Bronchial Thermoplasty in Severe Asthma
Severe adult asthmatics are defined partly by the need for high-dose inhaled corticosteroids (ICS) and inhaled bronchodilators1 and their higher incidence of nonadherence. However, in some cases, the clinical severity may reflect the ineffectiveness of the drugs prescribed rather than the patient’s adherence or severity of the underlying disease.2 Infection treated with the wrong antibiotic is an analogous example.
Although the National Asthma Education and Prevention Program Expert Panel Report 3 Guidelines for Diagnosis and Management of Asthma3 recommended ICS as first-line therapy and the mainstay of daily anti-inflammatory treatment for persistent asthma, there is no discussion of future discontinuation. Instead, the recommendation is to keep patients on the lowest effective dose of ICS, which provides a difficult challenge in clinical practice. The majority of adults rely on bronchodilators, either short-acting or long-acting beta-2 agonists (LABA) everyday despite daily use of ICS.
Pitfalls in Asthma Treatment
It is a common pitfall to think that ICS effectively controls symptoms and prevents the need for bronchodilators or exacerbations in all asthma patients. Recent studies suggest that 25% to 35% of patients with asthma may not improve lung function with ICS measured by quality of life (QOL) and exacerbation incidence. Patients who do not respond to ICS did just as well with placebo, whereas responders did very poorly with placebo with uncontrolled symptoms and exacerbations.4
Martin et al found that short-term response to ICS with regard to forced expiratory volume in 1 second (FEV1) improvement >5% after 6 weeks predicted long-term asthma control. The decision to use long-term ICS could be based on a short-term trial, or a clinical trial of each drug individually.
Another common pitfall is to presume that the prescribed asthma controller drugs for an individual patient must be working effectively. It is essential to objectively assess asthma control at every clinic visit (eg, use the Asthma Control Test) and not to assume that the asthma is well-controlled. Uncontrolled patients need to be carefully evaluated prior to a step-up in pharmacotherapy from moderate- to high-dose ICS+LABA with add-on omalizumab or mepolizumab, or bronchial thermoplasty (BT). A confounding comorbidity should be searched for and treated (Table 1).5
Another pitfall fraught with long-term safety concerns is to ascribe to the belief that asthma pharmacotherapy will eventually work even when annoying symptoms persist despite adhering to ICS+LABA for at least 3 to 6 months. LABA can improve lung function the first day of treatment but the effects of ICS may take 1 to 2 weeks if the patient is a responder. Leaving patients on ICS when it is ineffective can lead to unwanted oral thrush, viral infections, pneumonia, osteoporosis, and poor control of diabetes mellitus. The FDA notes that LABAs increase the risk of asthma-related deaths and must carry a black box warning. Note: LABAs are contraindicated for asthma, but not chronic obstructive pulmonary disease (COPD).
Pitfalls to Avoid in Severe Asthma
- To forget to confirm the diagnosis of asthma anew in difficult-to-control cases.
- To target treatment towards asthma severity instead of asthma control (eg, reducing impairment and risks from asthma, including acute exacerbations).
- o presume prescribed asthma controller drugs are working effectively, rather than objectively assessing asthma control at every clinic visit.
- To believe prescribed asthma pharmacotherapy will eventually work despite a good adherence to inhaled corticosteroids and long-acting beta-2 agonists for period of 3 to 6 months or longer.
- To presume patients have well-controlled asthma and are adherent to prescribed guideline-recommended pharmacotherapy in the absence of complaints, elicited, or volunteered. Inquire further.
- To leave asthma symptoms uncontrolled for longer than 3 to 6 months without considering alternative therapeutic options with omalizumab or mepolizumab and/or bronchial thermoplasty.
- To ignore confounding comorbidities (eg, gastroesophageal reflux, rhinosinsitis, vocal cord dysfunction, obstructive sleep apnea, allergic bronchopulmonary aspergillosis, and COPD in asthmatics) before declaring asthma is refractory to treatments.
- To maintain that bronchial thermoplasty is still experimental and its efficacy and safety not yet FDA approved.
- To employ bronchial thermoplasty without controlling confounding comorbidities first.
