Bronchial Thermoplasty Induced Airway Smooth Muscle Reduction and Clinical Response in Severe Asthma:The TASMA Randomized Trial

RATIONALE: Bronchial Thermoplasty (BT) is a bronchoscopic treatment for severe asthma targeting airway smooth muscle (ASM). Observational studies have shown ASM mass reduction after BT but appropriate control groups are lacking. Furthermore, as treatment response is variable, identifying optimal candidates for BT treatment is important. AIMS: First, to assess the effect of BT on ASM mass and second, to identify patient characteristics that correlate with BT-response. METHODS: Severe asthma patients (n=40) were randomized to immediate (n=20) or delayed (n=20) BT-treatment. Prior to randomization, clinical, functional, blood and airway biopsy data were collected. In the delayed control group, re-assessment, including biopsies, was performed after 6 months of standard clinical care, followed by BT. In both groups, post-BT data including biopsies were obtained after 6 months. ASM mass (% positive desmin or α-smooth muscle actin area in the total biopsy) was calculated with automated digital analyses software. Associations between baseline characteristics and Asthma Control and Asthma Quality of Life Questionnaire (ACQ/AQLQ) improvement were explored. RESULTS: Median ASM mass decreased by >50% in the immediate BT group (n=17) versus no change in the delayed control group (n=19) (p=0.0004). In the immediate group ACQ scores improved with -0.79 (-1.61;0.02 IQR) compared to 0.09 (-0.25;1.17 IQR) in the delayed group (p=0.006). AQLQ scores improved with 0.83 (-0.15;1.69 IQR) versus -0.02 (-0.77;0.75 IQR) (p=0.04). Treatment response in the total group (n=35) was positively associated with serum IgE and eosinophils, but not with baseline ASM mass. CONCLUSION: ASM mass significantly decreases after BT when compared to a randomized non-BT treated control group. Treatment response was associated with serum IgE and eosinophil levels but not with ASM mass. Clinical trial registration available at www.clinicaltrials.gov, ID:NCT0222539

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Propofol and Remifentanil Sedation for Bronchial Thermoplasty: A Prospective Cohort Trial

Bronchial thermoplasty (BT) is a rapidly emerging bronchoscopic treatment for patients with moderate-to-severe asthma. Different sedation strategies are currently used, ranging from mild midazolam sedation to general anesthesia requiring tracheal intubation. The aim of this study was to assess the feasibility, safety, and both patients' and bronchoscopists' satisfaction with propofol and remifentanil sedation administered by specialized sedation anesthesiology nurses during BT in severe asthma patients. A prospective observational cohort study in BT-treated severe asthma patients of the TASMA trial was designed. Patients were asked to rate their overall BT procedure satisfaction and tolerance with propofol/remifentanil sedation using a visual analogue scale (VAS) ranging from 0 to 10. Similarly, bronchoscopists were asked to rate patient cooperation and tolerance. Sedation-associated adverse events and the number of BT activations were recorded. Thirty-two BT procedures in 13 severe asthma patients were performed under moderate target-controlled infusion (TCI) propofol/remifentanil sedation. Patients' median VAS scores were as follows: overall satisfaction 9.6 (interquartile range [IQR] 8.5-10.0), dyspnea 0.0 (IQR 0.0-0.6), pain 0.1 (IQR 0.0-1.0), cough 0.5 (IQR 0.0-2.1), and anxiety 0.1 (IQR 0.0-0.7). Bronchoscopists' median VAS scores were as follows: overall patient cooperation 9.1 (IQR 8.5-9.6), dyspnea 0.3 (IQR 0.0-0.9), pain 0.2 (IQR 0.0-1.3), cough 1.2 (IQR 0.7-2.0), and discomfort 0.6 (IQR 0.3-1.5). All patients were willing to undergo the procedure again and would recommend this form of sedation to their best friend. One case of conversion to general anesthesia occurred and no serious adverse events were reported. Moderate sedation with propofol and remifentanil TCI provided by specialized sedation anesthesiology nurses is feasible and safe and results in high satisfaction rates of both patients and bronchoscopist

