Fig. 31.1
CT reconstruction of a patient with upper lobe predominant emphysema (Diseased lung is represented in blue). This patient with an FEV1 of 0.73 L (24% of predicted) was a candidate for endoscopic lung volume reduction, but a hereditary cardiomyopathy, frequent exacerbations, and pulmonary hypertension were considered contraindications to the procedure
In general, candidates for ELVR must suffer from severe emphysema and moderate to severe dyspnea despite optimal medical therapy. Patients with alpha-1 antitrypsin deficiency have been excluded from clinical trials, although as with other indications, ongoing trials are investigating the role of ELVR for those patients, including the use of coils and valves (NCT02273349 and NCT01357460), and at least one small series showed significant benefit from ELVR in that setting [9]. Ideal candidates for ELVR must be ambulatory and capable of walking at least 100 m with or without supplemental oxygen during a 6 min walk test. They must abstain from smoking and demonstrate severe obstruction on spirometry as well as air trapping and hyperinflation on plethysmography. ELVR should probably not be attempted in patients with residual volumes <175% of predicted. Patients with extremely low diffusing capacities, as well as those with severe gas exchange abnormalities, especially hypercapnic patients, are not considered good candidates for ELVR. Giant bullous or reactive airways disease, severe pulmonary hypertension, frequent exacerbations, or major medical comorbidities are also considered important contraindications. Patients with coexisting bronchiectasis, especially those colonized by P. aeruginosa, should not be treated, while patients with FEV1s less than 20–25% of the age-adjusted predicted value are generally not treated. Also, elderly patients have generally been excluded from clinical trials, so outcomes of ELVR in patients older than 75 are uncertain. Most procedures are performed under general anesthesia or deep sedation, so patients unable to tolerate either cannot be treated. One should keep in mind that each device or technique designed to achieve ELVR is unique, so indications, patient selection, and/or treatment strategy (i.e., unilateral vs. bilateral treatment) may vary.
Description of the Equipment Needed
ELVR can be performed in a variety of hospital settings. Many procedures are performed in the bronchoscopy suite and do not require special equipment beyond that which can generally be found in a well-stocked unit. A diagnostic or therapeutic flexible bronchoscope may be used, depending on the method chosen. Devices tend to require the larger 2.8 mm channel of the therapeutic bronchoscope. Vapor-induced ELVR requires special equipment unique to this procedure.
In general, deployment of most devices, including valves, is straightforward for an experienced bronchoscopist and requires little additional training (Fig. 31.2). That notwithstanding, valve removal can be quite challenging if not impossible in some cases. Coil therapy is best performed under fluoroscopic guidance, a technique familiar to many bronchoscopists who perform transbronchial biopsies or stent implantation. Some bronchoscopists use the Chartis™ system in order to assess fissure integrity and collateral ventilation, but others rely on CT scan data. Finally, some bronchoscopists prefer to treat patients under general anesthesia using the rigid bronchoscope or an endotracheal tube. Anesthesia support is mandatory in such cases, while others prefer conscious sedation which may be administered by the endoscopic team.
Fig. 31.2
Balloon calibration (a) and placement (b) of an IBV device in a patient with severe upper lobe predominant emphysema
Evidence-Based Review
Endobronchial Valves
Endobronchial valves were among the first devices to be developed for ELVR. They have been widely studied, and results from well-designed randomized trials are available and continue to enrich our understanding of how ELVR might benefit selected patients with severe emphysema. The landmark VENT , a multicenter randomized controlled trial, demonstrated that endobronchial valves can achieve modest statistically significant improvements in a variety of endpoints, including lung function, exercise capacity, and quality of life [10]. The study was completed in 2007 and enrolled 321 patients. It compared the safety and efficacy of endobronchial valve therapy employing a unilateral lobar approach in patients with heterogeneous emphysema with optimal medical care. Despite achieving statistical significance, the results were considered by many, including the FDA, underwhelming [11]. Improvements in FEV1 (60 mL), the 6 min walk distance (19 m), and reductions in the SGRQ scores with treatment (3.4 points) have been considered by some clinically insignificant. Careful scrutiny of VENT results, however, left much room for optimism. Improvements in the BODE index, more common among valve treated patients, are provocative since this index correlates well with prognosis in COPD [12]. In addition, patients with complete fissures who achieved a greater than 50% reduction in lobar volume demonstrated clinically relevant improvements in FEV1 (23%) which may have survival implications as demonstrated in a subsequent report from a group of investigators using the same valves as the VENT [13]. These authors found a survival benefit in a small cohort of patients among those who achieved atelectasis at the expense of more pneumothoraces, suggesting that ELVR may match surgical results in some patients with heterogeneous emphysema. A recently published study by Davey et al. confirmed the hypothesis that patients with intact interlobar fissures benefit from ELVR using endobronchial valves [14]. In that randomized, sham-bronchoscopy controlled trial, unilateral lobar occlusion with endobronchial valves placed in patients with heterogeneous emphysema and intact interlobar fissures as measured by CT was associated with significant improvements in lung function and quality of life. Results of the STELVIO randomized trial which assessed collateral ventilation using the Chartis™ system provided further evidence supporting this strategy [15]. In that study, patients treated with endobronchial valves showed a statistically significant benefit from valve treatment with improvements in FEV1, FVC, and 6MWT distance that were clinically relevant. The overall responder rate was 75% when the interlobar fissure was largely intact precluding significant collateral ventilation.
