ERJ Open Research

Mucociliary clearance is a key component of the pathophysiology of bronchiectasis but cilia function is poorly defined. This study aims to characterize nasal ciliary function in bronchiectasis and examine associations with disease severity, infection, inflammation and outcome. Adults with bronchiectasis and healthy volunteers were recruited to the international observational study EMBARC-BRIDGE. Individuals with a known diagnosis of Primary Ciliary Dyskinesia (PCD) were excluded. Nasal respiratory epithelium was sampled by brush biopsy. Ciliary function was assessed by high-speed video microscopy in primary samples and following re-differentiation in air-liquid interface (ALI) culture. Ciliary parameters (cilia length, angle, amplitude, clearance, frequency and ciliation) were quantified and compared with disease severity, microbiology, inflammation and future risk of exacerbations. 171 participants with bronchiectasis were recruited (54% female, age 68years (59-74)). Bronchiectasis nasal brushings showed greater epithelial disruption compared to healthy volunteers (p=0.0006). Six individuals with previously undiagnosed PCD were identified and excluded. In the remaining bronchiectasis cohort, ciliary beat frequency and length were similar to healthy controls. In contrast ciliary beat amplitude, angle, amplitude per second and clearance capacity, were significantly reduced (all p<0.001). These parameters were restored following ALI culture. Regenerated epithelia from bronchiectasis donors exhibited reduced ciliated area. Ciliary dysfunction was strongly associated with future risk of severe exacerbations. The upper airway epithelium is disrupted in bronchiectasis; ciliary movement is impaired and is associated with future risk of exacerbation. Ciliary dysmotility is reversible following ALI culture. This indicates that impaired ciliary function is secondary to the airway environment and therapeutically targetable.

Background Scalable, non invasive tools are critically needed to improve early lung cancer detection and optimize primary care referral pathways. We evaluated Inflammacheck, a point-of-care device utilizing exhaled breath condensate (EBC) H2O2 and physiological parameters with machine learning, for non-invasive lung cancer detection in a real-world screening population. Methods ExPeL study participants, from the UK Targeted Lung Health Check (TLHC) programme, included individuals with suspected lung cancer and low-risk ever-smoker controls. EBC was collected via Inflammacheck, measuring H2O2;, end-tidal CO2;, humidity, temperature, and exhalation flow rate. Multivariate analyses (PCA, LDA, Mahalanobis distance) assessed intrinsic group separation. SMOTE-balanced data trained supervised machine learning models (stacked and voting ensembles), which were then evaluated on held-out test sets. In parallel, untargeted LCMS metabolomics was performed to identify discriminatory molecular features. Results Analysing 34 participants with valid EBC data, 83% of cancer cases were early-stage (I or II), reflecting a screening population. Multivariate analysis clearly separated lung cancer and controls across PCA, LDA, and Mahalanobis mapping. The voting ensemble model achieved: Accuracy 85.7%, Sensitivity 80%, Specificity 100%, Precision (PPV) 100%, ROC AUC 0.90, MCC 0.73. Crucially, no false positives were identified. EBC variables revealed greater dispersion in cancer patients, reflecting physiological heterogeneity missed by univariate analysis. Untargeted metabolomics identified 2,132 features, with four key metabolites yielding an AUC of 0.969 for cancer discrimination. Discussion Inflammacheck effectively distinguishes early-stage lung cancer via a rapid, non-invasive breath test, findings which are highly relevant for primary care and screening triage, where non-specific symptoms and low prevalence pose challenges.

