Population studies have shown that one in three children will have at least one episode of wheezing before they reach their third birthday, rising to almost one in two (50%) by age 6 [
30,
49]. Unfortunately, the ability to predict who among these children will have
transient versus
persistent problems is poor. As such, epidemiological data, such as these, has limited clinical applicability. In this regard, prospective studies in which subjects were also phenotyped using a number of different clinical measures (e.g., lung function, BAL, etc.) showed considerable overlap between these groups [
13]. Therefore, at present, there are no diagnostic tools that can reliably predict the development of asthma among wheezy infants.
Noisy breathing is common among infants. It is important to note that it is difficult for parents to recognise wheezing, and accurately identifying wheezing by medical history is virtually impossible, as the term is used by parents and doctors to describe a variety of symptoms [
15]. Children with physician-confirmed wheezing have higher airway resistance than children with parent-reported wheeze [
47]. It may be that physician-confirmed wheezing can become important as a predictor for the development of asthma at older age. We observed that preschool children with an increased specific IgE and who also wheezed had a substantially increased chance of developing asthma by the time they reached school age [
25]. Unfortunately, in this study, wheezing was not reported by a physician. Devulapalli et al. demonstrated that a high severity score of obstructive airways disease by 2 years of age is a strong risk factor for, and may predict, current asthma at 10 years of age [
19]. Bronchial biopsies obtained from infants with confirmed wheezing have shown increased thickness of the reticular basal membrane and significantly greater eosinophilic inflammation compared with samples from children with parent-reported wheezing or control subjects [
59].
Early identification of asthma is mandatory in school children since early treatment in this age group can prevent exacerbations and deterioration of lung function. However, in preschool children, no such data are available. Recent early intervention studies with ICS in young children aimed at the prevention of asthma have shown no beneficial results with respect to the development of asthma [
11,
29,
52], and the results of therapeutic studies are conflicting.
Episodic viral wheeze [13]
Episodic viral wheeze has been defined recently by a European Respiratory Society task force to describe children who wheeze intermittently and are well between episodes. The efficacy of ICS in the treatment for episodic viral wheeze in preschool children is controversial. The majority of asthma exacerbations in school-aged children are associated with viral infections [
35], and this also holds true for the majority of wheezing episodes in preschool children [
77]. Intermittent versus daily ICS treatment in children was reviewed by the Cochrane Airways Group [
50]. Studies in children up to 17 years of age were included, but the review also contained studies conducted in preschool children. This review showed that children benefited from intermittent use of high-dose ICS (1,600–3,200 μg/day BDP or BUD) as evidenced by a reduction in the severity of symptoms. There was also a trend for reduced requirements of oral corticosteroids. More recently, a controlled, randomised, double-blind clinical trial of 750 μg FP versus placebo twice daily in 129 children who were 1–6 year of age with recurrent virus-induced wheezing showed a reduction in the use of rescue oral corticosteroids in the FP-treated patients [
24]. However, treatment with FP was associated with a smaller gain in height and weight. Among preschool children, no benefit was shown for continuous low-dose ICS treatment (400 μg/day BUD) with respect to a reduction in the number or the severity of wheezing episodes [
75]. Finally, a double-blind, placebo-controlled, randomised interventional study, primarily designed to assess whether or not treatment with intermittent courses of inhaled budesonide (400 μg/day) versus placebo for 2 weeks during wheezing episodes could delay progression to persistent wheezing, did not show any benefit of ICS during the first 3 years of life [
11].
Maintenance treatment with ICS in episodic viral wheeze in low-to-medium dosage seems not beneficial. Intermittent treatment with high-dose ICS during wheezing episodes has some beneficial effects but increases the risk of systemic side effects. An alternative possibility for this phenotype is treatment with montelukast, which reduced the rate of wheezing episodes in 549 preschool children with episodic viral wheeze by 32% compared to placebo [
12].
Multiple-trigger wheeze [13]
Multiple-trigger wheeze has been defined recently by a European Respiratory Society task force to describe children who wheeze both during and outside discrete episodes. The treatment of preschool children with multiple-trigger wheeze with ICS appears to be more successful than that of children with episodic viral wheeze. Children with multiple-trigger wheeze often develop symptoms after crying, laughter or exercise. Based on these findings, many believe that multiple-trigger wheeze resembles allergic asthma, but there is little direct evidence to support this. It remains unknown whether the histopathology of the airways from children with multiple-trigger wheeze resembles that of allergic asthma. However, a proportion of preschoolers with persistent wheeze do develop asthma in later life [
49,
78].
Kaditis et al. [
37] and Castro-Rodriguez et al. [
17] reviewed the literature on the efficacy of ICS in recurrent wheezing preschool children. Based on these systematic reviews, as well as a number of randomised, double-blind, placebo-controlled clinical trials published after this review was completed, it is concluded that continuous treatment with ICS decreases the number of days with symptoms among children with persistent wheezing, without preventing the need for hospitalisation [
14] and had less wheezing/asthma exacerbations and improved their symptoms and lung function, respectively [
17].
There is solid evidence that maintenance treatment with a low-to moderate dose of ICS decreases the number of days with asthma symptoms in children with multiple-trigger wheeze. However, Kaditis et al. [
37] questioned whether the relative benefit of continuous treatment with ICS (approximately 5% fewer symptom-free days versus placebo) is clinically significant and outweighs the possible side effects. Montelukast improved symptoms and achieved a 30% reduction in exacerbations in 689 preschool children with multiple-trigger wheeze [
41], but head-to-head comparisons with an inhaled corticosteroid are not available in the literature [
7,
13] (Table
1).
