The Inflammatory Profile of Exacerbations in Patients With Severe Asthma Receiving Tezepelumab (the TezEx Study): a Retrospective and Prospective Observational Study

Asthma is one of the most common chronic respiratory conditions in the world and is characterized by a diverse range of symptoms, including wheezing, shortness of breath, chest tightness, and cough, which vary over time. Among the asthmatic population, 3.6% have severe asthma, enduring persistent symptoms and uncontrolled disease despite adhering to high-dose inhaled therapy. They experience recurrent exacerbations and substantial steroid exposure as well as a poor quality of life, frequently leading to hospital admissions and heightened healthcare utilization.

Recent years have witnessed a concentrated effort to explore various inflammatory pathways implicated in asthma exacerbations. Thymic stromal lymphopoietin (TSLP), identified as an alarmin, plays a crucial role in type 2 immune responses and the promotion of T helper 2 (TH2) cell-mediated diseases, including asthma and atopic dermatitis. Research indicates that TSLP, released in response to airway epithelial stress induced by allergens, viruses, and airborne particles, serves as a key upstream mediator of the inflammatory response, influencing both T2 cytokine expression and asthma severity.

Tezepelumab, a human monoclonal antibody targeting TSLP activity, has demonstrated efficacy in reducing asthma exacerbations, improving asthma control and lung function in controlled studies including the NAVIGATOR and PATHWAY studies. Acting upstream in the inflammatory cascade, tezepelumab exhibits the ability to decrease T2 biomarkers such as FeNO, blood eosinophil, and IgE, suggesting its potential to suppress multiple pathways rather than focusing on a single downstream mediator. The CASCADE trial further supports TSLPs mechanistic roles by revealing a decrease in airway hyperresponsiveness and mucus plugging, suggesting additional benefits beyond the reduction of type 2 airway inflammation.

However, despite reduction eosinophil count and other T2 biomarkers, our real-world experience has shown that certain patients continue to have an exacerbation risk on tezepelumab.

A recent study showed that children established on anti-IL-5 therapy for severe asthma had eosinophil subpopulations to be significantly elevated in the airway that could contribute to exacerbations. It is unclear if the same or other inflammatory pathways continue to remain active in patients on anti-TSLP therapy as studies to explore this have not been conducted on tezepelumab.