Bronchial Thermoplasty

Bronchial thermoplasty (BT) is a modality for treating asthma and is thought to prevent the chronic structural changes that occur in airway smooth muscle (ASM) in individuals with asthma. ^[1] BT targets ASM via the delivery of a controlled specific amount of radiofrequency (RF) energy (RF ablation [RFA]) 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. Although advances in clinical and basic research over the past few decades have led to the development of effective treatments and dissemination of detailed disease management guidelines, ^{[2, 3, 4, 5]} difficult-to-treat asthma continues to affect 5-10% of adults with this disorder. ^[6]

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 three or four medications and long-term oral corticosteroids or frequent bursts. ^[7] The development of alternative therapies has offered the advantage of avoiding the major side effect of steroids. ^[8]

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. ^[9] This population not only is responsible for a large economic cost but also has a large impact on society in terms of missed work or school. ^[10]

Cost considerations

Though patients with severe asthma constitute 5-10% of the asthma population, severe asthma consumes a disproportionate percentage (~50%) of the global asthma budget, secondary to unscheduled physician visits, emergency department (ED) visits, and hospitalizations, along with the costs of pharmacotherapy.

The high use of resources for this group of patients, along with the increased morbidity and mortality, led to the formation of the European, American, and global severe asthma networks with the aim of achieving a better understanding of the pathogenesis and thereby becoming better able to direct optimal management. One of the major challenges in the treatment of asthma is how to select those patients that would respond best to a specific therapy. ^[11]

A 5-year budget impact analysis was performed in Italy. ^[12] This study, the first of its kind, evaluated adding adjuvant BT to the standard care with or without adjuvant omalizumab. The authors concluded that despite the increase in direct costs due to the add-on therapies, the overall long-term cost was less, with a decrease in the number of ED visits and hospitalizations. ^{[13, 12]}

In a study of commercially insured patients, based on a cost-effectiveness analysis evaluating 5-year healthcare utilization along with patient quality of life and adverse events, BT was shown to be a cost-effective treatment for patients with severe persistent asthma. ^[14]

Because BT is associated with a very high direct cost, insurance coverage has been a prominent issue. ^[15] In the United States, BT is covered by multiple commercial payers. It is also covered by multiple, though not all, health plans, and some health plans that do not routinely cover it may still consider it on a case-by-case basis and provide coverage on the basis of case-specific medical necessity.

Payers with noncoverage policies have typically used a number of reasons for maintaining such policies. Many plans have described BT as an “experimental and investigational” procedure, suggesting that further study is necessary before coverage is appropriate. It is always recommended that patients confirm commercial insurance coverage before starting this therapeutic modality.

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

These patients should be on stable maintenance asthma medications according to accepted guidelines, ^[16]  should have a prebronchodilator forced expiratory volume in 1 second (FEV₁) of 60% or more of predicted, and should 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 on the basis of the AIR 2 trial. The patient should be stable in terms of asthma status, defined as a postbronchodilator FEV₁ within 15% of baseline values with no respiratory tract infection or asthma exacerbations within the preceding 14 days. ^[13]

Asthma exists in multiple phenotypes, and current selection criteria for BT are based on severity rather than on phenotype. The use of biomarkers to predict response to BT has been studied. Histology has also been used to help identify different asthma phenotypes and thereby facilitate the identification of those who may respond to various different medical therapies. Phenotype-guided treatment may be expected to yield better treatment outcomes. ^[17]

One study looked into the role of endobronchial biopsy as part of the initial evaluation and as a postprocedural measure to evaluate for response. However, performing biopsies is not practical or safe enough to be considered part of the overall evaluation. Drawbacks include the risk of associated complications and the possibility of obtaining a nonrepresentative sample. ^{[6, 9]}

Gordon et al established a standardized histologic grading system that assessed both the structural and the inflammatory components on endobronchial biopsy. This system may prove helpful in offering a guide to patient selection and the choice of targeted anti-inflammatory medications or BT. ^[18]

Other modalities with the potential to replace biopsy in this setting are optical coherence tomography (OCT) and confocal microscopy (CFM) with or without high-resolution radial balloon-based endobronchial ultrasonography (US). OCT allows real-time microscopic evaluation of the mucosae and submucosae during bronchoscopy. Radial endobronchial US (EBUS) has also been used to evaluate changes in wall thickness and wall remodeling. Both of those modalities seem to be valuable tools, but further evaluation is warranted.

Checklists and validation tools have been developed and discussed in international meetings but require further study. ^{[10, 19]}

Contraindications for BT include the following:

• 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 BT if they had three or more hospitalizations for asthma, three or more lower respiratory tract infections, and four or more oral corticosteroids used for asthma in the previous year. ^{[20, 21, 22]}

Best practices

The National Asthma and Education and Prevention Program (NAEPP) Expert Panel Report 3 recommended add-on therapy with long-acting beta agonists, leukotriene modifiers, theophylline, and omalizumab in patients with difficult-to-treat asthma who take inhaled corticosteroids. ^[16]

Many of these add-on medications are expensive, have substantial side effects, and require adherence to daily administration or monthly or biweekly injections. These agents reduce inflammation or decrease airway narrowing by relaxing ASM but do not prevent the chronic structural changes that occur in ASM in individuals with asthma. Therefore, an alternative therapy is needed for this population. BT has been advanced as a potential solution for this unmet need.

