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INVITED REVIEW SERIES: UPDATE IN INTERVENTIONAL PULMONOLOGY SERIES EDITORS: FABIEN MALDONADO; ERIC S. EDELL; PATRICK J. BARRON AND REX C. YUNG
Bronchoscopic interventions for chronic obstructive pulmonary disease MASAMICHI MINESHITA1 AND DIRK-JAN SLEBOS2 1 Division of Respiratory and Infectious Diseases, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan, and 2Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
ABSTRACT Over the past decade, several non-surgical and minimally invasive bronchoscopic lung volume reduction (BLVR) techniques have been developed to treat patients with severe chronic obstructive pulmonary disease (COPD). BLVR can be significantly efficacious, suitable for a broad cohort of patients, and associated with a solid safety profile at a reasonable expense. The introduction of BLVR is also expected to accelerate the further development of interventional pulmonology worldwide. Recently, results from clinical studies on BLVR techniques have been published, providing valuable information about the procedure’s indications, contraindications, patient-selection criterion and outcomes. BLVR utilizing one-way endobronchial valves is gaining momentum as an accepted treatment in regular medical practice because of the identification of best responders. Patients with a heterogeneous emphysema distribution and without inter-lobar collateral ventilation show encouraging results. Furthermore, for patients with collateral ventilation, who are not considered candidates for valve treatment, and for patients with homogeneous emphysema, the introduction of lung volume reduction coil treatment is a promising solution. Moreover, with the development of newer treatment modalities, that is, biochemical sealant and thermal water vapor, the potential to treat emphysema irrespective of collateral flow, may be further increased. Nevertheless, patient selection for BLVR treatment will be crucial for the procedure’s success and should be performed using a multidisciplinary team approach. Correspondence: Dirk-Jan Slebos, Department of Pulmonary Diseases, AA11, University Medical Center Groningen, PO Box 30001, 9700RB Groningen, The Netherlands. Email: d.j.slebos @umcg.nl The Authors: Dr. Masamichi Mineshita is a pulmonary physician and bronchoscopist focusing on pharmacological and nonpharmacological treatments for patients with chronic obstructive pulmonary disease. Dr. Dirk-Jan Slebos is a pulmonary physician and interventional bronchoscopist, specializing in the development of innovative non-pharmacological treatments for patients with lung disease. Received 25 February 2014; invited to revise 1 April 2014; revised 30 May 2014; accepted 30 June 2014. © 2014 Asian Pacific Society of Respirology
Consequently, BLVR needs to be concentrated in highvolume centres that will offer better quality and experience with treatment challenges and adverse events.This review gives a general overview of BLVR from an expert and scientific perspective. Key words: bronchoscopic lung volume reduction, bronchoscopy, COPD, emphysema, lung volume reduction. Abbreviations: 6MWT, 6-min walk test; BLVR, bronchoscopic lung volume reduction; BTVA, bronchoscopic thermal vapor ablation; COPD, chronic obstructive pulmonary disease; CT, computed tomography; CV, collateral ventilation; EASE, exhale airway stents for emphysema; EBV, Zephyr endobronchial valve; ELS, emphysematous lung sealant; EWS, Endobronchial Watanabe Spigots; FEV1, forced expiratory volume in one second; IBV, spiration intrabronchial valve; LVRC, lung volume reduction coil; LVRS, lung volume reduction surgery; MDT, multidisciplinary team; MMRC, modified Medical Research Council; NETT, National Emphysema Treatment Trial; QOL, quality of life; RV, residual volume; SGRQ, St. George’s Respiratory Questionnaire; TLC, total lung capacity; VATS, video-assisted thoracoscopic surgery; VENT, Endobronchial Valve for Emphysema Palliation Trial.
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide; it results in an economic and social burden that is substantial and increasing.1 COPD is a preventable disease, but it is difficult to treat. Smoking cessation, bronchodilators, anti-inflammatory agents, proper nutrition, pulmonary rehabilitation and the use of oxygen are available options for treating COPD. All of these therapies aim to palliate the dyspnoea sensation, reduce the frequency and severity of exacerbations and improve exercise capacity and quality of life (QoL). However, in patients with severe COPD, the effects are generally marginal and cannot significantly improve limited exercise capacity and QoL. In selected patients with severe COPD, advanced surgical treatment options are available. Lung Respirology (2014) doi: 10.1111/resp.12362
2 transplantation for appropriate patients has shown to improve pulmonary function and QOL;2,3 however, the shortage of donor organs, various postoperative comorbidities and the major costs involved are important limiting factors for this treatment. Furthermore, the survival benefit that lung transplantation offers for COPD remains to be measured.4 Other surgical techniques used to treat emphysema include the excision of large bullae (bullectomy) and the resection of emphysematous lung tissue. Lung volume reduction surgery (LVRS) has also been performed to palliate the symptoms of severe emphysema.5 Surgical approaches include median sternotomy, unilateral or bilateral thoracotomy, video-assisted thoracoscopic surgery (VATS) with stapled, laser ablation6 or nonresectional LVRS.7 The supposed mechanisms by which LVRS relieves symptoms in COPD patients are as follows: (i) a reduction in hyperinflation, resulting in improved diaphragm and chest wall mechanics; (ii) an increase in elastic recoil pressure, which leads to augmented expiratory flow rates; and (iii) an improvement in gas exchange.8 In the patients with predominant upper-lobe emphysema and a low exercise capacity, LVRS had a substantial survival advantage, with improved exercise capacity and QoL compared with medical therapy.9 In comparison, with up to 5% 90-day mortality and more than 50% of patients having had at least one postoperative major complication, LVRS must be considered an invasive intervention associated with prohibitive risks. The majority of patients with COPD do not qualify for LVRS because of its strict indications, high costs and invasiveness. Furthermore, because there are only a few very highly experienced centres in the world, the number of patients who underwent LVRS is decreasing. Over the past decade, influenced by the LVRS’ apparent benefits in patients with upper-lobe predominant emphysema, non-surgical bronchoscopic approaches to reduce lung volume have been developed as potentially less invasive treatment options.10–13 Bronchoscopic lung volume reduction (BLVR) techniques have the potential of being significantly efficacious and suitable for a wider group of patients than the current surgical techniques with lower proceduralrelated mortality, morbidity and costs. Recently, an increasing number of original clinical studies on BLVR techniques have been published. These studies have provided valuable information about indications, contraindications, patient selection criterion and outcomes, although at this time, there is limited evidence to support BLVR in clinical practice compared with LVRS. In this review, we describe an overview of BLVR techniques, guidelines for BLVR treatment and future perspectives and challenges for BLVR from a scientific perspective.
