Bronchial thermoplasty decreases airway remodeling by inhibiting autophagy via the AMPK/mTOR signaling pathway.

Bronchial thermoplasty (BT), an effective treatment for severe asthma, requires heat to reach the airway to reduce the mass of airway smooth muscle cells (ASMCs). Autophagy is involved in the pathological process of airway remodeling in patients with asthma. However, it remains unclear whether autophagy participates in controlling airway remodeling induced by BT. In this study, we aim to elucidate the autophagy-mediated molecular mechanisms in BT. Our study reveal that the number of autophagosomes and the level of alpha-smooth muscle actin (α-SMA) fluorescence are significantly decreased in airway biopsy tissues after BT. As the temperature increased, BT causes a decrease in cell proliferation and a concomitant increase in the apoptosis of human airway smooth muscle cells (HASMCs). Furthermore, increase in temperature significantly downregulates cellular autophagy, autophagosome accumulation, the LC3II/LC3I ratio, and Beclin-1 expression, upregulates p62 expression, and inhibits the AMPK/mTOR pathway. Furthermore, cotreatment with AICAR (an AMPK agonist) or RAPA (an mTOR antagonist) abolishes the inhibition of autophagy and attenuates the increase in the apoptosis rate of HASMCs induced by the thermal effect. Therefore, we conclude that BT decreases airway remodeling by blocking autophagy induced by the AMPK/mTOR signaling pathway in HASMCs.

Exhaled breath analyses for bronchial thermoplasty in severe asthma patients.

BACKGROUND: Bronchial thermoplasty (BT) is a bronchoscopic treatment for severe asthma. Although multiple trials have demonstrated clinical improvement after BT, optimal patient selection remains a challenge and the mechanism of action is incompletely understood. The aim of this study was to examine whether exhaled breath analysis can contribute to discriminate between BT-responders and non-responders at baseline and to explore pathophysiological insights of BT. METHODS: Exhaled breath was collected from patients at baseline and six months post-BT. Patients were defined as responders or non-responders based on a half point increase in asthma quality of life questionnaire scores. Gas chromatography-mass spectrometry was used for volatile organic compounds (VOCs) detection and analyses. Analytical workflow consisted of: 1) detection of VOCs that differentiate between responders and non-responders and those that differ between baseline and six months post-BT, 2) identification of VOCs of interest and 3) explore correlations between clinical biomarkers and VOCs. RESULTS: Data was available from 14 patients. Nonanal, 2-ethylhexanol and 3-thujol showed a significant difference in intensity between responders and non-responders at baseline (p = 0.04, p = 0.01 and p = 0.03, respectively). After BT, no difference was found in the compound intensity of these VOCs. A negative correlation was observed between nonanal and IgE and BALF eosinophils (r = -0.68, p < 0.01 and r = -0.61, p = 0.02 respectively) and 3-thujol with BALF neutrophils (r = -0.54, p = 0.04). CONCLUSIONS: This explorative study identified discriminative VOCs in exhaled breath between BT responders and non-responders at baseline. Additionally, correlations were found between VOC's and inflammatory BALF cells. Once validated, these findings encourage research in breath analysis as a non-invasive easy to apply technique for identifying airway inflammatory profiles and eligibility for BT or immunotherapies in severe asthma.

Use of Quantitative CT Imaging to Identify Bronchial Thermoplasty Responders.

BACKGROUND: Bronchial thermoplasty (BT) is a treatment for patients with poorly controlled, severe asthma. However, predictors of treatment response to BT are defined poorly. RESEARCH QUESTION: Do baseline radiographic and clinical characteristics exist that predict response to BT? STUDY DESIGN AND METHODS: We conducted a longitudinal prospective cohort study of participants with severe asthma receiving BT across eight academic medical centers. Participants received three separate BT treatments and were monitored at 3-month intervals for 1 year after BT. Similar to prior studies, a positive response to BT was defined as either improvement in Asthma Control Test results of ≥ 3 or Asthma Quality of Life Questionnaire of ≥ 0.5. Regression analyses were used to evaluate the association between pretreatment clinical and quantitative CT scan measures with subsequent BT response. RESULTS: From 2006 through 2017, 88 participants received BT, with 70 participants (79.5%) identified as responders by Asthma Control Test or Asthma Quality of Life Questionnaire criteria. Responders were less likely to undergo an asthma-related ICU admission in the prior year (3% vs 25%; P = .01). On baseline quantitative CT imaging, BT responders showed less air trapping percentage (OR, 0.90; 95% CI, 0.82-0.99; P = .03), a greater Jacobian determinant (OR, 1.49; 95% CI, 1.05-2.11), greater SD of the Jacobian determinant (OR, 1.84; 95% CI, 1.04-3.26), and greater anisotropic deformation index (OR, 3.06; 95% CI, 1.06-8.86). INTERPRETATION: To our knowledge, this is the largest study to evaluate baseline quantitative CT imaging and clinical characteristics associated with BT response. Our results show that preservation of normal lung expansion, indicated by less air trapping, a greater magnitude of isotropic expansion, and greater within-lung spatial variation on quantitative CT imaging, were predictors of future BT response. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01185275; URL: www. CLINICALTRIALS: gov.

