Pre-school wheezers remain a poorly understood cohort of children despite seeing them every day in paediatric EDs. Unfortunately, the number of acute wheeze exacerbations coming through the doors is still rising, but are we equipped to manage these children?
In the UK, national guidance advises giving oral prednisolone early when treating paediatric asthma attacks. If the child doesn’t have a diagnosis of asthma but does have severe symptoms, steroids are still advised. However, they should be used with caution if the child ends up having multiple courses of oral steroids for frequent episodes of wheeze associated with viral infections.
When is it no longer bronchiolitis, and when does it become asthma?
The 2018 PREVIEW trial reported a significant reduction in length of stay (LOS) in children given prednisolone in Australia (24-71 months, mean 41 months) compared to placebo. It is hard to ignore the 170-minute difference in LOS. This difference was most noticeable in children with more severe presentations (measured by the Pulmonary Score). However, there was no difference in LOS (83 minutes for placebo vs 79 minutes for prednisolone) in participants who were discharged straight from the ED (32%).
Compare this with the Panickar et al. study from 2009. This reported no significant difference in LOS between prednisolone and placebo groups across 679 children with wheeze in the UK. The children were younger (10-72 months, mean 25 months) were younger. Perhaps these children had bronchiolitis, a disease where there is no evidence of the benefit of steroids.
Since the PREVIEW trial, there have been more negative trials. One such trial was the WASP trial, which involved 477 children in New Zealand. This trial showed no difference in PRAM score or LOS in the prednisolone group compared to placebo.
These three trials show how conflicting evidence leads to a lack of consensus, naturally leading to significant variation in guidance and practice.
Randomised controlled trials addressing the benefit of steroids in preschool wheeze have compared different cohorts, used different trial designs and measured different outcomes.
The most recent meta-analysis, published in 2016 (comparing eleven studies from 1986 to 2009), struggled to reach a consensus because the trials were too heterogeneous to make robust conclusions.
So, an up-to-date, high-quality meta-analysis is much needed. Fortunately, Lee et al. recently published a systematic review with an IPD meta-analysis to seek much-needed clarification on this topic.
Methods – What is an IPD meta-analysis?
Lee et al. performed a systematic review, but because of trial heterogeneity, they undertook an individual participant data (IPD) meta-analysis. This is a way to overcome different trial outcomes. It is particularly useful when drawing clear conclusions from the published data is impossible. An IPD approach is a collaborative exercise including the authors of included studies and stakeholders.
Whilst challenging and time-consuming, it has lots of advantages, including:
- use of unpublished data or unreported data
- use of incomplete studies
- overcoming reporting biases
- grouping specific populations
- using consistent units and measures of effect
- performing analysis of a broader range of outcomes than published in individual trials
- performing more comprehensive subgroup analyses
- report longer-term outcomes beyond that reported in individual trials
The authors’ systematic search resulted in twelve studies published from 1994-2020. Seven provided individual participant data (1728 children between 12-71 months) for the IPD meta-analysis.
This paper’s primary outcome was a change in wheeze severity score (WSS).
What is the Wheeze Severity Score?
You won’t have heard of the WSS as it was made specifically for this meta-analysis to standardise all the wheeze severity tools used in the different trials and transform them into a modified PRAM score. The score is a scale of 12 points, whereby <4 is considered mild, 5-8 is moderate, and >9 is considered severe. They looked at the change in WSS at 4 and 12 hours from baseline. Then, they looked at the length of stay (LOS).
The statistical analysis used was complex but essentially followed a two-step process.
Firstly, as multiple variables may contribute to a child’s response to oral corticosteroids, the authors used a multi-regression model to adjust for factors including age, personal allergy/atopy, parental allergies, and asthma.
Then, they repeated the analysis using a random-effects model. Each study was weighted proportionate to its contribution to the analysis.
They were then able to run their planned subgroup analysis and see which variables were important to the research question.
