In this study, we will investigate the effect of tezepelumab on the epithelial barrier function of the upper and lower airways in patients suffering from severe asthma with and without chronic rhinosinusitis with nasal polyps. This will be achieved by analysis of epithelial barrier function upon challenge with various harmful substances (e.g. cigarette smoke extract, allergens) in cultured primary respiratory tract epithelial cells. Furthermore we will assess changes in clinical parameters, cellular composition and inflammatory mediators.

The primary objective of the proposal is to investigate the effect of Tezepelumab on the epithelial barrier function of upper and lower airways. To that aim, epithelial cells from the upper and lower airways will be cultured to investigate the change in barrier function during Tezepelumab treatment in patients suffering from severe asthma in presence or absence of chronic rhinosinusitis with nasal polyps. In addition, mucus plugging will be quantified by computer tomography before and after Tezepelumab therapy. These data will be supplemented by cellular and mediator analyses as well as microbiome analyses. Thus, our study will unravel the molecular mechanisms and benefits underlying therapy with Tezepelumab in patients suffering from severe asthma with or without nasal polyps.

Objectives Primary objective: Effect of Tezepelumab treatment on the barrier function of upper and lower airways in patients suffering from severe asthma with and without CRSwNP. This will be achieved by analysis of epithelial barrier function upon challenge with various harmful substances (e.g. cigarette smoke extract, allergens, and rhinovirus) in cultured primary respiratory tract epithelial cells using the xCELLigence system for continuous monitoring of barrier function.

Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures

2. Age 18-99 years and willing to participate in the study

3. Have a recorded clinical diagnosis of asthma (ICD-10 Code: J45)

4. Undergo severe asthma treatment according to GINA/DAL treatment step 4 or 5

5. Meet the requirements for treatment of severe asthma with Tezepelumab defined as:

   • severe asthma that remains uncontrolled despite a high dosage of ICS/LABA, or that requires a high dose to prevent it from becoming uncontrolled. One of the following criteria needs to be fulfilled:

     • ACT <20, ACQ>0.75
     • During the last 12 months 2 courses of OCS for at least 3 days due to severe asthma symptoms
     • During last 12 months one exacerbation requiring hospitalization
     • Lung function: FEV1 <80% predicted

   • FeNO ≥ 20 ppB

   • had either ≥250 eosinophils /µl measured in the blood OR measurement of blood eosinophils ≥150 cells during reduction of OCS dosing or high dose ICS and/or one measurement of sputum eosinophils > 2% or BAL eosinophils > 2%

   • Group with polyps: Presence of nasal polyps as confirmed by endoscopy or CT according to the European Position Paper on Rhinosinusitis and Nasal Polyps Guidelines

6. mucus score of ≥ 1

7. Patients with a history of treatment with monoclonal antibodies for asthma or polyps will only be included if at least a washout period of 3 half-lives or 3 months have passed (whichever is longer)

Exclusion Criteria:

• 1. Patients with current therapy with biologics as well as therapy with biologics 12 weeks (3 half-lives) before the start of the study or history of therapy with tezepelumab 2. Pregnancy (as determined by urine pregnancy test) 3. Patients with severe anatomic variations or deviations that do not allow access to all areas in the nasal cavity or to perform bronchoscopy 4. Patients with any other confounding underlying lung disorder including but not limited to:

  • Bronchiectasis, pulmonary fibrosis, emphysema, primary ciliary dyskinesia

  • Cystic fibrosis, any known parasitic infections and lung cancer

    5. Patients with other causes of nasal polyps than Type 2 CRS inflammation 6. Patients with pulmonary conditions with symptoms of asthma and blood eosinophilia including but not limited to: Eosinophilic granulomatosis with polyangiitis (EGPA) allergic bronchopulmonary aspergillus and hypereosinophilic syndrome 7. Contraindications for endobronchial and/or transbronchial biopsy. 8. A mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study 9. Patients with clinically meaningful comorbidity as determined by the evaluating committee 10. Immunosuppressive treatment (e.g. cyclosporine) 11. Drug and alcohol abuse 12. Current smoker and former smokers if stopped smoking <6 months

Scientific Data will be shared in public available databases

from Dec 2025 with open end

those who are registerd with public databases or who contact the investigators via email