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Sharyn A Roodenburg,1,2 Karin Klooster,1,2 Jorine E Hartman,1,2 T David Koster,1,2 Marlies van Dijk,1,2 Dirk-Jan Slebos1,2 1Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; 2Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The NetherlandsCorrespondence: Sharyn A RoodenburgDepartment of Pulmonary Diseases, AA11, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713, GZ, The NetherlandsTel +31 50 361 9194Fax +31 050 3619320Email s.a.roodenburg@umcg.nlBackground: Endobronchial valve (EBV) treatment is an effective treatment for patients with severe emphysema. Revision bronchoscopies after endobronchial valve treatment can be essential to prolong the effect of treatment or address long-term complications.Purpose: To evaluate the indications, endoscopic findings and outcomes of revision bronchoscopies and investigate if any predictors for granulation tissue formation, after EBV treatment, can be identified.Patients and Methods: Patients who underwent EBV treatment between 2016 and 2019 in our hospital, as routine care, were included. If a patient underwent a revision bronchoscopy, data regarding revision bronchoscopies, including indication, finding, intervention and pulmonary function testing (PFT) after revision bronchoscopy were analysed.Results: One hundred seventy-nine patients were included of which 41% required at least one revision bronchoscopy. In 43% of the revision bronchoscopy patients, the indication was loss of initial treatment effect. In 53% of the revision bronchoscopy patients, granulation tissue was found to be the underlying cause. Valve replacement(s) were performed in 51% of the revision bronchoscopy cases. Permanent valve removal was required in 13% of all patients. Overall, revision bronchoscopies led to improvements in PFT outcomes for patients experiencing no or a loss of initial treatment effect. No clinically relevant predictors for granulation tissue formation were identified.Conclusion: Performing a revision bronchoscopy after EBV treatment is a useful procedure leading to an improved treatment effect in most patients. Granulation tissue formation, causing valve dysfunction, is the most common cause of longer term problems.Keywords: bronchoscopy, lung volume reduction, one-way valve, COPD

Arschang Valipour,1 Pallav L Shah,2 Felix J Herth,3 Christophe Pison,4 Christian Schumann,5 Ralf-Harto Hübner,6 Peter I Bonta,7 Romain Kessler,8 Wolfgang Gesierich,9 Kaid Darwiche,10 Bernd Lamprecht,11 Thierry Perez,12 Dirk Skowasch,13 Gaetan Deslee,14 Armelle Marceau,15 Frank C Sciurba,16 Reinoud Gosens,17 Jorine E Hartman,18 Francesca Conway,2 Marina Duller,1 Martin Mayse,19 Holly S Norman,19 Dirk-Jan Slebos18 On behalf of the AIRFLOW-2 Trial Study Group1Department of Respiratory and Critical Care Medicine, Karl-Landsteiner-Institute for Lung Research and Pulmonary Oncology, Krankenhaus Nord-Klinik Floridsdorf, Vienna, Austria; 2Royal Brompton & Harefield NHS Trust, Chelsea & Westminster Hospital and Imperial College, London, UK; 3Thoraxklinik, Department of Pneumology and Critical Care Medicine and Translational Lung Research Center Heidelberg (TLRCH), University of Heidelberg, Heidelberg, Germany; 4CHU Grenoble Alpes, Service Hospitalier Universitaire Pneumologie Physiologie; Université Grenoble Alpes, Grenoble, France; 5Clinic of Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care, Klinikverbund Allgaeu, Kempten and Immenstadt, Germany; 6Charité Universitätsmedizin Berlin, Medizinische Klinik m. Schw. Infektiologie und Pneumologie, Campus Virchow, Berlin, Germany; 7Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 8Service de Pneumologie, Nouvel Hôpital Civil, Université de Strasbourg, Strasbourg, France; 9Asklepios-Fachkliniken Munich-Gauting, Comprehensive Pneumology Center Munich, Gauting, Germany; 10Department of Pulmonary Medicine, Section of Interventional Pneumology, Ruhrlandklinik - University Hospital Essen, University of Duisburg-Essen, Essen, Germany; 11Department of Pulmonary Medicine, Kepler Universitatsklinikum GmbH, Linz, Austria; 12CHU de Lille – Hôpital Calmette, Lille, France; 13Department of Internal Medicine II - Cardiology/Pneumology, University of Bonn, Bonn, Germany; 14CHU de Reims, Hôpital Maison Blanche, Service de Pneumologie, Reims, France; 15Service de Pneumologie, Hôpital Universitaire Bichat, Paris, France; 16University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; 17Department of Molecular Pharmacology, University of Groningen, Groningen, the Netherlands; 18Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 19Nuvaira, Inc., Minneapolis, MN, USACorrespondence: Dirk-Jan SlebosDepartment of Pulmonary Diseases/Interventional Bronchoscopy AA11, University Medical Center Groningen, PO Box 30001, Groningen, the NetherlandsTel +31 503612357Fax +31503619320Email d.j.slebos@umcg.nlPurpose: COPD exacerbations are associated with worsening clinical outcomes and increased healthcare costs, despite use of optimal medical therapy. A novel bronchoscopic therapy, targeted lung denervation (TLD), which disrupts parasympathetic pulmonary innervation of the lung, has been developed to reduce clinical consequences of cholinergic hyperactivity and its impact on COPD exacerbations. The AIRFLOW-2 study assessed the durability of safety and efficacy of TLD additive to optimal drug therapy compared to sham bronchoscopy and optimal drug therapy alone in subjects with moderate-to-severe, symptomatic COPD two years post randomization.Patients and Methods: TLD was performed in COPD patients (FEV1 30– 60% predicted, CAT≥ 10 or mMRC≥ 2) in a 1:1 randomized, sham-controlled, double-blinded multicenter study (AIRFLOW-2) using a novel lung denervation system (Nuvaira, Inc., USA). Subjects remained blinded until their 12.5-month follow-up visit when control subjects were offered the opportunity to undergo TLD. A time-to-first-event analysis on moderate and severe and severe exacerbations of COPD was performed.Results: Eighty-two subjects (FEV1 41.6± 7.4% predicted, 50.0% male, age 63.7± 6.8 yrs, 24% with prior year respiratory hospitalization) were randomized. Time-to-first severe COPD exacerbation was significantly lengthened in the TLD arm (p=0.04, HR=0.38) at 2 years post-TLD therapy and trended towards similar attenuation for moderate and severe COPD exacerbations (p=0.18, HR=0.71). No significant changes in lung function or SGRQ-C were found 2 years post randomization between groups.Conclusion: In a randomized trial, TLD demonstrated a durable effect of significantly lower risk of severe AECOPD over 2 years. Further, lung function and quality of life remained stable following TLD.Clinical Trial Registration: NCT02058459.Keywords: COPD exacerbation, targeted lung denervation, bronchoscopy, COPD