BRONCHOSCOPIC LUNG VOLUME REDUCTION TECHNIQUES To date, many types of BLVR techniques have been developed and investigated, or are under developRespirology (2014)
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ment. In this review, we intend to summarize the most current and most investigated BLVR techniques (Table 1).14–24
Airway blocker The Endobronchial Watanabe Spigots (EWS; Novatech, La Ciotat, France) is made of silicone and is the only bronchial plug available on the market today.25 The EWS was initially introduced for pulmonary fistula and intractable pneumothorax management. Although the EWS has been used for pneumothorax with emphysema, results have only been reported in abstract form, and the efficacy of the EWS for BLVR has yet to be confirmed by randomized clinical studies. One-way endobronchial valves were developed at the start of this century.10 These devices block the airflow to the treated lobe during inspiration while permitting the emission of secretions and air from the lobe during expiration. They have been found to improve lung function, exercise tolerance and symptoms in patients with advanced heterogeneous and hyper-inflated emphysema. Two types of valves have acquired Conformité Européenne (CE) qualification and are available in some countries: the Zephyr endobronchial valves (EBV; Fig. 1; Pulmonx, Inc., Palo Alto, CA., USA) and the Spiration intrabronchial valves (IBV; Olympus Respiratory America, Redmond, WA., USA). Both devices are loaded in a delivery catheter that can be introduced through the working channel of a flexible bronchoscope. These valves are then expanded to their original form after reloading from the catheter. Knowledge about this technique has been accumulated from many clinical studies.14–18,26,27 Zephyr endobronchial valves Wan et al.26 reported on the first multicenter trial of BLVR using EBV. Their subgroup analysis revealed that EBV showed the greatest benefit in patients with unilateral and lobar exclusion. Based on these findings, Sciurba et al. conducted a randomized, prospective, multicentre study (Endobronchial Valve for Emphysema Palliation Trial (VENT)) to determine the safety and efficacy of unilateral complete isolation of the target lobe using EBV compared with standard medical care.14 Three hundred and twenty-one COPD patients with heterogeneous emphysema were enrolled and randomly assigned to the BLVR group (n = 220) or a control group (n = 101). At 6 months, a significant increase of 4.3% in forced expiratory volume over one second (FEV1) was observed in the EBV group, while a decrease of 2.5% was observed in the control group, with a similar between-group difference also observed for the 6-min walk test (6MWT). Radiographic evidence of emphysema heterogeneity and fissure completeness was found to enhance the effect of EBV treatment. Patients whose emphysema was evaluated as highly heterogeneous showed 10.7% improvement, and those with complete fissures had 16.2% improvement in FEV1 at 6 months after EBV placement. In contrast, there were insignificant changes in FEV1 at 6 months of 2.0% in patients with low heterogeneity and 2.5% in © 2014 Asian Pacific Society of Respirology
Design
© 2014 Asian Pacific Society of Respirology hetero
hetero
hetero
hetero
hetero
hetero
both
hetero both
hetero
homo
220
111
91
37
51
25
20
16
23
44
208
bilateral
unilateral
bilateral
bilateral
bilateral
unilateral
unilateral
bilateral
bilateral
unilateral
unilateral
Procedure: unilateral or bilateral
+7 m (3 months) +24 m (1 month)
−0.09 L (3 months) +16%## (1 month)
+46.5 m**
−7 m
−0.01 L
+51.2 m## (3 month)
+14.2%# (3 month)
+0.14 L**
+32.9%*
+11.8 m
+14.9%**
+31.2%**
+24.6 m
+43 feet
−0.04 L
+10.0%*
+15 m
+2.5%#
6MWT
+7%
+4.3%##
FEV1
13.6%
−14.0 points**
−2 points
8.7% (3 month)
10%
−8.0 points
−8.1 points# (3 month)
12%
−7.5 points*
31.3%
2% (1 month)
−10 points (1 month)
−14.9 points**
0 (3 month)
2.2%
−4.3 points (3 months)
−8.2 points**
10.8%
−5 points#
Pneumonia
3.2% (3 month)
SGRQ
−2.8 points#
Outcome at 6 months (unless otherwise stated)
2.5%
0%
8.7% (3 month)
6.3%
5%
0%
7.8% (1 month)
0 (3 month)
6.6%
5.4%
4.2% (3 month)
Pneumothorax
10.6%
20.4%
21.7% (3 month)
25%
15%
40%
2% (1 month)
1.1%
23.4%
7.9% (3 month)
Acute exacerbations (hospitalized)
Adverse event during 6 months (unless otherwise stated)
0
1 case
0 (3 month)
0
1 case
0
0 (1 month)
0 (3 month)
3 cases
0
1 case
Related death
* P < 0.05 compared to base line, ** P < 0.01 compared to base line, # P < 0.05 compared to control, ## P < 0.01 compared to control. 6MWT, 6-min walk test; EBV, Zephyr endobronchial valve; ELS, emphysematous lung sealant; FEV1, forced expiratory volume over one second; IBV, spiration intrabronchial valve; LVRC, lung volume reduction coil; SGRQ, St. George’s Respiratory Questionnaire.
One-way valve open, EBV14 randomized, multicenter open, EBV15 randomized, multicenter IBV16 open, observational, multicentre IBV17 single-blind, randomized, multicenter 18 EBV open, observational, multicentre Sealant 19 ELS open, observational, multicentre ELS20 open, observational, multicentre Coil LVRC21 open, observational LVRC22 open, randomized, multicenter Vapor InterVapor23 open, observational, multicentre Airway bypass Exhale24 double-blind, randomized, multi-centre
Technique
No. of patients treated
Emphysema phenotype: hetero, homo, or both
Table 1 Summary of reported bronchoscopic lung volume reduction trials
Bronchoscopic treatment of COPD
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a
c
b
d
patients with incomplete fissures. Regarding adverse events, there were increased rates of exacerbation requiring hospitalization and hemoptysis in the EBV group compared with the control group at 90 days. Pneumothorax lasting longer than 7 days occurred in 1.4% of patients in the EBV group 90 days after treatment. At 12 months, the difference in the composite rate for six major complications (death, empyema, massive hemoptysis, pneumonia distal to valves, pneumothorax duration of more than 7 days or ventilator-dependent respiratory failure for more than 24 h) between the EBV group (10.3%) and the control group (4.6%) were not significant. The rate of pneumonia in the target lobe for the EBV group was 4.2% at 12 months. The results of the European VENT study demonstrated efficacy and adverse event profiles after EBV treatment similar to those of the original VENT study.15 Although EBV patients with complete fissure and lobar occlusion achieved 80% target lobar volume reduction, emphysema heterogeneity was not critical for determining positive outcomes in the European cohort.
