Steroids for pre-school wheeze

Wheeze must be one of the most common paediatric presentations to the emergency department, and until now, most of us have been reassuring parents and sending them away without treatment. But should we be doing more? A paper released just last week suggests that we could.

Foster SJ, Cooper MN, Oosterhof S, Borland ML. Oral prednisolone in preschool children with virus-associated wheeze: a prospective, randomised, double-blind, placebo-controlled trial. The Lancet Respiratory Medicine. 2018 Jan 17.

Meredith Borland is a founding member of the PREDICT collaborative and has led several key studies in paediatric emergency medicine. She goes through the recent PREVIEW (Prednisolone Response Evaluation in Viral Induced Episodic Wheeze) study in this talk at DFTB18.

There are several controversies regarding preschool kids with wheeze, not least the challenge of diagnosing them. Many parents might bring their child to the ED thinking their offspring has asthma. Still, bronchodilator-responsive wheeze is widespread, and not all these children go on to be formally diagnosed as asthmatic.

So, what should we do in this middle group that doesn’t have bronchiolitis or asthma?

There has always been some uncertainty about the benefit of prednisolone for viral wheeze in preschool children. In 2009, Panickar et al. found that steroids did not positively affect wheezing in preschool children. Since then, our practice and treatment guidelines have changed despite questions about the applicability of this study.

This study aimed to assess the efficacy of oral prednisolone in children presenting to a paediatric emergency department with suspected viral wheeze.

The study had a clear objective, although the initial hypothesis was revised. The initial hypothesis (placebo is not inferior to prednisolone) was changed to prednisolone is superior to placebo. The authors explained that this change was made to ensure the results were comparable with existing literature in the field.

Population, patient and problem

Eligible patients were 2 to 6 years of age.

Patients were excluded with sats <92% in air, a silent chest, shock or sepsis, previous PICU admission with wheeze, prematurity, other cardiac or respiratory disease, likely alternative diagnosis for the wheeze, or steroid treatment within the preceding 14 days.

From an initial 3727 patients assessed for eligibility, 312 were assigned to placebo after exclusions and 312 to the prednisolone group. Following withdrawals, 300 were included in the analysis for the placebo group and 305 in the analysis for the prednisolone group.

Design

The study design was suitable for the objective and looked at the population we see regularly with viral wheeze. By excluding the 10-month to 2-year age group, the authors have removed the bronchiolitis age group.  These should be managed differently and respond to different treatments.

A sample size estimation was calculated. Appropriate outcome measures were considered, although the current article only aims to explore outcomes for up to seven days. We will need to wait for future publications to find out the rest of the results.

Intervention

The intervention was a three-day course of oral prednisolone (1mg/kg once daily).

The severity of the wheeze was assessed using a pulmonary score (calculated based on the severity of the wheeze). The family also completed a questionnaire about home management and previous symptoms. Finally, a viral swab was taken from each patient.

Measurements

The pulmonary score was the initial measurement. It should be noted that this score is not validated in children under five years of age. The score was calculated to help rate the severity of the patient’s symptoms and determine whether that severity affected the outcome.

Comparison

This was a randomised, double-blind trial. Patients were randomly allocated to either group. The placebo group received an identical medication bottle with contents that looked, smelled, and tasted like prednisolone.

Randomisation

Randomisation was carried out appropriately, and the study was double-blind. Placebo and prednisolone samples were made to be indistinguishable to the clinicians and the parents.

However, patients were given prednisolone if a clinician felt this was necessary. So, if a patient was admitted to the ward and a doctor felt that they should receive steroids, then they were given them.  23 patients in the placebo group were given steroids later by a clinician. It is unclear what happened to these patients in the analysis, but they were included in the placebo group for analysis. If anything, this would have made it more difficult to find a significant difference between the groups.

Outcomes

The primary outcome was the length of stay in the hospital. Secondary outcomes (in the first 7 days) included reattendance, readmission, salbutamol usage, and residual symptoms after discharge.

One of the initial primary outcomes was the length of stay in the Emergency Department. During recruitment, the authors established that this was not a helpful measurement. The length of stay in an emergency department will depend on many non-clinical factors, including bed availability, the use of an emergency short-stay unit, and the ability to work to the dreaded four-hour target. Because of these extrinsic factors, it was removed as a primary outcome, leaving the single primary outcome being the length of stay in the hospital until the patient was ready for discharge. Again, this change was clearly explained.