Jorrit BA Welling,1,2 Jorine E Hartman,1,2 Sonja WS Augustijn,1 Huib AM Kerstjens,1,2 Lowie EGW Vanfleteren,3 Karin Klooster,1,2 Dirk-Jan Slebos1,2 1University of Groningen, University Medical Center Groningen, Department of Pulmonary Diseases, Groningen, the Netherlands; 2Groningen Research Institute for Asthma and COPD, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 3COPD Center, Sahlgrenska University Medical Hospital and Institute of Medicine, Gothenburg University, Gothenburg, SwedenCorrespondence: Jorrit BA WellingDepartment of Pulmonary Diseases, University Medical Center Groningen, Groningen, the NetherlandsEmail j.b.a.welling@umcg.nlPurpose: Bronchoscopic lung volume reduction (BLVR) is a valuable treatment option for carefully selected patients with severe COPD. There is limited knowledge about the characteristics and outcomes of patients referred to a specialized center for BLVR. The study objectives were to investigate the selection rate for BLVR treatment in patients referred for this treatment and to investigate the differences between patients that were selected for BLVR and patients that were not.Patients and Methods: We performed a retrospective analysis of patients with severe COPD who were referred to our hospital to assess eligibility for BLVR treatment. Our parameters included demographics, comorbidity, chest computed tomography characteristics, reasons for rejection from BLVR treatment and patient survival.Results: In total, 1500 patients were included (mean age 62 years, 50% female and forced expiratory volume in 1 s 33% of predicted). Out of this group, 282 (19%) patients were selected for BLVR treatment. The absence of a suitable target lobe for treatment, an unsuitable disease phenotype and insufficient lung hyperinflation were the most important factors for not being selected. Patients that were selected for any BLVR option lived significantly longer than the group of patients that were not selected for BLVR (median 3060 versus 2079 days, P< 0.001).Conclusion: We found that only a small proportion of patients that are referred for BLVR treatment is eligible for a BLVR treatment, indicating a need for both better referral tools and for the development of new therapies for this group of patients. Furthermore, our data suggest that selection for BLVR is associated with a significant survival benefit.Keywords: bronchoscopic lung volume reduction, patient selection, endobronchial valves, lung volume reduction coils

In literature, it remains unclear how the friction coefficient of motor vehicle tyres and road surfaces is affected by velocity in vehicles fitted with antilock braking systems (ABS) compared to vehicles without ABS. In this paper, the effects of velocity on the friction coefficient of motor vehicle tyres and a paired road surface were examined. Tests were performed in a vehicle with ABS enabled and then disabled, allowing comparison between the two braking systems to be made. Braking, sufficient to cause skidding, was applied in a production large family sedan on a bitumen road surface. The friction coefficient of the vehicle tyres and bitumen road surface, during the skidding, was determined using a Vericombrake test computer fitted in the vehicle. Tests were conducted at a range of velocities between 32.8 km/h and 83.1 km/h, with the ABS being enabled and disabled. In both series of tests, peak maximum friction coefficient or minimum friction coeficient values were observed at around 40 km/h. With the ABS enabled, the lowest friction coefficient was observed at 41.9 km/h. When the ABS was disabled, the highest friction coefficient was observed at 42.2 km/h. As vehicle velocity was increased from 40 km/h, the friction coefficient of the vehicle tyres and road surface increased gradually when the ABS was enabled and decreased gradually when the ABS was disabled. Both series of tests showed evidence of plateau above 60 km/h. The vehicle with ABS enabled showed a decrease in the friction coefficient between 60 km/h and 80 km/h. The results suggest that a second peak may be observed around 70 km/h to 80 km/h or alternatively an ongoing plateau may occur. The friction coefficient of motor vehicle tyres and paired road surfaces is affected by velocity with both braking systems. The nature of the effect is dependent upon whether ABS is fitted and working.

A portable phoswich detector capable of differentiating between fast neutrons and thermal neutrons, and photons was developed. The detector design is based on the use of two solid-state scintillators with dissimilar scintillation time properties coupled with a single optical sensor: a 6Li loaded glass and EJ-299-33A plastic. The on-the-fly digital pulse shape discrimination and the wavelet treatment of measured waveforms were employed in the data analysis. The instrument enabled neutron spectrum evaluation.

Introduction: Bronchoscopic lung volume reduction (BLVR) using one-way endobronchial valves (EBV) is a guideline therapy for patients with severe emphysema without interlobar collateral ventilation, based on solid results from multiple randomized clinical trials (RCTs). However, whether its efficacy and safety in real-world clinical settings are comparable to those observed in RCTs has not been fully investigated. Additionally, recent reports on EBV therapy have focused on specialized populations (e.g. very low FEV 1 , very low D LCO ) that were not represented in the RCTs., Areas Covered: We have summarized the efficacy and safety of the publications on BLVR with EBVs in real-world settings and in specialized populations, and have discussed these findings in relation to the RCTs data., Expert Opinion: The benefits of BLVR with EBVs have effectively translated into real-world clinical practice with a tolerable safety profile. These benefits and acceptable safety profile were also observed in specialized populations not fully represented in RCTs. We believe it is crucial to establish a nationwide registry in each country to keep track of outcome for quality and consistency, and to have a multidisciplinary COPD team discussion in each treating institution to keep on ensuring the successful clinical practice of BLVR with EBVs.

Rationale and Aim: Patients with COPD often present with a significant number of comorbidities, which are thought to be related to a higher mortality risk. Our aim was to investigate the prevalence and impact of comorbidities on survival and quality of life (QoL), specifically in patients with emphysema characterised by severe lung hyperinflation., Patients and Methods: Data were prospectively collected from patients who visited our hospital for evaluating their eligibility for a bronchoscopic lung volume reduction treatment and were included in the Groningen Severe COPD cohort (NCT04023409). Comorbidities were patient-reported by a questionnaire and were validated with patients' medical records. QoL was assessed with the St Georges Respiratory Questionnaire., Results: We included 830 COPD patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage III and IV. The total number of comorbidities was an independent predictor of survival when adjusting for other factors influencing survival (HR 1.12, 95% CI 1.05-1.20, p<0.001). Of the individual comorbidities, pulmonary arterial hypertension (HR 1.53, 95% CI 1.01-2.32, p=0.045), low body mass index (HR 1.63, 95% CI 1.16-2.27, p=0.004) and anxiety (HR 1.46, 95% CI 1.11-1.92, p=0.007) were independently associated with worse survival. Moreover, patients having 3, 4 or >5 comorbidities had a significantly (all p<0.05) worse QoL, in comparison to patients without comorbidities., Conclusion: Our results show that comorbidities were associated with lower survival and poor QoL in emphysema patients characterised by severe hyperinflation. Appropriate treatment of treatable traits, including anxiety, low body mass index and pulmonary arterial hypertension, could lead to a survival benefit and improvement in QoL in this specific patient population., Competing Interests: Conflict of interest: D-J. Slebos reports grants or contracts from PulmonX Corp, USA; Nuvaira, USA; PulmAir, USA; and Apreo, USA (clinical trial expenses); consulting fees from Nuvaira, USA; MoreAir, USA; and Apreo, USA; payment or honoraria for lectures from PulmonX, USA; and support for attending meetings and/or travel from PulmonX, USA. Conflict of interest: K. Klooster reports support for attending meetings and/or travel from PulmonX; participation on a data safety monitoring or advisory board from Apreo. Conflict of interest: S.D. Pouwels reports support for the present manuscript from a Dutch Research Council (NOW) VENI grant (number 09150162010003). Conflict of interest: E.A.M.D. ter Haar and J.E. Hartman have nothing to disclose., (Copyright ©The authors 2024.)

