LungenClinic Grosshansdorf

IntroductionMicroscopy is a cornerstone for diagnostics in lung disease but was traditionally restricted to biopsies and explanted tissue. Microscopic optical coherence tomography (mOCT) produces images with microscopic resolution without the need for exogenous markers. As recently demonstrated in excised mouse tissue, the combination with dynamic contrast (dmOCT) generates high contrast images of airway tissue. DmOCT therefore has the potential to be used for virtual biopsies in humans.MethodsTo assess the potential of dmOCT combined with endoscopic imaging, we scanned excised human lung tissue through a custom-built endoscope optic and compared the resulting dmOCT images with conventional histologic sections of the same tissue. We also assessed if imaging time can be substantially reduced while keeping sufficient dmOCT image quality.ResultsEndoscopic dmOCT successfully visualized the epithelium and subepithelial tissue of human airways including smooth muscle cells and glands. The technique detected key structural changes such as inflammatory cell infiltration, basement membrane thickening, epithelial damage, and the transition to carcinoma in situ. In addition, dmOCT distinguished between different morphologies of human lung cancer present in the examined tissue. The image contrast for discriminating these structures remained sufficient even after the acquisition time was reduced to 0.054s.DiscussionWe have shown that dmOCT, when combined with endoscopic optics, reaches the image quality and imaging speed making its use for virtual biopsies in vivo realistic in the future.

Zusammenfassung Die vorliegende Arbeit nutzt den Forschungsstil der Grounded Theory, um eine Theorie über Fremddarstellung und Selbstbeschreibung weiblicher Führungskräfte zu entwickeln. Dabei orientiert sich das praktische Vorgehen der vorliegenden Arbeit an den Ausführungen von Strübing. In diesem Kapitel werden die zentralen Begriffe der Grounded Theory konkret ausdifferenziert und die Verfahrensschritte der Grounded Theory beleuchtet.

<bold>Background:</bold> Evaluation of multiple endpoints in clinical trials is often limited by endpoints of lower clinical importance. Win ratios are used to categorize multiple outcomes by clinical importance. <bold>Aims & Objectives:</bold> This post hoc analysis uses win ratios to compare dupilumab efficacy vs placebo in BOREAS and NOTUS. <bold>Methods:</bold> BOREAS (<ext-link>NCT03930732</ext-link>) and NOTUS (<ext-link>NCT04456673</ext-link>), phase 3 randomized, double-blind, placebo-controlled trials, enrolled patients with COPD, and type 2 inflammation (screening blood eosinophil count ≥300 cells/µL) on LABA/LAMA/ICS. Patients received add-on dupilumab 300 mg or placebo q2w for 52 weeks. Win ratio analysis compared each patient on dupilumab to each patient on placebo for time-to-event and occurrence-of-event. Endpoints were ordered based on clinical priority. <bold>Results:</bold> Evaluation of the pooled population (dupilumab n=938; placebo n=934) across multiple endpoints for occurrence-of-event showed patients receiving dupilumab being 32% more likely to avoid hierarchically important clinical deterioration compared with placebo (1.32; 95% CI 1.17, 1.49]) (<bold>Figure</bold>). Similar findings were seen for the time-to-event endpoints (win ratio 1.26; 95% CI 1.13, 1.40). <bold>Conclusions:</bold> Dupilumab vs placebo increased the odds of avoiding hierarchically worse clinical outcomes by 32% in patients with COPD and type 2 inflammation. <fig><object-id>erj;66/suppl_69/PA4572/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>

<bold>Rationale:</bold> Small airway dysfunction (SAD) is a key COPD feature and may occur in tobacco-exposed adults with normal spirometry. <bold>Objective:</bold> To investigate the prevalence of oscillometry-defined SAD and its associations with airway structure, QoL, and comorbidities in tobacco-exposed adults. <bold>Methods:</bold> In a sub-cohort (n=1,628) nested within a lung cancer screening trial, we assessed airway disease using preBD-spirometry, oscillometry, and AI-powered CT. Impaired airflow included airflow obstruction (AFO) and PRISm. Subjects with preserved airflow (PA), defined as FEV1 and FEV1/FVC > LLN, were further stratified as PA with SAD (PA-SAD) or normal lung function. SAD was defined as R5-19 or AX > ULN. CT biomarkers included airway wall thickness (AWT-Pi10), lumen diameter, branch count, and emphysema. QoL was measured using EQ-5D-5L. <bold>Results:</bold> The overall prevalence of SAD was 39%. SAD was present in 26% of subjects with PA and in 60% of those with impaired airflow. The frequency of AFO, PRISm, and PA-SAD was 21%, 15%, and 16%, respectively. PA-SAD subjects had lower EQ-5D-5L, greater AWT-Pi10, narrower lumen, fewer branches, and higher metabolic and CVD rates than those with normal lung function (all p <0.01). However, they had minimal emphysema and higher branch count than AFO. SAD in AFO or PRISm was linked to greater structural changes and more frequent CVD. SAD was associated with CVD (OR: 1.91, 95% CI: 1.55-2.36), even after adjusting for confounders and metabolic disease. <bold>Conclusion:</bold> SAD is common in tobacco-exposed adults and associated with airway remodeling, impaired QoL, and increased CVD risk, even in PA. PA-SAD is a distinct from AFO by preserved airway count and minimal emphysema.

