Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: Clinical and histopathologic correlations

doi:10.1016/j.jaci.2016.08.009

Journal of Allergy and Clinical Immunology

Volume 139, Issue 4, April 2017, Pages 1176-1185

https://doi.org/10.1016/j.jaci.2016.08.009 Get rights and content

Background

The effectiveness of bronchial thermoplasty (BT) has been reported in patients with severe asthma, yet its effect on different bronchial structures remains unknown.

Objective

We sought to examine the effect of BT on bronchial structures and to explore the association with clinical outcome in patients with severe refractory asthma.

Methods

Bronchial biopsy specimens (n = 300) were collected from 15 patients with severe uncontrolled asthma before and 3 months after BT. Immunostained sections were assessed for airway smooth muscle (ASM) area, subepithelial basement membrane thickness, nerve fibers, and epithelial neuroendocrine cells. Histopathologic findings were correlated with clinical parameters.

Results

BT significantly improved asthma control and quality of life at both 3 and 12 months and decreased the numbers of severe exacerbations and the dose of oral corticosteroids. At 3 months, this clinical benefit was accompanied by a reduction in ASM area (median values before and after BT, respectively: 19.7% [25th-75th interquartile range (IQR), 15.9% to 22.4%] and 5.3% [25th-75th IQR], 3.5% to 10.1%, P < .001), subepithelial basement membrane thickening (4.4 μm [25th-75th IQR, 4.0-4.7 μm] and 3.9 μm [25th-75th IQR, 3.7-4.6 μm], P = 0.02), submucosal nerves (1.0 ‰ [25th-75th IQR, 0.7-1.3 ‰] immunoreactivity and 0.3 ‰ [25th-75th IQR, 0.1-0.5 ‰] immunoreactivity, P < .001), ASM-associated nerves (452.6 [25th-75th IQR, 196.0-811.2] immunoreactive pixels per mm² and 62.7 [25th-75th IQR, 0.0-230.3] immunoreactive pixels per mm², P = .02), and epithelial neuroendocrine cells (4.9/mm² [25th-75th IQR, 0-16.4/mm²] and 0.0/mm² [25th-75th IQR, 0-0/mm²], P = .02). Histopathologic parameters were associated based on Asthma Control Test scores, numbers of exacerbations, and visits to the emergency department (all P ≤ .02) 3 and 12 months after BT.

Conclusion

BT is a treatment option in patients with severe therapy-refractory asthma that downregulates selectively structural abnormalities involved in airway narrowing and bronchial reactivity, particularly ASM, neuroendocrine epithelial cells, and bronchial nerve endings.

Section snippets

Subjects

Fifteen adult patients (27-69 years of age) who met the American Thoracic Society criteria for severe refractory asthma (American Thoracic Society/European Respiratory Society criteria)¹⁶ were recruited at the Pneumology A Department of the Bichat University Hospital (Paris, France) between January and December 2013 (Table I). Selection criteria were patients with uncontrolled severe asthma, as assessed by an Asthma Control Test (ACT) score of 15 or less, despite optimal management and maximal

Clinical effects of BT

Clinical and airway functional parameters were examined before and 3 and 12 months after BT (Table I). Although 6 of the 15 BT-treated patients with severe asthma still experienced uncontrolled asthma at 3 months, we found overall significantly higher scores on the ACT and AQLQ (P < .001 for both comparisons) and a lower number of severe exacerbations (P < .001), visits to the emergency department (P < .001), hospitalization for asthma (P < .01), and ICU visits (P < .001) than those measured

Discussion

The present study was aimed at investigating the clinical benefit of BT in patients with severe refractory asthma and at determining which alterations in the different bronchial structures were associated with clinical improvement.

BT significantly improved asthma control, as assessed by daily symptoms (ACT; +52%), rate of severe exacerbations, hospitalizations for asthma, ICU stays, and emergency department visits. These effects were accompanied by a significant reduction in maintenance doses

