New Study Reveals Three Inflammatory Pathways Causing Asthma Attacks in Treated Children

A recent multicenter clinical trial has discovered inflammatory pathways that contribute to asthma flare-ups in children despite treatment, as published in JAMA Pediatrics.

Eosinophilic asthma is characterized by high levels of eosinophils, a type of white blood cell involved in the body's immune response. While eosinophils typically help fight infections, in eosinophilic asthma, they accumulate in the lungs and airways, causing chronic inflammation, swelling, and damage to the respiratory system.

Eosinophilic asthma is driven by type 2 (T2) inflammation, an immune response involving cytokines that promote the production and activation of eosinophils. As a result, therapies targeting T2 inflammation are used to reduce eosinophil levels and prevent asthma flare-ups.

However, some children still experience asthma attacks even with targeted therapies against T2 inflammation, suggesting other inflammatory pathways play a role in exacerbations, said Rajesh Kumar, MD, Interim Division Head of Allergy and Immunology at Ann & Robert H. Lurie Children's Hospital of Chicago, who was a co-author of the study.

The study analyzed data from a previous clinical trial studying respiratory illnesses in children with eosinophilic asthma living in low-income urban areas across nine U.S. cities. Researchers compared the effects of mepolizumab—a biologic therapy that targets T2 inflammation—with a placebo over a 52-week period.

While mepolizumab significantly reduced the expression of eosinophil-associated T2 inflammation during asthma flare-ups, exacerbations still occurred.

"The previous trial raised questions about what happens when you take away some of the allergic inflammation using a biologic drug and why is it that some children experience exacerbations while others don't?" Dr. Kumar said. "Different types of inflammation—allergic and nonallergic—influence exacerbations, both viral and non-viral. We aimed for a more precise understanding of what drives these exacerbations in kids."

Using RNA sequencing of nasal samples collected during 176 episodes of acute respiratory illness, researchers identified three distinct inflammatory drivers behind asthma exacerbations: epithelial inflammatory pathways increased in mepolizumab-treated children regardless of viral infection; macrophage-driven inflammation linked specifically to viral respiratory illnesses; and mucus hypersecretion with cellular stress responses elevated in both treatment and placebo groups during flare-ups.

"We found that children who still experienced exacerbations on the drug had less allergic-type inflammation but other residual epithelial pathways driving some inflammatory response involved in exacerbation," Dr. Kumar said.

The study highlights asthma's complexity in children, emphasizing the need for more personalized treatment strategies, according to Dr. Kumar.

"There are multiple types of inflammatory responses involved in exacerbations and they vary based on whether patients have a virus or are using drugs to block different parts of the inflammatory response," Dr. Kumar said.

Asthma particularly affects children in urban communities disproportionality, and insights from this study could lead to precision interventions for children depending on what type of inflammation drives their asthma, potentially improving young patients' quality of life.

"This study gives a better understanding of persistent exacerbations and opens up potential new therapies or combinations based upon that."