INTRODUCTION — Emphysema is a form of chronic obstructive pulmonary disease (COPD) that is defined by abnormal and permanent enlargement of the airspaces distal to the terminal bronchioles and is associated with destruction of the alveolar walls. The destruction of alveolar walls causes loss of elastic recoil, early airway closure during exhalation, and air trapping in the distal air spaces. Alveolar wall destruction with formation of emphysematous blebs and bullae leads to loss of gas exchanging surface (also known as increased physiologic dead space). In addition, air trapping and hyperinflation press the diaphragm into a flat configuration, rather than its normal domed shape, and place all the muscles of respiration at a mechanical overstretch disadvantage. In combination, these processes lead to refractory dyspnea.
Lung volume reduction surgery (LVRS, also called reduction pneumoplasty or bilateral pneumectomy) is a surgical treatment for patients with advanced emphysema whose dyspnea is poorly controlled with the usual therapies (eg, short and long acting bronchodilators, inhaled glucocorticoids, supplemental oxygen, and pulmonary rehabilitation) [1]. LVRS entails reducing the lung volume by wedge excisions of emphysematous tissue. However, surgical morbidity is high and non-pulmonary comorbidities may preclude surgery.
Bronchoscopic lung volume reduction (bLVR) refers to techniques developed to treat hyperinflation due to emphysema via a flexible bronchoscope.
The devices and techniques for bLVR will be reviewed here. The general management of COPD, an overview of flexible bronchoscopy, and the roles of lung volume reduction surgery, bullectomy, and lung transplantation in the management of advanced COPD are discussed separately. (See "Stable COPD: Initial pharmacologic management" and "Flexible bronchoscopy in adults: Overview" and "Management of refractory chronic obstructive pulmonary disease" and "Lung volume reduction surgery in COPD" and "Lung transplantation: General guidelines for recipient selection".)
RATIONALE FOR LUNG VOLUME REDUCTION — The mechanisms by which lung volume reduction might provide benefit in patients with emphysema are not known with certainty. However, it is believed that the removal of diseased, hyperinflated areas of lung would have the following benefits:
●As overall hyperinflation decreases, diaphragm and chest wall mechanics would improve and work of breathing would decrease.
●The remaining lung tissue would have more normal elastic recoil pressure, thereby restoring the outward circumferential pull on the bronchioles and increasing expiratory airflow.
●With improved expiratory airflow, the amount of hyperinflation associated with exercise (also known as dynamic hyperinflation) would decrease, and thereby reduce exercise related dyspnea. (See "Dynamic hyperinflation in patients with COPD", section on 'Pathophysiology'.)
●Reducing the inhomogeneity of regional ventilation and perfusion would improve ventilation-perfusion matching and result in improved alveolar gas exchange and effectiveness of ventilation [2]. (See "Measures of oxygenation and mechanisms of hypoxemia".)
The rationale for lung volume reduction surgery (LVRS) is discussed in greater detail separately. (See "Lung volume reduction surgery in COPD", section on 'Rationale of LVRS'.)
Among selected patients with advanced upper lobe predominant emphysema, LVRS improved exercise capacity and in some patients, reduced mortality at two years. However, the morbidity of LVRS is substantial. (See "Lung volume reduction surgery in COPD", section on 'Primary endpoints' and "Lung volume reduction surgery in COPD", section on 'Complications' and "Lung volume reduction surgery in COPD", section on 'Long-term outcomes'.)
The rationale for bronchoscopic LVR (bLVR) is that the use of endoscopic methods (eg, valves, sealants, thermal ablation) to collapse areas of overinflated emphysematous lung would have a beneficial effect similar to resecting these areas during LVRS, but without the morbidity of surgery. Thus, patients who are not ideal surgical candidates might be able to undergo bLVR. Several bLVR techniques are reversible, which may contribute to increased safety. (See "Lung volume reduction surgery in COPD", section on 'Rationale of LVRS'.)
TECHNIQUES — Proposed techniques for bronchoscopic lung volume reduction (bLVR) include endobronchial placement of one-way valves, plugs and blockers, endobronchial instillation of biologic sealants, thermal airway ablation, and airway stents for decompression of bullae [3,4]. Endobronchial plugs and blockers were the initial method developed to promote resorption atelectasis, but the high rate of post-obstructive pneumonia and migration of the plugs and blockers has led to abandonment of these devices.
Endobronchial valves — One-way endobronchial valves (EBVs) have been designed for bronchoscopic placement based on the hypothesis that they will allow air and mucus to exit the treated area, but not allow air to re-enter. The goal of this treatment is to facilitate atelectasis of the emphysematous, hyperinflated lung distal to the valve. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Bronchoscopic LVR'.)
The two available valve designs differ in the mechanism by which the one-way valve is created; the Zephyr valve uses a duckbill shape (picture 1A-B) and the Spiration valve uses an umbrella shape (picture 2). Both valves are deployed within the bronchus.
Zephyr duckbill valve — The initial design of the Pulmonx endobronchial valve (EBV) system was that of a nitinol skeleton and a silicone body with a "duckbill" valve on the proximal end. The most recent version of this EBV, known as the Zephyr valve, maintains the "duckbill" mechanism (picture 1A-B). The US Food and Drug Administration (FDA) has approved the Zephyr Endobronchial Valve System for bronchoscopic implantation in lung regions with little to no collateral ventilation to treat patients with hyperinflation associated with severe emphysema [5,6].
●Patient selection – Based on the inclusion criteria for the pivotal clinical trials, candidate selection for Zephyr EBV placement will include a modified Medical Research Council dyspnea score ≥2 (table 1), postbronchodilator FEV1 between 15 and 45 percent predicted, total lung capacity ≥100 percent predicted, residual volume ≥175 percent predicted, DLCO ≥20 percent predicted, and a six-minute walk distance (6MWD) between 100 and 500 m, following supervised pulmonary rehabilitation (table 2) [6-8].
A key step in evaluation of potential patients is high resolution computed tomography (HRCT) to measure lobar volumes, determine the amount of emphysematous destruction of each lobe, and assess for high-to-complete fissure integrity [9]. The CT is also important to rule out other important diseases like bronchiectasis and assess nodules or other findings that may require additional evaluation.
●Valve placement – A specialized catheter to measure localized pressure and flow, known as the Chartis System, has been developed for bronchoscopic assessment of collateral ventilation, as absence of collateral ventilation improves the likelihood of resorption atelectasis following EBV placement [10-16].
During flexible bronchoscopy, the lobe with the greatest degree of emphysematous destruction is assessed for collateral ventilation with this system. If none is found, an EBV is deployed into that bronchus. The Zephyr EBV is deployed with a catheter that can be inserted through the working channel of a bronchoscope under direct vision. The deployment catheter also acts as a sizing mechanism, enabling the bronchoscopist to select the size valve that will best fit that bronchus. Three sizes of valve are available (4.0 low profile, 4.0, and 5.5, corresponding to the minimum width of the subsegment to be treated).
Additional EBVs are placed in other segments, depending on the HRCT distribution of emphysema and Chartis assessment of collateral ventilation; on average four valves (range two to eight) are implanted per patient [7,8].
●Efficacy – Several randomized trials and a multicenter registry have reported modest improvements in symptoms and lung function after bLVR with placement of Zephyr valves, but with a risk of pneumothorax of 25 to 30 percent [7,8,17-26]. These studies are described separately. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Bronchoscopic LVR'.)
Spiration umbrella valve — The Spiration EBV uses an umbrella-shaped nitinol framed prosthesis with a synthetic polymer cover (picture 2) [27]. The flexible nitinol frame allows for the valve to maintain contact with the airway wall and prevent air from passing inwards while allowing for mucus and air to escape. This creates a one-way valve effect with the intent of redirecting airflow to more normal areas and/or inducing atelectasis of the emphysematous area blocked by the valve. The US Food and Drug Administration (FDA) has approved use of the Spiration EBV in patients with breathlessness due to severe emphysema [28]. HRCT is used to help select appropriate patients by identifying those with ≥40 percent emphysema and intact or nearly intact fissures in the target lobe.
