Background:Macrolide antibiotics have immunomodulatory activity and when taken chronically reduce exacerbations of COPD. However, chronic use can cause bacterial resistance. EP395 (glasmacinal), a novel macrolide, is being developed as a treatment to reduce exacerbations of COPD without inducing antimicrobial resistance. Methods:In this double-blind, placebo-controlled, phase 2a trial (NCT05572333), patients (≥45 years old, diagnosed with COPD for ≥2 years and stable on at least one maintenance inhaled therapy) were randomised (2:1) to EP395 or placebo daily for 12 weeks. The primary objective was safety, with key secondary objectives assessing pharmacodynamic effects of EP395. Results:A total of 61 patients were randomised (42 EP395, 19 placebo). A 12-week course of EP395 was well tolerated: no serious adverse events were considered related to EP395, and adverse events occurred in similar proportions in both groups (64.3% EP395, 63.2% placebo). Four patients were withdrawn due to adverse events (three EP395, one placebo). Sputum neutrophil elastase and myeloperoxidase, mediators of neutrophil activation, were reduced with EP395 (treatment difference (log scale): neutrophil elastase -0.415 ng·mL-1, 95% CI -0.787 to -0.043 ng·mL-1, p=0.030; myeloperoxidase -0.282 ng·mL-1, 95% CI -0.640 to 0.076 ng·mL-1, p=0.119). Relative changes in neutrophil elastase and myeloperoxidase from baseline with EP395 were 66% and 75%, respectively, of those observed with placebo. Exploratory 16S rRNA sequencing of sputum showed EP395 had no detectable effect on the lung microbiome, including the proportion of pathogenic Proteobacteria species. Conclusion:In patients with stable COPD, EP395 for 12 weeks was well tolerated, demonstrated selective anti-inflammatory activity and had no detectable effect on the lung microbiome.

COPD remains a leading cause of morbidity and mortality, with outcomes stagnating relative to other long-term conditions. Current diagnostic pathways rely on spirometry, which detects airflow obstruction only after irreversible small airway and parenchymal damage has accrued, whereas pathogenic processes begin decades earlier. This review examines how understanding early pathogenic processes could inform alternative approaches to diagnosis and treatment. We highlight the contribution of developmental and environmental exposures, genetic susceptibility and epigenetic modification to disease initiation. We outline how these convergent mechanisms drive structural and functional abnormalities undetectable by conventional diagnostics but measurable with novel techniques. Advanced imaging-parametric response mapping, hyperpolarised gas magnetic resonance imaging and computed tomography-based vascular metrics-can detect emphysema, small airways disease and vascular pruning before spirometric thresholds are reached. Physiological tools including forced oscillation techniques and capnography show promise for early detection in primary care and may be scalable, affordable alternatives to spirometry. Biofluid-based platforms, including exhaled breath analysis, extracellular matrix neo-epitopes and blood-based inflammatory signatures, offer noninvasive phenotyping and risk stratification, though require validation and pathway integration. We argue for a shift from a spirometry-centric model to a multidimensional diagnostic framework integrating imaging, molecular, physiological and biomarker data. Recent longitudinal evidence, including diagnostic schemas combining imaging with symptom burden, indicates that such approaches identify high-risk individuals missed by spirometry alone. Proactive COPD detection in its earliest stages is therefore an essential step to altering disease trajectory and improving patient outcomes, and it is time our community looks beyond spirometry to deliver this.

