Bronchial Thermoplasty

Updated: Dec 15, 2015
  • Author: Said A Chaaban, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Overview

Background

Bronchial thermoplasty (BT) is a modality for treating asthma and is thought to prevent the chronic structural changes that occur in the airway smooth muscles (ASM) in individuals with asthma. Bronchial thermoplasty targets ASM by delivering a controlled specific amount of thermal energy (radiofrequency ablation) to the airway wall through a dedicated catheter.

Asthma is a complex inflammatory disorder of the airways characterized by airway hyperresponsiveness (AHR) and variable airflow obstruction. Within the next 10-20 years the prevalence of asthma is estimated to exceed 400-450 million.

Although advances in clinical and basic research over the past 30 years have led to the development of effective treatments and dissemination of detailed disease management guidelines, [1, 2] difficult-to-treat asthma continues to affect 5-10% of adults with this disorder. [3] Treating these patients is an ever-evolving challenge and is a major source of frustration for the patients and clinicians alike. Most patients with difficult-to-treat asthma require 3-4 medications and long-term oral corticosteroids or frequent bursts. [4] Presence of alternative therapies have offered the advantage of avoiding the major side effect of steroids. [5]

Despite these expensive therapies, patients with difficult-to-treat asthma account for a disproportionately high share of asthma-associated morbidity and mortality and continue to experience repeated symptoms, including potentially life-threatening exacerbations. [6] This population not only consumes a large economic cost but also has a large impact on society in terms of missed work or school. [7]

The National Asthma and Education and Prevention Program Expert Panel Report 3 recommends add-on therapy with long-acting beta agonists, leukotriene modifiers, theophylline, and omalizumab in patients with difficult-to-treat asthma who take inhaled corticosteroids. [8] Many of these add-on medications are expensive, have substantial side effects, and require adherence to daily medications or monthly or biweekly injections. These therapies reduce inflammation or decrease airway narrowing by relaxing ASM but do not prevent the chronic structural changes that occur in the ASM in individuals with asthma. Therefore, an alternative therapy is needed in this population. Bronchial thermoplasty is a new modality for treating asthma and is thought to provide the solution for this unmet need. Bronchial thermoplasty targets ASM by delivering a controlled specific amount of thermal energy (radiofrequency ablation) to the airway wall through a dedicated catheter.

Radiofrequency ablation has been used for the treatment of cardiac arrhythmias and lung cancer. The use of this technology to treat asthma began after tests of radiofrequency ablation in animals; [9] it was then used in the airways of patients scheduled to undergo surgery for proven lung cancer [10] and was later used in patients with asthma. [11]

Bronchial thermoplasty is performed via fiberoptic bronchoscopy in 3 separate procedures in which all accessible airways located beyond the mainstem bronchi (average of 3-10 mm in diameter) except for the right middle lobe are treated. The delivery of energy during bronchial thermoplasty uses continuous feedback to tightly control the degree and time of tissue heating to decrease ASM mass without airway perforation or stenosis.

Airway hyperresponsiveness (AHR) is invariably seen in persons with symptomatic asthma. It is widely accepted that the variable airflow obstruction that characterizes asthma is secondary to ASM contraction in response to various stimuli, including several inflammatory mediators. All of the conducting airways down to the level of the respiratory bronchioles are lined with smooth muscles, the mass of which increases asthma due to hyperplasia and hypertrophy. [12, 13] This increased ASM mass appears to be more susceptible to stimulation, resulting in a greater degree of AHR and airway narrowing for any given contraction. [14, 15]  Not only has BT been shown to reduce airway smooth muscles but also the amount of the vascular smooth muscle. In some forms of asthma, vascularization of the airway is increased. Dilation of the airway vascular bed induced by cold air may exacerbate an asthmatic attack. [16]

Animal studies have shown that the high temperature of bronchial thermoplasty disrupts the actin-myosin interaction through denaturating of the motor proteins, disrupting the ASM spasm cascade. [17]

Although studies have shown that the inflammation in the small airways is a prominent contributor to the pathophysiology of asthma, [18, 19] significant airflow obstruction and resistance occurs in the first 8 generations of the airway, indicating that the larger airways are involved in the disease process of asthma. [20]

The reason that BT has proven to be efficacious and has led to better symptom control and decrease in number of exacerbations is secondary to it targeting airway smooth muscles and the failure of current pharmacotherapy ability to immunomodulate the airway smooth muscles. There has been in vitro and in vivo reports revealing that the glucocorticoid anti-inflammatory effects are blunted in patients with severe asthma. [21]

The effect of bronchial thermoplasty could be attributed to the theory that “pacemakers” within the proximal airways control ASM contractility and that bronchial thermoplasty ablates these controlling centers, leading to the distal effect. [22] Another theory is that a phenotype of individuals with asthma has a prominent component of large airway inflammation and the modification in the adjacent structure in the airway leads to a decrease in the mucus gland hyperplasia, mucus production, and change in the airway autonomic tone, which can be contributing factor to the response in bronchial thermoplasty.