As usual, we were given I2 statistics to show the level of variation estimated from heterogeneity between trials. In an IPD analysis, you’d often expect these to be lower than in a standard systematic review.
Results – What did they find?
Change in Wheeze Severity Score
Using data from two studies, they found a significantly greater reduction in Wheeze Severity Score (-0.31 points at four hours in the prednisolone group compared to the placebo group).
This improvement difference was statistically significant (p=0·011), but it is important to remember that the WSS is scored out of 12, so this amounts to an additional 2.5% score reduction, on average, in the prednisolone group.
Using data from three studies (albeit fewer children), there was no evidence of an improvement in WSS between the two groups (p=0·68) at 12 hours.
Length of Stay
Using data from five studies (1452 children), they reported a significantly greater reduction in the LOS in the prednisolone group compared to the placebo group (mean difference –3·18 h p=0·0021). Interestingly, the mean LOS was reduced by a further 96 minutes in children with a history of wheeze/asthma diagnosis and a further 20 minutes in children with moderate-severe wheeze on arrival (compared to mild presentations).
Other findings
The authors found no evidence of longer-term benefits of prednisolone over placebo, such as revisits to the GP or ED, rehospitalisation rates, need for additional steroids, or time back to normal.
It’s worth noting that unlike the primary outcomes (change in WSS or LOS), where the heterogeneity scores were 0%, the I2 values were generally higher for these secondary analyses. There was greater heterogeneity between the individual studies’ findings.
Significantly more children with a personal or family history of allergies/eczema/asthma were found in the mild group (all P <0.05).
Only two interactions (wheeze severity at baseline and previous wheeze/asthma) were significant when the full two-step analysis was tested to find effect modifiers. These interactions didn’t have a statistically significant effect on the change between the two groups in WSS scores.
Other variables, including age, gender, personal/parental allergies, or parental asthma, did not modify the effects of prednisolone compared to placebo.
It is also worth noting that age was reported as a categorical variable for the final subgroup analysis, comparing under-3s to over-3s.
How good is the paper?
It’s undebatable that the authors have applied rigorous methodology to address this important research question. They conclude that their IPD meta-analysis shows that “children with acute preschool wheeze who received oral corticosteroids had statistically significant improvement in WSS at 4 hours and length of hospital stay.”
But how can we apply these findings in everyday practice?
Sadly, not all data was available for analysis at the IPD level, including the WASP study mentioned above, which had reported no significant effect on PRAM score or LOS in their population. Whilst it had been added to a sensitivity analysis, the total meta-analysis would have been more meaningful if more trials had been included at the IPD level.
What does this mean?
Unfortunately, it means that the primary outcome analysis was based on as few as 2 studies for WSS scores and 5 studies for LOS rather than the 12 initially highlighted in the search.
With so few studies in the final analysis, we must look back at the context in which they were run. A large proportion of the trials come from Finland (3) and the UK (2), as well as Australia (1) and the US (1), but only a small number took place in the ED. This limits the generalisability of the results for the practice of DFTB readers in acute paediatrics like me. Is my practice more akin to a Finnish inpatient setting or an ED setting in Perth? What other healthcare factors may be coming into play that have not been accounted for?
Ideally, an IPD analysis irons out these creases, but they may remain important when the analysis is limited to such few studies.
Using a score that’s not used in clinical practice may seem like it reduces the applicability of the findings. Still, ultimately, the authors have translated the studies to the well-established PRAM score. It incorporates the clinical signs we all use to assess a wheezy child (work of breathing, wheeze, air entry, and oxygen saturations), and its use in clinical guidance shows that it can be implemented into our clinical practice.
All trials compared placebo and prednisolone, but the dose and regime varied. Most treatment effects were seen in the short term, perhaps nullifying the benefit of longer prednisolone courses commonly prescribed. This highlights the need for research to look at the minimum requirement of steroids to obtain treatment benefits. Another key reason is that the authors reported a higher rate of vomiting in the prednisolone group, and we know that dexamethasone, the typically used alternative, is better tolerated in this population. Can we assume the treatment effects identified in this meta-analysis are the same for those working in settings that use dexamethasone?