Background Recent guidelines differ in how fractional exhaled nitric oxide (FeNO) is used to diagnose school-age asthma, either as one of several tests with a cut-off at 25 ppb or as a single rule-in test at 35 ppb. Evidence on its diagnostic performance and clinical utility in subgroups remain limited. Methods We analysed data from 1,979 school-age children in the Swiss Paediatric Airway Cohort referred for suspected asthma. We investigated FeNO performance with diagnosis by paediatric pulmonologists as reference standard using receiver operating characteristics curves, selected cut-offs and simulated predictive values across different prevalence. Subgroup analyses considered allergic sensitisation with allergic rhinitis and current inhaled corticosteroid (ICS) use. Results In the overall cohort (asthma diagnosis 70%), FeNO showed poor discrimination for asthma (AUC 0.66; 95% CI 0.64-0.68) with an optimal cut-off at 22 ppb. At 25 and 35 ppb, sensitivity was low (43%, 95% CI 40-46; 31%, 95% CI 29-34) and specificity moderate to high (84%, 95% CI 77-84; 90%, 95% CI 87-92). Positive predictive value at 35 ppb was 88% and was 57% when simulated at a prevalence of 30%. FeNO had no diagnostic value in non-sensitised children and lower performance in sensitised children with allergic rhinitis than in those without (AUC 0.59 vs 0.68). Current ICS use did not influence performance. Conclusion FeNO has limited diagnostic performance as a stand-alone test for school-age asthma, and underlying asthma prevalence and allergic characteristics should be considered in the interpretation.

RationaleSevere SARS-CoV-2 infection induces disrupted oropharyngeal and gut microbiota during acute disease which may persist and contribute to the development of post-acute pulmonary sequelae. To date, it is unclear whether dysbiosis following severe disease is linked to long-term pulmonary function impairment. ObjectivesTo determine associations between oropharyngeal and gut microbiota composition with lung function after severe COVID-19. Methods16S and internal transcribed spacer (ITS) rRNA amplicon sequencing were performed on oropharyngeal (16S and ITS) and rectal (16S) swabs at 3-, 6- and 12-months post-hospitalisation from 83 subjects previously admitted to the ICU with severe COVID-19 (Swiss COVIDlung study, NCT04581135). Subjects underwent 1-3 follow-up visits during which lung function testing was performed to investigate associations with microbiota composition. Measurements and Main ResultsThe oropharyngeal microbiota of subjects having suffered from COVID-19-related-severe acute non-cardiogenic hypoxemic respiratory failure with bilateral lung infiltrates (AHRF-BLI) was characterized by decreased -diversity and the presence of differentially abundant taxa. Subjects who recovered in lung function (TLC, FVC, FEV1 and DLCO >Lower Limit of Normal) had a distinct oropharyngeal and gut microbiota composition compared to those whose lung function never recovered. Fungal analysis of oropharyngeal samples revealed the presence of three distinct clusters which were characterized by distinct lung-function associated bacterial-fungal co-occurrence. ConclusionsThis study provide first insights into the role of the airway and gut microbiota in the development of long-term pulmonary sequelae after severe SARS-CoV-2 infection, shedding the light on the potential of the microbiota for preventive and therapeutic strategies in severe COVID-19.

Smoking Cessation Efforts for Patients with Asthma and COPD IntroductionSmoking cessation can alter the natural history of both COPD and asthma by reducing the frequency and severity of exacerbations and slowing disease progression. Accordingly, the Global Initiative for Asthma and the Global Initiative for Chronic Obstructive Lung Disease recommend that clinicians address smoking cessation at every visit using counseling and pharmacotherapy. MethodsThe Mount Sinai Health System includes seven hospitals and more than 400 outpatient locations in the New York metropolitan area, all using a unified electronic medical record (Epic). De-identified data from calendar year 2024 were extracted for individuals identified as current smokers via the EMR smoking status tool. Patients with asthma and/or COPD were identified using ICD-10 codes. Tobacco treatment was defined as receipt of counseling or pharmacotherapy, including varenicline, bupropion, or nicotine replacement therapy. ResultsAmong 961,997 patients, 58,566 (6.1%) were identified as current cigarette smokers. Across all health system encounters, 32.6% of smokers with both asthma and COPD were given any treatment, followed by 26.7% of smokers with COPD, 13.0% of smokers with asthma, and 9.9% of cigarette smokers without these conditions. Smokers seen in pulmonary clinics were the most likely to be given treatment (17.4%), followed next by primary care (6.6%).The most commonly used treatment for all cohorts and all treatment settings was nicotine with the exception of the pulmonary clinic where varenicline predominated. DiscussionDespite higher treatment rates among smokers with asthma and COPD, only one-third of those with either condition received cessation treatment over a full year, underscoring the need for sustained system-wide quality improvement efforts.