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Exhaled breath analyses for bronchial thermoplasty in severe asthma patients
2024, Respiratory Medicine
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.
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.
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).
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.
Airway wall extracellular matrix changes induced by bronchial thermoplasty in severe asthma
2024, Journal of Allergy and Clinical Immunology
Airway remodeling is a prominent feature of asthma, which involves increased airway smooth muscle mass and altered extracellular matrix composition. Bronchial thermoplasty (BT), a bronchoscopic treatment for severe asthma, targets airway remodeling.
We sought to investigate the effect of BT on extracellular matrix composition and its association with clinical outcomes.
This is a substudy of the TASMA trial. Thirty patients with severe asthma were BT-treated, of whom 13 patients were treated for 6 months with standard therapy (control group) before BT. Demographic data, clinical data including pulmonary function, and bronchial biopsies were collected. Biopsies at BT-treated and nontreated locations were analyzed by histological and immunohistochemical staining. Associations between histology and clinical outcomes were explored.
Six months after treatment, it was found that the reticular basement membrane thickness was reduced from 7.28 μm to 5.74 μm (21% relative reduction) and the percentage area of tissue positive for collagen increased from 26.3% to 29.8% (13% relative increase). Collagen structure analysis revealed a reduction in the curvature frequency of fibers. The percentage area positive for fibulin-1 and fibronectin increased by 2.5% and 5.9%, respectively (relative increase of 124% and 15%). No changes were found for elastin. The changes in collagen and fibulin-1 negatively associated with changes in FEV₁ reversibility.
Besides reduction of airway smooth muscle mass, BT has an impact on reticular basement membrane thickness and the extracellular matrix arrangement characterized by an increase in tissue area occupied by collagen with a less dense fiber organization. Both collagen and fibulin-1 are negatively associated with the change in FEV₁ reversibility.
Patient profiling to predict response to bronchial thermoplasty in patients with severe asthma
2023, Respiratory Investigation
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.
An underlying mechanism behind interventional pulmonology techniques for refractory asthma treatment: Neuro-immunity crosstalk
2023, Heliyon
Asthma is a common disease that seriously threatens public health. With significant developments in bronchoscopy, different interventional pulmonology techniques for refractory asthma treatment have been developed. These technologies achieve therapeutic purposes by targeting diverse aspects of asthma pathophysiology. However, even though these newer techniques have shown appreciable clinical effects, their differences in mechanisms and mutual commonalities still deserve to be carefully explored. Therefore, in this review, we summarized the potential mechanisms of bronchial thermoplasty, targeted lung denervation, and cryoablation, and analyzed the relationship between these different methods. Based on available evidence, we speculated that the main pathway of chronic airway inflammation and other pathophysiologic processes in asthma is sensory nerve-related neurotransmitter release that forms a “neuro-immunity crosstalk” and amplifies airway neurogenic inflammation. The mechanism of completely blocking neuro-immunity crosstalk through dual-ablation of both efferent and afferent fibers may have a leading role in the clinical efficacy of interventional pulmonology in the treatment of asthma and deserves further investigation.
Eosinophils and tissue remodeling: Relevance to airway disease
2023, Journal of Allergy and Clinical Immunology
The ability of human tissue to reorganize and restore its existing structure underlies tissue homeostasis in the healthy airways, but in disease can persist without normal resolution, leading to an altered airway structure. Eosinophils play a cardinal role in airway remodeling both in health and disease, driving epithelial homeostasis and extracellular matrix turnover. Physiological consequences associated with eosinophil-driven remodeling include impaired lung function and reduced bronchodilator reversibility in asthma, and obstructed airflow in chronic rhinosinusitis with nasal polyps. Given the contribution of airway remodeling to the development and persistence of symptoms in airways disease, targeting remodeling is an important therapeutic consideration. Indeed, there is early evidence that eosinophil attenuation may reduce remodeling and disease progression in asthma. This review provides an overview of tissue remodeling in both health and airway disease with a particular focus on eosinophilic asthma and chronic rhinosinusitis with nasal polyps, as well as the role of eosinophils in these processes and the implications for therapeutic interventions. Areas for future research are also noted, to help improve our understanding of the homeostatic and pathological roles of eosinophils in tissue remodeling, which should aid the development of targeted and effective treatments for eosinophilic diseases of the airways.
Effect of bronchial thermoplasty on static and dynamic lung compliance and resistance in patients with severe persistent asthma
2023, Respiratory Medicine
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.
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.
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.
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. R_L in 4 of 7 patients during quiet breathing and at higher respiratory frequencies decreased following BT.
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.

View all citing articles on Scopus

: Supported in part by Boston Scientific, Marlborough, Mass.

: Disclosure of potential conflict of interest: M. Pretolani receives grant support from MedImmune. G. Thabut serves as a consultant for GlaxoSmithKline and AstraZeneca and travel support from AstraZeneca. P. Chanez received an honorarium and personal fees from Boston Scientific; serves on the board for Chiesi, Novartis, AstraZeneca, GlaxoSmithKline, TEVA, Boston Scientific, ALK-Abelló, and Sanofi; receives grant support from Roche, AstraZeneca and Jannsen; and receives payments for lectures from Novartis, Boston Scientific, AstraZeneca, Chiesi, and ALK-Abelló. M. Aubier receives grant support from AstraZeneca, GlaxoSmithKline, Roche, and Boston Scientific. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: These authors contributed equally to this work.

View full text

Asthma and lower airway diseaseEffectiveness of bronchial thermoplasty in patients with severe refractory asthma: Clinical and histopathologic correlations

Background

Objective

Methods

Results

Conclusion

Section snippets

Subjects

Clinical effects of BT

Discussion

Lancet

J Allergy Clin Immunol

Chest

Respir Med

Ann Allergy Asthma Immunol

Chest

J Allergy Clin Immunol

Lab Invest

Curr Opin Pharmacol

Severe refractory asthma: an update

Eur Respir Rev

Monoclonal antibodies for the treatment of refractory asthma

Curr Opin Pulm Med

Asthma phenotypes: the evolution from clinical to molecular approaches

Nat Med

How variability in clinical phenotypes should guide research into disease mechanisms in asthma

Ann Am Thorac Soc

Noneosinophilic asthma in children: relation with airway remodelling

Eur Respir J

Lung damage and airway remodelling in severe asthma

Clin Exp Allergy

Asthma control during the year after BT

N Engl J Med

Safety and efficacy of BT in symptomatic, severe asthma

Am J Respir Crit Care Med

Effectiveness and safety of BT in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial

Am J Respir Crit Care Med

Asthma and lower airway disease
Effectiveness of bronchial thermoplasty in patients with severe refractory asthma: Clinical and histopathologic correlations