Open access Original research Bronchial Thermoplasty Global Registry (BTGR): 2-­year results Alfons Torrego ‍ ‍,1 Felix J Herth,2 Ana M Munoz-­Fernandez,3 Luis Puente,4 Nicola Facciolongo,5 Stephen Bicknell,6 Mauro Novali,7 Stefano Gasparini,8 Martina Bonifazi,8 Keertan Dheda,9 Felipe Andreo,10 Praha Votruba,11 David Langton,12 Javier Flandes,13 David Fielding,14 Peter I Bonta,15 Dirk Skowasch,16 Christian Schulz,17 Kaid Darwiche,18 Edmund McMullen,19 G. Mark Grubb,19 Robert Niven20 To cite: Torrego A, Herth FJ, ABSTRACT Munoz-­Fernandez AM, et al. Strengths and limitations of this study Objectives Bronchial thermoplasty (BT) is a device-­based Bronchial Thermoplasty treatment for subjects ≥18 years with severe asthma not Global Registry (BTGR): The Bronchial Thermoplasty Global Registry (BTGR): well controlled with inhaled corticosteroids and long-­acting 2-­year results. BMJ Open ► Was designed to collect data on subjects undergo- beta-­agonists. The Bronchial Thermoplasty Global Registry 2021;11:e053854. doi:10.1136/ ing bronchial thermoplasty treatment for asthma in bmjopen-2021-053854 (BTGR) collected real-­world data on subjects undergoing a ‘real-­world’ setting for 2 years at 18 clinical sites this procedure. ► Prepublication history and to investigate the effect of bronchial thermoplasty Design The BTGR is an all-­comer, prospective, open-­label, additional supplemental material on severe asthma exacerbations, emergency de- multicentre study enrolling adult subjects indicated for and for this paper are available partment visits and hospitalisations. treated with BT. online. To view these files, ► One limitation of this study was that it was registry-­ Setting Eighteen centres in Spain, Italy, Germany, the please visit the journal online based and, thus, was a single-­arm study with no (http://​dx.​doi.​org/​10.​1136/​ UK, the Netherlands, the Czech Republic, South Africa and comparator rather than a randomised controlled bmjopen-​2021-​053854). Australia trial. Participants One hundred fifty-­seven subjects aged ► Another limitation is that the level of investigator ex- Received 26 May 2021 18 years and older who were scheduled to undergo BT Accepted 25 November 2021 perience with the bronchial thermoplasty procedure treatment for asthma. Subjects diagnosed with other varied between clinical sites and some sites were medical conditions which, in the investigator’s opinion, inexperienced with the conduct of clinical studies. made them inappropriate for BT treatment were excluded. ► The BTGR was also limited by a high attrition rate at Primary and secondary outcome measures Baseline 2 years post-­treatment; approximately one-­third of characteristics collected included demographics, Asthma enrolled subjects dropped out of the study. Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT), medication usage, forced expiratory volume in one second and forced vital capacity, medical history, INTRODUCTION comorbidities and 12-­month baseline recall data (severe Asthma is a chronic condition of the airways exacerbations (SE) and healthcare utilisation). SE incidence and healthcare utilisation were summarised at 1 and 2 characterised by airway inflammation, excess years post-­BT. mucus production, airway hyperresponsive- Results Subjects’ baseline characteristics were ness and airway remodelling. Ten per cent representative of persons with severe asthma. A of patients have severe, poorly controlled comparison of the proportion of subjects experiencing asthma with frequent symptoms despite events during the 12 months prior to BT to the 2-­year optimal therapy with inhaled corticoste- follow-­up showed a reduction in SE (90.3% vs 56.1%, roids (ICS) and long-­acting bronchodilators p<0.0001), emergency room visits (53.8% vs 25.5%, (LABA), and this group accounts for more p<0.0001) and hospitalisations (42.9% vs 23.5 %, than 80% of the healthcare costs associated p=0.0019). Reductions in asthma maintenance medication with the disease.1–3 © Author(s) (or their dosage were also observed. AQLQ and ACT scores Bronchial thermoplasty (BT) is the only employer(s)) 2021. Re-­use improved from 3.26 and 11.18 at baseline to 4.39 and 15.54 at 2 years, respectively (p<0.0001 for both AQLQ U.S. Food and Drug Adminsitration (FDA)-­ permitted under CC BY-­NC. No commercial re-­use. See rights and ACT). approved non-­ pharmacologic procedure and permissions. Published by Conclusions The BTGR demonstrates sustained approved for the treatment of asthma. It BMJ. improvement in clinical outcomes and reduction in is indicated for patients 18 years and older For numbered affiliations see asthma medication usage 2 years after BT in a real-­world with severe persistent asthma who is not end of article. population. This is consistent with results from other BT well controlled with ICS and LABA. During randomised controlled trials and registries and further the BT procedure, radiofrequency energy is Correspondence to supports improvement in asthma control after BT. used to heat the airway walls in a controlled Dr Alfons Torrego; ​atorrego@​santpau.