- Email: [email protected]
Bronchial Thermoplasty
B ro n c h i a l Thermo plasty Gerard Cox, MB, FRCP(C), FRCP(I) KEYWORDS Asthma Thermoplasty Broncoconstriction Allergy
conventional asthma treatment.1,3,6,8 It is not surprising that airflow obstruction as a result of tissue changes in the airway does not improve with bronchodilators; antiinflammatory therapy that controls cellular changes including eosinophilia has also not been found to reverse remodeling of the airway walls.8 Thus, there is evident need for new approaches that target airway smooth muscle. Ideally, such a treatment should address both mechanisms of airway narrowing, that is, preventing bronchoconstriction and reducing the amount of muscle in the remodeled airway. Such an intervention should have a prolonged effect.
DEVELOPMENT OF THE ALAIR SYSTEM FOR BRONCHIAL THERMOPLASTY Thermoplasty refers to the use of heat to induce structural changes. Bronchial thermoplasty (BT) is performed during bronchoscopy using the Alair system, which comprises a specially designed treatment catheter and a radiofrequency (RF) controller.10 The energy delivered at each treatment site is about 18 W. This is substantially lower than the energy used in other procedures that use RF for cautery or tissue ablation. For example, the Prosiva system for treating benign prostatic hypertrophy delivers 30 W for 2 to 3 minutes and the COBRA surgical probe delivers up to 150 W. When passed through the working channel of an (adult) bronchoscope, the electrode array at the end of the catheter is expanded to touch the airway wall under direct vision. Once contact is achieved, a 10-second pulse of RF energy is delivered, and the array is collapsed and moved 5 mm proximally to the next treatment site.
Firestone Institute for Respiratory Health, St Joseph’s Healthcare Hamilton, 50 Charlton Avenue E, Hamilton, ON L8N 4A6, Canada E-mail address: [email protected] Clin Chest Med 31 (2010) 135–140 doi:10.1016/j.ccm.2009.09.003 0272-5231/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
Airway narrowing is a central event in asthma.1 Contraction of airway muscles, or bronchoconstriction, is a dynamic process that contributes to airway narrowing in asthma and has long been the target of treatment with drugs that cause muscle relaxation.1,2 Since inflammatory events underlie asthma, therapy typically includes antiinflammatory agents.3,4 The current standard-ofcare has been defined by a variety of expert groups and evidence-based guidelines for the treatment of asthma have been published.5 As asthma is most often mild or moderate, it can be appropriately managed provided there is adequate compliance with prescribed measures; typically included in these are bronchodilating and antiinflammatory medications.5 Asthma, by definition is a variable disease. When there is greater than normal natural variation in airflow, the illness can be provoked by a wide range of stimuli that include infectious, allergic, and environmental agents.6 Bronchoconstriction determines much of the short-term variability in airflow that characterizes asthma.1,6 Development of bronchoconstriction is facilitated because the airways in asthma are hyperresponsive in that they can constrict to a greater degree and are more sensitive than normal.7 In chronic asthma, certain characteristic structural abnormalities are found in the airway walls.8 These changes are collectively termed remodeling. Excessive accumulation of smooth muscle is typical of airway remodeling and has been found in the airways of patients with a range of severity of asthma.8,9 Such remodeling of the airway wall, with increased smooth muscle along with heightened connective tissue elements and mucus glands may contribute further to the airway narrowing that is fixed and largely resistant to
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Fig. 1. Histology of canine airway 3 years after treatment, stained with Masson’s trichrome. Control airway in the left panel was untreated and shows normal airway wall elements including bundles of smooth muscle. The panel on the right shows a treatment site, which contains reduced amounts of smooth muscle. In addition, the area previously occupied by muscle now contains connective tissue elements with no evidence of excessive collagen deposition or scarring.
The Alair system was developed over a series of preclinical studies and was first applied in the canine airway.11 The treatment effect was dependent on the temperature reached in the airway wall. During preclinical studies parameters for energy delivery, duration of treatment, and temperature were examined. The optimal parameters that led to stable partial reduction in muscle mass without excessive tissue injury were identified. Histologic examination of treated sites revealed that smooth muscle was replaced with connective tissue elements.11 Long-term studies of 3 years showed no evidence of scarring and the effect on reducing muscle mass was stable (Fig. 1). Functionally, airways treated with BT contracted less following methacholine instillation than untreated sites and this effect was related to the degree to which muscle was reduced (Fig. 2).11,12 High-resolution computed tomography (HRCT) has been used to examine structural and functional changes in airways over time.13 After BT, canine airways were significantly less sensitive to challenge with aerosolized methacholine. Bronchoconstriction of treated airways continues to some degree indicating that BT reduces, but does not completely ablate, the mass of airway smooth muscle.11 Furthermore, there was a detectable increase in the baseline diameter of treated airways consistent with lower tone as a result of the reduced amount of muscle present. That the maximal postbronchodilator diameter was similar in treated and control airways shows that relaxation is not impaired. Treated airways were more distensible suggesting that when muscle is replaced by connective tissue elements the stiffness or elasticity of the airway is not adversely affected.14 This functional outcome
echoes the histology findings, which showed no evidence of scar formation over 3 years following BT (see Fig. 1).
