Bronchial thermoplasty: interventional therapy in asthma

Abstract

Bronchial thermoplasty is a new treatment option for patients with severe bronchial asthma who remain symptomatic despite maximal medical therapy. The aim of this interventional therapy option is the reduction of smooth muscle in the central and peripheral airways in order to reduce symptomatic bronchoconstriction via the application of heat. A full treatment with bronchial thermoplasty is divided into three bronchoscopies. Randomized, controlled clinical trials have shown an increase in quality of life, a reduction in severe exacerbations, and decreases in emergency department visits as well as days lost from school or work. The trials did not show a reduction in hyperresponsiveness or improvement in forced expiratory volume in 1 s. Short-term adverse effects include an increase in exacerbation rate, an increase in respiratory infections and an increase in hospitalizations. In the 5-year follow up of the studies available there was evidence of clinical and functional stability of the treated patients. Further studies are necessary to identify an asthma phenotype that responds well to this treatment.

Introduction: pathomechanism of asthma

Asthma is a chronic inflammatory disease of the airways characterized by intermittent dyspnoea due to airway obstruction. The obstruction is reversible either spontaneously or with the aid of medication. Bronchial hyperresponsiveness is also an underlying mechanism of the disease.

Asthma is broadly divided into allergic (extrinsic) and nonallergic (intrinsic) asthma, which is often caused by respiratory infections, analgesics (aspirin and nonsteroidal anti-inflammatory drugs), chemical or toxic substances or gastroesophageal reflux disease. There can be an overlap between the different types of asthma.

Severe uncontrolled asthma is prevalent in 10% of patients with asthma and is associated with the highest morbidity [AWMF, 2011].

The airway wall consists of three layers: the endothelium (goblet cells), basal membrane (proteoglycanes, gylcosamine glycanes, collagen, elastin and fibronectin) and the smooth muscle layer. Changes within these three layers lead to a thickening of the membrane and hence to an obstruction [James et al. 2012; Knight and Holgate, 2003]. The cause is hyperplasia of the goblet cells, hypersecretion of viscous secretions as well as hyperplasia or hypertrophy of the smooth muscle [Aikawa et al. 1992; Ebina et al. 1993; James and Wenzel, 2007; Ordnoñez et al. 2001].

Airway smooth muscle is the main cause of bronchoconstriction in asthma in response to a multitude of inflammatory mediators. The smooth muscle can further entertain the inflammation by producing cytokines and chemokines [Berger et al. 2003, 2005]. Mast cells play an important proinflammatory role in activation and degranulation as well as production of further mediators (i.e. interleukin 4 and leukotriene B4), which in itself leads to hyperresponsiveness and an increase in smooth muscle [Begueret et al. 2007; Berger et al. 1999; James and Wenzel, 2007].

Treatment of asthma is guided by the disease activity [AWMF, 2011]. Therapy consists of a well established five-step treatment plan, including inhaled corticosteroids, short-acting β2 agonists, leukotriene receptor antagonists, phosphodiesterase inhibitors as well as oral corticosteroids and monoclonal immunoglobulin E antibodies in severe disease. These aim to reduce inflammation and dilate the bronchi by relaxing the smooth muscle.

Furthermore, the avoidance of toxic substances, airway stimuli and a reduction in allergens by a change of lifestyle factors should be recommended. Patient education and smoking cessation also play an important role in the treatment of asthma.

A new therapy option for patients with severe asthma and associated obstruction and hyperresponsiveness is bronchial thermoplasty [Mathew et al. 2012; Siddiqui et al. 2012]. Bronchial thermoplasty was licensed in Europe in September 2011 for patients over the age of 18 with severe persistent asthma whose asthma is uncontrolled despite maximal therapy. In the United States as well as in Asia the same criteria of accreditation apply. In the United States bronchial thermoplasty has been licensed since 2010.

Technique and practical application of bronchial thermoplasty

Bronchial thermoplasty is used for the reduction of smooth muscle in the central and peripheral airways. This leads to a reduction in bronchial obstruction and its associated symptoms.

