Rationale: In the WILLOW (Assessment of INS1007 in Participants with Non-Cystic Fibrosis Bronchiectasis) trial, the dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease activity and prolonged time to first exacerbation in patients with bronchiectasis. Objectives: We hypothesized that by reducing neutrophil serine proteases, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade. Methods: The WILLOW trial was a phase 2 randomized trial of brensocatib (10 and 25 mg) versus placebo. Sputum was collected at baseline, Week 4, Week 24 (end of treatment), and Week 28 (4 wk after treatment). The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3 were measured using ELISA, MUC5AC (mucin-5AC) using liquid chromatography-mass spectrometry, myeloperoxidase using immunoassay, and 45 inflammatory cytokines using the Olink Target 48 assay. The relationship between these markers and sputum neutrophil elastase was validated using the European Multicentre Bronchiectasis Audit and Research Collaboration BRIDGE (Bronchiectasis Research Involving Databases, Genomics and Endotyping) bronchiectasis cohort. Measurements and Main Results: Of 82 patients randomized to 10 mg brensocatib, 87 to 25 mg brensocatib, and 87 to placebo, 71, 71, and 73 with sputum available for at least two time points were included. SLPI and α-defensin-3 increased significantly with brensocatib compared with placebo at both Week 4 and Week 24. MUC5AC was reduced in response to treatment. Subanalysis showed that this was primarily among patients with high baseline neutrophil elastase. Myeloperoxidase did not change. Fifteen cytokines and chemokines increased significantly compared with placebo at Week 4 or 28. CXCL10, CCL8, CCL7, CCL3, and IL-6 increased at both doses at both time points. In the BRIDGE cohort, neutrophil elastase correlated inversely with SLPI, CCL13, IL-7, CCL11, CXCL10, CCL8, and CCL7, all markers increased by brensocatib. Conclusions: Brensocatib exerts broad antiinflammatory effects beyond its known effects on serine proteases. Clinical trial registered with www.clinicaltrials.gov (NCT03218917).

Bronchiectasis is a heterogeneous disease with multiple aetiologies and diverse clinical features. There is a general consensus that optimal treatment requires precision medicine approaches focused on specific treatable disease characteristics, known as treatable traits. Identifying subtypes of conditions with distinct underlying biology (endotypes) depends on the identification of biomarkers that are associated with disease features, prognosis or treatment response and which can be applied in clinical practice. Bronchiectasis is a disease characterised by inflammation, infection, structural lung damage and impaired mucociliary clearance. Increasingly there are available methods to measure each of these components of the disease, revealing heterogeneous inflammatory profiles, microbiota, radiology and mucus and epithelial biology in patients with bronchiectasis. Using emerging biomarkers and omics technologies to guide treatment in bronchiectasis is a promising field of research. Here we review the most recent data on biomarkers in bronchiectasis.

Bronchiectasis presents a significant challenge due to its rising prevalence, associated economic burden and clinical heterogeneity. This review synthesises contemporary understanding and literature of bronchiectasis exacerbations, addressing the transition from stable state to exacerbations, underlining the importance of early and precise recognition, rigorous severity assessment, prompt treatment, and prevention measures, as well as emphasising the need for strategies to assess and improve early and long-term patient outcomes. The review highlights the interplay between stable state phases and exacerbations in bronchiectasis, introducing the concept of "exogenous and endogenous changes in airways homeostasis" and the "adapted island model" with a particular focus on "frequent exacerbators", a group of patients associated with specific clinical characteristics and worse outcomes. The pathophysiology of exacerbations is explored through the lens of microbial and nonmicrobial triggers and the presence and the activity of comorbidities, elaborating on the impact of both exogenous insults, such as infections and pollution, and endogenous factors such as inflammatory endotypes. Finally, the review proposes a multidisciplinary approach to care, integrating advancements in precision medicine and biomarker research, paving the way for tailored treatments that challenge the traditional antibiotic paradigm.