Optical coherence tomography and confocal laser endomicroscopy in pulmonary diseases

Purpose of review Current imaging techniques (X-ray, computed tomography scan, ultrasound) have limitations in the identification and quantification of pulmonary diseases, in particular, on highly detailed level. The purpose of this review is to provide an overview of the current knowledge of innovative light-and laser-based imaging techniques that might fill this gap. Recent findings Optical coherence tomography (OCT) and confocal laser endomicroscopy (CLE) are high-resolution imaging techniques, which, combined with bronchoscopy, provide 'near histology' detailed imaging of the airway wall, lung parenchyma, mediastinal lymph nodes, and pulmonary vasculature. This article reviews the technical background of OCT and CLE, summarizes study results, and discusses its potential clinical applications for various pulmonary diseases. Summary Although investigational at the moment, OCT and CLE are promising innovative high-resolution optical imaging techniques for the airway wall, lung parenchyma, mediastinal lymph nodes, and pulmonary vasculature. Clinical applications might contribute to improved disease identification and quantification, guidance for interventions/biopsies, and patient selection for treatments. Development of validated identification and quantification image-analysis systems is key for the future application of these imaging techniques in pulmonary medicin

Acute Radiological Abnormalities after Bronchial Thermoplasty: A Prospective Cohort Trial

Background: Bronchial thermoplasty (BT) is a novel treatment for severe asthma based on radiofrequency energy delivery to the larger airways. Although impressive radiological abnormalities have been reported, the incidence, pattern, and behavior over time of acute radiological abnormalities following BT are not well established. Objective: To assess the incidence pattern and behavior over time of acute radiological abnormalities following BT. Methods: This is a prospective, observational imaging study of severe asthma patients participating in the TASMA trial. Imaging of the lung (chest X-ray and/or computed tomography [CT]) was performed routinely before and directly after BT, within 6 weeks and at 6 months' follow-up. Results: Thirty-four chest X-rays were performed within <5 h following 34 BT procedures in 12 patients. In 91% of cases, radiological abnormalities were seen, designated as peribronchial consolidations (97%) and/or atelectasis (29%). Ultra-low-dose (ULD) chest CTs were performed following 16 BT procedures showing abnormalities in all. Four different radiological patterns were identi-fied: peribronchial consolidations with surrounding ground glass opacities (94%), atelectasis (38%), partial bronchial occlusions (63%), and bronchial dilatations (19%). No bronchoscopic intervention was needed. At 6 months' follow-up, in a single patient, high-resolution chest CT showed a focal bronchiectasis in a single airway. Conclusions: There is a high incidence of acute radiological abnormalities after BT. Four distinct radiological patterns can be identified on ULD chest CT, which resolve without clinical impact in virtually all cases. (C) 2017 The Author(s) Published by S. Karger AG, Base

Resistance of the respiratory system measured with forced oscillation technique (FOT) correlates with bronchial thermoplasty response

BACKGROUND: Bronchial Thermoplasty (BT) is an endoscopic treatment for severe asthma using radiofrequency energy to target airway remodeling including smooth muscle. The correlation of pulmonary function tests and BT response are largely unknown. Forced Oscillation Technique (FOT) is an effort-independent technique to assess respiratory resistance (Rrs) by using pressure oscillations including small airways. AIM: To investigate the effect of BT on pulmonary function, assessed by spirometry, bodyplethysmography and FOT and explore associations between pulmonary function parameters and BT treatment response. METHODS: Severe asthma patients recruited to the TASMA trial were analyzed in this observational cohort study. Spirometry, bodyplethysmography and FOT measurements were performed before and 6 months after BT. Asthma questionnaires (AQLQ/ACQ-6) were used to assess treatment response. RESULTS: Twenty-four patients were analyzed. AQLQ and ACQ improved significantly 6 months after BT (AQLQ 4.15 (±0.96) to 4.90 (±1.14) and ACQ 2.64 (±0.60) to 2.11 (±1.04), p = 0.004 and p = 0.02 respectively). Pulmonary function parameters remained stable. Improvement in FEV1 correlated with AQLQ change (r = 0.45 p = 0.03). Lower respiratory resistance (Rrs) at baseline (both 5 Hz and 19 Hz) significantly correlated to AQLQ improvement (r = - 0.52 and r = - 0.53 respectively, p = 0.01 (both)). Borderline significant correlations with ACQ improvement were found (r = 0.30 p = 0.16 for 5 Hz and r = 0.41 p = 0.05 for 19 Hz). CONCLUSION: Pulmonary function remained stable after BT. Improvement in FEV1 correlated with asthma questionnaires improvement including AQLQ. Lower FOT-measured respiratory resistance at baseline was associated with favorable BT response, which might reflect targeting of larger airways with BT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02225392; Registered 26 August 2014