​cat Trial registration number NCT02104856. manner. The mechanism of action may be, in Torrego A, et al. BMJ Open 2021;11:e053854. doi:10.1136/bmjopen-2021-053854 1 Open access part, a lasting reduction in airway smooth muscle mass treatment with the Alair System (Boston Scientific Corpo- after the procedure and downstream mechanical and ration, Marlborough, Massachusetts). Subjects diagnosed physiological actions resulting from this reduction.4–10 with other medical conditions which, in the investigator’s Reduction in airway smooth muscle has been shown to opinion, made them inappropriate for BT treatment be associated with clinical improvement seen in patients were excluded. All medications were administered as part undergoing BT.5 6 Other structural and immunohistolog- of the local standard of care asthma treatment and for BT ical changes, including reduction in reticular basement procedures; there were no additional medication require- membrane thickness, reduction in collagen type I deposi- ments mandated by this registry. tion and changes in neuroendocrine cells and bronchial nerve endings, may also contribute to clinical improve- Treatment ment.4 5 11 12 All BTGR subjects were scheduled to undergo three bron- Several randomised controlled clinical trials of BT choscopy procedures performed approximately 3 weeks have been carried out in patients with moderate to apart. BT treatments were administered using the Alair severe asthma—including the AIR (Asthma Intervention Bronchial Thermoplasty System (Boston Scientific, Marl- Research), RISA (Research In Severe Asthma) and AIR2 borough, Massachusetts) per FDA labelling by the investi- (Asthma Intervention Research 2) studies.13–19 All of these gators and as previously described.15 16 randomised controlled trials (RCTs) have concluded that BT is a safe and effective procedure. Subjects enrolled Follow-up in these studies experienced improvements in asthma BTGR subjects were instructed to report any adverse control following BT, including decreased numbers of events (AEs) occurring as a result of the BT procedure asthma exacerbations, emergency room (ER) visits for to clinic staff at any time. Subjects were evaluated at 6 asthma and hospitalisations as well as improved quality weeks following the third BT procedure (the end of the of life as measured by Asthma Quality of Life Question- treatment period) and at 6, 12, 18 and 24 months after naire (AQLQ) scores.16 Clinical improvements persisted completion of the treatment period. The 6-­month and to at least 5 years after the last BT treatment.20 21 Addi- 18-­month evaluations were performed either by phone or tionally, several recent studies have examined the effec- in the clinic office; the 12-­month and 24-­month evalua- tiveness of BT outside the confines of an RCT, including tions were performed as office visits. the PAS2 study in the USA and Canada22 and a study in Australia in severe asthmatics.23 Data from both of these studies suggest that BT is safe and effective in populations Outcome measures of patients who may have more severe asthma than those The primary endpoint of the BTGR study was the propor- included in the previous RCTs. tion of subjects who experienced severe asthma exacer- Nevertheless, additional data outside RCT studies can bations at 1 and 2 years following BT treatment, which provide reassurance that these results can be duplicated were compared with the proportion of subjects who in clinical practice. The Bronchial Thermoplasty Global experienced severe exacerbations during the 12-­month Registry (BTGR) was designed to collect outcome data period prior to BT. Severe exacerbations were defined in on subjects undergoing BT procedures in a ‘real-­world’ a manner consistent with the National Asthma Education setting. In this manuscript, we describe the clinical and Prevention Program (NAEPP) Guidelines for the outcomes for BTGR subjects over the 2 years following Diagnosis and Management of Asthma as a worsening of BT treatment. asthma symptoms requiring the use of systemic cortico- steroids (tablets, suspension or injection).24 For patients already taking maintenance systemic corticosteroids, a METHODS severe exacerbation was defined as a worsening of asthma Study design symptoms requiring any increase in daily dose of systemic BTGR is a prospective, open-­ label, single-­ arm, obser- corticosteroids. vational registry (​ clinicaltrials.