Patient profiling to predict response to bronchial thermoplasty in patients with severe asthma.

Bronchial thermoplasty is the only device-based nonpharmacological treatment approach for severe asthma. Current guidelines are cautious in recommending bronchial thermoplasty because of unknown patient response prediction. Recent research on bronchial thermoplasty includes up-to-date, state-of-the-art, and recent-advances reviews. However, these reviews provide a broad and general discussion on equipment, technique, patient selection, and patient management, with little evaluation of the predictors of a beneficial response. Predicting an optimal response to bronchial thermoplasty in patients with severe asthma remains elusive. The lack of reliable predictive markers means that bronchial thermoplasty remains a last-line treatment and makes profiling for predicting the response or efficacy a topic of study. Genetic changes are associated with airway remodeling. A gap in the literature exists regarding patient profiling to predict the response to bronchial thermoplasty in patients with severe asthma. Therefore, recently published omics data and genetic associations regarding the response to bronchial thermoplasty therapy should be reviewed. We present an up-to-date review of recent publications profiling the response to bronchial thermoplasty in patients with severe asthma.

Safety and efficacy of bronchial thermoplasty in Australia 5 years post-procedure.

BACKGROUND AND OBJECTIVE: Outside clinical trials, there is limited long-term data following bronchial thermoplasty (BT). In a cohort of real-world severe asthmatics in an era of biological therapy, we sought to evaluate the safety and efficacy of BT 5 years post-treatment. METHODS: Every patient treated with BT at two Australian tertiary centres were recalled at 5 years, and evaluated by interview and record review, Asthma Control Questionnaire (ACQ), spirometry and high-resolution CT Chest. CT scans were interpreted using the modified Reiff and BRICS CT scoring systems for bronchiectasis. RESULTS: Fifty-one patients were evaluated. At baseline, this cohort had a mean age of 59.0 ± 11.8 years, mean ACQ of 3.0 ± 1.0, mean FEV1 of 55.5 ± 18.8% predicted, and 53% were receiving maintenance oral steroids in addition to triple inhaler therapy. At 5 years, there was a sustained improvement in ACQ scores to 1.8 ± 1.0 (p < 0.001). Steroid requiring exacerbation frequency was reduced from 3.8 ± 3.6 to 1.0 ± 1.6 exacerbations per annum (p < 0.001). 44% of patients had been weaned off oral steroids. No change in spirometry was observed. CT scanning identified minor degrees of localized radiological bronchiectasis in 23/47 patients with the modified Reiff score increasing from 0.6 ± 2.6 at baseline to 1.3 ± 2.5 (p < 0.001). However, no patients exhibited clinical features of bronchiectasis, such as recurrent bacterial infection. CONCLUSION: Sustained clinical benefit from BT at 5 years was demonstrated in this cohort of very severe asthmatics. Mild, localized radiological bronchiectasis was identified in a portion of patients without clinical features of bronchiectasis.

Effect of bronchial thermoplasty on static and dynamic lung compliance and resistance in patients with severe persistent asthma.