COVID-19 continues to present ongoing global health challenges driven by diverse immune responses and heterogeneous clinical outcomes. The ACCORD trial evaluated 3 investigational treatments-bemcentinib, tozorakimab, and zilucoplan-in patients hospitalized with COVID-19, each of which has demonstrated clinical efficacy. To better understand their molecular mechanisms, we conducted a mechanistic follow-up study, integrating transcriptomic and clinical data from 65 patients and applying cellular deconvolution, differential expression, coexpression, and pathway enrichment analyses to uncover treatment-specific immune responses. Each therapy induced transcriptional shifts and modulated distinct immune pathways implicated in severe disease. Bemcentinib primarily modulated myeloid cell populations and inflammatory signalling; zilucoplan enhanced B-cell signalling and lymphocyte-associated pathways; and tozorakimab exerted broad immune and cellular responses across immune cell types. Co-expression analysis revealed gene networks associated with clinical improvement, each driven by distinct treatment-specific hub genes, indicating diverse regulatory mechanisms across treatments. Improved outcomes correlated with gene expression shifts in 4 key immunological pathways: B-cell signalling, antiviral defense, innate inflammation, and platelet/coagulation activity. In contrast, nonresponders had persistent dysregulation of 1 or more of these gene signatures. Our findings define molecular signatures of treatment response and failure in COVID-19, providing mechanistic insight into how distinct therapies modulate the immune system. These insights support the need for adaptive precision medicine approaches tailored to individual, evolving immune trajectories. Moreover, the immunological mechanisms targeted by these repurposed immunomodulatory therapies may inform treatment strategies across a broader spectrum of immune-mediated diseases beyond COVID-19.

Extracellular matrix (ECM) dysregulation is a key process in the pathology of COPD. However, an inability to characterise ECM remodelling in vivo has limited our understanding of its relationship with functional decline and disease mechanisms. We aimed to quantify in vivo ECM remodelling using probe-based confocal laser endomicroscopy (pCLE) and determine associations with physiological, radiological, histological, and serological markers of COPD. 16 patients with COPD and 20 controls underwent pulmonary function testing, CT imaging, bronchoscopy, and pCLE. Alveolar morphometrics and elastin linearity scores (ELS) were quantified using a novel automated algorithm. Bronchial biopsies were analysed for elastin and collagen content. Serum biomarkers of elastin and collagen turnover were measured in a combined cohort of 54 COPD patients and 61 controls. Compared with never-smoking controls, current smokers without airflow obstruction demonstrated larger alveolar dimensions including increased alveolar opening area (AOA) (46,282 ± 16,805 vs. 33,549 ± 2,595 μm², p = 0.003). Alveolar dimensions were further increased in COPD, with larger AOA (56,468 ± 11,079 vs. 46,282 ± 16,805 μm², p < 0.001) compared with all controls. COPD was also associated with greater elastin fibre disorganisation (ELS 54.9 ± 6.0 vs. 47.5 ± 10.7, p = 0.032). Across the cohort, ELS correlated with airflow obstruction and surrogate markers of small airway disease. Airway collagen content was increased in COPD and correlated with ELS (r = 0.665, p = 0.005). COPD was associated with higher circulating elastin and collagen degradation biomarkers, including ELP-3, C1M, C6M, and EL-CG (all p < 0.05), which correlated with pCLE morphometrics. Using an innovative lung imaging technique, we provide the first objective quantification of in vivo airway elastic fibre disorganisation and demonstrate quantifiable lung microstructural changes that may precede abnormalities detected by established techniques. These quantifiable signals relate to biomarkers of lung ECM turnover, offering a new platform for early disease detection and mechanistic understanding of COPD.

Background Neutrophilic airway inflammation is associated with disease severity and exacerbation frequency in bronchiectasis. Neutrophil protease inhibition significantly reduced exacerbation rates in phase II and III trials in bronchiectasis, highlighting this disease feature as an important therapeutic target. Additional neutrophil targeting therapeutics are needed to reduce the burden of the disease. Herein, we describe the protocol for the AIR-NET trial, the first randomised, open-label, multifactorial, multicentre, adaptive platform trial for people with bronchiectasis, run via the EMBARC (European Multicentre Bronchiectasis Audit and Research Collaboration) network, to investigate the safety and efficacy of several repurposed anti-inflammatory treatments. Methods and analysis Participants with bronchiectasis confirmed by computed tomography, daily sputum production and evidence of active airway neutrophilic inflammation (based on a positive lateral flow test for neutrophil elastase (NE) activity), across 10 sites in the UK, will be randomised to one of several repurposed drugs with published evidence of effects on neutrophilic inflammation and acceptable safety profile (oral dose: disulfiram 400 mg once daily; dipyridamole 200 mg twice daily; doxycycline 100 mg once daily; n=42 per arm) or usual care, according to arm-specific eligibility criteria, and treated for 28 days. New arms will be added to the trial through an adaptive design. The primary end-point is change from baseline in sputum NE activity (a validated biomarker and surrogate of exacerbation risk) at day 28. Key secondary endpoints include time-to-first exacerbation, quality of life questionnaires, neutrophil function and safety. Summary AIR-NET will establish a multi-centre network with integrated clinical and translational capabilities for the investigation of therapies in bronchiectasis aiming to identify key anti-inflammatory mechanisms and effective re-purposed treatments.

