Endobronchial lung volume reduction for COPD

Chronic obstructive pulmonary disease (COPD), including shortness of breath, chronic cough and exercise intolerance, causes debilitating symptoms for patients. Prevalence data in the UK suggests that up to 4.7% of the population have clinically significant COPD but much of it remains undiagnosed.(1) The financial cost to the National Health Service is estimated at £800 million a year in direct costs alone.(2) Much of this cost is associated with admissions and medications in severe disease.

One of the major causes of breathlessness in COPD is emphysema. This refers to destruction and enlargement of the airspaces distal to the terminal bronchiole. Airways lose their elastic support, which causes early airway closure on expiration, and this is further compounded by inflammation and narrowing of airways, with a reduction in expiratory flow and resultant gas trapping. As a result, the lungs become hyper-inflated and respiratory muscles are stretched, meaning they work less efficiently. Healthier areas of lung may be compressed, which further worsens ventilation–perfusion matching. In this situation, medications only have limited effects at improving symptoms.

Lung volume reduction surgery (LVRS) was originally designed in the 1950s to address this problem by removing 20–30% of the most emphysematous lung; this allows healthier lung tissue to re-expand and allow the respiratory muscles to return to a more efficient state. LVRS became more popular in the 1990s as surgical techniques were refined. A series of trials, including the pivotal National Emphysema Treatment Trial, demonstrated improved lung function, exercise capacity, symptoms and survival in a subgroup of patients with low exercise capacity and upper lobe disease.(3) Despite the success, surgery came at a cost of significant surgical complications, prolonged hospital stays and a 5.2% mortality rate. This has limited the group of patients likely to be suitable for surgery and has given the impetus to develop less invasive and safer techniques.

Bronchoscopic lung volume reduction (BLVR) has been in development for more than ten years and comprises a variety of approaches. Table 1 lists the proposed mechanisms and techniques available for BLVR.

These techniques work by occluding a target lobe and preventing ventilation with subsequent collapse of the distal lung. This results in volume loss and allows re-inflation of healthier lung tissue with improved ventilation–perfusion matching. Early attempts involved the use of spiggots to occlude airways but were limited by expectoration of spiggotts and distal pneumonias. There are now two commercially available unidirectional airway valves: the Zephyr Valve (PulmonX, Redwood City, CA, US); and the Intrabronchial Valve (Olympus, Redmond, WA, US). Both allow exhaled air and secretions to be expelled through or around the valve but prevent ventilation to the distal lung. They can both be sited through flexible bronchoscopes under conscious sedation as in day case procedures.

The VENT trial has been the largest randomised controlled trial of valves published to date.(4) Zephyr valves were placed in the most diseased lobe to achieve unilateral occlusion. Only modest improvements in lung function, symptoms and six-minute walk distances (6MWD) were reported. However, in patients with heterogenous disease (a greater difference in the severity of emphysema between lobes) and intact interlobar fissures, the magnitude of improvement was much greater. The European arm of the trial also concluded that complete lobar occlusion was important to maximise the benefits with up to 26% improvement in forced expiratory volume in one second (FEV1), 22% improvement in 6MWD and a ten-point improvement in St George’s Respiratory Questionnaire (SGRQ) outcomes at six months.(5) These results are clinically very significant, even though only approximately 33–50% of patients in these studies having intact fissures. The degree to which the interlobar fissures are intact can be used as a surrogate marker for the presence of collateral ventilation between lobes.

Collateral ventilation describes ventilation of lobes or segments through extra-anatomical channels that bypass normal airways. Because they are not occluded by valves, they allow the lung to be ventilated by an alternative route and prevent the necessary collapse required to achieve success. The Chartis system has been developed to assess this in vivo before valve insertion and has been shown to help predict which patients may respond to valve treatment.(6) A combination of both computed tomography findings and Chartis improves success rates even further.

Spiration valves also appear effective when placed with a unilateral, lobar occlusive strategy. Eberhardt and colleagues have demonstrated that a unilateral occlusive approach is most successful with a 21.4% improvement in FEV1, a 16% increase in six-minute walk distance, and a 11.8 point fall in SGRQ scores at three months.(7)

Endobronchial valve insertion appears safe, with the most commonly reported complications being COPD exacerbation and small volume haemoptysis. Pneumothoraces are a more significant complication but have only been reported at rates below 5% in these studies. However, they are more common in patients who respond to treatment with significant volume loss. Valves are easily removed should the need arise.

Endobronchial valves are now perhaps the most established bronchoscopic lung volume reduction technique. The optimum strategy for placement in patients with heterogenous disease and intact fissures is becoming clear. However, further work to improve their efficacy and demonstrate cost-effectiveness will be needed before there is widespread uptake.

There are currently a number of other BLVR techniques at various stages of development, and these are discussed below (although there are currently no other commercially available BLVR devices in the UK).

The RePneu® lung volume reduction coil (PneumRx Inc., Mountain View, CA, US) is an implantable device made of nitinol wire, a super-elastic memory shape alloy. It is delivered as a straightened wire into the sub-segmental airways and recovers its predetermined shape upon deployment. This causes the surrounding lung to fold around the device with subsequent compression of the lung parenchyma. A reduction in the volume of the lung and increase in the elasticity of the lung tissue helps to redirect airflow and prevents early airway closure. The technique is unaffected by collateral ventilation and appears to be of use in both homogenous and heterogenous disease. However, if there is too much emphysematous destruction of the lung, the coil will not be able to achieve these effects.