RATIONALE: Bronchial thermoplasty (BT) reduces severity and frequency of bronchoconstriction and symptoms in severe, persistent asthmatics although it is usually not associated with change in spirometric variables. Other than spirometry. there are almost no data on changes in lung mechanics following BT. OBJECTIVE: To assess lung static and dynamic lung compliance (Cst,L and Cdyn,L, respectively) and static and dynamic lung resistance (Rst,L and Rdyn,L, respectively) before and after BT in severe asthmatics using the esophageal balloon technique. METHODS: Rdyn,L and Cdyn,L were measured at respiratory frequencies up to 145 breaths/min, using the esophageal balloon technique in 7 patients immediately before and 12-50 weeks after completing a series of 3 BT sessions. RESULTS: All patients experienced improved symptoms within a few weeks following completion of BT. Pre-BT, all patients exhibited frequency dependency of lung compliance, with mean Cdyn,L decreasing to 63% of Cst,L at maximum respiratory rates. Post-BT, Cst,L did not change significantly from pre-thermoplasty values, while Cdyn,L diminished to 62%% of Cst,L. In 4 of 7 patients, post-BT values of Cdyn,L were consistently higher than pre-BT over the range of respiratory rates. RL in 4 of 7 patients during quiet breathing and at higher respiratory frequencies decreased following BT. CONCLUSIONS: Patients with severe persistent asthma exhibit increased resting lung resistance and frequency dependence of compliance, the magnitudes of which are ameliorated in some patients following bronchial thermoplasty and associated with variable change in frequency dependence of lung resistance. These findings are related to asthma severity and may be related to the heterogeneous and variable nature of airway smooth muscle modeling and its response to BT.

Therapeutic response to bronchial thermoplasty: toward feasibility of patient selection based on modeling predictions.

Bronchial thermoplasty (BT) is a treatment for moderate-to-severe asthma in which the airway smooth muscle layer is targeted directly using thermal ablation. Although it has been shown to be safe and effective in long-term follow-up, questions remain about its mechanism of action, patient selection, and optimization of protocol based on structural phenotype. Using a cohort of 20 subjects who underwent thermoplasty and assessment by computed tomography (CT), we demonstrate that response to BT can be feasibly predicted based on pretreatment airway dimensions that inform a subject-specific computational model. Analysis revealed the need for CT assessment at total lung capacity, rather than functional residual capacity, which was less sensitive to the effects of BT. Final model predictions compared favorably with observed outcomes in terms of airway caliber and asthma control, suggesting that this approach could form the basis of improved clinical practice.NEW & NOTEWORTHY Bronchial thermoplasty is a treatment for asthma that targets the airway smooth muscle directly. We demonstrate the feasibility and constraints of predicting patient-specific response to thermoplasty using a computational model informed by pretreatment CT scans at different lung volumes. Predictions are compared with functional outcomes and posttreatment CT scans. This has the potential to form the basis for improved clinical practice.

Anxiety level in severe asthmatics undergoing bronchial thermoplasty procedure: An observational study.

Bronchial thermoplasty (BT) is one of the novel approved modalities in treating severe asthmatics to overcome their exacerbating symptoms such as increased anxiety. The purpose of this study was to evaluate anxiety level among severe asthmatics while undergoing BT procedure. This was an observational study where subjects self-evaluated their overall anxiety level using the burns anxiety inventory (BAI) questionnaire at baseline and prior to each of three BT treatments (broncho thermoplasty procedure 1, broncho thermoplasty procedure 2, and broncho thermoplasty procedure 3). The BAI questionnaire consisted of three different categories with each category having specific symptoms. Categories were grouped as: Anxious feelings, Anxious thoughts, and Physical symptoms. Subjects' Asthma Control Tests were also collected for analysis before and after the BT procedure. A total of 17 subjects with a mean age of 55.9 ±â€…14.5 years participated in the study. Fifty three percent were females (n = 9) and 41.2% (n = 7) were on prescribed anxiety medications. There was a significant drop in the patients' overall BAI anxiety level over time, P < .0001, in Anxious feelings (P = .0001), anxious thoughts (P = .001), and physical symptoms (P = .025). When analyzing the change in anxiety level among those who were not on prescribed anxiety medications, significant drop in overall anxiety level and in the subcategories were also noted. (P < .05). In addition, ACT scores showed a significant improvement (post vs pre) (18.5 ±â€…4.0 vs 13.3 ±â€…6.3, P = .03; Cohen's d = 0.73). This study shows the effectiveness of BT in decreasing severe asthmatic anxiety levels from baseline to last BT treatment and this benefit was mostly noted in those who were not on any anxiety medications. A limitation of this study is that all subjects were recruited from a single center. Therefore, to further validate the study findings, a multi-center study needs to be conducted with a larger sample size.

Immediate complications and flow volume changes during treatment phases of bronchial thermoplasty: a single-center descriptive study.

