Bronchial thermoplasty is a relatively new therapy for the management of severe asthma. It involves the direct bronchoscopic application of thermal energy to airways by a catheter-directed expandable basket. The airways of the lower and upper lobes are treated in 3 separate sessions spaced 3 weeks apart. The therapy targets airway smooth muscle, with studies showing a decrease in airway smooth muscle after bronchial thermoplasty therapy. After therapy, an improvement in quality of life and decrease in asthma exacerbations can be expected. Adverse events can occur with bronchial thermoplasty and careful patient selection is critical to ensure benefits outweigh the potential risks.
| AIR | Asthma Intervention Research |
| ASM | Airway smooth muscle |
| ATS | American Thoracic Society |
| BT | Bronchial thermoplasty |
| FEV 1 | Forced expiratory volume in 1 second |
| LABA | Long-acting β-agonist |
Key points
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Bronchial thermoplasty (BT) is a bronchoscopic procedure that involves the direct application of thermal energy to the airways and is performed at 3 separate sessions spaced 3 weeks apart.
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BT leads to the destruction of airway smooth muscle (ASM), because ASM plays an important role in the pathophysiology of asthma.
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The procedure is approved for patients with severe asthma and results in improvement in quality of life and decreased asthma exacerbations.
A video demonstrating BT accompanies this article at www.oto.theclinics.com
Introduction
Bronchial thermoplasty (BT) was approved by the Food and Drug Administration (FDA) in April 2010 and offers a novel add-on treatment of the management of severe asthma by reducing smooth muscle mass via direct application of thermal energy. Severe asthma is a widespread problem globally. There are 22.9 million Americans in the United States with asthma, and severe persistent asthma constitutes up to 12% yet disproportionately utilizes more direct and indirect health care dollars for asthma care.
Introduction
Bronchial thermoplasty (BT) was approved by the Food and Drug Administration (FDA) in April 2010 and offers a novel add-on treatment of the management of severe asthma by reducing smooth muscle mass via direct application of thermal energy. Severe asthma is a widespread problem globally. There are 22.9 million Americans in the United States with asthma, and severe persistent asthma constitutes up to 12% yet disproportionately utilizes more direct and indirect health care dollars for asthma care.
Severe asthma
Severe persistent asthma consists of asthma symptoms throughout the day, nighttime awakenings often 7 times a week, need for short-acting β-agonists several times a day, and extreme limitations in daily activity as well as forced expiratory volume in 1 second (FEV 1 ) less than 60% predicted (without medications). Risk factors for severe asthma include being female (postpuberty), obesity, black race, significant secondhand smoke exposure, and comorbidities of gastroesophageal reflux, sinus infections, and pneumonia. Although control is the ultimate goal in the management of asthma, complete control in many with severe persistent asthma is often elusive, leading to several terms to describe this patient group, including severe asthma , steroid-dependent or resistant asthma , difficult or poorly controlled asthma , and brittle or irreversible asthma . In 2000, the “Proceedings of the ATS Workshop on Refractory Asthma” agreed on the term, refractory asthma , to describe those asthma cases requiring a high amount of medications to maintain control or those cases of persistent symptoms, airflow obstruction, and frequent exacerbations despite high medication use. Diagnosis requires all other diseases with similar presenting symptoms to have been ruled out, comorbid conditions adequately managed, and medication technique and adherence issues addressed.
The lack of therapeutic effectiveness or response to traditional medications in this patient group raises the question of differing airway pathophysiology compared with mild or moderate asthmatics and has led to a discussion of asthma being a heterogeneous disease with varying manifestations or responses to treatment. Several distinct phenotypes are evolving when comparing clinical and physiologic features, prominence of biomarkers, age of disease onset, and response to therapy; however, additional research is needed for full characterization. The movement from symptom-based therapy decisions to medications or interventions targeting the underlying physiologic features of the disease will pave the way to personalized treatment plans, with the ultimate goal of improved control for refractory asthmatics.
