Classification and pharmacological treatment of preschool wheezing: changes since 2008

Introduction

Wheezing and shortness of breath in preschool children are among the most common presenting symptoms in paediatric practice. Approximately one in three children has at least one episode of wheeze before their third birthday [1, 2]. Parents vary considerably in their understanding of the term “wheeze” [3] but wheeze confirmed by a doctor is associated with lower airway obstruction [4]. Even among such children with doctor-confirmed wheeze, considerable clinical heterogeneity exists (table 1).

Due to this heterogeneity, and despite its common occurrence, relatively little evidence is available on the pathophysiology and treatment of wheezing in preschool children [9]. Many preschool children with wheeze become symptom-free between the ages of 3 and 8 years [1, 2, 10, 11]. This distinguishes preschool wheeze from the more persistent asthma in later childhood and adulthood, and illustrates the heterogeneity of wheeze in this age group. Until recently, however, international asthma management guidelines did not provide separate recommendations for preschool children. In 2008, a European Respiratory Society (ERS) Task Force published a report on the classification, diagnosis and management of preschool wheeze, based on a systematic and structured assessment of the literature available at that point in time [8]. One of the Task Force’s main findings was that “the evidence on which to base recommendations is limited” and that “The present recommendations are likely to change when more evidence becomes available.” The Task Force recommended distinguishing between two phenotypes based on temporal patterns of wheeze and proposed a differentiated approach to controller therapy (table 2) [8].

The ERS Task Force report has been widely cited (over 375 citations on October 1, 2013) and used. Despite the report’s care in outlining the limitations of the available evidence, the distinction between episodic viral wheeze (EVW) and multiple-trigger wheeze (MTW) has gained widespread acceptance in patient care [12, 13]. Meanwhile, however, concerns have been raised on the validity and usefulness of this phenotype classification. First, the distinction between EVW and MTW does not take severity or frequency of episodes into account. In clinical practice, however, these play a major role in deciding which affected children are prescribed daily controller therapy, although the evidence that any controller therapy affects the frequency or severity of wheeze with viral colds in preschool children is scant [5]. Second, it has been argued that the distinction between EVW and MTW is more a marker of disease severity than of different clinical phenotypes [14]. Results from several other studies, reviewed here, also suggest that the ERS Task Force report’s classification system and treatment recommendations should be reconsidered. Because of this, an international group of experts convened at the 2013 ERS Annual Congress to discuss the current state of the art of the classification and management of preschool wheeze, and to formulate a consensus statement on the current value of phenotyping preschool wheezing disorders into EVW and MTW, and the treatment approach associated with it. This article provides a summary of this consensus meeting (table 3).

Distinguishing between EVW and MTW

The group agreed that the distinction between EVW and MTW is not as clear-cut as the 2008 report may have suggested, and that it changes over time in many children [15]. Despite significant differences in clinical presentation, lung function and genetics between children with EVW and MTW phenotypes, there is a large overlap between the groups [16–19]. While some children retain a consistent pattern of EVW or MTW over longer periods, symptom patterns change over time in many [15]. The underlying airway pathology remains unclear in many preschool children with recurrent troublesome wheeze and this hinders the choice of the most effective controller therapy. The group agreed that wheeze in preschool children is probably the final common pathway of a range of pathophysiological mechanisms involving numerous risk factors and that it is impossible to break the patients down into mutually exclusive subgroups that remain consistent over time. While at the extremes, the differences between the phenotypes of EVW and MTW are clear-cut, in many cases, they are quantitative rather than qualitative.

The group agreed that the temporal pattern of wheeze during preschool years (EVW or MTW) is a relatively poor predictor of long-term outcome (transient versus persistent wheeze). Frequency and severity of wheezing episodes are stronger predictors of long-term outcome [11]. The majority of children with troublesome EVW referred to a secondary care clinic remained symptomatic at the age of 5–10 years and a number of these children had developed symptoms between episodes characteristic of MTW [20]. In addition, some group members felt that parents may under-report interval symptoms in preschool children because the symptoms during viral episodes are most troublesome, and viral episodes may persist for weeks and recur rapidly in autumn and winter.

Indications for and choice of controller therapy

The group agreed that the two main reasons for starting any controller therapy in preschool children with wheeze were frequent symptoms (on most days of the week, responding to β₂-agonists) or frequent and severe acute episodes. There was consensus that the current state of the evidence does not allow a clear-cut distinction between children who will respond to inhaled corticosteroids (ICS), to montelukast or to neither treatment. A trial performed in the 1990s in preschool children with only EVW did not show a beneficial effect of ICS on frequency and severity of episodes [21]. A more recent systematic review of randomised controlled trials showed that ICS are effective in reducing frequency of preschool wheeze episodes when trials are pooled irrespective of phenotype [22]. However, because data on wheeze phenotype were lacking in most studies, the review could neither confirm nor exclude a differential response to ICS in EVW or MTW. Atopy did not predict the response to ICS in this meta-analysis [22]. A recent report showed that the degree of asthma control achieved in 2–6 year old children was most strongly determined by their adherence to ICS treatment [23]. The lack of data on the symptom pattern in this study does not allow a firm conclusion whether this applies to both EVW and MTW. Two randomised trials compared the effect on day-to-day symptoms and exacerbation frequency of daily low-dose and intermittent high-dose nebulised ICS [24, 25]. Interval symptoms decreased more with continuous low-dose treatment in one study [25] but there was no difference in the number and severity of exacerbations in either study [24, 25]. Both studies used nebulised treatment, which is more cumbersome and less effective than a metered-dose inhaler (MDI)/spacer combination [26]. In direct comparisons, ICS are more effective than montelukast [27]. Only one such comparative trial has been performed in preschool children, in which budesonide was more effective in reducing wheeze exacerbations requiring oral corticosteroids than montelukast [28].

