The Quest for Safe and Effective Bronchoscopic Lung Volume Reduction—A Matter of Correct Scaffolding?

In this issue of the Journal, Tana and colleagues (pp. 1175–1184) deliver their results from the BREATHE trial evaluating the role of airway scaffolds for emphysema-related hyperinflation (1). This report tracked a cohort that underwent placement of a self-expanding nitinol airway scaffold to serve as a conduit from hyperinflated emphysematous lung parenchyma to central airways to decompress obstruction and improve quality of life. The authors screened 89 patients, with 60 getting treatment. Inclusion and exclusion criteria mimicked established parameters for bronchoscopic lung volume reduction (BLVR) with one-way endobronchial valves (EBVs), with a few exceptions (2). Qualitative computed tomography (CT) criteria included a requirement for at least one lobe to have emphysema with more than 35% destruction on the basis of –950 Hounsfield units, which may account for some of the efficacy data, as this has been utilized to aid patient selection in BLVR as well (3). Notably, the authors did not exclude patients on the basis of heterogeneity of emphysema or fissure intactness based on quantitative CT, giving these scaffolds the potential to be a more widely available therapy than EBVs.

In this first-in-human study, the primary outcome evaluated incidence of serious adverse events (SAEs). A total of 21.7% of the patients experienced an SAE in 6 months; however, no control arm served for comparison. There were 13 SAEs, the majority of which were pneumonia, chronic obstructive pulmonary disease (COPD) exacerbation, and respiratory tract infections. Given the novelty of this airway scaffold device, the most apt comparison can be drawn to the Exhale Airway Stents for Emphysema (or, EASE) trial published in 2011, where 14.4% of patients had a SAE in the first 6 months, with 11.2% in the sham group having an SAE (4). In contrast to EBVs, these airway scaffolds do appear to have a favorable safety profile from a pneumothorax perspective, as there were no reported lung collapses throughout the 6-month duration (5). This lack of periprocedural pneumothorax could obviate the need for 3-day hospitalizations postprocedurally and decrease resource consumption that can plague the creation of a one-way valve BLVR program (6). However, is a 21% SAE rate something that we are willing to accommodate as a community? This remains to be reconciled through further randomized study with both safety and efficacy outcomes.

Broadly speaking, persistent hyperinflation and elevated residual volume contribute significantly to dyspnea, reduced exercise capacity, and poor quality of life. Although pharmacologic therapy and pulmonary rehabilitation remain firstline treatments, the respiratory community has, for years, sought procedural solutions to relieve hyperinflation. Many approaches, all rooted in sound physiologic rationale, have been tested with limited and varying degrees of success. Lung volume reduction surgery demonstrated improvements in lung mechanics, particularly in patients with upper lobe predominant emphysema and low exercise tolerance. However, lung volume reduction surgery has largely fallen out of favor given high perioperative risk, complex patient selection, the emergence of less invasive alternatives, and few centers offering the procedure (7).

The current workhorse of minimally invasive procedural intervention for advanced COPD is the one-way EBV. This enables bronchoscopic exclusion of hyperinflated lobes, promoting atelectasis and lung deflation. There have been multiple randomized control trials that have shown improvements in FEV₁, exercise capacity, and subjective quality-of-life scores (8). Limitations of EBV therapy include complications such as a high pneumothorax rate, as well as less common SAEs, including device migration, granulation tissue, and infection. Selection criteria limit eligibility to those with a heterogeneous distribution of emphysema and high fissure integrity, preventing collateral ventilation (9). The CONVERT study will assess technology to reinforce patients’ fissures in instances of positive collateral ventilation, but this needs further safety and efficacy data (10). Other modalities of minimally invasive BLVR, such as endobronchial coils, thermal vapor ablation, and targeted lung denervation, either have proven ineffective or unsafe or have simply not been studied enough to be ready for widespread clinical adoption (11). Lung transplantation remains the ultimate intervention for select individuals with endstage disease and severe hyperinflation unresponsive to other therapies, although there are significant exclusion criteria and morbidities that limit its applicability.

The BLVR technology that is most like that used in the present study was described in the EASE trial. This also utilized endobronchial scaffolds, though with paclitaxel-coated endobronchial stents inserted into homogenous emphysema to reduce hyperinflation. This randomized, double-blind, sham-controlled trial enrolled 315 patients that showed no significant differences in the primary endpoints of forced vital capacity or subjective dyspnea score. This study was marred by well-known complications of larger endobronchial stents (12)—namely, mucous plugging and granulation tissue—which rendered many of the bypass stents useless and led to an increased incidence of COPD exacerbation and respiratory infections in the treatment group.

From a procedural aspect, the nitinol airway stents in the BREATHE trial appear to be well tolerated by both the patient and the bronchoscopist: 328 airway scaffolds were placed across 98 procedures, with a 92.4% success rate. Bronchoscopists commented that the stents were easy to place in almost all instances. Only 27 of the scaffolds required removal, and no injuries were reported related to removing a scaffold. Impressively, these scaffolds remained remarkably well in place despite 6 months of breathing, with only two possible migrations noted on follow-up bronchoscopy. This contrasts with the EASE trial, which had a stent loss rate of 13% at 6 months, as measured by CT.

It is important to note that the BREATHE trial was not powered for efficacy outcomes, so the statistically significant improvements in residual volume, spirometry, subjective quality-of-life and symptom scores, and exercise capacity are exciting but are greeted with mild skepticism, given the concern for Type I error until they are reproduced in a randomized controlled trial. This study also needs to iron out the methodology surrounding placement, as there was no uniformity in a single versus staged procedure, and the authors provided no instruction on what is optimal.

The BREATHE trial describes an airway scaffold procedure that has a safety profile similar to that of other minimally invasive modalities of BLVR while having “staying power” in the lungs at the 6-month mark with low migration rates. It is important to note that the lack of periprocedural pneumothorax coupled with broader inclusion criteria may lead to wider applicability. Efficacy data are a promising pilot to inform the population, and we look forward to the randomized controlled trial as we continue our quest for the procedural answer to hyperinflation.