Lung Denervation Therapy and Lung Volume Reduction Surgery

Number: 0160

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses lung denervation therapy and lung volume reduction surgery.

Medical Necessity

Aetna considers the following procedures as medically necessary when applicable criteria are met:
1. Lung Volume Reduction Surgery (LVRS)
  
  For members who meet the selection criteria outlined below. See 'Experimental and Investigational' section for additional information.
  
  The standards for pre-operative assessment and criteria for surgery have been evolving and have varied from institution to institution. There is medical consensus that the candidate for LVRS should have severe emphysema, disabling dyspnea, and evidence of severe air trapping.
  
  The selection criteria, which are based on the results of the National Emphysema Treatment Trial, are as follows:
  1. For members with cardiac ejection fraction less than 45 %, there is no history of congestive heart failure or myocardial infarction within 6 months of consideration for surgery; and
  2. The member has a history and physical examination consistent with emphysema; and
  3. The member has not smoked for 4 or more months; and
  4. The member has all of the following on pre-operative work-up:
    1. CT scan evidence of bilateral emphysema; and
    2. Forced expiratory volume in 1 second (FEV1) (maximum of pre- and post-bronchodilator values) less than or equal to 45 % of predicted and, if aged 70 year or older, FEV1 15 % of predicted or more; and
    3. Plasma cotinine less than or equal to 13.7 ng/ml (if not using nicotine products) or carboxyhemoglobin less than or equal to 2.5 % (if using nicotine products); and
    4. Post-bronchodilator total lung capacity (TLC) greater than or equal to 100 % of the predicted value and residual volume (RV) greater than or equal to 150 % of predicted value; and
    5. Resting partial pressure of carbon dioxide (PaCO2) less than or equal to 60 mm Hg on room air; and
    6. Resting partial pressure of oxygen (PaO2) 45 mm Hg or greater; and
    7. Six-minute walk test greater than 140 meters;
  5. The member should not have either of the following contraindications to LVRS:
    1. Post-bronchodilator FEV1 is 20 % or less than its predicted value and member has either:
      1. A carbon monoxide diffusion capacity (DLCO) is 20 % or less than its predicted value. (Persons in this category have been found to be at high risk for death after LVRS, with little chance of functional benefit); or
      2. A homogenous distribution of emphysema on CT scan; or
    2. Members with predominantly non-upper lobe emphysema and a high maximal work-load:
      1. For purposes of this policy, a high maximal workload is defined as a maximal workload (on cycle ergometry with an increment of 5 or 10 W/min after 3 mins of pedaling with the ergometer set at 0 W and the person breathing 30 % oxygen) above the sex-specific 40th percentile (25 W for women, 40 W for men);
      2. For purposes of this policy, predominantly non-upper lobe predominance of emphysema is defined to exclude disease on CT that is judged by the radiologist as affecting primarily the upper lobes of the lung, and to include disease that is judged to be predominantly lower lobe, diffuse, or predominantly affecting the superior segments of the lower lobes;
      Note: Persons with predominantly non-upper-lobe emphysema and a high maximal work-load have been found to have higher mortality from LVRS than from medical therapy alone, and have been found to have little chance of functional improvement regardless of the treatment they receive).
  6. The member should have none of the following exclusion criteria:
    1. Alpha-1 antitrypsin deficiency
    2. Clinically significant bronchiectasis
    3. Evidence of systemic disease or neoplasia that is expected to compromise survival
    4. Giant bulla (greater than 1/3 the volume of the lung in which the bulla is located)
    5. History of recurrent infections with clinically significant production of sputum
    6. Oxygen requirement greater than 6 L/min during resting to keep oxygen saturation greater than or equal to 90 %
    7. Pleural or interstitial disease which precludes surgery
    8. Previous lobectomy
    9. Previous LVRS (laser or excision)
    10. Pulmonary hypertension, defined as mean pulmonary artery pressure of 35 mm Hg or greater on right heart catheterization or peak systolic pulmonary artery pressure of 45 mm Hg or greater. (Right heart catheterization is required to rule out pulmonary hypertension if peak systolic pulmonary artery pressure is greater than 45 mm Hg on echocardiogram)
    11. Pulmonary nodule requiring surgery
    12. Resting bradycardia (less than 50 beats/min), frequent multifocal premature ventricular contractions (PVCs), of complex ventricular arrhythmia or sustained supraventricular tachycardia (SVT)
    13. Uncontrolled hypertension (systolic greater than 200 mm Hg or diastolic greater than 110 mm Hg)
    14. Unplanned weight loss greater than 10 % within 3 months prior to consideration for surgery.
    Aetna considers lung volume reduction surgery experimental and investigational for all other indications because its effectiveness for indications other than the ones listed above has not been established.
2. Bullectomy
  
  Bullectomy is considered medically necessary for the treatment of dyspneic members with giant bulbous emphysema when they have a single large bulla producing significant respiratory compromise (FEV1 of less than 50 % predicted).
  
  Video-Assisted Thoracoscopic (VATS) Blebectomy/Bullectomy is considered medically necessary for prevention of recurrence of pneumothorax.
  
  Aetna considers bullectomy experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.
3. Food and Drug Administration (FDA)-Approved Endobronchial Valve
  
  FDA-approved endobronchial valve (e.g., the Spiration Valve System and the Zephyr Valve System) is considered medically necessary for the bronchoscopic treatment of adult patients with hyperinflation associated with severe emphysema in regions of the lung that have little to no collateral ventilation.
Experimental and Investigational

The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established:
1. Thoracoscopic laser bullectomy in the treatment of members with emphysematous lung disease. Outcomes of thoracoscopic laser surgery for persons with diffuse disease need to be compared with current non-laser surgical techniques and medical therapy. Additionally, the long-term benefits of this surgery, including decreased symptoms and improved pulmonary function compared to persons without surgical intervention, need to be demonstrated.
2. Toracoscopic bullectomy using a trans-areolar approach in the treatment of primary spontaneous pneumothorax.
3. Bronchoscopic thermal vapor ablation for the treatment of emphysema.
4. Other bronchoscopic lung volume reduction procedures including biologic lung volume reduction (e.g., Aeris Therapeutics, Inc., Woburn, MA, Biologic Lung Volume Reduction [BLVR] System) for the treatment of emphysema and all other indications.
5. Targeted lung denervation (the dNerva Lung Denervation System) for the treatment of chronic obstructive pulmonary disease.

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
CPT codes covered if selection criteria are met :
31647	Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with balloon occlusion, when performed, assessment of air leak, airway sizing, and insertion of bronchial valve(s), initial lobe
31648	with removal of bronchial valve(s), initial lobe
31649	with removal of bronchial valve(s), each additional lobe (list separately in addition to code for primary procedure)
31651	with balloon occlusion, when performed, assessment of air leak, airway sizing, and insertion of bronchial valve(s), each additional lobe (list separately in addition to code for primary procedure[s])
32141	Thoracotomy major; with excision-plication of bullae, with or without any pleural procedure
32491	Removal of lung, other than total pneumonectomy; excision-plication of emphysematous lung(s) (bullous or non-bullous) for lung volume reduction, sternal split or transthoracic approach, with or without any pleural procedure
32655	Thoracoscopy, surgical; with excision-plication of bullae, including any pleural procedure [Video-assisted thoracoscopic (VATS) blebectomy/bullectomy]
32672	Thoracoscopy, surgical; with resection-plication for emphysematous lung (bullous or non-bullous) for lung volume reduction (LVRS), unilateral includes any pleural procedure, when performed
CPT codes not covered for indications listed in the CPB:
Bronchoscopic thermal vapor ablation, thoracoscopic bullectomy using a trans-areolar approach - - no specific code:
0781T	Bronchoscopy, rigid or flexible, with insertion of esophageal protection device and circumferential radiofrequency destruction of the pulmonary nerves, including fluoroscopic guidance when performed; bilateral mainstem bronchi [Targeted lung denervation]
0782T	unilateral mainstem bronchus [Targeted lung denervation]
Other CPT codes related to the CPB:
31622	Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; diagnostic, with cell washing, when performed (separate procedure)
31634	Bronchoscopy, rigid or flexible, including fluoroscopic guidance, when performed; with balloon occlusion, with assessment of air leak, with administration of occlusive substance (eg, fibrin glue), if performed
32124	Thoracotomy major; with open intrapleural pneumonolysis
32440 - 32488, 32501 - 32540	Excision of lung and pleura (other than for volume reduction)
88740	Hemoglobin, quantitative, transcutaneous, per day; carboxyhemoglobin
HCPCS codes covered if selection criteria are met:
Spiration Valve System - no specific code:
G0302	Preoperative pulmonary surgery services for preparation for LVRS, complete course of services, to include a minimum of 16 days of services
G0303	Preoperative pulmonary surgery services for preparation for LVRS, 10 to 15 days of services
G0304	Preoperative pulmonary surgery services for preparation for LVRS, 1 to 9 days of services
G0305	Post discharge pulmonary surgery services after LVRS, minimum of 6 days of services
ICD-10 codes covered if selection criteria are met:
J43.0 - J43.9	Emphysema [except due to alpha-1-antitrypsin deficiency]
J93.81 -J93.9	Other pneumothorax and air leak [Recurrence of pneumothorax]
ICD-10 codes not covered for indications listed in the CPB:
E88.01	Alpha-1-antitrypsin deficiency
I27.0 - I27.2	Other pulmonary heart diseases
I47.1	Supraventricular tachycardia
J44.0 – J44.9	Chronic obstructive pulmonary disease
J93.11	Primary spontaneous pneumothorax
R00.1	Bradycardia, unspecified

Background

Lung volume reduction surgery (LVRS) is a general term encompassing a variety of surgical procedures that are offered to alleviate the symptoms of advanced chronic obstructive pulmonary disease (COPD) due to emphysema. Currently the operations used to treat emphysema include the excision of large bullae by thoracotomy or thoracoscopy and the resection of diffusely emphysematous lung tissue.

This latter surgery, variably referred to as a lung reduction surgery, pneumectomy, and reduction pneumoplasty can be accomplished through a variety of incisions (sternotomy, clam shell, thoracotomy) or by thoracoscopy using a staple procedure or laser applications. Currently the choice of techniques depends on the surgical expertise and preference of the operator.

Based on results reported in peer review journals, abstracts and presentations at national meetings, LVRS appears efficacious for some, but not all, patients with advanced COPD due to emphysema.

Several centers have documented post-operative improvement in exertional dyspnea, measurements of pulmonary function, exercise capacity and objectively scored quality of life indices. Improvements in exercise capacity have been reported in patients undergoing a comprehensive program of pulmonary rehabilitation in preparation for surgery.

It appears that bilateral pneumectomy yields improvements in spirometry that are roughly twice as great as unilateral procedures.

In the one available randomized prospective trial that compared stapled lung reduction to laser bullectomy surgery, patients who received the latter procedure were more likely to develop a delayed pneumothorax and less likely to eliminate dependency on supplemental oxygen. Also, the mean post-operative improvement in the forced expiratory volume in 1 second (FEV1) at 6 months was greater in those who received the stapled lung reduction technique (32.9 % improvement) than the laser treatment (13.4 % improvement).

