Targeted Lung Denervation Research Articles

Chronic airway diseases: a new frontier in interventional pulmonology

As medical science has advanced, the incidence of central airway lesions, traditionally the primary focus of interventional pulmonology, has decreased significantly. However, the large population suffering from chronic airway diseases, coupled with unmet treatment needs and a high demand for new technologies and methods, has greatly driven the innovation and application of interventional respiratory techniques. The development and clinical application of techniques such as lung volume reduction, targeted lung denervation, pulsed electric field technology, bronchial thermoplasty, and regenerative medicine for chronic airway diseases are providing new treatment options. Chronic airway diseases are becoming a new frontier in interventional pulmonology.

Developing Interventions for Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is an incurable, progressive respiratory disease that may have a significant negative impact on the morbidity and mortality of affected patients. A substantial portion of the world's population is affected by COPD, and despite optimal medical management with medications, supplemental oxygen, and pulmonary rehabilitation, many patients are left debilitated because of this disease. Bronchoscopic treatment modalities offer a less-invasive method for the treatment of refractory COPD compared to surgical interventions and have expanded the potential therapeutic options for these patients. Bronchoscopic lung volume reduction is aimed at decreasing the hyperinflation and air trapping that occur in emphysema, and the most studied and successful intervention is endobronchial valve placement. Endobronchial coils, polymeric sealants, and thermal ablation are other researched alternatives. Additional interventional procedures are being investigated for the treatment of the mucus hypersecretion and cough that are associated with the chronic bronchitis phenotype of COPD and include targeted lung denervation, metered dose spray cryotherapy, deobstruction balloon, and bronchial rheoplasty. This review summarizes the most recent evidence pertaining to available therapies for the management of COPD, including chronic bronchitis, with a particular focus on bronchoscopic interventions.

Bronchoscopic Management of COPD and Advances in Therapy.

Chronic Obstructive Pulmonary Disease (COPD) is a highly prevalent and morbid disease marked by irreversible structural changes in the lungs. Bronchoscopic therapies have significantly expanded the treatment armamentarium for patients with persistent symptoms by reducing the physiologic detriments of hyperinflation in a less invasive fashion than surgical lung volume reduction. The spectrum of bronchoscopic techniques to reduce hyperinflation includes endobronchial valves, coils, thermal ablation, and biologic sealants. Other therapies focus on reducing parasympathetic tone and mucus hypersecretion and include targeted lung denervation, bronchial rheoplasty, and cryospray techniques. In this article, we will review the variety of techniques for bronchoscopic lung volume reduction, both established and investigational, along with their respective benefits and complications and will briefly review other investigational therapies for COPD.

Computed tomographic airway morphology after targeted lung denervation treatment in COPD

This post-hoc analysis of the AIRFLOW-2 trial investigated the changes in airway CT-parameters after targeted lung denervation (TLD) and whether these changes are associated with treatment response. In the treatment group (n = 32), an improvement in air trapping was significantly associated with an improvement in residual volume (RV). Furthermore, improvements in Pi10 and airway lumen were significantly associated with an improvement in both RV and FEV1. Our results could suggest that when improving airway characteristics like decreasing airway wall thickness and increasing the airway lumen, this leads to less air trapping and an improvement in clinical outcomes.

Crossover Patient Outcomes for Targeted Lung Denervation in Moderate to Severe Chronic Obstructive Pulmonary Disease: AIRFLOW-2

Background: Targeted Lung Denervation (TLD) is a potential new therapy for COPD. Radiofrequency energy is bronchoscopically delivered to the airways to disrupt pulmonary parasympathetic nerves, to reduce bronchoconstriction, mucus hypersecretion, and bronchial hyperreactivity. Objectives: This work assesses the effect of TLD on COPD exacerbations (AECOPD) in crossover subjects in the AIRFLOW-2 trial. Method: The AIRFLOW-2 trial is a multicentre, randomized, double-blind, sham-controlled crossover trial of TLD in COPD. Patients with symptomatic COPD on optimal medical therapy with an FEV1 of 30–60% predicted received either TLD or sham bronchoscopy in a 1:1 randomization. Those in the sham arm had the opportunity to cross into the treatment arm after 12 months. The primary end point was rate of respiratory adverse events. Secondary end points included adverse events, changes in lung function and health-related quality of life and symptom scores. Results: Twenty patients were treated with TLD in the crossover phase and were subsequently followed up for 12 months (50% female, mean age 64.1 ± 6.9 years). After TLD, there was a trend towards a reduction in time to first AECOPD (hazard ratio 0.65, p = 0.28, not statistically significant) in comparison to sham follow-up period. There was also a reduction in time to first severe AECOPD in the crossover period (hazard ratio 0.38, p = 0.227, not statistically significant). Symptom scores and lung function showed stability. Conclusions: AIRFLOW-2 crossover data support that of the randomization phase, showing trends towards reduction in COPD exacerbations with TLD.