HUMAN STUDIES OF BT BT was first applied in the human airway in patients who were scheduled for surgery for
Fig. 2. Relationship between the potential for stimulated bronchoconstriction and the amount of smooth muscle present in the airway wall, expressed as how much of the circumference of the airway contained recognizable muscle bundles. Untreated airways had almost complete circumferential muscle layer and narrowed by 80%. Treatment at increasing temperatures caused dose-dependent reduction in the amount of muscle, which correlated with diminished bronchoconstriction following local instillation of methacholine. (From Danek C, Lombard CM, Dungworth DL, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol 2004;97:1949; with permission.)
Bronchial Thermoplasty suspected lung cancer.15 At the time of bronchoscopy, which was performed 1 to 3 weeks before surgery, BT was performed in normal-appearing airways in the areas to be removed. Following resection, histologic comparison of treated and untreated sites showed less smooth muscle in airways treated with BT. The extent and nature of the treatment effects in the human airway closely resembled those documented in the canine airway.11,15 Over an interval of 1 to 3 weeks, there was evidence of resolution of the acute changes that follow treatment. The epithelium, which can be injured mechanically by the catheter and by heat, was largely reconstituted between the second and third weeks. As had been seen in the canine airway, the tissue changes were temperature dependent. Mayse and colleagues16 provided a description of how to use the Alair system for performing BT in patients with asthma. Although general anesthetic was used for the very first procedure, local anesthetic and moderate or conscious sedation are now standard.16,17 This is an outpatient procedure, performed in endoscopy or bronchoscopy units. Typically, it takes 3 separate procedures, usually 3 weeks apart, to treat the entire bronchial tree (except the right middle lobe because of concerns about causing the right middle lobe syndrome). All airways that can be accessed are targeted for treatment. The catheter is deployed only under direct vision; airways outside the bronchoscopic field of view are not treated. Thus, any treated airway can be inspected later in case there are any concerns. The Alair catheter must be partially expanded before it can be activated. Hence, it can treat airways with a diameter between 3 and 10 mm. The treatment begins as distally as possible. The RF energy is delivered at 5-mm intervals, providing continuous treatment to the airway (as the exposed section of the electrode is 5-mm long). In practice, each procedure lasts between 45 and 60 minutes; the duration is determined mainly by the number of treatment activations delivered. Since the endobronchial anatomy and caliber can vary considerably among patients, the number of activations per procedure is quite variable but is expected to average between 40 and 60. At the time of treatment, there is little if any evidence of heat effect. The most common observations are blanching of the airway when there is contact with electrode arms. A buildup of mucus on the electrode array may occur and may need to be removed to prevent the field of view being obscured. As a mechanical device is being deployed, superficial trauma to the airway is inevitable. Minor immediate bleeding, or more often oozing, is observed occasionally, but is
minimal and self-limited. Since the energy delivered is modest and the temperature in the tissues reaches 65 C, there is no evidence of tissues burning or of sparking.
