Patients with severe chronic obstructive pulmonary disease who fail maximal medical therapy have bronchoscopic options that can improve lung function, quality of life, and exercise performance. Those with upper lobe predominant emphysema can consider bronchoscopic lung volume reduction with endobronchial valves. Select patients with diffuse emphysema and severe hyperinflation can also be considered for endobronchial valves. Bronchoscopic techniques targeting cholinergic pathways and mucus hypersecretion are under development. Ultimately, patients with advanced chronic obstructive pulmonary disease who are not eligible for or have failed bronchoscopic interventions can consider lung volume reduction surgery or even lung transplantation, if free from major comorbidities.
Key points
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Endobronchial valves improve lung function, exercise performance, and quality of life in patients with severely hyperinflated emphysema with heterogeneous and homogeneous emphysema.
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Determining fissure integrity is key to successful bronchoscopic lung volume reduction and endobronchial valves should not be deployed if collateral ventilation between lobes exists.
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Bronchoscopic targeted lung denervation using radiofrequency ablation to alter the parasympathetic innervation of the airways is currently under investigation as a viable option for further decreasing acute exacerbations of chronic obstructive pulmonary disease.
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Bronchoscopic techniques to treat mucus hypersecretion and chronic bronchitis using liquid nitrogen cryospray and bronchial rheoplasty are in development.
Introduction
Although surgical interventions are beneficial in carefully selected patients who fail medical therapy, the associated morbidity and mortality makes many patients with severe chronic obstructive pulmonary disease (COPD) reluctant to undergo surgical intervention. Furthermore, those with lower lobe predominant emphysema are generally not considered candidates for lung volume reduction surgery and, although lung transplantation is the penultimate treatment for advanced lung disease, it has limited access owing to organ availability and strict selection criteria.
This review focuses on bronchoscopic interventions that expand treatment options for patients who have failed maximal medical therapy. Procedures include those that are approved the by US Food and Drug Administration (endobronchial valve [EBV] therapy for bronchoscopic lung volume reduction) and those that are currently being developed or undergoing evaluation in multicenter clinical trials (targeted lung denervation [TLD] and bronchoscopic treatments for chronic bronchitis).
Bronchoscopic approaches to lung volume reduction
There has been intense recent investigation into less invasive bronchoscopic procedures for lung volume reduction in patient with severely hyperinflated emphysematous. This interest has resulted in US Food and Drug Administration approval of 2 different types of EBVs. Other bronchoscopic techniques currently under investigation include endobronchial placement of self-activation coils, targeted destruction and remodeling of emphysematous tissue, and airway bypass stenting.
One-Way Endobronchial Valves
EBVs have been more extensively studied than any other bronchoscopic technique for lung volume reduction. EBVs are placed in the airway at the segmental or lobar level and are designed to block inspiration but permit exhalation of air and secretions. Optimal valve placement results in lobar atelectasis and a significant reduction in end-expiratory lung volumes. EBVs are placed in the most air trapped lobe owing to emphysematous destruction. There are 2 types of EBVs. The Spiration Intrabronchial Valve (Spiration, Olympus, Tokyo, Japan) system has an umbrella design, where an occlusive cover is stretched over a titanium wire frame that allows expired air and secretions to escape around the outer edges and the airway wall ( Fig. 1 ). The Zephyr valve (Pulmonx Inc., Neuchâtel Switzerland) is a cylindrical device with a duckbill 1-way valve placed in a nitinol wire cage, which permits expired air and secretions to escape through the center of the valve ( Fig. 2 ).
The Endobronchial Valve for Emphysema Palliation Trial (VENT) was the first prospective randomized trial to evaluate bronchoscopic lung volume reduction using the Zephyr valve. The VENT trial randomized 220 patients to EBV placement compared with 101 patients treated with maximal medical therapy alone. Valves were placed unilaterally targeting the lobe with the highest percentage of emphysema in the lung with the greatest degree of heterogeneity.
At 6 months, there were only modest improvements in the forced expiratory volume in 1 second (FEV 1 ) (+4.3%/34.5 mL) and 6-minute walk distance (+2.5%/9.3 m) in the EBV group compared with controls. Furthermore, there were modest differences in the quality of life, dyspnea, exercise performance, and supplemental oxygen use, all favoring the EBV group. Heterogeneity of emphysema between lobes in treated lung and the presence of complete fissures were the only factors predictive of improvements in the primary end points. For heterogeneity of emphysema, those with differences of 15% or greater in emphysema were found to have greater improvements in FEV 1 and 6-minute walk distance at 6 months. EBV patients with intact fissures had a 16.2% improvement in FEV 1 at 6 months and 17.9% at 12 months, whereas those with incomplete fissures had changes of FEV 1 of only 2.0% and 2.8% at 6 and 12 months, respectively.