​ gov) designed to collect Other outcome measures analysed in BTGR included outcome data as well as clinical and demographic char- procedural data (including procedure time, anaesthesia acteristics of patients undergoing BT treatment in the type, number of activations of the BT catheter and length ‘real-­world’ clinical setting. BTGR-­enrolled subjects from of hospital stay), the proportion and rate of emergency 23 January 2014 to 28 December 2016 at 18 centres in room (ER) visits during years 1 and 2 post-­BT, the propor- Spain, Italy, Germany, the UK, the Netherlands, the tion and rate of hospitalisations for asthma during years Czech Republic, South Africa and Australia, and the last 1 and 2 post-­BT, the proportion and rate of unscheduled patient completed follow-­up and exited the study on 26 office visits during years 1 and 2 post-­BT, respiratory AEs June 2019. occurring during both the treatment period and the post-­ treatment period, pulmonary function test results (FEV1), Study subjects use of asthma maintenance medications, AQLQ scores, Between 2014 and 2016, BTGR enrolled 157 subjects aged Asthma Control Test (ACT) scores and patient satisfac- 18 years and older who were scheduled to undergo BT tion survey scores. 2 Torrego A, et al. BMJ Open 2021;11:e053854. doi:10.1136/bmjopen-2021-053854 Open access AE monitoring Table 1 Baseline information and procedural A respiratory AE was defined as any sign, symptom, characteristics of subjects enrolled in the BTGR (N=157) illness, clinically significant abnormal laboratory value Variable All patients (N=157) or other adverse medical event associated with the respi- ratory system that appeared or worsened, regardless of Age (year) 49.8±12.7 (157) whether it was considered related to the BT procedure. Gender An AE was considered serious if it required or prolonged  Female 65.6% (103/157) hospitalisation, resulted in a permanent impairment of  Male 34.4% (54/157) body structure or function, required medical or surgical intervention to prevent such permanent damage or was Body mass index (kg/m2) 29.2±6.0 (156) life threatening or fatal. AEs were collected periproce- Medication usage durally (defined as the period beginning on the day of  ICS dose (μg/day)* 1721±1239 (150) the first BT procedure and ending 6 weeks after the last  LABA dose (μg/day)† 103.3±112.5 (125) BT procedure) and at each follow-­up visit in the post-­  SABA used 69.7% (106/152) treatment period.   Puffs per day for asthma 5.87±5.59 (106) symptoms Statistical analyses  OCS (prednisone) used 47.8% (75/157) Baseline demographics, clinical characteristics and outcomes were summarised with sample size, mean,   Mean dose (mg/day) 21.0±19.0 (75) SD, minimum and maximum for continuous variables  Omalizumab used 9.6% (15/157) and with proportions (numerator over denominator) Years since diagnosis 20.7±14.6 (155) for binary variables. To compare proportions, counts ERS/ATS guidelines on severe of events and means between baseline and 2 years, the asthma Fisher’s exact test, negative binomial test and t test were (ICS ≥2000 µg/day and LABA/ 95.5% (150/157) used, respectively. For the subgroup analyses, subgroups leukotriene modifiers) or ≥2 severe analysed were those based on gender, age (<40 and ≥40 exacerbations in 12 month prior to years), baseline body mass index (BMI) (≤30 and >30 kg/ first BT or m2) and smoking history as well as baseline AQLQ ≥1 hospitalisation in 12 months prior (≤4.0 and >4.0), baseline oral corticosteroid use, baseline to first BT or(post-­BD FEV1 <80% and postbronchodilator FEV1 % predicted (≤70% and>70%) FEV1/FVC<0.7) and number of complete catheter activations (≤140 and Patient questionnaires >140).25 A generalised linear mixed model with binomial  AQLQ 3.26±1.10 (148) error distribution was fit with factors of the subgroup,  ACT 11.18±4.01 (61) time and interaction of subgroup and time with subject as a random effect; if the interaction had a p value <0.10, Bronchoscopy information contrasts of time within subgroup and subgroup within  Number of complete activations 168.06±54.09 (157) time were performed to explore differences. SAS V.9.4  Number of incomplete activations 32.40±33.40 (151) (SAS Institute) was used for all analyses.  Number of total activations 199.23±74.98 (157) *Beclomethasone equivalent. Patient and public involvement †Salmeterol equivalent. Patients and the public were not involved in the design, ACT, Asthma Control Test; AQLQ, Asthma Quality of Life conduct, reporting or dissemination of this research. Questionnaire; BD, bronchodilator; BT, bronchial thermoplasty; BTGR, Bronchial Thermoplasty Global Registry; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; ICS, inhaled corticosteroids; LABA, long-­acting beta-­agonist; OCS, oral RESULTS corticosteroids; SABA, short-­acting beta-­agonist. Baseline demographics and clinical characteristics of BTGR subjects One hundred and fifty-­seven adult subjects (mean age Severe asthma exacerbations 49.8±12.7 