Spiration intrabronchial valves Sterman et al. conducted a multicentre pilot study consisting of 91 patients with severe obstruction, hyperinflation and upper lobe-predominant emphysema to reveal the safety and effectiveness of bilateral upper lobe occlusion using IBV.16 Although there were Respirology (2014)
Figure 1 (a) Schematic of a one-way endobronchial valve (EBV, Zephyr, Pulmonx Inc. CA, USA, printed with permission). (b) Bronchoscopic view of the deployment of an EBV at the distal side just outside the delivery catheter and its placement on a distal carina, after which the EBV can be released proximally. (c) Bronchoscopic view of EBV in situ on inspiration (valve closed to prevent air from entering) and (d) EBV during expiration (valve open to release air).
significant improvements in health-related QoL and a decrease in the treated upper lobe volume, FEV1, exercise tests and total lung volume did not show significant changes at 6 months. In this study, there were three deaths directly or indirectly related to pneumothorax. Because there were five pneumothoraxes in 17 patients with total occlusion of the left upper lobe, the authors recommend avoiding complete occlusion of the lobe until methods to predict the risk of pneumothorax are developed. After this pilot study, a multicentre, blinded, sham-controlled study was performed to assess the safety and effectiveness of bilateral incomplete upper lobe occlusion using IBV.17 Patients with upper lobe-predominant emphysema were randomized to bronchoscopy with (n = 37) or without (n = 36) IBV treatment. Outcomes were evaluated using the composite endpoints of the St. George’s Respiratory Questionnaire (SGRQ) total score (with responders defined as those who exhibit a change of ≥4 points) and lung volume changes measured with computed tomography (CT) scans at 3 months. There was a positive responder rate of 24% in the treated group versus 0% in the control group, with a significant volume shift in the treated group from the upper lobes to the non-treated lobes but only minimal changes in the control group. There were no differences in the incidence of adverse events in the treatment and control groups. No pneumothoraxes were reported in the treated group; however, there were © 2014 Asian Pacific Society of Respirology
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Bronchoscopic treatment of COPD
Figure 2 (a) The Chartis balloon for measuring collateral ventilation (Pulmonx Inc. CA, USA, printed with permission). (b) Bronchoscopic view of the Chartis balloon blocking the right lower lobe (RLL) entrance to measure collateral ventilation across the major fissure between the RLL versus the right upper lobe and right middle lobe (RML). (c) Example image of the Chartis system showing an absence of collateral ventilation (‘CV-negative’). The orange pattern shows the expired airflow (ml/min) breath-by-breath. The decreasing pattern indicates no collateral flow. The blue pattern shows the breath-by-breath negative intrapleural pressure (cmH2O), indicating a perfect balloon seal. (d) Example image of the Chartis system showing the presence of ‘CV-positive’ in a patent expiratory flow pattern, indicating no collateral flow.
a
no significant improvements in the mean SGRQ total score, pulmonary function tests and 6MWT when compared with the control group. The authors concluded that bilateral incomplete occlusion of the upper lobe using IBV was safe but not effective in the majority of patients. Eberhardt et al. compared the efficacy of unilateral complete lobar occlusion and bilateral incomplete lobar occlusion using IBV.27 Twenty-two patients with severe bilateral heterogeneous emphysema were randomized into unilateral or bilateral treatment groups. The unilateral treatment group showed significant improvements in pulmonary function tests, 6MWT, the modified Medical Research Council (MMRC) dyspnoea score and SGRQ scores compared with the bilateral treatment group at 90 days. There was one patient with pneumothorax in the unilateral group and two patients with transient respiratory failure in the bilateral group. Based on these results, unilateral IBV placement with complete occlusion seems to be effective compared with bilateral incomplete occlusion.
Inter-lober collateral ventilation Although lung volume reduction,10 reduction of dynamic hyperinflation28 and redirection of inspired air to the lesser diseased lung tissue29 have been reported as effective mechanisms, at the present time, complete lobar occlusion to produce the © 2014 Asian Pacific Society of Respirology
b
c
d
desired volume reduction is thought to be necessary to achieve significant clinical effectiveness.27,30 The presence of inter-lobar collateral ventilation (CV) interferes with lobar collapse despite the adequate positioning and function of one-way valves. Because more than half of severe emphysema patients have significant inter-lobar CV,31 the indirect evaluation of CV via the assessment of fissure completeness alone14 or, for greater accuracy, combined with direct CV measurements via an endobronchial catheter system (Fig. 2; Chartis System, Pulmonx Inc., Redwood, CA., USA)18,32 is indispensable for accurate patient selection.
Selection of the target lobe The selection of the target lobe for bronchial occlusion is crucial. Although the most affected emphysematous lobe is usually selected, confirmation by low-baseline regional perfusion of the target lobe may enhance clinical results.33 Furthermore, the existence of expandable ipsilateral lobes with less emphysematous destruction is required for desirable clinical effectiveness after valve treatment. Unilateral complete lobar occlusion using one-way valves in severe emphysema patients with negative or reduced inter-lobar CV is reported to achieve an increase of more than 20% in FEV1 and clinically significant improvements in exercise performance and QoL.14,15,18 Respirology (2014)
6 Management of pneumothorax after one-way endobronchial valve treatment Among the adverse events of this procedure, pneumothorax is the main complication directly related to the insertion of the valves. In an early report that attempted to occlude the bilateral upper lobes, three pneumothorax-related deaths were reported, and subsequently, this approach was quickly abandoned.16 Although pneumothorax-related deaths were not reported after unilateral occlusion was adopted, pneumothoraxes still occur. With the introduction of the Chartis system to select the best responders, the pneumothorax rate increased to an incidence between 10% and 25%. Pneumothoraxes after valve insertion are likely to occur in patients with resultant atelectasis, and most patients who develop pneumothorax are the best responders to one-way valve therapy.15 After treatment, the contracting lobe may cause a rupture in a bullous area because of pleural adhesions. If pneumothorax after valve treatment is mild and the patient does not complain of symptoms, the pneumothorax can be observed. Otherwise, pneumothorax should be managed by catheter drainage with an underwater seal. There are two treatment options for persistent air leaks over 7 days. One is the removal of at least one of the valves, which normally results in a quicker recovery time, with a replacement 2 months after pneumothorax recovery. If the air leak does not improve, all valves should be removed. If these procedures fail to control the air leak, VATS should be considered.34 The other treatment option is a conversion to VATS without removing the valves, because in many cases, the lesion causing the pneumothorax is a ruptured bulla of the expanding lobe. Ongoing trials In June 2011, a Dutch prospective randomized control trial (STELVIO trial, NTR2876) investigated the efficacy of EBV treatment in patients with high heterogeneity but with no collateral flow (measured with the Chartis system). This trial is expected to be completed by 2014. Additionally in 2013, a large multicentre randomized control trial (LIBERATE Trial, NCT01796392) began using the same approach as the Dutch trial. These trials should provide further insight into developing patient selection criterion and may possibly make inroads for BLVR in COPD treatment guidelines. Furthermore, regarding the 2013 IBV approach, a multicentre randomized control trial has begun to investigate the safety and effectiveness of IBV treatment focusing on lobar atelectasis in patients with complete inter-lobar fissure as assessed with CT (EMPROVE study, NCT01812447). Sealant To produce secure lung volume reduction by blocking abundant collateral ventilation pathways in emphysematous lesions, procedures that instill ‘sealant’ into the lung parenchyma to induce inflammation and subsequent fibrosis have been studied. BLVR using the administration of biological substances (fibrinogen biopharmaceutical suspension and thrombin Respirology (2014)
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solution) reduced lung volumes and improved pulmonary function in patients with advanced upper lobe emphysema with acceptable adverse events.35 Subsequently, biological substances were replaced with synthetic polymeric foam (emphysematous lung sealant (ELS); Aeris Therapeutics, Woburn, MA, USA). ELS foam sealant is prepared by adding a cross-link consisting of diluted, buffered pentane 1–5 dial in aqueous polymer solution containing 2% aminated polyvinylalcohol; 5 mL of this solution is mixed with 15 mL of air. A total of 20 mL ELS foam sealant is then instilled into the peripheral airways through a singlelumen catheter.19 Herth et al. treated 25 patients with upper lobe-dominant heterogeneous emphysema using ELS instillation into 2–4 sub-segments of the unilateral lung (Fig. 3). All procedures were well tolerated, and there were no treatment-related deaths within 90 days, although flu-like reactions beginning 8–24 h after treatment were observed in almost all patients. The efficacy results 24 weeks after ELS treatments were evaluated in 21 patients and showed significant improvement from baseline in FEV1 (+10.0 ± 19.8%), forced vital capacity (+15.8 ± 22.2%) and SGRQ total score (−7.5 ± 14.4 units).19 Kramer et al. performed a bilateral ELS treatment in patients with advanced emphysema. Ten patients with upper lobe-dominant emphysema and 10 patients with homogeneous emphysema were treated using ELS instillation into four sub-segments, two in each upper lobe. The upper lobe lung volume assessed via CT scan analysis decreased significantly (895 ± 484 mL) 3 months post-procedure, while other parameters, such as FEV1 (6 months; +31.2 ± 36.6%, 12 months; +25.0 ± 33.4%) and SGRQ (6 months; −8.0 ± 17.2 units, 12 months; −7.0 ± 15.8 units) also improved significantly.20 However, one case of treatment-related death was reported. In a randomized multicentre study (the AeriSeal System for HyPerInflation Reduction in Emphysema (ASPIRE), NCT01449292), patients with upper lungdominant heterogeneous emphysema were allocated to bilateral ELS treatment or optimal medical therapy, with the primary endpoint of changing baseline FEV1 measurement at 12 months after treatment. This trial started in June 2012 and was aborted in November 2013 because Aeris Therapeutics was not able to continue financing. Despite this early study closure, the results from the patients who were already included and treated will provide valuable information about the safety and efficacy of this treatment, especially regarding the use of sealant to treat patients with abundant collateral flow.
The lung volume reduction coil The lung volume reduction coil (LVRC; PneumRx, Inc., Mountain View, CA, USA), made of preformed nitinol wire, can perform lung volume reduction regardless of the presence of CV by ‘grasping’ lung parenchyma. The LVRC is deployed through a straight delivery catheter into sub-segmental airways using bronchoscopy. After its release from the delivery catheter under fluoroscopy, the LVRC immediately recovers its predetermined coil shape in the surrounding © 2014 Asian Pacific Society of Respirology
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Bronchoscopic treatment of COPD
Figure 3 (a) Bronchoscopic view of the AeriSeal biogel delivery catheter. (b) Visible proximal clot of biogel at the sub-segmental level. (c) Chest X-ray of an upper lobe-predominant emphysema patient before, and (d) 1 month after treatment with AeriSeal biogel with a visible tissue reaction to the sealant in both upper lobes (arrows) and visible volume reduction.
Figure 4 (a) Nitinol RePneu® lung volume reduction coil (PneumRx, Inc., CA, USA, printed with permission). (b) Right upper lobe X-ray detail posttreatment showing 10 lung volume reduction coils placed in the three upper lobe segments.
a
b
c
d
a
lung parenchyma (Fig. 4).36 Slebos et al. treated 16 severe heterogeneous emphysema patients using LVRC implantation and reported the device’s safety and effectiveness.21 Four patients were treated unilaterally, and 12 patients were treated bilaterally, for a total of 28 procedures using 260 coils (a median of 10 per procedure). There were no procedure-related technical events, and all coils were placed as planned. During the first 30 days after LVRC implantation, one case of pneumothorax, two cases of pneumonia, six cases of COPD exacerbation, four cases of chest pain, and 21 cases of mild ( 55% is key in identifying optimal BLVR candidates. The next step is to review CT scans to allocate patients to either a predominantly homogeneous emphysema group or a heterogeneous emphysema group. This process can be performed using sophisti© 2014 Asian Pacific Society of Respirology
cated CT software;42 however, the presence of a ‘target’ (i.e. a clearly damaged lobe vs a relatively well preserved adjacent lobe) can be well defined by ‘eyeballing’ with a standard CT reading package for axial, sagittal and coronal views. Chest CT can also be useful when checking contraindications for BLVR (Table 3). Respirology (2014)
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Table 3 General inclusion and exclusion criteria for bronchoscopic lung volume reduction Inclusion criteria • COPD • Non-smoker • Post-pulmonary rehabilitation • Pulmonary function: ○ FEV1 < 45% predicted ○ RV > 180% predicted ○ RV/TLC > 55% predicted
Exclusion criteria • Previous lobectomy or pneumonectomy • Severe bronchiectasis, recurrent hospitalizations for infectious lung disease • PaO2 < 6.0 kPa or PaCO2 > 8.0 kPa (at room air and sea level) • Right ventricular systolic pressure > 50 mm Hg (echocardiogram) • Significant cardiac comorbidity • Systemic anticoagulant therapy that cannot be withheld such as warfarin, coumarins, clopidogrel • Chest CT comorbidities: ○ unstable nodule ○ lung fibrosis ○ paraseptal emphysema ○ giant bullae ○ severe bronchiectasis ○ significant thoracic aneurism
COPD, chronic obstructive pulmonary disease; CT, computed tomography; FEV1, forced expiratory volume over one second; RV, residual volume; TLC, total lung capacity.
