Introduction
Asthma affects over 300 million people throughout the world, with a high burden of morbidity and mortality. According to World Health Organization (WHO) estimates, approximately 250, 000 people die prematurely each year from asthma. Approximately 5%–10% of patients with asthma are categorized as severe with failure of symptom control despite maximal inhaler therapy. The definition of severe asthma sometimes varies, but is generally characterized by recurrent exacerbations or ongoing symptoms despite maximal treatment. Frequent emergency room visits, unscheduled clinic visits, hospitalizations, missed school or work, and a reduced quality of life impact patients with severe asthma. About 1000 people die each day from asthma. Asthma is among the top 20 causes of years of life lived with disability. The significant global impact on health care costs and resource utilization is ongoing and exceeds 56 billion dollars annually in the United States alone. Asthma is a disease hallmarked by inflammation and hyperresponsiveness of the peripheral airways. When asthma is left unchecked, airway remodeling leads to increased airway smooth muscle (ASM) mass, mucus metaplasia, and airway wall fibrosis. The cornerstone of asthma therapy is a combination of both short- and long-acting beta-2 receptor adrenergic agonists, corticosteroids, leukotriene antagonists, and sometimes monoclonal antibody therapy. Chronic medical management of asthma focuses on bronchodilation and the reduction of airway inflammation, but the reversal of airway remodeling remains a challenge. Bronchial thermoplasty (BT) is a therapy that can reverse the effects of smooth muscle hypertrophy and other mucosal changes through the application of controlled thermal energy directly to airway walls. The approval of BT by the Food and Drug Administration (FDA) on April 27, 2010 has set a new paradigm in the treatment for moderate to severe persistent asthma.
Scientific Basis for Bronchial Thermoplasty
The direct application of controlled thermal energy of 65°C to the airway wall using a thermal energy probe deployed during bronchoscopy reduces ASM mass. Early studies in canines showed that the reduction in ASM mass could result in decreased bronchial constriction in response to various intrinsic and extrinsic inflammatory mediators. Reduction in ASM mass, type 1 collagen deposition, and reticular basement membrane thickness have been confirmed by biopsy in humans. BT causes a reduction in nerve fibers innervating the epithelium and ASM. BT changes epithelial cell phenotype leading to reduced mucin production and goblet cell hyperplasia, perhaps driven by decreased interleukin (IL)-13 expression. BT may also alter several other genes involved in pathogenesis of asthma and exert immunomodulatory actions by altering T-cell subpopulations in the airway. BT increases luminal airway volume and reduces gas trapping in small airways. These changes may not always be evident by spirometry or impedance oscillometry, but changes in ventilation can be quantified using advanced imaging techniques, such as hyperpolarized 3 He magnetic resonance imaging (MRI). However, the benefit of increased airway caliber in the absence of improvements in pulmonary function is not entirely clear. In summary, BT induces many changes in the airways, including reduction in ASM mass and nerve fibers, beneficial changes in the airway epithelium, and improves ventilation, potentially by increasing airway caliber.
Clinical Evidence from Human Studies
Miller and colleagues performed the first prospective feasibility study of BT in humans. BT was performed in eight patients preoperatively up to 3 weeks prior to the planned lung resection for suspected or proven lung cancer. Treatment was limited to the segmental bronchi planned to be removed. There were no adverse effects related to the procedure. There was no bronchoscopic evidence of scarring in the airways, and histologic examination confirmed a reduction in ASM in the treated airways and immediate peribronchial area.
Cox and colleagues performed the first nonrandomized feasibility study of BT in 16 patients with stable asthma and demonstrated a significant increase in methacholine PC20 and mean symptom-free days.
The Asthma Intervention Research (AIR) trial was the first randomized controlled trial enrolling 112 patients and compared BT plus standard-of-care therapy (inhaled corticosteroids [ICS] and long-acting beta agonists [LABA]) with standard-of-care therapy (ICS and LABA) alone in patients with moderate to severe persistent asthma. The trial demonstrated a significant decrease in the rate of mild exacerbations (not severe exacerbations) and an increase in morning peak expiratory flow rate among patients receiving BT compared to the control group. Long-term follow-up of BT patients revealed a stable rate of respiratory adverse events, without increase in emergency visits or hospitalizations for respiratory symptoms and stable lung function over 5 years.
The Research in Severe Asthma (RISA) trial was a randomized multicenter trial enrolling 34 patients with severe asthma. The patients were randomized to receive either BT or continue high-dose ICS and LABA. The trial showed a significant increase in prebronchodilator forced expiratory volume in the first second of expiration (FEV 1 ) and improvement in asthma control and quality of life in BT group compared to the control group. Long-term follow-up for 5 years revealed stable respiratory adverse events and decrease in hospitalizations and emergency department visits for respiratory symptoms.
The AIR2 trial was the first double-blind, sham-controlled randomized control trial of BT comparing the effectiveness and safety of BT versus a sham procedure in patients with severe asthma. A total of 288 patients were randomized to either BT or sham control. Primary outcome was the difference in asthma quality-of-life questionnaire (AQLQ) scores from baseline to average of 6, 9, and 12 months (integrated AQLQ). The improvement in integrated AQLQ score from baseline was superior in the BT group compared to the sham group. More BT patients (6% more) were hospitalized in the treatment period. BT patients experienced fewer exacerbations, emergency room visits, and days missed from work or school compared to the sham group. Five-year follow-up of BT-treated patients from AIR2 trial demonstrated 5-year durability of benefits of BT. BT-treated patients had fewer severe exacerbations and emergency visits on 5-year follow-up (average 5-year reduction of 44% in severe exacerbations and 78% for emergency visits) compared to those observed in the 12 months prior to their BT.