This study investigated the impact of bronchoscopic lung volume reduction treatment using endobronchial valves (EBV) on diaphragm configuration. We successfully analyzed the diaphragm index using a newly developed quantitative computed tomography (QCT) tool before and after EBV treatment in forty patients with severe emphysema. We evaluated whether changes in the diaphragm index were associated with improvements in forced expiratory volume in 1 s (FEV 1 ), residual volume (RV), Saint Georges Respiratory Questionnaire (SGRQ), and 6-min walking distance (6MWD) using Spearman's rho. The EBV treatment influenced the diaphragm configuration only on the treated side, resulting in an increased diaphragm curvature. There were significant associations of relative diaphragm index changes on the treated lung side or the entire diaphragm with improvements in FEV 1 and 6MWD. These findings provide valuable insights into how EBV treatment affects the diaphragm in COPD patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JTB and JEH have nothing to disclose. DJS reports to have received clinical trial expenses from Pulmonx Corp, USA, Nuvaira, USA, PulmAir, USA, Apreo, USA and FreeFlowMedical, consulting fees paid to the institution from Nuvaira, USA, MoreAir, USA, Apreo, USA and PulmonX, USA, payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events paid to the institution from PulmonX, USA and Nuvaira, USA and support for attending meetings and/or travel from PulmonX, USA. KK reports to have received payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from PulmonX., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Chronic hypercapnia, defined by elevated blood CO 2 levels, is a serious complication most prevalent in severe COPD. It negatively impacts quality of life, increases hospitalization rates, and elevates mortality risks. However, not all severe COPD patients develop chronic hypercapnia, and its underlying mechanisms remain unclear. Identifying clinical and pathophysiological predictors of hypercapnia is essential for tailored treatment strategies. This study investigates the relationship between hypercapnia and patient characteristics, lung function, and CT scan features to identify potential therapeutic targets., Methods: This cross-sectional study included 1526 COPD patients from three cohorts: a standard care cohort and two research cohorts (NCT04023409; NCT03053973). Data collected included demographic and clinical information, blood gases, lung function (FEV 1 , FVC, TLC, RV, DLCOc), and high-resolution CT scans (lung volumes, air trapping, emphysema scores, airway wall thickness (Pi10), and diaphragm indices)., Results: Hypercapnia prevalence increased with COPD severity. Hypercapnic patients were older, more likely to smoke, and had more comorbidities. They exhibited lower FEV 1 and FVC, and higher RV/TLC ratios, with CT scans showing lower emphysema scores and greater Pi10. Multivariate analysis identified lower PaO 2 , FEV 1 % predicted, and emphysema scores, along with higher RV/TLC ratios and NT-proBNP levels, as independent predictors of PaCO 2 , collectively explaining 46.3 % of the variance., Conclusion: COPD patients with chronic hypercapnia are characterized by higher smoking rates, lower PaO 2 levels, poorer lung function, less emphysema, and increased airway pathology. These findings underscore the multifactorial nature of hypercapnia in COPD, highlighting the need for personalized therapeutic strategies targeting these factors to improve outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dirk-Jan Slebos reports relationships with PulmonX Corp, USA (consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement), Nuvaira, USA (consulting or advisory, funding grants, and speaking and lecture fees), PulmAir, USA (funding grants), Apreo, USA (consulting or advisory and funding grants), MoreAir, USA (consulting or advisory), and FreeFlowMedical, USA (funding grants). Peter J. Wijkstra reports a relationship with the European Respiratory Society (board membership), ResMed (funding grants), and Philips (consulting or advisory and funding grants). Marieke L. Duiverman reports relationships with Vivisol (funding grants and speaking and lecture fees), ResMed (funding grants), Fisher & Paykel (funding grants), Löwenstein B.V. (funding grants), Sencure B.V. (funding grants), Chiesi (speaking and lecture fees), Breas (speaking and lecture fees), and AstraZeneca (speaking and lecture fees). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Assessment of static hyperinflation severity is crucial to identify COPD patients eligible for lung volume reduction. The current recommendation of residual volume ≥175% predicted may need to be reconsidered owing to potential differences between the Global Lung Function Initiative (GLI) and the European Community for Steel and Coal (ECSC) reference equations for residual volume and concerns about using percentage of predicted., Methods: We compared the residual volume reference values derived from the GLI and ECSC equations using mathematically simulated data and used a receiver operating characteristic curve to establish a new GLI-derived z-score cut-off for residual volume using body plethysmography data from patients with severe COPD., Results: The GLI reference equation for residual volume consistently yields a lower predicted residual volume for individuals with an average or below-average height (females ≤163 cm and males ≤177 cm). Our clinical cohort consisted of 1011 patients with COPD (graded using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria as 38% GOLD 3 and 59% GOLD 4). In this cohort, a GLI-derived residual volume z-score of ≥2.9 could accurately replace the ECSC-derived 175% predicted cut-off and a z-score of ≥3.5 was established for the 200% predicted cut-off., Conclusion: There are substantial differences in predicted residual volume values between the GLI and ECSC equations, with the GLI generally yielding a lower predicted residual volume in the majority of individuals. A GLI-derived residual volume z-score of ≥2.9 could be used to replace the currently used cut-off of ≥175% predicted to identify potential lung volume reduction candidates., Competing Interests: Conflict of interest: D-J. Slebos reports grants or contracts, consulting fees, honoraria, support for attending meetings and receiving materials from PulmonX, PneumRx and Nuvaira, and grants or contracts from Free Flow Medical, all outside the context of the submitted work. Conflict of interest: All other authors have nothing to disclose., (Copyright ©The authors 2024.)