COPD patients with the small airway diseasedominant phenotype are excluded from the currently available BLVR technique. For patients with heterogeneous emphysema, which can be either an upper or lower lobepredominant disease, the main fissure has to be assessed for completeness by a trained physician or radiologist using a thin-slice volume CT in three planes, although significant inter-observer variability has to be taken into account.43 After CT review and once the fissure of at least one of both lungs is near complete (>80%), we functionally assess collateral flow using the Chartis system. Patients who have no collateral flow are then treated using a lobar occlusion approach with one-way endobronchial valves.18 Patients who have an incomplete fissure (
INVITED REVIEW SERIES: UPDATE IN INTERVENTIONAL PULMONOLOGY SERIES EDITORS: FABIEN MALDONADO; ERIC S. EDELL; PATRICK J. BARRON AND REX C. YUNG
Bronchoscopic interventions for chronic obstructive pulmonary disease MASAMICHI MINESHITA1 AND DIRK-JAN SLEBOS2 1 Division of Respiratory and Infectious Diseases, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan, and 2Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
ABSTRACT Over the past decade, several non-surgical and minimally invasive bronchoscopic lung volume reduction (BLVR) techniques have been developed to treat patients with severe chronic obstructive pulmonary disease (COPD). BLVR can be significantly efficacious, suitable for a broad cohort of patients, and associated with a solid safety profile at a reasonable expense. The introduction of BLVR is also expected to accelerate the further development of interventional pulmonology worldwide. Recently, results from clinical studies on BLVR techniques have been published, providing valuable information about the procedure’s indications, contraindications, patient-selection criterion and outcomes. BLVR utilizing one-way endobronchial valves is gaining momentum as an accepted treatment in regular medical practice because of the identification of best responders. Patients with a heterogeneous emphysema distribution and without inter-lobar collateral ventilation show encouraging results. Furthermore, for patients with collateral ventilation, who are not considered candidates for valve treatment, and for patients with homogeneous emphysema, the introduction of lung volume reduction coil treatment is a promising solution. Moreover, with the development of newer treatment modalities, that is, biochemical sealant and thermal water vapor, the potential to treat emphysema irrespective of collateral flow, may be further increased. Nevertheless, patient selection for BLVR treatment will be crucial for the procedure’s success and should be performed using a multidisciplinary team approach. Correspondence: Dirk-Jan Slebos, Department of Pulmonary Diseases, AA11, University Medical Center Groningen, PO Box 30001, 9700RB Groningen, The Netherlands. Email: d.j.slebos @umcg.nl The Authors: Dr. Masamichi Mineshita is a pulmonary physician and bronchoscopist focusing on pharmacological and nonpharmacological treatments for patients with chronic obstructive pulmonary disease. Dr. Dirk-Jan Slebos is a pulmonary physician and interventional bronchoscopist, specializing in the development of innovative non-pharmacological treatments for patients with lung disease. Received 25 February 2014; invited to revise 1 April 2014; revised 30 May 2014; accepted 30 June 2014. © 2014 Asian Pacific Society of Respirology
Consequently, BLVR needs to be concentrated in highvolume centres that will offer better quality and experience with treatment challenges and adverse events.This review gives a general overview of BLVR from an expert and scientific perspective. Key words: bronchoscopic lung volume reduction, bronchoscopy, COPD, emphysema, lung volume reduction. Abbreviations: 6MWT, 6-min walk test; BLVR, bronchoscopic lung volume reduction; BTVA, bronchoscopic thermal vapor ablation; COPD, chronic obstructive pulmonary disease; CT, computed tomography; CV, collateral ventilation; EASE, exhale airway stents for emphysema; EBV, Zephyr endobronchial valve; ELS, emphysematous lung sealant; EWS, Endobronchial Watanabe Spigots; FEV1, forced expiratory volume in one second; IBV, spiration intrabronchial valve; LVRC, lung volume reduction coil; LVRS, lung volume reduction surgery; MDT, multidisciplinary team; MMRC, modified Medical Research Council; NETT, National Emphysema Treatment Trial; QOL, quality of life; RV, residual volume; SGRQ, St. George’s Respiratory Questionnaire; TLC, total lung capacity; VATS, video-assisted thoracoscopic surgery; VENT, Endobronchial Valve for Emphysema Palliation Trial.
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide; it results in an economic and social burden that is substantial and increasing.1 COPD is a preventable disease, but it is difficult to treat. Smoking cessation, bronchodilators, anti-inflammatory agents, proper nutrition, pulmonary rehabilitation and the use of oxygen are available options for treating COPD. All of these therapies aim to palliate the dyspnoea sensation, reduce the frequency and severity of exacerbations and improve exercise capacity and quality of life (QoL). However, in patients with severe COPD, the effects are generally marginal and cannot significantly improve limited exercise capacity and QoL. In selected patients with severe COPD, advanced surgical treatment options are available. Lung Respirology (2014) doi: 10.1111/resp.12362
2 transplantation for appropriate patients has shown to improve pulmonary function and QOL;2,3 however, the shortage of donor organs, various postoperative comorbidities and the major costs involved are important limiting factors for this treatment. Furthermore, the survival benefit that lung transplantation offers for COPD remains to be measured.4 Other surgical techniques used to treat emphysema include the excision of large bullae (bullectomy) and the resection of emphysematous lung tissue. Lung volume reduction surgery (LVRS) has also been performed to palliate the symptoms of severe emphysema.5 Surgical approaches include median sternotomy, unilateral or bilateral thoracotomy, video-assisted thoracoscopic surgery (VATS) with stapled, laser ablation6 or nonresectional LVRS.7 The supposed mechanisms by which LVRS relieves symptoms in COPD patients are as follows: (i) a reduction in hyperinflation, resulting in improved diaphragm and chest wall mechanics; (ii) an increase in elastic recoil pressure, which leads to augmented expiratory flow rates; and (iii) an improvement in gas exchange.8 In the patients with predominant upper-lobe emphysema and a low exercise capacity, LVRS had a substantial survival advantage, with improved exercise capacity and QoL compared with medical therapy.9 In comparison, with up to 5% 90-day mortality and more than 50% of patients having had at least one postoperative major complication, LVRS must be considered an invasive intervention associated with prohibitive risks. The majority of patients with COPD do not qualify for LVRS because of its strict indications, high costs and invasiveness. Furthermore, because there are only a few very highly experienced centres in the world, the number of patients who underwent LVRS is decreasing. Over the past decade, influenced by the LVRS’ apparent benefits in patients with upper-lobe predominant emphysema, non-surgical bronchoscopic approaches to reduce lung volume have been developed as potentially less invasive treatment options.10–13 Bronchoscopic lung volume reduction (BLVR) techniques have the potential of being significantly efficacious and suitable for a wider group of patients than the current surgical techniques with lower proceduralrelated mortality, morbidity and costs. Recently, an increasing number of original clinical studies on BLVR techniques have been published. These studies have provided valuable information about indications, contraindications, patient selection criterion and outcomes, although at this time, there is limited evidence to support BLVR in clinical practice compared with LVRS. In this review, we describe an overview of BLVR techniques, guidelines for BLVR treatment and future perspectives and challenges for BLVR from a scientific perspective.
