Interventional bronchoscopy for chronic obstructive pulmonary disease: more than a pipe dream

Chronic obstructive pulmonary disease (COPD) is the fifth greatest contributor to burden of disease and fifth overall cause of death among Australians.1 It most frequently results from cigarette smoking and leads to progressive small airway narrowing and emphysematous alveolar destruction. Symptoms include progressive dyspnoea, wheeze, and a persistent cough which may be accompanied by chronic sputum production. Patients are also prone to acute exacerbations that can result in hospitalisation, further lung function decline, respiratory failure or death. It is estimated that COPD costs the Australian community $8.8 billion in treatment and lost productivity annually.2

Comprehensive evidence‐based guidelines for the diagnosis and management of COPD in Australia and New Zealand are provided in the Lung Foundation Australia COPD‐X Plan.3 The cornerstones of management are smoking cessation, pulmonary rehabilitation and inhaled pharmacotherapy, with the aims of reducing symptoms, improving lung function and quality of life, and reducing the risk of exacerbations and mortality. For people with advanced disease, additional therapeutic options are limited. Prophylactic macrolide antibiotics may benefit patients with frequent exacerbations but are not widely advocated,4 long term oxygen therapy reduces mortality when COPD is associated with chronic hypoxia,5 and lung transplantation may be appropriate for select patients with limited comorbidities.6 Lung volume reduction is accepted as an additive therapy for certain patients with advanced emphysema refractory to medical treatment,6 but despite support from key international societies, in our experience it is not widely offered in Australia and New Zealand.

In this review, we describe the physiology of dyspnoea in COPD which explains the rationale behind lung volume reduction. We searched PubMed for randomised controlled trials (RCTs) investigating endoscopic lung volume reduction (ELVR) techniques, along with meta‐analyses, case series, subgroup analyses and expert consensus recommendations for the various approaches and their complications. We also review investigational lung volume reduction techniques, and endoscopic therapies which aim to treat chronic bronchitis.

A glossary of key terms is provided in Box 1.

Physiology

The causes of dyspnoea in COPD are numerous, with several processes often intertwined in a given individual. Destruction of elastin and collagen within lung tissue leads to reduced elastic recoil and loss of parenchymal attachments that support small airways. These pathological changes result in a reduced pressure gradient for airflow during expiration, and a propensity for the small airways to narrow and more readily collapse. This small airway narrowing is further compounded by airway inflammation and hyperplasia of mucin‐secreting cells. Together with the obliteration of terminal bronchioles, the overall airway surface area in the lung is reduced.7 Gas trapping within the lungs thereby ensues despite the patient’s expiratory effort. Over time, this results in a gradual increase in lung volume at rest known as hyperinflation.

Hyperinflation and gas trapping impede efficient function of the respiratory muscles, with the overexpanded lung displacing and flattening the diaphragm, impairing its movement during breathing. As a result, significantly more effort is required to expand the hyperinflated lung at higher volumes, which is further magnified during exercise.8 As respiratory demand increases with exercise, acute illness or anxiety, the combination of expiratory airflow limitation and higher respiratory rate leads to dynamic hyperinflation. In this instance, the airspaces fail to empty before the next inhalation begins, causing a progressive increase in end‐expiratory lung volume and compounding the gas trapping. This phenomenon results in increased work of breathing and contributes to the worsening dyspnoea and functional limitation that patients experience.9

Dyspnoea and exercise intolerance are exacerbated by mismatching of ventilation and perfusion, which occurs even in mild COPD and worsens with disease severity as a result of both alveolar destruction and airflow limitation.10 Physical inactivity is also common early in the disease course and predicts hospitalisation and all‐cause mortality, with activity levels tending to deteriorate considerably with disease exacerbations. Deconditioning prompts exercise intolerance, and the consequent muscle weakness leads to a cycle of deteriorating physical activity, frailty and impaired quality of life.11

Lung volume reduction surgery

Despite optimal medical therapy and smoking cessation, many patients remain highly symptomatic with poor quality of life.6 Lung volume reduction surgery (LVRS) was first introduced in 1957, aiming to mitigate the hyperinflation and gas trapping which accompany advanced COPD by resection of the most diseased areas of lung. This has been shown to improve lung elastic recoil, expiratory airflow and respiratory muscle function, while reducing dynamic and static hyperinflation, and potentially decompressing healthier lung tissue.8

In 2003, the seminal National Emphysema Treatment Trial12 found improvements in mortality, exercise capacity, lung function and symptoms following bilateral LVRS in a subgroup of patients with upper lobe predominant emphysema and poor baseline exercise tolerance. These improvements came at the cost of short term mortality of 5.2% in non‐high risk patients, significantly higher than standard of care. This effect was even more pronounced in a high risk subgroup with severely impaired lung function (forced expiratory volume in 1 second [FEV₁] ≤ 20% and either diffusion capacity for carbon monoxide ≤ 20% or homogeneous emphysema) who had a 90‐day mortality of 28.6% and were subsequently excluded from the study.