The EUROVENT study was also performed in 23 European sites where 111 patients were randomized to EBV and 60 to medical therapy. Although the study was underpowered compared with the US VENT study, the results were similar. At 6 months, there were modest improvements in FEV 1 , quality of life, and 6-minute walk distance in the EBV group compared with the control group that were either significant or nearly significant. Once again, those with complete fissures had better results with improvements in FEV 1 (16% vs 2%) when treated with EBV compared with medical therapy. The median reduction in target lobe volume reduction relative to baseline target lung volume reduction was greater in those with complete fissures compared with incomplete fissure. These 2 studies suggest that if collateral ventilation is absent then placement of EBVs can improve lung function and quality of life by reducing lung volumes.
There was debate over whether to perform unilobar total lobar collapse or bilateral subtotal lobar atelectasis to achieve volume reduction and decrease the risk of pneumothorax. Eberhardt and associates randomized 22 patients to unilateral treatment with the goal of total lobar occlusion or bilateral subtotal atelectasis. They found that those treated with unilateral lobar occlusion had significant improvements in FEV 1 and 6-minute walk test at 30 and 90 days compared with baseline. The subtotal lobar occlusion bilaterally treated group did not have a significant increase in FEV 1 or 6-minute walk test at 30 or 90 days.
Additionally, the unilateral lobar occlusion group had improvements in the quality of life as measured by the St George’s Respiratory Questionnaire (SGRQ) at 90 days, whereas the bilateral subtotal atelectasis arm did not. The unilateral treated group was significantly more likely to have radiologic evidence of atelectasis and volume reduction compared with the bilateral group. Based on these data, future clinical trials focused on treating 1 lobe with a goal of total lobar atelectasis.
Determining whether or not an individual has intact fissures can be determined by quantitative high-resolution computed tomography (HRCT) analysis of fissure integrity (FI) or balloon occlusion of the airway and monitoring flow with the Chartis system (Pulmonx Inc.). , The Chartis system measures collateral ventilation during bronchoscopy by inserting a balloon tipped catheter into the target bronchus via the working channel of the bronchoscope to occlude the airway. The balloon tipped catheter can measure flow and pressure at its distal tip and be used as a surrogate of FI if there is no flow and pressure rises with balloon occlusion of lobe targeted for EBV treatment. Fig. 3 A is an example of a collateral ventilation–negative patient clearly demonstrating cessation of flow and Fig. 3 B demonstrates a patient with positive collateral ventilation, indicating that the fissure is not intact. Alternatively, FI can be measured by quantitative analysis of HRCT imaging. Some EBV studies have used a FI of 90% or more complete as an acceptable parameter to proceed with EBV treatment. Neither technique is perfect, and the sensitivity and specificity for Chartis (Pulmonx, Inc.) has been reported to be 77.8% and 73.3%, respectively, whereas QCT analysis of FI it is 83.3% and 66.7%, respectively. Although it is essential to determine if there is collateral ventilation before EBV treatment it is not clear whether 1 method is better than the other or if both should be used.
Based on the VENT trial results, all subsequent EBV randomized controlled trials (RCTs) enrolled only those with intact fissures. In the TRANSFORM study, investigators compared 65 patients that had Zephyr EBVs (Pulmonx Inc.) inserted with 32 patients in the control arm. Patients were enrolled if Chartis assessment demonstrated collateral ventilation negative status. Other inclusion criteria included an FEV 1 of 15% to 45% predicted, a total lung capacity (TLC) of more than 100% predicted and a residual volume (RV) or more than 180% predicted, a heterogeneity score of greater than 10% between the targeted lobe and ipsilateral lobes, and a 6-minute walk distance between 150 and 450 m. Fifty-five percent of patients treated with EBVs had a greater than 12% improved in FEV 1 compared with controls. Additionally, there were significant improvements in 6-minute walk distance, quality of life measured by the SGRQ, and RV in those treated with EBVs compared with control.
The L ung Function I mprovement after B ronchoscopic Lung Volume Re duction with Pulmonx Endobronchial V a lves used in T reatment of E mphysema (LIBERATE) study recruited patients to determine the efficacy of the Zephyr valve (Pulmonx Inc.) in those with have intact fissures and at least 15% emphysema heterogeneity between lobes with more than 50% destruction in the targeted lobe. Patients had an FEV 1 between 15% and 45% predicted, a TLC of greater than 100% predicted, an RV of 175% predicted or greater, and a 6-minute walk distance between 100 and 500 m following a supervised pulmonary rehabilitation program. This was the largest and longest duration of follow-up EBV trial and enrolled a total of 190 patients: 128 EBV and 62 standard care. After 1 year, more patients had improvement in FEV 1 by 15% in the EBV group compared with standard care (47.7% vs 16.8%). Additionally, quality of life, 6-minute walk distance, and dyspnea significantly improved favoring EBV. The between-group differences for FEV 1 was 0.106, 6-minute walk distance was 39.31 m, and quality of life measured by the SGRQ was −7.05. The effect was durable and at 12 months 84.2% of EBV patients achieved target lobe volume reduction of 350 mL or greater with a mean decrease of 1.14 ± 0.70 L. These data demonstrate that EBV placement in severely hyperinflated gas trapped patients with heterogeneous disease and intact fissures had meaningful clinically important improvements in lung function, quality of life, and exercise performance that were durable out to 1 year.