The European Respiratory Society/American Thoracic Society (ERS/ATS) task force in 2014 strongly recommended consideration of bronchial thermoplasty in adults with severe asthma in a context of institutional review board (IRB)-approved systematic registry or as part of a clinical study. The quality of evidence behind this recommendation is labeled as very low, as it is considered as an add on resource without realizing the adverse effect of the procedure, patient selection, and uncertain improvement in symptoms and quality of life. Benefits and harm of the procedure maybe large and the long-term side effects are unknown. Studies are still needed to assess exacerbation rates and long-term effects on lung function. Studies evaluating which phenotypes will respond, effects on obstructed patients with an FEV1< 60%, and in patients in whom systemic steroids are used need to be examined. [23]

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Indications

Candidates for bronchial thermoplasty include adults with severe persistent asthma who require regular maintenance medications of inhaled corticosteroids (>1000 µg/day beclomethasone or equivalent) and a long-acting beta agonist (≥100 µg/day salmeterol or equivalent). These patients would have received add-on therapies such as leukotriene modifiers, omalizumab, and oral corticosteroids 10 mg/day or less.

These patients should be on stable maintenance asthma medications according to accepted guidelines, [8] have a prebronchodilator FEV1 of 60% or more of predicted, and have a stable asthma status (FEV1 within 10% of the best value, no current respiratory tract infection, and no severe asthma exacerbation within the preceding 4 weeks).

Patients are usually selected based on the AIR 2 trial. The patient should be stable in terms of his or her asthma status, defined as a post-bronchodilator FEV1 within 15% of their baseline values, and no respiratory tract infection or asthma exacerbations within the past 14 days. [24]

Asthma exists in multiple phenotypes and current selection criteria for BT is based on severity and not on phenotype. There has also been a trial evaluating use of biomarkers to predict response to BT. Histology has also been used to help identify different asthma phenotypes and thus help in identifying those who may respond to different medical therapies. One study looked into the role of endobronchial biopsy as part of initial evaluation and after the procedure to evaluate for response. Performing biopsies, on the other hand, is not practical or safe enough to be considered part of the overall evaluation. It adds risk of complications associated with endobronchial biopsies and the risk of obtaining a nonrepresentative sample. [3, 6] Gordon et al was able to establish a standardized histological grading system. This system assesses both the structural and the inflammatory components on endobronchial biopsy. It will need further study; however, it will help in offering a guide to patient selection and selection of targeted antiinflammatory medications or BT. [25]

 Other modalities that could replace the need for biopsy and were studied are the optical coherence tomography (OCT) and confocal microscopy (CFM) with or without high-resolution radial balloon-based endobronchial ultrasonography. OCT is a modality that allows for real time microscopic evaluation of the mucosae and submucosae during bronchoscopy. Radial endobronchial ultrasound has also been used to evaluate for wall thickness and wall remodeling changes. Both of those modalities seem to be valuable tools but need further evaluation. Checklists and validation tools have been developed and discussed in international meetings but require further studies prior to validating them. [7, 26]

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Contraindications

Contraindications to bronchial thermoplasty include the following:

  • The presence of an implantable electronic device
  • Known hypersensitivity to drugs used during bronchoscopy
  • Severe comorbid conditions that would increase the risk of adverse events

Patients are not considered candidates for bronchial thermoplasty if they had 3 or more hospitalizations for asthma, 3 or more lower respiratory tract infections, and 4 or more oral corticosteroids used for asthma in the previous year. [11, 27, 28]

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Technical Considerations

Bronchial thermoplasty is performed via fiberoptic bronchoscopy in 3 separate procedures in which all accessible airways located beyond the mainstem bronchi (an average of 3-10 mm in diameter) with the exception of the right middle lobe are treated. The delivery of energy during bronchial thermoplasty uses continuous feedback to tightly control the degree and time of tissue heating to decrease ASM mass without airway perforation or stenosis.