Table 1
Characteristics of episodic viral wheeze and of multiple-trigger wheeze
Definition | Wheezing during discrete time periods, often in association with clinical evidence of a viral cold | Wheezing that shows discrete exacerbations but also symptoms between episodes |
Triggers | Viral infections | Viral infections, tobacco smoke, allergen exposure, mist exposure, crying, exercise |
Possible underlying factors | Pre-existent impaired lung function, tobacco smoke exposure, prematurity, atopy | Eosinophilic inflammation? |
Continues treatment with ICS | Little or no benefit | Significant fewer days with symptoms |
Treatment with montelukast | Moderate benefit | Moderate reduction in exacerbations |
Long-term outcome | Declines over time (<6 year), can continue as episodic viral wheeze into school age, can change in multiple-trigger wheeze | Can continue as asthma into adulthood |
Newer, small particle ICS, such as ultrafine HFA-BDP aerosol (QVAR) and ciclesonide, may offer a potential benefit in preschool children. This resulted in a recommendation in the revised Dutch Paediatric Asthma Guidelines 2007 to treat children under 6 years with a small particle ICS [
32]. This recommendation is primarily based on a model-deposition study that is outlined below. The average particle size is smaller [median mass aerodynamic diameter (MMAD) of both compounds is 1.1 μm], the velocity of the particles leaving the inhaler on actuation is slower, the duration of the spray is longer and the temperature of the spray is warmer compared with that of traditional inhalers [
42]. As a result, a softer more gentle spray is produced, fewer particles impact on the oropharynx and more drug reaches the lung, particularly the small airways [
43]. These improved delivery characteristics may be particularly relevant for young children in whom a greater proportion of airways are classified as small (i.e. <2 mm in diameter) and airways resistance is low [
68].
In adults with asthma, ultrafine HFA-BDP aerosol provides equivalent asthma control at half the daily dose of conventional chlorofluorocarbon (CFC)-BDP [
18]. Two clinical studies with ultrafine HFA-BDP were performed in school children with asthma [
62,
66]. The first was a 6-month, open-label, randomised clinical trial that confirmed that asthma control can be well maintained in children aged 5–11 years when switching from a conventional CFC-BDP metered dose inhaler (MDI) inhaled via a spacer to ultrafine HFA-BDP (administered via an Autohaler®) at doses as low as 100–200 μg/day [
62]. A randomised controlled, double-blind, double-dummy clinical trial in school children aged 5–12 years with mild–moderate asthma showed that ultrafine HFA-BDP MDI and CFC-fluticasone MDI were equally effective in improving asthma control in children with mild–moderate asthma at the same daily dose and that the majority of children in both groups could reduce their daily dose to as low as 50 μg/day while maintaining good asthma control [
66]. In 2008, a Cochrane Systemic Review compared ciclesonide with other inhaled corticosteroids in children and adults with asthma [
48]. The majority of the studies were performed in asthma patients from 12 to 75 years of age. Three of the studies were performed in children, aged 6–11, 12–17 and 6–11 years, respectively [
57,
71,
73]. In 6–11-year-old children, a randomised, double-blind, double-dummy, three-arm, parallel group study showed that once daily ciclesonide (80 or 160 μg daily) administered via a MDI without a spacer had a clinical effect similar to that of FP (100 μg twice daily) administered via a MDI [
57]. The two other studies compared the efficacy of ciclesonide (320 and 160 μg once daily, respectively) with BUD (800 μg and 400 μg once daily, respectively). These studies were conducted over a period of 12 weeks in children with asthma ages 12–17 and 6–11 years, respectively, and the results showed similar efficacy with ciclesonide and BUD in a 1:2 dose ratio [
71,
74].
Unfortunately, the efficacy of small particle inhaled corticosteroids in preschool children has not yet been evaluated in prospective clinical trials. This is the reason that HFA-BDP in The Netherlands is registered from the age of 5 years and older. This is in contrast with the recommendation in the revised Dutch Paediatric Asthma Guidelines 2007 [
32]. The only study that suggests that small particle ICS may have an advantage in very young children is an infant model study. In an anatomically correct model of the upper airway of a 9-month-old infant, the SAINT model [
33], lung deposition of CFC-BDP (MMAD 3.5–4.0 μm) and ultrafine HFA-BDP (MMAD, 1.1 μm) was compared. The SAINT model was connected to a breathing simulator and a cascade impactor. This study showed that lung doses for ultrafine HFA-BDP were 25.4–30.7% over the range of tidal volumes evaluated (50–200 ml), while the lung doses for CFC-BDP ranged from 6.8% to 2.1% [
34]. The deposition of the small particles was relatively independent of tidal volume, which may be a theoretical advantage in young children. This study suggests that ultrafine HFA-BDP will be delivered in an increased lung dose in preschool children compared with an ICS that has a higher MMAD. However, these data must be interpreted with the caveat that drug delivery for individual patients in clinical practice also depends on other factors such as the inhalation technique and the cooperation of the child (Table
2).
Table 2
Current knowledge on ICS
ICs are the cornerstone of asthma treatment | Early intervention with ICS does not prevent the development of asthma | VEW and MTW are distinct phenotypes |
ICS reduce symptoms, improve lung function and prevent deterioration of lung function over time, improves BHR, reduces exacerbations in school aged children | Phenotypes VEW and MTW | MTW = asthma |
ICS are safe in low to moderate dose | ICS in EVW not efficacious, but more effective in MTW | Physicians confirmed wheezing predictive for asthma |
MTW resembles asthma | No clinical studies with small particle ICS in preschool children |
Parent reported wheeze is unreliable | No head to head studies ICS vs montelukast in preschool children |