INTRODUCTION: Bronchial thermoplasty (B.T.) is a therapeutic bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle mass. Immediate complications of B.T. include acute exacerbation of bronchial asthma, upper and lower respiratory tract infection, hemoptysis, among others. Our study assessed these immediate adverse events and the changes in forced expiratory volume in one second (FEV1%) measured four hours after each procedure from baseline. The study also aimed to examine the number of activations during each cycle of treatment and its correlation to the corresponding change in FEV1% from baseline. METHODS: A case-series analysis of 17 patients who underwent B.T. between 2014 and 2019 was done. Demographic, clinical characteristics, including pre and post-BT FEV1% measures, and the number of activations were obtained. RESULTS: Acute exacerbation of asthma was the commonest complication accounting for 33%, 57%, and 75% after BT1, BT2, and BT3, respectively. There was deterioration in FEV1% after each treatment phase, the most significant being in BT3. There was no correlation between the number of heat activations with the change in FEV1% from baseline. CONCLUSION: The number of activations in B.T. does not correlate with the immediate deterioration in FEV1%, although exacerbation of asthma is the commonest complication post-B.T.

A clinical and canine experimental study in small-airway response to bronchial thermoplasty: Role of the neuronal effect.

BACKGROUND: The effects of bronchial thermoplasty (BT) on smooth muscle (SM) and nerves in small airways are unclear. METHODS: We recruited 15 patients with severe refractory asthma, who received BT treatment. Endobronchial optical-coherence tomography (EB-OCT) was performed at baseline, 3 weeks' follow-up and 2 years' follow-up to evaluate the effect of BT on airway structure. In addition, we divided 12 healthy beagles into a sham group and a BT group, the latter receiving BT on large airways (inner diameter >3 mm) of the lower lobe. The dogs' lung lobes were resected to evaluate histological and neuronal changes of the treated large airways and untreated small airways 12 weeks after BT. RESULTS: Patients receiving BT treatment had significant improvement in Asthma Control Questionnaire (ACQ) scores and significant reduction in asthma exacerbations. EB-OCT results demonstrated a notable increase in inner-airway area (Ai) and decrease in airway wall area percentage (Aw%) in both large (3rd-to 6th-generation) and small (7th-to 9th-generation) airways. Furthermore, the animal study showed a significant reduction in the amount of SM in BT-treated large airways but not in untreated small airways. Protein gene product 9.5 (PGP9.5)-positive nerves and muscarinic receptor 3 (M3 receptor) expression in large and small airways were both markedly decreased throughout the airway wall 12 weeks after BT treatment. CONCLUSIONS: BT significantly reduced nerves, but not SM, in small airways, which might shed light on the mechanism of lung denervation by BT.

Transcriptome genetic differences between responders and non-responders before bronchial thermoplasty.

BACKGROUND: Bronchial thermoplasty (BT) is an endoscopic therapy used for the treatment of refractory asthma. Some predictive factors, for example the number of activations and severity of disease at baseline, have been used to determine the effectiveness of BT in treating patients with asthma. The aim of the present study was to comprehensively analyze RNA samples from the airway bronchial tissues of patients with severe asthma treated by BT, and to characterize each patient as a BT responder or non-responder. METHODS: Eight patients with severe asthma scheduled to undergo BT and bronchus biopsies were recruited before the procedures were conducted. Extracted RNA samples from bronchial tissues were sequenced and differential gene expression analysis was carried out.Results/discussion: Subjects with Asthma Quality of Life Questionnaire score changes ≥0.5 for a period of 12 months were considered BT responders. Non-responders had score changes <0.5 for 12 months. Histopathology findings were similar to those reported previously, and no significant differences in the expression of α-smooth muscle actin and protein gene product 9.5 were observed between responders and non-responders. Transcriptome analysis at baseline identified 67 genes that were differentially expressed between responders and non-responders, including SLPI, MMP3, and MUC19, which were upregulated in responders. Although the differentially expressed gene products may have conflicting effects, genes in the airway epithelium and extracellular matrix of patients with severe asthma may determine the BT response. Our results identified possible transcriptomic changes that could be used to identify BT responders.

Bronchial Thermoplasty in Patients With Severe Asthma at 5 Years: The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma Study.

