Asthma Intervention Research (AIR) Trial

Inclusion Criteria: Ambulatory adult; age 18-65 years Asthma requiring regular maintenance medication that includes inhaled corticosteroid (at least 200 μg beclomethasone per day or equivalent) AND long acting ß2 agonist (LABA) (at least 100 mg salmeterol per day or equivalent) Pre-bronchodilator FEV1 60-85% (patients stabilized on inhaled corticosteroids and long acting β2 agonists) PC20 < 8 mg/ml per methacholine inhalation test using standardized methods. Demonstration of worsening of asthma following 2-week withdrawal of LABA, as documented by either: an increase of at least 0.5 in the Juniper Asthma Control Questionnaire score, relative to the Questionnaire score in the 2 weeks preceding withdrawal of LABA, OR a decline of at least 5% in the average am Peak Expiratory Flow during the second week of LABA abstinence relative to the average am Peak Expiratory Flow during the week immediately preceding LABA withdrawal Non-smoker x 1 year or greater (if former smoker, less than 10 pack years total smoking history) Willingness and ability to give written Informed Consent Willingness and ability to comply with the study protocol, including requirements for taking and abstaining from medications. Exclusion Criteria: Participation in another clinical trial involving respiratory intervention that could affect the outcome measures of this study, either within 6 weeks of the pretreatment evaluation, or during the study period Current or recent respiratory tract infection (resolved less than 6 weeks from pretreatment evaluation) History of recurrent (³ 3 infections/year) lower respiratory tract infection requiring antibiotics. With the exception of the use of a prophylactic bronchodilator for exercise, requirement for more than 4 puffs in a 24-hour period of a short-acting b2-adrenergic agonist such as albuterol or salbutamol 100 mg/puff or equivalent within the seven days immediately prior to commencement of Enrollment Testing, Part I. Unstable asthma as defined by the need for an extra visit to a healthcare provider, increase in or introduction of new maintenance or symptom relieving medications (including new requirement for IV or nebulized medications) within 6 weeks of enrollment Use of an internal or external pacemaker or internal cardiac defibrillator Significant co-morbid illness such as cancer, renal failure, liver disease or cerebral vascular disease POST-bronchodilator FEV1 of less than 65%. Known systemic hypersensitivity or contraindication to methacholine chloride or other parasympathomimetic agents Known sensitivity to medications required to perform bronchoscopy, including lidocaine, atropine and benzodiazepines Use of a systemic b-adrenergic blocking agent Pregnancy Nursing mother History of epilepsy Cardiovascular disease, including bradycardia, angina, cardiac dysrhythmia, conduction defect or cardiac myopathy Myocardial infarction or stroke within 6 months of the pretreatment evaluation Any active disease left untreated, Bleeding diathesis, platelet dysfunction, thrombocytopenia with platelet count less than 125,000/mm2 or known coagulopathy (INR > 1.5) Use of anticoagulants Insulin-dependent diabetes Psychiatric disorder which in the judgement of the investigator could interfere with provision of informed consent, completion of tests, therapy, or follow-up Presence of segmental atelectasis, lobar consolidation, significant or unstable pulmonary infiltrate, or pneumothorax, confirmed on x-ray Interstitial lung disease Uncontrolled hypertension (>200 mmHg systolic or >100mmHg diastolic pressure) Known aortic aneurysm