Introduction: Currently, there is a lack of bronchoscopic lung volume reduction options that do not depend on fissure integrity. Endobronchial coils have been extensively studied to address this need but exhibited variable patient response and have been discontinued. Lung tension device (LTD) coils represent the next-generation coil treatment. This study aimed to evaluate safety, feasibility, and efficacy of LTD-coil treatment., Methods: Patients with advanced emphysema and hyperinflation were enrolled at two European sites. LTD-coils (Free Flow Medical, Fremont, CA, USA) were implanted in the two most destructed lobes, as determined by quantitative CT analysis, in two separate procedures. The primary endpoint was 3-month follow-up after the last treatment., Results: Fourteen patients (50% male, median age 64 years, FEV1 23%predicted, RV 249%predicted) received LTD-coil treatment: 12 received bilateral and 2 unilateral treatment. Six serious respiratory adverse events occurred within the initial 3 months posttreatment, including one device-associated death. Treatment significantly reduced in- and expiratory volume of the treated lobes (-410 [-710, -340], p = 0.004 and -650 [-730, -190] mL, p &lt; 0.001, respectively) and improved quality of life (SGRQ total score -4.6 [-21.0, -2.6], p &lt; 0.001). However, at a group level, no significant improvements in pulmonary function or 6-min walk distance were observed. Responder rates ranged from 18% to 54% for the different endpoints., Conclusion: This first-in-human study shows that the new LTD-coil procedure is feasible with a safety profile comparable to the previous coil treatment. While the treatment effectively reduced lobar volume and modestly improved quality of life up to 3 months' follow-up, at a group level it did not significantly enhance pulmonary function or exercise capacity., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

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., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: Severe chronic obstructive pulmonary disease (COPD) often results in hyperinflation and flattening of the diaphragm. An automated computed tomography (CT)-based tool for quantifying diaphragm configuration, a biomarker for COPD, was developed in-house and tested in a large cohort of COPD patients., Methods: We used the LungQ platform to extract the lung-diaphragm intersection, as direct diaphragm segmentation is challenging. The tool computed the diaphragm index (surface area/projected surface area) as a measure of diaphragm configuration on inspiratory scans in a COPDGene subcohort. Visual inspection of 250 randomly selected segmentations served as a quality check. Associations between the diaphragm index, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages, forced expiratory volume in 1 s (FEV1) % predicted, and CT-derived emphysema scores were explored using analysis of variance and Pearson correlation., Results: The tool yielded incomplete segmentation in 9.2% (2.4% major defect, 6.8% minor defect) of 250 randomly selected cases. In 8431 COPDGene subjects (4240 healthy; 4191 COPD), the diaphragm index was increasingly lower with higher GOLD stages (never-smoked 1.83 ± 0.16; GOLD-0 1.79 ± 0.18; GOLD-1 1.71 ± 0.15; GOLD-2: 1.67 ± 0.16; GOLD-3 1.58 ± 0.14; GOLD-4 1.54 ± 0.11) (p < 0.001). Associations were found between the diaphragm index and both FEV1% predicted (r = 0.44, p < 0.001) and emphysema score (r = -0.36, p < 0.001)., Conclusion: We developed an automated tool to quantify the diaphragm configuration in chest CT. The diaphragm index was associated with COPD severity, FEV1%predicted, and emphysema score., Relevance Statement: Due to the hypothesized relationship between diaphragm dysfunction and diaphragm configuration in COPD patients, automatic quantification of diaphragm configuration may prove useful in evaluating treatment efficacy in terms of lung volume reduction., Key Points: Severe COPD changes diaphragm configuration to a flattened state, impeding function. An automated tool quantified diaphragm configuration on chest-CT providing a diaphragm index. The diaphragm index was correlated to COPD severity and may aid treatment assessment., (© 2024. The Author(s).)

Introduction: Damage-associated molecular patterns (DAMPs) are endogenous danger signals that alert and activate the immune system upon cellular damage or death. It has previously been shown that DAMP release is increased in patients with COPD, leading to higher levels in extracellular fluids such as serum. In the current study we investigated whether the serum levels of DAMPs were associated with survival rates in COPD patients., Methods: A panel of seven DAMPs, consisting of HMGB1, fibrinogen, α-defensin, heat shock protein 70, S100A8, galectin-9 and double-stranded DNA (dsDNA), was measured in serum of 949 severe COPD patients. Maximally selected rank statistics was used to define cut-off values and a Cox proportional hazards model was used to evaluate the effect of high or low DAMP levels on 4-year survival. For DAMPs that were found to affect survival significantly, baseline characteristics were compared between the two DAMP groups., Results: Out of the seven DAMPs, only dsDNA was significantly associated with 4-year survival. Patients with elevated serum level of dsDNA had higher 4-year mortality rates, lower FEV 1 % predicted values and higher emphysema scores., Discussion: In conclusion, in a clinical cohort of 949 patients with moderate-to-severe COPD, elevated serum levels of dsDNA were associated with a higher risk of death. This study further illustrates the potential role of circulating DAMPs, such as dsDNA, in the progression of COPD. Together, the results of this study suggest that levels of circulating dsDNA might serve as an additional prognostic biomarker for survival in COPD patients., Competing Interests: Conflict of interest: All authors declare no conflicts of interest., (Copyright ©The authors 2024.)

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., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Conflict of interest: W. Timens declares consultancy payments to their institution from Merck Sharp & Dohme and Bristol Myers Squibb, in the 36 months prior to manuscript submission; as well as board membership of the Dutch Society of Pathology and membership of the Council for Research and Innovation of the Federation of Medical Specialists. Conflict of interest: D-J. Slebos declares grants or contracts to their institution from the following US companies in the 36 months prior to manuscript submission: PulmonX Corp., PneumRx/BTG/Boston Scientific, FreeFlowMedical, Nuvaira, PulmAir, GALA, CSA Medical and Apreo; consulting fees paid to their institution from PulmonX Corp., PneumRx/BTG/Boston Scientific, Nuvaira and Apreo; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from PulmonX Corp, PneumRx/BTG/Boston Scientific and Nuvaira; support for attending meeting and/or travel from PulmonX Corp., PneumRx/BTG/Boston Scientific and Nuvaira; and receipt by their institution of study material/devices from PulmonX Corp., PneumRx/BTG/Boston Scientific, FreeFlowMedical, Nuvaira, PulmAir, GALA and CSA Medical, all in the 36 months prior to manuscript submission. Conflict of interest: D.F. Choy is an employee of Genentech, Inc., a member of the Roche Group, and is a co-inventor, as part of that employment, for pending patents related to the diagnosis and treatment of chronic respiratory diseases. They also hold stocks and/or options in Roche. Conflict of interest: A. Chakrabarti is an employee of Genentech, Inc., a member of the Roche Group. Conflict of interest: M. Grimbaldeston is an employee of Genentech, Inc., a member of the Roche Group, and has received stock options. Conflict of interest: C.M. Rosenberger is an employee of Genentech, Inc., a member of the Roche Group, and has received support for attending conferences from their employer. They hold stocks and stock options in Roche. Conflict of interest: C-A. Brandsma declares a research grant from Genentech, related to the current manuscript. Conflict of interest: M. van den Berge declares a research grant from Genentech, related to the current manuscript. Conflict of interest: All other authors declare no competing interests., (Copyright ©The authors 2023.)

