A Cross-sectional Study Using Cardio-pulmonary Exercise Stress Testing to Understand Physiological Differences in t2-biomarker Low Severe Asthma

Introduction:

Asthma affects approximately 300 million people globally with a prevalence as high as 15% and was estimated to be the cause of 461,000 deaths in 2019. Asthma has a higher disability adjusted life-years per 100,000 population than diabetes and breast cancer, with much of this excess disability reported in the 10-20% of asthmatics who have challenging disease control. Traditionally, asthma management guidelines advocate a stepwise approach incrementally increasing CS along with other adjunctive therapies to achieve symptom control whilst reducing exacerbations. Current guidelines also recommend reducing CS after 3 months when optimal control is achieved. For many patients, this strategy works well, but in patients with severe asthma, symptoms often persist despite being on maximal treatment. At present, there is no standardised objective assessment tool when assessing patients with severe asthma who remain highly symptomatic.

Pathophysiology:

Asthma is underpinned by type-2 (T2) cytokine driven eosinophilic inflammation, with well-defined key inflammatory cytokines (interleukins (IL) -4, IL-5 and IL-13), and it is this inflammatory process which responds to CS treatment (6). All currently available new biologic therapies specifically target the T2-cytokine axis (IL-5 [mepolizumab, benralizumab and reslizumab], IL-4/13 [IL4R blockade -dupilumab]. Other drugs target upstream pathways by inhibiting epithelial alarmins [IL-33 and thymic stromal lymphopoietin (TSLP - Tezepelumab, currently not approved). These multiple new biologic treatments are primarily aimed at reducing acute asthma exacerbations and oral CS exposure. This inflammatory process can be assessed in the clinic using routinely measured biomarkers, blood eosinophil count (IL-5) and fractional exhaled nitric oxide (FeNO [IL-13]). Subsequently, patients are considered "T2-biomarker low" when FeNO <20 and blood eosinophils <150 (T2-biomarker low). Additional CS treatment or currently available biologic therapy has not proven to have any therapeutic benefit in patients who are T2 biomarker low. Furthermore, it is increasingly clinically recognised that symptoms of breathlessness and wheeze in this severe asthma population are often due to extra pulmonary co-morbidities (obesity and anxiety/depression). Treating these symptoms with CS or biologic therapy results in both treatment failure and the inappropriate continuation of high dose CS treatment leading to multiple side-effects.

Rationale for the study: