B ro n c h i a l T h e r m o p l a s t y Jessica Kynyk, MD, Cathy Benninger, Karen L. Wood, MD*

RN, MS, CNP,

KEYWORDS  Bronchial thermoplasty  Airway smooth muscle  Severe asthma KEY POINTS  Bronchial thermoplasty (BT) is a bronchoscopic procedure that involves the direct application of thermal energy to the airways and is performed at 3 separate sessions spaced 3 weeks apart.  BT leads to the destruction of airway smooth muscle (ASM), because ASM plays an important role in the pathophysiology of asthma.  The procedure is approved for patients with severe asthma and results in improvement in quality of life and decreased asthma exacerbations.

A video demonstrating BT accompanies this article at www.oto.theclinics.com

INTRODUCTION

Bronchial thermoplasty (BT) was approved by the Food and Drug Administration (FDA) in April 20101 and offers a novel add-on treatment of the management of severe asthma by reducing smooth muscle mass via direct application of thermal energy. Severe asthma is a widespread problem globally. There are 22.9 million Americans in the United States with asthma,2 and severe persistent asthma constitutes up to 12%3–5 yet disproportionately utilizes more direct and indirect health care dollars for asthma care.6–8 SEVERE ASTHMA

Severe persistent asthma consists of asthma symptoms throughout the day, nighttime awakenings often 7 times a week, need for short-acting b-agonists several times a day, and extreme limitations in daily activity as well as forced expiratory volume in 1 second (FEV1) less than 60% predicted (without medications).9 Risk factors for All of the authors report no financial conflicts of interest in relation to the completion of this research. Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA * Corresponding author. 201 Davis Heart and Lung Institute, 473 West 12th Avenue, Columbus, OH 43210. E-mail address: [email protected] Otolaryngol Clin N Am 47 (2014) 77–86 http://dx.doi.org/10.1016/j.otc.2013.09.007 0030-6665/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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Abbreviations AIR ASM ATS BT FEV1 LABA

Asthma Intervention Research Airway smooth muscle American Thoracic Society Bronchial thermoplasty Forced expiratory volume in 1 second Long-acting b-agonist

severe asthma include being female (postpuberty), obesity, black race, significant secondhand smoke exposure, and comorbidities of gastroesophageal reflux, sinus infections, and pneumonia.10 Although control is the ultimate goal in the management of asthma, complete control in many with severe persistent asthma is often elusive,11 leading to several terms to describe this patient group, including severe asthma, steroid-dependent or resistant asthma, difficult or poorly controlled asthma, and brittle or irreversible asthma.12 In 2000, the “Proceedings of the ATS Workshop on Refractory Asthma” agreed on the term, refractory asthma, to describe those asthma cases requiring a high amount of medications to maintain control or those cases of persistent symptoms, airflow obstruction, and frequent exacerbations despite high medication use.12 Diagnosis requires all other diseases with similar presenting symptoms to have been ruled out, comorbid conditions adequately managed, and medication technique and adherence issues addressed.12 The lack of therapeutic effectiveness or response to traditional medications in this patient group raises the question of differing airway pathophysiology compared with mild or moderate asthmatics12 and has led to a discussion of asthma being a heterogeneous disease with varying manifestations or responses to treatment.13 Several distinct phenotypes are evolving when comparing clinical and physiologic features, prominence of biomarkers, age of disease onset, and response to therapy; however, additional research is needed for full characterization.10,14,15 The movement from symptom-based therapy decisions to medications or interventions targeting the underlying physiologic features of the disease will pave the way to personalized treatment plans, with the ultimate goal of improved control for refractory asthmatics. PATHOPHYSIOLOGY

