Bronchial thermoplasty (BT) is a technique using radio-frequency energy in a controlled manner to provide thermal treatment to airways.1,2 Recently, the US Food and Drug Administration (FDA) approved this nonpharmacologic therapy for severe asthma in patients 18 years of age and older not well controlled with currently available medical therapies.3 Clinical trials of feasibility and efficacy have been performed that demonstrate BT can be safe and have an impact upon clinical metrics of asthma including symptoms, quality of life, and health care utilization.2,4-6 An overview of severe refractory asthma pathophysiology, a brief review of clinical trials with BT, and the current protocols and status of BT will be presented here. Illustration at right courtesy of Asthmatx
Overview of Severe Refractory Asthma, Candidates for Bronchial Thermoplasty
Asthma is a chronic inflammatory condition of the airways characterized by episodic symptoms of breathlessness, cough, and wheezing. Approximately 7% of the general population are affected with this chronic condition.7 In most cases, individuals with asthma are able to control their symptoms with proper adherence to anti-inflammatory therapies and avoidance of triggers. However, the burden of hospitalizations for asthma remains high, with more than 497,000 hospitalizations annually.7,8 The latest guidelines from the National Asthma Education and Prevention Program (NAEPP-2007) emphasized the importance of assessing asthma severity and control, including impairment (symptoms and limitations) and risk (likelihood of exacerbations) (see Figure).
To address the challenges in properly identifying and managing the approximately 5% to 10% of patients who have severe refractory asthma, the American Thoracic Society (ATS) hosted a workshop that helped to characterize this condition.9 Major characteristics of individuals with severe refractory asthma were defined as those who are adherent to and require treatment with continuous or near continuous (>50% of year) oral corticosteroids or need high-dose inhaled corticosteroids. In addition, two minor criteria are needed.10
The pathophysiology of asthma is chronic airway inflammation associated with increased airway reactivity and airflow obstruction. Histologic findings include excess mucus secretion, epithelial cell injury, and smooth muscle hypertrophy. These changes can lead to persistent airflow obstruction that can be difficult to manage and control, even with the best available medical therapies.7 Bronchoconstriction in asthma is characterized by increased airway smooth muscle (ASM), airway closure, and hyperresponsiveness temporarily reversed with acute bronchodilators, but long-lasting therapy is not available. This potential gap in the management of asthmatics is what is targeted by this new therapeutic modality, BT.
Development of Bronchial Thermoplasty for Asthma
Radio-frequency ablation therapy has been used in other medical conditions such as lung cancer and cardiac arrhythmias.11,12 The use of this technology to treat airway smooth muscle began with animal studies that showed the feasibility of using radio-frequency energy to decrease ASM.1 Subsequent clinical studies and trials in patients who were nonasthmatics or had mild to moderate persistent asthma, and finally moderate to severe refractory asthma, were performed and helped identify appropriate candidates, anticipated adverse events, and expected outcomes.2,4-6
Early animal studies in dogs demonstrated that applying thermal energy at 65°C and 75°C attenuated airway hyperresponsiveness as measured by methacholine bronchoprovocation up to 3 years after treatment.1 Altered ASM, defined as degenerating or absent muscle, was seen as early as 1 week after treatments and was inversely proportional to responsiveness.
A feasibility study in eight individuals scheduled to undergo lung resection for lung cancer was subsequently performed.2 Bronchial thermoplasty was performed in lobes to be resected 5 to 20 days prior to surgery. Histologic review of the resected and treated lungs demonstrated ASM alterations of approximately 50% of the area treated.2 There were no significant adverse events such as hemoptysis, respiratory infections, or excess bronchial irritation.
The first study of BT in mild to moderate persistent asthma was a prospective observational study in 16 patients.13 This relatively younger group had three treatments spaced 3 weeks apart. Although they were pretreated with prednisone, the patients’ most frequent side effects were symptoms of airway irritation such as cough, dyspnea, wheeze, and bronchospasm. There were no hospitalizations after the procedure. FEV1% predicted increased at 12 weeks and 1 year post-BT but showed no significant change at 2 years. In addition, this study demonstrated a steady improvement in symptom-free days up to 2 years after BT.13
To determine whether asthma control could be improved after BT, the Asthma Intervention Research (AIR) trial, a prospective randomized nonblinded study in moderate to severe asthma, was performed4; 112 adults on inhaled corticosteroids (ICS) and long-acting ß-agonists (LABA) were randomized to either BT with ICS and LABA versus ICS and LABA alone (usual care). With BT treatment, there was an encouraging reduction in the number of mild exacerbations with 10 fewer mild exacerbations per subject per year. Morning peak flow, rescue medication use, and Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores were all significantly improved.14,15 Not surprisingly, in this more unstable group, there were more adverse events and hospitalizations post-procedure in the BT group. Reasons for hospitalization included exacerbations of asthma, collapse of the left lower lobe, and pleurisy.4
Figure. Classifying asthma severity in youths >12 years of age and adults. From EPR-3: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm, page 74.