years) underwent BT; 153 of these subjects During the 12 months prior to BT treatment, 140/155 had all three BT procedures. These subjects were 65.6% (90.3%) of BTGR subjects had a severe asthma exacerba- women with a BMI of 29.2±6.0 kg/m2 and had been diag- nosed with asthma for 20.7±14.6 years prior to BT treat- tion, requiring administration of systemic corticosteroids. ment. Subjects had a mean AQLQ score of 3.26±1.10, a Two years after BT, only 55/98 (56.1%) experienced exac- mean ACT score of 11.18±4.01 at baseline, and based on erbations (p<0.0001 vs baseline; figure 1, top panel), which the ERS/ATS Guidelines for Severe Asthma,26 95.5% of represents a 37.9% relative reduction in severe exacerba- subjects were considered severe asthmatics. These data tions by year 2 after BT. As shown in figure 1 (top panel), are summarised in table 1. the data for severe exacerbations from BTGR recapitulate Torrego A, et al. BMJ Open 2021;11:e053854. doi:10.1136/bmjopen-2021-053854 3 Open access Similar to the data for severe exacerbations, the data for both ER visits and hospitalisations from BTGR also recapitulates historical data for these endpoints from previous studies of BT, including the AIR, RISA, AIR2 and PAS2 studies (figure 1, middle and bottom panels). Finally, there was a smaller reduction in unscheduled office visits, including those to urgent care facilities, after BT treatment in the BTGR population. During the year prior to BT, 92/156 (59.0%) of BTGR subjects had unscheduled office visits, but this was reduced to 48/98 (49.0%) during year two after BT treatment (p=0.12 vs baseline). Lung function Spirometry was performed at baseline and at each yearly follow-­up visit for BTGR subjects (online supplemental table 1). As shown, both FEV1 and forced vital capacity remained stable over the 2-­year study period, suggesting that BT did not adversely affect lung function in BTGR subjects. Maintenance medication usage in BTGR subjects Asthma maintenance medication usage at baseline and at 6 months, 1 year and 2 years after BT treatment is shown in table 2. As shown, 2 years after BT treatment, reductions in several asthma maintenance medications compared with baseline were observed. Mean daily ICS dose had been reduced from 1721±1239 µg/day to 1217±912 µg/day (p=0.013), and, importantly, the proportion of subjects using maintenance oral corticosteroids (OCS) was signifi- cantly reduced from 47.8% to 24.8% by 2 years after BT (p=0.0002). The proportion of subjects using biologics was also reduced from 9.6% at baseline to 5.7% at 2 years after BT (p=0.045). Figure 1 Severe exacerbations (top), emergency room visits (middle) and hospitalisations (bottom) for asthma at baseline Quality of life measures and patient satisfaction and at years 1 and 2 after BT treatment in BTGR subjects. questionnaires Historical data from the AIR2 (Asthma Intervention Research Significant improvements were seen in both quality of 2) and PAS2 (Post-­FDA Approval Clinical Trial Eveluating Bronchial Thermoplasty in Severe Persistent Asthma) studies life measures in BTGR subjects. As shown in figure 2, are given for comparison. BT, bronchial thermoplasty; BTGR, mean AQLQ scores rose from 3.26±1.10 at baseline to Bronchial Thermoplasty Global Registry; ER, emergency 4.39±1.50 2 years after BT (p<0.0001), and at 2 years after room. BT, 35/56 (62.5%) of BTGR subjects were classified as AQLQ-­based responders to BT (defined as those subjects experiencing an increase in AQLQ score of ≥0.5 from historical data from previous studies of BT, including the baseline after treatment). Similarly, ACT scores rose AIR, RISA, AIR2 and PAS2 studies.14 16 19 20 22 27 from 11.18±4.01 at baseline to 15.54±6.21 2 years after BT (p<0.0001). Healthcare utilisation When asked at the 24-­month visit if they would undergo Healthcare utilisation was also reduced after BT treat- BT again and if they would recommend BT to a friend ment (figure 1, middle and bottom panels). In the 12 months or family member, 87.3% and 94.9% of subjects, respec- prior to BT, 53.8% of the BTGR subjects visited an ER tively, replied yes. for asthma symptoms. During year 2 after BT, only 25/98 (25.5%) subjects visited the ER for asthma symptoms Adverse events (p<0.0001 vs baseline). The total number of procedure-­related respiratory AEs During the 12 months prior to BT treatment, 67/156 occurring during the BTGR are summarised in table 3. (42.9%) of BTGR subjects were hospitalised for asthma During the treatment period, 71/157 (45.2%) subjects symptoms. However, during year 2, only 23/98 (23.5%) experienced procedure-­related respiratory AEs related were hospitalised (p=0.019 vs baseline). to the BT procedure and 44/157 (28.0%) of these were 4 Torrego A, et al. BMJ Open 2021;11:e053854. doi:10.1136/bmjopen-2021-053854 Open access Table 2 Asthma