Quintupling Inhaled Glucocorticoids to Prevent Childhood Asthma Exacerbations

Abstract

Background: Asthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited.

Methods: We studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids.

Results: The rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06).

Conclusions: In children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

Figure 1. Trial Design and Enrollment

Panel A shows the trial design. All the children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned either to continue the same dose (low-dose group) or to use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, with two inhalations twice daily) for 7 days at the early signs of loss of asthma control (“yellow zone”). Panel B shows the number of participants who enrolled in the trial, underwent randomization, and completed the trial. Scores on the childhood Asthma Control Test (C-ACT) range from 0 to 27, with higher scores indicating greater control (minimally important difference, 2.0); among potential participants with a C-ACT score, a score of more than 19 was required for inclusion in the trial. FEV₁ denotes forced expiratory volume in 1 second.

Figure 2. Yellow Zones, Exacerbations, and Treatment Failure

Panel A shows the frequency of yellow-zone episodes, according to dose group. Panel B shows the time to the first exacerbation that was treated with systemic glucocorticoids (prednisone). Tick marks indicate censored data. Panel C shows the time to treatment failure.

Figure 3. Outcomes during Yellow-Zone Episodes

Panel A shows the mean symptom scores 7 days before and 14 days after the onset of yellow-zone alerts. The total symptom burden was assessed according to the area under the curve (AUC) for symptom scores. Panel B shows albuterol use, as assessed according to the number of inhalations per day during the same time period.