Fishman et al (2003) reported on the results of the National Emphysema Treatment Trial, a randomized, multi-center clinical trial comparing LVRS with medical treatment. A total of 1,218 patients with severe emphysema were randomly assigned to undergo LVRS or to receive continued medical treatment. Lung volume reduction surgery was found to improve exercise capacity in a significant proportion of patients, but to have no significant effect on overall mortality. After 24 months, exercise capacity had improved by more than 10 W in 15 % of the patients in the surgery group, as compared with 3 % of patients in the medical-therapy group.

Lung volume reduction surgery was found to yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity (Fishman et al, 2003). Among patients with predominantly upper-lobe emphysema and low exercise capacity, mortality was more than 50 % lower in the surgery group than in the medical-therapy group.

In contrast, LVRS was associated with an increase in mortality and negligible functional gain among patients with predominantly non-upper lobe emphysema and a high base-line exercise capacity (Fishman et al, 2003). Among patients with non-upper-lobe emphysema and high exercise capacity, mortality was twice as high in the surgery group as in the medical-therapy group.

Lung volume reduction surgery was also associated with an increase in mortality among persons who were, in previous reports (National Emphysema Treatment Trial Research Group, 2001) considered to be at high-risk of death after surgery, namely patients with a low FEV1 (20 % or less than predicted) and either homogenous emphysema or a very low carbon monoxide diffusing capacity (20 % or less than predicted) (Fishman et al, 2003). A meta analysis (Berger et al, 2005) reported that a selected subset of patients with advanced, heterogeneous emphysema and low exercise tolerance (as indexed by the 6-min walk distance) experienced better outcomes from LVRS than from medical therapy.

Functional benefits but no improvements in survival were found in patients with predominantly upper-lobe emphysema and a high base-line exercise capacity and patients with non-upper lobe emphysema and a low base-line exercise capacity (Fishman et al, 2003).

Patients usually need pulmonary rehabilitation after LVRS to better ensure return to function.

Stoller et al (2007) noted that the role of LVRS for individuals with alpha-1 antitrypsin (AAT) deficiency is unclear. These investigators evaluated the role of LVRS in individuals with severe deficiency of AAT, and analyzed outcomes within the National Emphysema Treatment Trial. Of 1,218 randomized subjects, 16 (1.3 %) had severe AAT deficiency (serum level less than 80 mg/dL) and a consistent phenotype (when available). Characteristics of these 16 patients were 87.5 % male; median serum AAT level of 55.5 mg/dL; age of 66 years; FEV1 27 % predicted; and 50 % had upper-lobe-predominant emphysema. All 10 subjects randomized to LVRS underwent the procedure. Although the small number of subjects hampered statistical analysis, 2-year mortality was higher with surgery (20 % versus 0 %) than with medical treatment. Comparison of outcomes between the 10 AAT-deficient and the 554 AAT-replete subjects undergoing LVRS showed a greater increase in exercise capacity at 6 months in replete subjects and a trend toward lower and shorter duration FEV1 rise in deficient individuals. The authors concluded that the findings of this study extended to 49 cases the published experience of LVRS in severe AAT deficiency. Although the small number of subjects precluded firm conclusions, trends of lower magnitude and duration of FEV1 rise after surgery in AAT-deficient versus AAT-replete subjects and higher mortality in deficient individuals randomized to surgery versus medical treatment suggest caution in recommending LVRS in AAT deficiency.

Giant bullous emphysema (GBE) is a rare subset of patients with COPD in whom single or multiple large bullae encompass 30 % or more of a hemi-thorax, often displacing potentially functional lung tissue as these large airspaces increase in volume. In appropriate cases, surgical resection of these bullae can restore significant pulmonary function and improve symptoms. Computed tomography (CT) scan is essential in evaluating these patients.

According to guidelines from the Institute for Clinical Systems Improvement (ICSI, 2004), bullectomy is indicated in these patients. This is in accordance with guidelines on COPD from the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) (NHLBI, 2005): “In carefully selected patients, this procedure is effective in reducing dyspnea and improving lung function. A thoracic computed tomography scan, arterial blood gas measurement, and comprehensive respiratory function tests are essential before making a decision regarding a patient's suitability for resection of a bulla.”

Furthermore, according to guidelines from National Institute for Clinical Excellence (NICE, 2004), patients who are breathless, and have a single large bulla on a CT scan and an FEV1 less than 50 % predicted should be referred for consideration of bullectomy.

In a prospective study, Palla and colleagues (2005) evaluated patients who have undergone elective surgery due to GBE, early and late mortality following surgery, the early and late reappearance of bullae, and the early and late modifications of clinical and functional data. A total of 41 consecutive patients who underwent elective surgery for GBE were studied both before and after undergoing bullectomy for a 5-year-follow-up period. Analyses were performed on the whole population and on 2 subgroups of patients who were divided on the basis of the absence of underlying diffuse emphysema (group A; n = 23) or the presence of underlying diffuse emphysema (group B; n = 18). The early mortality rate was 7.3 % (within the 1st year), and the late mortality rate was 4.9 % (overall mortality rate at 5 years, 12.2 %; mortality rate in group B, 27.8 %). Bullae did not re-appear and residual bullae did not become enlarged in any patients at the site of the bullectomy. During the follow-up, the dyspnea score was reduced significantly soon after bullectomy and up to the fourth year of follow-up; intra-thoracic gas volume also was reduced significantly (average, 0.7 L). The same was true for the FEV1 percent predicted and the FEV1/vital capacity ratio, which kept increasing until the 2nd year; then, from the 3rd year of follow-up these values were reduced, yet remained above the pre-bullectomy values until the 5th year of follow-up. When considered separately, the patients in group B appeared to be the most impaired, clinically and functionally (e.g., FEV1 showed a similar significant increase up to the 2nd year in both groups after surgery, while a different mean annual decrease was appreciable from the second to the 5th year of follow-up: group A, 25 ml/year; group B, 83 ml/year. Furthermore, patients in group B were the only ones who contributed to the mortality rate, on the whole showing a behavior similar to that of patients who had undergone LVRS. These investigators concluded that in patients with GBE who were enrolled in the study prospectively and were investigated yearly during a 5-year-follow-up period, bullectomy appears to have been fairly safe, and allowed clinical and functional improvement for at least 5 years. Better results may be expected in patients without underlying diffuse emphysema.

Donahue and Cassivi (2009) noted that currently alpha-1 antitrypsin deficiency (A1AD) is recognized in approximately 2 % of patients who have emphysema, although this may be an under-estimation of the prevalence of this disease. Given the relatively young age at which patients who have A1AD present with emphysema, therapies aimed at slowing the progression of this disease are imperative. In addition to abstaining from smoking, the use of augmentation therapy may benefit some patients who have moderate airflow obstruction. For patients who have severe airflow obstruction, the most effective therapy is surgical. Despite a possible increased risk for infectious complications, transplantation remains a viable option for these patients who have long-term results mirroring those of patients transplanted for smoking-related COPD. Given limited donor availability, however, LVRS must be considered in these patients possibly as definitive therapy but more likely as a bridge to transplantation. Lung volume reduction surgery for patients who have A1AD remains relatively uncommon despite a general perception that it remains a surgical option. In a survey of European thoracic surgical centers, Hamacher and colleagues found that 2/3 of respondents included A1AD in their list of indications for LVRS. Although the durability of the benefits derived from LVRS in patients who have A1AD seems inferior to that of patients who have COPD, the available data show improved 6-min walk distances and decreased dyspnea persisting for 1 to 2 years after LVRS in patients who had A1AD. The authors stated that further experience is needed to determine whether or not subgroups of patients who have A1AD, such as those who have clear heterogeneous distribution, may derive more long-lasting improvement from LVRS.

Since LVRS is associated with high morbidity, mortality, and cost, several bronchoscopic methods for reducing lung volume in patients with advanced emphysema have been developed and are currently being evaluated in clinical trials as potential alternatives to LVRS. These techniques include:

placement of endobronchial 1-way valves designed to promote atelectasis by blocking inspiratory flow;
formation of airway bypass tracts using a radiofrequency catheter designed to facilitate emptying of damaged lung regions with long expiratory times; and
instillation of biological adhesives designed to collapse and remodel hyper-inflated lung.

The limited clinical data currently available suggest that all 3 techniques are reasonably safe. However, efficacy signals have been substantially smaller and less durable than those observed after LVRS. Clinical studies to optimize patient selection, refine treatment strategies, characterize procedural safety, elucidate mechanisms of action, and characterize short- and long-term effectiveness of these approaches are ongoing (Ingenito et al, 2008).

Bronchoscopic placement of small self-expanding 1-way valves into airways is a minimally invasive approach currently under investigation as an alternative to open LVRS. The valves are designed to prevent incoming airflow from reaching over-inflated regions of the lung while permitting trapped gas to escape. In addition to isolating non-functional areas of the lungs, the valves have the potential to reduce hypoxemia and hypercarbia by directing airflow to areas where gas exchange is less impaired.

The Zephyr Endobronchial Valve (EBV) (Emphasys Medical, Inc., Redwood City, CA) consists of a 1-way silicone duckbill valve attached to a self-expanding nitinol stent retainer. It is currently being evaluated in a phase III clinical trial, the Endobronchial Valve for Emphysema PalliatioN Trial (VENT), that compares it to optimal medical management in patients aged 40 to 75 years with heterogeneous emphysema. Patients were randomized into 2 groups: EBV procedure (n = 180) and optimal medical therapy (n = 90). Efficacy end-points include pulmonary function, exercise tolerance, and quality of life compared to baseline at various times throughout the course of 1 year. The valves are designed to be removable so the procedure has the potential to be fully reversible. The device is not yet commercially available in the United States; however, in September 2007 Emphasys Medical, Inc. submitted a pre-market application to the U.S. Food and Drug Administration (FDA) seeking approval to market the device in the U.S.

The Umbrella Implantable IntraBronchial Valve (IBV) (Spiration, Inc., Redmond, WA) consists of a polyurethane membrane over an umbrella-shaped nitinol (nickel/titanium) frame. The proximal portion is made up of 6 support stents that expand radially. The valve is designed to limit airflow distally, but the membrane and support stents allow mucociliary clearance, air and mucous to flow proximally past the valve in order to allow decompression of collateral ventilation and to reduce the hazards of mucous impaction and obstruction pneumonia. The valve design includes a proximal center rod that allows re-positioning or removal if needed. The FDA approved the IBV Valve system to control prolonged air leaks of the lung or significant air leaks that are likely to become prolonged following lobectomy, segmentectomy or LVRS via the humanitarian device exemption process. It is also currently under investigation in the U.S. as a new treatment option for patients with severe emphysema, however, the effectiveness of this device has not been demonstrated in the peer-reviewed medical literature and it has not received FDA approval for this indication.

The Biologic Lung Volume Reduction (BLVR) System (Aeris Therapeutics, Inc., Woburn, MA) is an investigational procedure that uses pharmacologic agents to selectively collapse over-inflated regions of the lung. During a BLVR procedure, the physician targets diseased portions of the lung tissue with a bronchoscope and applies a washout solution to disrupt pulmonary surfactant and remove pulmonary epithelium. This causes air space to collapse on exhalation. A fibrin-based hydrogel is then applied to the treated tissue sealing it off from the rest of the lung and causing it to scar and shrink. The procedure is intended to reduce lung volume over a period of weeks as diseased lung tissue continues to collapse. It is performed in a hospital under general anesthesia and requires an overnight stay.

Aeris Therapeutics, Inc. is currently conducting a phase III study to evaluate the safety and effectiveness of the BLVR procedure. Unpublished results from two U.S. phase II studies indicated that the treatment was well-tolerated and improved pulmonary function in some emphysema patients.

The BLVR procedure may be a promising treatment for individuals with advanced upper lobe predominant emphysema; however, there is insufficient evidence of its effectiveness. Studies to determine patient selection, safety, mechanism of action, as well as short- and long-term effectiveness in patients with advanced emphysema are on-going.

In a pilot study, Snell et al (2009) reported the safety and feasibility of novel 2nd-generation bronchoscopic lung volume reduction (LVR) technology, independent of collateral ventilation. A total of 11 patients with severe heterogeneous emphysema underwent unilateral bronchoscopic application of vapor thermal energy (mean of 4.9 cal/g alveolar tissue; range of 3 to 7.5) with bronchial thermal vapor ablation (BTVA) aiming to induce a controlled inflammatory airway and parenchymal response with resultant LVR. Nine women and 2 men, with a mean age of 61 years, FEV1 of 0.77 +/- 0.17 L (32 % predicted), residual volume (RV) of 4.1 +/- 0.9 L (219 % predicted), and gas transfer of 7.8 +/- 2.2 (34 % predicted), underwent unilateral upper lobe treatments. Serious adverse events in 5 included probable bacterial pneumonia and exacerbations of airways disease in 2. Although no important FEV1 or RV changes occurred during 6 months of follow-up, gas transfer improved, 16 % to 9.0 % +/- 2.1 % (38 % predicted), the Medical Research Council Dyspnoea Score improved from 2.6 to 2.1, and the St. George Respiratory Questionnaire Total Score improved from 64.4 at baseline to 49.1. The authors conclued that these preliminary data on unilateral BTVA therapy confirm feasibility, an acceptable safety profile, and the potential for efficacy.

Eberhardt and colleagues (2009) stated that after bronchoscopic LVR, improvement in pulmonary function and exercising tolerance can be achieved in patients with severe heterogeneous lung emphysema. Feasibility and safety for 1-way valve placement in homogeneous emphysema were evaluated. A total of 10 patients entered this prospective study. In all cases, a homogeneous distribution was confirmed by computer analysis of the CT-scans. These researchers performed unilateral LVR and occluded the lobe with the lowest perfusion, measured by nuclear scintigraphy. Endpoints of the study were changes in lung function test, quality of life and 6-minute walk-test (6-MWT) at day 30 and 90 and the safety of the procedure. Pre-operative mean FEV1 was 0.93 L (range of 0.55 to 1.35 L), mean residual volume was 5.23 L (3.55 to 8.24 L) and 6-MWT was 325 m (150 to 480 m). Improvement of dyspnoe and exercising tolerance was reported in 7 cases. No major changes in lung function were evident at days 30 and 90. A trend towards improvement was observed in 6-MWT (DeltaMW + 10.4 +/- 9.8 %). One pneumothorax was noticed, in 1 case the valves were removed after 90 days because of recurrent infections. The authors concluded that the findings of this study showed that bronchoscopic LVR in patients with severe homogeneous emphysema is feasible and seems to be safe. In contrast to surgical LVR, patients may have a cinical benefit by bronchoscopic treatment. They stated that long-term follow-up and patient selection criteria have to be examined in larger trials.

In a clinical pilot study, Herth et al (2010) examined the safety and feasibility of a new endoscopic LVR approach independent of the effects of collateral ventilation (CV). Patients with severe emphysema were eligible. Inclusion and exclusion criteria were modeled after the National Emphysema Treatment Trial (NETT) study. Homogenous and heterogeneous disease was allowed. Treatment consisted of the placement of coils into the parenchyma of the most diseased area with the intent of achieving parenchymal compression. Primary end points were safety and feasibility assessments. Secondary endpoints were efficacy outcomes. A total of 11 patients underwent 21 procedures. Procedures were performed under general anesthesia and lasted 45 +/- 15 mins and per procedure 4.9 +/- 0.6 coils were placed. All procedures were well-tolerated. The total follow-up time was 7 to 11 months and in that time 33 adverse events were reported, none of them severe. No pneumothorax occurred. Efficacy seemed better in heterogeneous rather than homogenous disease. The authors concludedthat endoscopic LVR with coils is safe and feasible. Moreover, they stated that further studies of the efficacy are indicated.

Simoff et al (2013) noted that the management of obstructive lung disease, particularly emphysematous lung disease, is aggressively being pursued. The patient populations that will experience the greatest benefit with lung volume reduction are those that are the worst candidates for surgical intervention. Identifying a bronchoscopic approach that has a true impact on this patient population will be a major accomplishment in the management of patients with COPD. The authors highlighted the work currently ongoing in the area of bronchoscopic lung volume reduction. They stated that there are tools now clinically available in some locations throughout the world, but no standardized technique exists.

Song et al (2013) described the self-expanding endobronchial occluder, as utilized in bronchoscopic lung volume reduction, with a 36 month follow-up procedure. A total of 23 subjects with severe emphysema were recruited and underwent flexible bronchoscopic placement of self-expanding endobronchial occluders. Outcomes were assessed at 1 week, 1-month, 3-, 6-, 12-, 24-, and 36-month intervals. Feasibility, safety, and effectiveness were analyzed by means of pulmonary function testing, 6-min walk test, dyspnea score, BODE (body mass index, air-flow obstruction, dyspnea, and exercise capacity) index, and St George's Respiratory Questionnaire. A total of 58 self-expanding endobronchial occluders were implanted into 23 lobes previously selected. No displacement was found during the follow-up. Five subjects experienced post-operative complications of cough, and 6 subjects had lobar pneumonia, which were not located in any of the blocked segments. The FEV1 in 18 subjects was improved by greater than 15 %, compared with baselines (p < 0.001), and the mean first efficacy time and maximal efficacy time were 5.65 ± 1.51 months and 6.35 ± 3.08 months, respectively. No significant changes were observed in FVC or the ratio of residual volume to TLC. The 6-min walk distance, dyspnea score, and St George's Respiratory Questionnaire total score were improved in 22 subjects over a 24-month period, and a minority of subjects continued to improve through to the end of the study. Mean baseline BODE index had improved during follow-up, but not at the study's conclusion. The authors concluded that these preliminary findings demonstrated early significant improvements in pulmonary function, 6-min walk distance, dyspnea score, BODE index, and quality of life after placement of the self-expanding endobronchial occluder in bronchoscopic lung volume reduction. Its placement also proved both easy and safe. However, they noted that the initial improvements were maintained long-term for only a minority of subjects.

Stratakos et al (2013) stated that a number of bronchoscopic techniques have been developed under the term "bronchoscopic lung volume reduction", aiming to lower the complications and the cost while facilitating the procedure of lung volume approach in patients with emphysema. These include airway bypass by creation of airway/parenchyma communications, 1-way endobronchial valves occluding the airways of the targeted lobes, endobronchial coils which mechanically contract the parenchyma, hot vapor ablation thermally destroying the targeted sites and sealant that fill the alveoli with polymer material. These methods are generally simple and safe, with a favorable complications profile, requiring less infra-structure and interventional experience than the open surgical approach. Bronchial valves have produced promising results in a very narrow phenotype of emphysema patients and have the major advantage of being reversible in their action. Parenchymal interventions at the cost of producing permanent effects and a transient inflammatory syndrome, may be effective in larger group of patients regardless of the fissure integrity and the presence of collateral ventilation. The authors noted that new, more extensive multi-center studies are underway that aim at better selection and stratification of patients in order to further evaluate the safety and effectiveness of these techniques, before wider use of this revolutionary approach for severe lung emphysema can be advocated.

Shah and Herth (2014) stated that COPD is a major cause of morbidity and mortality worldwide. Emphysema is a component of COPD characterized by hyper-inflation resulting in reduced gas exchange and interference with breathing mechanics. Endoscopic lung volume reduction using 1-way valves to induce atelectasis of the hyper-inflated lobe has been developed and studied in clinical trials over the last decade. These investigators performed searches for appropriate studies on PubMed and Clinical Trials Databases using the search terms COPD, emphysema, lung volume reduction and endobronchial valves. The evidence from the randomized clinical trials suggested that complete lobar occlusion in the absence of collateral ventilation or where there is an intact lobar fissure are the key predictors for clinical success. Other indicators were greater heterogeneity in disease distribution between upper and lower lobes. The proportion of patients that respond to treatment improved from 20 % in the unselected population to 75 % with appropriate patient selection. The safety profile for endobronchial valves in this severely affected group of patients with emphysema was acceptable and the main adverse events observed were an excess of pneumothoraces. The authors concluded that selected patients have the potential of significant benefit in terms of lung function, exercise capacity and possibly even survival.

The GOLD’s clinical guideline on “Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease” (2013) states that “In a post-hoc analysis, BLVR (Bronchoscopic Lung Volume Reduction) in COPD patients with severe airflow limitation (FEV1 15 % - 45 % predicted), heterogeneous emphysema on computed tomography (CT) scan, and hyperinflation (total lung capacity [TLC] > 100 % and residual volume [RV] > 150 % predicted) has been demonstrated to result in modest improvements in lung function, exercise tolerance, and symptoms at the cost of more frequent exacerbations of COPD, pneumonia, and hemoptysis after implantation. Additional data are required to define the optimal technique and patient population”.

Furthermore, the ICSI’s clinical guideline on “Diagnosis and management of chronic obstructive pulmonary disease (COPD)” (Anderson et al, 2013) states that “Bronchoscopic LVR is being assessed in clinical trials; its role in management of COPD is yet to be defined”.

