Preschool wheezers To give steroids or not to give steroids. Have we gone full circle?

Rebecca Broomfield

With a busy family and work life my pile of “must read” journal articles grows larger and larger month by month. However, when the article below popped up on my twitter feed during January it was so relevant to what I do currently every shift and there are a significant number of differing views and options it immediately jumped to the top of the list! (And I actually read it!) The topic of whether to give steroids or not to give steroid when a preschool child presents with wheeze is one which causes huge debate and which I frequently question my own management on. A previous paper published by Panickar et al in 2009 changed our practise and guidelines, despite having questions about the applicability of the study. However, the paper outlined below suggests that we still have more to think about.
​

Oral Prednisolone in preschool children with virus-associated wheeze: a prospective, randomised, double-blind, placebo-controlled trial. 


S.J. Foster, M N Cooper, S Oosterhof, M L Borland
The Lancet Respiratory Medicine 2018 January 17

https://doi.org/10.1016/S2213-2600(18)30008-0

​

Study Aim
To assess the efficacy of oral prednisolone in children presenting to a paediatric emergency department with suspected viral wheeze.

The study was originally a non-inferiority trial designed to test the hypothesis that a placebo is non-inferior to prednisolone, the authors added in a superiority analysis, testing the hypothesis that prednisolone was superior to placebo. The secondary hypothesis was added after the data had been collected but prior to data analysis. 


Participants
Eligible patients were between 2- 6 years of age who presented to the paediatric emergency department in Princess Margaret Hospital, Perth, Australia and had a clinical diagnosis of wheeze combined with symptoms of a viral upper respiratory tract infection.

Patients were excluded with: Oxygen saturations <92% in air, a silent chest, shock or sepsis, previous PICU admission with wheeze, prematurity, other cardio-respiratory disease, likely alternative diagnosis for wheeze, steroid treatment within the preceding 14 days, allergy to prednisolone or previous study recruitment.

The eligibility criteria were suitable for the objective and looked at a population of children who regularly present with viral wheeze. The authors have excluded the bronchiolitis age group of children by excluding children under 2. This is important because they respond to different management.

Design
There were 3727 patients assessed for eligibility. After exclusions 312 were put into the placebo arm and 312 into the prednisolone arm. Following withdrawals 300 were included for analysis in the placebo group and 305 for the prednisolone group.

Prior to data collection the authors calculated a sample size in order to ensure significant results. This was calculated on the original aim of non-inferiority.

---

The study was a randomised double blind trial. Once eligible the participants were randomly assigned on a 1:1 basis to receive either 1mg/kg once daily of prednisolone or placebo. The placebo was formulated by the hospital and matched the prednisolone for volume, concentration, colour, smell and taste. The drugs were in matching bottles and randomisation was appropriate. The blinding for parents, patients, doctors, the research team and biostatician was kept until the statistical analysis was completed.

The initial drug dose was administered by a nurse but for the following 2 days were given by the parents at home. The severity of the wheeze was assessed prior to treatment using a calculated pulmonary score. The family completed a questionnaire about home management and previous symptoms and a viral swab was taken from each participant. Each patient was managed with bronchodilators in line with the hospital policy.

If the patient who was included in the study was admitted to the ward, and the admitting doctor felt that the patient should receive steroids, then these were given. 23 patients in the placebo group were given steroids in these circumstances. These patients were included in the intention to treat arm and the continuation of the study drug, alongside the prescribed prednisolone was at the discretion of the patient and their parents. They were included in the analysis and if anything would have made it more difficult to demonstrate a statistical significance between the groups.

A pulmonary symptom scoring system was used for each patient to group wheeze severities together for analysis which enabled comparisons between groups, and to assess whether initial symptom severity was responsible for patient outcomes. All staff were competent in its use, however, this has score not been validated in children less than 5 years old.


Outcomes
This paper only comments on some of the data collected during the trial, the remaining data on long term outcomes will be presented in further manuscripts. The initial dual primary outcomes were length of stay in the emergency department and the total length of stay within the hospital. Secondary outcomes (within the first 7 days after hospital discharge) included: reattendance, readmission, salbutamol usage and residual symptoms after discharge.