BACKGROUND: Bronchial thermoplasty is a device-based treatment for subjects ≥ 18 years of age with severe asthma poorly controlled with inhaled corticosteroids and long-acting beta-agonists. The Post-FDA Approval Clinical Trial Evaluating Bronchial Thermoplasty in Severe Persistent Asthma (PAS2) study collected data on patients with severe asthma undergoing this procedure. RESEARCH QUESTION: What are the 5-year efficacy and safety results in patients with severe asthma who have undergone bronchial thermoplasty? STUDY DESIGN AND METHODS: This was a prospective, open-label, observational, multicenter study conducted in the United States and Canada. Subjects 18 to 65 years of age who were taking inhaled corticosteroids ≥ 1,000 µg/d (beclomethasone or equivalent) and long-acting beta-agonists ≥ 80 µg/d (salmeterol or equivalent) were included. Severe exacerbations, hospitalization, ED visits, and medication usage were evaluated for the 12 months prior to and at years 1 through 5 posttreatment. Spirometry was evaluated at baseline and at years 1 through 5 posttreatment. RESULTS: A total of 284 subjects were enrolled at 27 centers; 227 subjects (80%) completed 5 years of follow-up. By year 5 posttreatment, the proportion of subjects with severe exacerbations, ED visits, and hospitalizations was 42.7%, 7.9%, and 4.8%, respectively, compared with 77.8%, 29.4%, and 16.1% in the 12 months prior to treatment. The proportion of subjects on maintenance oral corticosteroids decreased from 19.4% at baseline to 9.7% at 5 years. Analyses of subgroups based on baseline clinical and biomarker characteristics revealed a statistically significant clinical improvement among all subgroups. INTERPRETATION: Five years after treatment, subjects experienced decreases in severe exacerbations, hospitalizations, ED visits, and corticosteroid exposure. All subgroups demonstrated clinically significant improvement, suggesting that bronchial thermoplasty improves asthma control in different asthma phenotypes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT01350336; URL: www. CLINICALTRIALS: gov.

Bronchial Thermoplasty Global Registry (BTGR): 2-year results.

OBJECTIVES: Bronchial thermoplasty (BT) is a device-based treatment for subjects ≥18 years with severe asthma not well controlled with inhaled corticosteroids and long-acting beta-agonists. The Bronchial Thermoplasty Global Registry (BTGR) collected real-world data on subjects undergoing this procedure. DESIGN: The BTGR is an all-comer, prospective, open-label, multicentre study enrolling adult subjects indicated for and treated with BT. SETTING: Eighteen centres in Spain, Italy, Germany, the UK, the Netherlands, the Czech Republic, South Africa and Australia PARTICIPANTS: One hundred fifty-seven subjects aged 18 years and older who were scheduled to undergo BT treatment for asthma. Subjects diagnosed with other medical conditions which, in the investigator's opinion, made them inappropriate for BT treatment were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Baseline characteristics collected included demographics, Asthma Quality of Life Questionnaire (AQLQ), Asthma Control Test (ACT), medication usage, forced expiratory volume in one second and forced vital capacity, medical history, comorbidities and 12-month baseline recall data (severe exacerbations (SE) and healthcare utilisation). SE incidence and healthcare utilisation were summarised at 1 and 2 years post-BT. RESULTS: Subjects' baseline characteristics were representative of persons with severe asthma. A comparison of the proportion of subjects experiencing events during the 12 months prior to BT to the 2-year follow-up showed a reduction in SE (90.3% vs 56.1%, p<0.0001), emergency room visits (53.8% vs 25.5%, p<0.0001) and hospitalisations (42.9% vs 23.5 %, p=0.0019). Reductions in asthma maintenance medication dosage were also observed. AQLQ and ACT scores 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 and ACT). CONCLUSIONS: The BTGR demonstrates sustained improvement in clinical outcomes and reduction in asthma medication usage 2 years after BT in a real-world population. This is consistent with results from other BT randomised controlled trials and registries and further supports improvement in asthma control after BT. TRIAL REGISTRATION NUMBER: NCT02104856.

Safety of delivering bronchial thermoplasty in two treatment sessions.