●Valve placement – The valve can be deployed through the working channel of a flexible bronchoscope under direct vision. Valve sizes range from 5 to 7 mm. After the appropriate airways are selected, a calibrated balloon is used to determine the valve with the best fit for the airway. Then, under direct vision, the valve deployment device is passed through the working channel of the bronchoscope and the valve is deployed. If the valve needs to be repositioned or removed, a standard biopsy forceps is used to grab the central rod; when the rod is pulled, the umbrella collapses and can be removed. Several small modifications have been made on this valve, but the basic design has changed little (picture 2).
●Efficacy – Based on data from randomized trials and a systematic review, bronchoscopic treatment with the Spiration IBV provides meaningful improvement in several parameters including pulmonary function and quality of life (modified Medical Research Council [mMRC] dyspnea scale, St. George's Respiratory Questionnaire [SGRQ]), but impact on exercise capacity remains limited [27,29-32].
•A systematic review and meta-analysis of four trials (629 participants) found improvement in FEV1 (0.12 L; 95% CI 0.09-0.015), SGRQ quality of life (-12.27 points; 95% CI -15.84 to -8.70), and the mMRC dyspnea scale (-0.54 (95% CI -0.74 to -0.33) among participants with intact fissures (collateral ventilation unlikely), but not in the overall treatment group of patients with severe, heterogenous emphysema [33]. No improvement was noted in the six-minute walk distance (6MWD).
•A multicenter, open-label trial (EMPROVE) randomly assigned 172 participants with severe, heterogenous emphysema and intact fissures by high resolution computed tomography (HRCT) to placement of Spiration EBVs or medical management (2:1) [27]. At 6 and 12 months the IBV group had a relative improvement in FEV1 (0.101 L 95% Bayesian credible interval [BCI] 0.060–0.141) and 0.099 L (95% BCI 0.048–0.151), respectively. Quality of life, based on the SGRQ, and mMRC improved, but 6MWD did not. Serious adverse events were more common in the IBV group due to serious pneumothoraces in 12.4 percent of these patients.
•In a multicenter trial (REACH) of 107 participants with severe emphysema and intact interlobar fissures, placement of EBVs resulted in an increase in FEV1 (0.104 ± 0.18 versus 0.003 ± 0.15 L) compared with the control group (medical treatment) after three months [32]. The 6MWD did not improve significantly, although it was relatively better than the control group at six months due to a decrease in the control group. The SGRQ showed a significant relative improvement compared with control at one and six months with relative differences between the groups of 10.9, 7.2, and 10.5 points at 1, 3, and 6 months, respectively, which was significant at 1 and 6 months.
•A multicenter trial that randomly assigned 277 subjects to Spiration EBV treatment versus sham bronchoscopy found a decrease in lobar volume in treated lobes based on computed tomography, but no meaningful improvement in quality of life [31].
Coils — Nitinol coils (eg, Elevair coil system) behave like springs. They are passed through the working channel of a flexible bronchoscope in a straightened configuration into subsegmental airways and out into the lung parenchyma. As they are deployed, they resume their coiled shape and thereby collect and collapse the lung tissue in that area (image 1). A potential advantage may be that collateral ventilation would have no effect on this technique, as opposed to the valve techniques described above. (See 'Endobronchial valves' above.)
A few clinical trials have examined the effect of endobronchial coils in severe emphysema and have found a variable degree of benefit.
●A multicenter trial randomly assigned 315 patients with predominantly homogeneous emphysema and severe hyperinflation to one of two groups: usual care, including guideline based medications and pulmonary rehabilitation, or usual care plus bilateral placement of endobronchial coils [34]. For participants receiving coils, 10 to 14 coils were placed in one lung in the first procedure; four months later the procedure was repeated, placing 10 to 14 coils in the other lung. After one year, the group receiving coils experienced a small increase in their six-minute walk test distance and a small increase in FEV1; both changes were below the level considered clinically significant. Major complications occurred in 35 percent of the coil group versus 19 percent of the usual care group.