TREATING ASTHMA WITH THE ALAIR SYSTEM FOR BT BT for asthma was first studied in 16 patients with a range of asthma severity.17 This study showed that it was feasible to perform BT safely in patients with asthma. In addition, certain asthma parameters (numbers of symptom-free days and peak expiratory flows) showed improvements at 3 months. Bronchial hyperresponsiveness was reduced and this effect persisted beyond 12 months. Treatment was well tolerated and adverse events that occurred following bronchoscopy were managed with the same measures used to treat usual exacerbations of asthma symptoms. The impact of BT in 109 patients with moderate to severe asthma was examined in the Asthma Intervention Research (AIR) trial.18 Asthma severity was indicated by medication, all subjects were using at least 200 mg/d of inhaled corticosteroids (ICS) for maintenance treatment (Table 1). All subjects also required treatment with long-acting b-agonists (LABA) shown by deterioration in asthma control on withholding LABA for 2 weeks. The group that underwent treatment with the Alair system showed statistically significant reduction in their rates of mild exacerbations. They also enjoyed improvements in a number of other parameters including asthma quality of life, asthma control, use of rescue medication and numbers of symptom-free days (Table 2). Performing BT causes temporary worsening of asthma symptoms that usually begins on the day of the procedure. Subjects in the AIR trial had severe asthma to begin with; on occasion, their symptoms were severe enough to require hospital admission soon after treatment, which did not occur in the previous trial (Table 3). There were 6 hospitalizations among 55 subjects who had undergone 161 treatment procedures compared with 2 admissions for asthma deterioration in 54 control subjects. Reassuringly, these adverse events following BT are familiar problems that respond typically within 1 week to usual measures for care of asthma exacerbations. A population with even more severe asthma was enrolled in the Research in Severe Asthma (RISA) trial.19 The 32 subjects had higher requirements for maintenance medications that included oral corticosteroids (OCS), and had other evidence of more severe asthma than the subjects in either of the 2 previous trials (see Table 1). At 22 weeks
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Table 1 Comparison of inclusion criteria for clinical trials of BT for asthma
Age (y) ICS dose (mg/d) (beclomethasone or equivalent) LABA dose (mg/d) (salmeterol) OCS dose (mg/d) Pre-BD FEV1 (% predicted) Symptoms
Feasibility
AIR
RISA
AIR2
18–65 %1800
18–65 R200
18–65 >1500
18–65 >1000
0–100
R100
R100
R100
0 >65 (post-BD)
0 60–85
%30 R50
%10 R60
Not required
Worse with LABA withdrawal
Symptoms on R10/ 14 d, or rescue med use on R8/14 d
R2/28 d
after treatment, subjects followed an algorithm to taper their steroid dose providing control of their asthma did not deteriorate. This is the only time that reductions in antiinflammatory therapy were advocated in subjects undergoing BT. Because the therapeutic rationale for BT is that it reduces the amount of smooth muscle in the airway, it is expected that following successful treatment patients would still need to take their antiinflammatory medications.10 The difference in severe asthma is that patients may be taking excessive doses of steroids and that reduction in the dosage may be possible if asthma control is improved by some other means. According to various parameters, the group treated with the Alair system showed improvement in the control of their asthma.19 There were significantly greater improvements in asthma quality of life, asthma control questionnaire score, and use of rescue medications (see Table 2). Doses of steroids for maintenance treatment were reduced in both groups and the difference between them was not statistically different (the trial had insufficient power to detect this difference as only half of the subjects were taking oral steroids at entry).
There was an increase in the severity of adverse events encountered in the actively treated group compared with previous trials probably related to the severity of asthma of the subjects (see Table 3). There were 5 hospital admissions within 1 week of 45 procedures in the BT-treated group. Even though multiple studies reported benefits following treatment with BT, it should be recognized that there is substantial potential for placebo effect, especially with a novel procedure.20 Thus, the Asthma Intervention Research 2 (AIR2) trial was designed with a control group that underwent 3 bronchoscopies and sham treatment with the Alair system.21 This comprised placement of the treatment catheter in targeted airways, expansion of the electrode array but no delivery of RF energy when the controller was activated. The selection of subjects was designed to enroll subjects with asthma of sufficient severity to have large potential for benefit, but not so severe as to be at high risk of requiring hospitalization should asthma symptoms worsen post procedure.18,19 A total of 297 subjects with severe asthma and persistent symptoms were randomized 2:1 to active and sham control groups. The primary outcome was a
Table 2 Comparison among studies of outcomes indicating benefit from BT Feasibility
AIR
RISA
AIR2
Well tolerated PEF Symptom-free days Hyperresponsiveness
Exacerbations AQLQ Symptom-free days Rescue medications
AQLQ ACQ Rescue medications [Reduced oral steroids P 5 .12]
AQLQ Severe exacerbations ER visits Time lost from work/ school
Bronchial Thermoplasty