Different therapeutic strategies would need to be established for nonresponders to ICS. BT is an important, new FDA-approved option in the battle to control asthma and should be considered for patients age 18 and older with severe persistent asthma who remain symptomatic and uncontrolled despite taking high doses of ICS+LABA.6 BT is now included in the Global Initiative for Asthma (GINA) guidelines as a preferred add-on therapy at step 5 before oral corticosteroids.7
The effectiveness and safety of BT—ie, the bronchoscopic circumferential application of radiofrequency energy (temperature of 65ºF) to the bronchial airways—was demonstrated in 2010 in severe asthma, including refractory asthmatics.8 In 2010, the FDA Center for Devices and Radiological Health approved BT as the first medical device to treat severe and persistent asthma in certain adults.
The device is composed of a catheter with an electrode tip that delivers radiofrequency energy directly to the airways. A controller unit generates and controls the energy.
Inflammation causes the airways of patients who have asthma to swell and narrow, making breathing difficult by increasing the work of breathing. Bronchospasm from airway smooth muscle (ASM) contractions compound the problem, causing and difficulty breathing by further increasing airway resistance.
The radiofrequency energy reduces the thickness of ASM in the airways and can improve a patient’s ability to breathe. However, to benefit, patients will require multiple sessions targeting different areas in the lungs—eg, BT is applied first to the right lower lobe bronchial airways (sparing the right middle by protocol), then the bronchial airways of the left lower lobe are treated 2 to 3 weeks later, and both upper lobes airways are treated 2 to 3 weeks after that.
AIR2 Study Results
The FDA based its approval largely on data from the AIR2 study, a randomized, double-blind, sham bronchoscopy-controlled clinical trial in 6 countries. The objectives were to evaluate the effectiveness and safety of BT versus a sham bronchoscopy procedure in subjects with severe asthma who remain symptomatic despite treatment with high-dose ICS+LABA.8
There were a total of 288 adult subjects (age 18 to 65) who required daily high-dose ICS+LABA—190 of which underwent BT bronchoscopies and 98 sham bronchoscopies in 3 procedures that were 3 weeks apart. The primary outcome was the difference in Asthma Quality of Life Questionnaire (AQLQ) scores from baseline to average at 6, 9, and 12 months. The secondary outcomes included rescue medication use, FEV1, morning peak expiratory flow rates, and the percentage of symptom-free days.
The results showed improvement from baseline in the integrated AQLQ score—79% of BT and 64% of sham subjects achieved changes in AQLQ of ≥0.5. Note: 6% more BT subjects were hospitalized in the treatment period (up to 6 weeks pot- BT).
In the post-treatment period (6 to 52 weeks after BT), the BT group experienced fewer severe exacerbations, emergency department (ED) visits, and days missed from work or school compared with the sham group. No device-related deaths or major adverse events, such as pneumothorax, need for mechanical ventilation, airway stenosis or focal narrowing, occurred with BT.
Possible side effects during the course of treatment may include asthma attacks, wheezing, chest tightness or pain, atelectasis, hemoptysis, anxiety, headaches, and nausea. The majority of these adverse effects occurred within 1 day of the procedure and resolved with the standard of care within 7 days.8
Long-Term Safety of BT
The FDA required a 5-year post-approval study of the BT device to study its long-term safety and effectiveness and the results were recently published. BT-treated subjects from the AIR2 study were evaluated annually for 5 years to assess the long-term safety of BT and the durability of its treatment effect through a review of adverse events, exacerbations, hospitalizations, spirometries, and high-resolution chest CT scans.9
The sham patients in the AIR2 study exited at the end of year 1 while the BT patients were followed for another 4 years, to give a total follow-up period of 5 years. Of the 50 sham patients from the AIR2 trial, 50% had undergone BT since exiting the AIR2 trial. These included patients that had participated in the industry-sponsored PAS2 study or had BT outside the clinical trial setting.9
Of the 190 BT-treated subjects from the AIR2 trial, 162 or 85.3% completed the 5 years of follow-up. There was a reduction in the proportion of subjects experiencing severe exacerbations as compared to the sham group at 1 year after BT that was maintained over the subsequent 4 years of follow-up. The proportion of subjects experiencing severe exacerbations and ED visits, and the rates of events in each of years 1 to 5, remained low and were less than those observed in the 12 months before BT treatment.9
There were no notable increases in hospitalizations, asthma symptoms, or respiratory adverse events that were observed over the course of 5 years after BT. The average 5-year reduction the proportion of subjects experiencing severe exacerbations and ED visits was reduced 44% and 78%, respectively. Respiratory adverse events and respiratory-related hospitalizations remained unchanged in years 2 through 5 compared with the first year after BT. Pre-bronchodilator FEV1 values remained stable between years 1 and 5 after BT, despite an 18% reduction in average daily ICS dose.
