Chapter 20

Bronchial thermoplasty

Michel Aubier^1,2,3,4, Marie-Christine Dombret¹, Marie-Pierre Debray⁵ and Marina Pretolani^2,3,4

¹Dept of Pneumology A, Bichat-Claude Bernard University Hospital, Paris, France. ²Faculty of Medicine, Paris Diderot University, Paris, France. ³Laboratory of Excellence, INFLAMEX, Université Sorbonne Paris Cité and DHU FIRE, Paris, France. ⁴INSERM UMR1152, Physiopathology and Epidemiology of Respiratory Diseases, Paris, France.. ⁵Dept of Radiology, Bichat-Claude Bernard University Hospital, Paris, France.

Correspondence: Michel Aubier, INSERM UMR1152, Paris Diderot University, Faculty of Medicine, Bichat campus, 16 rue Henri Huchard, 75018 Paris, France. E-mail: michel.aubier@inserm.fr

Asthma affects >235 million people worldwide. Treatment focuses on monitoring asthma severity, assessing symptom control and eliminating or reducing exacerbations [1]. Most asthmatics can be well controlled using currently available inhaler therapy with controller medications such as inhaled cortocosteroids (ICS), short-acting β₂-agonists and long-acting β₂-agonists (LABAs). However, the daily lives of a small percentage (5–10%) of severely symptomatic patients are limited by their chronic condition [2].

Severe asthma is still defined as uncontrolled despite the use of high doses of ICS alongside a second controller medication (an anticholinergic inhaler or anti-leukotriene receptor antagonist) and/or systemic oral corticosteroids (OCS) [2]. These severe asthmatics have a high burden of disease with frequent asthma exacerbations and/or progressive lung function decline resulting in excessive use of healthcare resources [3].

Management of severe asthmatics is complicated by heterogeneity in the physiological, pathological and molecular airway abnormalities. Some specific asthma phenotypes have been identified on the basis of demographic, functional, pathological, inflammatory and clinical characteristics [4, 5]. Therapeutic options for these patients are limited and when asthma control is not achieved, add-on treatments with anti-immunoglobulin (Ig)E or anti-interleukin-5 (anti-IL-5) monoclonal antibodies driven by selected phenotypes are recommended [1]. However, the use of anti-IgE therapy remains restricted to patients with allergic sensitisation and an elevated serum IgE level [6, 7], and the use of anti-IL-5 agents is limited to patients with a predominant eosinophilic phenotype [8]. Several new biological therapies targeting specific mediators of the underlying immune response have yielded promising preliminary results, but they remain experimental and only appear effective in patients with severe asthma with a high type 2 T-helper cell phenotype [9, 10].

Persistent airway inflammation and remodelling are fundamental features of severe asthma [11, 12]. However, all treatments available thus far target inflammatory/immune airway abnormalities but not the remodelling component. Airway remodelling refers to the long-term microscopic structural changes observed in the bronchial wall. Remodelling in asthma typically manifests as epithelial cell hyperplasia, goblet cell metaplasia, sub-epithelial fibrosis, angiogenesis and an increase in airway smooth muscle (ASM) mass [13, 14]. These changes correlate with asthma severity, and with the degree or the reversibility of airflow obstruction [13, 14]. Several reports have highlighted the effect of increased ASM mass in severe asthma, particularly on airway hyperresponsiveness and permanent airflow limitation [12, 15].

Bronchial thermoplasty is based on the premise that ablation of the ASM will minimise brochoconstriction and will reduce asthma symptoms and exacerbations. As such, bronchial thermoplasty is the first asthma treatment that targets airway remodelling instead of modulating airway inflammation and bronchomotor tone. Therefore, bronchial thermoplasty represents an attractive alternative management strategy in patients with severe difficult-to-control asthma, using the available pharmacological treatments including the new biologics.

Bronchial thermoplasty is a device-based therapy that delivers controlled thermal energy to the airway wall as part of a series of three bronchoscopic procedures. In 2010, it was approved by the US Food and Drug Administration (FDA) for the treatment of severe persistent asthma in patients ≥18 years of age whose asthma is not well controlled with ICS and LABAs; in 2011, it was CE marked and has been available in Europe since that time. Bronchial thermoplasty is the subject of an important clinical development programme as well as a large body of published clinical work; however, many unresolved questions remain about the therapy.

In this chapter, we will begin by describing the procedure and presenting the results of the major clinical trials that have been published. We will then move on to consider the recent data on mechanisms of action. Finally, unresolved questions, such as patient selection in clinical practice, will be discussed.