maintenance medication usage in BGTR subjects 6-­month 1-­year 2-­year P value Medication Baseline follow-­up follow-­up follow-­up BL versus 2 years ICS dose (μg/day)* 1721±1239 (150) 1564±1323 (72) 1533±1006 (56) 1217±912 (46) 0.013 LABA dose (μg/day)† 103.3±112.5 (125) 95.4±97.9 (63) 85.6±75.4 (49) 100.5±180.3 (35) 0.91 OCS (prednisone) used 47.8% (75/157) 35.4% (45/127) 23.3% (27/116) 24.8% (26/105) 0.0002  Dose (mg/day) 21.0±19.0 (75) 16.3±14.2 (45) 17.2±11.9 (27) 15.2±12.8 (26) 0.15 Biologic used 9.6% (15/157) 3.9% (5/127) 3.4% (4/116) 5.7% (6/105) 0.35  Omalizumab 9.6% (15/157) 3.9% (5/127) 3.4% (4/116) 2.9% (3/105) 0.045  Benralizumab 0.0% (0/157) 0.0% (0/127) 0.0% (0/116) 1.9% (2/105) 0.16  Mepolizumab 0.0% (0/157) 0.0% (0/127) 0.0% (0/116) 1.0% (1/105) 0.40 P values are from the Fisher’s exact test for medication usage and a t-­test for dosage. *Beclomethasone equivalent. †Salmeterol equivalent. BTGR, Bronchial Thermoplasty Global Registry; ICS, inhaled corticosteroids; LABA, long-­acting beta-­agonists; OCS, oral corticosteroids. considered serious. While 61/98 (62.2%) and 19/98 Responder and subgroup analysis (19.4%) experienced respiratory AE and serious AE Because of the small number of subjects enrolled in during year 2 after BT, none of these was related to the the BTGR, we were unable to perform a true responder BT procedure. A listing of specific AEs considered related analysis to identify likely responders to BT. However, we to BT is shown in table 4, and a listing of unrelated AEs is analysed several pairs of mutually exclusive subgroups presented in (online supplemental table 1). Importantly, of BT subjects to see whether BT treatment was effec- no deaths were reported during the course of this study. tive in reducing the per cent of subjects with severe exacerbations, ER visits and hospitalisations. These subgroup analyses further confirmed that after BT, BTGR subjects experienced significant improvements in all three endpoints; however, we were unable to identify a specific subgroup of subjects for whom BT was most effective (online supplemental figures 1 and 2). DISCUSSION Previous clinical trials of BT (including the AIR, AIR2 and RISA trials) have shown that the procedure is safe and effective, but the subjects enrolled in these clinical trials may not be representative of the most severe asthma cases considered for BT treatment in a ‘real-­ world’ clinical practice. A few recent publications have reported on BT in more severe asthmatics who were older and had worse baseline lung function and quality of life.5 7–9 23 28 29 The data indicated a clinical improvement post-­BT in these subjects as well as acceptable rates of AEs. The results presented here from the BTGR recapitulate the results from previously published studies and indicate that in the BTGR population, subjects undergoing treatment with BT experienced reductions in severe asthma exacerba- tions and other healthcare utilisation as well as reductions in asthma maintenance medication usage, particularly OCS. Additionally, clinically meaningful improvements Figure 2 Asthma control test (ACT) values (top panel) and in quality of life, measured by both ACT and AQLQ, were asthma quality of life questionnaire (AQLQ) (bottom panel) at seen out to 2 years after BT treatment in the BTGR popu- baseline and at years 1 and 2 after bronchial thermoplasty lation, and these improvements in quality of life measures (BT) treatment. *Significantly different than 12 months before are similar to those reported in studies of current biologic BT (baseline). treatments for asthma.30 Torrego A, et al. BMJ Open 2021;11:e053854. doi:10.1136/bmjopen-2021-053854 5 Open access Table 3 Total procedure-­related adverse events observed in BGTR subjects Adverse events Treatment period* 1 year† 2 years‡ Procedure-­related events  Respiratory adverse events 45.2% (71/157) 2.4% (3/127) 0.0% (0/98)  Respiratory serious adverse events 28.0% (44/157) 0.8% (1/127) 0.0% (0/98) *Events between the date of the first BT procedure and 42 days after the last BT procedure. †Events between 43 and 365+42 days after last BT procedure. Patients count in the denominator if they had any one of the events between 43 days and 365+42 days after the last BT procedure or had ≥335+42 days follow-­up after the last BT procedure. ‡Events between 365+43 and 730+42 days after last BT procedure. Patients count in the denominator if they had any one of the events between 365+43 days and 730+42 days after the last BT procedure or had ≥700+42 days follow-­up after the last BT procedure. BT, bronchial thermoplasty; BTGR, Bronchial Thermoplasty Global Registry. The data from the BTGR add to the already-­published (figure 1). This suggests that BT is still effective and safe body of evidence demonstrating the safety and durable for patients with very