High-resolution CT scans from baseline to 5 years after BT showed no structural abnormalities that could be attributed to BT. There was no evidence of an increase in bronchiectasis, bronchiolitis obliterates, or pulmonary emphysema in any patient treated by BT.
This data demonstrate the 5-year durability of the benefits of BT with regard to both asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms) and safety.9
Another recent publication reported results in 10 patients who underwent endobronchial biopsies before and 12 weeks after BT (10 samples at each time point).11 A decrease in smooth muscle (20.8% vs 10.6%) and subepithelial glands was found. Basement membrane thickness, epithelial metaplasia, goblet cells, lymphatic, and blood capillary vessels did not change.
The UC Davis Experience
Since April 2011, we have treated 22 adult asthma patients with BT (age 20 to 80), of which there were 10 women and 12 men. Follow-up has been varied: 4 years for 4 patients, 3 years for 1 patient, 2 years for 5 patients, 1 year for 2 patients, and <1 year for 10. No deaths occurred.
Three patients reported no improvement after BT while 18 who rated their outcomes as outstanding (n=13) and good (n=5). Two patients previously improved with omalizumab were able to discontinue this drug. Six patients met the criteria for asthma-COPD overlap syndrome; of which, 5 rated their result between outstanding (n=4) and good (n=1).
Our own patient experiences and the published literature have highlighted the need to identify predictors of BT response earlier in the management of asthma symptoms and exacerbations. Objective patient selection for BT is essential to assure patient safety, reduce risks, and position patients for the most favorable outcomes (Table 2).
Our position is that the European Respiratory Society/American Thoracic Society statement12 stating that BT be performed only in the setting of a clinical study or independent registry, which cites the paucity of data regarding asthma phenotypes most likely to benefit or be harmed from BT, seemingly limits patient options and access to this FDA-approved therapy. That being said, we are indeed engaging patients in an International Review Board-approved protocol to evaluate gene expression changes in the airway epithelial cells of asthmatic patients undergoing BT.
In this regard, the more recent assessments of the data that included results from the 5-year follow-up have resulted in the inclusion of BT as a preferred add-on treatment option before oral corticosteroids in the treatment of severe asthmatics at step 5 of the GINA guidelines.7 Further support for BT has come from position statements by the American College of Asthma, Allergy and Immunology in 2015 and the American College of Chest Physicians and Interasma Global Asthma Association, both in 2014.
In a recent study funded by the National Institutes of Health, a number of predictors of response to BT were identified in 42 adults with severe persistent asthma.13 With a baseline post-bronchodilator FEV1 at 70% predicted, 80% required a burst of systemic corticosteroids the 12 months prior to BT or sham. Mean dosage of ICS was 2 mcg/d and average baseline AQLQ was 3.42.
Predictors of a clinically meaningful improvement in QOL as defined by at least a 0.5-point improvement in AQLQ score 1-year post-procedure included a shorter duration of asthma 19 years, as compared with an average of 45 years in nonresponders) and a greater number of severe exacerbations during the year prior to BT.
At least a 240 mcg/d dose reduction in inhaled corticosteroids or a 2.5 mg/d decrease in oral corticosteroids at 1-year post procedure is another yardstick of clinical improvement. Other predictors include age (55 years and older), a lower baseline AQLQ score (2.4 vs 4.0), and greater need for oral corticosteroids.
In addition, several quantitative metrics obtained through multi-detector CT scans of the chest showed promise as predictors of a corticosteroid dose reduction. Responders showed less baseline air trapping, with an average of 6.1% of the lung having a density below –850 Hounsfield units, compared with 12.1% in nonresponders. Responders also had less baseline emphysema-like lung, with 3.2% of the lung having a density below –950 Hounsfield units at total lung capacity, compared with 5.8% in nonresponders.
Patients with severe asthma represent only a minority of the total asthma population, but account for the majority of the mortality, morbidity, and healthcare-related cost of this chronic illness. The adherence rates are lower in the real world and adherence reduces asthma control to the point where uncontrolled asthma is more likely to be encountered than controlled asthma despite current pharmacotherapy with controller medications.
BT is not a cure for asthma.6 BT should be recommended after 2 independent assessments (by a referring physician and an asthmatologist) confirm that the indications for BT exist, precautions are recognized, and no contraindications are present. Appropriate patients for referral are those with uncontrolled symptoms despite adherence to their asthma action plan or those who are suffering serious adverse effects from their medications (eg, Cushing’s syndrome, diabetes mellitus, and osteoporosis).