The procedure

Bronchial thermoplasty is an endoscopic minimally invasive procedure that is based on local, radiofrequeny energy. Treatment requires a bronchoscope that is compatible with a radiofrequency catheter, and has an insertion diameter of 4.9–5.2 mm and a working channel of ≥2 mm. Larger bronchoscopes are less suitable as they reduce access to the distal airways. The catheter is placed in the distal aspect of the airway that is being treated and is advanced using visual guidance. The electrode’s array is then expanded to make contact with the airway wall, and a footswitch is activated to deliver radiofrequency energy via the Alair system (Boston Scientific, Natick, MA, USA) (figure 1). Each radiofrequency energy delivery or activation takes 10 s and heats the airway to 65°C. It is recommended that patients undergo three treatment sessions at ∼3-week intervals; it is essential that the patient recovers fully between treatments in order to proceed. The sequence of treatments is as follows: right lower lobe (first session), left lower lobe (second session), both upper lobes (third session). The right middle lobe is not treated as the guidelines for bronchial thermoplasty excluded this area based on the theoretical possibility of obstruction and right middle lobe syndrome [16]. Each bronchial thermoplasty session takes ∼30–45 min. Each bronchus is treated along its entire visible length, with each activation targeting a 5-mm section of bronchus 3–10 mm in diameter beginning at the periphery and moving proximally. Areas should not be retreated. Full treatment consists of ∼30–70 activations per lobe (depending on the specific anatomy); on average, 44 for the right lower lobe, 47 for the left lower lobe and 60 for the upper lobes [16]. The effectiveness of the treatment depends on how thoroughly the procedure is performed. An untreated segment may theoretically continue to constrict when stimulated, which may counteract treatment benefits. A meticulous technique and airway mapping are therefore very important. Activation of the bronchial thermoplasty catheter does not have a macroscopic effect on the bronchial mucosa but may cause transient blanching, which is represented by a whitening of the mucosa. This makes identification of the treated bronchi difficult; close attention is therefore required on the part of the bronchoscopist. Immediately following the procedure, close clinical monitoring is required as asthma symptoms are more common in the hours immediately following treatment. Patients receive oral prednisolone (50 mg per day) for 3 days before the day of and 1 day after the procedure. The procedure can be carried out under sedation or using general anaesthesia, depending on the resources available and the preferences of the physician/institution. Although carrying out bronchial thermoplasty may seem straightforward, it requires expertise in asthma management and interventional bronchoscopy. A multidisciplinary team that combines physicians with a specific interest in interventional endoscopy and those with an expertise in chronic airway disorders will ensure the best possible care for and that is most appropriate to the patient. Appropriate patient assessment and monitoring before, during and after the procedure has been well described elsewhere and can be performed in an inpatient or outpatient setting [17].

Figure 1. a) Schematic representation of the Alair catheter (Boston Scientific, Natick, MA, USA). b) The Alair radiofrequency generator (Boston Scientific). c) The Alair catheter during an activation of radiofrequency energy delivery to the airways.

Bronchial thermoplasty can only be considered for use in patients whose asthma is well-documented. Current warnings, precautions and exclusions include COPD, bronchiectasis, recurrent respiratory infections and any other uncontrolled significant respiratory disease. The treating facility (as well as the asthma specialist and the interventional bronchoscopist) should be familiar with the clinical course of their patients in order to ensure appropriate patient selection and to optimise asthma control, both prior to bronchial thermoplasty and throughout the treatment period. Bronchial thermoplasty treatment can temporarily worsen asthma symptoms, and the intensity of this can be proportional to the patient’s asthma severity [18]. The clinical benefits should be reassessed at the end of the treatment period (6 weeks after the final bronchoscopy). Pharmacological treatments should be adjusted to their lowest possible dosages, beginning with a reduction in OCS followed by a decrease in ICS and/or LABA if the asthma remains well-controlled [19].

Clinical evidence of bronchial thermoplasty in asthma patients

Efficacy

In 2006, COX et al. [16] reported the findings of an observational pilot study that explored the safety and clinical effects of bronchial thermoplasty. 16 patients with mild-to-moderate asthma reported improvements in: symptom-free days; morning peak expiratory flow 3 months afters bronchial thermoplasty treatment; and a reduction in airway hyperresponsiveness to methacholine. These improvements persisted for ≤3 years (this finding was not significant as a high number of patients were lost to follow-up, especially in the untreated group).

Following this initial study, three randomised clinical trials were carried out in patients with moderate-to-severe asthma [18, 20, 21].