Pneumonia is a clinical syndrome characterised by fever, cough and alveolar infiltration of purulent fluid, caused by infection with a microbial pathogen. It can be caused by infections with bacteria, viruses or fungi, but a causative organism is identified in less than half of cases. The most common type of pneumonia is community-acquired pneumonia, which is caused by infections acquired outside the hospital.Current guidelines for pneumonia diagnosis require imaging to confirm the clinical suspicion of pneumonia. Thus, imaging plays an important role in both the diagnosis and management of pneumonia, with each modality having specific advantages and limitations. Chest radiographs are commonly used but have limitations in terms of sensitivity and specificity. Lung ultrasound shows high sensitivity and specificity. Computed tomography scans offer higher diagnostic accuracy but involve higher radiation doses. Radiological patterns, including lobar, lobular and interstitial pneumonia, provide valuable insights into causative pathogens and treatment decisions. Understanding these radiological patterns is crucial for accurate diagnosis. In this review, we will summarise the most important aspects pertaining to the role of imaging in pneumonia and will highlight the imaging characteristics of the most common causative organisms.

Rationale: The dipeptidyl peptidase-1 (DPP1) inhibitor brensocatib, prolonged the time to first exacerbation and reduced sputum neutrophil elastase (NE) activity in non-cystic fibrosis bronchiectasis (NCFBE) patients in the WILLOW (NCT03218917) trial. Secretory leukocyte peptidase inhibitor (SLPI) is an antimicrobial and anti-inflammatory host defence peptide associated with lower disease severity in NCFBE. Since NE cleaves and inactivates SLPI, we hypothesised that brensocatib treatment would increase sputum SLPI levels. Methods: WILLOW was a phase 2b, randomized, double-blind, placebo-controlled trial of brensocatib (10mg and 25mg). SLPI was measured by ELISA in sputum supernatant at baseline and day 169 (end of treatment). This analysis includes brensocatib 25mg vs placebo in subjects with paired samples at both timepoints. Results: The WILLOW trial enrolled 256 subjects. 53 and 54 subjects in 25mg brensocatib and placebo group, respectively, are included in this analysis. Median sputum SLPI levels were similar at baseline in brensocatib and placebo (50ng/ml, interquartile range 16 to 265 vs 59ng/ml IQR 22 to 237, p=0.8). After 24 weeks of treatment, the placebo group showed no statistically significant change (median 123ng/ml, p=0.3). However, median SLPI levels increased to 335ng/ml with brensocatib (p<0.001). The linear mixed effects model showed that brensocatib significantly increased SLPI levels (p=0.02). Conclusions: Brensocatib 25mg significantly increased sputum SLPI levels indicating downstream effects of protease inhibition on host defence. Funded by Insmed Inc.

Introduction: Proteinase-3 (PR3) is a neutrophil serine protease similar in structure and function to neutrophil elastase (NE), a marker of disease severity and exacerbation risk in Bronchiectasis. PR3 is a target of the recently developed DPP1 inhibitors in clinical trials for bronchiectasis. We investigated whether sputum PR3 activity relates to disease severity in patients with adult bronchiectasis. Methods: PR3 activity was measured using ProAxis Protease Tag immunoassay in sputum supernatant from clinically stable patients enrolled in a pan-European multicentre observational study (EMBARC-BRIDGE study). Clinical severity markers included lung function, exacerbations, microbial infection, BSI score and radiological parameters. Results: 181 patients were included for analysis. Mean age was 65 (± 16) and 49.1% were female. Median sputum PR3 concentration was 373 ng/ml (IQR 139-1433). Median PR3 concentration was significantly higher patients with chronic P.aeruginosa infection at 1253 (IQR 638-7275) versus 227 (IQR 117-1069) (p=0.002). Sputum purulence (p=0.002), presence of mucus plugging (p=0.006) and consolidation (p=0.033) on chest CT, previous hospitalisation for bronchiectasis (p=0.014) and FEV1 <80% predicted (p=0.02) were also associated with increased PR3. BSI score, MRC dyspnoea score and number of exacerbations in the previous year had no significant relationship with PR3. Sputum PR3 correlated with sputum NE (r 0.556, p<0.001), and IL-8 (r 0.743, P<0.001). Conclusion: Sputum PR3 is raised in association with clinical and radiological markers of active lung inflammation and infection. Activity and effects of PR3 in bronchiectasis warrants further investigation.