Table 3 Comparison among studies of rates of hospitalization in the period following treatment bronchoscopy AIR
No. hospitalizations (no. of subjects) No of bronchoscopies Events/bronch (%)
RISA
AIR2
Alair (n 5 55)
Control (n 5 54)
Alair (n 5 15)
Control (n 5 17)
Alair (n 5 190)
Sham (n 5 98)
6 (4)
2 (2)
7 (4)
0 (0)
19 (16)
2 (2)
161
—
45
—
558
292
3.7
—
15.6
—
3.4
0.7
change in the asthma quality of life questionnaire (AQLQ) score. This improved in both groups, but to a statistically significant greater extent in the BT group compared with the sham group.22 Secondary outcomes showed trends for benefit from BT that were not statistically significant. Safety was reported by rates of hospitalization and other health care use at 2 time intervals: around the time of treatment and from then to the end of 1 year (see Table 2). The selection criteria were successful in excluding subjects at risk of severe asthma exacerbation following the procedure, and this was confirmed by the rate of hospitalization, which approximated that found in the AIR trial and was substantially less than in the RISA trial (see Table 3). Use of health care resources, such as unscheduled office or emergency department visits, and admissions were lower in the BT-treated group than the sham control group during the second interval of follow-up (see Table 2).22
LONG-TERM CLINICAL FOLLOW-UP There has been speculation from the very outset regarding the possibility of certain adverse outcomes developing late after BT. One specific concern relates to the potential for long-term damage to treated airways because of scar formation or to loss of integrity of the airway wall. It is now possible to begin to address such concerns with data from long-term follow-up of treated patients. HRCT examinations have been performed annually for 5 years in the subjects who participated in the feasibility trial. Treated airways appear normal, without evidence of either airway stenosis or dilation (bronchiectasis). There was also no evidence of damage to the parenchyma adjacent to treated airways indicating the treatment effect is limited to the airways. Longer term follow-up of subjects who were treated in the Feasibility, AIR, AIR2 and RISA trials
now exceeds 500 patient-years. The majority of subjects report either stable or improved control of their asthma. Pre- and postbronchodilator FEV1 has remained stable over 3 or more years in subjects who completed the first 3 studies. This experience suggests there are no late developing adverse consequences of treating asthmatic airways with BT.
SUMMARY Despite major progress in developing medical treatments for asthma, a substantial proportion of patients continue to suffer from inadequate control of their disease.23 In others, although their disease can be controlled this requires such high doses of medications that side effects are troublesome.24,25 Current treatments do not redress the excess smooth muscle mass that is present in the remodeled airway in chronic asthma. Thus, it is intriguing to consider the potential contribution of BT (a procedure that involves controlled heat treatment to reduce the mass of the airway smooth muscle) as an effective therapy for poorly controlled asthma. If effective, BT would reverse the excess accumulation of muscle in the airway and reduce the potential for bronchoconstriction. Although the short-term increase in asthma symptoms (requiring hospitalization at times) is evident, these should be weighed against the benefits that are present for a prolonged time (>1 year in all trials to date). Even though the results of 4 clinical trials show benefits following BT in patients with asthma ranging from mild to severe, it is most likely that this treatment will be indicated for patients with severe asthma that is not well controlled by combinations of currently available therapies. These are the patients who most need an additional effective asthma therapy and, based on the results of trials published to date, have the greatest potential to benefit from BT.
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Cox REFERENCES 1. Doherty DE. The pathophysiology of airway dysfunction. Am J Med 2004;117(Suppl 12A):11S–23S. 2. Sears MR, Lo¨vtall J. Past, present and future-b2adenoreceptor agonists in asthma management. Respir Med 2005;99:152–70. 3. Djukanovic R, Roche WR, Wilson JW, et al. Mucosal inflammation in asthma [State of the art]. Am Rev Respir Dis 1990;142:434–57. 4. Drazen JM. Asthma therapy with agents preventing leukotriene synthesis or action. Proc Assoc Am Physicians 1999;111:547–59. 5. Global Initiative For Asthma. Global strategy for asthma management and prevention. National Heart, Lung, and Blood Institute/World Health Organization. 2002. Publication Number 02-3659. Bethesda (MD): National Institutes of Health. 6. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006;368:780–93. 7. Cockroft DW, Killian DN, Mellon JJA, et al. Bronchial reactivity to inhaled histamine: a method and clinical survey. Clin Allergy 1977;7:235–43. 8. Bergeron C, Boulet LP. Structural changes in airway diseases: characteristics, mechanisms, consequences, and pharmacologic modulation. Chest 2006;129:1068–87. 9. Carroll N, Elliot J, Morton A, et al. The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405–10. 10. 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. 11. Danek C, Lombard C, Dungworth D, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol 2004;97:1946–53. 12. Miller P, Danek CJ, Cox G, et al. Development of a bronchoscopic technique for airway diameter measurement. Chest 2001;120:229S. 13. 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.