The early mortality seen with bilateral LVRS has been a key driver for development of less invasive, endoscopic means of achieving the same physiological benefits. Although unilateral thoracoscopic LVRS has significantly lower mortality by comparison, the risks of long post‐operative hospital stays, repeat operations for persistent air leaks, and cardiopulmonary morbidity remain.13

Endoscopic lung volume reduction

ELVR aims to achieve the physiological benefits of LVRS with shorter procedures, hospital stays and recovery periods, and lower risks in this vulnerable patient group, without the systemic catabolic state and deconditioning associated with surgery. The inclusion criteria established in the National Emphysema Treatment Trial formed the basis for ELVR candidacy,12 although patient selection remains the most challenging aspect of this field, guided mainly by expert recommendation.

Typical candidates for ELVR are highly symptomatic due to severe COPD despite optimal medical therapy, structured rehabilitation and smoking cessation. They have significant hyperinflation and gas trapping, demonstrated by elevated total lung capacity and residual volume measured during pulmonary function testing, with few additional respiratory or cardiac comorbidities. A general list of characteristics of ELVR candidates are provided in Box 2, based on international expert panel recommendations.14 It is important to note that these eligibility criteria are not absolute, and that certain factors, such as the magnitude of residual volume elevation, may be weighted more heavily depending on the institution. Specific disease characteristics, such as emphysema distribution and the presence or absence of collateral ventilation between lobes, further dictate suitability for ELVR techniques or LVRS. It is therefore recommended that lung volume reduction assessments and procedures are performed in specialist centres, and a multidisciplinary emphysema team involving respiratory physicians, interventional pulmonologists, thoracic surgeons, radiologists, respiratory physiotherapists, transplant physicians and nurse specialists is increasingly needed.15

Endobronchial valves

Lung volume reduction may be achieved through bronchoscopic placement of one‐way valves into segmental airways, which leads to deflation of the target lobe. The Zephyr endobronchial valve (PulmonX) has a silicone duckbill in a nitinol frame, and the Spiration valve system (Olympus) has an umbrella‐shaped polyurethane membrane mounted on a nitinol frame which minimises tissue contact (Box 3). The increasingly robust body of literature for endobronchial valve therapy has led to its recent recognition by the Global Initiative for Chronic Obstructive Lung Disease strategy with level A evidence,6 and the United Kingdom National Institute for Health and Care Excellence guidelines.16 Both valves were approved by the United States Food and Drug Administration in 2018 for use in ELVR.

The first multicentre, international RCT17,18 of Zephyr endobronchial valve placement yielded statistically significant but only modest clinical improvements in lung function, exercise capacity and symptoms following unilateral valve implantation in the most diseased lobe in a phenotypically diverse group of patients with COPD. Post hoc analyses indicated that patients with a heterogeneous distribution of emphysema and complete interlobar fissures had more successful volume reduction and far more meaningful outcomes. This led to the realisation that collateral ventilation, or the presence of channels which bypass the normal airways across interlobar fissures, was a key determinant of effective ELVR by means of airway occlusion.

This principle was tested in the randomised, sham‐controlled BeLieVeR‐HIFi19 study, in which the presence on imaging of intact interlobar fissures adjacent to the target lobe was used as a surrogate for absence of collateral ventilation. Patients also underwent bronchoscopic assessment for collateral ventilation using a dedicated catheter‐based system to measure airflow and pressure in the target airway while under balloon occlusion, although this was not used for inclusion. The STELVIO study20 further refined this process by using both radiologically intact fissures and absence of collateral ventilation by this system for patient selection. These trials alongside the IMPACT21 study, which focused on homogeneous emphysema, confirmed significant improvements in lung function and exercise capacity, with the greatest benefit seen in patients with intact fissures and heterogeneous emphysema (Box 4).

The most recent multicentre studies22,23 have focused on the patient group most likely to benefit from ELVR — individuals with heterogeneous emphysema and no collateral ventilation — and adopted a real world approach by permitting revision or replacement of their valves if lung volume reduction was unsatisfactory on high resolution computed tomography. Both studies confirmed clinically significant improvements in symptoms, exercise capacity, FEV₁, and gas trapping.