BACKGROUND: Bronchial thermoplasty (BT) is a novel endoscopic therapy for severe asthma. Traditionally it is performed in three separate treatment sessions, targeting different portions of the lung, and each requires an anaesthetic and hospital admission. Compression of treatment into 2 sessions would present a more convenient alternative for patients. In this prospective observational study, the safety of compressing BT into two treatment sessions was compared with the traditional 3 treatment approach. METHODS: Sixteen patients meeting ERS/ATS criteria for severe asthma consented to participate in an accelerated treatment schedule (ABT), which treated the whole left lung followed by the right lung four weeks later. The short-term outcomes of these patients were compared with 37 patients treated with conventional BT scheduling (CBT). The outcome measures used to assess safety were (1) the requirement to remain in hospital beyond the electively planned 24-h admission and (2) the need for re-admission for any cause within of 30 days of treatment. RESULTS: The total number of radiofrequency activations delivered in the ABT group was similar to CBT (187 ± 21 vs 176 ± 40, p = 0.326). With ABT, 11 in 31 admissions (37.9%) required prolonged admission due to wheezing, compared to 5.4% with CBT (p = 0.0025). The mean hospital length of stay with ABT was 1.8 ± 1.3 days, compared to 1.1 ± 0.4 days (p < 0.001). ICU monitoring was required on 5 occasions with ABT (16.1%), compared to 0.9% with CBT (p = 0.002). Subgroup analysis demonstrated that females were more likely to require prolonged admission (OR 11.6, p = 0.0025). The 30-day hospital readmission rate was similar for both groups (6.4% vs 5.4%, p = 0.67). All patients made a complete recovery after treatment with similar outcomes at the 6-month follow-up reassessment. CONCLUSION: This study demonstrates that ABT results in greater short-term deterioration in lung function associated with a greater risk of prolonged hospital and ICU stay, predominantly affecting females. Therefore, in females, these risks need to be balanced against the convenience of fewer treatment sessions. In males, it may be an advantage to compress treatment.

Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes.

BACKGROUND: Bronchial thermoplasty regulates structural abnormalities involved in airway narrowing in asthma. In the present study we aimed to investigate the effect of bronchial thermoplasty on histopathological bronchial structures in distinct asthma endotypes/phenotypes. METHODS: Endobronchial biopsies (n = 450) were collected from 30 patients with severe uncontrolled asthma before bronchial thermoplasty and after 3 sequential bronchial thermoplasties. Patients were classified based on blood eosinophils, atopy, allergy and smoke exposure. Tissue sections were assessed for histopathological parameters and expression of heat-shock proteins and glucocorticoid receptor. Proliferating cells were determined by Ki67-staining. RESULTS: In all patients, bronchial thermoplasty improved asthma control (p < 0.001), reduced airway smooth muscle (p = 0.014) and increased proliferative (Ki67 +) epithelial cells (p = 0.014). After bronchial thermoplasty, airway smooth muscle decreased predominantly in patients with T2 high asthma endotype. Epithelial cell proliferation was increased after bronchial thermoplasty in patients with low blood eosinophils (p = 0.016), patients with no allergy (p = 0.028) and patients without smoke exposure (p = 0.034). In all patients, bronchial thermoplasty increased the expression of glucocorticoid receptor in epithelial cells (p = 0.018) and subepithelial mesenchymal cells (p = 0.033) and the translocation of glucocorticoid receptor in the nucleus (p = 0.036). Furthermore, bronchial thermoplasty increased the expression of heat shock protein-70 (p = 0.002) and heat shock protein-90 (p = 0.001) in epithelial cells and decreased the expression of heat shock protein-70 (p = 0.009) and heat shock protein-90 (p = 0.002) in subepithelial mesenchymal cells. The effect of bronchial thermoplasty on the expression of heat shock proteins -70 and -90 was distinctive across different asthma endotypes/phenotypes. CONCLUSIONS: Bronchial thermoplasty leads to a diminishment of airway smooth muscle, to epithelial cell regeneration, increased expression and activation of glucocorticoid receptor in the airways and increased expression of heat shock proteins in the epithelium. Histopathological effects appear to be distinct in different endotypes/phenotypes indicating that the beneficial effects of bronchial thermoplasty are achieved by diverse molecular targets associated with asthma endotypes/phenotypes.

Safety and effectiveness of bronchial thermoplasty after 10 years in patients with persistent asthma (BT10+): a follow-up of three randomised controlled trials.

