Bronchial Thermoplasty for the Treatment of Asthma Neil Martin, MRCP, and Ian D. Pavord, DM, FRCP
Corresponding author Ian D. Pavord, DM, FRCP Department of Respiratory Medicine, Allergy and Thoracic Surgery, Institute for Lung Health, Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester LE3 9QP, United Kingdom. E-mail:
[email protected] Current Allergy and Asthma Reports 2009, 9:88–95 Current Medicine Group LLC ISSN 1529-7322 Copyright © 2009 by Current Medicine Group LLC
Asthma is an increasingly prevalent disease, particularly in industrialized countries. With modern treatment, many patients can expect good asthma control; however, a significant minority continue to have excessive symptoms. Bronchial thermoplasty is a novel approach to treating asthma in which the hypertrophied airway smooth muscle present in the asthmatic airway is specifically targeted and depleted using thermal energy. In this article, we review the early animal and human development of the technique, summarize the randomized trials carried out in patients to date, discuss proposed mechanisms of action, and suggest directions for future work.
trolled asthma—to reduce dependency on chronic drug therapy [7] and concern about potential adverse effects [8]. Alternative treatment options that do not increase the burden and cost of chronic drug therapy therefore may be particularly attractive for many patients. Chronic asthma is associated with underlying chronic airway inflammation and airway remodeling with thickening of airway walls, goblet cell hyperplasia, increased mucus secretion, increased vascularization, and hypertrophy of airway smooth muscle (ASM). These features generally are more prominent in patients with refractory asthma, and the persistence of symptoms and impaired lung function seen in this group may be directly related to these structural changes to the airway. The increased mass and contractile potential of ASM in response to a variety of stimuli are likely to be particularly important [9–11]. Against this background, there has been considerable interest in bronchial thermoplasty, a novel technique that specifically targets the ASM. This review looks at the concepts behind the development of this technique; reviews early experience in animal models and early human trials; and discusses in detail more recent randomized, controlled trial data, including an ongoing multicenter, blinded, randomized, controlled trial comparing the effects of bronchial thermoplasty and sham treatment.
Introduction Asthma is a complex inflammatory disorder of the airways characterized by airway hyperresponsiveness (AHR) and variable airflow obstruction. It is an increasingly prevalent disease, particularly in industrialized countries. Advances in clinical and basic research over the past 30 years have led to the development of effective treatments and dissemination of detailed disease management guidelines. As a result, many patients with asthma can expect good control of all manifestations of the disease [1,2]. However, a small but significant number of patients have persistent symptoms, impaired lung function, and frequent exacerbations despite apparently optimal drug therapy. This subgroup of patients with refractory asthma experiences substantial morbidity and excess mortality and consumes a significant proportion of health care expenditure. A pressing need exists for better therapeutic options in these patients [3–6]. There is also a desire—even in patients with con-
Pathophysiologic Basis of Bronchial Thermoplasty It is widely accepted that much of the variable airflow obstruction that underpins many of the clinical manifestations of asthma is related to airway narrowing and that this is due largely to the contraction of ASM in response to a variety of stimuli. AHR is invariably seen in patients with symptomatic asthma; it is widely assumed to relate to airway inflammation, although the exact mechanism of the association remains incompletely understood [11]. All the conducting airways down to the level of the respiratory bronchioles are lined with smooth muscle. By contracting, this ASM has the potential to shorten narrow airways and, if stimulated sufficiently, even narrow them to complete closure [12]. These narrowed airways require increased energy expenditure to maintain adequate airflow and are more likely to become flow limited at low lung volumes.
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Much of the therapeutic research in asthma has focused on preventing this ASM contraction and hence reducing variability in symptoms and airflow limitation. Treatment with short- or long-acting β-adrenergic agonists (LABAs) is currently used to achieve ASM relaxation; most patients with asthma achieve good control with these agents [13]. However, breakthrough symptoms and exacerbations still occur, and some patients respond poorly to all forms of treatment [2,13–17]. Thus, there is a need for alternative treatments that address ASM contraction.
