Lung volume reduction surgery is safe and feasible after initial endobronchial valve treatment for emphysema patients.

OBJECTIVES: Bronchoscopic lung volume reduction with endobronchial valves is a guideline treatment leading to improved pulmonary function, exercise tolerance and quality of life, in patients with advanced emphysema, severe hyperinflation and no collateral ventilation. After valve treatment, loss of the initial lung volume reduction effect can occur, as well as local valve-induced complications such as persistent haemoptysis. In these cases, a surgical lobectomy can be considered to achieve similar efficacy outcomes. We evaluated the safety and feasibility of a video-assisted thoracoscopic surgery lobectomy after valve treatment. METHODS: This single-centre retrospective study included patients who underwent an elective lobectomy after previous valve treatment. Data were evaluated for safety and efficacy for the additional surgical procedure. RESULTS: Twenty-one patients [73% female, median age 67 (7) years, forced expiratory volume in 1 s 29 (7) %pred, and residual volume 223 (58) %pred] were included. There was no 90-day mortality and there were no postoperative intensive care admissions. Pulmonary infections (14%) and prolonged air leak (14%) were the most common complications. In patients who underwent surgery due to loss or lack of effect of valve treatment, a lobectomy led to a significant improvement in pulmonary function; median forced expiratory volume in 1 s +75 (193) ml (P < 0.013), forced vital capacity +450 (572) ml (P = 0.001), residual volume -665 (715) ml (P = 0.005). In patients who underwent a lobectomy because of complications of valve treatment, all complications were resolved after surgery. CONCLUSIONS: We demonstrate that an elective lobectomy after an initial valve treatment is safe and feasible and restores the lung volume reduction effect.

Lung transplant airway complications treated with biodegradable airway stents: The Dutch multi-center experience.

INTRODUCTION: Treatment of post lung-transplant airway complications is challenging, and treatment with conventional airway stents is associated with adverse events. More recently, biodegradable airway stents (BDS) have been introduced and may be used to reduce these adverse events. In this study we explore the feasibility of treatment with BDS post lung transplant. METHODS: All patients treated with BDS in The Netherlands were included in this retrospective multicenter study. Feasibility, life span of the stent, occurrence of adverse events, and evolution of lung function were evaluated. RESULTS: Twelve patients (six malacia and six stenosis) received a total of 57 BDS, ranging from 1 to 10 BDS per patient. Six patients had been pretreated with conventional airway stents. Median stent life span was 112 days (range 66-202). No adverse events occurred during stent placement. In 5 out of 57 stent placements, a single additional bronchoscopy was necessary because of mucus accumulation (n = 4) or excessive granulation tissue (n = 1). All stent naïve patients became airway stent independent after treatment; all patients pretreated with conventional airway stents were still airway stent dependent at the end of follow up. CONCLUSION: Treatment with BDS is safe and feasible. Adverse events were mild and easily treatable. All patients with initial treatment with BDS were airway stent independent at the end of follow up with a median treatment of 4 BDS.

Impact of Endobronchial Valve Treatment on Lung Function Decline.

INTRODUCTION: Endobronchial valve (EBV) treatment has been shown to be beneficial for patients with severe emphysema. The forced expiratory volume in 1 s (FEV1) was found to be significantly higher compared to baseline for up to 3 years after treatment although the magnitude of improvement gradually decreases over time. So far, it has not been investigated whether this treatment decelerates the decline in lung function. Therefore, our aim was to investigate the lung function decline before and after EBV treatment. METHODS: We included patients who were treated with EBVs in our hospital, of whom pre-treatment spirometry results were available (at least 4 measurements within at least 2 years before treatment) and who had an annual FEV1 measurement up to 3 years after treatment. RESULTS: In total, 45 patients were included (73% female, FEV1: 28 ± 7% of predicted, residual volume: 232 ± 32% of predicted) who had a mean pre-treatment FEV1 decline of -64 mL/year. Mean FEV1 "decline" after treatment was +13 mL/year, since FEV1 was still above the baseline level at 3-year follow-up. However, the FEV1 decline between 1 and 3 years of follow-up was not significantly different compared to the pre-treatment decline (-73 mL/year, p = 0.179). CONCLUSIONS: Our results show that the EBV treatment does not influence the progression of disease in terms of lung function decline. However, the treatment does improve the FEV1 up to a level that is still comparable 3 years after treatment with the baseline level.