BACKGROUND: Bronchial thermoplasty is an endoscopic treatment for uncontrolled asthma. Previous randomised clinical trials have shown that bronchial thermoplasty reduces severe exacerbations in people with asthma. However, the long-term efficacy and safety of bronchial thermoplasty beyond 5 years is unknown. The BT10+ study aimed to investigate the efficacy and safety of bronchial thermoplasty after 10 or more years of follow-up. METHODS: BT10+ was an international, multicentre, follow-up study of participants who were previously enrolled in the AIR, RISA, and AIR2 trials and who had 10 or more years of follow-up since bronchial thermoplasty treatment. Data on patient demographics, quality of life, lung function, CT scans (AIR2 participants only), severe exacerbations, and health-care use during the previous year were collected at the BT10+ 10-year outcomes study visit. The primary effectiveness endpoint was durability of the thermoplasty treatment effect, determined by comparing the proportion of participants who had severe exacerbations during the first and fifth years after bronchial thermoplasty treatment with the proportion of participants who had severe exacerbations during the 12-month period before the BT10+ visit. The primary safety endpoint was the absence of clinically significant post-treatment respiratory image changes after bronchial thermoplasty, defined as bronchiectasis or bronchial stenosis as confirmed by pulmonary volumetric high-resolution CT scan at the BT10+ visit (AIR2 participants only). All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT03243292. The last patient was enrolled on Dec 11, 2018. The last patient completed follow-up on Jan 10, 2019. FINDINGS: The BT10+ study enrolled 192 (45%) of the 429 participants who were enrolled in the AIR, RISA, and AIR2 trials. The BT10+ participants comprised 136 who received bronchial thermoplasty (52% of the 260 participants who received bronchial thermoplasty in the original trials), and 56 sham or control participants (33% of 169 from the original trials). 18 (32%) sham or control participants received bronchial thermoplasty after the previous trials concluded. The participants included in BT10+ were followed for 10·8-15·6 years (median 12·1 years) post-treatment. Baseline characteristics were similar between participants enrolled in BT10+ and those not enrolled. Participants treated with bronchial thermoplasty had similar proportions of severe exacerbations at the BT10+ visit (34 [25%] of 136 participants) compared with 1 year (33 [24%] of 135 participants; difference 0·6%, 95% CI -9·7 to 10·8) and 5 years (28 [22%] of 130 participants; difference 3·5%, -6·7% to 13·6) after treatment. Quality of life measurements and spirometry were similar between year 1, year 5, and the BT10+ visit. At the BT10+ study visit, pulmonary high-resolution CT scans from AIR2 participants treated with bronchial thermoplasty showed that 13 (13%) of 97 participants had bronchiectasis. When compared with baseline high-resolution CT scans, six (7%) of 89 participants treated with bronchial thermoplasty who did not have bronchiectasis at baseline had developed bronchiectasis after treatment (5 classified as mild, 1 classified as moderate). Participants treated with bronchial thermoplasty after the original study and participants in the sham or control group also had reductions in severe exacerbations at the BT10+ visit compared with baseline. INTERPRETATION: Our findings suggest that efficacy of bronchial thermoplasty is sustained for 10 years or more, with an acceptable safety profile. Therefore, bronchial thermoplasty is a long-acting therapeutic option for patients with asthma that remains uncontrolled despite optimised medical treatment. FUNDING: Boston Scientific.

Clinical and histopathologic predictors of therapeutic response to bronchial thermoplasty in severe refractory asthma.

BACKGROUND: Phenotypes and endotypes predicting optimal response to bronchial thermoplasty (BT) in patients with severe asthma remain elusive. OBJECTIVE: Our aim was to compare the clinical characteristics and hallmarks of airway inflammation and remodeling before and after BT in responder and partial responder patients with severe asthma refractory to oral steroids and to omalizumab. METHODS: In all, 23 patients with severe refractory asthma were divided into BT responders (n = 15) and BT partial responders (n = 8), according to the decrease in asthma exacerbations at 12 months after BT. Clinical parameters were compared at baseline and 12 months after BT, and hallmarks of airway inflammation and remodeling were analyzed by immunohistochemistry in bronchial biopsy specimens before and 3 months after BT. RESULTS: At baseline, the BT responders were around 8 years younger than the BT partial responders (P = .02) and they had a greater incidence of atopy, higher numbers of blood eosinophils (both P = .03) and IgE levels, higher epithelial IFN-α expression, and higher numbers of mucosal eosinophils and IL-33-positive cells (P ≤ .05). A reduction in blood eosinophil count, serum IgE level, type 2 airway inflammation, and numbers of mucosal IL-33-positive cells and mast cells associated with augmented epithelial MUC5AC and IFN-α/ß immunostaining was noted after BT in responders, whereas the numbers of mucosal IL-33-positive cells were augmented in BT partial responders. Most of these changes were correlated with clinical parameters. Subepithelial membrane thickening and airway smooth muscle area were similar in the 2 patient groups at baseline and after BT. CONCLUSION: By reducing allergic type 2 inflammation and increasing epithelial MUC5AC and anti-viral IFN-α/ß expression, BT may enhance host immune responses and thus attenuate exacerbations and symptoms in BT responders. Instead, targeting IL-33 may provide a clinical benefit in BT partial responders.