Airway smooth muscle in asthma Views on the function of ASM range from it being of the “utmost functional importance” [18] to it being a vestigial tissue of no functional significance, analogous to the human appendix [19]. The latter view is supported to some degree by the lack of an identified disease entity or physiologic deficit associated with loss of ASM [20]. In asthma, smooth muscle mass is increased due to hyperplasia [21] and hypertrophy [22], the balance of which may vary with phenotype [23]. 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 [24–27]. Growing evidence also indicates that ASM acts as an effector cell that is important in orchestrating the inflammatory process and airway wall remodeling [28]. This may be the result of smooth muscle cell migration along chemotactic gradients and epithelial mesenchymal transition [29]. The interaction between ASM and infi ltrating mast cells may be particularly important, as this pathologic feature is consistently seen in patients with asthma [30,31] but not in patients with eosinophilic bronchitis, a condition associated with eosinophilic airway inflammation but not AHR. Much is still to be learned about how ASM relates to the clinical expression of asthma and disease progression, but there is sufficient evidence to speculate that ablation of ASM could result in long-term improvements in asthma control.
Where should treatment be targeted? Some controversy remains as to which generation of airways is most affected and contributes most to the airflow limitation seen in asthma. This issue is important in relation to bronchial thermoplasty, as the technique can only be used to treat airways of 3 mm or greater. Early morphometric models suggest that most baseline airway resistance is associated with the conducting airways (ie, those > 2 mm in diameter) [32,33]. How this is affected by smooth muscle contraction has never been fully modeled, and it has been postulated that smaller airways may be affected more by bronchoconstriction than larger cartilaginous airways. However, it has been demonstrated that large airway closure is possible in humans with enough stimulation and that this may actually have direct effects on small airway narrowing [34].
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Thus, whereas the exact locus of airway constriction in asthma remains to be fully elucidated, currently available data suggest that impairment of the ASM contractility in medium-sized airways could have a beneficial effect on asthma control and symptoms.
Bronchial Thermoplasty: Methodology Bronchial thermoplasty is a radiofrequency ablation technique used to selectively target ASM in medium-sized airways down to a diameter of 3 mm. The equipment uses the Alair system (Asthmatx, Mountain View, CA), which consists of a bronchial catheter and a radiofrequency generator. The catheter fits thorough the 2-mm working channel of a standard 5-mm fiberoptic bronchoscope and has an expandable four-electrode basket that has heating and temperature-sensing elements for feedback control. The basket is opened to allow the four electrode arms to make contact with the airway wall circumferentially (Fig. 1A). The generator system then delivers monopolar radiofrequency energy at 460 kHz, using active feedback to maintain the desired treatment temperature for 10 seconds. The technique is normally applied during multiple bronchoscopy visits several weeks apart. Lower lobes and upper lobes are treated on separate days; the right middle lobe is not treated, as a theoretical concern remains that the long and narrow airway leading to the right middle lobe may predispose to obstruction. Each treatment involves 30 to 45 activations that take a total of 30 to 60 minutes. The procedure is generally well tolerated provided that patients are given periprocedure corticosteroids, are optimally bronchodilated, and receive appropriate sedation (Table 1). Use of midazolam and a short-acting opioid (eg, alfentanil) works well, although some operators prefer general anesthesia. The optimum method, time interval between treatments, and number of procedures have yet to be clearly defi ned. At the time of treatment, there is little if any direct evidence of heat effect on the airway; occasionally, whitening of the mucosa can be seen, possibly as a result of some acute epithelial desquamation. Locally increased mucus production and transient bronchoconstriction may occur. After the procedure, there is usually a short-lived increase in the frequency of airway symptoms, such as cough, sputum, hoarseness, and dyspnea (Table 1).
Clinical Experience With Bronchial Thermoplasty Early animal models Initial studies carried out on canine airways helped to determine the safety and efficacy of radiofrequency ablation in the pulmonary tree (Fig. 1B). In the fi rst published study, Danek and colleagues [35] treated 11 mongrel dogs at varying temperatures of 55°C, 65°C, and 75°C. Treat-
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Figure 1. A, The bronchial thermoplasty technique. B, Treated canine airway after methacholine challenge (left) and constriction of untreated airway (arrow).