Pathophysiology
One important target of current asthma therapy is ASM because it is critically involved in asthma pathogenesis. Acutely, ASM cell contraction causes bronchoconstriction. Chronically, hypertrophy and hyperplasia of ASM are responsible for airway remodeling. Additionally, through interactions with other cells, such as mast cells, and by generating and releasing inflammatory mediators, ASM cells are responsible for some of the airway inflammation seen with asthma. Medications, such as short-acting bronchodilators, long-acting bronchodilators, leukotriene inhibitors, and theophylline, play an important role in asthma management by relaxing the ASM. BT is used as a new approach to treatment by structurally modifying the airway and destroying smooth muscle. If ASM is to be destroyed, it is important to believe that ASM does not have a physiologic role. Investigators have debated if ASM has a beneficial or physiologic role or whether it is similar to a vestigial organ and serves no useful purpose. This debate has not been settled; many researchers and clinicians have proposed possible roles for ASM. Refractory asthmatics present a crucial opportunity to better understand the underlying pathophysiology of asthma and the importance of targeting specific pathways for treatment. The complexity of the inflammatory cascade and chemoreceptors associated with asthma reduces the possibility of a single treatment approach for a cure. Although BT has been associated with reduced frequency of asthma exacerbations, some unknown factors persist because airway inflammation remains intact and medications remain necessary for management.
Results and efficacy
Preclinical Studies
In 2004, investigators published a study using radiofrequency ablation (BT) at 3 different temperatures in 11 dogs with some of the dogs followed as long as 3 years. The investigators found a significant reduction in airway hyperresponsiveness among the BT-treated (at 65°C or 75°C) versus untreated airways of the canines using local methacholine provocation directed to the treated airways. Histologic evaluation of the canine airways (up to 3 years after treatment) showed persistent ASM reduction and no evidence of smooth muscle regeneration. This study also established a correlation between the extent of reduction in ASM and improvement in airway hyperresponsiveness. These results were subsequently validated in 3 additional canine studies.
Human Studies
Lung cancer, no asthma
The first human feasibility study was conducted by Miller and colleagues. Nine subjects without asthma but with known lung cancer scheduled to undergo surgical resection participated in this study; however, only 8 underwent BT. BT was targeted to visually accessible airway segments, which were planned for surgical resection. All subjects had an office follow-up visit in-between the BT treatment and surgery. All patients tolerated the procedure well and there were no procedure-related complications (including respiratory tract infections, need for additional medications, supplemental oxygen, and unscheduled health care visits). Histologic evaluation of both the treated and untreated tissue was performed. An approximately 50% reduction in ASM was noted in airways of those treated to 65°C versus a 5% reduction among persons treated to 55°C. The investigators concluded that BT is well tolerated among humans and yielded significant reduction in ASM mass.
Mild to moderate asthma
Subsequent studies were conducted evaluating BT in asthmatic patients ( Table 1 ). The first was a nonrandomized prospective study of 16 patients with stable mild to moderate asthma ; 13 of the 16 subjects completed all 3 sessions and were followed for 2 years post-BT. There was a significant improvement in airway hyperresponsiveness but no improvement in FEV 1 after 2 years. BT was well tolerated among asthmatics; however, in comparison to the feasibility study, there were side effects. The most common adverse events were mild and consisted of
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Cough (94% of subjects)
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Chest discomfort (56%)
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Dyspnea (69%)
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Wheezing (50%)
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Bronchospasm (63%)
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Mucus production (50%)
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Fever (44%)
| Study | Study Design | Asthma Severity | Follow-up (y) | Improved Outcomes | Outcomes Without Change |
|---|---|---|---|---|---|
| Cox et al, | Prospective nonrandomized | Mild to moderate, stable asthma | 2 | AHR Symptom-free days Morning PEF Evening PEF | FEV 1 Rescue medicine usage |
| Cox et al, | Prospective randomized | Moderate to severe persistent asthma | 1 | Morning PEF Symptom-free days Quality-of-life scores Rescue medicine usage | AHR FEV 1 |
| Pavord et al, | Prospective randomized | Refractory asthma | 1 | Quality-of-life scores Rescue medicine usage Prebronchodilator FEV 1 | AHR Symptom-free days Morning PEF Evening PEF Postbronchodilator FEV 1 |
| Castro et al, | Randomized, double-blind, sham-controlled | Severe persistent asthma | 1 | Severe asthma exacerbations ED visits Missed work/school days | Pre- or postbronchodilator FEV 1 Rescue medicine usage Symptom-free days Morning PEF |
There were no postprocedure hospitalizations or severe adverse events related to BT.