Efficacy of bronchial thermoplasty in patients with severe asthma.

Objective: To investigate the efficacy and safety of bronchial thermoplasty (BT) in clinical practice in adults with severe, refractory asthma.Methods: Prospective, single-center, open, observational study comprising patients with uncontrolled asthma (asthma control questionnaire (ACQ) >1.5) and/or frequent exacerbations despite treatment with at least high dose inhaled corticosteroids plus a second controller. Efficacy outcomes was change from baseline 4, 8, 12 and 24 months in FEV1, FVC and FEV1/FVC ratio, asthma control questionnaire (ACQ) score and asthma quality of life score (mini-AQLQ). Results are presented as median with interquartile ranges (IQR). The following were recorded as adverse events: Un-scheduled health care contacts, rescue courses of oral corticosteroid (OCS) and/or antibiotics for exacerbation for exacerbations/respiratory tract infections (RTI).Results: Six-teen patients were enrolled (nine males, median age 50 years; 14 followed for 24 months). Compared to baseline, an improvement in FEV1, FVC, FEV1/FVC ratio, mini-AQLQ and ACQ was observed, i.e.FEV1 (IQR) 1.98 L (1.65-2.45) vs. 2.45 L (2.09-2.93) (p = 0.006), FVC (IQR) 3.23 L (2.76-4.05) vs. 3.75 L (3.22-4.36) (p = 0.041), FEV1/FVC 0.60 (IQR: 0.55-0.70) vs. 0.66 (IQR: 0.63-0.71) (p = 0.016), mini-AQLQ 4.0 (IQR: 3.2-4.9) vs. 5.6 (IQR 4.5-6.5) (p = 0.008, and ACQ 2.9 (IQR: 2.1-3.7) versus 1.5 (IQR 1.0-2.4) (p = 0.004). On the other hand, an increase was observed in unscheduled visits (p = 0.005), as well as use of OCS and antibiotics (p = 0.009 and p = 0.003, respectively).Conclusion: BT in adults with severe asthma improved ACQ, mini-AQLQ and lung function, but resulted in an increased frequency of unscheduled doctor-visits and rescue courses of OCS and antibiotics.

Bronchial thermoplasty reduces ventilation heterogeneity measured by multiple breath nitrogen washout.

BACKGROUND: Despite demonstrated symptomatic benefit from bronchial thermoplasty (BT), the underlying pathophysiological benefits have been uncertain. The purpose of the present study was to relate clinical benefit after BT to changes in lung physiology, focusing on ventilation homogeneity assessed using multiple breath nitrogen washout (MBNW), and how this may be affected by changes in airway volume and resistance. METHODS: Consecutive patients (n = 21) with severe asthma scheduled for BT, were evaluated at baseline, 6 weeks and 6 months after completion of treatment. Assessments included the Asthma Control Questionnaire (ACQ), medication usage, exacerbation frequency, spirometry, plethysmography and MBNW. Eighteen of these patients underwent detailed CT evaluation for the estimation of airway volume at baseline and then after the left lung had received BT treatment but prior to right lung treatment. Data are mean ± STDEV. RESULTS: Patients responded to BT with an improvement in ACQ from 3.4 ± 0.8 at baseline to 2.0 ± 1.1 at 6 months (p < 0.001). Steroid requiring exacerbations fell from 3.1 ± 2.9 in the 6 months prior to BT to 1.4 ± 1.7 following BT (p < 0.001). Significant reductions in maintenance oral steroid dosing and short acting beta agonist use were observed. Airway volume measured by CT scanning significantly increased after treatment. The FEV1 improved from 1.34 ± 0.65 l to 1.52 ± 0.76 l (p = 0.024). The Residual Volume fell from 2.87 ± 0.89 l to 2.71 ± 0.93 l (p = 0.008) and Total Airway Resistance (Raw) from 10.58 ± 6.56 to 7.64 ± 3.74 cmH2O.s.l-1 (p = 0.020). The Lung Clearance Index (LCI) was 187 ± 63% predicted at baseline and improved after treatment from 12.7 ± 3.3 to 11.8 ± 2.4 (p = 0.049). The improvement in LCI correlated with the improvement in Raw (r = 0.463, p = 0.035). CONCLUSION: Clinical benefit after BT is accompanied by improvements in lung physiology, including normalisation of lung homogeneity that seems to be driven by airway dilation and reduced resistance.