Introduction: Although temporal variation is the hallmark of asthma, recommended diagnostic approaches largely rely on single clinic-based measurements. Ambulatory monitoring captures diurnal and day-to-day variability and may therefore enhance diagnostic accuracy. We evaluated the clinical feasibility and potential utility of home spirometry and fractional exhaled nitric oxide (FeNO) monitoring in asthma diagnosis. Methods: Symptomatic, untreated adults with GP-suspected asthma underwent diagnostic tests including bronchodilator reversibility, in-clinic FeNO, blood eosinophil counts and bronchial challenge. Participants measured spirometry and FeNO four times daily over one week; during the second week spirometry were measured twice daily. The reference standard was provided (asthma/not-asthma) by an expert panel of at least two asthma specialists based on clinical history and the results of all in-clinic testing; home spirometry (except for peak expiratory flow) and FeNO measurements were blinded to the panel. Results: Of 67 eligible participants, 51(76%) were recruited, and 38 had asthma confirmed or excluded by the panel. 1058 home spirometry measurements were obtained from 37(73%) participants; 848 home FeNO readings were obtained from 39(76%) participants. Among those completing at least one home measurement, median (IQR) adherence was 66.7(58.6-97.6)% for spirometry and 78.5(51.8-103.6)% for FeNO. Collection of health impact data for economic evaluation was feasible. In participants with a confirmed diagnostic outcome who completed home measurements (FeNO: n=32; spirometry: n=28), the putative home-testing metrics demonstrated high sensitivities at [&ge;]90% specificity, and outperformed peak expiratory flow diurnal variability. Incorporating home testing into the BTS/NICE/SIGN 2024 diagnostic pathway had the potential to reduce reliance on bronchial challenge testing by 57%. Conclusions: Home spirometry and FeNO testing and the prospective collection of health-economic data in the diagnostic setting were feasible. Home-based testing strategy showed early potential to improve asthma diagnosis and pathway efficiency. These findings support further evaluation through an adequately powered diagnostic accuracy study and health-economic assessment.

BackgroundRecurrent sore throat affects a small minority of adults but can cause substantial morbidity. Evidence to guide tonsillectomy eligibility in adults is limited, and current criteria are extrapolated from paediatric populations. We aimed to describe the epidemiology, management, and prognosis of adult sore throat in UK primary care. MethodsUsing CPRD Aurum (2010-2020 adults with a first coded episode of sore throat or tonsillitis were identified and matched to controls. Episode frequency, antibiotic use, ENT referral, and tonsillectomy were analysed. Predictors of recurrent episodes ([&ge;]3 in 365 days), referral, and tonsillectomy were assessed using time-to-event, multinomial logistic, and multilevel mixed-effects regression models. FindingsOf 4.45 million adults, 1.70 million (38.3%) had [&ge;]1 episode; most (61.5%) had only one, but 4.1% experienced [&ge;]3 within 1 year. Recurrent episodes were more common in younger females and those from more deprived areas. Only 21,869 patients (0.5% of the exposed cohort) underwent tonsillectomy, and just 25.7% of these met Paradise criteria at any time; conversely, only 13.9% of those meeting criteria underwent surgery. Patients who had a tonsillectomy tended to be younger, female, and from less deprived areas. Pre-tonsillectomy episode rates were unexpectedly low, but the data indicated that individuals with high baseline burden continue to experience elevated episode rates over several years. ConclusionsRecurrent sore throat is uncommon, but those affected face substantial disease burden. Current tonsillectomy patterns are poorly aligned with disease burden and show inequities by deprivation. Earlier identification of adults likely to develop recurrent episodes, and more timely surgical intervention, may improve patient outcomes and the cost-effectiveness of tonsillectomy.

ImportanceChronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality in the United States (US), largely driven by cigarette smoking and characterized by progressive lung injury. While e-cigarettes are promoted as a less harmful alternative to cigarette smoking, their long-term health effects, including the impact of prolonged use on COPD incidence among adults who have smoked, are not well understood. ObjectiveTo evaluate the prospective association between duration of e-cigarette use and incident COPD among US adults aged 40 years or older with a history of cigarette smoking, and to determine whether baseline respiratory symptoms modify this association. Design, Settings, and ParticipantsWe used data from Waves 4 to 7 (2017-2022) of the Population Assessment of Tobacco and Health (PATH) Study, a nationally representative US longitudinal cohort study. Our analysis included adults aged 40 years or older who currently or formerly smoked cigarettes. Main Outcomes and MeasuresThe outcome was incident, self-reported COPD diagnosis. The main exposure was the time-varying duration of e-cigarette use. Baseline functionally important respiratory symptoms were defined by a validated index. Multivariable models adjusted for demographics, COPD risk factors, and detailed tobacco use history, including cigarette smoking status, time since quitting, and pack-years. ResultsAmong 4,895 adults aged 40 year or older who currently or formerly smoked cigarettes, 408 reported an incident COPD diagnosis. Among individuals with baseline respiratory symptoms, longer e-cigarette use duration was associated with increased COPD risk (adjusted hazard ratio [AHR]: 1.28, 95% CI: 1.16, 1.40), whereas no significant association was observed among those without baseline respiratory symptoms (AHR: 1.01, 95% CI: 0.92, 1.12). Results were consistent after adjusting for cumulative cigarette exposure and other risk factors and remained robust across multiple sensitivity analyses. Conclusion and RelevanceProlonged e-cigarette use may increase COPD risk among individuals with pre-existing respiratory vulnerabilities. Although switching from combustible cigarettes remains an important harm reduction strategy, behavioral counseling and pharmacotherapy should be prioritized for those at high risk for COPD, with e-cigarette cessation support available to high-risk former smokers. Continued surveillance and research are warranted as e-cigarette products and use patterns evolve. Key PointsO_ST_ABSQuestionC_ST_ABSDoes longer e-cigarette use increase COPD risk in adults with a smoking history? FindingsIn this national cohort study of U.S. adults aged 40+ who currently or formerly smoked, e-cigarette duration was associated with higher self-reported COPD incidence among individuals with respiratory symptoms at baseline (adjusted hazard ratio [AHR] 1.28, 95% CI 1.16, 1.40) but not among those without symptoms (AHR 1.01, 95% CI 0.92, 1.12). MeaningProlonged e-cigarette use may increase COPD risk among individuals with respiratory vulnerabilities. While cigarette cessation should remain the priority, evidence-based e-cigarette cessation strategies are needed to prevent long-term use in this population.