In its ruling denying approval for the Zephyr device (Fig. 31.3) employed in the VENT (a self-expanding nitinol stent with a silicon one-way duckbill valve), the FDA expressed concern regarding the complications of ELVR, including a major increase in the number of hospitalizations for COPD exacerbations in the treatment arm (17 vs. 1) and other complications such as hemoptysis [11]. Fear of the risks undermined the modest benefits of the trial. As a result, more research was requested. Such research is ongoing, including trials investigating patient selection and collateral ventilation, ELVR with valves in patients with less severe obstruction, and treatment of patients with homogeneous emphysema. Furthermore, two studies including long-term follow-up of patients treated with endobronchial valves have shown a significant survival benefit in ELVR responders [13, 16]. An ongoing German multicenter study (NCT01580215) is evaluating long-term follow-up with survival of 5 years posttreatment as a key outcome.
Fig. 31.3
Duck-billed shaped endobronchial valves (Zephyr). Courtesy Dr. Dutau
Results from a randomized sham-bronchoscopy controlled trial using the Spiration IBV system (an umbrella-shaped, self-expanding device) were reported some years ago (Fig. 31.4). This smaller trial kept patients blinded for 3 months [17]. The treatment strategy differed significantly from the VENT, since it focused on a bilateral approach purposefully avoiding lobar occlusion by sparing a segmental or subsegmental bronchus in the right upper lobe as well as the lingula on the left side. The trial failed to achieve clinically relevant improvements in hard outcomes such as FEV1 , gas exchange , or exercise capacity but demonstrated statistically significant improvements in a combined endpoint including quality of life and regional lung volume changes as measured by CT. At the conclusion of the Spiration trial, 31% of the treated patients demonstrated an improvement of 8 points in the SGRQ score and a significant regional lung volume reduction in the treated upper lobes. The companion and larger US trial using the IBV system but prolonging blinded follow-up to 6 months was also underwhelming [18]. In that trial, only 6 out of 121 patients in the treatment arm were considered responders. Although lobar volume changes were significantly better in the treated arm vs. control (−224 mL vs. −17 mL), there were no significant differences in quality of life as measured by the St. George’s Respiratory Questionnaire. As expected, serious adverse events were more common in the treatment group (14.1%) compared with the control group (3.7%), although most were neither procedure nor device related (Fig. 31.5). The disappointing results of the bilateral approach avoiding lobar collapse coupled with demonstrable improvements by responders with intact fissures treated with the lobar occlusion method have rendered the strategy used in the Spiration trials obsolete. Interestingly, a pilot trial seeking lobar occlusion found significant improvements in lung function and more impressive reductions in SGRQ scores in patients who achieved atelectasis with the IBV system [19]. The risks associated with this complication motivated the subsequent change in treatment strategy. However, it is clear from the available evidence that while avoiding atelectasis improves safety, it does so at the expense of efficacy. The ongoing EMPROVE study (NCT01812447) will explore the efficacy of the IBV system using the unilateral complete occlusion approach.
Fig. 31.4
Chest radiograph of a patient with upper lobe predominant severe emphysema treated with ten endobronchial valves (IBV). The characteristic umbrella-shaped valves can be seen in both upper lobes. Lobar occlusion was avoided in this patient
Fig. 31.5
Endobronchial valves (IBV) in the right upper lobe 3 years after deployment
Perhaps the most striking finding of the Spiration trials was the impressive magnitude of the placebo effect. Many patients undergoing sham bronchoscopy reported significant benefits in quality of life. Such findings match results from a bronchial thermoplasty trial employing sham bronchoscopy [20]. Clearly, the placebo effect has a significant impact in device-related interventions and should be taken into account in trials using soft endpoints such as quality of life as the primary outcome.