ment and control sites were carefully mapped within the same animal, and airways were tested for hyperresponsiveness to methacholine. Animals were followed up for 3 years, and histologic comparisons were made between the treated and untreated airways at intervals of 1, 6, 12, and 157 weeks. In total, more than 300 individual airway sites in 11 dogs were examined. A significant difference was noted in AHR to methacholine in airways treated at 75°C compared with controls, and this was still evident at 3 years. Treatments at 55°C showed no significant difference, and those treated at 65°C were significantly different initially, but this varied throughout the course of the follow-up study. The findings from direct visualization of the airway were supported by a study that used high-resolution CT to determine airway caliber [36]. Untreated control airways showed no evidence of ASM alteration. In treated airways, there was degenerative change with absence or replacement of ASM by spindle-shaped fibroblasts that progressed to an increase in immature collagen and ASM alteration at 12 weeks to a reduction in ASM and its replacement by a thin layer of mature collagen at 157 weeks. At no point was there any evidence of ASM regeneration. Importantly, there also was no evidence of change in the lung parenchyma. Early histologic specimens showed evidence of mucosal edema, which had resolved by week 6. Direct visual examination of the airways under bronchoscopy showed evidence of tissue blanching at higher temperatures, with some residual erythema at week 1 and complete resolution by week 6. There were also a few instances of retained mucus, and four dogs had a transient cough in the post-treatment period.
Initial human studies In the first use of bronchial thermoplasty, nine patients scheduled to undergo lung resection for suspected or proven lung cancer consented to treatment in the 1- to 3week period before their scheduled resection [37]. Eight had treatment carried out; one patient withdrew due to anatomic distortion of the upper airways. As in the canine model, treatment created a blanching of the airways, some mucus plugging, and mild cough but no serious adverse events, and all patients proceeded to surgical resection as planned. Histologic examination of the airways showed acute epithelial damage and regeneration with alterations in ASM, but only at the higher temperature used (65°C). The changes involved about 50% of the circumferential airway and were limited to the airway wall. Only a small amount of adjacent lung parenchymal pneumonitis was seen. This pilot study provided some reassurance that the potentially beneficial changes seen in the canine airway are also evident in humans treated with a less intensive regime. Further proof-of-effect trial data were acquired in 16 patients with stable asthma recruited from two institutions and followed up for 2 years after treatment [38••]. All patients were pretreated with systemic corticosteroids to minimize systemic side effects of treatment, and treatment was carried out under general or conscious sedation. The treatments were performed over three visits, each 3 weeks apart for each lower lobe and the upper lobes. Adverse events were mainly mild to moderate (Table 1). Only three (1%) severe adverse events were reported, none of which was related to the treatment or the asthma. Most occurred and resolved within the first week after treatment. Patients had improved prebronchodilator FEV1 (forced expiratory
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Table 1. Summary of adverse events by participant frequency (%) in all individuals included in clinical trials of bronchial thermoplasty Treated group Adverse event
Control group
Cox et al. [38••] AIR 1 [39••] (n = 16) (n = 55)
RISA [41••] (n = 15)
AIR 1 [39••] (n = 54)
RISA [41••] (n = 17)
13
23.5
Wheezing
50
61.8
73.3
Cough
94
52.7
73.3
18.5
35.3
Chest discomfort
56
47.3
40
20.4
5.9
Dyspnea
69
70.9
60
33.3
41.2
Productive cough
50
40
53.3
11.1
29.4
Sputum discolored
SNS
10.9
33.3
0
0
Nasal congestion
13
12.7
20
11.1
17.6
Nasopharyngitis
SNS
SNS
20
SNS
17.6
Pharyngolaryngeal pain Atelectasis Bronchial irritation
26
SNS
20
SNS
5.9
SNS
SNS
6.7
SNS
0
13
9.1
13.3
SNS
0
Lower respiratory tract infection
SNS
SNS
13.3
SNS
29.4
Upper respiratory tract infection
SNS
12.7
6.7
3.7
17.6
63
7.3
SNS
SNS
SNS
Bronchospasm Dry mouth
SNS
3.6
SNS
0
SNS
Night awakenings
SNS
40
SNS
9.3
SNS
Abnormal chest sounds
SNS
5.5
SNS
SNS
SNS
Fever
44
SNS
SNS
SNS
SNS
Headache
25
SNS
SNS
SNS
SNS
Hemoptysis
19
SNS
SNS
SNS
SNS
Localized heat
6
SNS
SNS
SNS
SNS
Retained mucus
13
SNS
SNS
SNS
SNS
Hypoxemia
6
SNS
SNS
SNS
SNS
Hoarseness
6
SNS
SNS
SNS
SNS
Lower back pain
6
SNS
SNS
SNS
SNS
AIR—Asthma Intervention Research trial; RISA—Research in Severe Asthma trial; SNS—symptom not scored.