Targeted lung denervation modulates the mucosal epithelial transcriptome in COPD.

This study shows that TLD reduces airway epithelial expression of genes related to acetylcholine processing and airway inflammation, which may help to elucidate the mechanism for its effect of reducing severe exacerbations in COPD https://bit.ly/3dWcqZk.

Rate of lung function decline slows in the 3 years after targeted lung denervation in COPD

Targeted lung denervation (TLD) is a novel bronchoscopic treatment for COPD GOLD-D patients. The TLD treatment disrupts the peribronchial vagal innervation of the airways by radiofrequency energy, and consequently decreases the release of acetylcholine [1]. TLD has shown to have a positive effect on the occurrence of COPD exacerbations after treatment [1]. Recently, it was shown that 3 years after TLD treatment the lung function was stable compared to before treatment [2]. However, it is not known how this relates to the lung function decline before treatment.

Safety of denervation following targeted lung denervation therapy for COPD: AIRFLOW-1 3-year outcomes

BackgroundTargeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up.MethodsTLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life.ResultsThree-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed.ConclusionTLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up.

New bronchoscopic treatment modalities for patients with chronic bronchitis.

Chronic bronchitis is a chronic, progressive disease that is difficult to treat. Despite much effort, patients remain highly symptomatic. Currently, a number of innovative bronchoscopic treatments for this disease are under investigation. Liquid nitrogen metered cryospray, bronchial rheoplasty and balloon desobstruction all aim to destroy the hyperplastic goblet cells and excess submucous glands using different strategies. These therapies are in an early phase of clinical research and larger randomised controlled trials are needed to confirm the pilot data available and to evaluate the treatment durability. The fourth technique, targeted lung denervation (TLD), aims to decrease the release of acetylcholine, which regulates smooth muscle tone and mucus production by ablating the parasympathetic nerves running alongside the main bronchi. Evaluation of this treatment is at a more advanced stage and promising effects on exacerbation frequency have been shown. However, confirmation of the benefit in improvement in chronic bronchitis symptoms is still needed.

Bronchoscopic management of asthma, COPD and emphysema.

In recent years, many bronchoscopic techniques have been developed in chronic obstructive airway inflammatory diseases, including asthma, COPD and emphysema. The main techniques with available data from randomised controlled trials are: 1) bronchial thermoplasty in asthma; 2) valves, coils and thermal vapor ablation in emphysema; and 3) targeted lung denervation in COPD. The objectives of this article are to describe the levels of evidence for efficacy and safety, long-term follow-up results beyond 1 year, and current recommendations for clinical practice from international guidelines for each technique.

Research progress of targeted lung denervation for moderate to severe chronic obstructive pulmonary disease

Research progress of targeted lung denervation for moderate to severe chronic obstructive pulmonary disease

Two-Year Outcomes for the Double-Blind, Randomized, Sham-Controlled Study of Targeted Lung Denervation in Patients with Moderate to Severe COPD: AIRFLOW-2.

PurposeCOPD exacerbations are associated with worsening clinical outcomes and increased healthcare costs, despite use of optimal medical therapy. A novel bronchoscopic therapy, targeted lung denervation (TLD), which disrupts parasympathetic pulmonary innervation of the lung, has been developed to reduce clinical consequences of cholinergic hyperactivity and its impact on COPD exacerbations. The AIRFLOW-2 study assessed the durability of safety and efficacy of TLD additive to optimal drug therapy compared to sham bronchoscopy and optimal drug therapy alone in subjects with moderate-to-severe, symptomatic COPD two years post randomization.Patients and MethodsTLD was performed in COPD patients (FEV1 30–60% predicted, CAT≥10 or mMRC≥2) in a 1:1 randomized, sham-controlled, double-blinded multicenter study (AIRFLOW-2) using a novel lung denervation system (Nuvaira, Inc., USA). Subjects remained blinded until their 12.5-month follow-up visit when control subjects were offered the opportunity to undergo TLD. A time-to-first-event analysis on moderate and severe and severe exacerbations of COPD was performed.ResultsEighty-two subjects (FEV1 41.6±7.4% predicted, 50.0% male, age 63.7±6.8 yrs, 24% with prior year respiratory hospitalization) were randomized. Time-to-first severe COPD exacerbation was significantly lengthened in the TLD arm (p=0.04, HR=0.38) at 2 years post-TLD therapy and trended towards similar attenuation for moderate and severe COPD exacerbations (p=0.18, HR=0.71). No significant changes in lung function or SGRQ-C were found 2 years post randomization between groups.ConclusionIn a randomized trial, TLD demonstrated a durable effect of significantly lower risk of severe AECOPD over 2 years. Further, lung function and quality of life remained stable following TLD.Clinical Trial RegistrationNCT02058459.

