Impact and timing of pulmonary rehabilitation in patients undergoing bronchoscopic lung volume reduction with endobronchial valves: A multicentre randomized controlled trial in patients with severe emphysema.

BACKGROUND AND OBJECTIVE: Both bronchoscopic lung volume reduction with endobronchial valves (BLVR-EBV) and pulmonary rehabilitation (PR) are effective treatments for improving exercise capacity and patient-reported outcomes in patients with severe Chronic Obstructive Pulmonary Disease (COPD). According to current recommendations, all BLVR-EBV patients should have undergone PR first. Our aim was to study the effects of PR both before and after BLVR-EBV compared to BLVR-EBV alone. METHODS: We included patients with severe COPD who were eligible for BLVR-EBV and PR. Participants were randomized into three groups: PR before BLVR-EBV, PR after BLVR-EBV or BLVR-EBV without PR. The primary outcome was change in constant work rate cycle test (CWRT) endurance time at 6-month follow-up of the PR groups compared to BLVR-EBV alone. Secondary endpoints included changes in 6-minute walking test, daily step count, dyspnoea and health-related quality of life. RESULTS: Ninety-seven participants were included. At 6-month follow-up, there was no difference in change in CWRT endurance time between the PR before BLVR-EBV and BLVR-EBV alone groups (median: 421 [IQR: 44; 1304] vs. 787 [123; 1024] seconds, p = 0.82) or in any of the secondary endpoints, but the PR after BLVR-EBV group exhibited a smaller improvement in CWRT endurance time (median: 107 [IQR: 2; 573], p = 0.04) and health-related quality of life compared to BLVR-EBV alone. CONCLUSION: The addition of PR to BLVR-EBV did not result in increased exercise capacity, daily step count or improved patient-reported outcomes compared to BLVR-EBV alone, neither when PR was administered before BLVR-EBV nor when PR was administered after BLVR-EBV.

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.

Optimizing clinical outcomes for bronchoscopic lung volume reduction with Zephyr® valves.

Bronchoscopic lung volume reduction treatment with Zephyr one-way valves is an effective guideline-based treatment option for patients with severe emphysema and hyperinflation. However, in some cases the treatment response is less than anticipated or there might be a loss of initial treatment effect. Reasons for the lack of response can include incorrect assessment of collateral ventilation, improper valve placement, or patient related factors. Loss of initial benefit can be due to granulation tissue formation and subsequent valve dysfunction, or there may be side effects such as excessive coughing or infectious problems. Careful follow-up after treatment with valves is important and evaluation with a CT scan and/or bronchoscopy is helpful if there is no improvement after treatment or loss of initial benefit. This paper aims to describe the most important causes and provide a strategy of how to approach and manage these patients.

The agreement between bronchoalveolar lavage, bronchial wash and sputum culture: a retrospective study.

PURPOSE: Bronchoalveolar lavage is commonly used in clinical practice for unresolved pneumonia. However, bronchoalveolar lavage is not suitable for all patients as it is an invasive procedure and can worsen oxygenation. The diagnostic value of bronchial wash and sputum has been debated extensively over the years. In this study, we aim to compare the diagnostic value in several pathogens of bronchoalveolar lavage and bronchial wash, and secondarily bronchoalveolar lavage and sputum. METHODS: We retrospectively included all adult patients in our hospital who underwent bronchoalveolar lavage, bronchial wash, and where sputum sampling was done between January 1st of 2018 and December 31st of 2021. The intraclass correlation coefficient was computed for the three tests. RESULTS: In total, 308 patients were included. We found a level of correlation of 0.819 and 0.865, respectively, between bronchoalveolar lavage and bronchial wash for two pathogens: Staphylococcus aureus and Pseudomonas aeruginosa. For Stenotrophomonas maltophilia and Aspergillus fumigatus, we found an intraclass correlation coefficient of 0.568 and 0.624, respectively. Between bronchoalveolar lavage and sputum, we found varying levels of agreement. CONCLUSION: Our study shows reasonably well agreement levels between bronchoalveolar lavage and bronchial wash, suggesting that bronchial wash could potentially be an alternative to bronchoalveolar lavage.

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.

Treatable traits in advanced emphysema patients eligible for bronchoscopic lung volume reduction with endobronchial valves.