A bronchial gene signature specific for severe COPD that is retained in the nose.

Introduction: A subset of COPD patients develops advanced disease with severe airflow obstruction, hyperinflation and extensive emphysema. We propose that the pathogenesis in these patients differs from mild-moderate COPD and is reflected by bronchial gene expression. The aim of the present study was to identify a unique bronchial epithelial gene signature for severe COPD patients. Methods: We obtained RNA sequencing data from bronchial brushes from 123 ex-smokers with severe COPD, 23 with mild-moderate COPD and 23 non-COPD controls. We identified genes specific to severe COPD by comparing severe COPD to non-COPD controls, followed by removing genes that were also differentially expressed between mild-moderate COPD and non-COPD controls. Next, we performed a pathway analysis on these genes and evaluated whether this signature is retained in matched nasal brushings. Results: We identified 219 genes uniquely differentially expressed in severe COPD. Interaction network analysis identified VEGFA and FN1 as the key genes with the most interactions. Genes were involved in extracellular matrix regulation, collagen binding and the immune response. Of interest were 10 genes (VEGFA, DCN, SPARC, COL6A2, MGP, CYR61, ANXA6, LGALS1, C1QA and C1QB) directly connected to fibronectin 1 (FN1). Most of these genes were lower expressed in severe COPD and showed the same effect in nasal brushings. Conclusions: We found a unique severe COPD bronchial gene signature with key roles for VEGFA and FN1, which was retained in the upper airways. This supports the hypothesis that severe COPD, at least partly, comprises a different pathology and supports the potential for biomarker development based on nasal brushes in COPD.

The impact of emphysema heterogeneity on treatment response after endobronchial valve treatment.

Background: Lung volume reduction with endobronchial valves can significantly improve functional outcomes in patients with advanced emphysema. The extent and spatial distribution pattern of emphysema shows considerable heterogeneity, which might affect response to endobronchial valve treatment. Our aim was to study the effect of emphysema heterogeneity on change in clinical outcomes after endobronchial valve treatment. Methods: Data were collected from our national registry of patients who received endobronchial valve treatment between 2016 and 2020. We assessed the association between the heterogeneity index, absolute difference in destruction between the target and ipsilateral lobe, and relative change in forced expiratory volume in 1 s (FEV1), residual volume (RV), St George's Respiratory Questionnaire (SGRQ) and 6-min walk distance (6MWD) at 6-week, 6-month and 12-month follow-up. Results: In total, 236 patients were included. Heterogeneity index was significantly associated with improvements in FEV1, RV and 6MWD at all follow-up visits, and in SGRQ at the 6- and 12-month follow-up visits. The majority of patients, independent of heterogeneity index, showed clinically meaningful improvements based on minimal important difference thresholds. Conclusions: Heterogeneity index influences the degree of clinical improvement after endobronchial valve treatment where in general a more heterogeneous distribution translates to larger improvements. However, patients with a more homogeneous distribution also showed clinically meaningful improvements. Therefore, we believe emphysema heterogeneity alone should not be used as a decisive patient selection criterion, but should be weighed in the context of all other relevant patient and target lobe characteristics when deciding on a patient's treatment eligibility.

Response to endobronchial valve treatment: it's all about the target lobe.

Background: Bronchoscopic lung volume reduction using endobronchial valves (EBV) has been shown to be beneficial for severe emphysema patients. The most important predictor of treatment response is absence of collateral ventilation between the treatment target and ipsilateral lobe. However, there are still a substantial number of nonresponders and it would be useful to improve the pre-treatment identification of responders. Presumably, predictors of response will be multifactorial, and therefore our aim was to explore whether we can identify response groups using a cluster analysis. Methods: At baseline and 1 year follow-up, pulmonary function, exercise capacity and quality of life were measured. A quantitative chest computed tomography scan analysis was performed at baseline and 2-6 months follow-up. The cluster analysis was performed using a hierarchical agglomerative method. Results: In total, 428 patients (69% female, mean±sd age 61±8 years, forced expiratory volume in 1 s 27±8% predicted, residual volume 254±50% pred) were included in our analysis. Three clusters were generated: one nonresponder cluster and two responder clusters. Despite solid technical procedures, the nonresponder cluster had significantly less clinical response after treatment compared to the other clusters. The nonresponder cluster was characterised by significantly less emphysematous destruction, less air trapping and a higher perfusion of the target lobe, and a more homogeneous distribution of emphysema and perfusion between the target and ipsilateral lobe. Conclusions: We found that target lobe characteristics are the discriminators between responders and nonresponders, which underlines the importance of visual and quantitative assessment of the potential treatment target lobe when selecting patients for EBV treatment.

