Mepolizumab is a biologic asthma therapy that targets a type of inflammation called type 2 (T2). It was approved by the FDA in 2015 and has been shown to be effective in studies of adults with asthma. In the treatment of children, however, while mepolizumab reduces T2 inflammation, asthma attacks still occur in many children.
A recent study took a closer look at extensive data from an investigation of the causes of pediatric asthma attacks that persisted despite this immune-based therapy. Researchers showed that while mepolizumab blunts the T2 type inflammation, as it does in adults, several other inflammatory pathways were discovered in some children with persistent asthma attacks. Thus, the study showed that pediatric asthma’s mechanisms are more complex than first assumed: there are more inflammatory pathways in children with asthma than the one subdued by mepolizumab.
Asthma attacks are the leading cause of hospitalizations and critical complications in children with asthma. The new biologic therapies, such as mepolizumab, have helped to reduce the frequency and severity of these episodes, but not all children respond fully. And as all pediatricians acutely know, children are not small adults: diseases frequently affect them differently, and they often respond differently to drugs and therapies than adults do. This study examined those differences through rigorous data collection, identification, and evaluation with revealing and potentially beneficial results.
In a collaboration between leading researchers in the Childhood Asthma in Urban Settings (CAUSE) consortium, Daniel Jackson, MD, professor in the Division of Allergy, Immunology, and Rheumatology, and Matthew C. Altman of the Benaroya Research Institute (BRI), and their teams investigated the underlying molecular mechanisms of asthma attacks that occurred despite treatment with mepolizumab. The results of their research were recently published in JAMA Pediatrics, “Inflammatory Pathways in Residual Asthma Exacerbations Among Mepolizumab-Treated Urban Children.” James Gern, MD, professor in the same division and vice chair of research for the Department of Pediatrics, was a co-author of the study.
Two editorials in the issue also address the research, describing its new evidence and the benefits for future work identifying the multiple inflammatory pathways of pediatric asthma. (One is entitled “Discovering Residual Pathways Driving Asthma Exacerbations in the Era of Biologic Therapy,” The other is entitled “Pediatric Airway Biology and Transcriptomic Assessment of Therapies.”)
The study was a secondary analysis of the extensive samples and data collected from a previous study. This clinical trial, conducted in children from low-income urban centers in nine U.S. cities, was a double-blind, placebo-controlled, parallel group, randomized clinical trial. It was first published in The Lancet in August 2022.
The objective of the deeper analysis of these data, uniquely collected during acute asthma episodes, was to identify the other possible inflammatory routes — those not affected by mepolizumab treatment — that continued to drive urban children’s asthma attacks. The data analysis for this secondary investigation was performed from September 2022 to April 2025. The primary data were obtained from nasal samples obtained during acute respiratory illnesses, as colds are the most common trigger of an asthma attack. The primary measurements of those samples were transcriptomic modular analysis of gene expression (RNA sequences).
The investigation found that the children who received mepolizumab showed a decreased expression of the common T2 inflammation, which was expected. However, there was an increased expression of signs of epithelial and macrophage inflammatory pathways, as well as higher mucus secretion, and cellular stress response pathways. The study findings showed these alternative inflammatory pathways were mechanisms of residual acute asthma attacks in children who received mepolizumab. And further, these multiple inflammatory pathways can independently contribute to asthma attacks.
The future benefit of the study is clear. It points the way to further focused research through a clearer understanding of the greater complexity of pediatric asthma at the molecular level.
“Urban children with asthma experience a disproportionate burden of asthma with the highest rates of asthma attacks and hospitalizations. Our study, funded by the NIH, uniquely sampled the airways of children receiving a biologic therapy targeting type 2 inflammation during their respiratory illnesses, such as colds, in order to specifically identify the pathways that led to an asthma attack despite this treatment,” Jackson said. “This approach opens the door to identify more personalized and targeted strategies for both the treatment and prevention of asthma attacks in children.”