In the Research in Severe Asthma (RISA) trial, patients with severe asthma undergoing BT were studied for safety, changes in asthma symptoms, and ability to reduce daily inhaled or oral cortico-steroids.5 Patients with severe asthma on high-dose inhaled corticosteroids (>750 µg fluticasone-equivalent/day), on prednisone =30 mg/day, with prebronchodilator FEV1 percent predicted of =50%, and with positive methacholine bronchoprovocation were randomized to receive either BT (n=17) or medical management (n=17). During the period in which corticosteroid doses were kept stable, there was improvement in prebronchodilator FEV1, reduction in rescue inhaler use, and improved AQLQ/ACQ scores. Corticosteroids were then reduced up to 52 weeks after BT, and there was continued improvement in rescue medication use and AQLQ/ACQ scores. There were a higher number of and more serious adverse events in these patients with severe asthma in the postprocedure period; however, long-term adverse effects were not seen.5
The latest trial evaluating this new therapeutic modality with respect to asthma control scores, rescue medication use, and FEV1 in patients with severe asthma was the AIR2 trial.6 In this study, the control group received a bronchoscopy but no radio-frequency energy was delivered across the BT catheter (“sham” control group). Results showed a significant improvement in asthma quality of life in the BT group (Figure 1). There was also a significant decrease in severe exacerbations and 84% reduction in emergency department visits in those receiving BT. Interestingly, there was a significant and clinically meaningful (>0.5 change in the AQLQ score) improvement in quality of life in 64% of the sham group, although a larger proportion (79%) of the BT-treated group improved.16 Adverse events occurred in both groups; but during the treatment phase, 16 of the BT group needed hospitalizations for respiratory symptoms compared to two in the sham group. Therefore, this study demonstrates long-term improved asthma quality of life and decreased health care utilization in patients with severe asthma treated with BT.6
To summarize, these clinical trials demonstrate the feasibility, relative safety, and improved clinical outcomes in adult patients with severe asthma who undergo BT when medical therapies do not control their symptoms. Long-term studies are ongoing to evaluate the duration of effect and safety of BT.
Bronchial Thermoplasty Instruments and Performance
Bronchial thermoplasty is performed with a device called the Alair® System (Asthmatx Inc, Sunnyvale, Calif), which is designed to deliver a specific amount of radio-frequency (thermal) energy through a dedicated catheter. The catheter is deployed through a 2.0 mm working channel of a flexible bronchoscope (typical outer diameter 4.9 mm). Typically, the bronchoscopist directs and places the catheter in place, while the assistant (often a respiratory therapist or physician) under direct vision deploys the electrode array. The array is manually expanded to make contact with the airway walls and has a 5 mm treatment area of exposed electrodes on each of the four struts. The bronchoscopist or assistant will then activate the controller device to deliver the thermal energy. As the energy is delivered via the electrodes, the control unit measures electrical resistance converted to thermal energy and will stop when an appropriate dosage is given. This thermal energy is responsible for altering the airway smooth muscle. In this manner, this team will treat distal airways measuring as small as 3 mm in diameter and work proximally to sequentially treat all airways to the level of the mainstem lobar bronchi.
Patients are assessed prior to and on the day of the procedure to ensure disease stability (postbronchodilator FEV1 percent predicted within 10% of baseline values, no evidence of asthma exacerbation or active infection) similar to the protocol used for the AIR2 trial before proceeding with the treatment.6 Patients are pretreated with 50 mg/day of prednisone 3 days prior and day of the procedure. Nebulized albuterol (2.5 to 5.0 mg) is given prior to the procedure, and screening spirometry is performed by the respiratory therapist. A full course of treatment requires three separate bronchoscopic procedures. Each is separated by approximately 2 to 3 weeks.