BT should not be recommended for asthma patients who are well-controlled on regularly scheduled ICS+LABA because of patient’s wishes to avoid taking medications daily.
Not all patients with severe persistent asthma are good candidates for BT. Avoid referring patients if they are classified as the most severe of severe persistent asthma patients because of the higher risk of complications that can be expected to occur with BT. An experienced asthma team of pulmonologists, anesthesiologists, pulmonary nurse specialists, and/or registered respiratory therapists should be involved whenever BT is considered.
Patients who undergo BT should be on stable asthma medications and have stable asthma status without active pulmonary infection (viral or bacterial or both), asthma exacerbation, coagulopathy (eg, bleeding disorder, coumadin, novel oral anticoagulant; aspirin is considered safe for BT), or changing dosages of prednisone 2 weeks before the proposed BT procedure.
BT has not been studied for use in asthma patients with a pacemaker, internal defibrillator, or other implanted electronic device. Also, those patients with known sensitivities to lidocaine, atropine, benzodiazepines, or propofol should not undergo BT unless alternative medications can be used. BT has not been studied for success in retreatment of the same area of the lung.
Not all patients will be able to stop their daily medications after BT but a 20% reduction in ICS and oral corticosteroids can be expected after BT in addition to an improvement in their QOL and exacerbation frequency.
The final pitfall is to avoid thinking that BT is still experimental and not FDA approved. BT is currently performed at over 350 centers in the United States with over 3000 patients treated since approval of BT by the FDA. Transparent discussion of the evidence (or lack thereof) for BT and institutional experience with it continues in the published literature. Only through such open discourse can patients ultimately benefit from new, safe, and effective treatments.14,15
Ken Y. Yoneda, MD, is a professor of medicine in the division of pulmonary, critical care, and sleep medicine and director of the bronchial thermoplasty program at the University of California, Davis.
Nicholas J. Kenyon, MD, is a professor of medicine and chief of the division of pulmonary, critical care, and sleep medicine at the University of California, Davis.
Samuel Louie, MD, is a professor of medicine in the same division at the University of California, Davis.
- US Department of Health and Human Services. National Asthma Education and Prevention Program Expert Panel Report 3 Guidelines for Diagnosis and Management of Asthma. October 2007. www.nhlbi.nih.gov/files/docs/guidelines/asthsumm.pdf. Accesed May 2015.
- Weinstein AG. Improving adherence to asthma therapies. Curr Opin Pulm Med. 2015;21(1):86-94 .
- US Department of Health and Human Services. Expert Panel Report 3: Guidelines for the diagnosis and management of asthma. August 28, 2007. www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf. Updated April 2013. Accessed May 2015.
- Martin RJ, Szefler SJ, King TS, et al. The Predicting Response to Inhaled Corticosteroids Efficacy (PRICE) Trial. J Allergy Clin Immunol. 2007;119(1):73-80.
- Louie S, Zeki AA, Schivo M, et al. The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmaco-therapeutic considerations. Expert Rev Clin Pharmacol. 2013;6(2):197-219.
- Cayetano KS, Chan AL, Albertson TE, Yoneda KY. Bronchial thermoplasty, chaning treatment paradigm for severe persistent asthma. Clinic Rev Allerg Immunol. 2012;
- Global Initiative For Asthma. Global Strategy for Asthma Management and Prevention 2014. May 2014. www.ginasthma.org/local/uploads/files/GINA_Report2015_Tracked.pdf. Accessed May 2015.
- Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med. 2010;181(2):116-124.
- Personal communication with Narinder Shargill, PhD, Boston Scientific.
- Weschler M, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. Allergy Clin Immunol. 2013;132(6):1295-1302.
- Pretolani M, Dombret MC, Thabut G, et al. Reduction of airway smooth muscle mass by bronchial thermoplasty in patients with severe asthma. Am J Respir Crit Care Med. 2014;190(12):1452-1454.
- Chung KF, Wsenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.
- Sarikonda K, Sheshadri A, Koch T, et al. Predictors of bronchial thermoplasty response in patients with severe refractory asthma. Am J Respir Crit Care Med. 2014;189:A2429.
- Iyer VN, Lim KG. Bronchial thermoplasty: reappraising the evidence (or lack thereof). Chest. 2014;146(1):17-21.
- Castro M, Cox G, Weschsler ME, Niven RM. Bronchial thermoplasty: ready for prime time–the evidence is there! Chest. 2015;