Dose Escalation of ICS to Prevent Exacerbations? Children Versus Adults

Asthma exacerbations are common, costly, and may lead to progressive loss of lung function over time, as well as increase disease severity over time. When patients with asthma are in the “yellow zone,” clinicians often need to act quickly to help their patients regain control of their asthma symptoms. There is a need to better understand what treatments are appropriate in the short-term while patients are in the yellow zone. To help clarify the differences in treatment between children and adults while in the yellow zone, Daniel Jackson, MD, an Associate Professor of Pediatrics from the University of Wisconsin-Madison, School of Medicine and Public Health, presented on “Dose Escalation of Inhaled Corticosteroids (ICS) to Prevent Exacerbations—Children Versus Adults.”

The National Asthma Education and Prevention Program (NAEPP) Guidelines for the Diagnosis and Management of Asthma (EPR-3) recommend the following treatments for patients in the yellow zone: increasing the use of short-acting beta agonists (SABA) and not doubling ICS use (although quadrupling ICS use may be beneficial). To assess whether quintupling the ICS dose when patients are in the yellow zone was effective, Dr. Jackson and his colleagues performed a blinded, randomized clinical trial in children aged 5 to 11 years with mild to moderate asthma and a history of exacerbations, who were treated with low-dose ICS.

The trial randomized participants to a high-dose ICS arm and a low-dose ICS arm, where the participants used low dose ICS daily and were assigned either high dose ICS (5x) or low dose ICS when they had an asthma exacerbation. The primary outcome was the rate of asthma exacerbations, with secondary outcomes of time to first asthma exacerbation treated with oral corticosteroids, rate of treatment failure, symptoms during yellow zone episodes, albuterol use during yellow zone episodes, and growth. Of 444 enrolled participants, 192 participants completed the study with 98 in the low-dose ICS arm and 94 in the hig- dose ICS arm. There were no significant differences between study arms for the rate of asthma exacerbations, as well as the other secondary outcomes (except for growth). A dose-response effect on growth was observed in younger children, and a significant decrease in growth was observed in the high dose ICS arm.

Based on these results, Dr. Jackson urged that “[t]he routine use of this strategy [quintupling ICS dose] in asthma treatment plans should be reconsidered.”

Another recently published study in the New England Journal of Medicine by McKeever et al.¹ used a different study design. Its authors examined the quadrupling ICS dose in aborting asthma exacerbations in adolescents and adults with persistent asthma and a history of exacerbations treated with ICS and with/without long-acting beta agonists (LABA). This was an unblinded pragmatic clinical trial that separated participants into a quadrupling group and a non-quadrupling group. The primary outcome was time to exacerbation, which resulted in a statistically significant difference between groups with a relative risk of 0.81 for exacerbations for participants in the quadrupling arm. The authors concluded that quadrupling the ICS dose to control asthma exacerbations may not be clinically meaningful given the potential toxicity from ICS.

The results from both of these studies suggest that the clinical relevance for increased ICS dosing in the yellow zone should be reconsidered.

Citations

1. McCeever T, Mortimer K, Wilson A, et al. N Engl J Med. 2018; 378:902-910.