Introduction Quantitative assessment of emphysema, gas trapping and airway wall thickness on CT correlates with chronic obstructive pulmonary disease (COPD) disease severity and exacerbation risk. In stable COPD, airway wall thickness is associated with prior myocardial infarction. Cardiac disease is often undiagnosed in COPD, and the risk of cardiac events following hospitalised exacerbations of COPD (ECOPD) is high. CT scans during hospitalised exacerbations may help clinicians identify patients with heart disease.Methods As part of the SCATECOPD study (IRAS 277817), patients with ECOPD underwent a detailed cardiac assessment encompassing an ECG, echocardiogram, CT coronary calcium score, and inspiratory and expiratory CT chest. Expiratory gas trapping (Exp%856), emphysema (Insp%950) and airway wall thickness (Pi10) were compared with clinical and cardiac data.Results 56 participants were recruited: 33 (58.9%) were female, with a mean (SD) age of 72.5 (6.5) years. The mean forced expiratory volume in 1 s was 50.6% predicted (SD 19.2), consistent with moderate-to-severe COPD.Cardiac assessment identified moderate–severe left ventricular systolic dysfunction (LVSD) in 10.7%, heart failure without moderate–severe LVSD in 25.0% and right heart failure in 17.9%; these were newly diagnosed in 8.9%, 23.2% and 14.3%, respectively. Severe coronary artery disease was found in 43.1%. Airway wall thickness was significantly negatively correlated with left ventricular ejection fraction. Emphysema and gas trapping correlated with spirometric airflow obstruction and showed weaker associations with cardiac dysfunction.Conclusion Quantitative CT performed during ECOPD may offer opportunistic insights into cardiac health, particularly through Pi10. Further research is warranted to evaluate its utility as a screening tool in COPD admissions.

Abstract Background Asthma and COPD are long-term respiratory conditions that require active self-management to improve quality of life and reduce health care burdens. Digital health interventions (DHIs) are increasingly used to support behavior change, symptom monitoring, and medication adherence, offering new opportunities for personalized care and real-time feedback. Understanding patient engagement with digital tools is essential for optimizing intervention design, improving clinical outcomes, and addressing potential inequalities in access and effectiveness. This review is informed by a novel conceptual foundation combining the Analyzing and Measuring Usage and Engagement Data (AMUsED) framework (for the analysis of digital engagement) and layered vulnerabilities (an intersectional approach). Together, these frameworks enable a more nuanced examination of how engagement is shaped by user behavior and structural factors. Objective This study aims to evaluate how diverse patient groups engage with digital self-management interventions for asthma and COPD by examining the reporting of demographic characteristics, outcome measures, and usage data. The review also explores how these data types are combined in analysis, how authors interpret results, and the extent to which current reporting practices support equitable and meaningful evaluation of digital interventions. Methods A 2-phase study selection process was applied. First, empirical studies were systematically identified if they reported demographic characteristics, clinical outcome measures, and usage data. Second, reported usage measures were reviewed to identify measures that were meaningful across interventions, defined as numerically comparable measures without subjective user input. Descriptive thematic analysis was conducted to map key concepts across studies, and patient and public involvement sessions were used to contextualize findings and inform interpretation of the results. Results Twenty-seven studies met the inclusion criteria. Four comparable usage measures were identified, with studies reporting a mean of 2.15 (SD 0.74) usage measures. Thirteen (48.1%) studies reported 2 or more types of outcome measures (disease-specific self-reported, physiological, or other self-reported). Age, sex, and disease severity were reported in all studies, but characteristics linked to health inequalities were underreported; for example, 8 (29.6%) studies reported ethnicity and 2 (7.4%) reported socioeconomic status. Seventeen (62.9%) studies did not combine demographic, outcome, and usage data in analysis. Thematic analysis identified three cross-cutting issues: (1) limited characterization of engagement patterns, (2) dominance of single-trait demographic analysis, and (3) inconsistent conceptualization of health care support. Conclusions This review is the first to integrate the AMUsED framework with layered vulnerabilities and to map how demographic, outcome, and usage data are reported and combined in digital self-management research. By identifying structural gaps in reporting and analysis, the review provides recommendations for more equitable and analytically rigorous digital health research. Strengthening reporting practices, particularly through richer usage data and intersectional analyses, will support clinicians, developers, and policymakers in tailoring digital self-management tools to diverse patient populations and improving real-world effectiveness.