One important target of current asthma therapy is ASM because it is critically involved in asthma pathogenesis. Acutely, ASM cell contraction causes bronchoconstriction. Chronically, hypertrophy and hyperplasia of ASM are responsible for airway remodeling.9 Additionally, through interactions with other cells, such as mast cells, and by generating and releasing inflammatory mediators, ASM cells are responsible for some of the airway inflammation seen with asthma.16 Medications, such as shortacting bronchodilators, long-acting bronchodilators, leukotriene inhibitors, and theophylline, play an important role in asthma management by relaxing the ASM. BT is used as a new approach to treatment by structurally modifying the airway and destroying smooth muscle. If ASM is to be destroyed, it is important to believe that ASM does not have a physiologic role. Investigators have debated if ASM has a beneficial or physiologic role or whether it is similar to a vestigial organ and serves no useful purpose.17 This debate has not been settled; many researchers and clinicians have proposed possible roles for ASM.18 Refractory asthmatics present a crucial opportunity to better understand the underlying pathophysiology of asthma and the

Bronchial Thermoplasty

importance of targeting specific pathways for treatment. The complexity of the inflammatory cascade and chemoreceptors associated with asthma reduces the possibility of a single treatment approach for a cure. Although BT has been associated with reduced frequency of asthma exacerbations, some unknown factors persist because airway inflammation remains intact and medications remain necessary for management. RESULTS AND EFFICACY Preclinical Studies

In 2004, investigators published a study using radiofrequency ablation (BT) at 3 different temperatures in 11 dogs with some of the dogs followed as long as 3 years. The investigators found a significant reduction in airway hyperresponsiveness among the BT-treated (at 65 C or 75 C) versus untreated airways of the canines using local methacholine provocation directed to the treated airways.19 Histologic evaluation of the canine airways (up to 3 years after treatment) showed persistent ASM reduction and no evidence of smooth muscle regeneration. This study also established a correlation between the extent of reduction in ASM and improvement in airway hyperresponsiveness. These results were subsequently validated in 3 additional canine studies.20–22 Human Studies Lung cancer, no asthma

The first human feasibility study was conducted by Miller and colleagues.23 Nine subjects without asthma but with known lung cancer scheduled to undergo surgical resection participated in this study; however, only 8 underwent BT. BT was targeted to visually accessible airway segments, which were planned for surgical resection. All subjects had an office follow-up visit in-between the BT treatment and surgery. All patients tolerated the procedure well and there were no procedure-related complications (including respiratory tract infections, need for additional medications, supplemental oxygen, and unscheduled health care visits). Histologic evaluation of both the treated and untreated tissue was performed. An approximately 50% reduction in ASM was noted in airways of those treated to 65 C versus a 5% reduction among persons treated to 55 C. The investigators concluded that BT is well tolerated among humans and yielded significant reduction in ASM mass. Mild to moderate asthma

Subsequent studies were conducted evaluating BT in asthmatic patients (Table 1). The first was a nonrandomized prospective study of 16 patients with stable mild to moderate asthma24; 13 of the 16 subjects completed all 3 sessions and were followed for 2 years post-BT. There was a significant improvement in airway hyperresponsiveness but no improvement in FEV1 after 2 years. BT was well tolerated among asthmatics; however, in comparison to the feasibility study, there were side effects. The most common adverse events were mild and consisted of       

Cough (94% of subjects) Chest discomfort (56%) Dyspnea (69%) Wheezing (50%) Bronchospasm (63%) Mucus production (50%) Fever (44%)

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Table 1 Summary of bronchial thermoplasty clinical trials Study

Study Design

Asthma Severity

Follow-up (y)

Improved Outcomes

Outcomes Without Change

Cox et al,24

Prospective nonrandomized

Mild to moderate, stable asthma

2

AHR Symptom-free days Morning PEF Evening PEF

FEV1 Rescue medicine usage

Cox et al,25

Prospective randomized

Moderate to severe persistent asthma

1

Morning PEF Symptom-free days Quality-of-life scores Rescue medicine usage

AHR FEV1

Pavord et al,26

Prospective randomized

Refractory asthma

1

Quality-of-life scores Rescue medicine usage Prebronchodilator FEV1

AHR Symptom-free days Morning PEF Evening PEF Postbronchodilator FEV1

Castro et al,27

Randomized, double-blind, sham-controlled

Severe persistent asthma

1

Severe asthma exacerbations ED visits Missed work/school days

Pre- or postbronchodilator FEV1 Rescue medicine usage Symptom-free days Morning PEF