Endobronchial Valve Treatment Does Not Cause Significant Nickel Deposition in Lung Tissue.

Bronchoscopic lung volume reduction using endobronchial valves (EBVs) is a treatment option for patients with severe emphysema. These EBVs are made out of a nitinol mesh covered by a silicone layer. Nitinol is an alloy of nickel and titanium and is commonly used in implantable medical devices because of its biocompatibility and memory-shape properties. However, there are some concerns that nickel ions can be released from nitinol-containing devices which might cause adverse health effects, especially in patients with a known nickel hypersensitivity. In vitro, it was found that EBV release significant amounts of nickel in the first hours. Our aim was to assess the nickel concentration in lung tissue from a patient who previously underwent EBV treatment but, due to treatment failure, underwent lung volume reduction surgery and to compare this to a reference sample. We found no significant difference in the median nickel concentration between the EBV-treated patient and the non-EBV-treated patient (0.270 vs. 0.328 µg/g, respectively, p = 0.693) and these concentrations were also comparable to previously published nickel concentrations in human lung tissue samples not having any medically implanted devices in the lung. Our results suggest that there is no significant long-term nickel deposition in lung tissue after EBV treatment.

Improved exercise capacity results in a survival benefit after endobronchial valve treatment.

BACKGROUND: Bronchoscopic lung volume reduction using endobronchial valves (EBV) is a treatment option for selected patients with advanced emphysema. The treatment significantly improves pulmonary function, exercise capacity, quality of life, and potentially improves survival. Our main aim was to assess whether treatment response significantly influences survival time after EBV treatment. METHODS: We evaluated treatment response at 6-week and 1-year follow-up of all patients treated with EBVs between 2008 and 2020. Survival status was retrieved on December 1, 2021. Patients were defined as responders or non-responders based on known minimal important differences for FEV1, residual volume (RV), RV/Total Lung Capacity (TLC) ratio, 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), target lobe volume reduction (TLVR), and complete lobar atelectasis. Uni- and multivariate cox regression models were used to evaluate the effect of response on survival time. RESULTS: A total of 428 patients were included. EBV treatment resulted in significant improvements in pulmonary function, exercise capacity and quality of life. Median survival was 8.2 years after treatment. SGRQ and 6MWD response were independent predictors for improved survival time (Hazard Ratio (HR) 0.50 [0.28-0.89], p = .02 and HR 0.54 [0.30-0.94], p = .03, respectively). The presence of a complete lobar atelectasis did not significantly affect survival, neither did pulmonary function improvements. CONCLUSIONS: Our results suggest that improvement in exercise capacity and quality of life after EBV treatment are associated with a survival benefit, independent of improvements in pulmonary function, reduction in target lobe volume or the presence of complete lobar atelectasis.

Prevalence and Impact of COVID-19 among Severe COPD Patients post Bronchoscopic Lung Volume Reduction Treatment with Endobronchial Valves.

BACKGROUND: The COVID-19 pandemic has a great impact on numberless aspects of our society. In our bronchoscopic lung volume reduction interventional program, we work with severe COPD patients on a daily basis. OBJECTIVES: We were interested in the prevalence and outcome of COVID-19, impact of the pandemic on daily life, and the vaccination coverage in our severe COPD patients who have been treated with one-way endobronchial valves. METHOD: A questionnaire, which consisted of questions related to the infection rate, treatment, and outcome of COVID-19 infections; feelings of anxiety related to the pandemic; adherence to preventive measures; and willingness to be vaccinated; was sent to our patients in June 2021. RESULTS: The questionnaire was sent to 215 patients, and the response rate was 100%. The vaccination rate was 97% in our surveyed population. The majority of patients (63%) indicated that they were quite or very anxious to get infected with COVID-19. Twenty-five (11.5%) patients were diagnosed with COVID-19, with none of these patients having been vaccinated at the time of infection. The infection rate reported in this study is comparable to that of the general Dutch population. However, the hospital admission rate and mortality rates are higher. CONCLUSIONS: Our results show that the SARS-CoV-2 infection rate in severe COPD patients treated with endobronchial valves was comparable with the general population; however, the hospital admission and mortality rates were worse.