Introduction: Olfactomedin-4 (OLFM4) defines an anti-inflammatory subset of neutrophils and is present in only around 30% of peripheral blood neutrophils. Knockout of OLFM4 enhances responses to bacterial infection suggesting that OLFM4 suppresses host clearance of bacteria. We investigated airway levels of OLFM4 and their relationship to bacterial infection in bronchiectasis. Methods: Sputum OLFM4 concentration was measured by ELISA in sputum samples from the pan-European, multicentre EMBARC-BRIDGE study. Clinical severity markers included microbial infection, lung function, exacerbations, BSI score and radiological parameters. Results: 181 patients were included. Mean age was 65 (± 16) and 49.1% were female. Median OLFM4 concentration was 785ng/ml (IQR 115-6267). OLFM4 concentration correlated positively with sputum PR3 (r 0.715, p<0.001), NE (r 0.402, p<0.001) and IL-8 (r 0.665, p<0.001). P.aeruginosa infection (p=0.005), sputum purulence (p<0.001), and presence of mucus plugging on chest CT (p=0.024) were associated with higher sputum OLFM4. OLFM4 sputum levels were also higher in patients with a history of severe exacerbations, higher exacerbation frequency and lower FEV1 but differences were not statistically significant. Conclusion: Sputum OLFM4 correlates with markers of neutrophil activation and clinical severity in bronchiectasis.

The Greater Glasgow & Clyde NHS Trust Community Respiratory Response Team was established to manage patients with chronic respiratory disease at home during the COVID-19 pandemic. The team aimed to avert hospital admission while maximally utilising remote consultations. This observational study analysed outcomes of the triage pathway used, use of remote consultations, hospital admissions and mortality among patients managed by the team. Patients’ electronic health records were retrospectively reviewed. Rates of emergency department attendance, hospital admission and death within 28 days of referral were compared across triage pathways. Segmented linear regression was carried out for emergency admissions in Greater Glasgow and Clyde pre- and post- Community Respiratory Response Team implementation, using emergency admissions for chronic obstructive pulmonary disease in the rest of Scotland as control and adjusting for all-cause emergency admissions. The triage category correlated with hospital admission and death. The red pathway had the highest proportion attending the emergency department (21%), significantly higher than the amber and green pathways ( p = 0.03 and p = 0.004, respectively). The highest number of deaths were in the blue “end-of-life” pathway ( p < 0.001). 87% of interactions were undertaken remotely. Triage severity appropriately led to targeted home visits. No nosocomial COVID-19 infections occurred among patients or staff. The Community Respiratory Response Team was associated with a significant decrease in emergency admissions (RR = 0.96 for each additional month under the Poisson model) compared to the counterfactual if the service had not been in place, suggesting a benefit in reducing secondary care pressures. The Community Respiratory Response Team effectively managed patients with chronic respiratory disease in the community, with an associated reduction in secondary care pressures during the COVID-19 pandemic.

Introduction: The Community Respiratory Response Team (CRRT) was established to manage patients within Greater Glasgow & Clyde NHS Trust with chronic lung disease at home during the COVID-19 pandemic. Methods: Electronic health records of CRRT patients referred in May 2020 were retrospectively reviewed. The relationship between CRRT triage pathway and emergency department (ED) attendance, hospital admission and death within 28 days of referral was assessed. Results: Figure 1 shows CRRT patient triage and outcomes. Mean patient age was 69 years (median 71; IQR 62-79). 86% of consultations were conducted remotely; mean 4.4 consultations/patient; 35% received a home visit. No nosocomial COVID-19 infections occurred. Excepting the blue "end of life care" triage pathway, higher triage category was associated with higher rates of ED attendance, hospital admission and death. One death in the green triage group was due to a non-respiratory cause. Patients triaged red or amber were more likely to receive more than one consultation. In particular, patients with COPD in red and amber triage groups were more likely to have multiple CRRT consultations or a home visit. Conclusions: CRRT triage pathways effectively predicted risk of ED attendance, admission and death. Such pathways provide a safe and effective means to prioritise community multidisciplinary respiratory care.