Abbreviations: AHR, airway hyperresponsiveness; ED, emergency department; PEF, peak expiratory flow. Data from Refs.24–27

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There were no postprocedure hospitalizations or severe adverse events related to BT. The Asthma Intervention Research (AIR) Trial was the first randomized multicenter study evaluating BT25; 112 subjects with moderate to severe persistent asthma were enrolled and randomized to either inhaled corticosteroid with a long-acting b-agonist (LABA) or BT plus combination inhaled corticosteroid and LABA. Subjects were followed for 2 years. The study showed an improvement in asthma symptoms; however, no difference in airway hyperresponsiveness was observed. Adverse events were common immediately post-treatment in the BT cohort, with 4 subjects requiring hospitalization for asthma exacerbations. Again a majority of adverse events were mild and mainly consisted of cough, dyspnea, wheezing, and chest tightness. The major limitation of this study was its nonblinded study design and lack of sham control leading to a potential placebo effect. Although the safety and efficacy of BT among mild, moderate, and severe persistent asthma had been evaluated, the question remained as to whether patients with refractory asthma could benefit from this novel asthma therapy. Pavord and colleagues26 performed a randomized trial aimed at evaluating the efficacy of BT among symptomatic severe asthmatics; 34 subjects with refractory asthma were enrolled in this yearlong, multinational study comparing BT with a control, medical management arm. Subjects in this study were on higher doses of inhaled corticosteroids and oral prednisone in comparison with previously published studies. At completion of the study, subjects in the BT arm had a significant reduction in use of short-acting b-agonist, improvement in prebronchodilator FEV1, but not postbronchodilator FEV1, and improved Asthma Control Questionnaire scores compared with subjects in the medical therapy arm. During the treatment period, 7 hospitalizations for respiratory symptoms occurred in 4 of the 15 BT patients compared with none in the control arm. Two hospitalizations were secondary to segmental collapse of the recently treated lobe whereas 5 were for asthma exacerbations. Aside from the treatment portion of the study, hospitalization rates were similar for the two groups. Although each of these studies highlights efficacy, safety, and complications associated with BT among small and specific asthma populations, they had significant limitations. In 2010, the Asthma Intervention Research 2 Trial (AIR2) trial, a randomized, double-blinded, sham-controlled study, was published.27 In order to achieve the double-blind design, subjects were evaluated by a blinded assessment team and treatments were conducted by an unblinded bronchoscopy team. The sham bronchoscopy used a sham radiofrequency controller, which was indistinguishable with the exception of no deliverable energy; 288 subjects with severe asthma were enrolled. The Asthma Quality of Life Questionnaire scores were significantly improvement from baseline in the BT group compared with the sham group. More remarkably, the study showed a significant reduction in severe exacerbations, emergency department visits, and missed work/school days post-BT. Adverse events were mostly mild to moderate in severity and consisted mainly of symptoms of airway inflammation. Again, the BT group had a higher postprocedure hospitalization rate (8.4%–2% of the sham group), and severe adverse events included 1 episode of hemoptysis requiring bronchial artery embolization. Since the definitive study for BT by Castro and colleagues,27 its use for the treatment of adults greater than or equal to 18 years with severe persistent asthma that is uncontrolled despite inhaled corticosteroids and LABA has been approved by the FDA. Despite FDA approval, its efficacy and safety continue to be studied. There are few data on the long-term benefits. Further research is needed to determine the long-term safety and efficacy of BT on asthma as well as specific patient selection recommendations to determine which asthma phenotypes respond the best to BT.

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Fig. 1. The Alair Bronchial Thermoplasty System control unit with the catheter on top. (Courtesy of Boston Scientific Corporation, Natick, MA.)