Due to the prolonged procedure time (30–60 min) and to avoid possible complications, the treatment is divided into three sessions. According to study protocol the right lower lobe is treated in the first session, followed by the left lower lobe and in the third and final session both upper lobes are treated. The middle lobe is omitted due to a possible risk of middle lobe syndrome [Gudmundsson and Gross, 1996]. The three bronchoscopies are performed within 3–6 weeks of each other.

Bronchial thermoplasty is performed with the Alair system (Boston Scientific, Natick, MA, USA), which applies controlled heat via radiofrequency waves during the bronchoscopy. The system consists of a radiofrequency generator (Figure 1(a)) and a single use catheter with a basket carrying four expandable electrodes (Figure 1(b)). Due to the monopolar nature of this method it is important to fit the patient with a grounding plate in order to complete the electricity circle.

Figure 1.

(a) Alair radiofrequency generator (Boston Scientific, Natick, MA, USA). (b) Alair catheter (Boston Scientific). (Images provided courtesy of Boston Scientific. © 2013 Boston Scientific Corporation or its affiliates. All rights reserved.)

Bronchial thermoplasty can be performed under local anaesthesia or general anaesthesia.

The oxygen content of inspired air should not exceed 40% to avoid endobronchial ignition. Three days prior to and 2 days after the procedure, patients receive 50 mg prednisolone as anti-inflammatory therapy. Anticoagulation with aspirin can be continued; clopidogrel and warfarin as well as the newer generation anticoagulants need to be stopped prior to the procedure.

During each bronchoscopy an inspection of the airways is performed and when there is inflammation or damage to the mucosa after previous thermoplasty the repeated application of thermoplasty should be critically evaluated [Castro et al. 2010a].

The thermoplasty catheter is inserted via the working channel of a flexible bronchoscope (Figure 2(a)) and bronchi of 3–10 mm can be reached. The basket at the end of the catheter is then expanded with the manually operated handle so that all four electrodes are in contact with the mucosa (Figure 2(b)). The energy is subsequently activated via a foot pedal. Each application lasts for 10 s and is accompanied by a sound signal. If there is not sufficient contact of all four electrodes with the mucosal wall a warning signal is emitted and no electrical activity can be applied.

Figure 2.

(a) Alair catheter in airway with closed electrode basket. The first black line indicates a distance of 5 mm. (b) Alair catheter in the airway with opened electrode basket.

As soon as an application has been placed the basket is closed and the catheter is drawn back 5 mm in an atraumatic manner. Once the basket is pulled back it is expanded again and the next application can be performed. To gauge the distance the catheter is fitted with black lines indicating 5 mm (Figure 2(a, b)).

The bronchoscopist should have an overview of the already treated and still to be treated areas to avoid double treatment or omission of treatment of one or more areas. Due to the variability of the bronchial anatomy of each patient, the number of activations during each bronchoscopy lies between 40 and 100. Each bronchoscopy takes approximately 30–60 min [Cox, 2010].

The energy applied by the electrodes is transformed into heat on contact with the mucosa. The feedback with the generator guarantees an exact temperature of 65°C and a 10 s activation. An energy level of 18 W is reached during the procedure [Cox, 2010]. The temperature of 65°C results in a reduction in smooth muscle by approximately 50%, avoiding complete destruction and protecting the peripheral tissue [Danek et al. 2004; Miller et al. 2005]. The heat process leads to apoptosis, autophagy and necrotic cell death of the smooth muscle [Janssen, 2012].

Contraindications to bronchial thermoplasty are known intolerances to medication used during bronchoscopy, relevant comorbidities which might increase the risk of peri-interventional complications as well as a pacemaker or defibrillator.

Regular clinical follow ups should be performed after the treatment has been completed. Follow up is recommended after 30, 90, 180 and 360 days.