Introduction:Disease-modifying treatments such as monoclonal antibodies can be highly effective in chronic inflammatory diseases such as COPD, but often fail in clinical trials due to heterogeneity of inflammation and imperfect tools to stratify patients to select optimal therapeutic approaches. Molecular imaging provides the potential to transform precision medicine in this field. Methods:We developed and tested a novel molecular imaging platform using therapeutic monoclonal antibodies labelled with SPECT-CT detectable markers to quantify in vivo tumour necrosis factor (TNF) involved in chronic lung inflammation in humans. We undertook a proof-of-concept clinical study involving participants with COPD and healthy controls. Participants underwent SPECT-CT imaging at 6- and 24 h following injection of 99mTc-anti-TNF. Segmentation of lung regions and 99mTc-anti-TNF activity quantification was undertaken using novel semi-automated and AI-driven approaches. Results:A significant increase in normalised activity, representing increased TNF inflammatory activity, was seen between the two time-points in the COPD group (mean±sd: 64.88±31.04%, p=0.029) and not in healthy controls (35.38±34.33%, p=0.110). However, analysis at a single time-point revealed higher normalised activity in the healthy group. We demonstrated that pulmonary blood vessel density and degree of emphysema were strongly correlated with this activity signal and identified as confounding factors, highlighting the need to address differences in target-organ characteristics in COPD. Experimental methods to adjust for these factors were developed for organ-specific signal quantification. Conclusions:We report novel analysis techniques for molecular imaging of the human lung, presenting a platform which provides new insights into complex inflammatory disease and future precision medicine approaches.

Objectives Patient information sheets (PISs) and informed consent forms (ICFs) are essential tools to communicate and document informed consent for clinical trial participation. These documents need to be easily understandable, especially when used to take informed consent from acutely unwell patients. Health literacy guidance recommends written information should be at a level between reading ages 9–11. We aimed to assess the readability and complexity of PISs/ICFs used for clinical trials of acute therapies during the COVID-19 pandemic.Design Retrospective document analysis.Setting PISs/ICFs used in trials involving pharmaceutical interventions recruiting hospitalised patients with COVID-19 during the first year of the pandemic were sourced from hospitals across the UK.Primary and secondary outcome measures PISs/ICFs were assessed for length, approximate reading time and subsection content. Readability and language complexity were assessed using Flesch-Kincaid Grade Level (FKGL) (range 1–18; higher is more complex), Gunning-Fog (GFOG) (range 1–20; higher is more complex) and Flesch Reading Ease Score (FRES) (range 0–100; below 60 is ‘difficult’ for comprehension).Results 13 documents were analysed with a median length of 5139 words (range 1559–7026), equating to a median reading time of 21.4 min (range 6.5–29.3 min) at 240 words per minute. Median FKGL was 9.8 (9.1–10.8), GFOG 11.8 (10.4–13) and FRES was 54.6 (47.0–58.3). All documents were classified as ‘difficult’ for comprehension and had a reading age of 14 years old or higher.Conclusions All PISs/ICFs analysed contained literary complexity beyond both recommendations and the reading level of many in the UK population. Researchers should seek to improve communications to improve trial volunteer comprehension and recruitment.

Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by airway obstruction and inflammation. Non-typeable Haemophilus influenzae (NTHi) lung infections are common in COPD, promoting frequent exacerbations and accelerated lung function decline. The relationship with immune responses and NTHi are poorly understood. Herein, we comprehensively characterized the respiratory microbiome and mycobiome of patients while investigating microbial dynamics and host immune changes attributable to NTHi killing activity. Mild-to-moderate COPD patients encompassing frequent and infrequent exacerbators and healthy volunteers (HV) were enrolled. Microbial composition, proteomics and NTHi killing activity was analyzed using bronchoalveolar lavage fluid (BALF). In addition, antigen–antibody titers in sera to COPD pathogens were determined using a multiplex assay. Differential abundance analysis revealed an enrichment of Actinobacteria and Bacteroidetes in the BALF of COPD and HV subjects respectively. Significant differences in the IgA titer response were observed against NTHi antigens in COPD vs. HV. Notably, there was also significantly greater killing activity against NTHi in BALF from COPD vs. HV subjects (OR = 5.64; 95

INTRODUCTION:Hospital attendances due to respiratory infection peak in winter, contributing to pressures within acute services. We assessed the prevalence of suspected respiratory infection within acute medical admissions during winter and evaluated performance against recommendations for initial assessment. METHODS:Data were collected through the Society for Acute Medicine (SAM) Benchmarking Audit, comprising a hospital-level survey and 24-hour patient-level data collection for unplanned acute medical attendances on 22 February 2024. Performance metrics assessed included those from the SAM's clinical quality indicators (CQI) for medical admissions, and British Thoracic Society (BTS) guidelines for community acquired pneumonia. RESULTS:Data were available for 4390 patients at 76 hospitals. Suspected respiratory infections accounted for 22.8% of all unplanned medical attendances; these patients were older (age ≥70 years: 58.2% vs 44.7%, p<0.001) and had higher National Early Warning Score 2 (NEWS2) scores (NEWS2 ≥3: 63.8% vs 23.8%, p<0.001) than those without respiratory infection; they were more likely to be assessed in the emergency department (80.8% vs 63.7%, p<0.001), and had lower rates of discharge without overnight admission (14.9% vs 35.9%, p<0.001). 71.0% of patients underwent a chest X-ray within 4 hours of arrival; 27.0% were reported within 12 hours. Antibiotics were administered ≥4 hours from arrival in 32.9%. Performance against these indicators varied between hospitals. Nine hospitals (12.7%) had a separate respiratory admission service; this was not associated with improved performance against SAM CQIs or BTS guidance. CONCLUSION:Respiratory infections contribute significantly to acute medical attendances via the emergency department. There remains significant scope to improve key steps in initial assessment and management.

Background:Inhaled nebulised unfractionated heparin (UFH) has a strong rationale as a treatment for severe respiratory infections, including COVID-19, due to its antiviral, anti-inflammatory, and anti-coagulant properties, which may prevent viral entry, lung injury progression, and pulmonary thrombosis. We aimed to evaluate the efficacy of inhaled nebulised UFH to prevent intubation or death in hospitalised COVID-19 patients. Methods:In this prospective, a priori set up and defined, collaborative meta-trial of six randomised clinical studies, adult hospitalised but not intubated COVID-19 patients were randomly assigned to inhaled nebulised UFH on top of standard of care or standard of care alone. The dose and method of nebulisation was specific to each study. The primary outcome was intubation or death, assessed at the longest follow-up after randomisation. The meta-trial was registered at ClinicalTrials.gov ID NCT04635241. Findings:Between June 2020 and December 2022, 478 patients from 10 hospitals in six countries (Argentina, Brazil, Egypt, Indonesia, Ireland and USA) were enrolled. The odds ratio (OR) for intubation or death was 0.43 (0.26-0.73, p = 0.001); the OR for in-hospital mortality was 0.26 (0.13-0.54, p < 0.001) with inhaled nebulised UFH compared to standard of care alone. There were no safety issues reported, including no instances of pulmonary or systemic bleeding in the nebulised UFH group. Interpretation:In patients hospitalised but not intubated for COVID-19, inhaled nebulised UFH prevented intubation and reduced mortality, without causing pulmonary or systemic bleeding. Funding:The Sponsor of the meta-trial was the INHALE-HEP Collaborative Research Group (CRG); investigators of each contributing study were members of the INHALE-HEP CRG. No funding was received for the meta-trial. The Brazilian study was funded by The J.R. Moulton Charity Trust. The Irish study was funded by a Grant from Science Foundation Ireland to Cúram, the SFI's Centre for Research in Medical Devices (Research Centre Award Reference: 13/RC/2073).