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 (FEV 1 ), 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 FEV 1 , 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., Competing Interests: Conflict of interest: K. Klooster reports support for attending meetings from PulmonX, outside the context of the submitted work. Conflict of interest: D-J. Slebos reports grants or contracts, consulting fees, honoraria, support for attending meetings and receiving materials from PulmonX, PneumRx and Nuvaira, and grants or contracts from Free Flow Medical, all outside the context of the submitted work. Conflict of interest: S.A. Roodenburg and J. Hartman report no conflicts of interest., (Copyright ©The authors 2023.)

Background: The Constant Work Rate Cycle Test (CWRT) is a commonly used and sensitive test to detect treatment success in patients with Chronic Obstructive Pulmonary Disease (COPD). Earlier, the Minimal Important Difference (MID) of the CWRT was estimated at 101 s (or 34%) change from baseline based on one well executed study. However, this study was performed in a population of patients with mild-to-moderate COPD, and we have learned that MIDs might be quite different in patients with severe COPD. Therefore, we aimed to establish the MID of the CWRT in patients with severe COPD., Methods: We included 141 patients with severe COPD, who underwent either pulmonary rehabilitation, bronchoscopic lung volume reduction with endobronchial valves, or a sham bronchoscopy as a control group. CWRT workload was set at 75% of the peak work capacity, as determined by an incremental cycle test. We used the change in 6-min walking test (6-MWT), forced expiratory volume in 1s (FEV 1 ), residual volume (RV), and St. George's Respiratory Questionnaire (SGRQ) total score as anchors to calculate the MID., Results: All anchors had an association of ≥0.41 with change in CWRT. The MID estimates for the different anchors were: 6-MWT 278 s (95%), FEV 1 273 s (90%), RV 240 s (84%), and SGRQ 208 s (71%). The average of these four MID estimates resulted in an MID of 250 s (or 85%)., Conclusion: We established the MID for CWRT at 250 s (or 85%) change from baseline in patients with severe COPD., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Conflict of interest: D-J. Slebos reports grants or contracts from PulmonX Corp., PneumRx/BTG/Boston Scientific, FreeFLowMedical, Nuvaira, PulmAir, GALA, CSA Medical and Apreo, outside the submitted work; consulting fees from PulmonX Corp., PneumRx/BTG/Boston Scientific, Nuvaira and Apreo, outside the submitted work; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from PulmonX Corp., PneumRx/BTG/Boston Scientific and Nuvaira, outside the submitted work; support for attending meetings and/or travel from PulmonX Corp., PneumRx/BTG/Boston Scientific and Nuvaira, outside the submitted work; and his institution is in receipt of study material/devises from PulmonX Corp., PneumRx/BTG/Boston Scientific, FreeFLowMedical, Nuvaira, PulmAir, GALA and CSA Medical, outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

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 FEV 1 , 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., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

This post-hoc analysis of the AIRFLOW-2 trial investigated the changes in airway CT-parameters after targeted lung denervation (TLD) and whether these changes are associated with treatment response. In the treatment group (n = 32), an improvement in air trapping was significantly associated with an improvement in residual volume (RV). Furthermore, improvements in Pi10 and airway lumen were significantly associated with an improvement in both RV and FEV 1 . Our results could suggest that when improving airway characteristics like decreasing airway wall thickness and increasing the airway lumen, this leads to less air trapping and an improvement in clinical outcomes., Competing Interests: Declaration of competing interest DJS is a PI for Nuvaira, USA and reports consultancy fees from Nuvaira paid to the institution. AV reports speaker fees from Nuvaira in the past. PS reports clinical trial expenses reimbursed to the host institutions in the past 36 months. CP reports payments for lectures and to CHUGA to conduct phase 3 trials from Nuvaira (AIRFLOW 2 and 3 trials), GSK, AZ, Boehringer Ingelheim, Novartis and Chiesi. JH and FH have nothing to disclose., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

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., Competing Interests: Conflict of interest: K. Klooster reports payment or honoraria for lectures from PulmonX and Boehringer. D-J. Slebos reports grants or contracts from PulmonX, PneumRx/BTG/Boston Scientific, FreeFlowMedical and Nuvaira (principal investigator and advisor, to institution); consulting fees, payment or honoraria for lectures, support for attending meetings and/or travel, and receipt of study material and medical devices to institution from PulmonX, PneumRx and Nuvaira. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Rationale: Pulmonary hyperinflation in patients with chronic obstructive pulmonary disease has been related to smaller cardiac chamber sizes and impaired cardiac function. Currently, bronchoscopic lung volume reduction (BLVR) with endobronchial valves is a treatment option to reduce pulmonary hyperinflation in patients with severe emphysema. Objectives: We hypothesized that reduction of hyperinflation would improve cardiac preload in this patient group. In addition, we investigated whether the treatment would result in elevated pulmonary artery pressures because of pulmonary vascular bed reduction. Methods: We included patients with emphysema and severe hyperinflation (defined by a baseline residual volume >175% of predicted) who were eligible for BLVR with endobronchial valves. Cardiac magnetic resonance imaging was obtained one day before treatment and at 8-week follow-up. Primary endpoint was cardiac preload, as measured by the right ventricle end-diastolic volume index. As secondary endpoints, we measured indexed end-diastolic and end-systolic volumes of the right ventricle, left atrium, and left ventricle; pulmonary artery pressures; cardiac output; ejection fraction; and strain. Measurements and Main Results: Twenty-four patients were included. At 8-week follow-up, right ventricle end-diastolic volume index was significantly improved (+7.9 ml/m 2 ; SD, 10.0; P  = 0.001). In addition to increased stroke volumes, we found significantly higher ejection fractions and strain measurements. Although cardiac output was significantly increased (+0.9 L/min; SD, 1.5; P  = 0.007), there were no changes in pulmonary artery pressures. Conclusions: We found that reduction of hyperinflation using BLVR with endobronchial valves significantly improved cardiac preload, myocardial contractility, and cardiac output, without changes in pulmonary artery pressures. Clinical trial registered with www.clinicaltrials.gov (NCT03474471).