●In a multicenter trial, 100 patients with severe emphysema (FEV1 <50 percent of predicted and residual volume >220 percent of predicted) were randomly assigned to undergo endobronchial deployment of nitinol coils (approximately 10 coils per lobe in two lobes, one on each side) or usual care [35]. Two-thirds of the patients had homogeneous emphysema, considered an unfavorable pattern for surgical LVRS. At six months, 36 percent of the coil group experienced more than a 54 m improvement in the six-minute walk distance, compared with 18 percent in the control group. The improvements in FEV1 and lung function at 6 and 12 months were significantly greater in the coil group. Pneumonia was the most frequent serious adverse event, occurring in 18 percent of the coil group and 4 percent of the control group.
●In a multicenter, observational study, 60 patients with severe heterogeneous emphysema (mean FEV1 30.2 percent predicted) underwent bronchoscopic placement of nitinol coils (55 bilateral, 5 unilateral) with a median of 10 coils per lobe [36]. Serious adverse events included seven COPD exacerbations, four pneumothoraces, and one episode of hemoptysis. After 6 and 12 months, modest but sustained improvements were noted in quality of life, FEV1 (approximately 110 mL at both time points), and six-minute walk distance (approximately 30 and 51 meters, respectively).
●In two smaller observational studies with a combined total of 23 patients, coil placement was associated with improved pulmonary function and exercise tolerance [37,38]. Adverse effects included hemoptysis (12 patients), transient chest pain (4 patients), dyspnea (10 patients), exacerbation of COPD (3 patients), and pneumothorax (1 patient).
Biologic lung volume reduction — Biologic lung volume reduction uses direct application of a sealant/remodeling system to collapse areas of emphysema. The initial method applied fibrin-thrombin mixtures to selected endobronchial locations to collapse hyperinflated areas of emphysematous lung through resorptive atelectasis [39,40]. Although this method was partially successful, a revised technique, called BioLVR, was developed, adding chondroitin sulfate and poly-L-lysine to the fibrin mixture. A hydrogel is created when the fibrin and thrombin solutions mix, theoretically providing a scaffold for fibroblast attachment and collagen synthesis that promotes scarring and prevents future recanalization and ventilation of the treated area. It is thought that the hydrogel sealant will block the interalveolar and bronchiolar-alveolar pores and channels, eradicating collateral ventilation, and thus promoting resorptive atelectasis [41]. An alternative method uses a synthetic polymeric foam sealant called emphysematous lung sealant (ELS).
The procedure is performed under conscious sedation via flexible bronchoscopy. The bronchoscope is introduced into an airway leading to emphysematous alveoli and moved into wedged position, completely occluding the segment or subsegment to be treated. Suction is applied through the bronchoscope to collapse the distal airways in that segment [41,42]. An enzymatic primer solution (eg, porcine trypsin) is instilled to promote detachment of epithelial cells from the target region. After two minutes, the primer is removed by suction and 10 mL of cell culture media is used to wash out residual primer. Next, a dual lumen catheter with the thrombin mixture in one lumen and the fibrin mixture in the other is placed through the wedged bronchoscope. The contents of the two lumens are instilled, followed by 60 mL of air to push the solutions distally. The solutions mix as they are simultaneously delivered to the distal airway and alveoli. The liquid component is thought to fill the alveoli prior to complete polymerization, thus blocking collateral ventilation. Each subsegmental application takes approximately 10 minutes and four to eight subsegments are treated during a single procedure.
The technique has been used in a sheep model of papain induced emphysema [43,44]. After BioLVR, a 16 percent reduction in total lung capacity and a 55 percent reduction in residual volume were noted. At autopsy, no evidence was found of the abscess formation, infection, or granulomas. Scar formation was seen in 91 percent of treated segments [44].