The role of eosinophils in COPD and their utility as biomarkers for cytokine targeting monoclonal therapies remains unclear. We investigated the distribution of eosinophils across different tissue compartments in COPD and analysed gene expression to understand the possible mechanistic drivers of eosinophilic inflammation in COPD. Blood and BAL from ex-smoking volunteers with mild/moderate COPD (n = 31) and healthy ex-smoking controls (n = 20), and bronchial biopsy tissue in a subcohort (n = 19 and n = 8, respectively) was analysed. Differentially-expressed genes (DEGs) were characterised using RNASeq. Proteomic analysis of BAL was conducted using mass-spectrometry. COPD subjects had more eosinophils in blood and lung tissue compared to controls, with increased eosinophil protein CLC/Galectin-10 in BAL. However, peripheral blood eosinophil counts related poorly to numbers in lung tissue (rho = -0.09192, p = 0.3541) or proportions in BAL (rho = 0.01762, p = 0.4632). Tissue IL-5Rα expression was higher in frequent exacerbators and related to tissue eosinophils, but not peripheral blood eosinophils. Higher blood eosinophils were associated with DEGs that differed with compartment. Higher tissue eosinophil levels were associated with IL-13-induced DEGs including POSTN in bronchial brushes and CCL26 in bronchial biopsies. Gene-set enrichment analysis on data from brushings revealed significant enrichment of IL-4/IL-13, but not IL-5, pathways associated with eosinophil presence. Eosinophilic lung inflammation is related to exacerbation frequency, but lung eosinophils are not predicted by blood eosinophil counts in COPD. Our data suggest IL-13-mediated pathways may be responsible for the presence of tissue eosinophils in COPD. Further work to establish more predictive biomarkers of lung eosinophil biology are required to unlock this axis to optimised treatment.

Adherence to self-management plans leads to improved health outcomes among COPD patients. This study investigated an existing digital health intervention, myCOPD, available via the NHS to support self-management. This is the first study that combines the analysis of patient and professional perspectives regarding the delivery and engagement of a digital self-management intervention for COPD. The aim was to develop an understanding of perceived barriers to and facilitators of delivery and engagement of myCOPD. This study was conducted across two clinical settings: community pulmonary rehabilitation and hospital discharge. Participants completed qualitative semi-structured interviews. A reflexive approach to abductive thematic analysis was adopted using NVivo 14 for initial coding and the development of themes. This study suggests that patient characteristics (multimorbidity, perceived digital ability, and socioeconomic status) potentially influence engagement. The study associated healthcare settings with passive and proactive approaches to delivering myCOPD. Healthcare settings and styles of delivery, in turn, have the potential to influence types of engagement among patients via single-aspect and multifaceted engagement. Descriptions of these two types of engagement were associated with two types of benefits (targeted behaviour change and wider lifestyle adjustments). These factors seemingly affect perceptions of barriers to and facilitators of engagement with myCOPD. This study suggests that myCOPD can provide a range of benefits that meet recommendations of the care pathway for COPD patients. The consideration of patient characteristics may improve engagement with, and evaluation of, myCOPD, particularly for those negotiating multimorbidity. The intervention content was consistent at both sites, and the demographic characteristics were ostensibly similar; consequently, the healthcare setting and delivery site are highlighted as important factors for facilitating engagement. Further integration and sustained engagement may develop from considering how and when specific frontline teams are most able to support delivery and engagement and if any additional resources are needed. N/A