Targeted lung denervation in sheep: durability of denervation and long-term histologic effects on bronchial wall and peribronchial structures

BackgroundTargeted lung denervation (TLD), a novel bronchoscopic procedure which attenuates pulmonary nerve input to the lung to reduce the clinical consequences of neural hyperactivity, may be an important emerging treatment for COPD. While procedural safety and impact on clinical outcomes have recently been reported, the mechanism of action has not been reported. We explored the long-term pathologic and histopathologic effects in a sheep model of ablation of bronchial branches of the vagus nerve using a novel dual-cooled radiofrequency ablation catheter.MethodsNineteen sheep underwent circumferential ablation of both main bronchi with simultaneous balloon surface cooling using a targeted lung denervation system (Nuvaira, Inc., USA). Animals were followed over an extended time course (30, 365, and 640 days post procedure). At each time point, lung denervation (axonal staining in bronchial nerves), and effect on peribronchial structures near the treatment site (histopathology of bronchial epithelium, bronchial cartilage, smooth muscle, alveolar parenchyma, and esophagus) were quantified. One way analysis of variance (ANOVA) was performed to reveal differences between group means on normal data. Non-parametric analysis using Kruskal-Wallis Test was employed on non-normal data sets.ResultsNo adverse clinical effects were observed in any sheep. Nerve axon staining distal to the ablation site was decreased by 60% at 30 days after TLD and efferent axon staining was decreased by >70% at 365 and 640 days. All treated airways exhibited 100% epithelial integrity. Effect on peribronchial structures was strictly limited to lung tissue immediately adjacent to the ablation site. Tissue structure 1 cm proximal and distal to the treatment area remained normal, and the pulmonary veins, pulmonary arteries, and esophagus were unaffected.ConclusionsThe denervation of efferent axons induced by TLD therapy is durable and likely a contributing mechanism through which targeted lung denervation impacts clinical outcomes. Further, long term lung denervation did not alter the anatomy of the bronchioles or lung, as evaluated from both a gross and histologic perspective.

Feasibility, effectiveness, and safety of a novel cryo-balloon targeted lung denervation technique in an animal model

Background and objectiveTargeted lung denervation (TLD) is a pulmonary interventional procedure for COPD that aims to disrupt parasympathetic nerve input to the lung to reduce the clinical consequences of cholinergic hyperactivity. TLD has been proven to be a safe procedure and effectively alleviate symptoms and reduce the onset of exacerbation. In the present study, we developed a novel cryo-balloon TLD system and evaluated its feasibility, safety, and effectiveness. MethodsA preclinical study was performed on twelve sheep, four were tested for airway resistance alterations before and after TLD, two were tested for the Hering-Breuer reflex (HBR) and the remaining six sheep were evaluated for 28 days to assess the safety and effectiveness of the procedure. ResultsAfter an observation period of 28 days, significant disruption of vagal innervation to the lung could be validated by both histological and physiological assessments. The operation time was shorter than traditional procedure, with minimal adjacent tissue injury and no device-related adverse events. ConclusionsThe novel cryo-balloon TLD procedure was feasible, safe, and effective. In comparison with the traditional procedure, this treatment system required shorter operation time and caused less denervation-induced damage to adjacent tissues.

Safety and Adverse Events after Targeted Lung Denervation for Symptomatic Moderate to Severe Chronic Obstructive Pulmonary Disease (AIRFLOW). A Multicenter Randomized Controlled Clinical Trial.