Effect of Chest Computed Tomography Kernel Use on Emphysema Score in Severe Chronic Obstructive Pulmonary Disease Patients Evaluated for Lung Volume Reduction.

BACKGROUND: Chest computed tomography (CT) emphysema quantification is a vital diagnostic tool in patient evaluation for bronchoscopic lung volume reduction (BLVR). Smooth kernels for CT image reconstruction are generally recommended for quantitative analyses. This recommendation is not always followed, which may affect quantification of emphysema extent and eventually, treatment decisions. OBJECTIVE: The main goal is to demonstrate the influence of CT reconstruction kernels on emphysema quantification in patients with severe COPD, considered for BLVR. METHODS: Chest CT scans were acquired with one multi-detector CT system and reconstructed using three different kernels: smooth, medium smooth, and sharp. Other parameters were kept constant. Emphysema scores (ESs), meaning the percentage of voxels below -950 Hounsfield units, were calculated and compared to the smooth reference kernel using paired t tests. Bland-Altman plots were made to assess the biases and limits of agreement between kernels. RESULTS: Ninety-eight COPD patient CT scans were analyzed. The sharp kernel had a systematic bias of 6.2% and limits of agreement of 16.6% to -4.2% compared to the smooth kernel. The medium smooth kernel had a systematic bias of 5.7% and limits of agreement of 9.2% and 2.2% compared to the smooth kernel. The ES differed, for a single patient, up to 18% for different kernels. CONCLUSIONS: Chest CT kernel reconstruction can lead to a significant difference in emphysema severity quantification. This may cause invalid treatment selection in COPD patients evaluated for BLVR. Standardization of a smooth CT kernel setting and/or normalization to a standard kernel is strongly recommended.

Bronchoscopic Lung Volume Reduction in Patients with Emphysema due to Alpha-1 Antitrypsin Deficiency.

BACKGROUND: Bronchoscopic lung volume reduction using one-way endobronchial valves (EBVs) is a valid therapy for severe emphysema patients. However, alpha-1 antitrypsin (AAT)-deficient patients were excluded from the majority of clinical trials investigating this intervention. OBJECTIVES: The aim of this study was to investigate the feasibility, efficacy, and safety of EBV treatment in patients with AAT deficiency (AATD) or a reduced AAT level. METHOD: A retrospective analysis was performed of all patients treated with EBV with confirmed AATD or with a reduced AAT serum level at the University Medical Center Groningen between 2013 and 2021. Baseline and 6-month follow-up assessment included chest CT, pulmonary function measurement, 6-min walking distance (6MWD), and St. George's Respiratory Questionnaire (SGRQ). RESULTS: In total, 53 patients were included, 30 patients in the AATD group (AAT <0.6 g/L or confirmed ZZ phenotype) and 23 patients in the reduced AAT group (AAT 0.6-1 g/L). In both groups, all response variables improved significantly after treatment. There was a median increase in forced expiratory volume in 1 s of 105 mL (12% relative) and 280 mL (31% relative) in the AATD and reduced AAT groups, respectively. 6MWD increased by 62 min and 52 min, and SGRQ decreased by 12.5 patients and 18.7 patients, respectively. A pneumothorax occurred in 10% and 13% of patients, and no patients died. CONCLUSIONS: EBV treatment in patients with emphysema and AATD or a reduced AAT level is feasible and results in significant improvements in pulmonary function, exercise capacity, and quality of life and has an acceptable safety profile.

Long-term follow-up after bronchoscopic lung volume reduction valve treatment for emphysema.

