Study identifies three inflammatory pathways underlying childhood asthma attacks

A recent multicenter clinical trial has identified inflammatory pathways that contribute to asthma exacerbations in children despite treatment, according to results 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 usually 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 caused by T2 inflammation, an immune response involving cytokines that stimulate the formation and activation of eosinophils. Therefore, drugs aimed at suppressing T2 inflammation are used to reduce eosinophil levels and prevent asthma exacerbations.

But even with targeted therapy for T2 inflammation, some children still experience asthma attacks, suggesting that other inflammatory pathways are involved in causing flare-ups, says Rajesh Kumar, MD, acting chief of allergy and immunology at Lurie Children's Hospital of Chicago and a co-author of the paper.

In the study, the researchers analyzed data from a previous clinical trial of respiratory disease in children with eosinophilic asthma from low-income urban areas in nine U.S. cities. The researchers compared the effects of mepolizumab, a biologic drug that targets T2 inflammation, with a placebo over 52 weeks.

Although mepolizumab significantly reduced the expression of eosinophil-associated T2 inflammatory markers during asthma exacerbations, exacerbations continued to occur.

“Previous research led us to ask: What happens when you take away some of the allergic inflammation with a biologic, and why do some kids still have flares and others don’t?” says Dr. Kumar. “Allergic and various types of non-allergic inflammation interact in flares, both viral and non-viral. We were looking for a more precise way to understand what mechanisms underlie flares in children.”

Using RNA sequencing from nasal samples collected during 176 episodes of acute respiratory illness, the researchers identified three distinct inflammatory mechanisms that drive asthma exacerbations. First, epithelial inflammatory pathways, which were upregulated in children treated with mepolizumab, regardless of the presence of a viral infection; second, macrophage-mediated inflammation, which is associated specifically with viral respiratory illness; and third, pathways related to mucus hypersecretion and cellular stress, which were upregulated in both the drug and placebo groups during exacerbations.

“We found that children who continued to have flares despite taking the drug had less allergic inflammation, but they still had other epithelial pathways that triggered the inflammatory response that leads to flares,” Dr. Kumar said.

The study highlights the complexity of asthma in children and the need for personalised treatment strategies, he adds.

“There are different types of inflammatory responses that trigger flares differently depending on whether the patient has a viral infection or which components of the inflammatory response are blocked by drugs,” explains Dr. Kumar.

Because asthma still disproportionately affects children in low-income urban communities, the study's findings could pave the way for targeted interventions in children based on the type of inflammation driving their exacerbations, improving the quality of life for young patients, he said.

"This study gives us a better understanding of the reasons for persistent flares and opens up opportunities to develop new drugs or combination therapy regimens based on this knowledge."