In a recent meta‐analysis of these trials, endobronchial valve placement in a lobe without collateral ventilation was associated with clinically significant improvements in subjective and objective respiratory outcomes. The St George’s Respiratory Questionnaire is a validated tool which measures the impact of respiratory symptoms on quality of life, producing a score from 0 to 100, with higher values corresponding with quality of life impairment and the minimum clinically important difference being 4 points.3 Scores reduced by a mean of 9.13 points, and distance walked in 6 minutes improved by 49 metres. Improvement in gas trapping was reflected by mean reduction in residual volume of 0.57 L, with airflow improvement indicated by mean increase in FEV₁ of 22%.24 Improvements in gas transfer capacity,25 ventilation and perfusion matching,26 and reductions in dynamic hyperinflation during exercise27 have also been reported. Small case series have also suggested the feasibility of endobronchial valve placement in patients with emphysema secondary to α‐1 antitrypsin deficiency,28 and in patients with FEV₁ ≤ 20% of predicted29 or with diffusion capacity for carbon monoxide ≤ 20% of predicted30 without excess adverse events.

The most common complication of effective endobronchial valve placement is pneumothorax, owing to a combination of rapid expansion of the adjacent untreated lobe and tearing of fragile lung tissue or adhesions. While this occurs in up to 25% of cases,24 most would consider the risk acceptable given intercostal drains are universally required following LVRS, and rates of prolonged air leak and re‐operation in that cohort are typically high.13 Pneumothorax after endobronchial valve insertion does not influence survival, and in fact appears to be a marker of successful lobar collapse and volume reduction, which in itself is associated with a survival advantage.31 Less frequently encountered complications include infection distal to the valves, haemoptysis, or valve migration or displacement from granulation tissue formation. Further bronchoscopies may be needed to treat complications, or to revise valve placement if the desired effect is not achieved or is lost.

Two RCTs have investigated the Spiration valve system in patients without collateral ventilation to date: REACH32 and EMPROVE.33 These trials reported significant improvements in FEV₁ of up to 23% at 12 months and improvement in dyspnoea and quality of life metrics, with the most common complication being pneumothorax, although seemingly at lower rates than in the Zephyr endobronchial valve trials.34 There have not yet been any RCTs directly comparing the two valve types, although a prospective study comparing outcomes of unilateral thoracoscopic LVRS and bronchoscopic endobronchial valve placement is currently underway (ISRCTN19684749).

The published RCTs to date have reported improved outcomes up to 1 year, with the available long term follow‐up data suggesting the benefit gradually declines, likely due to disease progression in the non‐targeted lung. In spite of this, some patients have maintained improvements in symptoms, exercise capacity and lung function at 3 years.35 Longer term data for patients treated with either or both types of valves indicate that treatment responders who develop lobar atelectasis have an improved 5‐year survival of 65%, compared with 44% in those with no lobar volume reduction31 (Box 5).

Biological lung volume reduction

Targeted instillation of a synthetic compound containing glutaraldehyde and polyvinyl alcohol is the basis of biological or polymeric lung volume reduction. This irreversible technique instigates a localised inflammatory response leading to volume loss independent of collateral ventilation, and although the initial prospective study demonstrated effective volume reduction and improvement in lung function and symptoms,36 the larger ASPIRE randomised study raised safety concerns regarding the inflammatory response to the polymer.37 The ASPIRE study was terminated early by the sponsor for financial reasons. This has been revisited with a staged treatment algorithm using lower doses to mitigate the inflammatory response in a completed but as yet unreported trial (NCT02877459).

Our group recently reported combining the use of carefully targeted small doses of the polymer in a patient with collateral ventilation, aiming to seal the leak across the fissure and leading to its cessation without any significant inflammatory response. This was then followed by successful valve placement with collapse of the target lobe.38 Prospective series using this combined approach, and separate trials using autologous blood to terminate collateral ventilation before valve placement (NTR5007; NCT03010449) are underway, aiming ultimately to increase the numbers of patients who may benefit from valve placement.

Bronchial thermal vapour ablation

Bronchial thermal vapour ablation is an irreversible means of segmental ELVR which does not depend on the absence of collateral ventilation for success. Thermal energy is delivered by means of heated water vapour through a balloon‐tipped catheter at bronchoscopy to induce a localised inflammatory reaction in the most diseased lung segments. This then heals with a fibrotic response and subsequent volume loss, with many patients experiencing a localised inflammatory response and systemic features of fatigue, influenza‐like symptoms, or temporary worsening of their respiratory symptoms.39

International multicentre studies have demonstrated improvements in FEV₁ of up to 15% at 6 months, with symptomatic improvement and effective volume loss in the target segments.40,41 Post hoc analyses have also indicated that collateral ventilation does not appear to impact clinical outcomes.42 Current recommendations are for treatment of up to three upper lobe segments over two sessions to mitigate the local inflammatory response.39 Research is ongoing in refining this technique, with optimisation of the thermal energy dose required to effect volume loss while reducing the morbidity of a severe inflammatory response through a staged approach, and we await studies on the use of bronchial thermal vapour ablation in patients with homogeneous and lower lobe predominant disease.