severe asthma. effectiveness of BT in a study population that is more However, this study had several important limitations representative of those seen in clinical practice outside that warrant discussion. Despite the lack of data defining the setting of RCTs, in which more restrictive inclusion patient populations that respond best to BT, several and exclusion criteria may not allow treatment of the recent guidelines have recommended BT treatment for most severe asthmatics. BTGR was an all-­comers registry specific subsets of asthmatics. Most recently, an expert study, and, therefore, there were few inclusion and exclu- consensus panel that examined the fundamental guiding sion criteria for enrolment when compared with many principles for severe asthma treatment-­identified BT as previous studies of BT, including the AIR, RISA, AIR2 the preferred treatment option for severe asthmatics and PAS2 studies. The more restrictive eligibility criteria suffering from non-­allergic, non-­eosinophilic (non-­TH2) employed in these previous studies ensured that many asthma with variable airflow obstruction as demonstrated potential subjects with very severe asthma who would by bronchodilator reversibility, who experience persistent normally be seen in the course of ‘real-­world’ clinical symptoms despite treatment with triple therapy. These practice were not included in those clinical trials of BT; guidelines also state that BT should be considered an however, these very ill subjects were not excluded from alternative treatment option for patients with severe BTGR. Despite the enrolment of subjects with more eosinophilic or allergic asthma, particularly in patients severe asthma in BTGR, improvements in asthma control who do not respond to treatment with anti-­IgE and/or as indicated by reductions in severe exacerbations, ER anti-­IL5 therapies.31 A recent study by Langton et al indi- visits and hospitalisations during BTGR, which were cated that, in fact, BT treatment was as effective as mepo- comparable to those observed in the previous studies lizumab treatment in this patient population.32 However, Table 4 Reported asthma-­related or bronchial thermoplasty-­related adverse events in BTGR subjects Event All (N) Treatment period (N) 1 year (N) 2 years (N) Asthma (wheezing/bronchospasm) 293 100 115 71 Lower respiratory infection (bronchitis, pneumonia) 82 28 35 17 Upper respiratory tract infection (influenza, viral, sinusitis) 53 16 26 7 Dyspnoea/breathlessness 21 13 2 3 Haemoptysis 13 12 1 0 Cough 13 5 6 1 Mucous production/plugging 13 10 3 0 Atelectasis 11 11 0 0 Laryngitis, laryngospasm, candidiasis 11 7 1 3 Chest pain/discomfort 8 6 0 2 Respiratory distress/respiratory failure 5 2 3 0 Pneumothorax 2 2 0 0 *In addition, one patient was reported as having bronchomalacia in the treatment period. This was presumed to be a new bronchoscopic finding rather than a sequela of treatment. BTGR, Bronchial Thermoplasty Global Registry. 6 Torrego A, et al. BMJ Open 2021;11:e053854. doi:10.1136/bmjopen-2021-053854 Open access 18 additional data on asthma phenotypes that respond best Respiratory Department, Ruhrlandklinik—West German Lung Center, University to BT are required, and, unfortunately, baseline data on Medicine Essen, Essen, Germany 19 Boston Scientific Corp, Marlborough, Massachusetts, USA asthma phenotype were not routinely collected as a part 20 Respiratory Department, Central Manchester University Hospitals NHS Foundation of the BTGR. Thus, we are unable to address the critical Trust, Manchester, UK question of whether BT is particularly effective for specific phenotypes in this study population. Another limitation Acknowledgements The authors wish to thank Carlos Martinez-­Rivera (Hospital of this registry was that the clinical study sites had varying Universitari Germans Trias i Pujol, CIBERES, Badalona, Barcelona/ES) for significant degrees of experience with the conduct of clinical studies, contributions to data collection during the conduct of this study. The authors also wish to thank the following employees of Boston Scientific, the sponsor of this and this may have contributed to the high patient attri- study: Frances Nolan, RN for contributions to clinical trial management and Jennifer tion rate seen in this study. Additionally, not all baseline L. Olson, PhD for editorial assistance with this manuscript. measurements were required to be collected, and some Contributors Study design, study coordination and manuscript first and final draft: sites did not routinely collect this information, leading to AT, FJFH and RN. Overal responsible of the content and guarantor: AT. Patients’ variability in the number of subjects that could be anal- recruitment and follow-­up: AT, FJFH, RN, AM-­F, LP, NF, SB, MN, SG, MB, KD, FAG, PV, ysed based on these measures. Finally, the