Cohen (2014) noted that COPD is a progressive, debilitating disease that in its final stages cripples the patient. The disappointing results of the National Emphysema Treatment Trial study led to a decrease in the acceptance of LVRS as a therapy. Thus, it became clear that debilitated COPD patients would need innovative alternative non-surgical procedures to potentially alleviate their symptoms. This investigator addressed the various techniques of BLVR. In recent years, a variety of non-invasive BLVR procedures were developed in the hope of improving the respiratory status of these patients. Bronchoscopic lung volume reduction aims to decrease the extent of hyper-inflation due to emphysema and result in a beneficial effect similar to that from surgical resection. The most widely used BLVR devices are: endobronchial valves, foam sealant, metallic coils, airway bypass stents and vapor thermal ablation. In the USA, BLVR remains in the experimental phase. The treatment modalities should be individually tailored for each patient. Endobronchial valves are designed to exclude the most affected emphysematous regions from ventilation in order to induce lobar absorption atelectasis. Airway bypass stents target homogenous emphysema, whereas valves and thermal vapor ablation target heterogeneous emphysema. Biological sealants and endoscopic coil implants have been used in both homogenous and heterogeneous emphysema. The author concluded that BLVR appears to be safer than surgery and presents an attractive alternative for the treatment of COPD patients. Unfortunately, the outcome data to date are inconclusive; the procedures remain experimental and any benefits unproven. However, the data that are emerging continue to appear promising.

An assessment by the Ludwig Boltzmann Institute for Health Technology Assessment of endobronchial valve implantation for emphysema (Wild, 2018) concluded that “The available evidence suggests that the investigated intervention ‘endobronchial valve implantation in selected patients with severe pulmonary emphysema’ is more effective but less safe than drug therapy”.

Bronchoscopic Lung Volume Reduction for the Treatment of Severe Emphysema

Deslee et al (2016) stated that therapeutic options for severe emphysema are limited. Lung volume reduction using nitinol coils is a bronchoscopic intervention inducing regional parenchymal volume reduction and restoring lung recoil. These researchers evaluated the safety, effectiveness, cost, and cost-effectiveness of nitinol coils in treatment of severe emphysema. They performed a multi-center 1:1 randomized superiority trial comparing coils with usual care at 10 university hospitals in France. Enrollment of patients with emphysema occurred from March to October 2013, with 12-month follow-up (last follow-up, December 2014). Patients randomized to usual care (n = 50) received rehabilitation and bronchodilators with or without inhaled corticosteroids and oxygen; those randomized to bilateral coil treatment (n = 50) received usual care plus additional therapy in which approximately 10 coils per lobe were placed in 2 bilateral lobes in 2 procedures. The primary outcome was improvement of at least 54 m in the 6-minute walk distance (6MWD) at 6 months (1-sided hypothesis test). Secondary outcomes included changes at 6 and 12 months in the 6MWD, lung function, quality of life as assessed by St George's Respiratory Questionnaire (range of 0 to 100; 0 being the best and 100 being the worst quality of life; minimal clinically important difference, greater than or equal to 4), morbidity, mortality, total cost, and cost-effectiveness. Among 100 patients, 71 men and 29 women (mean age of 62 years) were included. At 6 months, improvement of at least 54 m was observed in 18 patients (36 %) in the coil group and 9 patients (18 %) in the usual care group, for a between-group difference of 18 % (1-sided 95 % confidence interval [CI] 4 % to infinity [∞]; p = 0.03). Mean between-group differences at 6 and 12 months in the coil and usual care groups were +0.09 L (95 % CI: 0.05 L to ∞) (p = 0.001) and +0.08 L (95 % CI: 0.03 L to ∞) (p = 0.002) for forced expiratory volume in the first second, +21 m (95 % CI: -4 m to ∞) (p = 0.06) and +21 m (95 % CI: -5 m to ∞) (p = 0.12) for 6MWD, and -13.4 points (95 % CI: -8 points to ∞) and -10.6 points (95 % CI: -5.8 points to ∞) for St George's Respiratory Questionnaire (1-sided p < .001 for both). Within 12 months, 4 deaths occurred in the coil group and 3 in the usual care group. The mean total 1-year per-patient cost difference between groups was $47,908 (95 % CI: $47,879 to $48,073) (p < 0.001); the incremental cost-effectiveness ratio was $782,598 per additional quality-adjusted life-year. The authors concluded that in this preliminary study of patients with severe emphysema followed-up for 6 months, bronchoscopic treatment with nitinol coils compared with usual care resulted in improved exercise capacity with high short-term costs. They stated that further investigation is needed to evaluate durability of benefit and long-term cost implications. The major drawbacks of this study were:

its relatively small sample size and
there was no pre-selection of patients for heterogeneous emphysema.

In an editorial that accompanied the afore-mentioned study, Sciurba et al (2016) stated that “Should the emerging data from larger pivotal trials support the meaningful clinical, albeit palliative, responses observed in preliminary trials, physicians caring for patients with COPD should not delay in providing evidence-based interventions that offer realistic hope to patients with few other choices to relieve their symptoms and improve their quality of life”.

Endobronchial Valves for Advanced Emphysema

Liu and colleagues (2015) performed a meta-analysis to evaluate the safety and effectiveness of bronchoscopic lung volume reduction with endobronchial valves (EBV) for advanced emphysema. A systematic search was performed from PubMed, Embase, CNKI, Cochrane Library database. Randomized control clinical trials on treatment of emphysema for 3 to 12 months with the EBV compared with standard medications and sham EBV were reviewed. Inclusion criteria were applied to select patients with advanced emphysema treated with EBV. The primary outcome was the percentage of the FEV1 (FEV1%). Secondary outcomes included St George's Respiratory Questionnaire (SGRQ) score, the distance of the 6MWD test, the Modified Medical Research Council (MMRC) dyspnea score, cycle ergometry workload, and the rate of the 6 major complications at 3 or 12 months. Fixed- or random-effects models were used and weighted mean differences (WMD), relative risks (RR) and 95 % CI were calculated. A total of 3 trials (565 patients) were considered in the meta-analysis; EBV patients yielded greater increases in FEV1% than standard medications (WMD = 6.71; 95 % CI: 3.31 to 10.10; p = 0.0001), EBV patients also demonstrated a significant change for SGRQ score (WMD = -3.64; 95 % CI: -5.93 to -1.34; p = 0.002), MMRC dyspnea score (WMD = -0.26; 95 % CI: -0.44 to -0.08; p = 0.004), and cycle ergometry workload (WMD = 4.18; 95 % CI: 2.14 to 6.22; p < 0.0001). A similar level was evident for 6MWD (WMD = 11.66; 95 % CI: -3.31 to 26.64; p = 0.13); EBV may increase the rate of hemoptysis (RR = 5.15; 95 % CI: 1.16 to 22.86; p = 0.03), but didn't increase the adverse events (AES) including mortality, respiratory failure, empyema, pneumonia, pneumothorax. The overall rates for complications compared EBV with standard medications and sham EBV was not significant (RR = 2.03; 95 % CI: 0.98 to 4.21; p = 0.06). The authors concluded that EBV lung volume reduction for advanced emphysema showed superior efficacy and a good safety and tolerability compared with standard medications and sham EBV. Moreover, they stated that more randomized controlled trials (RCTs) are needed to pay more attention to the long-term safety and effectiveness of bronchoscopic lung volume reduction with EBV in advanced emphysema.

In a prospective, randomized, parallel-group, double-blind, sham-controlled trial, Zoumot and associates (2015) examined if it is possible to identify patients prospectively who will reliably benefit from EBV placement. The study was performed at a single specialist center. Adult patients with heterogeneous emphysema and a target lobe with intact inter-lobar fissures were eligible if they had significant gas trapping (total lung capacity greater than 100 % predicted, residual volume greater than 150 % predicted), breathlessness [MMRC dyspnea score of greater than or equal to 3] and exercise limitation (6MWD of less than 450 m). Subjects were on optimized pharmacotherapy and were non-smokers. Study participants were randomized to either unilateral lobar EBV placement aiming to achieve lobar atelectasis or bronchoscopy and “sham” valve placement. The primary end-point was improvement in FEV1 in the treatment arm compared with the control arm measured 90 days post-procedure. Secondary end-points were change in lung volumes, gas transfer, exercise capacity (both walking and endurance cycle ergometry) and health-related quality of life (QOL). In total, 50 patients were recruited, 25 to each arm; 62 % were male and mean (standard deviation) FEV1% predicted was 31.7 % (10.2 %). The primary end-point of the study was met as FEV1 increased by 24.8 % [95 % CI: 8.0 % to 41.5 %] in the treatment arm and by 3.9 % (95 % CI: 0.7 % to 7.1 %) in the control arm [between-group difference 20.9 % (95 % CI: 4.3 % to 37.5 %); p = 0.033]. There were both statistically and clinically significant improvements in lung volumes and carbon monoxide gas transfer as well as endurance time and dynamic hyper-inflation during cycle ergometry; 2 deaths occurred in the treatment arm and 1 control patient was unable to attend for follow-up assessment because of a prolonged pneumothorax; 2 pneumothoraxes occurred in the treatment arm. The authors concluded that with appropriate selection of patients through a multi-disciplinary team it is possible to produce a significant improvement in lung function through lobar occlusion with EBVs in heterogeneous emphysema. Moreover, they stated that prospective trials are needed to compare the effect of BLVR with surgical approaches in terms of magnitude and duration of benefit.

