Efficacy of Bronchoscopic Thermal Vapor Ablation and Lobar Fissure Completeness in Patients with Heterogeneous Emphysema

Endoscopic lung volume reduction imitates the effects of lung volume reduction surgery (LVRS). LVRS was initially developed in the 1950s to achieve lung volume reduction in patients with advanced chronic obstructive pulmonary disease and emphysema in order to improve exercise capacity and quality of life [1,2]. The positive results of this surgical principle were confirmed in the National Emphysema Treatment Trial, a randomized controlled clinical trial in 1,218 patients demonstrating that patients with upper lobe-predominant emphysema undergoing LVRS experienced significant improvement in clinical outcome measurements [3]. However, this trial revealed a high short-term mortality rate along with prolonged hospitalizations in a subset of these patients. Therefore, different bronchoscopic approaches have been explored to achieve comparable positive results to those with LVRS but with less morbidity and mortality [4].

Endoscopic techniques for lung volume reduction vary in use depending on the distribution of emphysema and integrity of interlobar fissures on multislice computed tomography (CT). The best known bronchoscopic technique is the implantation of one-way valves in bronchi feeding destroyed lung lobes, preventing continuous ventilation and thus causing atelectasis to achieve a regional reduction in lung volume [5,6,7,8]. Despite complete obstruction of the feeding bronchi by valves, patients may not develop atelectasis, which is probably due to collateral ventilation from adjacent lobes associated with less beneficial effects. Therefore, it is thought that collateral ventilation is the most relevant factor responsible for valve therapy failure. In the Endobronchial Valves for Emphysema Palliation Trial comparing endobronchial valve (EBV) treatment in patients with heterogeneous emphysema versus standard medical care, CT fissure completeness was analyzed as a surrogate for collateral ventilation [8]. The results of this randomized controlled study in 321 patients confirmed that fissure completeness was associated with improvement in clinical outcome following EBV treatment, thus providing a rationale for selection of emphysema patients (i.e. heterogeneous emphysema and complete interlobar fissures). Therefore, alternative interventional approaches are desired that may also be used in patients with radiographically incomplete interlobar fissures.

Bronchoscopic thermal vapor ablation (BTVA) is a permanent, non-blocking technique based on delivering heated water vapor via a disposable bronchoscopic catheter to emphysematous lung parenchyma within a targeted region [9,10]. The vapor induces an inflammatory reaction with subsequent fibrosis, resulting in lung volume reduction. The hypothesis is that this remodeled lung tissue does not inflate and therefore is highly unlikely to reinflate as a result of interlobar collateral ventilation.

The objective of this retrospective analysis was to evaluate the impact of fissure integrity on clinical outcomes following BTVA in patients with heterogeneous emphysema.

In this analysis, the CT scan data from 44 patients with heterogeneous emphysema who were treated by BTVA in two similar prospective open-label single-arm 1-year safety and efficacy clinical trials were analyzed retrospectively. These two prospective trials, whose protocols were approved by the relevant institutional review boards or ethics committees, were performed in the USA, Europe and Australia.

The enrollment criteria for the patients have been reported previously [10]. Briefly, patients with advanced upper lobe-predominant emphysema documented by thin-section non-enhanced multislice CT with a heterogeneity index (tissue to air ratio of the lower to the upper lobe) of ≥1.2, forced expiratory volume in 1 s (FEV₁) between 15 and 45% predicted, residual volume (RV) >150% predicted and total lung capacity >100% predicted were enrolled. All patients received BTVA in the right upper lobe or left upper lobe, excluding the lingula, as previously described [10]. The clinical outcome measures in the analysis in this report include spirometry, body plethysmography, single-breath diffusing capacity (diffusing capacity of the lung for carbon monoxide), 6-min walk test, lung volume reduction measured by quantitative analysis of CT and health-related quality of life documented by the St. George’s Respiratory Questionnaire (SGRQ) and modified Medical Research Council (mMRC) dyspnea scale at baseline and 3 and 6 months after treatment.