volume in 1 second) at 12 weeks and 1 year, but this was not significant by 2 years (Table 2). During the first 12 weeks, there was also a statistically significant increase in symptom-free days and peak expiratory flow (PEF) and a decrease in AHR (Table 2). The reduction in AHR persisted throughout the 2-year post-treatment period, although some changes were also made to the inhaled medications taken by the study group during this time, complicating the interpretation of these changes. None of the patients required hospitalization or oral corticosteroids or had asthma exacerbations as a consequence of the treatment. Overall early experience with bronchial thermoplasty provided a strong basis for larger, more rigorous randomized, controlled trials involving a more relevant patient population and testing treatment’s effect on a wider range of outcomes.
Randomized, controlled trials The Asthma Intervention Research (AIR) trial randomized 112 patients at 11 treatment centers in four countries [39••]. Entry criteria were broad, with an age range of 18 to 65 years and symptoms and treatment regimen in keeping with moderate to severe persistent asthma as defi ned by the Global Initiative for Asthma criteria. All patients required at least moderate doses of inhaled corticosteroids and LABAs to maintain asthma control, had an FEV1 of 60% to 85% predicted, a methacholine PC 20 (provocative concentration causing a 20% drop in FEV1) of 8 mg/mL or less, and had been stable for 6 weeks before study entry. Smokers and those with a recent history of infection were excluded. To ensure a population that had room for improvement, patients were required to have a 0.5 or greater increase in the
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Table 2. Summary of results (presented as change from baseline) from all clinical trials of bronchial thermoplasty published to date* Results
Cox et al. [38••] †
AIR [39••]
RISA [41••]
Methacholine PC20 (doubling concentration)
2.77
1.31
0.45
AQLQ (1–7; minimal clinically significant change 0.5)
NM
1.3†
1.53†
ACQ (0–6; minimal clinically significant change 0.5)
NM
–1.2†
–0.99†
Symptom-free days, %
73†
40.6†
21.6
Symptom scores (0–18)
NM
–1.9
†
Prebronchodilator FEV1, % predicted
3.5
2.3
38.8†
39.3†
Morning PEF, L/min
–1.8 14.9†
†
24.4
Minor exacerbations per 12 mo
NM
–0.16
NS
Severe exacerbations per 12 mo
NM
NS
NS
Evening PEF, L/min
41.1†
NM
14.9
NS
–3.7
–26.6†
Rescue medication use, puffs/7 d
*Where possible, data are given for the 12-month time point. † Statistically significant result. ACQ—Asthma Control Questionnaire; AIR—Asthma Intervention Research trial; AQLQ—Asthma Quality of Life Questionnaire; FEV1—forced expiratory volume in 1 second; NM—not measured; NS—not significant (actual data not published); PC20 —provocative concentration causing 20% drop in FEV1; PEF—peak expiratory flow; RISA—Research in Severe Asthma trial.