In a preliminary human study of biologic lung volume reduction, 22 patients with upper lobe predominant emphysema were treated with 20 mL of hydrogel/subsegment and 28 with 10 mL/subsegment [45]. The six month follow-up revealed a greater improvement in FVC, FEV1, and RV in the higher dose group compared with the low dose. No significant change in the six-minute walk test was seen in either group, compared with baseline. Chest computed tomography at six months revealed scarring and atelectasis in the previously hyperinflated area in the high-dose, but not the low dose group (image 2). Similar findings were reported in a study of 25 patients with bilateral homogeneous emphysema in whom high or low dose hydrogel was administered to eight subsegments [46].
A separate observational study compared the effect of contiguous single lobe versus scattered double lobe BioLVR for upper lobe predominant emphysema [47]. Targeting a single lobe led to a greater improvement in forced expiratory volume in one second at 12 weeks after the procedure, than treating scattered subsegments in both upper lobes. It is hypothesized that full treatment of one lobe prevented collateral ventilation leading to sustained lobar collapse and a better functional result [42]. Phase III studies of BioLVR are not planned.
Initial tests of the ELS (AeriSeal) were performed in 25 patients with heterogeneous emphysema [48]; modest improvements in air trapping and gas transfer were noted among patients with GOLD stage III, but not among those with GOLD stage IV (table 3). The number of subsegment sites treated at one time varied from two to four. Five patients underwent a second instillation of ELS and additional clinical benefit was noted in two. In a randomized trial, 57 patients were randomly assigned to ELS (two subsegments in each upper lobe) plus medical therapy or medical therapy alone and followed for six months. Significant improvements from baseline were noted in lung function, dyspnea, and quality of life at three months when compared to control, and the benefits persisted for six months [49]. However, clinically important adverse events requiring hospitalization occurred in 44 percent of the treatment group in addition to two deaths. The study was terminated early due to financial problems.
Over 90 percent of patients treated with biologic lung volume reduction experience flu-like symptoms, such as fever, dyspnea, pleuritic chest pain, nausea, headache, malaise, and leukocytosis within 24 hours of the procedure [42,48]. These symptoms resolve in 24 to 48 hours.
Thermal airway ablation — The technique of thermal airway ablation involves using a specialized catheter via a flexible bronchoscope to administer steam vapor directly to segmental airways [50]. The procedure utilizes a reusable vapor generator with a disposable bronchoscopic catheter that delivers heated water vapor to the targeted airways. During the procedure, a vapor occlusion balloon is inflated to protect other airways from the heated vapor. The goal is to induce an inflammatory response that will result in occlusion and atelectasis of that segment. It is hoped that the complication rate will be lower than with bronchial valve techniques, as no foreign body is left in place. The procedure is typically performed under general anesthesia.
In a multicenter observational study, 44 patients with upper lobe predominant emphysema underwent unilateral bronchoscopic thermal airway ablation or sham bronchoscopy [51]. At six months, FEV1 was improved by 141 +/- 26 mL over baseline; exercise tolerance and quality of life also improved. Adverse events included exacerbations of COPD, pneumonia, lower respiratory tract infection, and hemoptysis. One patient died during an exacerbation of COPD, two months after the procedure.
Airway bypass procedure — Airway bypass or extra anatomic bronchial fenestration is a technique used to decompress areas of emphysema by placing a drug eluting stent through a bronchial wall into an area with severe emphysematous disease (picture 3). Because of collateral ventilation, emphysematous alveoli receive ventilation through interalveolar pores, accessory respiratory bronchioles, and interlobar pathways across fissures, despite airways obstruction [41]. The degree of collateral ventilation is thought to increase as homogeneity of emphysema increases [52]. The airway bypass technique was developed with the idea that decompression of emphysematous areas would lead to decreased trapped gas and hyperinflation, and allow the chest to resume normal shape and muscle capacity, resulting in better lung function and decreased dyspnea.
A preclinical study using explanted emphysematous lungs found that expiratory airflow almost doubled with placement of five stents and was approximately 50 percent greater than control with three stents [53]. In an animal model, most airway bypass stents became occluded within one week, so drug eluting stents were developed, first mitomycin and then paclitaxel [54,55].