All 44 enrolled patients underwent multislice CT prior to treatment for the diagnosis and characterization of emphysema, which was used in our retrospective study for fissure analysis performed by a single chest radiologist blinded to any clinical information (C.P.H.). The treated lobar fissure was analyzed visually on non-enhanced preinterventional multislice CT [median 64 lines (range 4–128), median slice thickness 0.75 mm (0.5–1.5 mm)]. On the right side, the treated upper lobe is separated from the middle lobe by the small fissure as well as from the lower lobe by the upper half of the large fissure. The effective right fissure was therefore calculated as consisting of half of the apical part of the large plus small fissure. The left large fissure, which was divided into an apical, middle and basal part for easier visual assessment, was calculated as one third each (fig. 1). Incompleteness of the small fissure, the upper half of the right large fissure and three thirds of the left large fissure was visually estimated in 5% increments using a DICOM work station. The relative amount of fissure incompleteness was multiplanar reformat and caliper.

Clinical efficacy outcomes of the 44 patients 6 months after treatment in these studies have been previously reported [10]. Associations between fissure integrity and change in efficacy outcomes after 6 months were calculated using Pearson correlation coefficients.

Clinical efficacy outcomes of these patients have been reported previously [10]. Briefly, the mean ± SD improvements at 6 months were as follows: FEV₁ +140.8 ± 26.3 ml; forced vital capacity +271.0 ± 71.9 ml; RV –406.0 ± 112.9 ml; SGRQ total score –14.0 ± 2.4; mMRC score –0.9 ± 0.2 s and 6-min walk distance (6MWD) +46.5 ± 15.0 m (p < 0.001 for all). The body mass index, airflow obstruction, dyspnea and exercise capacity score declined by 1.4 ± 0.27 at 6 months (p < 0.001).

Of the 44 patients with heterogeneous emphysema, 24 received BTVA in the right upper lobe and 20 patients were treated in the left upper lobe. The results of the fissure analysis are summarized in table 1 for patients treated in the right upper lobe and in table 2 for patients treated in the left upper lobe. The calculated relevant fissure incompleteness (bridge) was 13% (range 0–63). Of 44 patients, 38 (86%) had incompleteness in the relevant fissure. Only 6 patients had complete fissures for the treated lobe, all of whom received BTVA in the left upper lobe.

To assess the relationship between fissure integrity and clinical outcome measures, Pearson correlation coefficients were calculated. These results, summarized in table 3, demonstrate that there is no relationship or only a minimal one between the fissure integrity and FEV₁ (r = 0.17; fig. 2a), RV (r = –0.18; fig. 2b), RV/total lung capacity (r = –0.14), lung volume reduction measured by CT (r = –0.27), 6MWD (r = 0.00; fig. 2c) and SGRQ (r = –0.10; fig. 2d) following BTVA.

BTVA is one of the minimally invasive bronchoscopic techniques used to achieve lung volume reduction in patients with severe emphysema. It imitates the principle of LVRS with the aim of reduction of lung hyperinflation but with less morbidity and mortality. One of the advantages of this technique is that interlobar collateral ventilation has no to minimal impact on BTVA-induced lung volume reduction, as demonstrated in the current study.

In recent years, different endoscopic methods for lung volume reduction were developed, varying in functional principle and reversibility [4]. The first technique consisted of the implantation of one-way valves, which cause lung volume reduction through atelectasis. This technique has been explored in human subjects in single-center pilot studies and in larger multicenter studies [5,6,7,8] that revealed physiological benefits and lung volume reduction in patients with strongly heterogeneous emphysema and complete interlobar fissure on multislice CT but showed inconsistent effects in patients with incomplete interlobar fissures. It is thought that CT fissure completeness is a surrogate measurement of interlobar collateral ventilation. In the early 1900s, Van Allen et al. [11] recognized the existence of collateral ventilation in the lung. While collateral ventilation is also present in the normal lung, its importance in the distribution of ventilation is negligible. However, the incompleteness of interlobar fissures and thus collateral ventilation increase in clinical relevance in chronic obstructive pulmonary disease and emphysema in that collateral ventilation is responsible for the failure of endoscopic lung volume reduction by valve implantation. Therefore, fissure analysis prior to the procedure should predict the success or failure of valve treatment. In addition to the analysis of interlobar fissures, a catheter-based system can quantify the collateral ventilation prior to the procedure in order to select emphysema patients who would potentially benefit from valve therapy [12]. Thereby, both methods, namely fissure analysis by assessment of CT as well as measurement of collateral ventilation using a catheter-based system, are suitable for predicting the outcome following endoscopic lung volume reduction. One retrospective study comparing the catheter-based measurement of collateral ventilation to CT fissure analysis prior to the implantation of EBVs confirmed that both methods have comparable accuracy for predicting the target lobe volume reduction [13].