Procedures are performed under moderate conscious sedation (typically using fentanyl, midazolam, and topical lidocaine) with either a transoral or transnasal approach with supplemental oxygen provided in a monitored environment. Careful application of lidocaine at the vocal cords and in the areas to be treated is key to minimize coughing during the procedure. Treatment sessions are designed to treat each lower lobe in separate procedures and then bilateral upper lobes in a third procedure to minimize the impact on respiratory symptoms. A meticulous mapping of the airway is maintained during treatments on a bronchial airway map to ensure treatment sites are not skipped or overlapped. Each procedure usually requires approximately 50 to 75 activations of the device and up to 40 to 60 minutes of procedure time. A second assistant is often needed to record the number and location of activations as well as to monitor the patient’s vital signs during the procedure. A recovery observation time of 3 to 4 hours and evaluation of postprocedure FEV1 percent predicted to within 10% to 20% of baseline are recommended. An additional 50 mg dose of prednisone is prescribed for the day after the procedure.17
FDA Approval and Long-Term Follow-up
In 2010, the FDA approved the Alair System for severe refractory asthma in adults.3 Individuals 18 years of age and older who have well-documented severe persistent asthma not well controlled on ICS and LABA and without any significant contraindications to bronchoscopy can be evaluated for BT. This evaluation is often performed by a specialist in asthma care and may or may not be the bronchoscopist performing BT. The FDA has required a postapproval study based on the long-term follow-up of patients in the AIR2 trial to evaluate durability of effectiveness of BT. A second postapproval study will be a prospective, open label, single arm, multicenter study conducted in the United States to demonstrate durability of treatment effect and to evaluate the short-term and longer-term safety profile of BT in the intended use population.
BT is a new therapeutic modality for the treatment of severe refractory asthma not well controlled on high-dose ICS and LABA therapy. Clinical trials, including randomized prospective trials with control groups, have demonstrated an acceptable safety profile while improving asthma quality of life, symptoms, and health care utilization over 1 year. Patient screening for eligibility, selection, and ongoing management are key factors in improving outcomes and minimizing adverse respiratory events. The respiratory therapist plays a key role in assisting the bronchoscopist in the appropriate preparation of the patient, conduct of the procedure, and postprocedure monitoring. As BT becomes widely available, dedicated respiratory therapists with asthma expertise will be needed for this procedure.
Sumita B. Khatri, MD, MS, is co-director, Asthma Center, and Thomas R. Gildea, MD, MS, is head, Section of Bronchoscopy, Cleveland Clinic Respiratory Institute, Cleveland. Mario Castro, MD, MPH, is professor of medicine and pediatrics, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St Louis. For further information, contact [email protected]
- Danek CJ, Lombard CM, Dungworth DL, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol. 2004;97:1946-53.
- Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest. 2005;127:1999-2006.
- US Food and Drub Administration. Approval of Alair Bronchial Thermoplasty System: Alair Catheter and Alair RF Controller. 2010. Available at: [removed]www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/~[/removed]. Accessed November 30, 2010.
- Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. 2007;356:1327-37.
- Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med. 2007;176:1185-91.
- Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181:116-24.
- NHLBI. Expert Panel Report 3 (EPR3): Guidelines for the Diagnosis and Management of Asthma Full Report 2007. Available at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed November 30, 2010.
- National Center for Health Statistics Focus Area 24 Respiratory Diseases Progress Review. Available at: www.cdc.gov/nchs/ppt/hp2010/focus_areas/fa24_2.pp. Accessed November 30, 2010.
- Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med. 2000;162:2341-51.
- Moore WC, Bleecker ER, Curran-Everett D, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol. 2007;119:405-13.
- Ambrogi MC, Fanucchi O, Lencioni R, Cioni R, Mussi A. Pulmonary radiofrequency ablation in a single lung patient. Thorax. 2006;61:828-9.
- Benussi S, Cini R, Gaynor SL, Alfieri O, Calafiore AM. Bipolar radiofrequency maze procedure through a transseptal approach. Ann Thorac Surg. 2010;90:1025-7.
- Cox G, Miller JD, McWilliams A, Fitzgerald JM, Lam S. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med. 2006;173:965-9.
- Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of impairment of health related quality of life in asthma: development of a questionnaire for use in clinical trials. Thorax. 1992;47:76-83.
- Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999;14:902-7.
- Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a disease-specific Quality of Life Questionnaire. J Clin Epidemiol. 1994;47:81-7.
- Mayse ML, Laviolette M, Rubin AS, et al. Clinical pearls for bronchial thermoplasty. J Bronchol. 2007;14:115-23.