During the data collection it was felt the initial primary outcome; length of stay within the emergency department, was not reflective of the clinical condition as it was dependent on many non clinical factors. The study therefore only looked at an outcome of total length of stay in hospital until the participant was fit for discharge. This change was clearly outlined by the authors and appropriate for the aim of the study.

Analysis
The study groups were well balanced and the authors found no significant differences between groups in: baseline demographics; pulmonary score at presentation; personal or family history of atopy; use of salbutamol before attendance to the department. Categorical variables were analysed using a χ2 test or fishers exact test and continuous variables were compared using Students t test. Therefore a previously identified risk factor of personal or family history of atopy did not affect the outcomes in this study.

Linear regression is the main analysis used to see if outcomes differ for the 2 groups. The authors conclude:

• Placebo treatment was inferior to prednisolone
  

• Length of stay until ready for discharge was significantly reduced in the prednisolone group compared to the placebo group. Unadjusted ratio of geometric mean of 0.79 (95% CI 0.64-0.97; p=0.0227)
  

• 199 patients were discharged straight from the emergency department and had a length of stay <4 hours. (99 from placebo arm, 100 from prednisolone arm) No difference in length of stay was found between the arms of these patients.
  

• Patients in the prednisolone group had a reduced risk of their length of stay exceeding 7 hours (adjusted relative risk 0.82, 95% CI 0.69-0.96; p=0.0166) or 12 hours (adjusted relative risk 0.67, 95% CI 0.51-0.86; p= 0.0018)
  

Subgroup analyses:

• Within the mild subgroup prednisolone was associated with a reduced risk of length of stay exceeding 12 hours. (adjusted RR 0.63, 95%CI 0.42-0.96; p= 0.0329)
  
• There was no difference found in those with a moderate pulmonary score.
  
• Within the severe subgroup prednisolone was associated with a reduced risk of length of stay exceeding 7 hours (adjusted RR 0.76, 95% CI 0.58-0.99; p=0.0428)
  
  

• In patients who had received inhaled salbutamol prior to attendance prednisolone was associated with an overall reduced length of stay and reduced risk of length of stay exceeding 7 hours or 12 hours which was independent of the pulmonary score at presentation.
  
• There were no significant findings between groups based on the presence or absence of viral antigens. Prednisolone was associated with a reduced risk of length of stay exceeding 12 hours in both groups.
  
• In patients who had a prior diagnosis of asthma prednisolone was associated with a significantly reduced risk of length of stay exceeding 7 hours or 12 hours. 
  

Secondary outcomes assessed were around representation post discharge. 26 patients re-attended (15 from prednisolone arm and 13 from the placebo arm). 3 patients from the prednisolone group and 2 patients from the placebo group were then prescribed steroids. One patient, from the prednisolone group needed admission to PICU. The statistical analysis of the reattenders (secondary outcomes) was not made clear within the article.

Discussion
The authors discuss their results in regards to the Panickar 2009 paper; they postulate that the study design could go some way to explaining the different outcome. The authors outline that they have tried to address some of the identified limitations found in the 2009 paper. These include the exclusion of children under 2 years old, thus reducing the likelihood for inclusion of patients with bronchiolitis.

They urge some caution within their subgroup analysis conclusions as the sample size was smaller than the sample size used for calculating the general conclusion, also the patients were not randomly allocated to the arms based on the severity of symptoms or the use of salbutamol prior to attendance.

This presentation is something we see daily in the emergency department and children’s assessment unit. It is an area for which I don’t feel that we have fully understood all the physiology behind the presentations. There are most likely many phenotypes of childhood wheeze. More research is definitely needed in order to assess the need for steroids and how to select the patients who would benefit from them. I look forward to reading further papers on the more long term conclusions of this trial. I think that I will still continue to judge the need for steroids on a patient by patient basis. Questioning with each patient whether they should or should not receive steroids. (And we’ve not even touched on Dexamethasone vs. Prednisolone!)

It would be great to hear your views on this topic, I encourage you to comment on the blog or tweet me. (@RCBroomfield)

Have a lovely February
Rebecca

The previous paper referenced can be found at:
Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, Grigg J. Oral Prednisolone for preschool children with acute virus induced wheezing, New England Journal of Medicine. 2009 Jan 22;360(4);329-38