BRONCHOSCOPIC LUNG VOLUME REDUCTION TECHNIQUES To date, many types of BLVR techniques have been developed and investigated, or are under developRespirology (2014)
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ment. In this review, we intend to summarize the most current and most investigated BLVR techniques (Table 1).14–24
Airway blocker The Endobronchial Watanabe Spigots (EWS; Novatech, La Ciotat, France) is made of silicone and is the only bronchial plug available on the market today.25 The EWS was initially introduced for pulmonary fistula and intractable pneumothorax management. Although the EWS has been used for pneumothorax with emphysema, results have only been reported in abstract form, and the efficacy of the EWS for BLVR has yet to be confirmed by randomized clinical studies. One-way endobronchial valves were developed at the start of this century.10 These devices block the airflow to the treated lobe during inspiration while permitting the emission of secretions and air from the lobe during expiration. They have been found to improve lung function, exercise tolerance and symptoms in patients with advanced heterogeneous and hyper-inflated emphysema. Two types of valves have acquired Conformité Européenne (CE) qualification and are available in some countries: the Zephyr endobronchial valves (EBV; Fig. 1; Pulmonx, Inc., Palo Alto, CA., USA) and the Spiration intrabronchial valves (IBV; Olympus Respiratory America, Redmond, WA., USA). Both devices are loaded in a delivery catheter that can be introduced through the working channel of a flexible bronchoscope. These valves are then expanded to their original form after reloading from the catheter. Knowledge about this technique has been accumulated from many clinical studies.14–18,26,27 Zephyr endobronchial valves Wan et al.26 reported on the first multicenter trial of BLVR using EBV. Their subgroup analysis revealed that EBV showed the greatest benefit in patients with unilateral and lobar exclusion. Based on these findings, Sciurba et al. conducted a randomized, prospective, multicentre study (Endobronchial Valve for Emphysema Palliation Trial (VENT)) to determine the safety and efficacy of unilateral complete isolation of the target lobe using EBV compared with standard medical care.14 Three hundred and twenty-one COPD patients with heterogeneous emphysema were enrolled and randomly assigned to the BLVR group (n = 220) or a control group (n = 101). At 6 months, a significant increase of 4.3% in forced expiratory volume over one second (FEV1) was observed in the EBV group, while a decrease of 2.5% was observed in the control group, with a similar between-group difference also observed for the 6-min walk test (6MWT). Radiographic evidence of emphysema heterogeneity and fissure completeness was found to enhance the effect of EBV treatment. Patients whose emphysema was evaluated as highly heterogeneous showed 10.7% improvement, and those with complete fissures had 16.2% improvement in FEV1 at 6 months after EBV placement. In contrast, there were insignificant changes in FEV1 at 6 months of 2.0% in patients with low heterogeneity and 2.5% in © 2014 Asian Pacific Society of Respirology
Design
© 2014 Asian Pacific Society of Respirology hetero
hetero
hetero
hetero
hetero
hetero
both
hetero both
hetero
homo
220
111
91
37
51
25
20
16
23
44
208
bilateral
unilateral
bilateral
bilateral
bilateral
unilateral
unilateral
bilateral
bilateral
unilateral
unilateral
Procedure: unilateral or bilateral
+7 m (3 months) +24 m (1 month)
−0.09 L (3 months) +16%## (1 month)
+46.5 m**
−7 m
−0.01 L
+51.2 m## (3 month)
+14.2%# (3 month)
+0.14 L**
+32.9%*
+11.8 m
+14.9%**
+31.2%**
+24.6 m
+43 feet
−0.04 L
+10.0%*
+15 m
+2.5%#
6MWT
+7%
+4.3%##
FEV1
13.6%
−14.0 points**
−2 points
8.7% (3 month)
10%
−8.0 points
−8.1 points# (3 month)
12%
−7.5 points*
31.3%
2% (1 month)
−10 points (1 month)
−14.9 points**
0 (3 month)
2.2%
−4.3 points (3 months)
−8.2 points**
10.8%
−5 points#
Pneumonia
3.2% (3 month)
SGRQ
−2.8 points#
Outcome at 6 months (unless otherwise stated)
2.5%
0%
8.7% (3 month)
6.3%
5%
0%
7.8% (1 month)
0 (3 month)
6.6%
5.4%
4.2% (3 month)
Pneumothorax
10.6%
20.4%
21.7% (3 month)
25%
15%
40%
2% (1 month)
1.1%
23.4%
7.9% (3 month)
Acute exacerbations (hospitalized)
Adverse event during 6 months (unless otherwise stated)
0
1 case
0 (3 month)
0
1 case
0
0 (1 month)
0 (3 month)
3 cases
0
1 case
Related death
* P < 0.05 compared to base line, ** P < 0.01 compared to base line, # P < 0.05 compared to control, ## P < 0.01 compared to control. 6MWT, 6-min walk test; EBV, Zephyr endobronchial valve; ELS, emphysematous lung sealant; FEV1, forced expiratory volume over one second; IBV, spiration intrabronchial valve; LVRC, lung volume reduction coil; SGRQ, St. George’s Respiratory Questionnaire.
One-way valve open, EBV14 randomized, multicenter open, EBV15 randomized, multicenter IBV16 open, observational, multicentre IBV17 single-blind, randomized, multicenter 18 EBV open, observational, multicentre Sealant 19 ELS open, observational, multicentre ELS20 open, observational, multicentre Coil LVRC21 open, observational LVRC22 open, randomized, multicenter Vapor InterVapor23 open, observational, multicentre Airway bypass Exhale24 double-blind, randomized, multi-centre
Technique
No. of patients treated
Emphysema phenotype: hetero, homo, or both
Table 1 Summary of reported bronchoscopic lung volume reduction trials
Bronchoscopic treatment of COPD
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a
c
b
d
patients with incomplete fissures. Regarding adverse events, there were increased rates of exacerbation requiring hospitalization and hemoptysis in the EBV group compared with the control group at 90 days. Pneumothorax lasting longer than 7 days occurred in 1.4% of patients in the EBV group 90 days after treatment. At 12 months, the difference in the composite rate for six major complications (death, empyema, massive hemoptysis, pneumonia distal to valves, pneumothorax duration of more than 7 days or ventilator-dependent respiratory failure for more than 24 h) between the EBV group (10.3%) and the control group (4.6%) were not significant. The rate of pneumonia in the target lobe for the EBV group was 4.2% at 12 months. The results of the European VENT study demonstrated efficacy and adverse event profiles after EBV treatment similar to those of the original VENT study.15 Although EBV patients with complete fissure and lobar occlusion achieved 80% target lobar volume reduction, emphysema heterogeneity was not critical for determining positive outcomes in the European cohort.