Background: Multiple studies have shown that patients with severe emphysema can significantly benefit from bronchoscopic lung volume reduction endobronchial valve (EBV) treatment up to 1 year after treatment. However, hardly any data exist on longer term follow-up, especially on quality of life. Our aim was to investigate long-term follow-up after EBV treatment up to 3 years including quality of life in a real-life routine clinical setting. Methods: We retrospectively included patients who underwent EBV treatment in our hospital in the Netherlands at least 3 years prior. Patients were invited for annual visits to our hospital, and spirometry, body plethysmography, 6-min walk distance (6MWD) test and St George's Respiratory Questionnaire (SGRQ) were performed during these visits. Results: At 1-, 2- and 3-year follow-up, data were available from 189, 146 and 112 patients, respectively. Forced expiratory volume in 1 s, residual volume and SGRQ total score significantly improved up to 3 years after treatment compared with baseline, and 6MWD up to 2 years after treatment. In general, the magnitude of improvements gradually decreased over time. Conclusions: Our results show that patients can benefit at least up to 3 years after EBV treatment. For the first time we found that patients can also benefit in terms of quality of life in the long term, which is an important outcome for this group of patients with end-stage COPD.

A multicenter, prospective, single-arm clinical investigation of a modified staged treatment algorithm using the AeriSeal system - The STAGE trial.

INTRODUCTION: Treatment with AeriSeal is an alternate treatment option to achieve lung volume reduction in patients with severe COPD and emphysema who are not eligible for valve treatment. This study aimed to assess the safety and mode of action of a modified staged treatment algorithm with a staged treatment with lower dose of AeriSeal. METHODS: We performed a prospective, multicenter feasibility study. AeriSeal was administered during two sequential bronchoscopies: 2 subsegments of a lobe treated with two 5 mL doses, followed by two 10 mL doses in a contralateral lobe after 6 weeks. RESULTS: A total of 14 patients (36% male, mean FEV1 28.4% ± 6.7% of predicted) were enrolled. Ten patients completed both treatments, four were treated unilaterally. AeriSeal treatment resulted in significant TLVR (median 220.5 mL) at 3 months follow up. There were no significant changes from baseline at 12 months in lung function, exercise capacity and quality of life. During the 3-month post-treatment period, respiratory SAEs included 5 COPD exacerbations in 4 (28.6%) subjects, post-treatment acute inflammatory response (PAIR) in 2 (14.3%) subjects, and 1 respiratory failure event in 1 (7.1%) subject. CONCLUSION: The staged and lower dosed administration of AeriSeal does not impact the overall safety profile in terms of reducing the type and frequency of respiratory SAEs previously reported for a single-stage treatment. A larger volume of AeriSeal than used in this study may be necessary to provide meaningful clinical benefits.

Bronchoscopic Lung Volume Reduction Coil Treatment for Severe Emphysema: A Systematic Review and Meta-Analysis of Individual Participant Data.

BACKGROUND: Lung volume reduction coil (LVR-coil) treatment provides a minimally invasive treatment option for severe emphysema patients which has been studied in multiple clinical trials. OBJECTIVES: The aim of the study was to assess the effect of LVR-coil treatment on pulmonary function, quality of life, and exercise capacity using individual participant data. METHOD: PubMed, Web of Science, and EMBASE were searched until May 17, 2021. Prospective single-arm and randomized controlled trials that evaluated the effect of LVR-coil treatment on forced expiratory volume in 1 s (FEV1), residual volume (RV), St. George Respiratory Questionnaire (SGRQ) total score, and/or 6-min walk distance (6MWD) and were registered in an official clinical trial database were eligible for inclusion. Individual patient data were requested, and a linear mixed effects model was used to calculate overall treatment effects. RESULTS: Eight trials were included in the final analysis, representing 680 individual patients. LVR-coil treatment resulted in a significant improvement in FEV1 at 3- (0.09 L [95% confidence interval (95% CI): 0.06-0.12]) and 6-month follow-up (0.07 L [95% CI: 0.03-0.10]), a significant reduction in RV at 3- (-0.45L [95% CI: -0.62 to -0.28]), 6- (-0.33L [95% CI: -0.52 to -0.14]), and 12-month follow-up (-0.36L [95% CI: -0.64 to -0.08]), a significant reduction in SGRQ total score at 3- (-12.3 points [95% CI: -15.8 to -8.8]), 6- (-10.1 points [95% CI: -12.8 to -7.3]), and 12-month follow-up (-9.8 points [95% CI: -15.0 to -4.7]) and a significant increase in 6MWD at 3-month follow-up (38 m [95% CI: 18-58]). CONCLUSIONS: LVR-coil treatment in emphysema patients results in sustained improvements in pulmonary function and quality of life and shorter lived improvements in exercise capacity. Since the owner of this LVR-coil has decided to stop the production and newer generations LVR-coils are currently being developed, these results can act as a reference for future studies and clinical guidance.