manufacturer DL, JFA, DF, PIB, DS, CS and KD. Trial manager: GMG. Data analysis: EMcM. Final version of the manuscript: AT, FJFH, RN, AM-­F, LP, NF, SB, MN, SG, MB, KD, FAG, PV, of the Alair BT system (Boston Scientific Corporation) DL, JFA, DF, PIB, DS, CS, GMG, EMcM and KD. sponsored this study, and one of the authors of this manu- Funding This study was sponsored by Boston Scientific Corporation, Marlborough, script is a full-­time employee of the study sponsor. MA, USA. In conclusion, the data from the BTGR demonstrate Competing interests FH received personal fees for ad board activities and lecture sustained improvement in clinical outcomes and reduction fees from Pulmonx, BTG, Olympus, and Uptake. AMF reports the receipt of grants in asthma medication usage 2 years after BT in a real-­world from Boston Scientific during the conduct of this study. LP reports personal fees population. This is consistent with the results from other BT and others from AstraZeneca, grants and other fees from GlaxoSmithKline, grants and personal fees from Esteve, personal fees and other fees from Boehringer, RCTs and registries and further supports improvement in other fees from Teva, personal fees and other fees from Novartis, other fees from asthma control after BT, suggesting that BT is an effective Chiesi, grants from Menarini, personal fees from MSD and Boston Scientific outside and safe therapeutic option for severe asthmatics. Future the submitted work. MN reports other fees from Boston Scientific. MB reports personal fees from Roche and Boehringer-­Ingelheim outside the submitted work. randomised controlled studies designed to further investi- DF reports other fees from Boston Scientific during the conduct of the study. PIB gate the responses to BT in participants with specific asthma reports grants, non-­financial support, and other fees from Boston Scientific during phenotypes and/or studies designed to identify specific the conduct of the study. KD reports grants from Boston Scientific outside the responders to BT would be beneficial. Additional clin- submitted work. GMG is a full-­time employee of Boston Scientific, the sponsor of this study. RN reports grants and personal fees from Boston Scientific outside the ical studies designed to investigate whether BT treatment submitted work. can reduce the use of OCS in asthmatics and/or compare Patient consent for publication Not applicable. responses to BT to those seen with the newer biologic medi- cations are also warranted. Ethics approval This study involves human participants and was approved by The study was approved by the Ethics committee at each participating site. These committees were as follows: Comité Ético de Investigación Clínica Hospital General Author affiliations Universitario Gregorio Maranon for Hospital General Universitario Gregorio Maranon 1 Respiratory Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (number 347/13), Comité Ético de Investigación Clínica de la Fundacio de Gestio 2 Thoraxklinik, University of Heidelberg, Heidelberg, Baden-­Württemberg, Germany Sanitaria del Hospital de la Santa Creu I Sant Pau de Barcelona for Hospital de la 3 Respiratory Department, Hospital Josep Trueta, Girona, Catalunya, Spain Santa Creu i Sant Pau (#13/173), Ethics Committee at General University Hospital, 4 Respiratory Department, Hospital General Universitario Gregorio Marañon-­Facultad Prague for Klinika Tuberkulozy a Respiracnich Onemocneni (number 1882/13 S-­IV/ de Medicina Universidad Complutense, Madrid, Spain ZP), Ethics Committee of the Medical Faculty HD for Thoraxklinik, University of 5 AUSL-­IRCCS Reggio Emilia Pulmonology Unit, IRCCS Reggio Emilia Pulmonology Heidelberg (number S-­613/2013), NHS Greater Glasgow and Clyde Health Board for Unit, Santa Maria Nuova, Italy Gartnavel General Hospital (number GC14RM003; 14/NW/0068), University Hospital 6 Respiratory Department, Gartnavel General Hospital, Glasgow, UK of South Manchester NHS Foundation Trust for Wythenshawe Hospital University 7 Respiratory Department, Azienda Ospedaliera Spedali Civili di Brescia, Brescia, of Manchester (number 2014AS005; 14/NW/0068), Provincial Ethics Committee of Lombardia, Italy the Province of Brescia for Azienda Ospedaliera Spedali Civili di Brescia (number 8 Respiratory Department, Università Politecnica delle Marche, Ancona, Marche, Italy NP 1513), Comitato Etico Provinciale di Reggio Emilia for Arcispedale Santa Maria 9 Respiratory Department, University of Cape Town, Cape Town, South Africa Nuova (number 2015/0027339), HREC Faculty of Heath Sciences Universiy of 10 Pulmonology Department, Hospital Universitari Germans Trias i Pujol—CIBERES, Cape Town for University of Cape Town (number 723/2014), Fundación Jiménez Badalona, Barcelona, Spain Diaz Comité Ético de Investigación Clínica for Hospital Universitario