Airways and Bronchial Thermoplasty Airways and Bronchial Thermoplasty
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Outcomes

Patients are expected to have respiratory-related adverse events such as cough, wheezing, and chest tightness during the treatment period. Most of these symptoms occur within 1 day of the procedure and resolve in an average of 7 days with standard therapy.

It remains unclear why an intervention aiming at reduction of smooth muscle mass would not affect FEV1. Since the number of exacerbations is reduced with no change in FEV1, a role may exist for alteration in the response to the inflammatory triggers in addition to a reduction in the smooth muscle mass. [7]

Outcomes from the latest randomized, double-blind, sham-controlled, clinical trial showed significant reduction in severe asthma exacerbation, emergency department visits, and days missed out of work or school in the posttreatment period. [27]

Recurrent lung atelectasis secondary to fibrin plugs has been reported as an early complication of BT. In the susceptible patient, high thermal stimulation may lead to an inflammatory reaction with microvascular alteration either induced by heat or the release of inflammatory mediators. [29]

Lung abscess has also been described as a direct complication, thus collecting and publishing safety data continues to be important. [30]

To date, the longest study assessing efficacy and safety is up to five years. No studies have yet evaluated the length of the beneficial effect or the safety of the treatment. Further studies examining patient selection and methods for evaluating effectiveness are needed, and also recommended by the ERS and ATS guidelines. [26]

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Cost

Though patients with severe asthma constitute 5-10 % of the asthma population, severe asthma consumes a disproportionate amount from the global asthma budget, around 50%, secondary to the unscheduled physician visits, ED visits, and hospitalizations along with costs of pharmacotherapy. The high use of resources for this group of patients, along with the increased morbidity and mortality, has led to the formation of the European, American, and global severe asthma networks to further understand the pathogenesis and thus direct optimal management. One of the challenges in persons with asthma is the selection of the patients that would respond to a specific therapy. [31]

A five year budget impact analysis was performed in Italy. This study was the first of its kind and it evaluated adding adjuvant BT to the standard care with or without adjuvant omalizumab. The study concluded that despite the increase in direct costs due to the add on therapies, the overall long-term cost was less, with decrease in the number of ED visits and hospitalizations. [24, 32]

In commercially insured patients and based on a cost-effectiveness analysis evaluating 5-year health care utilization along with patient quality of life and adverse events, BT is shown to be a cost-effective treatment for patients with severe persistent asthma. [33]

BT comes at a very high direct cost, thus insurance coverage has been a prominent issue. Multiple commercial payers cover bronchial thermoplasty in the United States. This procedure is also covered by multiple health plans but not all, and some health plans would still consider the procedure on a case by case request and may provide coverage based on case specific medical necessity. Payers with noncoverage policies have typically used a number of reasons for maintaining their noncoverage policies. Many plans describe the BT procedure as “experimental and investigational,” suggesting further study is necessary before the procedure should be covered. It is always recommended to confirm commercial insurance coverage before patients start this modality of treatment.

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Areas of Research

Asthma is a heterogeneous disease with different phenotypes, which would explain why not all patients with severe asthma respond to this treatment. Biopsies, pulmonary function tests (PFTs), exhaled nitric oxide, and sputum eosinophils have been studied as markers to evaluate for treatment response; however, those markers cannot provide information regarding remodeling happening at the airway level. Computed tomography of the chest and MRI of the chest with inhaled contrast would provide an indirect evaluation of the airway. The optical coherence tomography (OCT) is a new imaging technique that is minimally invasive and offers the benefit of visualizing airway remodeling. This is an important modality that has been studied for the selection process of BT. A pilot study was performed on 2 patients with a conclusion that a larger study was required to evaluate whether OCT can help in selecting persons with asthma who will benefit from this treatment and to evaluate the long-term effect of the treatment. [34]

OCT may be considered an effective screening tool for BT. The TASMA trial, a large multicenter, randomized, international trial, is investigating BT patients by OTC next to airway biopsies and X-ray imaging to evaluate for the immediate and late effects of this treatment on the airway smooth muscles. [35, 36]

Helium magnetic resonance imaging and multidetector CT has been validated for the quantification of regional pulmonary ventilation at the segmental level. The importance of those imaging studies is that they allow for the regional structure-function relationships. This would help in the pretreatment and posttreatment assessments for BT. Ventilation defects are increased in the pretreatment but get better in the posttreatment period. [37]

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