Survival in COPD patients treated with bronchoscopic lung volume reduction.

BACKGROUND AND OBJECTIVE: Severe COPD patients can significantly benefit from bronchoscopic lung volume reduction (BLVR) treatments with coils or endobronchial valves. However, the potential impact of BLVR on survival is less understood. Therefore, our aim was to investigate the survival rate in patients who are evaluated for BLVR treatment and whether there is a difference in survival rate between patients who undergo BLVR treatment and patients who do not. METHODS: We included patients with COPD who visited our hospital for a consultation evaluating their eligibility for BLVR treatment and who performed pulmonary function tests during this visit. Furthermore, vital status was verified. RESULTS: In total 1471 patients were included (63% female, mean age 61 years). A total of 531 patients (35%) died during follow-up and the median survival time of the total population was 2694 days (95% confidence interval(CI) 2462-2926) which is approximately 7.4 years. The median survival time of patients who were treated with BLVR was significantly longer compared to patients who were not treated with BLVR (3133 days versus 2503 days, p < 0.001), and BLVR was found to be an independent predictor of survival when adjusting for other survival-influencing factors such as age, gender or severity of disease. CONCLUSIONS: Our results suggest that bronchoscopically reducing lung volume in patients with severe hyperinflation may lead to a survival benefit for a population with a severely reduced life expectancy.

Evaluation of spirometry-gated computed tomography to measure lung volumes in emphysema patients.

INTRODUCTION: In emphysema patient being evaluated for bronchoscopic lung volume reduction (BLVR), accurate measurement of lung volumes is important. Total lung capacity (TLC) and residual volume (RV) are commonly measured by body plethysmography but can also be derived from chest computed tomography (CT). Spirometry-gated CT scanning potentially improves the agreement of CT and body plethysmography. The aim of this study was to compare lung volumes derived from spirometry-gated CT and "breath-hold-coached" CT to the reference standard: body plethysmography. METHODS: In this single-centre retrospective cohort study, emphysema patients being evaluated for BLVR underwent body plethysmography, inspiration (TLC) and expiration (RV) CT scan with spirometer guidance ("gated group") or with breath-hold-coaching ("non-gated group"). Quantitative analysis was used to calculate lung volumes from the CT. RESULTS: 200 patients were included in the study (mean±sd age 62±8 years, forced expiratory flow in 1 s 29.2±8.7%, TLC 7.50±1.46 L, RV 4.54±1.07 L). The mean±sd CT-derived TLC was 280±340 mL lower compared to body plethysmography in the gated group (n=100), and 590±430 mL lower for the non-gated group (n=100) (both p<0.001). The mean±sd CT-derived RV was 300±470 mL higher in the gated group and 700±720 mL higher in the non-gated group (both p<0.001). Pearson correlation factors were 0.947 for TLC gated, 0.917 for TLC non-gated, 0.823 for RV gated, 0.693 for RV non-gated, 0.539 for %RV/TLC gated and 0.204 for %RV/TLC non-gated. The differences between the gated and non-gated CT results for TLC and RV were significant for all measurements (p<0.001). CONCLUSION: In severe COPD patients with emphysema, CT-derived lung volumes are strongly correlated to body plethysmography lung volumes, and especially for RV, more accurate when using spirometry gating.

Biodegradable Stent Placement for Airway Kinking After Bronchoscopic Lung Volume Reduction Treatment.

Symptomatic airway kinking after bronchoscopic lung volume reduction with endobronchial valves is rare. Owing to the development of the desired lobar atelectasis, the position of the airways of the nontreated lobe changes, and that might lead to invalidating symptoms. We present a case of a patient with symptomatic airway kinking after treatment with endobronchial valves, who was successfully treated with a single placement of a biodegradable stent. Placement of a biodegradable stent can be considered for symptomatic patients with airway kinking.