14. Brown RH, Wizeman W, Danek C, et al. Effect of bronchial thermoplasty on airway distensibility. Eur Respir J 2005;26:277–82. 15. Miller JD, Cox G, Vincic L, et al. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest 2005;127:1999–2006. 16. Mayse ML, Laviolette M, Rubin AS, et al. Clinical pearls for bronchial thermoplasty. J Bronchol 2007; 14:115–23. 17. Cox G, Miller JD, McWilliams A, et al. Bronchial thermoplasty for asthma. Am J Respir Crit Care Med 2006;173:965–9. 18. Cox G, Thomson NC, Rubin AS, et al. AIR Study Group. Asthma control during the year after bronchial thermoplasty. N Engl J Med 2007;356: 1327–37. 19. Pavord ID, Cox G, Thomson NC, et al. RISA Trial. Study Group Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med 2008;176:1185–91. 20. Wechsler ME. Bronchial thermoplasty for asthma: a critical review of a new therapy. Allergy Asthma Proc 2008;29:365–70. 21. Cox G, Israel E, Jarjour N, et al. AIR2 Trial: execution of a sham-controlled double-blind study of a novel device for the treatment of severe asthma. Am J Respir Crit Care Med 2009;179:A2787. 22. 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 2009. [Epub ahead of print]. 23. Dolan CM, Fraher KE, Bleecker ER, et al. TENOR Study Group. Design and baseline characteristics of the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) study: a large cohort of patients with severe or difficult-totreat asthma. Ann Allergy Asthma Immunol 2004; 92(1):32–9. 24. Peters SP, Ferguson G, Deniz Y, et al. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med 2006;100: 1139–51. 25. Beasley R. Unmet need in inadequately controlled asthma. Respirology 2007;12(Suppl 3):S18–21.
conventional asthma treatment.1,3,6,8 It is not surprising that airflow obstruction as a result of tissue changes in the airway does not improve with bronchodilators; antiinflammatory therapy that controls cellular changes including eosinophilia has also not been found to reverse remodeling of the airway walls.8 Thus, there is evident need for new approaches that target airway smooth muscle. Ideally, such a treatment should address both mechanisms of airway narrowing, that is, preventing bronchoconstriction and reducing the amount of muscle in the remodeled airway. Such an intervention should have a prolonged effect.
DEVELOPMENT OF THE ALAIR SYSTEM FOR BRONCHIAL THERMOPLASTY Thermoplasty refers to the use of heat to induce structural changes. Bronchial thermoplasty (BT) is performed during bronchoscopy using the Alair system, which comprises a specially designed treatment catheter and a radiofrequency (RF) controller.10 The energy delivered at each treatment site is about 18 W. This is substantially lower than the energy used in other procedures that use RF for cautery or tissue ablation. For example, the Prosiva system for treating benign prostatic hypertrophy delivers 30 W for 2 to 3 minutes and the COBRA surgical probe delivers up to 150 W. When passed through the working channel of an (adult) bronchoscope, the electrode array at the end of the catheter is expanded to touch the airway wall under direct vision. Once contact is achieved, a 10-second pulse of RF energy is delivered, and the array is collapsed and moved 5 mm proximally to the next treatment site.
Firestone Institute for Respiratory Health, St Joseph’s Healthcare Hamilton, 50 Charlton Avenue E, Hamilton, ON L8N 4A6, Canada E-mail address: [email protected] Clin Chest Med 31 (2010) 135–140 doi:10.1016/j.ccm.2009.09.003 0272-5231/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
Airway narrowing is a central event in asthma.1 Contraction of airway muscles, or bronchoconstriction, is a dynamic process that contributes to airway narrowing in asthma and has long been the target of treatment with drugs that cause muscle relaxation.1,2 Since inflammatory events underlie asthma, therapy typically includes antiinflammatory agents.3,4 The current standard-ofcare has been defined by a variety of expert groups and evidence-based guidelines for the treatment of asthma have been published.5 As asthma is most often mild or moderate, it can be appropriately managed provided there is adequate compliance with prescribed measures; typically included in these are bronchodilating and antiinflammatory medications.5 Asthma, by definition is a variable disease. When there is greater than normal natural variation in airflow, the illness can be provoked by a wide range of stimuli that include infectious, allergic, and environmental agents.6 Bronchoconstriction determines much of the short-term variability in airflow that characterizes asthma.1,6 Development of bronchoconstriction is facilitated because the airways in asthma are hyperresponsive in that they can constrict to a greater degree and are more sensitive than normal.7 In chronic asthma, certain characteristic structural abnormalities are found in the airway walls.8 These changes are collectively termed remodeling. Excessive accumulation of smooth muscle is typical of airway remodeling and has been found in the airways of patients with a range of severity of asthma.8,9 Such remodeling of the airway wall, with increased smooth muscle along with heightened connective tissue elements and mucus glands may contribute further to the airway narrowing that is fixed and largely resistant to
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Cox
Fig. 1. Histology of canine airway 3 years after treatment, stained with Masson’s trichrome. Control airway in the left panel was untreated and shows normal airway wall elements including bundles of smooth muscle. The panel on the right shows a treatment site, which contains reduced amounts of smooth muscle. In addition, the area previously occupied by muscle now contains connective tissue elements with no evidence of excessive collagen deposition or scarring.