van Agteren and colleagues (2017) noted that in the recent years, a variety of BLVR procedures have emerged that may provide a therapeutic option to participants suffering from moderate-to-severe COPD. In a Cochrane review, these investigators examined the effects of BLVR on the short- and long-term health outcomes in participants with moderate-to-severe COPD and determined the effectiveness and cost-effectiveness of each individual technique. Studies were identified from the Cochrane Airways Group Specialised Register (CAGR) and by hand-searching of respiratory journals and meeting abstracts. All searches were current until December 7, 2016. They included RCTs and studies reported as full text, those published as abstract only and unpublished data, if available. Two independent review authors assessed studies for inclusion and extracted data. Where possible, data from more than 1 study were combined in a meta-analysis using RevMan 5 software. One RCT of 95 participants found that AeriSeal compared to control led to a significant median improvement in FEV1 (18.9 %, interquartile range (IQR): -0.7 % to 41.9 % versus 1.3 %, IQR: -8.2 % to 12.9 %), and higher QOL, as measured by the SGRQ (-12 units, IQR: -22 units to -5 units, versus -3 units, IQR: -5 units to 1 units), p = 0.043 and p = 0.0072, respectively. Although there was no significant difference in mortality (odds ratio (OR) 2.90, 95 % CI: 0.14 to 62.15), AEs were more common for participants treated with AeriSeal (OR 3.71, 95 % CI: 1.34 to 10.24). The quality of evidence found in this prematurely terminated study was rated low-to-moderate. Treatment with airway bypass stents compared to control did not lead to significant between-group changes in FEV1 (0.95 %, 95 % CI: -0.16 % to 2.06 %) or SGRQ scores (-2.00 units, 95 % CI: -5.58 units to 1.58 units), as found by one study comprising 315 participants. There was no significant difference in mortality (OR 0.76, 95% CI 0.21 to 2.77), nor were there significant differences in adverse events (OR 1.33, 95% CI 0.65 to 2.73) between the 2 groups. The quality of evidence was rated moderate-to-high. Three studies comprising 461 participants showed that treatment with endobronchial coils compared to control led to a significant between-group mean difference in FEV1 (10.88 %, 95 % CI: 5.20 % to 16.55 %) and SGRQ (-9.14 units, 95 % CI: -11.59 units to -6.70 units). There were no significant differences in mortality (OR 1.49, 95 % CI: 0.67 to 3.29), but AEs were significantly more common for participants treated with coils (OR 2.14, 95 % CI: 1.41 to 3.23). The quality of evidence ranged from low-to-high. Five studies comprising 703 participants found that endobronchial valves versus control led to significant improvements in FEV1 (standardized mean difference (SMD) 0.48, 95 % CI: 0.32 to 0.64) and scores on the SGRQ (-7.29 units, 95 % CI: -11.12 units to -3.45 units). There were no significant differences in mortality between the 2 groups (OR 1.07, 95 % CI: 0.47 to 2.43), but AEs were more common in the endobronchial valve group (OR 5.85, 95 % CI: 2.16 to 15.84). Participant selection played an important role as absence of collateral ventilation was associated with superior clinically significant improvements in health outcomes. The quality of evidence ranged from low-to-high. In the comparison of partial bilateral placement of intra-bronchial valves to control, 1 trial favored control in FEV1 (-2.11 % versus 0.04 %, p = 0.001) and 1 trial found no difference between the groups (0.9 L versus 0.87 L, p = 0.065). There were no significant differences in SGRQ scores (MD 2.64 units, 95 % CI: -0.28 units to 5.56 units) or mortality rates (OR 4.95, 95 % CI: 0.85 to 28.94), but AEs were more frequent (OR 3.41, 95 % CI: 1.48 to 7.84) in participants treated with intra-bronchial valves. The lack of functional benefits may be explained by the procedural strategy used, as another study (22 participants) compared unilateral versus partial bilateral placement, finding significant improvements in FEV1 and SGRQ when using the unilateral approach. The quality of evidence ranged between moderate-to-high. One study of 69 participants found significant mean between-group differences in FEV1 (14.70 %, 95 % CI: 7.98 % to 21.42 %) and SGRQ (-9.70 units, 95 % CI: -15.62 units to -3.78 units), favoring vapor ablation over control. There was no significant between-group difference in mortality (OR 2.82, 95 % CI: 0.13 to 61.06), but vapor ablation led to significantly more AEs (OR 3.86, 95 % CI: 1.00 to 14.97). The quality of evidence ranged from low-to-moderate. The authors concluded that results for selected BLVR procedures indicated they could provide significant and clinically meaningful short-term (up to 1 year) improvements in health outcomes, but this was at the expense of increased AEs. They stated that the currently available evidence is insufficient to assess the effect of BLVR procedures on mortality. These findings were limited by the lack of long-term follow-up data, limited availability of cost-effectiveness data, significant heterogeneity in results, presence of skew and high CIs, and the open-label character of a number of the studies.

The Australian Safety and Efficacy Register of New Interventional Procedures – Surgical’s Technology Brief Update on “Endobronchial valves for patients with advanced heterogeneous emphysema” (ASERNIP, 2017) stated that “the evidence base describing the use of endobronchial valves remains immature. Data collected under the auspices of prospective evaluation clinical trials conducted in a highly selective group of patients should be encouraged. HealthPACT does not support public investment in endobronchial valves in routine clinical practice at this time”.

The National Institute for Clinical Excellence’s guidance on “Endobronchial valve insertion to reduce lung volume in emphysema” (NICE, 2017) provided the following recommendations:

Current evidence on the safety and efficacy of endobronchial valve insertion to reduce lung volume in emphysema is adequate in quantity and quality to support the use of this procedure provided that standard arrangements are in place for clinical governance, consent and audit.
Patient selection should be done by a multi-disciplinary team experienced in managing emphysema, which should typically include a chest physician, a radiologist, a thoracic surgeon and a respiratory nurse.
Patients selected for treatment should have had pulmonary rehabilitation.
The procedure should only be done to occlude volumes of the lung where there is no inter-lobar collateral ventilation, by clinicians with specific training in doing the procedure.

Global Initiative for Chronic Obstructive Lung Disease’s “Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease” (GOLD, 2018) reviewed 5 studies published between 2010 and 2016 on the use of endobronchial vale for the treatment of advance emphysema. It noted that “choosing bronchoscopic lung reduction (coil placement or endobronchial valve) or surgical resection (lung volume reduction surgery, LVRS) to treat hyper-inflation in an emphysematous patient depends on a number of factors. These include: the extent and pattern of emphysema identified on high-resolution computed tomography (HRCT); the presence of interlobar collateral ventilation measured by fissure integrity on HRCT or physiological assessment (endoscopic balloon occlusion and flow assessment); local proficiency in the performance of the procedures; and patient and provider preferences”. It stated the following:

In selected patients with heterogeneous or homogeneous emphysema and significant hyper-inflation refractory to optimized medical care, surgical or bronchoscopic modes of lung volume reduction (e.g., endobronchial 1-way valves or lung coils) may be considered.
In selected patients with advanced emphysema bronchoscopic intervention reduces end-expiratory lung volume and improves exercise tolerance, health status and lung function at 6 to 12 months following treatment. Endobronchial valve (Evidence: B); lung coils (Evidence: B).

On June 29, 2018, the FDA approved the Zephyr Endobronchial Valve (Zephyr Valve) that is indicated for the treatment of breathing difficulty associated with severe emphysema. The Zephyr Valve device is contraindicated for patients with active lung infections; those who are allergic to nitinol, nickel, titanium or silicone; active smokers and those who are not able to tolerate the bronchoscopic procedure. Patients who have had major lung procedures, heart disease, large bubbles of air trapped in the lung or who have not responded to other treatments should talk with their providers to determine if the Zephyr Valve device is appropriate for them.

The Spiration Valve System

On December 3, 2018, the FDA approved the Spiration Valve System for the treatment of adult patients whose lungs are over-inflated by trapped air due to severe emphysema and who are not feeling better despite drugs, pulmonary rehabilitation, and oxygen therapy.

Li and colleagues (2019) noted that COPD has become a leading cause of morbidity and mortality in China, with tobacco smoke, air pollution, and occupational biohazards being the major risk factors. The REACH trial is a prospective, multi-center RCT undertaken in China to examine the safety and effectiveness of the Spiration Valve System (SVS) compared to standard medical care in COPD patients with severe emphysema. Patients with severe airflow obstruction, hyper-inflation, and severe dyspnea with interlobar fissure integrity were evaluated for enrollment. A total of 107 subjects were randomized in a 2: 1 allocation ratio to either the treatment group (SVS valves and medical management) or the control group (medical management alone). The 3-month primary end-point showed statistically significant improvement in FEV1 in the treatment group compared to the control group (0.104 ± 0.18 versus 0.003 ± 0.15 L, p = 0.001), with the difference being durable through 6 months. Statistically significant target lobe volume reduction was achieved at 3 months (mean change of 684.4 ± 686.7 ml) and through 6 months (757.0 ± 665.3 ml). Exercise function and QOL measures improved in the treatment group, but showed a deterioration in the control group. The serious AE (SAE) rate was 33 % in the treatment group and 24.2 % in the control group. The predominance of SAEs were acute exacerbations of COPD in both groups. There was 1 death in the control group and no deaths in the treatment group. The authors concluded that the SVS represents a novel approach for the treatment of severe emphysema with a clinically acceptable risk-benefit profile.

In a multi-center, open-label RCT, Criner and associates (2019) examined the safety and effectiveness of the SVS versus optimal medical management. Participants aged greater than or equal to 40 years of age with severe, heterogeneous emphysema were randomized 2:1 to SVS with medical management (treatment) or medical management alone (control). The primary efficacy outcome was the difference in mean FEV1 from baseline to 6 months. Secondary effectiveness outcomes included: difference in FEV1 responder rates, target lobe volume reduction, hyper-inflation, health status, dyspnea, and exercise capacity. The primary safety outcome was the incidence of composite thoracic SAE. All analyses were conducted by determining the 95 % Bayesian credible intervals (BCI) for the difference between treatment and control arms. Between October 2013 and May 2017, a total of 172 participants (53.5 % men, mean age of 67.4 years) were randomized to treatment (n = 113) or control (n = 59). Mean FEV1 showed statistically significant improvements between the treatment and control groups - between-group difference at 6 and 12 months, respectively of 0.101 liters (95 % BCI: 0.060 to 0.141) and 0.099 liters (95 % BCI: 0.048 to 0.151). At 6 months, the treatment group had statistically significant improvements in all secondary end-points except 6MWD. Composite thoracic SAE incidence through 6 months was greater in the treatment group (31.0 % versus 11.9 %), primarily due to a 12.4 % incidence of serious pneumothorax. The authors concluded that in patients with severe heterogeneous emphysema, the SVS showed significant improvement in multiple efficacy outcomes, with an acceptable safety profile.

Digital Chest Drainage System for Pos-Operative Chest Tube Management After Pulmonary Resection

In a prospective, randomized study, Takamochi and associates (2018) examined if a digital thoracic drainage system (group D) is clinically useful compared with a traditional thoracic drainage system (group T) in chest tube management following anatomic lung resection. Patients scheduled to undergo segmentectomy or lobectomy were prospectively randomized before surgery to group D or T. A stratification randomization was performed according to the following air leak risk factors: age, sex, smoking status, and presence of emphysema and/or chronic obstructive pulmonary disease. The primary end-point was the duration of chest tube placement. No statistically significant differences were found between groups D (n = 135) and T (n = 164) with regard to the duration of chest tube placement (median, 2.0 versus 3.0 days; p = 0.149), duration of hospitalization (median of 6.0 versus 7.0 days; p = 0.548), or frequency of post-operative AEs (25.1 % versus 20.7 %; p = 0.361). In subgroup analyses of the 64 patients with post-operative air leak (20 in group D and 44 in group T), the duration of chest tube placement (median of 4.5 versus 4.0 days; p = 0.225) and duration of post-operative air leak (median of 3.0 versus 3.0 days; p = 0.226) were not significantly different between subgroups. The authors concluded that the use of a digital thoracic drainage system did not shorten the duration of chest tube placement in comparison to a traditional thoracic drainage system after anatomic lung resection.

Wang and colleagues (2019) stated that several RCTs and observational studies have compared the efficacy of digital chest drainage system versus traditional chest drainage system. However, the results were inconsistent. These investigators searched the Web of Science and PubMed for observational studies and RCTs that compared the effect of digital chest drainage system with traditional chest drainage system after pulmonary resection. A total of 8 studies (5 RCTs and 3 observational studies) comprising 1,487 patients met the eligibility criteria. Compared with the traditional chest drainage system, digital chest drainage system reduced the risk of prolonged air leak (PAL) (RR = 0.54, 95 % CI: 0.40 to 0.73, p < 0.0001), and shortened the duration of chest drainage (SMD = - 0.35, 95 % CI: -0.60 to -0.09, p = 0.008) and length of hospital stay (SMD = - 0.35, 95 % CI: -0.61 to -0.09, p = 0.007) in patients after pulmonary resection. The authors concluded that digital chest drainage system is expected to benefit patients to attain faster recovery and higher life quality as well as to reduce the risk of postoperative complications. Moreover, these researchers stated that further RCTs with larger sample size are needed to elucidate the advantages of digital chest drainage system.

