Current drug therapies: relievers and preventers

β-Agonists are still the first-line reliever medication for managing acute asthma. A Cochrane review comparing the use of holding chambers (spacers) and nebulisers for β-agonist treatment of acute asthma has confirmed that β-agonists are effective using either mode of delivery in children as young as two years of age presenting to emergency departments.4 A recent randomised trial of salbutamol, again comparing spacer versus nebuliser delivery, in children less than two years of age presenting to the emergency department with "moderate to severe" wheezing also confirmed the benefit of β-agonists in this age group.5 Thus, despite the apparent age effect on bronchodilator responsiveness,2 β-agonists appear to be effective even in infancy.

One issue that needs to be resolved is whether all wheezy infants will respond to bronchodilators. For example: (a) what is the role of bronchodilators in infants with bronchiolitis? and (b) are β-agonists effective for treating children under two years of age with recurrent (not persistent) wheeze associated with upper respiratory tract viral infections? A recently completed Cochrane review of this issue concluded that there was no evidence of a clear benefit from using β-agonists in the management of recurrent wheeze in the first two years of life, although the available evidence was conflicting.6 The authors suggested that further studies should only be performed if the patient group could be clearly defined and there was a suitable outcome parameter for measuring a response.

A Cochrane review of combined inhaled anticholinergics and β2-agonists for initial treatment of acute asthma in children aged 18 months to 17 years concluded that this combination of therapies, used in multiple doses, effectively improved lung function and also reduced hospital admissions, particularly in patients with severe acute asthma.7 For infants with airway obstruction, it has been suggested that anticholinergics may be more beneficial than β-agonists, because of the relatively high contribution of cholinergic-mediated mechanisms compared with the relative paucity of β-receptors in this age group. However, there is no consensus on this issue. The identification of specific subgroups of wheezy infants who respond better to this treatment may help clarify the role of anticholinergics in this age group.

A recent systematic review of inhaled disodium cromoglycate (DSCG) as maintenance therapy in children with asthma aged 0–18 years concluded that there was insufficient evidence of benefit from DSCG and that it should no longer be recommended as a first-line prophylactic agent in childhood asthma.8 However, the review highlighted the variable methodological quality of the studies. Furthermore, the patients studied had moderate to severe persistent asthma, and daily symptom scores were used as the outcome measure.

In contrast, extrapolating from studies in older children, it appears that nedocromil sodium may still be of benefit in children with milder forms of asthma.9 The Childhood Asthma Management Program study demonstrated a significant reduction in urgent-care visits and prednisone courses over 4–6 years in the nedocromil-treated children compared with those receiving placebo.9

Leukotriene-receptor antagonists have also been shown to benefit children aged 2–5 years with persistent asthma,10 and may be a potential alternative to cromones and inhaled corticosteroids (ICS) in this age group. Given the apparent lack of efficacy of inhaled corticosteroids in children with predominantly episodic viral wheeze,3 further studies are required of the role of non-steroidal medications for children with this wheezing phenotype.

The role of inhaled corticosteroids (ICS) in the management of childhood asthma has recently been reviewed.11 A systematic review of randomised trials examining the effectiveness of prophylactic ICS in children with asthma aged 0–18 years concluded that they were effective, compared with placebo, in improving both clinical outcomes (symptom scores and β-agonist use) and laboratory measurements (peak expiratory flow).12 Most of the patients had persistent symptoms: there was a trend for ICS to be more effective in reducing symptoms when used at higher doses, and when used in older children and in children with more severe disease.

In contrast, ICS have not been shown to benefit children with predominantly episodic viral wheeze3 (although only two randomised studies of children with this asthma phenotype have been performed to date, one of which was in preschool children). In particular, no reduction in hospitalisation, oral corticosteroid use or frequency and duration of acute episodes could be demonstrated. Thus, it is important to target the appropriate wheezing phenotype for treatment with ICS to maximise clinical benefit.

An important issue is whether ICS may have the potential for more side effects in infants and young children (particularly those with unresponsive wheeze) than in older children.1 Of particular concern is statural growth. Although ICS have been shown to cause a short-term reduction in linear growth, especially in children with mild asthma,9,11 long-term treatment does not appear to affect final adult height.11 However, these studies have been done in older children, and it is unclear whether initiating therapy in early infancy may have a more detrimental effect on growth. Furthermore, there is concern that early use of ICS in infancy may impair lung growth or enhance the development of the TH2-type immune response, thus promoting, rather than suppressing, the development of asthma.

Recent studies have suggested that targeted use of ICS according to wheezing phenotype may be useful.13-15 Kajosaari et al13 examined the effect of either seven days' or two months' treatment with nebulised budesonide during and after respiratory syncytial virus bronchiolitis. At two years' follow-up, 37% of children in the control group (symptomatic treatment only) were requiring asthma medication, compared with 18% in the seven-day budesonide group and 12% in the two-month budesonide group, suggesting a benefit of early treatment with ICS on subsequent wheezing episodes. Chavasse et al14 targeted infants with recurrent wheeze and a history of atopy (personal, or in a first-degree relative). In this group of infants, over a 12-week period, fluticasone provided a better outcome than placebo in terms of mean daily symptom scores and symptom-free days. In another study, Roorda et al15 found that the subgroup of wheezy preschool children (aged 12–47 months) most likely to respond to fluticasone were those with frequent symptoms and/or a family history of asthma. These studies demonstrate the importance of studying specific subgroups of young children with wheezing phenotype to better understand the role of ICS in their treatment.

Another unresolved issue is whether early treatment with ICS has the potential to prevent the persistent chronic inflammatory response that may lead to airway remodelling and impaired lung function.1 The Childhood Asthma Management Program study,9 the first prospective study to examine this issue, failed to demonstrate any additional benefit of budesonide over nedocromil or placebo in terms of final lung function after 4–6 years of treatment.9 However, that study was undertaken in older children with mild to moderate persistent asthma and mean lung function in the normal range. As airway inflammation appears to commence early in life in children who go on to develop persistent wheezing, it may be important to target this population in early childhood in order to prevent loss of lung function. Further studies are required in young children with the atopic wheezing phenotype to test this hypothesis.