Studies in bronchial thermoplasty

The first study was performed in a canine model in 2004 to prove safety and feasibility of this system. The effects of a transient application of relatively low thermal energy were examined to determine whether smooth muscle cells could be destroyed selectively without significant changes to neighbouring airway tissue. This study examined the short- and long-term effects of the application of radiofrequency energy to the airways and showed a significant reduction in the reaction to locally applied methacholine after bronchial thermoplasty [Danek et al. 2004]. The first study in humans was performed in 2005 in nine patients without asthma who were undergoing lung resection. Patients received bronchial thermoplasty in the lobe that was due to be resected 1–3 weeks prior to lobectomy [Miller et al. 2005]. Based on the canine study, the lower temperature of 55°C was expected to result in minor changes to the airway wall, while a higher temperature of 65°C caused a significant reduction in smooth muscle cells.

In both studies the histological assessment of the treated lobe showed that thermal damage such as erythema and oedema caused by the radiofrequency treatment was limited to the bronchial wall and the peribronchial region. It was also shown that the smooth muscle layer was reduced by 50% [Miller et al. 2005]. The reduction in smooth muscle correlated with the reduction in hyperresponsiveness in dogs [Danek et al. 2004].

The observed changes in mucus consistency, erythema and airway narrowing were milder than those observed in the preclinical canine study. The reduction in mucus glands showed regeneration after a prolonged period following bronchial thermoplasty [Miller et al. 2005; Danek et al. 2004].

Studies in patients with bronchial asthma

Inclusion criteria

To date, four studies in patients with asthma treated with bronchial thermoplasty have been published. Two studies were performed in patients with stable and moderate asthma. Sixteen patients were included in the first study performed by Cox and colleagues [Cox et al. 2006]. A total of 112 patients were included in a subsequent randomized, controlled, multicentre study named Asthma Intervention Research (AIR) [Cox et al. 2007]. Inclusion criteria were forced expiratory volume in 1 s (FEV₁) greater than 80% [Cox et al. 2006], and in the AIR trial, FEV₁ of 60–85% [Cox et al. 2007]. Exclusion criteria were recurrent infective exacerbations in the previous year (two to three per year). To test the safety in patients with severe symptomatic asthma, a small randomized, controlled trial was performed in 2007 which included 32 patients [Research in Severe Asthma Trial (RISA)] [Pavord et al. 2007]. Patients with severe obstruction were included (FEV₁ > 50%) and patients on high-dose inhaled (>750 μg fluticasone) and oral corticosteroids (up to 30 mg per day) were also included in this trial. The largest trial to date included 288 patients in 30 international centres (AIR2). The design of this study was randomized, double blind and sham controlled. Patients in the control arm of the study received a bronchoscopy and thermoplasty without transmission of energy via the generator. An inclusion criterion of FEV₁ greater than 60% and exclusion criterion of three or more exacerbations in the preceding year put into perspective the severity of asthma in this study [Castro et al. 2010b].

Study results

A reduction in airway hyperresponsiveness after bronchial thermoplasty was shown in the animal data in 2004 [Cox et al. 2006] as well as the human data published by Cox and colleagues [Cox et al. 2006]. Subsequent studies were unable to confirm these results [Cox et al. 2007].

Cox and colleagues were able to show an improvement in early morning peak expiratory flow measurements as well as an increase in symptom-free days 12 weeks after the intervention. The increase in symptom-free days was statistically significant in 67% of patients, increasing from 50% to 73% symptom-free days (p = 0.015). FEV₁ remained unchanged [Cox et al. 2006, 2007].

The primary endpoint of the AIR study was the frequency of mild exacerbations after a 2-week omission of a long-acting ß2 agonist 3, 6 and 12 months after bronchial thermoplasty. The thermoplasty group showed a significant reduction in mild exacerbations, improvements in early morning peak flow measurements, Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire scores, as well as an increase in symptom-free days and a reduction in their rescue medication. On extrapolating the data this is a reduction of 10 exacerbations per patient per year, and an increase in 86 symptom-free days per patient per year. Bronchial hyperresponsiveness and FEV₁ did not differ much between groups [Cox et al. 2007]. In view of the nonblinded nature of this study and a resulting potential placebo effect, interpretation of the study results is limited. Similar results, however, were shown in severe asthma in the RISA trial. The thermoplasty group showed a persistent improvement in asthma symptoms as well as a decrease in use of rescue medication. It was also noted that more patients were weaned off their oral steroids during the study [Pavord et al. 2007].