Airway Bypass Tracts
While most ELVR techniques are designed to promote lung volume reduction by limiting flow to the most affected lung parenchyma, Broncus (Mountain View, CA) developed a technique which reduces air trapping by promoting nonanatomic collateral flow. This method of ELVR is known as the Exhale™ emphysema treatment system shunned atelectasis, currently an essential goal of valve treatment, striving instead to create airway fenestrations in order to facilitate exhalation of trapped air. A Doppler system was used in order to avoid damaging major vessels and select the appropriate site for stent deployment using a needle. This approach reduced end-expiratory volume without altering lung recoil and could be tested in patients with both homogeneous and heterogeneous emphysema.
Preliminary evidence treating explanted lungs was quite encouraging. Improvements in FEV1 following deployment of multiple stents in one small study of 12 explanted lungs were dramatic [21]. Outcomes in vivo however were frustrating, mostly as a consequence of stent occlusion by granulation tissue. Drug eluting stents have been created to avoid this complication and seem to work in animal studies, prolonging patency [22]. An open-label study of the drug-eluting stents showed that the Exhale™ system can reduce hyperinflation for a limited time in a selected group of patients with severe emphysema [23]. Unfortunately, while results at 1 month were impressive including improvements in FEV1 , quality of life, and total lung capacity in more than 30 treated patients, results at 6 months were less encouraging. Post-procedure complications including COPD exacerbations were relatively frequent, and one patient died as a consequence of massive hemoptysis induced by stent implantation.
The Exhale™ system was used in a multicenter randomized, sham-bronchoscopy controlled trial known as EASE (Exhale Airway Stents for Emphysema) [24]. Three hundred and fifteen patients with severe hyperinflation defined as a ratio of residual volume to total lung capacity of ≥0.65 from 38 centers worldwide were enrolled. Patients were followed for 12 months. Treated patients did not achieve the co-primary endpoints of a 12% improvement in FVC and one-point improvement in the mMRC dyspnea score when compared to controls, though the latter did show a statistically significant improvement. Only 30 out of 208 treated patients met the co-primary endpoint, although a considerable mean reduction in residual volume averaging 0.5 L was achieved in 40% of the treated patients. This finding predicted clinical success. The 6-month composite primary safety endpoint combining five severe adverse events was 14.4% for the treatment arm which compared favorably with 11.2% for the control group and was judged non-inferior. This ELVR technique is currently not available in the USA or Europe [25].
Biologic/Polymer Lung Volume Reduction
Biologic lung volume reduction, unlike its predecessors, was not device based. This method of ELVR, developed by Aeris Therapeutics (Woburn, MA), sought to achieve its goals employing tissue engineering principles [26]. Remodeling of damaged lung parenchyma by the next-generation polymer-based treatment created progressive atelectasis in treated subsegments of the upper lobes, thus promoting true lung volume reduction (Figs. 31.6 and 31.7). The ability of the polymer to spread through the airway limited the impact of collateral ventilation , a major concern with endobronchial valves. Treatment was found to be irreversible and frequently associated with considerable, though relatively brief, inflammation which mandated prophylactic treatment with steroids and antibiotics, akin to a COPD exacerbation in most treated patients. A preliminary small open-label phase I trial showed the treatment to be safe and moderately effective in a small group of patients [27]. Results from a phase 2 clinical trial enrolling 50 patients were subsequently reported [28]. High-dose therapy was effective in that trial and yielded sustained benefits, but COPD exacerbations were frequent, occurring in 28% of treated patients. A subsequent trial enrolling patients with homogeneous emphysema also showed benefit with high-dose treatment and had a similar safety profile [29]. Evidence from three separate clinical trials demonstrated the benefit of polymer treatment independent of fissure integrity, rendering it a promising option for ELVR in patients with significant collateral ventilation [30]. A prospective multicenter randomized trial of polymer-induced lung volume reduction known as the ASPIRE trial (NCT01449292) was initiated but terminated prematurely for lack of funding. Ninety-five patients had been randomized prior to study termination. FEV1, dyspnea scores, and quality of life showed improvements at 3 months following treatment. The benefit was sustained at 6 months, but unfortunately 44% of treated patients required hospitalization, and two deaths were reported (p = 0.01) [31]. The premature termination of the study was a blow to the technique, but following the acquisition of Aeris Therapeutics by Pulmonx, AeriSeal® received CE mark approval at the end of 2015 and is currently pending re-introduction in 2016 (Fig. 31.8).