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., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: New advanced bronchoscopic treatment options for patients with severe chronic obstructive pulmonary disease (COPD) have led to increased interest for COPD phenotyping, including fissure completeness. Objectives: We investigated clinical, environmental, and genetic factors contributing to fissure completeness in patients with and without COPD. Methods: We used data from 9,926 participants of the COPDGene study who underwent chest computed tomographic (CT) scans. Fissure completeness was calculated from CT scans after quantitative CT analysis at baseline and 5-year follow-up. Clinical and environmental factors, including sex, race, smoking, COPD, emphysema, maternal smoking during pregnancy and maternal COPD, were tested for impact on fissure completeness. Genome-wide association analyses were performed separately in non-Hispanic White subjects and African American subjects. Measurements and Main Results: African American subjects had significantly higher fissure completeness than non-Hispanic White subjects for all three fissures ( P  < 0.001). There was no change in fissure completeness between baseline and 5-year follow-up. For all fissures, no clinically relevant differences in fissure completeness were found for other clinical or environmental factors, including COPD severity. Rs2173623, rs264866, rs2407284, rs7310342, rs4904145, rs6504172, and rs7209556 showed genome-wide significant associations with fissure completeness in non-Hispanic White subjects. In African American subjects, rs264866, rs4904145 and rs6504172 were identified as significant associations. Rs2173623, rs6504172, and rs7209556 lead to WNT5A and HOXB antisense RNA expression, which play an important role during embryogenesis. Conclusions: Fissure completeness is genetically determined and not dependent on age, sex, smoking status, the presence and severity of COPD (including exacerbation frequency), maternal smoking during pregnancy, or maternal COPD.

Purpose: For this study, we aimed to compare dynamic hyperinflation measured by cardiopulmonary exercise testing (CPET), a six-minute walking test (6-MWT), and a manually paced tachypnea test (MPT) in patients with severe emphysema who were treated with endobronchial coils. Additionally, we investigated whether dynamic hyperinflation changed after treatment with endobronchial coils., Methods: Dynamic hyperinflation was measured with CPET, 6-MWT, and an MPT in 29 patients before and after coil treatment., Results: There was no significant change in dynamic hyperinflation after treatment with coils. Comparison of CPET and MPT showed a strong association (rho 0.660, p < 0.001) and a moderate agreement (BA-plot, 202 ml difference in favor of MPT). There was only a moderate association of the 6-MWT with CPET (rho 0.361, p 0.024)., Conclusion: MPT can be a suitable alternative to CPET to measure dynamic hyperinflation in severe emphysema but may overestimate dynamic hyperinflation possibly due to a higher breathing frequency.

Purpose: For a successful bronchoscopic lung volume reduction coil treatment it is important to place the coils in the most emphysematous lobes. Therefore assessment of the lobe with greatest destruction is essential. Our aims were to investigate the level of agreement among expert reviewers of HRCT-scans in emphysema patients and the comparison with QCT (quantitative computed tomography) software., Method: Five experienced CT-assessors, conducted a visual assessment of the baseline HRCT-scans of emphysema patients who participated in the RENEW bronchoscopic lung volume reduction coil study. On the same HRCT-scans, a QCT analysis was performed., Results: In total 134 HRCT-scans were rated by all 5 experts. All 5 CT-assessors agreed on which was the most destructed lobe in 61 % of the left lungs (ƙ:0.459) and 60 % of the right lungs (ƙ:0.370). The consensus of the 5 assessors matched the QCT in the left lung for 77 % of the patients (ƙ:0.425) and in the right lung for 82 % (ƙ:0.524)., Conclusions: Our results show that the interobserver agreement between five expert CT-assessors was only fair to moderate when evaluating the most destructed lobe. CT-assessor consensus improved matching with QCT determination of lobar destruction compared to individual assessor determinations. Because some CT-features are associated with treatment outcomes and important for optimal patient selection of bronchoscopic lung volume reduction treatment, we recommend including more than one CT-reviewer and supported by QCT measurements., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up., Methods: TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life., Results: Three-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV 1 , FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed., Conclusion: TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up.

Chronic bronchitis is a chronic, progressive disease that is difficult to treat. Despite much effort, patients remain highly symptomatic. Currently, a number of innovative bronchoscopic treatments for this disease are under investigation. Liquid nitrogen metered cryospray, bronchial rheoplasty and balloon desobstruction all aim to destroy the hyperplastic goblet cells and excess submucous glands using different strategies. These therapies are in an early phase of clinical research and larger randomised controlled trials are needed to confirm the pilot data available and to evaluate the treatment durability. The fourth technique, targeted lung denervation (TLD), aims to decrease the release of acetylcholine, which regulates smooth muscle tone and mucus production by ablating the parasympathetic nerves running alongside the main bronchi. Evaluation of this treatment is at a more advanced stage and promising effects on exacerbation frequency have been shown. However, confirmation of the benefit in improvement in chronic bronchitis symptoms is still needed., Competing Interests: Conflict of interest: J.E. Hartman has nothing to disclose. Conflict of interest: J.L. Garner has nothing to disclose. Conflict of interest: P.L. Shah reports personal fees from Boston Scientific, CSA Medical, Creo Medical, Nuvairia Olympus, Medtronic and PneumRX/BTG as consultant on scientific advisory boards, and sponsorship from Imperial College for a bronchoscopy course by from ERBE, Cook Medical, Medtronic, Boston Scientific, Broncus, Pulmonx, Olympus and PneumRX/BTG, outside the submitted work. He has been an investigator on clinical trials with bronchial thermoplasty, endobronchial valves, endobronchial coils, thermal ablation and the airway bypass procedure. Conflict of interest: D-J. Slebos reports grants, non-financial support and other from Nuvaira Inc.; grants and non-financial support from CSA medical and PneumRx/BTG; and grants, personal fees and non-financial support from PulmonX Inc., outside the submitted work., (Copyright ©ERS 2021.)

Competing Interests: Disclosure: K.K. received travel reimbursement and speakers fee from PulmonX Inc. D.-J.S. received travel reimbursement and speakers fee from PulmonX Inc. and is adviser for CSA medical and Nuvaira. The remaining authors have no conflict of interest or other disclosures.

Rationale: Bronchoscopic lung volume reduction with endobronchial valves (EBVs) significantly improves clinical outcomes in patients with severe emphysema. However, patient-reported outcomes like patient satisfaction and patient-specific treatment goals were never investigated. Objectives: To investigate the patient-satisfaction level 1 year after treatment and patient-specific goals before and 1 year after EBV treatment. Furthermore, the study aimed to investigate whether the level of patient satisfaction or change in goals was associated with change in the clinical outcome. Methods: We prospectively included patients who underwent EBV treatment as part of regular care in our hospital and asked patients to report and score their personal treatment goals on the patient-specific complaint (PSC) questionnaire at baseline and after 1 year of follow-up and to complete a patient-satisfaction questionnaire at 1 year of follow-up. Results: Of the 134 patients who were treated with EBV, 109 filled out the patient-satisfaction questionnaire and 88 filled out the PSC questionnaire at baseline and 1 year after treatment. When adjusting for the patients who were lost to follow-up, 91% of the patients in total would recommend the EBV treatment to other patients. Seventy-five percent of the patients were (very) satisfied with the treatment and 11% were (very) unsatisfied. The three most frequently reported patient-specific goals to improve were walking (reported by 77% of the patients), taking a shower/washing/getting dressed (35%), and completing household chores (32%). Both the total PSC questionnaire sum score (mean change, -6.01 ± 6.0) and all individual reported goals significantly improved 1 year after treatment ( P  < 0.001). Furthermore, a higher patient-satisfaction level and larger improvement in goals was significantly associated with an improvement in forced expiratory volume in 1 second, residual volume, dyspnea severity, and quality of life. Conclusions: We found that the patient-satisfaction level is high and patient-specific goals significantly improve 1 year after EBV treatment. We believe that the individual patient's goals are important in the process of shared decision-making before treatment, as they can be used to identify unrealistic expectations beforehand and prevent disappointment afterward.Clinical trial registered at clinicaltrials.gov (NCT02815683).