In the AIR2 trial the primary endpoint was an improvement in AQLQ scores 6, 9 and 12 months following bronchial thermoplasty. A total of 79% of patients in the thermoplasty group and 64% of patients in the control group showed a significant improvement in AQLQ (thermoplasty 1.35 ± 1.1, sham bronchoscopy 1.16 ± 1.23). Even in the control group, the improvement in AQLQ was higher than had been expected. This is most likely due to a placebo effect as well as the improved medical care patients received during study participation. The difference in the primary endpoint between groups is below the clinically relevant difference in AQLQ of 0.5 points or more.

The secondary endpoints are particularly interesting in the AIR-2-trial. As shown in the previous studies, the thermoplasty group demonstrated a significant reduction in severe exacerbations (reduction of 32%), visits to the emergency department (reduction of 84%), days lost at work or school (reduction of 66%, 6–52 weeks after bronchial thermoplasty). Exacerbations and hospitalizations within 6 weeks after the intervention were not included in this analysis [Castro et al. 2010b].

Short-term results after bronchial thermoplasty

All studies showed a short-term clinical deterioration up to 6 weeks after bronchial thermoplasty. Immediately after the intervention patients had an increase in mild exacerbations such as respiratory symptoms or infections and resulting hospitalizations (thermoplasty group 8.4%, sham bronchoscopy group 2%) [Castro et al. 2010b]. These complications usually occurred between the first and seventh day post intervention. The increased frequency in respiratory complications in the thermoplasty group was equivalent to the control group after 6 weeks [Cox et al. 2007]. On later follow up the rate of respiratory complications in the treatment group decreased from 85% to 70%, whereas the rate in the control group increased from 76% to 80% [Castro et al. 2010b].

In rare instances atelectasis and pleuritis were observed, and there was one case of severe haemoptysis with the need for bronchial artery embolization. Overall patients with mild and severe asthma tolerated the procedure very well.

Long-term data up to 5 years

The follow-up data of the above-mentioned studies show a clinical, functional and radiological stability over a period of 3–5 years after bronchial thermoplasty.

In three of the mentioned studies a computed tomography scan of the thorax was performed 1 or 2 years after the intervention. These scans showed no evidence of structural changes such as bronchiectasis, bronchial wall thickening, bronchial dilatation, parenchymal damage, development of emphysema or bronchiolitis obliterans [Castro et al. 2010b; Cox et al. 2006, 2007].

A large number of patients from the AIR trial were followed up for up to 5 years after the procedure (45 of 52 treated patients and 24 of 49 patients in the control group). In the first 2 years after bronchial thermoplasty the treatment group had more hospitalizations due to respiratory symptoms. In comparison to the control group, however, this was not statistically significant. The rate of complications remained stable 2–5 years after the procedure. There was no increased incidence of hospitalizations or emergency room visits. Neither vital capacity nor FEV₁ decreased over a period of 5 years in the thermoplasty group [Cox et al. 2007].

A total of 92% of patients in the thermoplasty group in the AIR2 trial were examined after 2 years. The rate of respiratory complications (asthma exacerbations, visits to the emergency department, hospitalizations) was lower in the second year (23%) after thermoplasty in comparison to the first year (30%). The positive effect after thermoplasty persisted after 2 years [Castro et al. 2011; Cox et al. 2007]. So far no follow up of the control group has been performed.

The absence of clinical complications as well as the stability in lung function testing over a period of 5 years makes bronchial thermoplasty a safe procedure [Silvestri et al. 2012; Thomson et al. 2011].

Current studies

In a recently published study, 33 patients with severe persistent asthma underwent bronchoscopy with bronchoalveolar lavage and endobronchial biopsies. The control group of 41 patients also had a bronchoscopy with endobronchial biopsy for other medical indications.