Non-Invasive Positive Pressure Ventilation for Prevention of Complications After Pulmonary Resection in Lung Cancer Patients

Torres and colleagues (2019) stated that pulmonary complications are often observed during the post-operative period following lung resection for patients with lung cancer. Some situations such as intubation, a long stay in the intensive care unit (ICU), the high cost of antibiotics and mortality may be avoided with the prevention of post-operative pulmonary complications. Non-invasive positive pressure ventilation (NIPPV) is widely used in hospitals, and is thought to reduce the number of pulmonary complications and mortality after this type of surgery. In a Cochrane review, these researchers evaluated the safety and effectiveness of NIPPV for preventing complications in patients following pulmonary resection for lung cancer. They searched the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, LILACS and PEDro until December 21, 2018, to identify potentially eligible trials. These investigators did not use any date or language restrictions in the electronic searches. They searched the reference lists of relevant papers and contacted experts in the field for information about additional published and unpublished studies. They also searched the Register of Controlled Trials (www.controlled-trials.com) and ClinicalTrials.gov (clinicaltrials.gov) to identify ongoing studies. These researchers considered randomized or quasi-randomized clinical trials that compared NIPPV in the immediate post-operative period after pulmonary resection with no intervention or conventional respiratory therapy. Two authors collected data and assessed trial risk of bias. Where possible, they pooled data from the individual studies using a fixed-effect model (quantitative synthesis), but where this was not possible they tabulated or presented the data in the main text (qualitative synthesis). Where substantial heterogeneity existed, these researchers applied a random-effects model. Of the 190 references retrieved from the searches, 7 RCTs (1 identified with the new search) and 1 quasi-randomized trial fulfilled the eligibility criteria for this review, including a total of 486 patients; 5 studies described quantitative measures of pulmonary complications, with pooled data showing no difference between NIPPV compared with no intervention (RR 1.03; 95 % CI: 0.72 to 1.47); 3 studies reported intubation rates and there was no significant difference between the intervention and control groups (RR 0.55; 95 % CI: 0.25 to 1.20); 5 studies reported measures of mortality on completion of the intervention period. There was no statistical difference between the groups for this outcome (RR 0.60; 95 % CI: 0.24 to 1.53). Similar results were observed in the subgroup analysis considering ventilatory mode (bi-level versus continuous positive airway pressure (CPAP). No study evaluated the post-operative use of antibiotics; 2 studies reported the length of ICU stay and there was no significant difference between the intervention and control groups (MD -0.75; 95 % CI: -3.93 to 2.43); 4 studies reported the length of hospital stay and there was no significant difference between the intervention and control groups (MD -0.12; 95 % CI: -6.15 to 5.90). None of the studies described any complications related to NIPPV. Of the 7 included studies, 4 were considered as “low risk of bias” in all domains, 2 were considered “high risk of bias” for the allocation concealment domain, and 1 of these was also considered “high risk of bias” for random sequence generation. One other study was considered “high risk of bias” for including subjects with more severe disease. The new study identified could not be included in the meta-analysis as its intervention differed from the other studies (use of pre- and post-operative NIPPV in the same population). The authors concluded that this review demonstrated that there was no additional benefit of using NIPPV in the post-operative period after pulmonary resection for all outcomes analyzed (pulmonary complications, rate of intubation, mortality, post-operative consumption of antibiotics, length of ICU stay, length of hospital stay and adverse effects related to NIPPV). However, the quality of evidence was “very low”, “low” and “moderate” since there were few studies, with small sample size and low frequency of outcomes. These researchers stated that new well-designed and well-conducted randomized trials are needed to answer the questions of this review with greater certainty.

Bronchoscopic Thermal Vapor Ablation for the Treatment of Upper-Lobe Emphysema

Snell and associates (2012) noted that the need for a less invasive procedure than surgical lung volume reduction that can produce consistent improvements with reduced morbidity remains a medical goal in patients with emphysema. These investigators examined the effect of bronchoscopic thermal vapor ablation (BTVA) on lung volumes and outcomes in patients with emphysema. A total of 44 patients with upper lobe-predominant emphysema were treated unilaterally with BTVA. Entry criteria included: age of 40 to 75 years, FEV1 of 15 % to 45 % predicted, previous pulmonary rehabilitation and a heterogeneity index (tissue/air ratio of lower lobe/upper lobe) from HRCT of greater than or equal to 1.2. Changes in FEV1, SGRQ, 6MWD, MMRC dyspnea score, and hyperinflation were measured at baseline, and 3 and 6 months post-BTVA. At 6 months, mean ± SE FEV1 improved by 141 ± 26 ml (p < 0.001) and RV was reduced by 406 ± 113 ml (p < 0.0001). SGRQ total score improved by 14.0 ± 2.4 points (p < 0.001), with 73 % improving by greater than or equal to 4 points. Improvements were observed in 6MWD (46.5 ± 10.6 m) and MMRC dyspnea score (0.9 ± 0.2) (p < 0.001 for both). Lower respiratory events (n = 11) were the most common AE and occurred most often during the initial 30 days. The authors concluded that BTVA therapy resulted in clinically relevant improvements in lung function, QOL and exercise tolerance in upper lobe predominant emphysema. Moreover, these researchers stated that future studies are needed to corroborate the findings with larger sample sizes and a control arm.

The authors stated that these conclusions must be tempered by the relatively small sample size (n = 44) and single-arm, open trial design. Future studies will need to consider incorporation of a control arm. Optimally, the control arm should include a sham procedure. Nevertheless, the changes from baseline in the current study showed consistent efficacy across multiple end-points that demonstrated improvements in physiology, symptoms, exercise tolerance and health-related QOL with nominal p-values < 0.05. It must be recognized that this patient population with GOLD stage III and IV disease remained symptomatic at study entry with significant impairments in health-related QOL despite previous participation in pulmonary rehabilitation and prescription of pharmacotherapy. Another potential limitation was the wider-spread applicability given that only patients with upper lobe predominant emphysema were studied. Additional studies should therefore be directed to those patients with lower lobe disease to evaluate the overall benefit-risk. The National Emphysema Treatment Trial (NETT) data suggested that improvements in the BODE score may be associated with improved survival. Whether this observation can be extended to BTVA (a decrease of 1.4 points over 6 months) will require longer term follow-up.

Gompelmann and colleagues (2018) stated that BTVA represents one of the endoscopic lung volume reduction (ELVR) techniques that aims at hyper-inflation reduction in patients with advanced emphysema to improve respiratory mechanics. By targeted segmental vapor ablation, an inflammatory response led to tissue and volume reduction of the most diseased emphysematous segments. So far, BTVA has been demonstrated in several single-arm trials and 1 multi-national RCT to improve lung function, exercise capacity, and QOL in patients with upper lobe-predominant emphysema irrespective of the collateral ventilation. In this review, these researchers emphasized the practical aspects of this ELVR method. Patients with upper lobe-predominant emphysema, FEV1 between 20 % and 45 % of predicted, RV greater than 175 % of predicted, and DLCO greater than or equal to 20 % of predicted can be considered for BTVA treatment. Prior to the procedure, a special software assists in identifying the target segments with the highest emphysema index, volume and the highest heterogeneity index to the untreated ipsilateral lung lobes. The procedure may be performed under deep sedation or preferably under general anesthesia. After positioning of the BTVA catheter and occlusion of the target segment by the occlusion balloon, heated water vapor is delivered in a pre-determined specified time according to the vapor dose. After the procedure, patients should be strictly monitored to proactively detect symptoms of localized inflammatory reaction that may temporarily worsen the clinical status of the patient and to detect complications. The authors concluded that as the data were still very limited, BTVA should be performed within clinical trials or comprehensive registries where the product is commercially available.

Furthermore, the National Institute for Health and Care Excellence’s interventional procedures guidance on “Bronchoscopic thermal vapor ablation for upper-lobe emphysema” (NICE, 2019) provided the following recommendations:

Current evidence on the safety and efficacy of bronchoscopic thermal vapor ablation for upper-lobe emphysema is inadequate in quantity and quality. Therefore the procedure should only be used in the context of research.
Further research should evaluate safety and efficacy in the short- and long-term and include details of patient selection. NICE may update the guidance on publication of further evidence.

Zarogoulidis and colleagues (2020) noted that BLVR is a novel approach for the treatment of emphysema. Several techniques are available to accomplish BLVR including BTVA. This technique is easy to perform and considered safe due to its gradual effect. These investigators discussed BTVA in detail in this editorial. They discussed their experience with BTVA in detail including patient selection, equipment, procedure, post-procedural care and complications. These researchers also reviewed the literature to determine the pros and cons for its use. Other modalities such as endobronchial valves, coils and lung sealants were also briefly discussed. The authors concluded that vapor ablation is a novel and safe approach in inducing lung volume reduction in emphysema patients. The effects were gradual, and thus potentially making it safer than other minimally invasive modalities. Pneumonitis and infection were common side effects. Just as in other BLVR techniques, a case-by-case evaluation is needed to determine the right candidate for BTVA. The authors concluded that further larger studies are needed before BTVA becomes standard of care in treatment of patients with emphysema.

Wang and associates (2020) stated that COPD is a prevalent and progressive disease. The recently developed BLVR techniques offer personalized therapeutic options in subgroups of patients with severe emphysema; EBV/IBV achieve lung volume reduction by lobar atelectasis. The lung volume reduction coils (LVRCs) and BTVA induce tissue compression, either mechanically or through inflammatory processes. While the effects of EBV/IBV are reversible by removing the implants, the effects of LVRC are partially reversible and that of BTVA is irreversible. The presence of inter-lobar CV impacts on EBV/IBV treatment outcome due to its mechanism of action; thus, using radiological and endoscopic techniques to evaluate CV has a vital importance. The authors concluded that current evidence of BLVR demonstrates acceptable safety and short-term clinical efficacy; however, head-to-head trials are lacking, and further research is needed to establish long-term clinical benefit, durability, and cost-effectiveness of these techniques.

Thoracoscopic Bullectomy Using a Trans-Areolar Approach in the Treatment of Primary Spontaneous Pneumothorax

An UpToDate review on definitive treatment and prevention of pneumothorax (Light & Lee, 2020) recommended video-assisted thoracoscopic surgery (VATS) apical blebectomy/bullectomy simultaneously with pleurodesis based upon retrospective data that report recurrence rates <5 percent using this combined approach. The authors noted, however, that data are conflicting and some surgeons perform pleurodesis alone based upon data that report lower recurrence rates in patients with VATS-directed insufflation of talc compared with bullectomy alone (0.3 versus 3.8 percent), while others perform blebectomy/bullectomy alone based upon data that report recurrence rates <9 percent with bullectomy alone.