Results

The author’s analysis looked at four key areas:

1. In patients with a pulmonary score of <5 (mild), prednisolone reduced the risk of a length of stay over 12 hours. In patients with a pulmonary score of >5 (severe), prednisolone reduced the risk of length of stay exceeding 7 hours. There was no significant difference in those with a pulmonary score of 5 (moderate)
2. Prednisolone was more effective in children who had salbutamol at home before presentation. In this group, patients receiving prednisolone had an overall reduced length of stay and were less likely to have stays exceeding 7 or 12 hours. This was independent of their pulmonary score on presentation. The authors state that this demonstrates that if a patient has already tried and failed with bronchodilators, then early prednisolone may be helpful.
3. There were no significant findings between groups based on the presence or absence of viral antigens.
4. In children with a diagnosis of asthma, prednisolone was associated with a reduced risk of length of stay exceeding 7 hours or 12 hours (although this isn’t the same as having presented previously with wheezing or using an inhaler before).

Interestingly, none of the results were significant in the group discharged within four hours.

Family history or personal history of atopy, although previously identified as a major risk factor for ongoing wheeze did not affect the outcomes in this study. At pre-school age, they do not modify steroid responsiveness in viral-induced wheeze

Secondary outcomes were around representation post-discharge. 26 patients re-attended (15 in the prednisolone group and 13 in the placebo group). Of the re-attenders, some were prescribed steroids (3 in the prednisolone group and 2 in the placebo group),  One patient (from the prednisolone group) was admitted to PICU. 

Analysis

The two study groups were comparable, with no significant differences in demographics, pulmonary score, history of atopy, or previous salbutamol use. This is demonstrated in Table 1, however the statistical analysis is not explained here (i.e. how did the authors confirm that there was no difference between the group). It may be that a t-test or chi-squared test was conducted here to compare the two groups, but this is not mentioned in the article. The authors assert no differences in the various parameters without reporting the statistical evidence from the tests.

The numbers add up consistently, and side effects were reported. Two children (one from each group) were reported to be hyperactive—an interesting result given the anecdotal advice often given to parents (and received from parents) about the effects of prednisolone.

The data are suitable for analysis, and the methods used are appropriate. However, their statistical analysis is not easy to follow. Chi-squared and t-tests are referred to as well as linear regression. It is not clear what questions these different analyses were used to answer. The chi-squared and t-tests were likely used to explore whether the groups differed, but they do not seem to be reported in this article. The linear regression is the main analysis used to determine whether the two groups’ outcomes differ.

The article did not fully explain the statistical analysis of the re-attenders (secondary outcomes). Although the initial plan for secondary outcomes was stated to be in the first seven days post-discharge, these were reported over three months.

Discussion

The results are discussed in relation to prior evidence (specifically Panickar et al.), and the study was designed and analysed with comparable studies and future meta-analyses in mind.

The authors spent time discussing the reasons for the change in age range. Panickar et al. included patients from 10 months of age, but this study only included patients from 2 years of age. The author explained that this was to exclude patients with bronchiolitis from their study. It should be noted that Panickar et al. included patients from 10 months of age. The 10-month to 2-year group will include bronchiolitis, which is known to be non-responsive to steroids and, therefore, may have affected the conclusions of Panickar et al..

Will I change my practice? – Damian Roland

In my first year as a doctor, my hospital’s management of children with wheeze was to give nebulisers and steroids and, if it was their first presentation, order an X-ray. Since then, evidence has suggested that steroids may not be useful in children not formally diagnosed with asthma and that an X-ray isn’t a helpful initial test.

As my experience has grown, I increasingly recognise several phenotypes of the “wheezy child” that don’t fit nicely into the current evidence. There is certainly a group of children below the age of five who appear steroid-responsive. Anecdote suggests they are likely to have atopic backgrounds (or come from families with a strong atopic history) and are at the more acutely unwell end of the acuity spectrum. This observation has face validity as it makes sense these children would have greater steroid responsiveness. So what should we make of the fact atopy wasn’t a risk factor? Which inflammatory pathway is the steroid then acting on?

This study isn’t going to change what I currently do as I think it supports my intuition that, as yet, we still don’t have a good diagnostic system for infant and childhood wheeze. A theory which would support both the Panickar and Foster work is that there are different cohorts of children between the age of 1-5 who present with similar symptomatology but for different pathophysiological reasons. The spectrum of bronchiolitis to viral wheeze to asthma is not precise enough to guide the most effective management. As recent discussion around dexamethasone and prednisolone has shown, if we can’t define the group we are treating, how can we adequately assess the response to treatment?

What I will be doing is thinking carefully about the diagnosis in patients I see or are reviewed by me and asking, “Why shouldn’t this patient have steroids?”