Functional capacity, muscle strength, and patient-reported outcome measures are important indicators of health. In chronic obstructive pulmonary disease (COPD), these traits are often impaired beyond normal age-related decline. Substantial variability exists in both COPD and healthy populations, the biological basis of which remains poorly understood. Given the known contribution of genetics to complex traits, genetic factors may partly explain this variability. This study aimed to identify genetic variants associated with measures used to characterise extrapulmonary traits in COPD. Genome-wide association studies were conducted on the Lab3R-ESSUA cohort for the 6-minute walk test (6MWT), the 1-minute sit-to-stand test (1-min STS), the quadriceps maximal voluntary contraction (QMVC), the handgrip muscle strength, and the chronic airways assessment test (CAAT), adjusting for age, sex, body mass index, pack-years and ancestry. Variants with P<1E-05 were selected for replication in the EARLYCOPD cohort, and effects compared between COPD and healthy populations (two-way ANOVA). A total of 639 participants (364 people with COPD, 275 healthy; 75% male, median age 67 years; BMI of 27 Kg/m2; 10 pack-years) were included. Significant variants were identified for the 6MWT (rs1108983:G, {beta}=-186.5m, P=4.8E-08), the 1-min STS (rs5889103:GTT, {beta}=4.2reps, P=4.8E-08), the Handgrip (rs67352743:A, {beta}=-4.4Kg, P=2.8E-08), and for the CAAT (rs11747040:C, {beta}=4.4points, P=4.0E-09; rs11041680:A, {beta}=-2.6points, P=2.5E-08). Effects were independent of COPD diagnosis. Replication in EARLYCOPD (n=282) confirmed one SNP for 6MWT and three for CAAT. These findings highlight genetic contributions to functional capacity, muscle strength, and disease burden. COPD-related impairments appear to build on pre-existing genetic predisposition, contributing to disease heterogeneity.

Asthma is a chronic respiratory illness that causes mild to severe inflammation throughout narrowed airways. During allergic airways inflammation, autophagy prevents extensive lung tissue impairment while inducing a protective anti-pathogen response and macrophages in the lung to maintain homeostasis. Previous studies of autophagy genes and asthma have shown an association with variants in ATG5, but a comprehensive analysis of autophagy related genes and asthma has not been performed. Here we utilize summary statistic data generated from a two-stage genome-wide association study (GWAS) of asthma in the UK Biobank. We examined variants in 21 autophagy related genes and found statistically significant associations for 28 variants in two genes in the discovery dataset and nominally significant replication for 16 of these variants, all annotated to ATG4B. This is the first evidence of an association with variants in ATG4B with asthma which provides a novel potential for future drug development.

BackgroundBronchiectasis is a debilitating respiratory condition characterized by chronic cough with expectoration of thick sputum. It accounts for significant morbidity and mortality, especially when associated with exacerbations. Assessing the health-related quality of life (HR-QoL) of patients with bronchiectasis is important to ascertain the impact of the disease on day-to-day life, as well as to gauge the effect of targeted interventions. Conventionally used methods for assessing HR-QoL such as the St. Georges Respiratory Questionnaire (SGRQ) are time-consuming and have limitations in day-to-day application. The Bronchiectasis Health Questionnaire (BHQ) is a novel, compact tool used for assessing the HR-QoL, and has been validated for use in Korean and Turkish populations. MethodsWe attempted to develop and validate the Hindi version of the Bronchiectasis Health Questionnaire (BHQ) in Indian adults with bronchiectasis. We assessed the correlation between the Hindi BHQ (H-BHQ) scores and other measures of lung health including the Hindi version of the COPD Assessment Tool (H-CAT), pulmonary function tests and the bronchiectasis severity index (BSI). In addition, we assessed the correlation between the H-BHQ scores and the number of exacerbations and hospital admissions in the previous year. ResultsA total of 145 subjects with bronchiectasis were included. The mean ({+/-} SD) H-BHQ total score was 49.10 {+/-} 10.3. The H-BHQ score correlated well with the H-CAT score (Correlation coefficient -0.6534, p value < 0.0001) and the mMRC scale (Correlation coefficient of -0.4459,p value < 0.0001). The H-BHQ score also had a moderate correlation with the number of exacerbations and low correlation with hospital admissions in the previous year, with correlation coefficients of -0.4193 (p < 0.0001) and -0.3030 (p < 0.0001), respectively. The correlation between the H-BHQ and the Bronchiectasis Severity Index (BSI) score was weak (Correlation coefficient of -0.3012, p value < 0.01). ConclusionThe H-BHQ offers a simple and convenient method to assess the HR-QoL in patients with bronchiectasis, and correlates well with other measures of respiratory health, including the H-CAT, the mMRC score and the number of exacerbations and hospital admissions in the previous year.