The Asthma Intervention Research (AIR) Trial [20] was a randomised, controlled study performed in 112 asthma patients, all of whom required treatment with ICS and LABA. 56 of the patients received bronchial thermoplasty and 56 received standard care. The trial measured the average frequency of mild exacerbations during LABA withdrawal periods. The group treated with bronchial thermoplasty presented fewer average mild exacerbations than the control group during the LABA withdrawal period at 1 year. Asthma control improved after bronchial thermoplasty, patients had more symptom-free days and quality of life was significantly better compared with the control group. Subjects treated with bronchial thermoplasty also used fewer rescue medications, equating to approximately two fewer canisters of short-acting bronchodilators per year. Morning peak flow measurements were better than in the control group, but no differences were noted in prebronchodilator FEV₁ % predicted airway hyperresposiveness between patients receiving bronchial thermoplasty and control patients.

The smaller Research in Severe Asthma (RISA) Trial [18], performed following the results of the AIR Trial [20], was designed to evaluate bronchial thermoplasty in patients with severe, symptomatic asthma. RISA was a randomised, controlled safety study in performed 32 severe patients whose asthma was uncontrolled despite high doses of ICS. In the study, 15 patients received bronchial thermoplasty and 17 continued with usual care. After the initial evaluation, forced steroid withdrawal took place between weeks 22 and 36 in an attempt to wean patients off ICS and OCS. Although subjects who underwent bronchial thermoplasty were on reduced maintenance therapy following the steroid-wean phase, they showed improved quality of life compared with control subjects. The group treated with bronchial thermoplasty also showed improved asthma control and a reduction in the use of rescue medications prior to the forced-steroid withdrawal period. Despite a decrease in medication use following the steroid-wean phase, the bronchial thermoplasty group continued to show a reduction in the use of short-acting bronchodilators, more symptom-free days and maintenance of an improved Asthma Control Questionnaire (ACQ) score. In bronchial thermoplasty subjects, the use of OCS and ICS fell by 63.5% and 28.6%, respectively, compared with 26.2% and 20% in the control group. In spite of the decrease in maintenance therapy, significant improvements were seen in quality of life and asthma symptom scores 4 months after the steroid-wean phase.

Although the findings of the AIR and RISA trials showed improvements in some clinical outcomes, the unblinded nature of these studies raised questions regarding a possible pacebo effect rather than real efficacy of bronchial thermoplasty. The AIR2 trial [21] was designed specifically to address this limitation [18, 20].

The AIR2 Trial, the largest pivotal study, was double-blinded, randomised, sham-controlled and enrolled patients who had uncontrolled asthma despite high doses of ICS and LABAs [21]. The Trial assigned 288 patients with severe asthma 2:1 to bronchial thermoplasty (190 patients) or sham bronchoscopy (98 patients). The sham thermoplasty treatment reproduced all the audio and visual signals of bronchial thermoplasty but the catheter did not deliver any radiofrequency energy. The treatment was administered by an unblinded bronchoscopy team and all the assessments and follow-up visits were conducted by a blinded team. The primary outcome measure of the study was the change from baseline in the average group mean Asthma-related Quality of Life (AQLQ) score. The bronchial thermoplasty group demonstrated superior AQLQ scores compared with the sham-control group, as well as a greater proportion with a clinically meaningful improvement in AQLQ (≥0.5) in the intent-to-treat and per-protocol groups (79% versus 64% and 81% versus 63%; posterior probability of superiority (PPS) 99.6% and 99.9%, respectively). A significant reduction was noted in the number of bronchial thermoplasty subjects with worsening asthma compared with sham-control subjects in the post-treatment period (27.3% versus 42.9%, respectively; PPS 99.7%). No difference was noted in the number of symptom-free days, the use of rescue medications or the total asthma symptom score. In comparison with the sham-control group, the bronchial thermoplasty group demonstrated fewer: severe exacerbations (−32%; PPS 95.5%); visits to emergency care (−84%; PPS 99.9%); and days absent from work or school (−66%; PPS 99.3%). There was no change in respiratory function at 1 year post-treatment.

The three trials showed improvements in different outcomes, such as AQLQ, asthma control and exacerbations following bronchial thermoplasty. These improvements were noted 1 year after the last thermoplasty session. Of the patients enrolled in the AIR2 Trial [21] and randomly assigned to bronchial thermoplasty, 162 (85%) underwent a 5-year follow-up evaluation [22]. There were persistent reductions in severe exacerbations and emergency department visits over 5 years compared with the year prior to BT. However, it should be noted that the patients enrolled in the control group were not followed-up because it was deemed unethical and impossible to withhold potential new therapies for this long-duration follow-up. The findings of the AIR2 Trial led to approval by the FDA as a treatment option in patients with moderate-to-severe uncontrolled asthma.

