We report that a daily low-dose regimen of budesonide inhalation suspension was not superior to an intermittent high-dose regimen, administered for 7 days during a predefined respiratory tract illness, with respect to the frequency of exacerbations (the primary outcome) in preschool-age children at risk for asthma and future exacerbations. In addition, there was no significant between-group difference in respiratory symptoms (symptom severity during respiratory tract illnesses, episode-free days, and bronchodilator use) or quality of life. These findings occurred in the context of similar rates of reported adherence and identification of nasal viruses in the two study groups.
The treatment of preschool-age children with recurrent wheezing is complex, since most of these children do not have persistent asthma, as defined by regular symptoms, and the diagnosis is difficult to confirm. U.S. guidelines8
recognize this complexity in regard to diagnosis and management and recommend daily therapy with inhaled glucocorticoids as the preferred option for young children with recurrent wheezing and risk factors for persistent asthma (i.e., positive values on the modified API),8
although this treatment does not alter the course of the disease after the inhaled glucocorticoids are discontinued.9
Guidelines of the Global Initiative for Asthma (GINA)23
also recommend daily controller therapy, including the use of inhaled glucocorticoids, for young children with intermittent wheezing, a history suggestive of asthma, and at least three wheezing episodes in the previous year. The guidelines caution against the use of daily high-dose therapy with inhaled glucocorticoids for prolonged periods, given the reported effect of such use on growth, and advise using the lowest dose necessary for asthma control.8
In this context, the inability to show the superiority of a daily low-dose regimen of budesonide over an intermittent high-dose regimen may be important in the preparation of future guidelines.
The efficacy of daily low-dose inhaled glucocorticoids, as compared with placebo, has been documented in studies ranging from 1.5 to 12 months and involving preschool-age children with positive values on the modified API,9
risk factors for asthma,24–26
frequent recurrent wheezing or asthma symptoms,27,28
or physician-diagnosed asthma.13,29
A recent meta-analysis30
and both the EPR-3 national guidelines8
and GINA guidelines23
for infants and preschool-age children support these findings. In the PEAK trial, the daily low-dose inhaled glucocorticoid that was shown to be efficacious was fluticasone administered in a metered-dose inhaler, but there has been no evidence that efficacy differs when other inhaled glucocorticoids are used in clinically similar doses.8,10
In preschool-age children who entered a trial with frequent symptoms, the percentage of symptom-free days was higher among those receiving daily inhaled glucocorticoids than among those receiving placebo, but the comparison between daily use and as-needed use was not significant.31
On the other hand, the use of intermittent high-dose inhaled glucocorticoids for specified periods was more effective than placebo in preschool-age children with intermittent, recurrent wheezing12,32,33
and in those at high risk for asthma but with low levels of respiratory impairment.11
Thus, we determined that a placebo group was not indicated for our study, which involved children who had low impairment but were at high risk for emerging, persistent asthma and recurrence of an asthma exacerbation, a decision that was approved by the independent oversight boards.
Budesonide inhalation suspension was selected for the daily low-dose inhaled glucocorticoid since it was the only such drug approved by the Food and Drug Administration for daily use in children between the ages of 1 and 4 years at recommended starting daily doses of 0.5 to 1.0 mg on the basis of pivotal trials of budesonide versus placebo in children between the ages of 1 and 8 years.13–15
In post hoc analyses, daily doses of 0.5 and 1.0 mg of budesonide were similarly effective in children under the age of 4 years and in those 4 years of age or older.34
Budesonide in a daily dose of 0.5 mg was also associated with fewer exacerbations and less impairment than was cromolyn17
in young children. The efficacy of once-daily budesonide by nebulization (including a dose of 0.5 mg) has been summarized previously.35
In addition, guidelines recommend a daily dose of 0.5 mg of budesonide as a low-dose inhaled glucocorticoid.8,23
As compared with placebo, budesonide was efficacious without retarding growth when used in an intermittent high-dose regimen of 1 mg twice daily for 7 days with each respiratory tract illness in preschool-age children.11
Our findings may not be applicable to young children whose asthma was different from or more severe than that of the children in our study. Daily36
use of inhaled glucocorticoids or even short courses of oral glucocorticoids started at the onset of wheezing episodes38,39
may not be efficacious in preschool-age children with a first episode, with transient or infrequent wheezing, or without an asthma diagnosis or a high risk of asthma.
Although the observed exacerbation rates in the two study groups were numerically similar, our results do not show with certainty that the two treatments were equally effective. The uncertainty is reflected in the confidence interval for the relative rate of exacerbations, which extends from approximately 0.7 to 1.35, so our data do not rule out the possibility that either treatment could be up to 35% more effective than the other. The advantage of the intermittent regimen over the daily regimen cannot be based on differential effects on growth, but rather on a reduced exposure to inhaled glucocorticoids (approximately 100 mg less during the course of a year, or a reduction in exposure by a factor of 3.3). The non-completion rate was higher than anticipated but similar in the two groups, as were the characteristics of the children who did not complete the study.
A major advantage of an intermittent regimen of inhaled glucocorticoids is that its initiation occurs early during a predefined respiratory tract illness on the basis of individualized symptoms that historically have occurred before the onset of wheezing.11
This strategy avoids the use of inhaled glucocorticoids for each upper respiratory tract illness and thus allows for the benefits of the regimen at considerably lower cumulative levels of exposure. In our study, intermittent budesonide was initiated on average once every 3.5 months, in contrast to a monthly rate when such therapy was started preemptively with each upper respiratory tract infection.12
This finding may explain the adverse effects on growth in the latter study,12
as compared with our approach.11
Nevertheless, parents require careful, individualized instruction on when to start budesonide in order to ensure that this intermittent approach is used appropriately, as detailed previously11,19
(Fig. S2 in the Supplementary Appendix
In summary, our trial compared the efficacy of an early intermittent high-dose regimen of budesonide for respiratory tract illness with that of a daily low-dose regimen, with the latter recommended by current guidelines for preschool-age children with recurrent wheezing episodes and positive values on the modified API. We conclude that for such children who have had one or more exacerbations requiring the use of systemic glucocorticoids, urgent or emergency medical visits, or hospitalizations during the previous year but a documented history of low impairment from asthma, the daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen initiated during a predefined respiratory tract illness in reducing exacerbations. Moreover, the daily low-dose regimen was associated with more frequent administration of and greater exposure to budesonide.