Lin and associates (2016) stated that conventional tri-portal VATS is the classic approach for the diagnosis and treatment of primary spontaneous pneumothorax (PSP). The researchers stated that trans-areolar pulmonary bullectomy rarely has been attempted. These researchers examined the safety and feasibility of this novel minimally invasive technique in managing PSP. From January 2013 to December 2014, a total of 112 male patients with PSP underwent trans-areolar pulmonary bullectomy by use of a 5-mm thoracoscope. All procedures were carried out successfully, with a mean operating time of 26.5 mins. The mean length of trans-areolar incision for the main operation was 2.0 ± 0.2 cm, the mean length of incision for the camera port was 0.6 ± 0.1 cm, and the mean post-operative cosmetic score was 3.0 ± 0.8. All patients regained consciousness rapidly after surgery; 107 patients (95.5 %) were discharged on post-operative day (POD) 2 or 3, with the remainder discharged on POD 4 or 5. Post-operative complications were minor. At post-operative month (POM) 6, there was no obvious surgical scar on the chest wall, and no patient complained of post-operative pain. No recurrent symptoms were observed; 1-year follow-up revealed an excellent cosmetic result and degree of satisfaction. The authors concluded that trans-areolar pulmonary bullectomy was a safe and effective therapeutic procedure for PSP caused by pulmonary bullae. The incision was hidden in the areola with excellent cosmetic effects. These investigators stated that this novel procedure showed promise as a treatment of PSP.

Yazawa and colleagues (2020) stated that PSP is a common disease among young patients, especially men. While the most common thoracoscopic approach is tri-portal, the trans-areolar approach is rare. These investigators examined the feasibility of thoracoscopic pulmonary bullectomy using a trans-areolar approach for treatment of PSP. A total of 10 patients with PSP who underwent thoracoscopic trans-areolar pulmonary bullectomy were prospectively enrolled in this study between September 2017 and March 2018. For all 10 patients, these researchers examined the peri-operative outcomes, post-operative complications, recurrence, wound-related pain, and cosmetic satisfaction regarding the surgical wound. The mean patient age was 18.9 ± 4.2 years; 3 patients were affected on the right side and 7 patients were affected on the left side. Bullae and blebs were localized at the apex of the affected lung in all patients. All procedures were completed using a trans-areolar approach without additional ports or conversion to thoracotomy in any patient. The mean operative time was 39.8 ± 8.6 mins. The mean volume of blood lost during surgery was extremely small in all patients. The duration of post-operative drainage was 1 day, while the length of post-operative hospital stay was 2 days in all patients. No morbidities or recurrence of PSP occurred during the study period. The mean cosmetic satisfaction scores of the surgical wound were 3.3 and 3.2 on POD 7 and POM 12. The mean numerical rating scale (NRS) score was 1.5 on POD 7; all patients were pain-free at POM 12. The authors concluded that trans-areolar thoracoscopic pulmonary bullectomy for treatment of PSP was feasible and safe, with a high degree of satisfaction for post-operative pain and cosmetics. This new approach could be a novel option for surgical treatment of PSP.

The authors stated that the drawbacks of this study were the small number of patients (n = 10) and the single-arm design of the trial. However, this was the first study to prospectively examine the efficacy of thoracoscopic trans-areolar pulmonary bullectomy. In the future, these investigators will carry out a prospective study to compare the trans-areolar and uni-portal approaches.

Use of Polyglycolic Acid Patch in the Treatment of Pneumothorax by Thoracoscopic Bullectomy

Mao and colleagues (2020) noted that a polyglycolic acid (PGA) patch is often used in pulmonary bullae resection, but consensus has not been reached on its effect on patient recovery. These investigators carried out a systematic review and meta-analysis of studies of PGA for bullectomy. They performed a comprehensive literature search using ScienceDirect, Embase, Ovid Medline, PubMed, the Cochrane Library, Scopus, and Google Scholar. Clinical trials that compared PGA versus non-PGA for bullectomy were selected. The clinical end-points included post-operative recurrence, average post-operative air leakage, prolonged air leaks, drainage tube removal time, and post-operative hospital stay. A total of 8 articles (1,095 patients) were included. Compared to the non-PGA approach, the PGA approach was associated with lower rates of post-operative recurrence (95 % CI: 0.16 to 0.39, p < 0.00001),) and of prolonged air leaks (95 % CI: 0.29 to 0.72, p = 0.0007); a shorter time of drainage tube removal (95 % CI: - 1.36 to - 0.13, p = 0.02). The time of average post-operative air leakage, post-operative hospital stay and operative time did not show a significant difference between the 2 groups. The authors concluded that in the treatment of pneumothorax by thoracoscopic bullectomy, the use of a PGA patch could reduce the recurrence of pneumothorax, and reduce the time of thoracic drainage and prolonged post-operative air leakage. Moreover, it did not increase operation time. However, the use a PGA patch couldn’t shorten the hospitalization time and average post-operative air leakage. Because of limitations of the included studies, however, this conclusion still needs to be verified by more high-quality RCT literature. Important data such as intra-operative bleeding volume and post-operative complications are expected to be discussed in more large-scale, high-quality RCTs in the future.

The authors stated that this study had several drawbacks. First, there are only 1,095 patients included in the literature, and most of them were retrospective research, among which only 3 RCTs affected the value of meta-analysis conclusions. Second, the main research subjects included in the literature were mainly Chinese and Japanese, which may have resulted in some selection bias. Third, in calculating pneumothorax recurrence, the studies varied greatly in the follow-up time reported, which may indirectly lead to deviation in the final number, which may also affect the results. Finally, these researchers were unable to compare important data such as intra-operative bleeding volume, and post-operative complications (pulmonary infection, heart rate arrhythmia, pleural effusion, etc.) because they were not reported in the relevant literature.

Targeted Lung Denervation (dNerva Lung Denervation System) for the Treatment of Chronic Obstructive Pulmonary Disease

Targeted Lung Denervation (TLD; Nuvaira, Inc., Minneapolis, MN) is a non-surgical, out-patient procedure that entails passing the specialized, dNerva Catheter via a flexible bronchoscope to complete a full circumferential radio-frequency ablation (RFA) in the main bronchi of each lung. It is used for the treatment of chronic obstructive pulmonary disease (COPD). The ablation supposed creates permanent disrupts of pulmonary nerve input to the lung to reduce the clinical consequences of neural hyperactivity.

Slebos et al (2019) stated that TLD is a bronchoscopic RFA therapy for COPD; it permanently disrupts parasympathetic pulmonary nerves to decrease airway resistance and mucus hyper-secretion. In a multi-center, randomized, sham bronchoscopy-controlled, double-blind trial, these researchers examined the safety and impact of TLD on respiratory AEs. This study enrolled patients with symptomatic (modified Medical Research Council [mMRC] dyspnea scale score, 2 or higher; or COPD Assessment Test [CAT] score, 10 or higher) COPD (FEV1, 30 % to 60 % predicted). The primary endpoint was the rate of respiratory AEs between 3 and 6.5 months after following randomization (defined as COPD exacerbation, tachypnea, wheezing, worsening bronchitis, worsening dyspnea, influenza, pneumonia, other respiratory infections, respiratory failure, or airway effects requiring therapeutic intervention). Blinding was maintained through 12.5 months. A total of 82 patients (50 % women; mean ± SD: age of 63.7 ± 6.8 years; FEV1, 41.6 % ± 7.3 % predicted; mMRC dyspnea scale score, 2.2 ± 0.7; CAT score, 18.4 ± 6.1) were randomized 1:1. During the pre-defined 3- to 6.5-month window, patients in the TLD group experienced significantly fewer respiratory AEs than those in the sham group (32 % versus 71 %, p = 0.008; OR, 0.19; 95 % CI: 0.0750 to 0.4923, p = 0.0006). Between 0 and 12.5 months, these findings were not different (83 % versus 90 %; p = 0.52). The risk of COPD exacerbation requiring hospitalization in the 0- to 12.5-month window was significantly lower in the TLD group than in the sham group (hazard ratio [HR], 0.35; 95 % CI: 0.13 to 0.99; p = 0.039). There was no statistical difference in the time to 1st moderate or severe COPD exacerbation, patient-reported symptoms, or other physiologic measures over the 12.5 months of follow-up. The authors concluded that patients with symptomatic COPD treated with TLD combined with optimal pharmacotherapy had fewer study-defined respiratory AEs, including hospitalizations for COPD exacerbation. Moreover, these researchers stated that these findings merit further larger-scale studies to substantiate the effect of TLD on exacerbation rates.

The authors stated that drawbacks of this study included the relatively small study size, the short time window during which the primary endpoint was assessed, and the use of investigator definitions for the respiratory AEs used. In addition, owing to anatomical limitations (esophageal proximity), not all patients could receive a full circumferential treatment, resulting in potential under-treatment. The focus of this trial was on safety, which made the interpretation of the observed reduction in severe COPD exacerbations in the TLD group complex. Although the rate of COPD exacerbations was an a priori secondary endpoint with a pre-defined definition consistent with previous studies applying this endpoint, the study did rely on physicians to independently apply that definition to each event. With this limitation in mind and with the primary focus of the study being safety, the data on changes in COPD exacerbations in this study were presented as secondary respiratory safety measures and not as an efficacy endpoint as it was defined in the protocol. This was done with the acceptance that a larger study is needed to more precisely determine the impact of TLD on COPD exacerbations.

Valipour et al (2020) noted that COPD exacerbations are associated with worsening clinical outcomes and increased healthcare costs, despite use of optimal medical therapy. A novel bronchoscopic therapy, TLD, which disrupts parasympathetic pulmonary innervation of the lung, has been developed to reduce clinical consequences of cholinergic hyperactivity and its impact on COPD exacerbations. The AIRFLOW-2 study examined the durability of safety and effectiveness of TLD additive to optimal drug therapy compared to sham bronchoscopy and optimal drug therapy alone in subjects with moderate-to-severe, symptomatic COPD 2 years post-randomization. TLD was carried out in COPD patients (FEV1 30 % to 60 % predicted, CAT score of 10 or higher, or mMRC dyspnea scale score of 2 or higher) in a 1:1 randomized, sham-controlled, double-blinded multicenter study (AIRFLOW-2) using a novel lung denervation system. Subjects remained blinded until their 12.5-month follow-up visit when control subjects were offered the opportunity to undergo TLD. A time-to-first-event analysis on moderate and severe and severe exacerbations of COPD was performed. A total of 82 subjects (FEV1 41.6 % ± 7.4 % predicted, 50.0 % men, age of 63.7 ± 6.8 years, 24 % with prior year respiratory hospitalization) were randomized. Time-to-first severe COPD exacerbation was significantly lengthened in the TLD arm (p = 0.04, HR = 0.38) at 2 years post-TLD therapy and trended towards similar attenuation for moderate and severe COPD exacerbations (p = 0.18, HR = 0.71). No significant changes in lung function or COPD specific St. George’s Respiratory Questionnaire (SGRQ-C)) were found 2 years post-randomization between groups. The authors concluded that in a randomized trial, TLD demonstrated a durable effect of significantly lower risk of severe acute exacerbation of COPD (AECOPD) over 2 years. Furthermore, lung function and QOL remained stable following TLD.