The Alair system was developed over a series of preclinical studies and was first applied in the canine airway.11 The treatment effect was dependent on the temperature reached in the airway wall. During preclinical studies parameters for energy delivery, duration of treatment, and temperature were examined. The optimal parameters that led to stable partial reduction in muscle mass without excessive tissue injury were identified. Histologic examination of treated sites revealed that smooth muscle was replaced with connective tissue elements.11 Long-term studies of 3 years showed no evidence of scarring and the effect on reducing muscle mass was stable (Fig. 1). Functionally, airways treated with BT contracted less following methacholine instillation than untreated sites and this effect was related to the degree to which muscle was reduced (Fig. 2).11,12 High-resolution computed tomography (HRCT) has been used to examine structural and functional changes in airways over time.13 After BT, canine airways were significantly less sensitive to challenge with aerosolized methacholine. Bronchoconstriction of treated airways continues to some degree indicating that BT reduces, but does not completely ablate, the mass of airway smooth muscle.11 Furthermore, there was a detectable increase in the baseline diameter of treated airways consistent with lower tone as a result of the reduced amount of muscle present. That the maximal postbronchodilator diameter was similar in treated and control airways shows that relaxation is not impaired. Treated airways were more distensible suggesting that when muscle is replaced by connective tissue elements the stiffness or elasticity of the airway is not adversely affected.14 This functional outcome
echoes the histology findings, which showed no evidence of scar formation over 3 years following BT (see Fig. 1).
HUMAN STUDIES OF BT BT was first applied in the human airway in patients who were scheduled for surgery for
Fig. 2. Relationship between the potential for stimulated bronchoconstriction and the amount of smooth muscle present in the airway wall, expressed as how much of the circumference of the airway contained recognizable muscle bundles. Untreated airways had almost complete circumferential muscle layer and narrowed by 80%. Treatment at increasing temperatures caused dose-dependent reduction in the amount of muscle, which correlated with diminished bronchoconstriction following local instillation of methacholine. (From Danek C, Lombard CM, Dungworth DL, et al. Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs. J Appl Physiol 2004;97:1949; with permission.)
Bronchial Thermoplasty suspected lung cancer.15 At the time of bronchoscopy, which was performed 1 to 3 weeks before surgery, BT was performed in normal-appearing airways in the areas to be removed. Following resection, histologic comparison of treated and untreated sites showed less smooth muscle in airways treated with BT. The extent and nature of the treatment effects in the human airway closely resembled those documented in the canine airway.11,15 Over an interval of 1 to 3 weeks, there was evidence of resolution of the acute changes that follow treatment. The epithelium, which can be injured mechanically by the catheter and by heat, was largely reconstituted between the second and third weeks. As had been seen in the canine airway, the tissue changes were temperature dependent. Mayse and colleagues16 provided a description of how to use the Alair system for performing BT in patients with asthma. Although general anesthetic was used for the very first procedure, local anesthetic and moderate or conscious sedation are now standard.16,17 This is an outpatient procedure, performed in endoscopy or bronchoscopy units. Typically, it takes 3 separate procedures, usually 3 weeks apart, to treat the entire bronchial tree (except the right middle lobe because of concerns about causing the right middle lobe syndrome). All airways that can be accessed are targeted for treatment. The catheter is deployed only under direct vision; airways outside the bronchoscopic field of view are not treated. Thus, any treated airway can be inspected later in case there are any concerns. The Alair catheter must be partially expanded before it can be activated. Hence, it can treat airways with a diameter between 3 and 10 mm. The treatment begins as distally as possible. The RF energy is delivered at 5-mm intervals, providing continuous treatment to the airway (as the exposed section of the electrode is 5-mm long). In practice, each procedure lasts between 45 and 60 minutes; the duration is determined mainly by the number of treatment activations delivered. Since the endobronchial anatomy and caliber can vary considerably among patients, the number of activations per procedure is quite variable but is expected to average between 40 and 60. At the time of treatment, there is little if any evidence of heat effect. The most common observations are blanching of the airway when there is contact with electrode arms. A buildup of mucus on the electrode array may occur and may need to be removed to prevent the field of view being obscured. As a mechanical device is being deployed, superficial trauma to the airway is inevitable. Minor immediate bleeding, or more often oozing, is observed occasionally, but is
minimal and self-limited. Since the energy delivered is modest and the temperature in the tissues reaches 65 C, there is no evidence of tissues burning or of sparking.