Fundacion 11 Respiratory Department, Klinika Tuberkulozy a Respiracnich Onemocneni, Prague, Jimenez Diaz (number EOH 2014/35), Comitè d’Ètica de la Investigació del Hospital Czech Republic U. Germans Trias i Pujol for Hospital Germans Trias I Puyol (number PI-­14-­049), 12 Respiratory Department, Frankston Hospital Peninsula Health, Frankston, Victoria, Independent Ethics Committee of Marche Region (CER) for Azienda Ospedaliero Australia Universitaria Ospedali Riuniti (number 2015 0380 OR), Peninsula Health HREC for 13 Respiratory Department, Hospital Universitario Fundacion Jimenez Diaz— Peninsula Health (number LRR/15/PH/12), Royal Brisbane and Women’s Hospital CIBERES IIS-­FJD, Madrid, Spain HREC for Royal Brisbane and Women’s Hospital (number HREC/15/QRBW/448), 14 Respiratory Department, Royal Brisbane and Women’s Hospital—Brisbane/AUS, Regensburg University Ethics Committee for University Hospital Regensburg Brisbane, Queensland, Australia (number 15-­103-­0256), Ethics Committee Faculty Of Medicine Of Duisburg-­ 15 Department of Respiratory Medicine, Amsterdam University Medical Centers, Essen University for Ruhrlandklinik, Westdeutsches Lungenzentrum (number Amsterdam, The Netherlands 16-­6850-­BO), Ethics Committee - Medical Faculty, Bonn for Universitätsklinikum 16 Department of Cardiology and Pneumology, University of Bonn, Medizinische Bonn (number 061/16), and AMC Medical Ethics Review Committee for Academic Klinik II, Bonn, Germany Medical Center (number W16_186 # 16.243). Participants gave informed consent to 17 Respiratory Department, University Hospital Regensburg, Regensburg, Bayern, participate in the study before taking part. Germany Provenance and peer review Not commissioned; externally peer reviewed. Torrego A, et al. BMJ Open 2021;11:e053854. doi:10.1136/bmjopen-2021-053854 7 Open access Data availability statement Data are available upon reasonable request. The data 12 Salem H I, Biardel S, Chakir J, et al. Effects of bronchial thermoplasty and study protocol for this clinical trial may be made available to other researchers (Bt) on airways in severe persistent asthma. American Journal of in accordance with the Boston Scientific Data Sharing Policy (https://www.​ Respiratory and Critical Care Medicine 2014;189. bostonscientific.​com/​en-​US/​data-​sharing-​requests.​html). For questions related to 13 Castro M, Cox G. Asthma outcomes from bronchial thermoplasty in the AIR2 trial. Am J Respir Crit Care Med 2011;184:743–4. Boston Scientific Data Sharing Requests contact ​ClinicalSolutions@​bsci.​com. 14 Castro M, Rubin A, Laviolette M, et al. Persistence of effectiveness Supplemental material This content has been supplied by the author(s). It has of bronchial thermoplasty in patients with severe asthma. Ann Allergy not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been Asthma Immunol 2011;107:65–70. peer-­reviewed. Any opinions or recommendations discussed are solely those 15 Castro M, Musani AI, Mayse ML, et al. Bronchial thermoplasty: a novel technique in the treatment of severe asthma. Ther Adv Respir of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and Dis 2010;4:101–16. responsibility arising from any reliance placed on the content. Where the content 16 Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: includes any translated material, BMJ does not warrant the accuracy and reliability long-­term safety and effectiveness in patients with severe persistent of the translations (including but not limited to local regulations, clinical guidelines, asthma. J Allergy Clin Immunol 2013;132:1295–302. terminology, drug names and drug dosages), and is not responsible for any error 17 Castro M, Rubin AS, Laviolette M, et al. Two-­Year persistence of and/or omissions arising from translation and adaptation or otherwise. effect of bronchial thermoplasty (Bt) in patients with severe asthma: AIR2 trial. Chest2010;138:768A. Open access This is an open access article distributed in accordance with the 18 Wechsler ME, Shah PL, Niven R, et al. Benefits of bronchial Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which thermoplasty persist out to 5 years in patients with severe asthma. permits others to distribute, remix, adapt, build upon this work non-­commercially, American Journal of Respiratory and Critical Care Medicine and license their derivative works on different terms, provided the original work is 2013;187. properly cited, appropriate credit is given, any changes made indicated, and the use 19 Pavord I. 5-­Year safety of bronchial thermoplasty demonstrated in patients with severe refractory asthma: research in severe asthma is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. (RISA) trial. Am J Respir Crit Care Med 2011;183:A6382. 20 Castro M, Rubin AS, Laviolette M, et al. 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