Tezepelumab is a treatment that is approved by NICE (National Institute for Health and Care Excellence, https://www.nice.org.uk/) for patients with severe asthma, that remains poorly controlled despite high dose inhaled glucocorticosteroid medication.

The goal of this observational study is to learn why some patients with severe asthma continue to have asthma flare ups despite being on tezepelumab.

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.

This projects primary aim is to investigate the clinical, physiological and inflammatory characteristics of asthma exacerbations that persist despite tezepelumab therapy in patients with severe asthma.

Study Hypothesis:

In patients with severe uncontrolled asthma, who have been established on tezepelumab, asthma exacerbations may reflect both persistent T2 and non-T2 driven events.

Adult patients with poorly-controlled severe asthma who either meet NICE criteria to begin biologic therapy with tezepelumab or within 36 weeks of being established on it will be invited to participate in the study at Guys Severe Asthma Centre. Tezepelumab will be given according to UK NICE severe asthma guidance with 210mg sc dosing every 4 weeks. 150 participants will be recruited and followed up for 48 weeks (until they complete one year on tezepelumab).

These potential participants will receive written information about the study in the form of a patient information sheet (PIS). The patient would be adviced to contact the clinical team when there is a deterioration in their asthma control. These patient will then have further assessments performed alongwith tests when seen in person.

The study is exploratory and will assess deteriorations in asthma control (exacerbations) to characterise the clinical severity of each exacerbation and the airway and systemic inflammatory phenotype associated with these events. Clinical assessment and management of each exacerbation will be in line with standard clinical guidelines.

At all visits unless otherwise stated, the following will be collected (not limited to):

Clinical observations Information regarding their asthma symptoms and adverse events Clinical examination (if required) Asthma control score and quality of life questionnaire (ACQ-6) Blood samples will be collected and breathing tests will be performed (spirometry, fractional exhaled nitric oxide (FeNO)).

In patients who have had deterioration in asthma control, will have blood, nasal and sputum samples collected at their exacerbation visit and stable state at one year. The above samples will also be collected for a group (~25) of patients who remain in clinical and/or biological remission on tezepelumab at the end of one year.

Inclusion Criteria:

• Patients who qualify for tezepelumab according to NICE eligibility criteria and yet to begin treatment or those patients within 36 weeks (+/-8 weeks) since their first dose of tezepelumab at the Guy's severe asthma centre.
• Age ≥ 18 and ≤ 80 years at tezepelumab initiation.
• Able and willing to provide written informed consent and to comply with the study protocol, including being able to attend for assessment during a symptomatic deterioration.

Exclusion Criteria:

• Other clinically significant medical disease that is likely, in the opinion of the investigator, to require a change in biologic therapy or impact the ability to participate in the study.
• History of current alcohol, drug, or chemical abuse or past abuse that would impair or risk the subject's full participation in the study, in the opinion of the investigator.
• Other severe eosinophilic lung disease including EGPA, chronic eosinophilic pneumonia and ABPA
• Severe bronchiectasis on CT causing daily sputum production
• Maintenance therapy with an antibiotic including azithromycin or doxycycline
• Inability to give written informed consent

Adult patients with poorly-controlled severe asthma who meet NICE criteria to commence/on biologic therapy with tezepelumab.

No individual participant data will be shared or made available to researchers outside of the site research team where the patient is based, and GSTT asthma research team.