TECHNIQUE

BT administers controlled radiofrequency waves to the airways using the Alair System (Boston Scientific, Natick, Massachusetts) (Video 1, Fig. 1), which consists of a radiofrequency generator and a disposable bronchial catheter with an expandable basket consisting of 4 electrodes. BT is typically performed via 3 bronchoscopy sessions spaced 3 weeks apart. Accessible distal airways of all lobes except the right middle lobe are treated (Fig. 2). Each lower lobe’s airways are treated separately during 1 of the first 2 sessions. Both upper lobes are treated during the third and final session.28 Systemic steroids, usually prednisone (50 mg), are typically administered for 5 days starting 2 to 3 days prior to BT to minimize postprocedure inflammation. Preprocedure assessment typically includes establishment of baseline spirometry, screening to ensure no evidence of an acute asthma exacerbation or upper respiratory tract

Fig. 2. The electrode basket is expanded in the airways, making contact with the wall for application of thermal energy.

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infection, and administration of a short-acting bronchodilator just prior to the bronchoscopy. Once the preprocedure assessment has been completed and informed consent obtained, the patient is prepped for bronchoscopy. A grounding pad is applied to the patient’s torso and connected to the radiofrequency generator. Sedation for BT is accomplished with a combination of local anesthesia and either deep or moderate sedation. A standard adult bronchoscope is then advanced through the vocal cords and a detailed airway examination with particular attention to previously treated airways is completed. The procedure is aborted if signs of active infection or evidence of inadequate airway healing are seen. The bronchoscope is then advanced to the most distal airways of the targeted lobe(s) while maintaining view of the airway wall. Next the electrode basket is advanced through the working channel of the bronchoscope and expanded until it contacts the airway walls (see Fig. 2). After sufficient airway contact with the basket is ensured, the operator delivers 10 seconds29 of thermal energy yielding a target tissue temperature of 65 C.19,23 The electrode basket is then collapsed and retracted 5 mm to the site of the next treatment. This process is repeated in a distal to proximal fashion ensuring contiguous but nonoverlapping applications.30 The on-line video clip (supplementary online data) demonstrates application of energy in a live procedure. Each BT session lasts approximately 40 to 60 minutes.29 A preprocedure treatment plan is crucial to ensure no airway segments undergo duplicate or missed treatments. Additionally, close monitoring of oxygenation during the procedure with supplemental oxygen less than fraction of inspired oxygen (FiO2) less than 40% is needed to prevent airway fire. On completion of the session, the bronchoscope is removed and the patient closely monitored in recovery. Once the patient has recovered from sedation and the FEV1 is 80% or greater of the preprocedure FEV1, the patient may be discharged to home with close follow-up. Detailed instructions on when to contact the physician and schedule follow-up should be included in the postprocedure plan. PRACTICAL APPLICATIONS Patient Selection

The only approved indication for BT based on studies to date is severe asthma not adequately controlled with maximal medical therapy in patients over the age of 18. There are, however, several contraindications listed by the FDA. These include  Presence of an implanted electronic device, such as a pacemaker or defibrillator  Sensitivities to any of the medications necessary for bronchoscopy  Patients previously treated with BT should not be treated again in the same area. BT should also be deferred when any of these conditions is present:    

Active respiratory infection Asthma exacerbation within 2 weeks Coagulopathy Patient unable to stop taking anticoagulant medications

Because the AIR2 study was the definitive study, the inclusion and exclusion criteria used for this study should be kept in mind. Subjects were included between the ages of 18 and 65 years old diagnosed with asthma and requiring moderate to high doses of inhaled corticosteroids and a LABA. Subjects could be on other asthma maintenance medications, including oral corticosteroids, provided the dose was less than 10 mg/d. Stability on the medications was required for a minimum of 4 weeks prior to the procedure and the subjects had prebronchodilator FEV1 60% or greater predicted as well