Optical coherence tomography for identification and quantification of human airway wall layers

High-resolution computed tomography has limitations in the assessment of airway wall layers and related remodeling in obstructive lung diseases. Near infrared-based optical coherence tomography (OCT) is a novel imaging technique that combined with bronchoscopy generates highly detailed images of the airway wall. The aim of this study is to identify and quantify human airway wall layers both ex-vivo and in-vivo by OCT and correlate these to histology. Patients with lung cancer, prior to lobectomy, underwent bronchoscopy including in-vivo OCT imaging. Ex-vivo OCT imaging was performed in the resected lung lobe after needle insertion for matching with histology. Airway wall layer perimeters and their corresponding areas were assessed by two independent observers. Airway wall layer areas (total wall area, mucosal layer area and submucosal muscular layer area) were calculated. 13 airways of 5 patients were imaged by OCT. Histology was matched with 51 ex-vivo OCT images and 39 in-vivo OCT images. A significant correlation was found between ex-vivo OCT imaging and histology, in-vivo OCT imaging and histology and ex-vivo OCT imaging and in-vivo OCT imaging for all measurements (p < 0.0001 all comparisons). A minimal bias was seen in Bland-Altman analysis. High inter-observer reproducibility with intra-class correlation coefficients all above 0.90 were detected. OCT is an accurate and reproducible imaging technique for identification and quantification of airway wall layers and can be considered as a promising minimal-invasive imaging technique to identify and quantify airway remodeling in obstructive lung disease

Bronchial Thermoplasty-Induced Acute Airway Effects Assessed with Optical Coherence Tomography in Severe Asthma

Background: Bronchial thermoplasty (BT) is an endoscopic treatment for severe asthma targeting airway smooth muscle (ASM) with radiofrequent energy. Although implemented worldwide, the effect of BT treatment on the airways is unclear. Optical coherence tomography (OCT) is a novel imaging technique, based on near-infrared light, that generates high-resolution cross-sectional airway wall images. Objective: To assess the safety and feasibility of OCT in severe asthma patients and determine acute airway effects of BT by OCT and compare these to the untreated right middle lobe (RML). Methods: Severe asthma patients were treated with BT (TASMA trial). During the third BT procedure, OCT imaging was performed immediately following BT in the airways of the upper lobes, the right lower lobe treated 6 weeks prior, and the untreated RML. Results: 57 airways were imaged in 15 patients. No adverse events occurred. Three distinct OCT patterns were discriminated: low-intensity scattering pattern of (1) bronchial and (2) peribronchial edema and (3) high-intensity scattering pattern of epithelial sloughing. (Peri)bronchial edema was seen in all BT-treated airways, and less pronounced in only 1/3 of the RML airways. These effects extended beyond the ASM layer and more distal than the directly BT-treated areas and were reduced, but not resolved, after 6 weeks. Epithelial sloughing occurred in 11/14 of the BT-treated airways and was absent in untreated RML airways. Conclusions: Acute BT effects can be safely assessed with OCT and 3 distinct patterns were identified. The acute effects extended beyond the targeted ASM layer and distal of directly BT-treated airway areas, suggesting that BT might also target smaller distal airways