The Asthma Intervention Research (AIR) Trial was the first randomized multicenter study evaluating BT ; 112 subjects with moderate to severe persistent asthma were enrolled and randomized to either inhaled corticosteroid with a long-acting β-agonist (LABA) or BT plus combination inhaled corticosteroid and LABA. Subjects were followed for 2 years. The study showed an improvement in asthma symptoms; however, no difference in airway hyperresponsiveness was observed. Adverse events were common immediately post-treatment in the BT cohort, with 4 subjects requiring hospitalization for asthma exacerbations. Again a majority of adverse events were mild and mainly consisted of cough, dyspnea, wheezing, and chest tightness. The major limitation of this study was its nonblinded study design and lack of sham control leading to a potential placebo effect.
Although the safety and efficacy of BT among mild, moderate, and severe persistent asthma had been evaluated, the question remained as to whether patients with refractory asthma could benefit from this novel asthma therapy. Pavord and colleagues performed a randomized trial aimed at evaluating the efficacy of BT among symptomatic severe asthmatics; 34 subjects with refractory asthma were enrolled in this yearlong, multinational study comparing BT with a control, medical management arm. Subjects in this study were on higher doses of inhaled corticosteroids and oral prednisone in comparison with previously published studies. At completion of the study, subjects in the BT arm had a significant reduction in use of short-acting β-agonist, improvement in prebronchodilator FEV 1 , but not postbronchodilator FEV 1 , and improved Asthma Control Questionnaire scores compared with subjects in the medical therapy arm. During the treatment period, 7 hospitalizations for respiratory symptoms occurred in 4 of the 15 BT patients compared with none in the control arm. Two hospitalizations were secondary to segmental collapse of the recently treated lobe whereas 5 were for asthma exacerbations. Aside from the treatment portion of the study, hospitalization rates were similar for the two groups.
Although each of these studies highlights efficacy, safety, and complications associated with BT among small and specific asthma populations, they had significant limitations. In 2010, the Asthma Intervention Research 2 Trial (AIR2) trial, a randomized, double-blinded, sham-controlled study, was published. In order to achieve the double-blind design, subjects were evaluated by a blinded assessment team and treatments were conducted by an unblinded bronchoscopy team. The sham bronchoscopy used a sham radiofrequency controller, which was indistinguishable with the exception of no deliverable energy; 288 subjects with severe asthma were enrolled. The Asthma Quality of Life Questionnaire scores were significantly improvement from baseline in the BT group compared with the sham group. More remarkably, the study showed a significant reduction in severe exacerbations, emergency department visits, and missed work/school days post-BT. Adverse events were mostly mild to moderate in severity and consisted mainly of symptoms of airway inflammation. Again, the BT group had a higher postprocedure hospitalization rate (8.4%–2% of the sham group), and severe adverse events included 1 episode of hemoptysis requiring bronchial artery embolization.
Since the definitive study for BT by Castro and colleagues, its use for the treatment of adults greater than or equal to 18 years with severe persistent asthma that is uncontrolled despite inhaled corticosteroids and LABA has been approved by the FDA. Despite FDA approval, its efficacy and safety continue to be studied. There are few data on the long-term benefits. Further research is needed to determine the long-term safety and efficacy of BT on asthma as well as specific patient selection recommendations to determine which asthma phenotypes respond the best to BT.
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