BackgroundCystic Fibrosis (CF) is a lethal genetic condition affecting over 100,000 people worldwide, characterised by multi-organ dysfunction and a progressive lethal lung disease. The disease occurs due to faulty cystic fibrosis transmembrane conductance regulator (CFTR) ion channels effecting flow of chloride, bicarbonate and water out of cells. This causes thick mucus with repeated bacterial infections, systemic inflammation and a decrease in lung function. CFTR modulator therapies have shown variable improvements in lung function and reduction in exacerbation frequency. Basal cells within the lung act as a stem cell for repair following injury and can repopulate the epithelial layer. This process is dysfunctional in CF causing progressive damage. Spontaneous lung repair is well described but not well characterised. Nothing is known about the effects of CFTR modulator therapy on these cells, but this could be of major consequence for people with CF (pwCF). AimsTo determine the effects of CFTR modulator therapy on the activity of CF basal cells and relate this to progenitor function and to study the effects of CFTR modulators on systemic inflammation and clinical outcomes. MethodsClinical information, blood and nasal brushes were obtained from pwCF prior to commencing modulator therapy and at multiple time points up until 1 year of treatment. 10 pwCF were recruited to undertake thoracic CT scans pre-treatment and at 1 year of therapy. Nasal samples were used to isolate basal cells and serum to study systemic markers of inflammation. RNA sequencing of basal cells was undertaken by Ilumina Novoseq to a depth of 20 million read pairs and gene ontology analysis was performed. Functional assays of basal cell activity were carried out. Proteomic analysis and ELISAs were undertaken to determine changes in inflammatory cytokines within the serum across the first year of treatment. Quantitative results were generated by Lung Quantification (LungQ) analysis with qualitative reports from independent radiologists. Results were compared with clinical outcomes. Results110 pwCF were recruited in total who commenced a commercially available CFTR modulator therapy. Serum samples were collected from 77pwCF, nasal brushes obtained from 40 pwCF and 10 completed their CT scans following 1 year of highly effective CFTR modulator therapy. Systemic IL-6, CRP and calprotectin (a biomarker of CF exacerbation) were all significantly reduced with highly effective CFTR modulator treatment. Clinical results were in keeping with those seen in published CFTR modulator clinical trials with improvement in lung function, weight, and exacerbation frequency. Subjective improvements were seen in all 10 CT scans following 1 year of modulator therapy. Significant reductions were seen in airway wall thickening and reduction in thoracic lymphadenopathy were also observed. Basal cell RNA sequencing showed that the relative expression of 2570 genes were significantly different following treatment with CFTR modulators. Ontology analysis showed enrichment in multiple pathways including cilliagenesis and Notch signalling, a key pathway in lung tissue development and homeostasis. Functional assays exhibited a deficit in repair mechanisms of the CF basal cell compared to healthy controls, and reduction in progenitor function. ConclusionsAlthough CFTR modulators improve multiple clinical and radiological outcomes, they also have impacts on basal cell function. There are however, limited impacts on systemic inflammation and more work is needed in this area to understand the disease process.

BackgroundIn patients requiring respiratory support, clinicians rely on physical exam, radiologic, laboratory, and ventilator-derived measures for the provision of sufficient support while minimizing ventilator and "work of breathing" induced lung injury. Point of care lung ultrasound (LUS) is a widely available tool in hospital and clinic environments. To date, LUS has not been used to evaluate lung strain. MethodsWe collected LUS images in four anesthetized, neuromuscularly blocked, and mechanically ventilated pigs being used for another experiment. A feature tracking tool was developed which tracked echo-bright lung structures in ten second clips obtained in triplicate of the right and left, upper and lower lung fields using tidal volumes of 4, 6, 8, 10, and 12 mL/kg. Pleural lines were manually drawn and a program for quantifying lung strain developed with assistance from Anthropic Claude Artificial Intelligence tool. Structures were identified in inspiratory and expiratory frames and tracked bidirectionally with median strain per frame used for calculations. ResultsTriplicate measures of lung ultrasound images in four pigs had a median coefficients of variation of 35% (23-47% IQR) and linear modeling of strain with tidal volumes of 4-12 mL/kg showed positive correlation with R2 value ranging from 0.89 to 0.97. Strain measurements were similar after bronchial administration of 1.5M hydrochloric acid. ConclusionsRegional lung strain quantification using LUS is a viable and potentially useful tool for respiratory support management.