Rationale: Targeted lung denervation (TLD) is a bronchoscopic radiofrequency ablation therapy for chronic obstructive pulmonary disease (COPD), which durably disrupts parasympathetic pulmonary nerves to decrease airway resistance and mucus hypersecretion.Objectives: To determine the safety and impact of TLD on respiratory adverse events.Methods: We conducted a multicenter, randomized, sham bronchoscopy–controlled, double-blind trial in patients with symptomatic (modified Medical Research Council dyspnea scale score, ≥2; or COPD Assessment Test score, ≥10) COPD (FEV1, 30–60% predicted). The primary endpoint was the rate of respiratory adverse events between 3 and 6.5 months after randomization (defined as COPD exacerbation, tachypnea, wheezing, worsening bronchitis, worsening dyspnea, influenza, pneumonia, other respiratory infections, respiratory failure, or airway effects requiring therapeutic intervention). Blinding was maintained through 12.5 months.Measurements and Main Results: Eighty-two patients (50% female; mean ± SD: age, 63.7 ± 6.8 yr; FEV1, 41.6 ± 7.3% predicted; modified Medical Research Council dyspnea scale score, 2.2 ± 0.7; COPD Assessment Test score, 18.4 ± 6.1) were randomized 1:1. During the predefined 3- to 6.5-month window, patients in the TLD group experienced significantly fewer respiratory adverse events than those in the sham group (32% vs. 71%, P = 0.008; odds ratio, 0.19; 95% confidence interval, 0.0750–0.4923, P = 0.0006). Between 0 and 12.5 months, these findings were not different (83% vs. 90%; P = 0.52). The risk of COPD exacerbation requiring hospitalization in the 0- to 12.5-month window was significantly lower in the TLD group than in the sham group (hazard ratio, 0.35; 95% confidence interval, 0.13–0.99; P = 0.039). There was no statistical difference in the time to first moderate or severe COPD exacerbation, patient-reported symptoms, or other physiologic measures over the 12.5 months of follow-up.Conclusions: Patients with symptomatic COPD treated with TLD combined with optimal pharmacotherapy had fewer study-defined respiratory adverse events, including hospitalizations for COPD exacerbation.Clinical trial registered with www.clinicaltrials.gov (NCT02058459).

Interventional Bronchoscopy in the Management of Chronic Obstructive Lung Disease

Background: Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, hyperinflation and reduced gas exchange that lead to progressive dyspnea. Pulmonary rehabilitation, lifestyle changes, pharmacotherapy, long-term oxygen therapy, noninvasive ventilation and surgical therapeutic approaches are the basic management strategies. Purpose: In the last 15 years, various bronchoscopic therapeutic modalities have emerged for severe COPD. The aim of this review is to summarize the effects of these bronchoscopic treatments compared with lung rehabilitation and pharmacological therapies. Methods: A PubMed search for the eligible studies and reviews on interventional bronchoscopy and COPD has been conducted. Results: Bronchoscopic lung volume reduction (LVR) techniques are targeted to reduce hyperinflation. The efficacy of reversible valve implantation has been confirmed in several randomized controlled trials. It provides clinical benefit in the absence of interlobar collateral ventilation. Nonblocking bronchoscopic LVR with coils, thermal vapor or sealants is independent of collateral ventilation but has not been studied sufficiently. Partially irreversible coil implantation leads to parenchymal compression while irreversible LVR with thermal vapor or sealants induce an inflammatory reaction. Targeted lung denervation ablates parasympathetic pulmonary nerves in COPD for sustainable bronchodilation, and liquid nitrogen metered cryospray destroys hyperplastic goblet cells and excessive submucous glands in the central airways to induce mucosal regeneration in chronic bronchitis. Conclusion: The best-examined bronchoscopic LVR method is the valve therapy. The data from the other modalities are still limited. Further studies are required to select the patients that will optimally benefit from a particular treatment and to predict and treat the procedure-related complications.

Interventionen beim Asthma COPD

Advanced emphysema and asthma constitute major health burden worldwide and are associated with significant morbidity and mortality. Pharmacological options are limited. Researches are being carried out aiming to modify the natural course of both the diseases. Lung volume reduction surgeries are performed in advanced emphysema but are associated with significant morbidity and prolonged hospital stay. Various minimally invasive bronchoscopic methods have been developed with the goal of achieving clinical benefits of volume reduction surgery but lower complications. Bronchial thermoplasty is a bronchoscopic method of delivering controlled heat in the airways to reduce airway smooth muscle mass, thereby reducing bronchoconstriction in patients with severe asthma who remain uncontrolled despite optimal medical therapy. Various randomised controlled trials have been performed to evaluate the safety and efficacy of various endoscopic treatments like valves, coils, use of sclerosants and targeted lung denervation for severe emphysema and bronchial thermoplasty in severe asthma. The current review summaries the clinical trial evidence available for lung volume reduction in emphysema and thermoplasty in asthma and provide guidance for optimal patient selection for various therapies available.