Lung volume reduction coils

Endobronchial coils compress hyperinflated lung tissue to restore tension and elastic recoil through deployment of several nitinol rods into target segments, which coil immediately after insertion. This process aims to tether collapsible airways and improve airway resistance, while simultaneously effecting volume reduction independent of collateral ventilation. International RCTs to date have indicated modest improvements in lung function and symptoms, with homogeneous emphysema patients being well represented in these studies.43,44,45 Adverse events include pneumonia, exacerbations of COPD, and pneumothorax. Improved transplant‐free 5‐year survival of 67% in responders with volume loss versus 36% in non‐responders was reported in secondary analysis of RESET trial participants.46 At the time of writing, endobronchial coils are not available in Australia or New Zealand.

Airway bypass

Implantation of artificial airways which bypass the narrowed and collapsible native bronchi has been studied bronchoscopically and surgically. Improvements in lung function in the post‐operative period have been demonstrated but have not proven durable.47,48 These artificial airways appear prone to occlusion, which has limited their efficacy, and they are not in current use.

Targeted therapies for chronic bronchitis

There are now several investigational endoscopic technologies focusing on treatment of chronic bronchitis, rather than emphysema and hyperinflation. These include a system that utilises a liquid nitrogen cryospray catheter to ablate surface epithelium with goblet cell hyperplasia, with the goal of allowing normal epithelium to regenerate (NCT03893370).

Results of the first in‐human study of bronchial rheoplasty for the treatment of chronic bronchitis have recently been reported.49 This endoscopic procedure applies unheated, pulsed electric fields to the airways to reduce the excessive numbers of mucus‐producing cells, based on pre‐clinical studies demonstrating epithelial ablation followed by regeneration of more normal epithelium. The study population with prominent symptoms of chronic bronchitis experienced a significant symptomatic improvement and histological evidence of reduced goblet cell hyperplasia with complications mainly comprising COPD exacerbations.

Targeted lung denervation

Targeted lung denervation uses radiofrequency ablation to disrupt parasympathetic signalling with the aim of decreasing airway resistance and mucus hypersecretion. The AIRFLOW trial prospectively compared targeted lung denervation with sham procedures in a randomised, double‐blind fashion and found fewer respiratory adverse events in a predefined timeframe. Recruitment is underway for a larger randomised, sham‐controlled trial to primarily investigate the rates of exacerbations following targeted lung denervation.50

Conclusion

Lung volume reduction is a therapeutic option for many patients with advanced emphysema who remain highly symptomatic despite maximal medical therapy and for whom few other treatments are available. While inhaled pharmacotherapy, smoking cessation and pulmonary rehabilitation are mandatory evidence‐based therapies for this patient group, a growing array of endoscopic procedures are now available as an alternative to surgery for highly selected patients. Patient selection for lung volume reduction is individualised and complex, and multidisciplinary emphysema teams are increasingly recommended for both assessment and treatment in high volume specialised centres.

The inclusion of ELVR in international expert guidelines and the expanding evidence base highlight the need for awareness of this treatment option. With more research into patient selection, the longer term effects of ELVR, and comparative studies between different endoscopic techniques and surgery, it appears inevitable that these treatments will continue to shift from their position as a niche therapy in Australia and New Zealand towards the mainstream.

Box 3 – Endobronchial valve systems

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A: Zephyr (PulmonX) endobronchial valves deployed in segmental airways. B: Spiration (Olympus) valve system deployed in segmental airways. C: Zephyr endobronchial valve; image supplied by PulmonX. D: Spiration valve system; image supplied by Olympus.

Box 4 – Heterogeneous and homogeneous emphysema

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A: Heterogeneous emphysema, more severely affecting the right upper lobe, with complete horizontal and oblique fissures. B: Homogeneous emphysema affecting all right lobes to similar degree, with incomplete horizontal fissure and complete oblique fissure.

Box 5 – Lung volume reduction following endobronchial valve placement

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A: Chest x‐ray of patient before endobronchial valve placement. B: Early post‐operative volume loss following placement of endobronchial valves in left upper lobe, with elevation of left hemidiaphragm.