Safety profile

Adverse events in the initial treatment period

In comparison with controls, subjects treated with bronchial thermoplasty have been shown to present with more symptoms that are typical of asthma (e.g. cough, wheeze, expectoration, dyspnoea, nocturnal awakening), as well as occasional general symptoms such as fever, in the hours following treatment [18, 21]. These symptoms usually resolve after 7 days but have lead to hospital admission in 3.4% of bronchoscopies in moderate-to-severe asthma [21] and 15.4% of severe asthma cases [18]. This underlines the importance of optimising asthma control prior to the first bronchial thermoplasty treatment and ensuring close monitoring in the days following treatment. In AIR2, one patient presented with significant haemoptysis in the right upper lobe 1 month after the last session and required bronchial artery embolisation. Slight bleeding had been observed during the treatment of this lobe and it was felt that this complication was related to the treatment [21]. Acute bronchospasm can occur during the intervention and may require termination of the procedure.

Long-term safety

Asthma is associated with structural and inflammatory abnormalities of the bronchial mucosa [11, 12], and the application of controlled thermal energy (65°C) raises the question as to whether bronchial thermoplasty induces further injury to the bronchial wall. After long term follow-up in the four clinical trials, no evidence of treatment-related airway stenosis or bronchiectasis was found. After 1 year of follow-up, none of the trials documented any bronchial damage.

In two studies of patients with moderate-to-severe asthma, pre-bronchodilator FEV₁ remained stable during a 5-year follow-up period [22, 23]. In the AIR Trial, follow-up at 5 years was performed in a small group with the most severe asthma (45 patients receiving bronchial thermoplasty and 24 controls) [24]. All patients underwent annual evaluation, including spirometry, static lung volumes, diffusing capacity, bronchoprovocation testing and chest radiography. There were no decrements in spirometry, lung volume or diffusion capacity test results, and no significant changes in chest radiographs. Follow-up of patients enrolled in the RISA Trial [18] was limited to subjects who underwent bronchial thermoplasty, with 14 of the 15 consenting to 4 years of follow-up after the first year [23]. As in the AIR Trial, no deterioration of pulmonary function was noted over the 5-year study.

Mechanisms underlying the effect of bronchial thermoplasty

There are a number of possible mechanisms of action that alone, or in combination, might explain the beneficial effects of bronchial thermoplasty. To date no unique mechanism has been formally identified.

As ASM mass is one of the major characteristics of airway remodelling in severe asthma patients [12, 15], the first and best documented mechanism of action is a reduction in the bronchial wall smooth muscle. A number of reports have emphasised the effects of increased ASM mass in severe asthma, particularly on airway hyperresponsiveness and permanent airflow limitation [12, 15].

Preclinical studies have shown that bronchial thermoplasty reduces ASM mass in a canine model of asthma, which was associated with a long-term reduction in airway hyperresponsivness. The effectiveness of bronchial thermoplasty on reducing the ASM in patients with severe asthma patients was first demonstrated by PRETOLANI et al. [25]. The study analysed the ASM mass percentage (ASM area as a percentage of the total biopsy aerea) in airway biopsies 15 days before the first bronchial thermoplasty session and 3 months after three bronchial thermoplasty sessions performed in 10 severe asthma patients. A reduction in ASM mass from 20.25% before bronchial thermoplasty to 7.28% (60%) was found. Following the study by PRETOLANI et al. [25], DENNER et al. [26] observed an ASM reduction from 38% before the first bronchial thermoplasty session to 16% (58%) 6 weeks after the first bronchial thermoplasty session (taken during the third thermoplasty session) in 11 patients. This was confirmed with an ASM reduction from 12.9% before the first bronchial thermoplasty session to 4.6% (64%) 3 weeks after the first thermoplasty (taken during the second session) in another 17 severe asthma patients [27]. Most recently, PRETOLANI et al. [28] confirmed an ASM mass reduction (ASM area as a percentage of the submucosal tissue area) from 19.7% to 5.2% (73%) in 15 severe patients who were selected on a baseline ASM mass of ≤15%. This reduction in ASM area correlated with several clinical outcomes at 3 months: improved asthma control and quality of life; a decrease in severe exacerbations, hospitalisation and visits to the emergency department for asthma. Importantly, all correlations were maintained at 1 year after bronchial thermoplasty (table 1).

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