INTRODUCTION: Patients with advanced emphysema eligible for bronchoscopic lung volume reduction (BLVR) using endobronchial valves (EBV) are characterized by severe static lung hyperinflation, which can be considered a treatable trait. Other treatable traits (TTs), which are assumed to be present in this highly selected patient group, have not been studied in detail nor how they may affect health-related quality of life (HRQL). AIMS: We aimed to evaluate a spectrum of TTs in COPD patients eligible for EBV treatment and their association with HRQL. METHODS: The SoLVE study (NCT03474471) was a prospective multicenter randomized controlled trial to examine the impact of pulmonary rehabilitation in COPD patients receiving EBV. The presence/absence of 16 TTs was based on pre-defined thresholds. HRQL was assessed with the St. George's Respiratory Questionnaire (SGRQ). Subjects were stratified into two groups, using the median split method, into higher or lower SGRQ total score. Logistic regression assessed the odds ratio (OR) of having a higher SGRQ total score per TT. RESULTS: Ninety-seven subjects were included, the mean number of TTs per patient was 8.1 ± 2.5. Low physical activity (95%), poor exercise capacity (94%) and severe fatigue (75%) were the most prevalent TTs. The sum of TTs present in a subject was associated with the SGRQ total score (r = 0.53; p < 0.001). Severe fatigue, depression, and anxiety were predictors of having a higher SGRQ total score. CONCLUSIONS: A high prevalence and co-occurrence of multiple TTs were identified in emphysema patients eligible for EBV. Patients with a higher number of TTs were more likely to have worse HRQL.

Alternative Splicing Is a Major Factor Shaping Transcriptome Diversity in Mild and Severe Chronic Obstructive Pulmonary Disease.

The role of alternative splicing in chronic obstructive pulmonary disease (COPD) is still largely unknown. We aimed to investigate the differences in alternatively splicing events between patients with mild-to-moderate and severe COPD compared with non-COPD control subjects and to identify splicing factors associated with aberrant alternative splicing in COPD. For this purpose, we performed genome-wide RNA-sequencing analysis of bronchial brushings from 23 patients with mild-to-moderate COPD, 121 with severe COPD, and 23 non-COPD control subjects. We found a significant difference in the frequency of alternative splicing events in patients with mild-to-moderate and severe COPD compared with non-COPD control subjects. There were from two to eight times (depending on event type) more differential alternative splicing events in the severe than in the mild-to-moderate stage. The severe COPD samples showed less intron retention and more exon skipping. It is interesting that the transcript levels of the top 10 differentially expressed splicing factors were significantly correlated with the percentage of many alternatively spliced transcripts in severe COPD. The aberrant alternative splicing in severe COPD was predicted to increase the overall protein-coding capacity of gene products. In conclusion, we observed large and significant differences in alternative splicing between bronchial samples of patients with COPD and control subjects, with more events observed in severe than in mild-to-moderate COPD. The changes in the expression of several splicing factors correlated with prevalence of alternative splicing in severe COPD. Alternative splicing can indirectly impact gene expression by changing the relative abundance of protein-coding isoforms potentially influencing pathophysiological changes. The results provide a better understanding of COPD-related alternative splicing changes.

Surgical and bronchoscopic pulmonary function-improving procedures in lung emphysema.

COPD is a highly prevalent, chronic and irreversible obstructive airway disease without curative treatment. Standard therapeutic strategies, both non-pharmacological and pharmacological, have only limited effects on lung function parameters of patients with severe disease. Despite optimal pharmacological treatment, many patients with severe COPD still have a high burden of dyspnoea and a poor quality of life. If these patients have severe lung emphysema, with hyperinflation as the driver of symptoms and exercise intolerance, lung volume reduction may be an effective treatment with a significant impact on lung function, exercise capacity and quality of life. Currently, different lung volume reduction approaches, both surgical and bronchoscopic, have shown encouraging results and have been implemented in COPD treatment recommendations. Nevertheless, choosing the optimal lung volume reduction strategy for an individual patient remains challenging. Moreover, there is still room for improving durability of effect and safety in all available procedures. Ongoing and innovative research is essential to push this field forwards. This review provides an overview of results and limitations of the current lung volume reduction options for patients with severe lung emphysema and hyperinflation.

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.

The development, validation, and in vivo testing of a high-precision bronchial epithelial lining fluid sampling device.

