Common Gene Variant May Blunt Asthma Drug Response in Children During Viral Illness

A genetic variant carried by roughly sixty percent of the population may change how children with asthma respond to mepolizumab, a biologic therapy widely used to treat asthma flares, according to a study published in the Journal of Allergy and Clinical Immunology. The research, led by investigators at Ann & Robert H. Lurie Children’s Hospital of Chicago, suggests that children carrying a variant in the SERPINE1 gene may experience heightened airway inflammation when the drug is given during a viral illness, rather than the calming effect clinicians would typically expect. The finding points toward a future in which a simple genetic profile could help pediatricians decide, before treatment begins, whether mepolizumab is the right choice for a particular child.

The SERPINE1 gene carries the instructions for producing a protein known as plasminogen activator inhibitor-1, or PAI-1. This protein is a central player in the body’s clotting and tissue-repair systems, but it also participates in inflammatory and fibrotic processes, including the scarring of tissue that follows injury or chronic irritation. The variant examined in the study is remarkably common, present in an estimated sixty percent of people. Because it is so widespread, any influence it exerts on asthma treatment response could affect a very large share of the pediatric asthma population, making the result potentially significant for clinical practice even before confirmatory trials are completed.

According to the study, the variant causes cells to produce more PAI-1 protein during a viral illness. That excess PAI-1 activity appears to have two consequences in the airway. First, it promotes more scarring of airway tissue, the kind of fibrotic remodeling that can permanently reduce lung function over time in children with severe or exacerbation-prone asthma. Second, it dampens the antiviral response, weakening one of the airway’s key defenses against the respiratory viruses that frequently trigger asthma attacks. Together, these effects help explain earlier observations that children carrying this variant are more likely to suffer asthma exacerbations when they catch viral infections.

The most striking element of the new work, however, concerns what happens when mepolizumab enters the picture. Mepolizumab is a monoclonal antibody that blocks interleukin-5, a signaling molecule that drives the development and survival of eosinophils, the white blood cells implicated in many cases of severe asthma. In patients without the SERPINE1 variant, the study found that the drug did not stimulate the damaging inflammatory changes observed during viral illness. In patients with the variant, by contrast, combining the drug with a viral infection appeared to activate additional inflammatory pathways that damage the airway. In other words, the same treatment that helps many children may, in the presence of this genetic background, be associated with more of the inflammation it is meant to control.

Senior author Rajesh Kumar, MD, Interim Division Head of Allergy and Clinical Immunology at Lurie Children’s and Professor of Pediatrics at Northwestern University Feinberg School of Medicine, framed the results as a mechanistic advance. He noted that previous studies had already linked the variant to a higher likelihood of asthma exacerbations during viral illness, and that the new findings offer a clearer understanding of how that increased risk arises. By tracing the pathway from gene to protein to airway inflammation, the study connects a population-level observation to a biological mechanism, which is the kind of evidence needed to justify genotype-guided treatment decisions.

The implications for precision medicine are considerable. Kumar emphasized that the findings may lead to future studies designed to identify patients for whom mepolizumab may not work as well, and who may even develop more of other types of inflammation that the drug does not block. Knowing this in advance, he argued, would allow clinicians to weigh alternative therapeutic options earlier in a child’s care rather than discovering a poor response only after months of treatment. Biologic therapies such as mepolizumab are expensive and require regular injections, so the ability to predict response from a genetic marker would spare families both the burden of ineffective treatment and the risks of uncontrolled disease.

For the study, Kumar and colleagues analyzed data and nasal samples collected from children aged six to seventeen with exacerbation-prone asthma who had participated in earlier research. Using nasal samples is a practical and informative approach in asthma studies because the lining of the nose reflects the mucosal environment of the respiratory tract, where viral infections first encounter airway tissue and where the earliest inflammatory events of an exacerbation unfold. Examining gene expression and protein activity in these samples allowed the team to observe, at the molecular level, how the SERPINE1 variant altered the airway’s behavior during viral illness and in the presence of mepolizumab.

Kumar was careful to note the limits of what the study can claim. The results show what is happening in the airway of patients with the variant during viral illness and in response to the drug, rather than what would be observed in clinical outcomes, because the study was not powered to reach a clinical conclusion. Sample size and study design constrain how strongly molecular findings can be translated into statements about exacerbation rates, hospitalizations, or symptom scores. Nevertheless, based on the known function of the inflammatory pathways involved, Kumar said he would expect that the presence of the variant in a child with asthma could translate into worse responses to mepolizumab in terms of asthma outcomes, a hypothesis that larger prospective trials would need to test.

The mechanistic picture that emerges is one in which a common genetic difference creates distinct responses to the same therapy. During a viral illness, children with asthma who carry the variant may experience more inflammation from the airway lining than children without it, and that underlying difference reshapes how the airway reacts when mepolizumab is administered. Because PAI-1 sits at the intersection of clotting, tissue remodeling, and inflammation, its overproduction during infection may tip the airway toward a profibrotic, poorly antiviral state that interleukin-5 blockade alone cannot correct. This may also explain why the drug does not block all the inflammatory activity observed in variant carriers: mepolizumab targets one specific immune pathway, while the variant-driven changes involve broader tissue-level processes.

Kumar described the work as a step toward treating asthma according to each child’s individual genetic makeup, and expressed enthusiasm about the potential of precision medicine to improve asthma outcomes for children. Asthma remains one of the most common chronic diseases of childhood, and exacerbation-prone asthma in particular imposes a heavy toll of emergency visits, missed school, and long-term lung function decline. If a routinely available genetic marker can flag children who are unlikely to benefit from a given biologic, clinicians could move toward earlier, better-matched therapies and avoid the trial-and-error that currently characterizes much of severe asthma management. The study, published in the Journal of Allergy and Clinical Immunology, adds to a growing body of evidence that the genetics of the airway’s repair and antiviral systems, and not only the immune pathways targeted by drugs, shape how children respond to asthma treatment.

Subject of Research: Effect of the SERPINE1 gene variant on children's inflammatory response to the asthma drug mepolizumab during viral illness

Article Title: Children with common genetic variant may have more inflammation in response to asthma drug

Article References: Children with common genetic variant may have more inflammation in response to asthma drug. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: asthma, SERPINE1, PAI-1, mepolizumab, pediatrics, precision medicine, viral illness, airway inflammation, biologics, genetic variant, eosinophils, exacerbations