The authors stated that the small sample size was an enhanced limitation in this study. While an improvement in the time-to-first event was observed in the TLD group, this result was found in a relatively small study size. This sample size was further decreased after approximately 50 % of control subjects crossed-over before the 2-year follow-up visit, which likely resulted in a healthier group (i.e., subjects who had a higher symptomatic disease characteristic were more likely to undergo TLD, which is a well-known challenge of cross-over design).

Slebos et al (2020) stated that targeted lung denervation (TLD) is a bronchoscopically delivered ablation therapy that selectively interrupts pulmonary parasympathetic nerve signaling. The procedure has the potential to alter airway smooth muscle tone and reactivity, decrease mucous secretion, and reduce airway inflammation and reflex airway hyper-responsiveness. Secondary outcome analysis of a previous randomized, sham-controlled trial showed a reduction in moderate-to-severe exacerbations in patients with COPD after TLD treatment. A pivotal trial, AIRFLOW-3 has been designed to examine the safety and effectiveness of TLD combined with optimal medical therapy to reduce moderate or severe exacerbations throughout 1 year, compared with optimal medical therapy alone. The study design is a multi-center, randomized, full sham bronchoscopy controlled, double-blind trial that will enroll 400 patients (1:1 randomization). Key inclusion criteria are FEV1/FVC less than 0.7, FEV1 30 % to 60 % of predicted, post-bronchodilator, 2 or more moderate or 1 severe COPD exacerbations in the previous year, and CAT score of 10 or higher. Primary objective will be the comparison of moderate or severe COPD exacerbations through 12 months of TLD therapy with optimal medical therapy versus optimal medical therapy alone. The sham group will be allowed to cross-over at 1 year. Patients will be followed for up to 5 years. The authors concluded that this multi-center, randomized, full sham bronchoscopy controlled, double-blind AIRFLOW-3 trial will examine the effectiveness of TLD to reduce moderate or severe COPD exacerbations beyond optimal medical therapy alone. The target population are patients with COPD, who suffer persistent symptoms and exacerbations despite optimal treatment, defining an unmet medical need requiring novel therapeutic solutions.

Pison et al (2021) noted that TLD is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study examined the safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis examined the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow-up. TLD was carried out in a prospective, energy-level randomized (29 W versus 32 W power), multi-center study. Additional patients were enrolled in an open-label confirmation phase to confirm improved gastro-intestinal (GI) safety following procedural modifications. Durability of TLD was examined at 1-, 2-, and 3-year post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and QOL. Three-year follow-up data were available for 73.9 % of patients (n = 34). The annualized rate of moderate-to-severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and QOL (SGRQ-C and CAT scores) remained stable over 3 years of follow-up. No new GI AEs and no unexpected serious AEs were observed. The authors concluded that TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious AEs related to denervation therapy. Clinical stability in lung function, QOL, and exacerbations were observed in TLD treated patients over 3 years of follow-up.

The authors stated that this study had several drawbacks, mainly the small cohort size, and the lack of a sham-control group. However, a strength of this study was its high retention via 3 years of follow-up, which is rare in early-stage device trials. Moreover, any placebo effect assumed by the open-label design would not be expected to impact 2- or 3-year measures. The absence of decline 3 years post-treatment compared with baseline supports stability for lung function and QOL life in this study and both were consistent with the stable rate of exacerbations observed in this study. These observations will need to be confirmed in an ongoing large-scale, sham-controlled randomized trial (AIRFLOW-3) comparing the effectiveness of TLD plus optimal medical care for patients with moderate-to-severe COPD against optimal medical care for COPD.

In a review on “Bronchoscopic management of asthma, COPD and emphysema”, Perotin et al (2021) stated that the level of evidence is currently too low with available data from only 1RCT to include TLD in therapeutic guidelines for COPD management. These investigators stated that additional RCTs are needed to confirm promising results, especially regarding the impact on severe COPD exacerbation.

Mehra et al (2022) noted that pulmonary parasympathetic activity is enhanced in COPD and may play a critical role in the airway obstruction, airway hyper-responsiveness, and increased mucus production characteristic of this condition; therefore, inhaled anticholinergic therapies have been the mainstay of COPD treatment. Similarly, disruption of pulmonary parasympathetic nerves in patients with COPD has the potential to provide long-lasting anticholinergic effects with reduction of symptoms and exacerbations. These investigators stated that TLD is a novel bronchoscopic therapy that disrupts the afferent and efferent pulmonary branches of the vagus nerve along the outside of the main stem bronchi using RFA. Initial studies have reported the safety and feasibility of TLD and have shown trends toward improvements in symptoms and exacerbations; and its effectiveness is currently being examined in the pivotal AIRFLOW-3 (Evaluation of the Safety and Efficacy of TLD in Patients With COPD) Trial. Determining the appropriate RFA parameters in TLD is challenging because there are few direct assessments of afferent/efferent function. Because TLD also targets lung afferents, evaluation of cardiopulmonary reflexes such as respiratory sinus arrhythmia pre- and post-treatment may have the potential to examine the extent of pulmonary vagal denervation achieved with this approach.

Conway et al (2022) stated that TLD is a potential new therapy for COPD. In this novel approach, RF energy is bronchoscopically delivered to the airways to disrupt pulmonary parasympathetic nerves, to reduce bronchoconstriction, mucus hypersecretion, and bronchial hyperreactivity. These researchers examined the effect of TLD on AECOPD in cross-over subjects in the AIRFLOW-2 Trial. Patients with symptomatic COPD on optimal medical therapy with an FEV1 of 30 % to 60 % predicted received either TLD or sham bronchoscopy in a 1:1 randomization. Those in the sham arm had the opportunity to cross into the treatment arm after 12 months. The primary endpoint was rate of respiratory AEs; secondary endpoints included AEs, changes in lung function and health-related QOL and symptom scores. A total of 20 patients were treated with TLD in the cross-over phase and were subsequently followed-up for 12 months (50 % women, mean age of 64.1 ± 6.9 years). After TLD, there was a trend towards a reduction in time to first AECOPD (HR 0.65, p = 0.28, not statistically significant) in comparison to sham follow-up period. There was also a reduction in time to 1st severe AECOPD in the cross-over period (HR 0.38, p = 0.227, not statistically significant). Symptom scores and lung function showed stability. The authors concluded that the AIRFLOW-2 cross-over data supported that of the randomization phase, showing trends towards reduction in COPD exacerbations with TLD.

The authors stated that the main drawback of this study was the small number of subjects and the known heterogeneity in the timing of COPD exacerbation events within a given group of patients. Although this analysis of cross-over subjects was not powered for any outcome, the observed HRs for time-to-1st-event were consistent with previous studies of TLD in a similar patient population. For moderate or severe AECOPD, the current study’s HR of 0.65 was similar to the 0.66 value observed during the randomized phase of AIRFLOW-2. The severe AECOPD HRs were also similar with values 0.38 and 0.35, respectively. Another drawback was the challenge in recording methods of exacerbations. As patients were frequently provided with a “rescue pack” of antibiotics, they often self-medicated for what they perceived to be an exacerbation without a medical consultation. This was a common drawback to many studies evaluating exacerbations. There was also recall bias as many patients did not remember the episodes in which they had needed their rescue pack in the previous year. Beyond patients acting as their own controls, the study attempted to further mitigate risk of recall bias, by providing patients with a memory aid where they were advised to document the details of any exacerbations or infections. Medication use was also recorded by the patient and researcher. In addition, patients were regularly contacted by the study team who also kept a record of patient-reported exacerbations.

In a post-hoc analysis of the AIRFLOW-2 Trial, Hartman et al (2022a) reviewed the changes in airway CT-parameters following TLD and examined if these changes were associated with treatment response. In the treatment group (n = 32), an improvement in air trapping was significantly associated with an improvement in residual volume (RV). In addition, improvements in Pi10 (the square root of wall area at airways with a perimeter of 10 mm) and airway lumen were significantly associated with an improvement in both RV and FEV1. The authors concluded that these findings could suggest that when improving airway characteristics like decreasing airway wall thickness and increasing the airway lumen, this resulted in less air trapping and an improvement in clinical outcomes.

Hartman et al (2022b) stated that therapeutic options for severe asthma are limited, especially in those patients who do not meet criteria for biologicals; TLD is the bronchoscopic RFA of the peri-bronchial vagal nerve trunks to reduce cholinergic stimulation of airway smooth muscle and submucosal glands. These investigators described the experience of the first 2 asthma patients treated with TLD worldwide. The subjects were 54 and 51 years of age, and both had severe asthma (GINA 5) (FEV1: 53 % and 113 % of predicted; AQLQ scores: 5.3 and 4.4). Both subjects were treated with TLD in a single day-case procedure under general anesthesia. Lung function, health status, and AE data were collected at baseline and 12 months after TLD. No treatment-related serious AEs were reported up to 12 months. Cough symptoms improved in both subjects, and 1 subject reported a marked reduction in rescue medication use at 6 months. There were no significant changes in spirometry, lung volumes, or health status. The authors concluded that TLD was carried out safely in both subjects; however, more evidence is needed to clarify the safety and effectiveness of TLD in severe asthma. Thus, further investigation of the treatment in severe asthma patients would be useful.

Herth et al (2022) noted that until now, interventional therapies for patients with COPD have been available in the form of lung volume reduction procedures as end-stage options. To-date, the range of indications is expanding to include earlier stages of the diseases. Lung denervation is available for moderate COPD, and patients with chronic bronchitis are being examined for endoscopic goblet cell ablation. Rheoplasty, metered spray cryo technique, and Karakoca resector balloon are used for this indication. However, for patients with severe uncontrolled asthma, several techniques are available today. In addition to thermoplasty, new and currently under investigation is the TLD. Most of these techniques are currently being examined in large pivotal studies and it will soon become clear which technique will be used in the different forms and stages of obstructive diseases.

Furthermore, an UpToDate review on “Management of refractory chronic obstructive pulmonary disease” (Ferguson and Make, 2022) does not mention targeted lung denervation as a management / therapeutic option.

References

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Last Review 03/16/2023

Effective: 05/19/1997

Next Review: 02/08/2024
Review History
Definitions

Lung Denervation Therapy and Lung Volume Reduction Surgery

Table Of Contents

Policy

Scope of Policy

Medical Necessity

Lung Volume Reduction Surgery (LVRS)

Bullectomy

Food and Drug Administration (FDA)-Approved Endobronchial Valve

Experimental and Investigational

CPT Codes / HCPCS Codes / ICD-10 Codes

CPT codes covered if selection criteria are met :

CPT codes not covered for indications listed in the CPB:

Bronchoscopic thermal vapor ablation, thoracoscopic bullectomy using a trans-areolar approach - - no specific code:

Other CPT codes related to the CPB:

HCPCS codes covered if selection criteria are met:

Spiration Valve System - no specific code:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB: