Approximately 5% of asthma patients suffer from severe asthma that is characterized by frequent asthma exacerbations resulting in significant morbidity and excessive utilisation of health care resources. Therefore, there is a strong need for improved therapeutic strategies for these patients. Insight in the pathogenesis and molecular pathways active in severe asthma is crucial to reach this goal.

Bronchial Thermoplasty (BT) is a novel, innovative device-based treatment of severe asthma that is based on local, radiofrequent energy delivery in larger airways during bronchoscopy.

Hypothesis:

BT-induced clinical improvement in severe asthma is a consequence of reduction in airway smooth muscle (ASM) mass and (contractile/immunomodulatory) function, inflammation, neural innervation and/or vascular integrity resulting in altered airway remodelling. BT target identification and severe asthma phenotyping are critical for improved patient selection for BT and fundamental to discover novel, specific signalling pathways active in severe asthma.

This study has a two-fold purpose:

1. to unravel the targets of BT in severe asthma (how does it work?) which is fundamental for better patient selection (who benefits most?) and further improvement of BT technology and novel asthma therapy development (how to treat better?). These objectives can only be achieved by linking patient-reported outcomes to airway structure/function, which is the principal aim of the study proposed.
2. to investigate clinical outcome analyses

Inclusion Criteria:

1. Males or females age 18 or greater and 65 or less

2. The diagnosis of asthma confirmed by at least one of the following as assessed at least once during the past 5 years before the study:

   • Reversibility to β2-agonists ≥12% predicted and ≥200ml after 400μg inhaled salbutamol or equivalent
   • Bronchial hyper-responsiveness to methacholine or histamine
   • Peak-flow variability of >20% over a period of 14 days
   • Fall in FEV1 >12% and >200ml when tapering treatment (ICS, oral steroid, LABA and/or LTRA).

3. Subject is taking regular maintenance medication (GINA step 4-5) for past 6 months that includes:

   • Inhaled corticosteroid at a dosage ≥500μg fluticasone equivalent per day AND
   • Long acting ß2-agonist at a dosage of ≥100μg per day salmeterol dose aerosol or equivalent).

4. Per protocol bronchial hyper-responsiveness to methacholine (PC20<4 mg/ml)

5. Other asthma medications are acceptable (such as Leukotriene modifiers, Theophylline, Omalizumab treatment (or discontinuation for at least 6 months) Systemic corticosteroid use (≤20mg/day prednisone equivalent))

6. Pre-bronchodilator FEV1 ≥50% predicted (stabilized on ICS/LABA) and post-bronchodilator FEV1 ≥60%

7. ACQ >1,5 for 2 weeks

8. Non-smoker for 1 year or more (former smoker ≤15 pack years)

9. Ability to undergo bronchoscopy and BT in the opinion of the investigator.

10. Ability and willingness to provide informed consent.

11. For women of childbearing potential: non pregnant, non-lactating, and agree to practice an adequate birth control method for the duration of the study.

Exclusion Criteria:

1. Asthma exacerbation during the prior 4 weeks.
2. Subject has 5 or more hospitalizations for exacerbations of asthma in the previous year or 1 or more ICU admission for mechanical or endotracheal intubation for asthma in the previous year.
3. Respiratory tract infection within past 4 weeks
4. Subject has a known sensitivity to medications required to perform bronchoscopy
5. Subject is using immunosuppressant therapy other than oral steroid therapy
6. Subject is on anticoagulant medication including anti-platelet agents.
7. Subject has bleeding diathesis, platelet dysfunction, thrombocytopenia with platelet count less than 125,000/mm2 or known coagulopathy (INR >1.5).
8. Subject has other respiratory diseases including interstitial lung disease, emphysema, cystic fibrosis, mechanical upper airway obstruction, Churg-Strauss syndrome, and allergic bronchopulmonary aspergillosis (total IgE of >1000 Units/mL with positive specific IgE to aspergillus and evidence of central bronchiectasis).
9. Subject has segmental atelectasis, lobar consolidation, significant or unstable pulmonary infiltrate, or pneumothorax, confirmed on x-ray. Bronchiectasis on HR-CT-of the chest, both centrally or peripherally will be excluded.
10. Subject has clinically significant cardiovascular disease, including myocardial infarction, angina, cardiac dysrhythmia, conduction defect, cardiomyopathy, aortic aneurysm, or stroke at the discretion of the investigator
11. Subject has uncontrolled hypertension (>200mmHg systolic or >100mmHg diastolic pressure).
12. Subject uses an internal or external pacemaker or cardiac defibrillator.
13. Other chronic diseases that in the opinion of the investigator would prevent participation in the trial or put the participant at risk by participation, e.g. liver, kidney, or nervous system
14. Current smokers, and a history of cigarette smoking with >15 pack years total
15. Use of investigative drugs or intervention trials in the 4 months prior to enrolment or during the duration of the study
16. Any condition or compliance issue which in the opinion of the investigator might interfere with participation inthe study
17. BMI >35
18. Pre-bronchodilator FEV1 <1.2L
19. Extreme coughing