TREATING ASTHMA WITH THE ALAIR SYSTEM FOR BT BT for asthma was first studied in 16 patients with a range of asthma severity.17 This study showed that it was feasible to perform BT safely in patients with asthma. In addition, certain asthma parameters (numbers of symptom-free days and peak expiratory flows) showed improvements at 3 months. Bronchial hyperresponsiveness was reduced and this effect persisted beyond 12 months. Treatment was well tolerated and adverse events that occurred following bronchoscopy were managed with the same measures used to treat usual exacerbations of asthma symptoms. The impact of BT in 109 patients with moderate to severe asthma was examined in the Asthma Intervention Research (AIR) trial.18 Asthma severity was indicated by medication, all subjects were using at least 200 mg/d of inhaled corticosteroids (ICS) for maintenance treatment (Table 1). All subjects also required treatment with long-acting b-agonists (LABA) shown by deterioration in asthma control on withholding LABA for 2 weeks. The group that underwent treatment with the Alair system showed statistically significant reduction in their rates of mild exacerbations. They also enjoyed improvements in a number of other parameters including asthma quality of life, asthma control, use of rescue medication and numbers of symptom-free days (Table 2). Performing BT causes temporary worsening of asthma symptoms that usually begins on the day of the procedure. Subjects in the AIR trial had severe asthma to begin with; on occasion, their symptoms were severe enough to require hospital admission soon after treatment, which did not occur in the previous trial (Table 3). There were 6 hospitalizations among 55 subjects who had undergone 161 treatment procedures compared with 2 admissions for asthma deterioration in 54 control subjects. Reassuringly, these adverse events following BT are familiar problems that respond typically within 1 week to usual measures for care of asthma exacerbations. A population with even more severe asthma was enrolled in the Research in Severe Asthma (RISA) trial.19 The 32 subjects had higher requirements for maintenance medications that included oral corticosteroids (OCS), and had other evidence of more severe asthma than the subjects in either of the 2 previous trials (see Table 1). At 22 weeks
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Table 1 Comparison of inclusion criteria for clinical trials of BT for asthma
Age (y) ICS dose (mg/d) (beclomethasone or equivalent) LABA dose (mg/d) (salmeterol) OCS dose (mg/d) Pre-BD FEV1 (% predicted) Symptoms
Feasibility
AIR
RISA
AIR2
18–65 %1800
18–65 R200
18–65 >1500
18–65 >1000
0–100
R100
R100
R100
0 >65 (post-BD)
0 60–85
%30 R50
%10 R60
Not required
Worse with LABA withdrawal
Symptoms on R10/ 14 d, or rescue med use on R8/14 d
R2/28 d
after treatment, subjects followed an algorithm to taper their steroid dose providing control of their asthma did not deteriorate. This is the only time that reductions in antiinflammatory therapy were advocated in subjects undergoing BT. Because the therapeutic rationale for BT is that it reduces the amount of smooth muscle in the airway, it is expected that following successful treatment patients would still need to take their antiinflammatory medications.10 The difference in severe asthma is that patients may be taking excessive doses of steroids and that reduction in the dosage may be possible if asthma control is improved by some other means. According to various parameters, the group treated with the Alair system showed improvement in the control of their asthma.19 There were significantly greater improvements in asthma quality of life, asthma control questionnaire score, and use of rescue medications (see Table 2). Doses of steroids for maintenance treatment were reduced in both groups and the difference between them was not statistically different (the trial had insufficient power to detect this difference as only half of the subjects were taking oral steroids at entry).