The biopsies were examined for inflammation and structural changes, such as submucosal and epithelial change. Gordon and colleagues developed a grading system for endobronchial biopsies, including the presence or absence of epithelial changes, intraepithelial inflammation, basement membrane thickening, prominent smooth muscle, irregularity of elastic fibres and submucosal mucous glands.

In three patients endobronchial biopsies were taken before and after bronchial thermoplasty. In comparison to the control group, patients with severe asthma had more intraepithelial eosinophils (67% versus 17%, p < 0.001), more submucosal eosinophilic airway inflammation (79% versus 54%, p < 0.05) and lymphocytes (61% versus 27%, p = 0.005), more prominent smooth muscle (88% versus 29%, p < 0.001) and goblet cell hyperplasia (47% versus 22%, p = 0.004). No significant difference in the structure of the epithelial and basal membrane layer was shown. Following bronchial thermoplasty, airway smooth muscle was reduced and was partially replaced by fibrosis [Gordon et al. 2013].

In a recent case report hyperplasia of the smooth muscle was still present after completion of treatment [Doeing et al. 2013a].

Follow up of eight patients with severe uncontrolled asthma with a fixed obstruction and FEV₁ of 51.8% (±8.6%) and three hospitalizations in the previous 12 months showed no increased rate of exacerbations or drop in FEV₁ 15–72 weeks following bronchial thermoplasty. Therefore, the treatment also appears to be safe for patients with severe obstruction [Doeing et al. 2013b].

Critical appraisal and future of bronchial thermoplasty

Bronchial thermoplasty is approved for patients with severe persistent asthma in whom all other therapy options have been exhausted. Due to the limitations regarding inclusion and exclusion criteria of the above-mentioned studies the results cannot be generalized. Patients with severe asthma and more than three exacerbations a year have so far been excluded from the larger studies.

A brief worsening of asthma symptoms as well as a lack of data regarding long-term complications are weighed against a possible improvement in asthma control and improvement in quality of life. The durability of the clinical benefit and the long-term complications (more than 5 years) are currently unknown.

Studies to obtain data regarding long-term safety and long-term effect of bronchial thermoplasty (over 5 years) need to be performed. Questions regarding the cause of failure of the treatment still remain unanswered [Doeing et al. 2013a]. Repeated treatment with bronchial thermoplasty after insufficient clinical improvement is currently not licensed.

The high cost of the three bronchoscopies, the materials involved (i.e. the catheter) and the cost of post-procedure complications need to be considered and weighed up against the reduction in exacerbations and improvement in quality of life. A cost-effectiveness analysis has not been performed to date. The treatment involving three bronchoscopies is an invasive procedure which poses potential risks for the patients. Hence this treatment should only be performed by experienced interventional bronchoscopists to minimize the risks for the patients [Wahidi and Kraft, 2012].

Bronchial thermoplasty cannot be a substitute for the established five-step treatment plan of conservative therapy or change in lifestyle. It is currently merely an additional treatment option for patients with uncontrolled severe asthma.

There remains a range of unanswered questions with regards to thermoplasty. There is only a very limited amount of preclinical information about the mechanism of action and the published clinical data are also limited. To more clearly understand the pathomechanisms and the cause of failure of therapy the structural changes of the airways need to be examined in clinical studies. It will be interesting to examine biopsies from patients post thermoplasty with regards to inflammatory markers and immunomodulatory effects of the treatment. We need larger studies to be able to identify the asthma phenotype most likely to respond to such an interventional technique as bronchial thermoplasty.

Conclusion

Bronchial thermoplasty is a novel therapy for patients with severe asthma who remain symptomatic despite maximal medical therapy. Clinical studies performed to date show a reduction in rate of exacerbations, emergency department visits and days lost from work, and an improvement in quality of life.

Short-term complications are respiratory infection and increased hospitalizations. Adequate patient selection and interventional management are essential as well as the procedure being performed by an experienced bronchoscopist.

Further studies are necessary to evaluate the long-term clinical effect, the long-term complications and to understand the pathomechanisms of bronchial thermoplasty.