In our retrospective study, preinterventional CT scans were available for assessment of fissure integrity. Fissure analysis utilizing CT in these 44 patients with heterogeneous emphysema revealed a high prevalence of incomplete interlobar fissures. Incompleteness of interlobar fissures was documented by CT in 86% of patients and thereby predicted failure of possible valve treatment. Fissure integrity was not assessed a priori and was not a criterion for entry into the study. While fissure incompleteness was observed in a high proportion of patients, further data are needed to evaluate the prevalence of complete fissures in a larger population of patients and considering factors such as chronic obstructive pulmonary disease stage, heterogeneity or genesis of emphysema.

On the basis of failure of valve treatment in patients with incomplete fissures, techniques that provide physiological improvement despite the presence of collateral ventilation through these incomplete fissures need to be explored.

BTVA is an irreversible non-blocking technique based on delivering heated water via a disposable bronchoscopic catheter to emphysematous lung parenchyma. The vapor induces a localized inflammatory reaction within the targeted lobe with subsequent fibrosis resulting in lung volume reduction. In 2009, a prospective study with 11 patients suffering from severe upper lobe-predominant emphysema confirmed the feasibility of unilateral BTVA at a lower dose than the current study with an acceptable safety profile and the potential for reducing dyspnea (mMRC dyspnea score) and improving health-related quality of life (SGRQ) [9]. Furthermore, CT scan analysis demonstrated loss of volume in the targeted lobe. The safety and efficacy results of the prospective multicenter trial of 44 patients with upper lobe-predominant emphysema confirmed the efficacy and safety of BTVA therapy [10]. Improvements in spirometry, body plethysmography, exercise capacity measured by 6MWD and health-related quality of life were statistically significant, and efficacy findings were stable over 3–6 months. The most common adverse events were lower respiratory tract events that were accompanied by any of the following symptoms: fatigue, fever, cough, sputum, dyspnea and hemoptysis. The reaction appears to peak within the first 2–4 weeks and gradually resolves within 8–12 weeks of BTVA. One fatal event due to end-stage chronic obstructive pulmonary disease with respiratory failure occurred 67 days after the procedure.

In our retrospective analysis of these previously reported 44 patients, the interlobar fissures were analyzed on multislice CT scans, and the relationship between fissure integrity and clinical outcome measures was documented. The results showed that there is no to minimal association between efficacy following BTVA and fissure integrity. This observation is most likely explained by the mechanism of action, which does not rely on obstruction of large airways (i.e. valves). With BTVA, it is expected that ventilation would not occur in the remodeled areas of lung tissue, which are highly unlikely to reinflate as a result of interlobar collateral ventilation. Therefore, BTVA as a non-blocking technique provides successful, minimally invasive endoscopic lung volume reduction despite the presence of collateral ventilation through incomplete fissures. The efficacy of other non-blocking techniques of endoscopic lung volume reduction, such as polymeric lung volume reduction as well as the implantation of coils, may also be independent of collateral ventilation; however, at present data are not available to substantiate this premise. In the future, the extent of fissure integrity should be considered in the decision to use either valve implantation or non-blocking techniques like BTVA in emphysema patients with heterogeneous disease. CT analysis as well as invasive measurement of collateral ventilation using a special catheter provide an option to quantify collateral ventilation prior to endoscopic lung volume reduction and will thus influence the patient selection for valve treatment or BTVA. Valve therapy seems to be successful in the case of complete interlobar fissure, while BTVA seems to be effective in cases of incomplete fissures as well as in cases of complete interlobar fissures, thus providing a wider range of indication than valve treatment. However, to date BTVA has only been used in upper lobe-predominant emphysema, whereas valve treatment can be used in upper lobe- as well as in lower lobe-predominant emphysema. Furthermore, it should be noted that valves can potentially be removed, whereas BTVA is an irreversible technique in poorly functioning tissue but with no foreign bodies left behind.

In summary, BTVA is a novel, minimally invasive endoscopic technique delivering heated water vapor in an emphysematous destroyed lung area to induce fibrosis with subsequent lung volume reduction. A feature of this technique is the relative independence of its beneficial effects from fissure integrity. Thus, BTVA can also be successfully used in patients with upper lobe-predominant emphysema with incomplete interlobar fissures who might not benefit from implantation of one-way valves.