Background: So far, 3 randomized controlled trials have shown that the endobronchial treatment using coils is safe and effective. However, the more exact underlying mechanism of the treatment and best predictors of response are unknown., Objectives: The aim of the study was to gain more knowledge about the underlying physiological mechanism of the lung volume reduction coil treatment and to identify potential predictors of response to this treatment., Methods: This was a prospective nonrandomized single-center study which included patients who were bilaterally treated with coils. Patients underwent an extensive number of physical tests at baseline and 3 months after treatment., Results: Twenty-four patients (29% male, mean age 62 years, forced expiratory volume in 1 s [FEV1] 26% pred, residual volume (RV) 231% pred) were included. Three months after treatment, significant improvements were found in spirometry, static hyperinflation, air trapping, airway resistance, treated lobe RV and treated lobes air trapping measured on CT scan, exercise capacity, and quality of life. The change in RV and airway resistance was significantly associated with a change in FEV1, forced vital capacity, air trapping, maximal expiratory pressure, dynamic compliance, and dynamic hyperinflation. Predictors of treatment response at baseline were a higher RV, larger air trapping, higher emphysema score in the treated lobes, and a lower physical activity level., Conclusions: Our results confirm that emphysema patients benefit from endobronchial coil treatment. The primary mechanism of action is decreasing static hyperinflation with improvement of airway resistance which consequently changes dynamic lung mechanics. However, the right patient population needs to be selected for the treatment to be beneficial which should include patients with severe lung hyperinflation, severe air trapping, and significant emphysema in target lobes., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: No currently approved intervention counteracts airway metaplasia and mucus hypersecretion of chronic bronchitis in COPD. However, metered cryospray (MCS) delivering liquid nitrogen to the tracheobronchial airways ablates abnormal epithelium and facilitates healthy mucosal regeneration. The objective of this study was to evaluate the feasibility, efficacy and safety of MCS in chronic bronchitis., Methods: Patients with a forced expiratory volume in 1 s of 30-80% predicted who were taking optimal medication were recruited. Primary outcomes were feasibility (completion of treatments), efficacy (3-month change in St George's Respiratory Questionnaire (SGRQ)) and safety (incidence of adverse events). Secondary outcomes were lung function, exercise capacity and additional patient-reported outcomes., Results: 35 patients, 19 male/16 female, aged 47-76 years, Global Initiative for Chronic Obstructive Lung Disease grade I (n=3), II (n=10) and III (n=22), underwent staggered liquid nitrogen treatments to the tracheobronchial tree. 34 patients completed three treatments, each lasting 34.3±12.1 min, separated by 4-6 weeks; one withdrew after the first treatment. ∼1800 doses of MCS were delivered. Clinically meaningful improvements in patient-reported outcomes were observed at 3 months: change in SGRQ -6.4 (95% CI -11.4 to -1.3; p=0.01), COPD Assessment Test (CAT) -3.8 (95% CI -6.4 to -1.3; p<0.01) and Leicester Cough Questionnaire (LCQ) 21.6 (95% CI 7.3 to 35.9; p<0.01). Changes in CAT were durable to 6 months (-3.4, 95% CI -5.9 to -0.9; p=0.01); changes in SGRQ and LCQ were durable to 9 months (-6.9, 95% CI -13.0 to -0.9; p=0.03 and 13.4, 95% CI 2.1 to 24.6; p=0.02, respectively. At 12 months, 14 serious adverse events were recorded in 11 (31.4%) subjects; six (43%) moderate and eight (57%) severe. Nine were respiratory-related: six exacerbations of COPD, two pneumonias and one case of increased coughing; all recovered without sequelae. None were serious device- or procedure-related adverse events., Conclusion: MCS is safe, feasible and associated with clinically meaningful improvements in multidimensional patient-reported outcomes., Competing Interests: Conflict of interest: J.L. Garner has nothing to disclose. Conflict of interest: T. Shaipanich has nothing to disclose. Conflict of interest: J.E. Hartman has nothing to disclose. Conflict of interest: C.M. Orton has nothing to disclose. Conflict of interest: C. Caneja has nothing to disclose. Conflict of interest: K. Klooster has nothing to disclose. Conflict of interest: J. Thornton has nothing to disclose. Conflict of interest: D.D. Sin has received honoraria for speaking engagements from AstraZeneca and Boehringer Ingelheim, and funding for research projects from AstraZeneca, Boehringer Ingelheim and Merck. Conflict of interest: D.J. Slebos reports grants and non-financial support from, and was PI for and advisor to CSA Medical, USA, during the conduct of the study; grants and non-financial support from, and was PI for and advisor to PulmonX, USA, Nuvaira, USA and PneumRx/BTG, USA, and was PI for and advisor to FreeFlowMedical, USA, outside the submitted work. Conflict of interest: P.L Shah was reimbursed by CSA Medical for travel expenses incurred during the training with the medical device and trial protocol development; the hospital was reimbursed for all clinical trial related costs, and reports personal fees from CSA Medical, Boston Scientific, Broncus, Creo Medical, Nuvaira, Olympus, Medtronic and PneumRX/BTG as consultant on scientific advisory board; and sponsorship to Imperial College for a bronchoscopy course from ERBE, Cook medical, Medtronic, Boston Scientific, Broncus, Pulmonx, Olympus and PneumRX/BTG, outside the submitted work., (Copyright ©ERS 2020.)

