One Step Forward, Two Steps Back: Bronchial Thermoplasty for Asthma

Increased airway smooth muscle mass and contractility contribute to bronchoconstriction, airflow limitation, and respiratory symptoms in asthma. These observations have led to interest in decreasing airway smooth muscle mass using bronchial thermoplasty as a nonpharmacologic approach to improving asthma control in individuals with severe asthma. Bronchial thermoplasty involves the delivery of thermal energy to the airway wall of medium to large airways through three separate bronchoscopic procedures.

The AIR2 (Asthma Intervention Research) trial, the largest study of bronchial thermoplasty to date, was a sham-controlled clinical trial of nearly 290 adults with severe asthma (1). Participants in both the bronchial and sham thermoplasty groups reported improvements in asthma quality of life over 12 months (the primary outcome), which was assessed by the Asthma Quality of Life Questionnaire (AQLQ). Importantly, both groups reported more than twice the minimum important difference for the AQLQ. However, the difference between groups in the AQLQ was modest and less than the minimum important difference over 12 months. Although some secondary outcomes favored bronchial thermoplasty (asthma exacerbations treated and days lost from school or work) over 12 months, there were no differences between groups in respiratory symptoms, rescue medication use, or lung function. Also, 8% of participants undergoing bronchial thermoplasty (vs. 2% in the sham group) required hospitalizations because of procedure-related complications.

Long-term follow-up in 85% participants in the AIR2 study who received bronchial thermoplasty demonstrated similar rates of asthma exacerbations and lung function over the next 5 years as those demonstrated in the first 12 months (2). The lack of a control group during the long-term follow-up limited the ability to understand the durability of the effects of bronchial thermoplasty. Guidance from experts who developed the 2020 Global Strategy for Asthma Management and Prevention (GINA) report (3) suggests that bronchial thermoplasty is not ready for prime time. The GINA report noted the large placebo effect with bronchial thermoplasty and an increase in asthma exacerbations over the first 3 months after the procedure. Moreover, it is not clear which patients with severe asthma are more likely to benefit from bronchial thermoplasty than be harmed by it. Overall, the GINA expert panel concluded that additional studies comparing long-term outcomes in both the active and sham-treated patients are needed.

It is in this context that the multicenter randomized clinical trial led by Goorsenberg and colleagues and reported in this issue of the Journal (pp. 175–184) offers new data (4). The TASMA (Unravelling Targets of Therapy in Bronchial Thermoplasty in Severe Asthma) study sought to quantify the effects at 6 months of bronchial thermoplasty on airway smooth muscle mass (percentage of positive stained desmin and α-smooth muscle actin compared with the total biopsy area) and to identify characteristics associated with improved asthma control and asthma quality of life. Forty participants (mean age, 20 yr) were enrolled in the Netherlands and the United Kingdom and underwent a research bronchoscopy to obtain measurements of baseline airway smooth muscle mass from endobronchial biopsies and then were randomized to immediate or delayed (after 6 mo) bronchial thermoplasty. Unfortunately, this study did not include a sham thermoplasty control group.

Consistent with AIR2 study findings, the authors of the TASMA study reported postprocedure asthma exacerbations, including nine hospitalizations. At 6 months, there was significant improvement in asthma control and asthma quality of life after bronchial thermoplasty compared with delayed treatment. Improvements in these TASMA participant-reported measures are difficult to interpret given the large placebo effect observed in the sham group in the AIR2 study. There were also no significant differences between groups in lung function, airway hyperreactivity, or fraction of expired nitric oxide.

Importantly, Goorsenberg and colleagues report a significant reduction in desmin-positive and α-smooth muscle actin–positive airway smooth muscle mass (primary endpoint) after randomization to bronchial thermoplasty compared with pharmacologic asthma care alone. Unexpectedly, the airway smooth muscle mass (values at baseline, change over 6 mo, or at 6 mo) was not associated with Asthma Control Questionnaire or AQLQ improvement. These findings challenge the scientific premise for the use of bronchial thermoplasty in asthma and suggest that patient selection for bronchial thermoplasty based on airway smooth muscle analysis is not likely to be productive. Time to take two steps back!