The procedure can be carried out under conscious sedation and takes approximately 45 minutes to complete. It is designed as a staged bilateral treatment, with a second procedure to treat the contralateral lung performed one-to-three months following the initial treatment. The procedure is safe, although pneumothorax, minor haemoptysis, COPD exacerbations and pneumonias have been reported as complications but are relatively uncommon. The largest study to date recruited 46 patients, randomised one:one to best medical care or best medical care plus staged bilateral treatments, showed improvements in FEV1, residual volume and 6MWT.

These devices appear particularly promising as they have the potential to treat patients with both homogenous and heterogenous disease. Although these devices are now commercially available in mainland Europe (but not the UK), further work is underway with a larger, pivotal, multicentre, randomised controlled trial for the purposes of Food and Drug Administration approval in the US, with results expected in approximately three years’ time. These coils are designed to be removable but little information on the success rate

and complications of this has been published.

These agents reduce lung volume through tissue remodelling. An inflammatory reaction is initiated by direct instillation of the agent or steam into the subsegmental airways. This is followed by scar formation, and because the scar tissue occupies a much smaller volume than the emphysematous lung from which it derives, the process reduces overall lung volume. They are unaffected by collateral ventilation as they act at the parenchymal level. However, the full effect is not achieved for several weeks due to time taken for scar formation.

The Aeriseal system is a synthetic polymer developed for use with flexible bronchoscopy as a day-case procedure. Two agents are mixed and instilled into two-to-three subsegments at each treatment. As it polymerises, it expands and fills the airways and parenchyma, initiating the inflammatory reaction. The procedure takes only a few minutes to complete but a second bronchoscopy is often needed to complete treatment to a lobe. An uncontrolled trial of unilateral treatment demonstrated significant improvements in FEV1 (+10%), residual volume/total lung capacity (RV/TLC) ratio (–7.4%), modified Medical Research Council dyspnoea scale (mMRC) (–1.0 points), 6MWD (+28.7m) and SGRQ (–9.9 points).(9) Bilateral treatment has shown impressive reductions in lobar volumes and a more marked improvement in FEV1 (+25%). The improvements are more evident in patients with heterogenous disease.(10)

This technique is attractive because it is relatively easy and quick to perform. The procedure is well tolerated, although patients are likely to experience a post-procedure flu-like illness at 8–24 hours. This usually consists of breathlessness, fever, chest pain and associated chest radiograph infiltrates with raised inflammatory markers. Exacerbations of COPD and pneumonia are also described. The optimum treatment approach in terms of dose and number of segments to treat has not yet been defined and more definitive efficacy data is needed. A larger, randomised control trial of the Aeriseal system is currently underway. As this procedure is not reversible, longer-term safety data will be important.

Bronchial thermal vapour ablation uses a calculated dose of thermal energy, delivered in the form of steam to the target segments. The procedure is relatively easy to perform and completed in 30 minutes for treatment of one lobe. Despite promising results – FEV1 +17%, SGRQ –14 points, mMRC –0.9, MWD +46.5m(11) – this technology has recently been withdrawn owing to an unacceptable side effect profile. Whether it is relaunched at a later date and with revised dosing criteria remains to be seen.

Airway bypass techniques take advantage of collateral ventilation by creating low resistance extra-anatomic channels that allow exhaled air to bypass the high-resistance airways in COPD. Two devices have been trialled: the Exhale drug-eluting stent (Broncus Technologies, Mountain View, CA, US), which vented air into the major airways; and the transthoracic pneumonostomy (Portaero), which vented air directly through the chest wall. Despite very promising early results, neither device has been shown to provide long-term benefit owing to the occlusion of either the device lumen (Exhale stent) or the pneumonostomy tract (Portaero).

There are currently no such devices either available or in trials, although the concept of airway bypass for reducing hyperinflation in homogenous emphysema is still valid. If a device can be designed that does not suffer from the problems of lumen occlusion, then potentially more durable improvements in lung function and symptoms could be achieved. This is of particular interest, as treatment options for homogenous emphysema are currently more limited than heterogenous emphysema.

The future of BLVR is promising. Studies have shown these techniques to be less invasive and safer than surgery  as away of performing lung volume reduction; however, they have yet to be conclusively proven to be efficacious. At present, much of the evidence is from small, uncontrolled series but randomised controlled trials are either underway or being planned. This should provide us with the data necessary to ensure that we select the most suitable patients and continue to refine the techniques to make them as efficacious as possible.

• Hyperinflation of the lungs is a key cause of breathlessness in COPD.
• Bronchoscopic lung volume reduction offers the potential for less invasive and safer treatments compared to lung volume reduction surgery.
• Endobronchial valves are effective in patients with heterogenous emphysema and intact interlobar fissures.
• Further trials are underway, examining the effectiveness of lung volume reduction coils, bronchial thermal vapour ablation and airway sealants.
• Airway bypass techniques for homogenous emphysema have not yet proved to be effective.

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