In 2014, a European Respiratory Society (ERS)/American Thoracic Society (ATS) task force strongly recommended consideration of BT for adults with severe asthma in the context of an institutional review board (IRB)-approved systematic registry or as part of a clinical study. ^[4] The quality of evidence behind this recommendation was labeled as very low, in that BT was considered as an add-on resource without a firm understanding of adverse effects, appropriate patient selection, or the degree of improvement in symptoms and quality of life to be expected.

In the 2020 focused updates ^[23] to their 2007 asthma management guidelines, ^[16] the Expert Panel Working Group of the National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC) made a conditional recommendation against BT in individuals aged 18 years or older who have persistent asthma. The Expert Panel noted, however, that BT might be considered in these individuals if they place a low importance on harms (short-term exacerbation of symptoms, unknown long-term side effects) and a high importance on potential benefits (improved quality of life, slightly reduced exacerbations).

Although the benefits of BT may be large, the potential harm may be large as well, and the long-term side effects are unknown. Further study is needed to assess exacerbation rates and long-term effects on lung function. It remains to be determined which phenotypes will respond best to BT, what the effects may be on obstructed patients with an FEV₁ higher than 60%, and what the applicability of the procedure may be in patients receiving systemic steroid therapy.

Procedural planning

BT targets ASM through the delivery of a controlled specific amount of thermal energy (ie, RFA) to the airway wall through a dedicated catheter. RFA has been used for the treatment of cardiac arrhythmias and lung cancer. First applied to the treatment of asthma in animal studies, ^[24]  it was then used in the airways of patients scheduled to undergo surgery for proven lung cancer ^[25] and was subsequently employed in patients with asthma. ^[20]

BT is performed via fiberoptic bronchoscopy in three separate procedures that treat all accessible airways located beyond the mainstem bronchi (average diameter, 3-10 mm), with the exception of the right middle lobe. The delivery of energy during bronchial thermoplasty uses continuous feedback to tightly control the degree and time of tissue heating so as to decrease ASM mass without airway perforation or stenosis. (See the image below.)

AHR is invariably seen in persons with symptomatic asthma. It is widely accepted that the variable airflow obstruction characteristic of 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 muscle, the mass of which increases asthma due to hyperplasia and hypertrophy. ^{[26, 27]} 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. ^{[28, 29]}

BT has been shown to reduce not only ASM mass but also the amount of 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. ^[30]

Animal studies have shown that the high temperature produced by BT hinders the actin-myosin interaction through denaturating of the motor proteins, thereby disrupting the ASM spasm cascade. ^[31]

Although studies have shown that inflammation in the small airways is a prominent contributor to the pathophysiology of asthma, ^{[32, 33]} significant airflow obstruction and resistance occur in the first eight generations of the airway, indicating that the larger airways are involved in the disease process of asthma. ^[34]

The reason why BT has proved efficacious and has led to better symptom control and decrease in number of exacerbations is secondary to its targeting of ASM and the failure of current pharmacotherapy to immunomodulate ASM. In-vitro and in-vivo reports have found the glucocorticoid anti-inflammatory effects to be blunted in patients with severe asthma. ^[35]

One theory to explain the effect of BT is that “pacemakers” within the proximal airways control ASM contractility and that BT ablates these controlling centers, leading to the distal effect. ^[36] Another theory is that a particular asthma phenotype includes a prominent component of large-airway inflammation and that modification of the adjacent structure in the airway leads to decreased mucous gland hyperplasia, reduced mucus production, and altered airway autonomic tone, which may contribute to the response to BT. Heat shock proteins may play a role. ^[37]

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 is unclear why an intervention aiming at reduction of smooth-muscle mass would not affect FEV₁. Given that the number of exacerbations is reduced with no change in FEV₁, it may be that altered response to the inflammatory triggers plays a role in addition to the reduction in smooth-muscle mass. ^[10]

Outcomes from one randomized double-blind sham-controlled clinical trial showed significant reduction in severe asthma exacerbation, ED visits, and days missed out of work or school in the posttreatment period. ^[21]

Earlier studies did not assess efficacy and safety beyond 5 years. The BT10+ study, published in 2021, followed 192 patients (136 in the BT group and 56 in the control group) who had previously been enrolled in the AIR, RISA, and AIR2 studies with the aim of investigating the efficacy and safety of BT after 10 or more years. ^[38]  The primary efficacy endpoint was the durability of the treatment effect; the primary safety endpoint was the absence of clinically significant post-BT respiratory image changes. The investigators found that the efficacy of BT was sustained for 10 years or longer with an acceptable safety profile.