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as documentation of airway hyperresponsiveness through methacholine challenge. Additionally, the subjects were nonsmoking for at least 1 year with no more than a 10 pack/y smoking history and at least 2 days of asthma symptoms during the preceding 4 weeks.27 Key exclusion criteria were life-threatening asthma (intubated for asthma during their lifetime, hospitalized in intensive care within the previous 24 months, more than 3 asthma exacerbations requiring hospitalizations, 3 or more lower respiratory infections, or 4 steroid bursts in the previous 12 months); chronic sinus disease; other respiratory disease, such as emphysema; and use of immunosuppressants, b-adrenergic blocking agents, anticoagulants, or implanted electrical devices.27 Follow-Up

Patients should be followed closely after the procedure to monitor for adverse events associated with BT (Table 2). Although there is no standard established follow-up, one schedule entails contacting the patients by phone several times after the procedure (1, 2, and 7 days after the procedure, for example) followed by an office visit 2 weeks after each BT session. Because a majority of adverse events occur closely after BT, patients may resume their normal follow-up schedule for severe asthma after the 2-week visit. Potential Safety Concerns

BT remains controversial among providers for refractory asthmatics in part because of few data on long-term safety and effectiveness and less specificity in knowing which severe asthma phenotypes are more likely to benefit.31 Also concerning is the applicability of BT to this patient group because a result of the strict inclusion and exclusion criteria used in the initial trials would have excluded many refractory asthmatics.27 In the first feasibility study in human subjects, treated airways showed approximately 50% reduction in the smooth muscle mass (2 weeks post-treatment); however, this has not correlated with improvements in FEV1 in subjects evaluated in the effectiveness and safety studies, suggesting additional inquiry is needed to fully understand the physiologic effect in the post-BT airway.23,25,31–33 Case reports and larger formal studies mandated by the FDA are forthcoming and may help clarify these issues.1 In the interim, safety studies have been reassuring up to 5 years postprocedure with stable lung function, consistently higher quality-of-life scores, and reduced exacerbations in treated subjects, offering a novel treatment option to those who are significantly limited by their disease.25,27,33,34

Table 2 Potential adverse events associated with bronchial thermoplasty and in the postprocedure period Wheezing

Cough

Chest discomfort

Dyspnea

Sputum production

Nasal/chest congestion

Bronchospasm

Night awakenings

Respiratory tract infections

Atelectasis

Throat irritation/pain

Hypoxia

Fever

Hemoptysis

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SUMMARY

BT is a novel therapy for severe asthma. It involves 3 separate bronchoscopic procedures spaced 3 weeks apart. During the procedure, radiofrequency waves are applied to the airways. The procedure results in decreased asthma symptoms and exacerbations and an increased quality of life. Pathologically, the application of thermal energy results in a reduction of ASM, which is believed the basis for symptomatic improvement. Complications can develop from the procedure, however, and patients need to be chosen carefully and followed closely afterward. SUPPLEMENTARY DATA

Supplementary video related to this article is found at http://dx.doi.org/10.1016/j.otc. 2013.09.007. (Video; Courtesy of Boston Scientific Corporation, Natick, MA). REFERENCES

1. Alair Bronchial Thermoplasty System -P080032. 2010 May 19, 2010 [cited 2013 June 21]; Available from: http://www.accessdata.fda.gov/cdrh_docs/pdf8/ P080032b.pdf. 2. American Lung Association Lung Disease Data: 2008. 2008 [cited 2013 June 21]; Available from: http://www.lung.org/assets/documents/publications/lung-diseasedata/LDD_2008.pdf. 3. Birnbaum HG, Ivanova JI, Yu AP, et al. Asthma severity categorization using a claims-based algorithm or pulmonary function testing. J Asthma 2009;46: 67–72. 4. Michelson PH, Williams LW, Benjamin DK, et al. Obesity, inflammation, and asthma severity in childhood: data from the National Health and Nutrition Examination Survey 2001-2004. Ann Allergy Asthma Immunol 2009;103:381–5. 5. Clark NM, Dodge JA, Shah S, et al. A current picture of asthma diagnosis, severity, and control in a low-income minority preteen population. J Asthma 2010;47:150–5. 6. Cisternas MG, Blanc PD, Yen IH, et al. A comprehensive study of the direct and indirect costs of adult asthma. J Allergy Clin Immunol 2003;111:1212–8. 7. Ivanova JI, Bergman R, Birnbaum HG, et al. Effect of asthma exacerbations on health care costs among asthmatic patients with moderate and severe persistent asthma. J Allergy Clin Immunol 2012;129:1229–35. 8. Szefler SJ, Zeiger RS, Haselkorn T, et al. Economic burden of impairment in children with severe or difficult-to-treat asthma. Ann Allergy Asthma Immunol 2011; 107:110–9.e111. 9. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol 2007;120:S94–138. 10. Jarjour NN, Erzurum SC, Bleecker ER, et al. Severe asthma: lessons learned from the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Am J Respir Crit Care Med 2012;185:356–62. 11. Chipps BE, Zeiger RS, Borish L, et al. Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. J Allergy Clin Immunol 2012;130:332–42.e310. 12. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations, and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med 2000;162:2341–51.