Respiratory Sinus Arrhythmia Attenuation via Targeted Lung Denervation in Sheep and Humans

Background: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung. Parasympathetic input to the heart originating from the lungs contributes to respiratory sinus arrhythmia (RSA) and disruption of pulmonary nerves via TLD may impact RSA. Objective: The aim of this study was to assess the potential of TLD to affect RSA in sheep and humans. Methods: TLD was performed in 5 sheep and 9 humans using a novel lung denervation system (Nu­vaira Inc., Minneapolis, MN, USA) with an electrocardiogram collected before and after the procedure. Frequency domain analysis of heart rate variability was performed in 5 sheep and 6 humans with presence of RSA approximated as high-frequency power (HF power). Results: HF power decreased in 3 of 5 sheep with 1 animal reaching less than 7% of its baseline HF power 30 days after TLD. The average treatment location was more distal in the remaining 2 animals, which did not exhibit RSA attenuation, suggesting diminished denervation. HF power decreased in 5 of 6 humans, with 3 subjects reaching less than 50% of their baseline HF power 90 days after TLD. Conclusions: TLD appeared to attenuate RSA in both sheep and human cohorts of this sub-study. Further confirmation in humans is necessary to allow for RSA attenuation to be used as a marker of successful lung denervation via TLD.

Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients

Rationale: Targeted lung denervation (TLD) is a novel bronchoscopic treatment for the disruption of parasympathetic innervation of the lungs. Objectives: To assess safety, feasibility, and dosing of TLD in patients with moderate to severe COPD using a novel device design. Methods: Thirty patients with COPD (forced expiratory volume in 1 s 30–60%) were 1:1 randomized in a double-blinded fashion to receive TLD with either 29 or 32 W. Primary endpoint was the rate of TLD-associated adverse airway effects that required treatment through 3 months. Assessments of lung function, quality of life, dyspnea, and exercise capacity were performed at baseline and 1-year follow-up. An additional 16 patients were enrolled in an open-label confirmation phase study to confirm safety improvements after procedural enhancements following gastrointestinal adverse events during the randomized part of the trial. Results: Procedural success, defined as device success without an in-hospital serious adverse event, was 96.7% (29/30). The rate of TLD-associated adverse airway effects requiring intervention was 3/15 in the 32 W versus 1/15 in the 29 W group, p = 0.6. Five patients early in the randomized phase experienced serious gastric events. The study was stopped and procedural changes made that reduced both gastrointestinal and airway events in the subsequent phase of the randomized trial and follow-up confirmation study. Improvements in lung function and quality of life were observed compared to baseline values for both doses but were not statistically different. Conclusions: The results demonstrate acceptable safety and feasibility of TLD in patients with COPD, with improvements in adverse event rates after procedural enhancements.

Physiologic and histopathologic effects of targeted lung denervation in an animal model.

Parasympathetic efferent innervation of the lung is the primary source of lung acetylcholine. Inhaled long-acting anticholinergics improve lung function and symptoms in patients with chronic obstructive pulmonary disease. Targeted lung denervation (TLD), a bronchoscopic procedure intended to disrupt pulmonary parasympathetic inputs, is an experimental treatment for chronic obstructive pulmonary disease. The physiologic and histologic effects of TLD have not previously been assessed. Eleven sheep and two dogs underwent circumferential ablation of the main bronchi with simultaneous balloon surface cooling using a lung denervation system (Nuvaira, Inc., Minneapolis, MN). Changes in pulmonary air flow resistance were monitored before and following TLD. Four animals were assessed for the presence or abolishment of the sensory axon-mediated Hering-Breuer reflex before and following TLD. Six sheep were histologically evaluated 30 days post-TLD for the extent of lung denervation (axonal staining) and effect on peribronchial structures near the treatment site. No adverse clinical effects were seen in any treated animals. TLD produced a ~30% reduction in pulmonary resistance and abolished the sensory-mediated Hering-Breuer reflex. Axonal staining was consistently decreased 60% at 30 days after TLD. All treated airways exhibited 100% epithelial integrity. Damage to other peribronchial structures was minimal. Tissue 1 cm proximal and distal to the treatment was normal, and the esophagus and periesophageal vagus nerve branches were unaffected. TLD treatment effectively denervates the lung while protecting the bronchial epithelium and minimizing effects on peribronchial structures.NEW & NOTEWORTHY The feasibility of targeted lung denervation, a new minimally invasive therapy for obstructive lung disease, has been demonstrated in humans with preliminary clinical studies demonstrating improvement in symptoms, pulmonary function, and exercise capacity in patients with chronic obstructive pulmonary disease. This preclinical animal study demonstrates the ability of targeted lung denervation to disrupt vagal inputs to the lung and details its physiologic and histopathologic effects.