Asthma Control Questionnaire (ACQ) score [40] or a greater than 5% drop in morning PEF during a 2-week period when LABAs were withdrawn. Patients had three treatment sessions over 6 to 9 weeks with the Alair system. Controls had similarly spaced visits for clinical review and spirometric assessment. Treated patients and controls had the same dose of systemic steroid administered before and after each visit. Follow-up visits were carried out at 3, 6, and 12 months, each time after the withdrawal of LABAs for 2 weeks. All participants kept a symptom diary; recorded daily changes in PEF, the use of rescue medication, and symptom scores; and completed an ACQ at assessment. The primary outcome was exacerbations, defi ned as one or more of the following occurring during the LABA withdrawal period: a reduction in the morning PEF of at least 20% below average on 2 consecutive days, the need for three or more puffs of rescue medication greater than the average use in the week before LABA withdrawal, and/or nocturnal awakening caused by asthma symptoms. The number of exacerbations in the treatment group was significantly reduced compared with the control arm at 3 and 12 months (Table 2). The reduction at 6 months was not statistically significant. The fi ndings could be extrapolated to 10 fewer minor exacerbations per patient per year in the treatment group. Fewer severe exacerbations were seen in the treatment group, although few episodes occurred, and the difference was not statistically significant. At 12 months, there were significantly greater improvements in the bronchial thermoplasty group than in the control group in morning PEF, Asthma Qual-
ity of Life Questionnaire (AQLQ) scores, percentage of symptom-free days, symptom scores, and rescue medication use (Table 2). However, unlike previous human and canine studies, no changes in AHR were seen at any point after treatment. Adverse events increased in the treatment group during the treatment period, and although most were minor increases in cough, sputum, and dyspnea, there was an increase in hospitalization for asthma exacerbation (Table 1). In one patient, mucus plugging resulted in collapse of the most recently treated lobe. By 6 weeks post-treatment, the number of adverse events was similar in both groups. A post hoc analysis of the data looking at patients on high-dose corticosteroids at baseline (> 1000 μg of beclomethasone or equivalent) showed a greater beneficial effect of treatment with no increase in adverse events. Overall, the fi ndings of the AIR trial on asthma control 12 months after bronchial thermoplasty were promising. However, the lack of change in AHR was surprising. It could have reflected the increased variability of this measure in patients with more severe asthma assessed across different sites. One major concern is the nonblinded nature of this trial and the degree to which a placebo effect could have affected the outcome. However, the most clear results were seen with relatively objective measures, such as morning PEF and exacerbation frequency calculated from diary measurements. The AIR trial continues to follow up the participants; thus far, there is no suggestion that treatment is associated with delayed adverse effects. The Research in Severe Asthma (RISA) trial [41••] was designed to test the safety of bronchial thermoplasty in individuals with severe, persistent asthma as defi ned by
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the Global Initiative for Asthma criteria [42]. Secondary objectives included evaluation of the effect of bronchial thermoplasty on asthma symptoms and daily medication requirements. Inclusion criteria included age 18 to 65 years, high-dose inhaled corticosteroids (> 750 μg fluticasone propionate or equivalent), and treatment with LABAs. All participants had evidence of airflow obstruction, AHR, or reversible airflow obstruction, and all had uncontrolled symptoms despite therapy. The trial was conducted at eight sites in three countries and randomized 34 patients. After a 2-week run-in phase, participants were randomized to the control or treatment group. Treatment was the same as described in the AIR study. Patients next entered a 16-week steroidstable period (weeks 6–22) followed by an attempt to wean steroids (weeks 22–36) and then a reduced steroid phase (weeks 36–52). There was an excess of adverse events in the treatment group and a suggestion that adverse events were more prevalent in this population than had been seen in earlier populations (Table 1). Adverse events included an excess of hospitalizations for asthma exacerbations and two incidences of lobar collapse due to mucus plugging. However, this settled quickly after the first week, and adverse event incidence was similar in the two groups from week 6 onward. Individuals in the treatment group had a significant decrease in use of rescue medication and improvements in asthma control scores (ACQ and AQLQ) during the steroid-stable phase. This continued throughout the reduction in daily steroid use and the reduced steroid phase; thus, treated patients had better asthma control than controls despite having reduced steroid use throughout the trial. There were also significant improvements in prebronchodilator FEV1 in the treated group but, interestingly, not in PEF, postbronchodilator FEV1, or methacholine PC 20 between the treatment and control groups. The fi ndings of the RISA study support the results of the AIR trial post hoc analysis in that asthmatics with more severe disease appeared to respond better to treatment, albeit with increased immediate morbidity.
Mechanisms of Action Bronchial thermoplasty’s postulated mechanism of action is that the heat applied to the airway results in selective destruction of ASM. This is supported to a degree by the early studies in canine and human airways [35,37], which showed early ASM changes followed by replacement of ASM by fibrous connective tissue, at least in the canine airways. No long-term follow-up histology is available in humans, and both randomized, controlled trials in humans have failed to show the improvements in AHR that were demonstrated in the canine model and early human work.
