We have demonstrated that, in preschool children with moderate-to-severe intermittent wheezing, neither budesonide nor montelukast initiated at early signs of RTI increase the proportion of EFDs over a twelve-month period relative to conventional therapy, nor was there an effect on oral corticosteroid rescue, asthma health care utilization (urgent care visits, emergency department or hospitalizations), or quality of life. However, budesonide or montelukast initiated at early signs of RTI significantly reduce episode severity relative to conventional therapy, with montelukast reducing wheezing, trouble breathing and activity limitation and budesonide reducing trouble breathing and activity limitation, despite the use of four-times daily albuterol during the peak symptom period of the first 48 hours of illnesses.
Our findings are consistent with a recent trial of episodic montelukast treatment in children 2-14 years of age with intermittent asthma, which noted modest reductions in symptom scores (14%) and nocturnal awakenings (8.6%), a 28.5% reduction in unscheduled health care utilization 19
, but no effect on use of oral corticosteroids or beta-agonists. Conversely, another recent trial found no effect of ICS initiated after 3 days of wheezing on episode severity in young children aged one month to two years 28
, although the lack of effect observed may have been due to the relatively late initiation of therapy relative to the onset of symptoms.
Our results extend these observations in at least two ways: first, we directly compared the effects of intervention with both ICS and montelukast within the same trial and second, we demonstrated a differential response during RTI to both episodic ICS and LTRA therapy based upon two indicators of heterogeneity in terms of baseline disease severity among the enrolled population - API status (a priori analysis) and prior oral corticosteroid use (post hoc analysis). Children with positive APIs or prior oral corticosteroid use derived significantly greater benefit from study medications than children with negative APIs or lack of prior oral corticosteroid use in terms of 40-54% reductions in episode severity as reflected by trouble breathing and interference with activity scores AUC. The absence of detectable effect in the API negative group may be due, in part, to the smaller sample and effect sizes, and thus lower power, in this subgroup relative to the API positive group (94 vs. 144 participants, respectively).
During the study, eighty two percent of days outside of RTI, corresponding to a mean of 5.74 EFD per week, were considered EFDs, confirming the low frequency of asthma-like symptoms outside of episodes that were severe. These findings corroborate clinical experience for the existence of a “severe intermittent wheezing” 27
phenotype in early childhood, that is, children with low impairment but high risk. The new findings of more clinical benefit being demonstrable in a subgroup of these children (those with a positive API) raises an important clinical question. Should these positive API children be treated episodically, given the evidence for some benefits to be gained during the wheezing episode, or should they be treated as if they had persistent asthma -- that is, with daily long term control medication?
The primary outcome, EFDs, is a frequently used measure for asthma control and reflects the multiple components of asthma disease burden. While often informative in comparing the effects of long-term controller medications for asthma in patients with chronic symptoms, it could be argued that this measure may not have been sufficiently sensitive to detect treatment effects among children with an episodic disorder such as severe intermittent asthma. However, there were no differences in prednisolone use between treatment groups, and thus our results would have been comparable had oral corticosteroid use, rather than EFDs, served as the primary outcome measure.
Regarding progression of the illness to the point of prednisolone use, it is possible that the initiation of high dose budesonide or montelukast therapy after symptom onset and presumably following stimulation of the immune response usually triggered by an acute viral infection, was incapable of changing the natural course of each such episode. Initiation of therapy too late into the development of an RTI may also have contributed to these findings. However, while it is possible that earlier initiation may have improved the treatment effects, most parents were not confident that some very early (and likely nonspecific) symptoms would be followed by wheezing, and thus were directed to not start study medication for what appeared to be trivial symptoms. Alternatively, despite having 90% statistical power to detect a 0.5 standard deviation unit difference in effect sizes for secondary outcomes, the lack of effect of study therapies on oral corticosteroid use may have been the result of inadequate statistical power for this secondary outcome.
The use of long term control medication has been examined for the outcome of attenuating either the frequency and/or severity of lower respiratory tract symptoms initiated by RTI with inconsistent findings. Some studies suggest that continuous use of ICS for four to six months in young children with episodic wheezing does not reduce oral corticosteroid use or episode severity 29-31
. On the other hand, in preschool children with intermittent wheezing and a positive modified API, continuous use of ICS for two years led to significant improvements in illness burden including increasing EFDs and decreasing oral corticosteroid use, although it was accompanied by a statistically significant, but mild and apparently transient reduction in linear growth velocity 25
. Daily administration of montelukast has been shown to reduce the rate of protocol-defined exacerbations, but not oral corticosteroid use, among 2-5 year old children with intermittent asthma symptoms 32
. Our results suggest that the episodic use of an inhaled corticosteroid (such as budesonide) or a leukotriene receptor antagonist (such as montelukast) can decrease an important source of respiratory morbidity, namely symptom burden during acute RTI, in these children, particularly those with high risk to develop subsequent asthma (e.g. positive asthma predictive index). Comparisons between intermittent and continuous therapy (or both) with these two controllers are needed, particularly among children at greatest risk for the persistence of asthma symptoms, to determine which of these two approaches is associated with greater efficacy, less parental and child burden, and fewer undesirable side effects.
This clinical trial was conducted in order to address a very important clinical question — is the episodic use of an inhaled corticosteroid or a leukotriene modifier effective in decreasing the morbidity associated with severe intermittent wheezing in preschool children? The clinical strategies examined in this trial are commonly used in clinical practice today. Our findings provide new insights into whether this treatment approach is rational in three important ways. First, this study demonstrates that, while there was no significant effect of these therapies on episode free days over a one year period, there was statistically significant, albeit modest, reduction in symptom burden during respiratory tract illnesses. Second, we were able to demonstrate that there was also variability in the response to these interventions, with children possessing risk factors for asthma at school entry (i.e. positive asthma predictive indices) or greater illness severity (i.e. use of oral corticosteroids in the preceding year) having a greater likelihood of experiencing a clinical benefit with these therapeutic strategies during respiratory tract illnesses. Finally, we have demonstrated that the two strategies, high dose inhaled corticosteroids and leukotriene receptor antagonists, provided very similar effects.