The airway bypass procedure is performed under general anesthesia using a flexible bronchoscope. First, the bronchoscope is passed to an area of known emphysema and a Doppler probe is used to identify a segmental bronchus that is free of blood vessels [41]. Next, a special transbronchial balloon dilation needle is passed through the wall of the bronchus into the adjacent alveolus, creating a fenestration. Finally, a delivery catheter carrying a drug-eluting stent is passed through the fenestration, and the stent is deployed to maintain patency of the fenestration.
Despite evidence of benefit in a preliminary study [56], a multicenter randomized trial (Exhale Airway Stents for Emphysema [EASE trial]) that included 208 subjects with severe homogeneous emphysema did not demonstrate benefit in the co-primary endpoints (improvement in forced vital capacity or modified Medical Research Council dyspnea scale) [57]. This technology is not being pursued further.
OUTCOME MEASURES — The ideal outcome measures for assessing efficacy of lung volume reduction procedures are not known. As the main goal is to reduce dyspnea and improve quality of life, measures of dyspnea, performance of activities of daily living, and quality of life are key. Radiographic, static and dynamic lung volume measures should also be assessed, as these are objective end-points and as most devices aim to improve lung function by reducing hyperinflation. Functional measures such as the six-minute walk distance may also be helpful.
CLINICAL TRIAL SITES — A listing of active clinical trials in this area may be found at www.clinicaltrials.gov using the search terms "bronchoscopy" and "emphysema."
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)
SUMMARY AND RECOMMENDATIONS
●The rationale for lung volume reduction surgery (LVRS) is that removing emphysematous, hyperinflated areas of lung will decrease hyperinflation, improve diaphragm and chest wall mechanics, and decrease work of breathing. Bronchoscopic lung volume reduction (bLVR) was developed to collapse areas of emphysematous lung in hopes of having the same effect on respiratory function as LVRS, but without the morbidity and mortality of surgery. (See 'Rationale for lung volume reduction' above.)
●Patients who might be considered for bLVR in the future would likely have to meet inclusion and exclusion criteria similar to those of the National Emphysema Treatment Trial (NETT) (table 4). (See 'Rationale for lung volume reduction' above.)
●Proposed techniques for bLVR include endobronchial placement of one-way valves, plugs, and coils; biologic sealants; thermal ablation; and airway stents for decompression [3]. The use of plugs, blockers, and stents has been abandoned due to adverse effects. (See 'Techniques' above.)
●Two types of endobronchial valves (EBV) are available for bLVR. The Zephyr EBV uses a duckbill mechanism (picture 1A and picture 1B), while the Spiration EBV is umbrella-shaped and expands on inhalation and contracts on exhalation (picture 2). Both EBVs prevent air from entering the bronchus during inhalation, but allow air and secretions to pass around or through the device during exhalation, thus leading to atelectasis of the lobe. EBV placement may be an option for patients with hyperinflation due to severe emphysema who remain symptomatic despite optimal medical therapy and pulmonary rehabilitation (table 2) and who have a high degree of fissure integrity based on high resolution computed tomography or other testing. Placement of EBVs requires specialized training and equipment. (See 'Endobronchial valves' above and "Management of refractory chronic obstructive pulmonary disease", section on 'Bronchoscopic LVR'.)
●Biologic lung volume reduction uses bronchoscopic instillation of a sealant (eg, a fibrin-thrombin-polymer mixture) to collapse areas of emphysema. (See 'Biologic lung volume reduction' above.)
●The technique of thermal airway ablation involves administering steam vapor directly to segmental airways via a flexible bronchoscope. The goal is to induce an inflammatory response that will result in occlusion and atelectasis of that segment. (See 'Thermal airway ablation' above.)
●Based on available evidence, endobronchial placement of a drug-eluting stent through the bronchial wall to decompress over-inflated areas of emphysema does not appear to improve physiology or dyspnea in patients with severe homogeneous emphysema. (See 'Airway bypass procedure' above.)
●A listing of active clinical trials for bLVR may be found at www.clinicaltrials.gov using the search terms "bronchoscopy" and "emphysema."
