Bronchial Thermoplasty

Introduction

Bronchial thermoplasty (BT) is a non-­ pharmacological endoscopic procedure that decreases airway smooth muscle (ASM) by applying thermal energy [1]. Multiple randomized controlled trials (RCTs) including Asthma Intervention Research (AIR), Research in Severe Asthma (RISA), and AIR2 demonstrated that BT reduced exacerbations and improved quality of life while maintaining a good safety pro le [2]. The initial improvement in quality of life and decrease in the rate of severe exacerbations at 1-year post-BT have been shown to be persistent with long-term data extending out to 10 years of post-BT treatment [3, 4]. Careful patient selection is the key. BT therapy is performed in three separate bronchoscopic sessions 3 weeks apart [2].

Mechanism of Action

In subsets of severe asthmatics, airway remodeling driven by increased airway smooth muscle (ASM) mass in the absence of infammation may be the underlying pathophysiology explaining the refractoriness to anti-infammatory therapies in these

E. Yavarovich (*)

Lahey Hospital & Medical Center, Pulmonary & Critical Care Medicine, Burlington, MA, USA e-mail: ekaterina.yavarovich@lahey.org

patients [1]. In addition, ASM function normally aids in mucus clearance, augmentation of lymphatic and venous fow, and structure protection, and plays a role in the effectiveness of cough and dead space. In patients with severe asthma, ASM mass can increase signi cantly. Bronchial thermoplasty directly reduces the amount of ASM in patients with asthma [5, 6]. However, this improvement in airway remodeling is not consistently associated with improvement in clinical outcomes. Small imaging studies demonstrate objective improvement in computed tomography (CT) airway volume after BT compared to not-treated airways at 4 weeks [7]. CT imaging showed persistently reduced airway wall thickness and decreased air trapping 2 years after BT [7, 8].

Beyond direct reduction in ASM, potential mechanisms of ASM include reduced infammatory mediators and lasting changes in the histopathology of airways. The ASMATHERM study examined the correlation between clinical and histopathological changes in patients who underwent BT comparing preand 3 months post-BT [6]. The study found BT at 1 year results in reductions in ASM area, neuroendocrine epithelial cells, and nerve endings, while there was no change in hypertrophy or hyperplasia of mucous glands and goblet cells [1, 6]. Other studies suggest BT may decrease the expression of airway infammatory markers and production of protein-­like interleukin (IL)-13, which is responsible for mucus secretions and goblet cell hyperplasia [1, 9].

Efcacy and Safety

Trials

The rst randomized control trial for BT was the Asthma Intervention Research (AIR) trial [10, 11]. AIR was an unblinded, prospective, randomized controlled trial (RCT) that enrolled 112 patients with moderate to severe asthma comparing BT to standard of care (forced expiratory volume in one second (FEV1) 72.7% in the BT group vs. 76.1% in the control group) [10]. Patients were followed for 12 months and the study met the primary endpoint showing a reduction in exacerbation rates at 12 months (change in frequency per subject per week: −0.16 ± 0.37 vs. 0.04 ± 0.29; p = 0.005) [10]. Additionally, there was an improvement in secondary endpoints in BT-treated patients in the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) [2, 10, 11].

The second trial was Research in Severe Asthma (RISA), which evaluated BT in severe asthmatics alone (prebronchodilator FEV1: 62.9% in BT group vs. 66.4% in control group) [12]. RISA trial was also unblinded, RCT of 32 patients. The primary endpoint was safety and efficacy. BT group had short-term increase in hospitalizations due to asthma symptoms in 4 of 15 BT-treated patients. Two patients developed lobar collapse and one needing bronchoscopic aspiration. Despite this, at oneyear follow-up, there was a persistent improvement in asthma symptoms ACQ (−1.04 to ±1.03 vs. –0.13 to ±1.00; p = 0.02) and a decrease in rescue medications in the BT group (−25.6 to ±31.2 vs. –6.1 to ±12.4 puffs/7 d; p < 0.05) [3, 12].

The criticism of both AIR and RISA trials is they were unblinded. AIR2 trial was the rst BT study to utilize sham bronchoscopy study, which was a multicenter, double-blinded RCT that enrolled 288 patients with severe persistent asthma (FEV1: 77.8% in the BT group and 79.7% in the control group) [2, 13]. AIR2 trial’s primary endpoint was an improvement in AQLQ by 0.5 or greater, with secondary endpoint reduction in severe exacerbations, emergency depart-

ment (ER) visits, and days missed from school/ work at 12 months post-BT [2]. Due to results from the AIR2 trial, BT was approved by Food and Drug Administration (FDA) for treatment of uncontrolled severe persistent asthma despite long-acting beta blocker (LABA) and inhaled corticosteroid (ICS) [11], although this approval was contingent based on the post-FDA approval study (PAS2) three-year post-marketing research. See Table 36.1 for summary of BT studies.

Short Term: Threeto Five-Year Studies

PAS2 study followed the 190 patients treated with BT from AIR2 trials for 3 years. The results of the PAS2 trial con rmed results from AIR2 with a 45% decrease in severe exacerbations, a 55% decrease in emergency room visits, and a 40% decrease in hospitalizations [14].

AIR, RISA, and AIR2 all had long-term fol- low-­up ve-year study. All studies found stable FEV1 and long-term safety, and persistent ­reduction in hospitalizations and emergency department visits at 5 years [15–17].

Long Term: Ten-Year Study

Recent data have been published on safety and effectiveness of BT after 10 years (10.8– 15.6 years; median 12.1 years) post-treatment, from AIR, RISA, and AIR2 trials, which is demonstrated in the BT10+ study [4]. About half of the AIR, RISA, and AIR2 trial participants were enrolled: 192/429 or 45% [4]. Of these, 136 subjects received bronchial thermoplasty, and 56 were sham or control patients who did not undergo BT. The proportion of severe exacerbations were similar at 1 year (24%), 5 years (22%), and 10 years (25%) in BT group. Additional sustained effect was observed in quality of life measures and spirometry at 1, 5, and 10 years. After the trial concluded, the results were similar for 18/56 control/sham patients treated with BT [4]. See Table 36.1 for summary of studies.