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There are also no data on whether airway innervation, blood supply, inflammatory cell recruitment, epithelial cell function, and mucus production are affected by the treatment. Theoretically, alteration of any or all of these could result in improvements in asthma control irrespective of changes in ASM. Both randomized, controlled human trials have shown marked improvements in subjective outcomes of asthma control (eg, symptom scores, use of rescue medication) but failed to show evidence of change in objective measurements of control (postbronchodilator FEV1, AHR). This suggests that treatment may result in altered perception of asthma symptoms, perhaps by modulating neural pathways to and from the airways [43].
Remaining Questions The fi ndings of the AIR and RISA trials have aroused considerable interest and debate. One consistent view is that a blinded, randomized, controlled trial using “sham” bronchial thermoplasty is needed to determine the technique’s true efficacy. To fulfi ll this objective, the AIR 2 trial was established [44]. This randomized, double-blind, sham-controlled study aims to evaluate the safety and effectiveness of bronchial thermoplasty in patients with symptomatic severe asthma. In common with previous trials, it will recruit patients between 18 and 65 years of age who meet criteria for refractory or severe asthma and who are on high doses of inhaled corticosteroids (> 1000 μg beclomethasone or equivalent per day) and on LABA medications. The inclusion criteria specifically aim to recruit patients with evidence of AHR (PC20 < 8 mg/mL) with reduced AQLQ scores and who are symptomatic on their current treatment regimens. The study aims to recruit 225 patients, 150 in the treatment arm and 75 in the control group. All patients will be treated by two teams: a bronchoscopy team and a blinded assessment team who will do all follow-up after standard and sham treatment. Sham treatment will involve three bronchoscopies with the same timing, premedication, and duration as active treatment and with sham activation of the Alair system in a manner directly analogous to the active treatment, but with no thermal energy. By necessity, the operator and his/ her team will be aware that sham treatment is being given, but these individuals will not be involved in any post-treatment assessments. The patient and all other investigators will be unable to distinguish between sham and active treatment. Proposed primary end points will be changes in AQLQ scores from baseline and at 3, 6, 9, and 12 months. Secondary end points will include changes in symptom-free days, symptom scores, morning PEF, AQLQ scores, individual AQLQ domain scores, ACQ scores, rescue medication usage, and prebronchodilator
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FEV1. Other characterized variables to be examined will include AHR, asthma exacerbations, change in asthma medications, and time off LABAs at end of trial. The group aims to report on these data at 12 months, but prolonged follow-up will continue to 5 years post-treatment. This trial is specifically designed to reduce any concerns about a placebo effect of the treatment; it is due to report in the very near future. Other than the suggestion that patients with more severe asthma respond better to bronchial thermoplasty, little is known about whether subgroups who do particularly well with treatment can be identifi ed. This is an important question, as the treatment is labor intensive, relatively costly, and has the potential to cause permanent changes to the airway. It is becoming clear that a great deal of heterogeneity exists in the expression of airway infl ammation and dysfunction in asthma, and in refractory asthma in particular [45]. There is no a priori reason to suspect that bronchial thermoplasty will alter airway infl ammation, so it may not be a good treatment option in patients with infl ammation-predominant disease who have a prominent cough and sputum production and who are at risk of sputum retention. In contrast, patients with noneosinophilic disease, who often have isolated ASM dysfunction, may do particularly well, as this population does not respond well to corticosteroid treatment [46]. More work investigating the relationship between treatment response and baseline patient characteristics will be an important priority if the technique is shown to be effective in the sham-controlled, blinded trial.
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Conclusions Applying thermal energy to the airway in the form of bronchial thermoplasty results in the selective destruction of ASM; this is replaced by fibrous connective tissue. In early animal and human studies, this was associated with a reduction in objective measurements of asthma control, such as AHR. However, in the two published randomized, controlled trials on this technique, there has been a failure to show improvements in AHR, although there have been significant improvements in more subjective measurements of asthma control. Neither trial was blinded, and concern remains about a significant placebo effect of the treatment. The soon-to-report AIR 2 trial, which is randomized and blinded with a sham treatment arm, has been designed to try to address these issues in more detail.
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Disclosures Dr. Pavord received payments for his work in the AIR and RISA clinical trials. No other potential confl icts of interest relevant to this article were reported.
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