<bold>Background:</bold> Dupilumab, a fully human monoclonal antibody that blocks the IL-4/13 receptor, showed efficacy in patients with moderate-to-severe asthma and type 2 inflammation (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥20 ppb) in the QUEST trial (<ext-link>NCT02414854</ext-link>). <bold>Aims and Objectives:</bold> To assess type 2 inflammation biomarkers in patients from QUEST stratified by baseline inhaled corticosteroid (ICS) dose (low/medium vs high) and clinical remission status after dupilumab treatment. <bold>Methods:</bold> Patients received either add-on dupilumab 200/300 mg or volume-matched placebo q2w for 52 weeks. Clinical remission was defined as meeting the following criteria at Week 52: no exacerbations or oral corticosteroid use during study period, stable (pre- or post-bronchodilator FEV₁ decrease <5% from baseline) or improved lung function, and 5-item Asthma Control Questionnaire score <1.5. <bold>Results:</bold> Dupilumab vs placebo significantly decreased blood eosinophils in patients without clinical remission on low/medium-dose ICS at baseline (<italic>P</italic>=0.0247); no differences were seen in the other subgroups (<bold>Table</bold>). FeNO was significantly reduced in all patients who received dupilumab vs placebo (P<0.0001 for all subgroups) (<bold>Table</bold>). <bold>Conclusions:</bold> Dupilumab reduced FeNO regardless of baseline ICS dose or remission status; blood eosinophil count remained similar across groups. <fig><object-id>erj;66/suppl_69/PA1500/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>

<bold>Introduction:</bold> Peripheral muscle dysfunction has important clinical implications for people with chronic obstructive pulmonary disease (COPD). However, its development over time remain unclear. <bold>Objectives:</bold> To evaluate long-term changes in peripheral muscle function and assess the relation with exacerbations history in people with COPD. <bold>Methods:</bold> This is a secondary analysis of the Mobilise-D observational study. Participants with COPD were recruited at 7 sites across Europe with visits spaced 6 months apart. Peripheral muscle function was assessed yearly as the maximal isometric quadriceps (QMVC) & handgrip strength (HGS), and the time of the 5-repetition sit-to-stand test (5STS). Patients were classified based on their baseline GOLD stage A-B-E. <bold>Results:</bold> A total of 601 people completed the baseline assessment (37% women, mean±SD age=68±8 years and percentage of predicted FEV₁=54±20%). After adjusting for age and sex, QMVC (n=431) and HGS (n=464) declined respectively by 3.3±2.2% and 2.8±1.3% (both p<0.05) after one year compared to baseline. After two years, QMVC and HGS showed an additional decrease of 0.8±2.4% and 2.2±1.3% (both p<0.001), respectively. In contrast, 5STS (n=447) did not show significant changes between visits (14.6±0.2s; 14.7±0.3s; 14.5±0.3s). A small subgroup (n=41) of participants with frequent exacerbations had 13.5% lower baseline QMVC and 21% slower 5STS (both p<0.05) compared to others. However, further comparison between subgroups lacked power due to participants withdrawals. <bold>Conclusions:</bold> Peripheral muscle strength declines over two-years in COPD, but the 5STS was not sensitive to long-term changes. GOLD-E patients had lower limb muscle function but many dropped out of subsequent assessments.

<bold>Background</bold> Neutrophil elastase (NE) is activated by CatC, and increased airway NE activity is linked to poor outcomes in people with bronchiectasis (BE). We report the effects of the CatC inhibitor BI 1291583 on NE activity in people with BE in the AIRLEAF^® study. <bold>Methods</bold> AIRLEAF^® enrolled 322 adults with BE, examining once-daily BI 1291583 administration (1/2.5/5 mg doses) vs placebo up to 48 weeks. Participants had a history of pulmonary exacerbations (PExs) requiring antibiotic treatment in the year prior to screening (≥2 PExs or 1 PEx with St. George’s Respiratory Questionnaire [SGRQ] Symptoms score >40). Free sputum NE activity was measured at baseline and over time, using a fluorescent substrate-based enzymatic activity assay. Descriptive statistics for absolute NE activity over time were calculated; change from baseline in sputum NE activity and corresponding NE inhibition were estimated using a mixed model with repeated measures. <bold>Results</bold> At baseline, mean sputum NE activity was similar across all treatment groups, with no differences in participants who had ≥2 PExs or 1 PEx with SGRQ Symptoms score >40. Higher baseline NE activity (p<0.01) was observed in those positive for <italic>P. aeruginosa</italic> and those from East Asia. At Weeks 12 and 24, placebo-corrected-mean-adjusted NE inhibition was 24.1% and 44.9%, 78.4% and 78.9%, and 80.2% and 90.8% in the BI 1291583 1 mg, 2.5 mg, and 5 mg groups, respectively. <bold>Conclusions</bold> Dose-dependent NE inhibition was seen with BI 1291583. However, the 2.5 mg dose achieved the greatest clinical efficacy in AIRLEAF^®;¹ several mechanisms may be responsible for this. ¹Chalmers JD, <italic>et al.</italic> Eur Respir J 2025;65:2401551