Spiration intrabronchial valves Sterman et al. conducted a multicentre pilot study consisting of 91 patients with severe obstruction, hyperinflation and upper lobe-predominant emphysema to reveal the safety and effectiveness of bilateral upper lobe occlusion using IBV.16 Although there were Respirology (2014)
Figure 1 (a) Schematic of a one-way endobronchial valve (EBV, Zephyr, Pulmonx Inc. CA, USA, printed with permission). (b) Bronchoscopic view of the deployment of an EBV at the distal side just outside the delivery catheter and its placement on a distal carina, after which the EBV can be released proximally. (c) Bronchoscopic view of EBV in situ on inspiration (valve closed to prevent air from entering) and (d) EBV during expiration (valve open to release air).
significant improvements in health-related QoL and a decrease in the treated upper lobe volume, FEV1, exercise tests and total lung volume did not show significant changes at 6 months. In this study, there were three deaths directly or indirectly related to pneumothorax. Because there were five pneumothoraxes in 17 patients with total occlusion of the left upper lobe, the authors recommend avoiding complete occlusion of the lobe until methods to predict the risk of pneumothorax are developed. After this pilot study, a multicentre, blinded, sham-controlled study was performed to assess the safety and effectiveness of bilateral incomplete upper lobe occlusion using IBV.17 Patients with upper lobe-predominant emphysema were randomized to bronchoscopy with (n = 37) or without (n = 36) IBV treatment. Outcomes were evaluated using the composite endpoints of the St. George’s Respiratory Questionnaire (SGRQ) total score (with responders defined as those who exhibit a change of ≥4 points) and lung volume changes measured with computed tomography (CT) scans at 3 months. There was a positive responder rate of 24% in the treated group versus 0% in the control group, with a significant volume shift in the treated group from the upper lobes to the non-treated lobes but only minimal changes in the control group. There were no differences in the incidence of adverse events in the treatment and control groups. No pneumothoraxes were reported in the treated group; however, there were © 2014 Asian Pacific Society of Respirology
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Bronchoscopic treatment of COPD
Figure 2 (a) The Chartis balloon for measuring collateral ventilation (Pulmonx Inc. CA, USA, printed with permission). (b) Bronchoscopic view of the Chartis balloon blocking the right lower lobe (RLL) entrance to measure collateral ventilation across the major fissure between the RLL versus the right upper lobe and right middle lobe (RML). (c) Example image of the Chartis system showing an absence of collateral ventilation (‘CV-negative’). The orange pattern shows the expired airflow (ml/min) breath-by-breath. The decreasing pattern indicates no collateral flow. The blue pattern shows the breath-by-breath negative intrapleural pressure (cmH2O), indicating a perfect balloon seal. (d) Example image of the Chartis system showing the presence of ‘CV-positive’ in a patent expiratory flow pattern, indicating no collateral flow.
a
no significant improvements in the mean SGRQ total score, pulmonary function tests and 6MWT when compared with the control group. The authors concluded that bilateral incomplete occlusion of the upper lobe using IBV was safe but not effective in the majority of patients. Eberhardt et al. compared the efficacy of unilateral complete lobar occlusion and bilateral incomplete lobar occlusion using IBV.27 Twenty-two patients with severe bilateral heterogeneous emphysema were randomized into unilateral or bilateral treatment groups. The unilateral treatment group showed significant improvements in pulmonary function tests, 6MWT, the modified Medical Research Council (MMRC) dyspnoea score and SGRQ scores compared with the bilateral treatment group at 90 days. There was one patient with pneumothorax in the unilateral group and two patients with transient respiratory failure in the bilateral group. Based on these results, unilateral IBV placement with complete occlusion seems to be effective compared with bilateral incomplete occlusion.
Inter-lober collateral ventilation Although lung volume reduction,10 reduction of dynamic hyperinflation28 and redirection of inspired air to the lesser diseased lung tissue29 have been reported as effective mechanisms, at the present time, complete lobar occlusion to produce the © 2014 Asian Pacific Society of Respirology
b
c
d
desired volume reduction is thought to be necessary to achieve significant clinical effectiveness.27,30 The presence of inter-lobar collateral ventilation (CV) interferes with lobar collapse despite the adequate positioning and function of one-way valves. Because more than half of severe emphysema patients have significant inter-lobar CV,31 the indirect evaluation of CV via the assessment of fissure completeness alone14 or, for greater accuracy, combined with direct CV measurements via an endobronchial catheter system (Fig. 2; Chartis System, Pulmonx Inc., Redwood, CA., USA)18,32 is indispensable for accurate patient selection.
Selection of the target lobe The selection of the target lobe for bronchial occlusion is crucial. Although the most affected emphysematous lobe is usually selected, confirmation by low-baseline regional perfusion of the target lobe may enhance clinical results.33 Furthermore, the existence of expandable ipsilateral lobes with less emphysematous destruction is required for desirable clinical effectiveness after valve treatment. Unilateral complete lobar occlusion using one-way valves in severe emphysema patients with negative or reduced inter-lobar CV is reported to achieve an increase of more than 20% in FEV1 and clinically significant improvements in exercise performance and QoL.14,15,18 Respirology (2014)
6 Management of pneumothorax after one-way endobronchial valve treatment Among the adverse events of this procedure, pneumothorax is the main complication directly related to the insertion of the valves. In an early report that attempted to occlude the bilateral upper lobes, three pneumothorax-related deaths were reported, and subsequently, this approach was quickly abandoned.16 Although pneumothorax-related deaths were not reported after unilateral occlusion was adopted, pneumothoraxes still occur. With the introduction of the Chartis system to select the best responders, the pneumothorax rate increased to an incidence between 10% and 25%. Pneumothoraxes after valve insertion are likely to occur in patients with resultant atelectasis, and most patients who develop pneumothorax are the best responders to one-way valve therapy.15 After treatment, the contracting lobe may cause a rupture in a bullous area because of pleural adhesions. If pneumothorax after valve treatment is mild and the patient does not complain of symptoms, the pneumothorax can be observed. Otherwise, pneumothorax should be managed by catheter drainage with an underwater seal. There are two treatment options for persistent air leaks over 7 days. One is the removal of at least one of the valves, which normally results in a quicker recovery time, with a replacement 2 months after pneumothorax recovery. If the air leak does not improve, all valves should be removed. If these procedures fail to control the air leak, VATS should be considered.34 The other treatment option is a conversion to VATS without removing the valves, because in many cases, the lesion causing the pneumothorax is a ruptured bulla of the expanding lobe. Ongoing trials In June 2011, a Dutch prospective randomized control trial (STELVIO trial, NTR2876) investigated the efficacy of EBV treatment in patients with high heterogeneity but with no collateral flow (measured with the Chartis system). This trial is expected to be completed by 2014. Additionally in 2013, a large multicentre randomized control trial (LIBERATE Trial, NCT01796392) began using the same approach as the Dutch trial. These trials should provide further insight into developing patient selection criterion and may possibly make inroads for BLVR in COPD treatment guidelines. Furthermore, regarding the 2013 IBV approach, a multicentre randomized control trial has begun to investigate the safety and effectiveness of IBV treatment focusing on lobar atelectasis in patients with complete inter-lobar fissure as assessed with CT (EMPROVE study, NCT01812447). Sealant To produce secure lung volume reduction by blocking abundant collateral ventilation pathways in emphysematous lesions, procedures that instill ‘sealant’ into the lung parenchyma to induce inflammation and subsequent fibrosis have been studied. BLVR using the administration of biological substances (fibrinogen biopharmaceutical suspension and thrombin Respirology (2014)