Based on these findings, a number of current guidelines do not distinguish between wheeze phenotypes. Using GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology, the Dutch Paediatric Respiratory Society recently recommended using ICS as the first choice of maintenance treatment in all preschool children, irrespective of phenotype [29]. A similar recommendation was issued by GINA (Global Initiative for Asthma) [30]. The British Thoracic Society guideline also does not provide a phenotype-directed treatment recommendation for preschool children with recurrent wheeze [31].

In preschool children, both montelukast and ICS are usually well tolerated with few side effects. Recent evidence suggests significant behavioural problems as a side-effect of montelukast in a small proportion of young children with wheeze [32]. This has also been described in case reports of children using ICS [33] but this side-effect appears to be very rare in preschool children [34]. Concerns remain, however, over the effects of ICS on height growth. Therapy with ICS is associated with a 0.5–1-cm reduction in height growth during the first year of treatment [35]. Although this effect does not accumulate after longer follow-up, the increased risk of this systemic side effect in the youngest children calls for caution in prescribing ICS to young children with wheeze [36]. ICS, while effective in reducing (in particular, interval) symptoms, do not change the long-term course or persistence of the disease [35, 37].

Based on these considerations, the group agreed that the decision to start maintenance treatment is primarily determined by the severity and frequency of wheeze episodes. There was consensus that ICS are the first-choice maintenance therapy for MTW. In EVW, either ICS or montelukast may be prescribed. Any treatment given should be viewed as a therapeutic trial; regular scheduled follow-up is essential to review the response to treatment. If there is no benefit of the controller therapy started after 2–3 months, it should be discontinued and the child investigated further. If symptoms resolve during controller therapy, this may be due either to an effect of treatment or to the favourable natural history of preschool wheezing. This can only be distinguished by withdrawing treatment after the child has become symptom free and to restart treatment only if symptoms recur.

Treatment of acute exacerbations of wheeze

Inhaled bronchodilators remain the treatment of choice for symptoms of wheeze and shortness of breath in young children, although the evidence supporting their usefulness is limited [38]. A large and well-designed randomised controlled trial in children aged 10 months to 6 years with acute virus-induced wheeze showed no beneficial effect of a 5-day course of 10–20 mg oral prednisolone once a day on duration and severity of symptoms [39]. Similarly, a course of oral corticosteroids started at home by parents was ineffective in reducing the burden or duration of acute wheeze in preschool children [40]. Although these studies used a relatively low dose of prednisolone and included many children with mild symptoms, the results call for restraint in the use of systemic corticosteroids in the treatment of acute exacerbations of wheeze in this age group. Pre-emptive use of high-dose ICS (fluticasone 1500 μg per day), although effective in reducing severity of wheeze exacerbations, did not reduce acute care visits or hospital admissions and was associated with growth reduction [41].

Based on the available evidence, the group reached the consensus that the large majority of preschool children with an acute exacerbation of wheeze can be treated with only inhaled bronchodilators. The group also agreed not to treat children who do not require hospitalisation with systemic corticosteroids, and to limit the use of prednisolone in hospitalised patients to those with very severe wheeze and dyspnoea, requiring frequent inhalations and supplemental oxygen or respiratory support.

Future priorities

The consensus group discussed priorities for further research and agreed on the following (table 4). Ongoing research efforts are needed to improve our understanding of the nature and underlying mechanisms of wheeze in preschool children [9]. This can best be achieved by collecting high-quality data on a large number of patient characteristics, including symptom pattern and severity, atopic sensitisation and other allergic disease, family history of both atopy and respiratory symptoms, and environmental exposures such as indoor allergens, tobacco smoke exposure and traffic air pollution [42]. In addition, better biomarkers of treatment response (including but not limited to genetic studies) are needed [42]. We need better ways to assess and record (parental perception of) symptoms in young children. Finally, the group felt that well-designed trials are needed to study the effect of continuous ICS treatment delivered by MDI/spacer combination on the frequency and severity of acute episodes in preschool children with recurrent wheeze, and to analyse whether treatment response varies by wheeze phenotype (using different definitions), symptom pattern, severity, genotype, other characteristics or combinations of such variables (predictive indices) [11, 43].

Conclusions and implications for practice

Wheeze patterns in young children vary over time and with treatment. The decision to start any controller therapy is most strongly determined by the pattern, frequency and severity of symptoms. Any preschool child with troublesome recurrent wheeze could be started on either ICS or montelukast. The consensus group agrees that all children using controller therapy must be reviewed regularly to evaluate the response to treatment and any changes in symptom pattern. Atopy does not predict the response to controller therapy. Oral prednisolone is not required in the large majority of preschool children with an acute wheeze exacerbation and should be reserved for those with most severe symptoms. The evidence base for understanding the pathophysiology and treatment of preschool wheezing is still limited. Therefore, additional high-quality studies with a clear and comprehensive description of study subjects are needed.