Research in Severe Asthma (RISA) Trial

Inclusion Criteria: * Ambulatory adult; age 18-65 years * Asthma requiring regular maintenance medication that includes high dose inhaled corticosteroid AND long acting β2 agonist (LABA) with or without other asthma maintenance medications. Oral prednisone ≤30 mg/day, leukotriene modifiers, theophylline or other asthma control drugs may be prescribed at the physician's discretion. * Pre-bronchodilator forced expiratory volume in one second (FEV1) ≥50% predicted (patients stabilized on inhaled corticosteroids (ICS) and long acting β2 agonists) * PC20 \< 4 mg/ml per methacholine inhalation test using standardized methods, for patients with pre-bronchodilator FEV1 ≥60% predicted (or FEV1 \> lower limit defined by individual hospital protocol). PC20 is the provocative concentration of Provocholine® (a brand of methacholine chloride) resulting in a drop of FEV1 of 20% or more from Baseline * Reversible bronchoconstriction during the 12 months prior to enrollment, as demonstrated by an increase in FEV1 of at least 12% 30 minutes after 4 puffs of short-acting β2 agonist, for patients with pre-bronchodilator FEV1 \< 60% predicted (or FEV1 \< lower limit defined by individual hospital protocol) * Patient must be symptomatic, despite medication with high dose inhaled corticosteroids and LABA, by at least one of the following: 1. Use of rescue medication (short-acting β2 agonist) at least 8 of the 14 days prior to enrollment OR 2. Daytime symptoms at least 10 of the 14 days prior to enrollment * Non-smoker x 1 year or greater (if former smoker, less than 10 pack years total smoking history) * Patient must be suitable for bronchoscopy in the opinion of the investigator or per hospital guidelines * 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, within 6 weeks prior to randomization. Patients will be disqualified from the study if they enter another study or fail to comply with prescribed asthma medications. * Use of immunosuppressant therapy (e.g., methotrexate). * Current or recent lower respiratory tract infection (resolved less than 6 weeks from enrollment testing) * History of recurrent (no more than three in the last three months) lower respiratory tract infection requiring antibiotics * Presence of other respiratory diseases including emphysema, cystic fibrosis, vocal cord dysfunction, mechanical upper airway obstruction, obstructive sleep apnea, Churg-Strauss syndrome, cardiac dysfunction, allergic bronchopulmonary aspergillosis * DLCO (diffusion capacity) \< 70% predicted * Uncontrolled sinus disease * Uncontrolled gastro-esophageal reflux disease * Use of implanted electronic device such as a pacemaker or internal cardiac defibrillator * Use of external pacemaker * Significant co-morbid illness such as cancer, renal failure, liver disease or cerebral vascular disease * Post-bronchodilator FEV1 of less than 55% predicted * Known systemic hypersensitivity or contraindication to methacholine chloride or other parasympathomimetic agents * Known sensitivity to medications required to perform bronchoscopy, including lidocaine, atropine, benzodiazepines and opioids * Use of a systemic b-adrenergic blocking agent * Other medical criteria.