Data also demonstrate the effectiveness of the Spiration Intrabronchial Valve (Spiration, Olympus) to perform bronchoscopic lung reduction. REACH compared the Spiration Valve System (SVS) to maximal medical therapy in a total of 107 patients. They enrolled patients with an FI of at least 90% as determined by quantitative HRCT analysis. Patients all had 15% or greater heterogeneity scores between ipsilateral lobes and similar to other trials; inclusion criteria included a FEV 1 of 45% predicted or greater, a TLC of at least 100% predicted, and an RV of at least 150%. The primary end point was change in FEV 1 at 3 months. At 3 months, the FEV 1 improved by 0.104 ± 0.178 L in the SVS group compared with 0.003 ± 0.147 L in controls. When the responder rate for FEV 1 improvement was defined as 15%, the responder rates for SVS were 49%, 48%, and 41% at 1, 3, and 6 months, respectively, compared with 22%, 13%, and 21% in controls. Quality of life significantly improved as measured by the SGRQ at 6 months in the SVS group compared with controls.
The EMPROVE study using SVS (Spiration, Olympus) was a RCT which enrolled 113 patients in the SVS arm and 59 in the control arm. Inclusion criteria were similar to that of the REACH study. The primary outcome for the study was the mean change in FEV 1 at 6 months compared with baseline, but data in this study were reported out to 12 months. At 6 months, the FEV 1 improved by 0.099 L in the SVS group and the FEV 1 decreased by 0.002 L in controls for a between-group difference of 0.101 L. The improvement of FEV 1 was durable out to 12 months. Secondary end points demonstrated a significant difference for the between-group differences of targeted lobar volume (−0.974 L), SGRQ (−13.0), and dyspnea as measured by the Modified Medical Research Council score (−0.6), but not the 6-minute walk distance at 6 months. Taken together, these 2 RCTs demonstrated that SVS (Spiration, Olympus) improves lung function, dyspnea, and quality of life in patients with heterogeneous emphysema that have severe airflow obstruction (FEV 1 of ≤45% predicted), hyperinflation (TLC of >100% predicted), and gas trapping (RV of >150% predicted).
Endobronchial Valves for Homogeneous Emphysema
Patients with advanced homogeneous emphysema have little options after maximal medical therapy as surgical lung volume reduction surgery is contraindicated, thus leaving only lung transplantation as a less than ideal option owing to its increased morbidity, mortality, and limited availability. The use of EBVs has been studied in homogeneous disease although to a lesser degree than heterogeneous disease. One RCT used the Zephyr valve (Pulmonx Inc.) and enrolled 93 patients with severe homogeneous emphysema, an FEV 1 of 15% to 45% predicted, a TLC of greater than 100% predicted, and an RV of at least 200% predicted to either EBV placement plus standard care or to standard care alone. Homogeneous emphysema was defined as a heterogeneity score of 15% or less between the target and ipsilateral nontarget lobe as determined by QCT analysis of HRCT. Additionally, patients had to have a 20% or less difference in perfusion between the right and left lungs as measured by perfusion scintigraphy. Patients were enrolled into the study if there was no evidence of collateral ventilation as measured by Chartis (Pulmonx Inc.). The mean difference in FEV 1 between groups at 3 months was 17.0% favoring the EBV group. There were significant improvements in quality of life (−9.6 points SGRQ), 6-minute walk distance (+40 m), and RV (−480 mL) in the EBV group. These data suggest that carefully selected patients with homogeneous emphysema will benefit from EBV placement.
Complications Associated with Endobronchial Valve Placement
Although EBV placement is associated with less morbidity than lung volume reduction surgery there are significant complications associated with the procedure. The 2 most common complications include acute exacerbation of COPD and pneumothorax. Table 1 lists the rates for these complications for the RCTs that enrolled patients with intact fissures. Most studies have reported a pneumothorax rate of 25% to 34%. , , The REACH trial had fewer episodes of pneumothorax compared with other reports. Although the reason for this finding is not clear, the investigators suggest that it may be due to conservative postprocedure care (6-day hospitalization and bed rest), less emphysema in the ipsilateral lobe relative to treatment lobe, or possibly less experience with EBV placement. Most, but not all, pneumothoraces required chest tube placement. Published guidelines suggest when valves should be removed or if surgical intervention is required. The majority of pneumothoraces occur within the first few days after EBV placement and for this reason patients are usually hospitalized for 3 or 4 days after EBV placement to monitor for pneumothorax development. Mortality after EBV placement in the 2 largest trials to date is reported at 3.1% and 5.3%. Other reported complications include hemoptysis, valve migration/expectoration, pneumonia, and formation of granulation tissue.