Overall, the authors reported good-quality trials with a low risk of bias. The highest quality evidence supports most outcomes, and just “moderate-quality” evidence supports the change in WSS at 4 hours and time back to normal. However, there were key differences between the trials, such as participant age, whereby the mean age ranged from 15.9 months to 40.9 months. This is a broad definition of “pre-school” wheeze, and whilst this addresses a large population, the concerns mentioned above of including children under two prevail. Technically, the results show that a 2-year-old with severe wheeze is more likely to respond to prednisolone than a 6-year-old with mild wheezing, but I wonder to what extent this reflects the common practice and how quickly these findings will start to influence our prescribing.
Another key variation between studies is the participants’ history of previous wheezing, which has been identified as one of the most important take-home messages. While some of the Finnish trials recruited children with their first wheeze episode, others had a majority or all of their participants with recurrent wheezing, which is a significantly different approach to recruitment.
What does it mean to our patients?
During an evening shift in a busy paediatric ED with no beds, you might be thinking, how do I discharge patients home both safely and as quickly as possible?
Is a 2.5% improvement in WSS going to help you make a decision about prescribing steroids?
To determine what’s important to healthcare professionals (HCPs), the authors surveyed 44 countries. The outcome HCPs thought most important was length of stay, followed by improvement in WSS, then “time back to normal”. They suggested that 5.5 hours was a clinically important length of stay difference and an improvement of 41% / 50% at 4 / 12 hours (respectively)in Wheeze Severity Score was significant. When these results were shown to a small group of parents and HCPs, length of stay became less of a priority. Reattendance to GP/ED was more important. HCPs and parents felt that improving WSS was the number one priority.
Interestingly, these survey results show that improving WSS by -0.3 points with prednisolone was not important, and the improvement in length of stay fell short of ideal.
While reducing time in the ED undoubtedly reduces the burden on health services, we should be mindful of what families feel is important. Multiple courses of steroids are not without side effects. Whilst the incidence of adverse events was low in this meta-analysis, this reflects adverse event reporting in RCTs rather than reality.
Corticosteroids impact the child’s immune system. There is an increased risk of pneumonia and sepsis in the 31-90 days after prescription and an increased risk of fractures, GI bleeds and sub-optimal growth. Paediatricians should critically weigh up the findings of this paper against the side effects of corticosteroids and make a balanced decision with families.
Clinicians in the UK should continue to follow BTS guidance that targets corticosteroids in children with severe presentations and a diagnosis of asthma. This study contradicts the idea of exercising caution in children with recurrent wheezing. Clinicians should continue to exercise caution in preschool children with mild wheezing.
The Bottom Line
Prednisolone probably reduces the hospital length of stay in preschoolers with wheeze – especially in severe cases.
Prednisolone probably reduces the hospital length of stay in preschoolers with recurrent presentations of wheeze or a previous diagnosis of asthma.
Prednisone probably reduces the severity of wheezing within the first four hours, but the benefit is probably negligible by 12 hours.
The effect of dexamethasone in this cohort has not been studied.
Future of Pre-School Wheeze
Whilst Lee et al. report many valuable findings, this study also highlights some of the important unanswered questions.
Despite IPD data, this study was limited by the nuances of preschool wheeze phenotypes and highlights the need for future research in this field.
Risk factors such as atopy and allergy were often reported in the history rather than comparing phenotypical biomarkers, though some studies by Jarrti et al. used IgE testing. Future studies looking at specific phenotypes and endotypes markers of preschool wheeze responsive to corticosteroids may include allergen sensitisation tests, eosinophil levels or even breath tests.
Research is needed to determine if these investigations are useful outside of the clinic setting.
References
BTS_SIGN Guideline for the management of asthma 2019.pdf.
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