There was an increase in the severity of adverse events encountered in the actively treated group compared with previous trials probably related to the severity of asthma of the subjects (see Table 3). There were 5 hospital admissions within 1 week of 45 procedures in the BT-treated group. Even though multiple studies reported benefits following treatment with BT, it should be recognized that there is substantial potential for placebo effect, especially with a novel procedure.20 Thus, the Asthma Intervention Research 2 (AIR2) trial was designed with a control group that underwent 3 bronchoscopies and sham treatment with the Alair system.21 This comprised placement of the treatment catheter in targeted airways, expansion of the electrode array but no delivery of RF energy when the controller was activated. The selection of subjects was designed to enroll subjects with asthma of sufficient severity to have large potential for benefit, but not so severe as to be at high risk of requiring hospitalization should asthma symptoms worsen post procedure.18,19 A total of 297 subjects with severe asthma and persistent symptoms were randomized 2:1 to active and sham control groups. The primary outcome was a
Table 2 Comparison among studies of outcomes indicating benefit from BT Feasibility
AIR
RISA
AIR2
Well tolerated PEF Symptom-free days Hyperresponsiveness
Exacerbations AQLQ Symptom-free days Rescue medications
AQLQ ACQ Rescue medications [Reduced oral steroids P 5 .12]
AQLQ Severe exacerbations ER visits Time lost from work/ school
Bronchial Thermoplasty
Table 3 Comparison among studies of rates of hospitalization in the period following treatment bronchoscopy AIR
No. hospitalizations (no. of subjects) No of bronchoscopies Events/bronch (%)
RISA
AIR2
Alair (n 5 55)
Control (n 5 54)
Alair (n 5 15)
Control (n 5 17)
Alair (n 5 190)
Sham (n 5 98)
6 (4)
2 (2)
7 (4)
0 (0)
19 (16)
2 (2)
161
—
45
—
558
292
3.7
—
15.6
—
3.4
0.7
change in the asthma quality of life questionnaire (AQLQ) score. This improved in both groups, but to a statistically significant greater extent in the BT group compared with the sham group.22 Secondary outcomes showed trends for benefit from BT that were not statistically significant. Safety was reported by rates of hospitalization and other health care use at 2 time intervals: around the time of treatment and from then to the end of 1 year (see Table 2). The selection criteria were successful in excluding subjects at risk of severe asthma exacerbation following the procedure, and this was confirmed by the rate of hospitalization, which approximated that found in the AIR trial and was substantially less than in the RISA trial (see Table 3). Use of health care resources, such as unscheduled office or emergency department visits, and admissions were lower in the BT-treated group than the sham control group during the second interval of follow-up (see Table 2).22
LONG-TERM CLINICAL FOLLOW-UP There has been speculation from the very outset regarding the possibility of certain adverse outcomes developing late after BT. One specific concern relates to the potential for long-term damage to treated airways because of scar formation or to loss of integrity of the airway wall. It is now possible to begin to address such concerns with data from long-term follow-up of treated patients. HRCT examinations have been performed annually for 5 years in the subjects who participated in the feasibility trial. Treated airways appear normal, without evidence of either airway stenosis or dilation (bronchiectasis). There was also no evidence of damage to the parenchyma adjacent to treated airways indicating the treatment effect is limited to the airways. Longer term follow-up of subjects who were treated in the Feasibility, AIR, AIR2 and RISA trials
now exceeds 500 patient-years. The majority of subjects report either stable or improved control of their asthma. Pre- and postbronchodilator FEV1 has remained stable over 3 or more years in subjects who completed the first 3 studies. This experience suggests there are no late developing adverse consequences of treating asthmatic airways with BT.
SUMMARY Despite major progress in developing medical treatments for asthma, a substantial proportion of patients continue to suffer from inadequate control of their disease.23 In others, although their disease can be controlled this requires such high doses of medications that side effects are troublesome.24,25 Current treatments do not redress the excess smooth muscle mass that is present in the remodeled airway in chronic asthma. Thus, it is intriguing to consider the potential contribution of BT (a procedure that involves controlled heat treatment to reduce the mass of the airway smooth muscle) as an effective therapy for poorly controlled asthma. If effective, BT would reverse the excess accumulation of muscle in the airway and reduce the potential for bronchoconstriction. Although the short-term increase in asthma symptoms (requiring hospitalization at times) is evident, these should be weighed against the benefits that are present for a prolonged time (>1 year in all trials to date). Even though the results of 4 clinical trials show benefits following BT in patients with asthma ranging from mild to severe, it is most likely that this treatment will be indicated for patients with severe asthma that is not well controlled by combinations of currently available therapies. These are the patients who most need an additional effective asthma therapy and, based on the results of trials published to date, have the greatest potential to benefit from BT.
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