Introduction: Analysis of respiratory biomarkers or pharmaceutical drug concentrations in bronchial epithelial lining fluid (bELF) using a high-precision sampling method is crucial for effective clinical respiratory diagnostics and research. Here, we utilized a cellulose matrix as an absorptive probe for bELF sampling, subsequently testing the design of a device and sampling technique in vivo. Methods: The absorptive matrix [Whatman® qualitative filter paper (Grade CF-12)] was first tested through tissue-contact experiments on porcine airway tissue. The absorption and elution capacity of the matrix, as well as the laboratory processing and analysis method, was validated with a range of Interleukin-8 (CXCL8) and C-Reactive protein (CRP) stock solutions. Subsequently, the device's design was optimized for universal in-house production and both, safe and efficient sampling. The airway sampling method was then tested in a group of 10 patients with Chronic Obstructive Pulmonary Disease (COPD). For each patient, a bELF sample was obtained using the newly developed bELF probe, as well as a reference 20 mL saline bronchial wash sample. Supernatants were assessed, using an immunoassay, for levels of the pro-inflammatory markers CXCL8, Myeloperoxidase (MPO), and CRP. The bELF samples were compared to bronchial wash. Results: The Whatman® qualitative filter paper (Grade CF-12) bELF probes adhered to porcine airway tissue, softening slightly upon wetting. The material maintained architectural integrity following the removal of the probes, leaving no residual fibers on the porcine airway mucosa. The bELF probe design was optimized for bronchoscopic delivery and in-house production. On average, a fully saturated bELF probe carried 32 µL of protein-rich fluid. The mean return of CXCL8 and CRP from samples collected from a serial dilution series (1, 5, 10, 20 ng/mL) was 69% (range 48%-87%). The bELF probe detected, on average, 7 (MPO), 14 (CRP), and 59 (CXCL8) times higher equivalent inflammatory protein concentrations in the collected bELF probe samples compared to the bronchial wash. Conclusion: The bELF probe is an effective absorptive technology for high-precision bELF sampling without dilution. With a simple in-house production procedure and bronchoscopic sampling technique, this method can be introduced in any bronchoscopic center for a consistent sampling of bELF.

Emphysema subtyping on thoracic computed tomography scans using deep neural networks.

Accurate identification of emphysema subtypes and severity is crucial for effective management of COPD and the study of disease heterogeneity. Manual analysis of emphysema subtypes and severity is laborious and subjective. To address this challenge, we present a deep learning-based approach for automating the Fleischner Society's visual score system for emphysema subtyping and severity analysis. We trained and evaluated our algorithm using 9650 subjects from the COPDGene study. Our algorithm achieved the predictive accuracy at 52%, outperforming a previously published method's accuracy of 45%. In addition, the agreement between the predicted scores of our method and the visual scores was good, where the previous method obtained only moderate agreement. Our approach employs a regression training strategy to generate categorical labels while simultaneously producing high-resolution localized activation maps for visualizing the network predictions. By leveraging these dense activation maps, our method possesses the capability to compute the percentage of emphysema involvement per lung in addition to categorical severity scores. Furthermore, the proposed method extends its predictive capabilities beyond centrilobular emphysema to include paraseptal emphysema subtypes.

Host-device interactions: exposure of lung epithelial cells and fibroblasts to nickel, titanium, or nitinol affect proliferation, reactive oxygen species production, and cellular signaling.

Endoscopic implantation of medical devices for the treatment of lung diseases, including airway stents, unidirectional valves and coils, is readily used to treat central airway disease and emphysema. However, granulation and fibrotic tissue formation impairs treatment effectiveness. To date little is known about the interaction between implanted devices, often made from metals, such as nickel, titanium or nitinol, and cells in the airways. Here, we study the response of lung epithelial cells and fibroblasts to implant device materials. The adhesion and proliferation of bronchial epithelial cells and lung fibroblasts upon exposure to 10 × 3 × 1 mm pieces of nickel, titanium or nitinol is examined using light and scanning electron microscopy. Pro-inflammatory cytokine mRNA expression and release, signaling kinase activity and intracellular free radical production are assessed. Nitinol, and to a lesser extent nickel and titanium, surfaces support the attachment and growth of lung epithelial cells. Nitinol induces a rapid and significant alteration of kinase activity. Cells directly exposed to nickel or titanium produce free radicals, but those exposed to nitinol do not. The response of lung epithelial cells and fibroblasts depends on the metal type to which they are exposed. Nitinol induces cellular surface growth and the induction of kinase activity, while exposure of lung epithelial cells to nickel and titanium induces free radical production, but nitinol does not.