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13. Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010;126:926–38. 14. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716–25. 15. Carolan BJ, Sutherland ER. Clinical phenotypes of chronic obstructive pulmonary disease and asthma: recent advances. J Allergy Clin Immunol 2013;131:627–34 [quiz: 635]. 16. Black JL, Panettieri RA Jr, Banerjee A, et al. Airway smooth muscle in asthma: just a target for bronchodilation? Clin Chest Med 2012;33:543–58. 17. Mitzner W. Airway smooth muscle: the appendix of the lung. Am J Respir Crit Care Med 2004;169:787–90. 18. Panettieri RA Jr, Kotlikoff MI, Gerthoffer WT, et al. Airway smooth muscle in bronchial tone, inflammation, and remodeling: basic knowledge to clinical relevance. Am J Respir Crit Care Med 2008;177:248–52. 19. Danek CJ, Lombard CM, Dungworth DL, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol 2004;97:1946–53. 20. Brown R, Wizeman W, Danek C, et al. Effect of bronchial thermoplasty on airway closure. Clin Med Circ Respirat Pulm Med 2007;1:1–6. 21. Brown RH, Wizeman W, Danek C, et al. Effect of bronchial thermoplasty on airway distensibility. Eur Respir J 2005;26:277–82. 22. Brown RH, Wizeman W, Danek C, et al. In vivo evaluation of the effectiveness of bronchial thermoplasty with computed tomography. J Appl Physiol 2005;98: 1603–6. 23. Miller JD, Cox G, Vincic L, et al. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005;127:1999–2006. 24. Cox G, Miller JD, McWilliams A, et al. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006;173:965–9. 25. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356:1327–37. 26. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2007;176:1185–91. 27. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, doubleblind, sham-controlled clinical trial. Am J Respir Crit Care Med 2010;181:116–24. 28. Cox PG, Miller J, Mitzner W, et al. Radiofrequency ablation of airway smooth muscle for sustained treatment of asthma: preliminary investigations. Eur Respir J 2004;24:659–63. 29. Cox G. Bronchial thermoplasty. Clin Chest Med 2010;31:135–40. Table of Contents. 30. Mayse ML, Rubin A, Lampron N, et al. Clinical pearls for bronchial thermoplasty. Journal of Bronchology & Interventional Pulmonology 2007;14:115–23. 31. Wahidi MM, Kraft M. Bronchial thermoplasty for severe asthma. Am J Respir Crit Care Med 2012;185:709–14. 32. Cayetano KS, Chan AL, Albertson TE, et al. Bronchial thermoplasty: a new treatment paradigm for severe persistent asthma. Clin Rev Allergy Immunol 2012;43:184–93. 33. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med 2011;11:8. 34. Doeing DC, Mahajan AK, White SR, et al. Safety and feasibility of bronchial thermoplasty in asthma patients with very severe fixed airflow obstruction: a case series. J Asthma 2013;50:215–8.

Bronchial thermoplasty.

Bronchial thermoplasty is a relatively new therapy for the management of severe asthma. It involves the direct bronchoscopic application of thermal en...
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