that OCS reduced LOS, risks of revisit to GP/ED or rehospitalisation, or additional need for subsequent steroids or doses of bronchodilator (or short-acting beta-2-agonist, SABA). However, analyses were substantially restricted due to heterogeneous eligibility criteria and different summary estimates between the studies.

In the first stage of Phase Two, LOS was the most preferred outcome measure for the HPs (n = 255), whereas the change in WSS was the priority for parents (n = 10). In the second stage, seven HPs and nine parents participated in the consensus group meeting and agreed that change in WSS should be the top priority of the treatment. This result was used as a primary outcome for the IPD meta-analysis.

In Phase Three, the IPD meta-analysis showed that compared to the placebo group, the change in WSS at 4 hours in the OCS group showed a mean difference (MD) of -0.31 (95% CI = -0.38 to -0.24, I2 = 0.0%) in the two studies where data were available after adjusting for age (months), allergies and parental allergies. For the change in WSS at 12 hours, the MD in three studies was -0.02 (95% CI = -0.17 to 0.14, I2 = 0.0%). In five studies, OCS treatment was associated with an MD in LOS of -3.18 hours (95% CI = -4.43 to -1.93, I2= 0.0%). For revisit to GP/ED and rehospitalisation, the pooled ORs in seven studies were respectively 1.11 (95% CI =0. 86 to 1.43, I2= 0.0%) and 0.94 (95% CI = 0.38 to 2.32, I2= 20.3%). According to subgroup analyses, OCS had a preferential benefit for children with moderate-to-severe wheeze, especially those with previous wheezing/asthma, history of allergies or parental allergy/asthma.

In Phase Four, the DOOR analysis demonstrated the possibility of understanding the global patient experience using a composite of efficacy and safety data of OCS for preschool wheeze. However, the DOOR did not support the benefits of OCS treatment for preschool wheeze when considering the change in WSS, repeat healthcare service utilisation and AEs simultaneously. Although this study successfully constructed the DOOR outcome representing the total patient experience with the OCS course, there remain limitations in applying DOOR because it relies on the availability of data and the outcome definitions.

CONCLUSION: This is the first study exploring a consensus outcome measure, performing IPD meta-analyses and applying DOOR methodology to assess the efficacy of OCS for preschool wheeze. It succeeded in incorporating stakeholders' perspectives in evidence synthesis using IPD from seven clinical trials. It provided more reliable evidence of OCS effects and found that OCS is beneficial for short-term outcomes (e.g., reduction in LOS) rather than longer-term outcomes. Thus, this thesis provides important insights into OCS use in the ED setting concerning risk factors. At the same time, it points out what needs to be improved in parent/patient involvement, data recording, and sharing to yield high-quality evidence.