Background and Objective: The RENEW trial demonstrated that bronchoscopic lung volume reduction using endobronchial coils improves quality of life, pulmonary function and exercise performance. In this post hoc analysis of RENEW, we examine the mechanism of action of endobronchial coils that drives improvement in clinical outcomes., Methods: A total of 78 patients from the RENEW coil-treated group who were treated in one or both lobes that were deemed as the most destroyed were included in this retrospective analysis. Expiratory and inspiratory HRCT scans were used to assess lobar volume change from baseline to 12 months post coil treatment in treated and untreated lobes., Results: Reduction in lobar RV in treated lobes was significantly associated with favourable clinical improvement. Independent predictor of the change in RV and FEV 1 was the change in lobar RV reduction in the treated lobes and for change in 6MWD the absence of cardiac disease and the change in SGRQ, while the independent predictor of change in SGRQ was the change in 6MWD., Conclusion: Our results suggest that residual lobar volume reduction in treated lobes measured by QCT is the driving mechanism of action of endobronchial coils leading to positive clinical outcomes. However, the improvement in exercise capacity and quality of life seems to be affected by the presence of cardiac disease., (© 2020 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Change in patient's personal treatment goals is an important patient-reported outcome and can be measured by the patient-specific complaints (PSC) questionnaire. This paper establishes the MID for this questionnaire as -5.9 points. https://bit.ly/3kwvWKM., Competing Interests: Conflict of interest: J.E. Hartman has nothing to disclose. Conflict of interest: K. Klooster reports a speaker's fee and travel reimbursement from PulmonX outside the submitted work. Conflict of interest: T.D. Koster has nothing to disclose. Conflict of interest: M. van Dijk has nothing to disclose. Conflict of interest: D-J. Slebos reports grants and nonfinancial support from, and work as a principal investigator and investigator from PulmonX, CA, USA, and PneumRx/BTG, outside the submitted work., (Copyright ©ERS 2020.)

Background and Purpose: In patients with severe emphysema, dynamic hyperinflation is superimposed on top of already existing static hyperinflation. Static hyperinflation reduces significantly after bronchoscopic lung volume reduction (BLVR). In this study, we investigated the effect of BLVR compared to standard of care (SoC) on dynamic hyperinflation., Methods: Dynamic hyperinflation was induced by a manually paced tachypnea test (MPT) and was defined by change in inspiratory capacity (IC) measured before and after MPT. Static and dynamic hyperinflation measurements were performed both at baseline and 6 months after BLVR with endobronchial valves or coils (treatment group) or SoC (control group)., Results: Eighteen patients underwent BLVR (78% female, 57 (43-67) years, FEV 1 25(18-37) %predicted, residual volume 231 (182-376) %predicted). Thirteen patients received SoC (100% female, 59 (44-74) years, FEV 1 25 (19-37) %predicted, residual volume 225 (152-279) %predicted. The 6 months median change in dynamic hyperinflation in the treatment group was: + 225 ml (range - 113 to + 803) (p < 0.01) vs 0 ml (- 1067 to + 500) in the control group (p = 0.422). An increase in dynamic hyperinflation was significantly associated with a decrease in residual volume (r = - 0.439, p < 0.01)., Conclusion: Bronchoscopic lung volume reduction increases the ability for dynamic hyperinflation in patients with severe emphysema. We propose this is a consequence of improved static hyperinflation.

Background: Bronchoscopic lung volume reduction techniques are minor invasive treatment modalities for severely hyperinflated emphysema patients. The severity of static lung hyperinflation determines eligibility and success rate for these treatments. However, it is not exactly known what parameter should be used to optimally reflect hyperinflation. Commonly used parameters are residual volume (RV) and the RV/Total lung capacity (TLC) ratio. Other parameters reflecting hyperinflation are Inspiratory Capacity/TLC and forced vital capacity., Objectives: To define which of these function parameters is the most optimal reflection of hyperinflationin in relation to patient-related outcomes., Methods: In a retrospective cohort study, data from measurements during baseline visits of eight studies were pooled. Primary outcomes were RV/TLC ratio and RV as percentage of predicted (RV%pred), both measured by bodyplethysmography, compared to the patient-related outcome variables: 6-min walk distance (6MWD), the St. George's Respiratory Questionnaire (SGRQ), and the modified Medical Research Council (mMRC)., Results: Two hundred seventy-four COPD patients (mean age 59 years; 66% female), FEV 1 0.74 ± 0.28 L, RV 4.94 ± 1.06 L, 6MWD of 339 ± 95 m, were included in the analysis. Significant correlations (all p < 0.01) were found between RV%pred and 6MWD (r =  - 0.358), SGRQ (r = 0.184), and mMRC (r = 0.228). Also, there was a significant correlation between RV/TLC ratio and 6MWD (r =  - 0.563), SGRQ (r = 0.289) and mMRC (r = 0.354). Linear regression analyses showed that RV/TLC ratio was a better predictor of patient outcomes than RV%pred., Conclusion: This study demonstrates that both RV/TLC ratio and RV%pred are relevant indicators of hyperinflation in patients with severe emphysema in relation to patient-related outcomes. RV/TLC ratio is more strongly related to the patient-related outcomes than RV%pred.

Although accelerometers are extensively validated to estimate energy expenditure in patients with COPD, they show significant differences in non-worn time and type of activity registration http://bit.ly/32fa7WR., Competing Interests: Conflict of interest: M.C. van der Molen has nothing to disclose. Conflict of interest: J.E. Hartman has nothing to disclose. Conflict of interest: L.E.G.W. Vanfleteren reports grants, personal fees and nonfinancial support from Pulmonx, personal fees and nonfinancial support from Menarini, grants and personal fees from Astrazeneca, personal fees from Chiesi, GSK, Novartis and Boehringer, and grants and nonfinancial support from Fisher & Paykel, outside the submitted work. Conflict of interest: D-J. Slebos has nothing to disclose., (Copyright ©ERS 2020.)

Background: Currently, patients with COPD who are evaluated for bronchoscopic treatments are routinely screened for pulmonary hypertension (PH) and systolic left ventricle dysfunction by echocardiography., Objectives: We evaluated the prevalence of PH and systolic left ventricle dysfunction in this patient group and investigated if the previously proposed CT-derived pulmonary artery to aorta (PA:A) ratio >1 and PA diameter measurements can be used as alternative screening tools for PH., Methods: Two hundred fifty-five patients were included in this retrospective analysis (FEV1 25%pred, RV 237%pred). All patients received transthoracic echocardiography and chest CT scans on which diameters of the aorta and pulmonary artery were measured at the bifurcation and proximal to the bifurcation., Results: Following echocardiography, 3 patients (1.2%) had PH and 1 (0.4%) had systolic left ventricle dysfunction. Using a PA:A ratio >1, only 10.3% of the patients with a right ventricular systolic pressure (RVSP) ≥35 mm Hg were detected and none of the patients with an RVSP >50 mm Hg were detected. Patients with an RVSP ≥35 mm Hg had significantly higher PA diameters (29.5 vs. 27.5 mm; p = 0.02) but no significantly different PA:A ratios. All patients with an RVSP >50 mm Hg had PA diameters >30 mm., Conclusions: The prevalence of PH and systolic left ventricle dysfunction is low in this preselected cohort of patients with severe COPD. In this population, a PA:A ratio >1 is not a useful cardiac screening tool for PH. A PA diameter >30 mm could substitute for routinely performed echocardiography in the screening for PH in this patient group., (© 2020 The Author(s) Published by S. Karger AG, Basel.)