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solution) reduced lung volumes and improved pulmonary function in patients with advanced upper lobe emphysema with acceptable adverse events.35 Subsequently, biological substances were replaced with synthetic polymeric foam (emphysematous lung sealant (ELS); Aeris Therapeutics, Woburn, MA, USA). ELS foam sealant is prepared by adding a cross-link consisting of diluted, buffered pentane 1–5 dial in aqueous polymer solution containing 2% aminated polyvinylalcohol; 5 mL of this solution is mixed with 15 mL of air. A total of 20 mL ELS foam sealant is then instilled into the peripheral airways through a singlelumen catheter.19 Herth et al. treated 25 patients with upper lobe-dominant heterogeneous emphysema using ELS instillation into 2–4 sub-segments of the unilateral lung (Fig. 3). All procedures were well tolerated, and there were no treatment-related deaths within 90 days, although flu-like reactions beginning 8–24 h after treatment were observed in almost all patients. The efficacy results 24 weeks after ELS treatments were evaluated in 21 patients and showed significant improvement from baseline in FEV1 (+10.0 ± 19.8%), forced vital capacity (+15.8 ± 22.2%) and SGRQ total score (−7.5 ± 14.4 units).19 Kramer et al. performed a bilateral ELS treatment in patients with advanced emphysema. Ten patients with upper lobe-dominant emphysema and 10 patients with homogeneous emphysema were treated using ELS instillation into four sub-segments, two in each upper lobe. The upper lobe lung volume assessed via CT scan analysis decreased significantly (895 ± 484 mL) 3 months post-procedure, while other parameters, such as FEV1 (6 months; +31.2 ± 36.6%, 12 months; +25.0 ± 33.4%) and SGRQ (6 months; −8.0 ± 17.2 units, 12 months; −7.0 ± 15.8 units) also improved significantly.20 However, one case of treatment-related death was reported. In a randomized multicentre study (the AeriSeal System for HyPerInflation Reduction in Emphysema (ASPIRE), NCT01449292), patients with upper lungdominant heterogeneous emphysema were allocated to bilateral ELS treatment or optimal medical therapy, with the primary endpoint of changing baseline FEV1 measurement at 12 months after treatment. This trial started in June 2012 and was aborted in November 2013 because Aeris Therapeutics was not able to continue financing. Despite this early study closure, the results from the patients who were already included and treated will provide valuable information about the safety and efficacy of this treatment, especially regarding the use of sealant to treat patients with abundant collateral flow.
The lung volume reduction coil The lung volume reduction coil (LVRC; PneumRx, Inc., Mountain View, CA, USA), made of preformed nitinol wire, can perform lung volume reduction regardless of the presence of CV by ‘grasping’ lung parenchyma. The LVRC is deployed through a straight delivery catheter into sub-segmental airways using bronchoscopy. After its release from the delivery catheter under fluoroscopy, the LVRC immediately recovers its predetermined coil shape in the surrounding © 2014 Asian Pacific Society of Respirology
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Bronchoscopic treatment of COPD
Figure 3 (a) Bronchoscopic view of the AeriSeal biogel delivery catheter. (b) Visible proximal clot of biogel at the sub-segmental level. (c) Chest X-ray of an upper lobe-predominant emphysema patient before, and (d) 1 month after treatment with AeriSeal biogel with a visible tissue reaction to the sealant in both upper lobes (arrows) and visible volume reduction.
Figure 4 (a) Nitinol RePneu® lung volume reduction coil (PneumRx, Inc., CA, USA, printed with permission). (b) Right upper lobe X-ray detail posttreatment showing 10 lung volume reduction coils placed in the three upper lobe segments.
a
b
c
d
a
lung parenchyma (Fig. 4).36 Slebos et al. treated 16 severe heterogeneous emphysema patients using LVRC implantation and reported the device’s safety and effectiveness.21 Four patients were treated unilaterally, and 12 patients were treated bilaterally, for a total of 28 procedures using 260 coils (a median of 10 per procedure). There were no procedure-related technical events, and all coils were placed as planned. During the first 30 days after LVRC implantation, one case of pneumothorax, two cases of pneumonia, six cases of COPD exacerbation, four cases of chest pain, and 21 cases of mild ( 55% is key in identifying optimal BLVR candidates. The next step is to review CT scans to allocate patients to either a predominantly homogeneous emphysema group or a heterogeneous emphysema group. This process can be performed using sophisti© 2014 Asian Pacific Society of Respirology
cated CT software;42 however, the presence of a ‘target’ (i.e. a clearly damaged lobe vs a relatively well preserved adjacent lobe) can be well defined by ‘eyeballing’ with a standard CT reading package for axial, sagittal and coronal views. Chest CT can also be useful when checking contraindications for BLVR (Table 3). Respirology (2014)
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Table 3 General inclusion and exclusion criteria for bronchoscopic lung volume reduction Inclusion criteria • COPD • Non-smoker • Post-pulmonary rehabilitation • Pulmonary function: ○ FEV1 < 45% predicted ○ RV > 180% predicted ○ RV/TLC > 55% predicted
Exclusion criteria • Previous lobectomy or pneumonectomy • Severe bronchiectasis, recurrent hospitalizations for infectious lung disease • PaO2 < 6.0 kPa or PaCO2 > 8.0 kPa (at room air and sea level) • Right ventricular systolic pressure > 50 mm Hg (echocardiogram) • Significant cardiac comorbidity • Systemic anticoagulant therapy that cannot be withheld such as warfarin, coumarins, clopidogrel • Chest CT comorbidities: ○ unstable nodule ○ lung fibrosis ○ paraseptal emphysema ○ giant bullae ○ severe bronchiectasis ○ significant thoracic aneurism
COPD, chronic obstructive pulmonary disease; CT, computed tomography; FEV1, forced expiratory volume over one second; RV, residual volume; TLC, total lung capacity.
COPD patients with the small airway diseasedominant phenotype are excluded from the currently available BLVR technique. For patients with heterogeneous emphysema, which can be either an upper or lower lobepredominant disease, the main fissure has to be assessed for completeness by a trained physician or radiologist using a thin-slice volume CT in three planes, although significant inter-observer variability has to be taken into account.43 After CT review and once the fissure of at least one of both lungs is near complete (>80%), we functionally assess collateral flow using the Chartis system. Patients who have no collateral flow are then treated using a lobar occlusion approach with one-way endobronchial valves.18 Patients who have an incomplete fissure (