The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) is a prospective, observational, multicenter study designed to confirm the safety and efficacy of BT in clinical practice. The primary endpoint is the proportion of subjects experiencing severe exacerbations during the subsequent 12-month period for years 2, 3, 4, and 5 compared with the first 12-month period after BT. PAS2 data show that BT is safe and associated with lower rates of severe asthma exacerbations, emergency visits, and hospitalization at 3 years after BT (45%, 55%, and 40% decrease, respectively) compared to the 12 months before BT.
Burn and colleagues analyzed the efficacy and safety of BT in the UK and found mean improvement in AQLQ score at 12 months and a significant reduction in hospital admissions at 24 months follow-up without any deterioration in FEV 1 , consistent with other clinical trials.
Preprocedure Management Overview and Patient Selection
Patient selection remains a key component to successful outcomes as described in the literature. A multidisciplinary approach in the setting of an asthma center with nurse practitioner, clinical pharmacist, and physician allows for a complete assessment of the patient, socioeconomic support, awareness about asthma, technique and compliance with inhaler usage, environmental exposures, tobacco history, and evaluation of other underlying diseases that may directly impact asthma care, such as rhinitis or sinusitis, atopy, immunodeficiency, gastroesophageal reflux, and obesity. Patients should be evaluated for other diseases that can mimic asthma, such as cardiac disease, vocal cord dysfunction, structural tracheal diseases, connective tissue diseases, or vasculitis syndromes. A thorough clinical assessment to identify factors to improve the patient’s asthma symptoms is necessary to more accurately rate the severity of the disease while screening for the potential role for BT in moderate to severe persistent asthma ( Fig. 12.1 ).
Practically speaking, many clinicians continue to adhere to the inclusion and exclusion criteria reported in the prior clinical trials. The series of clinical trials have developed specific selection criteria as well as general considerations for patient selection for bronchial thermoplasty ( Boxes 12.1 and 12.2 ). Future studies and outcome reports will be needed to determine if a broader range of patients will benefit from BT, such as those with severely impaired lung function.
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Adult age 18 to 65 years
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Diagnosis of asthma and taking regular maintenance medication to include inhaled corticosteroid (ICS) at a dosage >1000 µg beclomethasone daily or equivalent and long-acting beta-2 agonist (LABA) at a dosage ≥100 µg daily of salmeterol or equivalent
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In addition to ICS and LABA, the patient may be on leukotriene antagonists, anti-IgE, other biologic therapies, or oral corticosteroids at a dosage of up to 10 mg daily or 20 mg every other day
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Stability of asthma symptoms on maintenance medications
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No current respiratory tract infection or severe asthma exacerbation within 4 weeks preceding a scheduled bronchial thermoplasty (BT)
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No unstable or untreated comorbid condition that would increase the risk of bronchoscopy
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Prebronchodilator forced expiratory volume in the first second of expiration (FEV 1 ) ≥60% predicted
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Postbronchodilator FEV 1 ≥65% predicted
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FEV 1 within 10% of the individual’s best value
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Patient had at least 2 days of asthma symptoms in the last 4 weeks
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Nonsmoker for 1 year or more and less than a 10-pack-year tobacco history
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Able to undergo an outpatient bronchoscopy
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No contraindications to medications required to perform bronchoscopy (lidocaine, opiates, benzodiazepines)
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Participation in another clinical trial within 6 weeks of baseline period of study enrollment
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Patient requires rescue medication over the last week of a 4-week medication stable period, exceeding average of eight puffs per day of short-acting bronchodilator, or four puffs per day of long-acting rescue bronchodilator, or two nebulizer treatments per day
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Postbronchodilator FEV 1 <65%
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History of life-threatening asthma: past intubations for asthma, ICU admission for asthma in the past 2 years
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Three or more hospitalizations for asthma exacerbation in the prior year
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Four or more infections of the lower respiratory tract requiring antibiotics in the past year
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Four or more pulses of systemic corticosteroids for asthma symptoms in the past year
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Known sensitivity to medications required to perform bronchoscopy
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Concomitant respiratory diseases such as tracheal stenosis, tracheobronchomalacia, emphysema, cystic fibrosis, bronchiectasis, vocal cord dysfunction, mechanical upper airway obstruction, Churg-Strauss syndrome, and allergic bronchopulmonary aspergillosis
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Segmental atelectasis, lobar consolidation, significant or unstable pulmonary infiltrate, or pneumothorax confirmed on chest radiograph
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Significant cardiovascular disease, including myocardial infarction, angina, cardiac dysfunction, cardiac dysrhythmia, conduction defect, cardiomyopathy, or stroke
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Known aortic aneurysm
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Comorbid illness: cancer, renal failure, liver disease, or cerebral vascular disease
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Uncontrolled hypertension; systolic pressure >200 mmHg or diastolic pressure >100 mmHg
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Implanted electrical stimulation device such as pacemaker, cardiac defibrillator, deep nerve, or brain stimulator
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Coagulopathy; international normalized ratio (INR) >1.5
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Inability to discontinue anticoagulants or antiplatelets prior to the procedure
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Known bleeding disorder
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Prior treatment with bronchial thermoplasty
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Age <18 years
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Pregnancy
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