BackgroundSocial deprivation impacts chronic disease and acute admission outcomes. In interstitial lung disease (ILD), prior British Thoracic Society registry data for idiopathic pulmonary fibrosis has shown high deprivation was associated with poorer long-term outcomes. However, its impact on acute admissions in ILD is not known. MethodsWe undertook a multicentre, retrospective study of ILD-related admissions between 1st January 2017 and 31st December 2019 across 11 hospitals in the North West of England, utilising available real-world data. We determined social deprivation geographically by the 2019 English Indices of Deprivation deciles. The primary outcome was 90-day all-cause mortality. Results999 admissions met the inclusion criteria. 327/999 (32.7%) of admissions came from individuals geographically in the most deprived 20%. Across 999 admissions, in unadjusted survival analysis we observed a non-linear relationship between deprivation and 90-day all-cause mortality. In complete case multivariate modelling, deprivation demonstrated borderline significant association with all-cause mortality (HR 1.038, 95% CI 1.00 - 1.077, p = 0.050). However, this effect was lost in pooled analysis using multiple imputation (HR 1.001, 95% CI 0.971 - 1.033, p = 0.928). Male sex and pre-admission long-term oxygen were consistently associated with increased 90-day all-cause mortality across both models. Lower TLCO values were significantly associated with increased 90-day mortality in pooled analysis. ConclusionWe observe a high burden of acute ILD-related hospital admission amongst the most deprived 20%, suggesting geographical deprivation may impact acute healthcare seeking behaviours. Once admitted, the impact of deprivation appears more complex and multifactorial. Further studies which assess geographical and individual-level deprivation are needed to validate our findings. Key Messages What is already known on the topic?The British Thoracic Society idiopathic pulmonary fibrosis registry has previously demonstrated that higher social deprivation is associated with worse long-term outcomes. In other respiratory diseases, social deprivation impacts acute admission patterns and outcomes. What this study addsTo the best of our knowledge, this is the first study examining the relationship between social deprivation and acute ILD-related admission outcomes. This study demonstrates high acute admission burden from the geographically most deprived 20%. Once admitted, the association between geographical social deprivation and mortality outcomes appears complex and multifactorial in our modelling. How this may affect research, practice or policyThis study highlights the acute admission burden from highly deprived communities and the need for additional research to further understand the individual-level and geographical-level deprivation patients with ILD experience. We suggest the need for community outreach to build trust with deprived communities, alongside increasing awareness amongst patients, caregivers and primary care physicians in such communities. Deprivation must remain an important consideration in any new service or intervention to prevent worsening of health inequalities.

The ERS/ATS22 interpretative flowchart classifies diffusing capacity (DLco) into 5 scenarios with associated pathophysiology, and has not been tested on large patient groups. We aimed to obtain a more layered DLco interpretation, by interrogating DLco components Kco and VA, and by estimating lung inflation during the DLco test to identify the presence of restriction, which crucially impacts Kco interpretation. By assessing a "low VA" against lung inflation, a novel 9-scenario DLco classification with associated pathophysiology can be obtained. Lung patients from a tertiary center were classified according to the ERS/ATS22 chart and the novel 9-scenario one. Besides a control group of healthy subjects (n=303), disease groups under study were the following : asthma (n=1615), COPD (n=1338), CF (n=108), extrapulmonary restriction (n=122), ILD (n=98), post-COVID (n=193). Except for COPD, the prevalence of "normal DLco" (ERS/ATS22) was generally greater than that of "normal VA and normal Kco" (9-scenario); this discrepancy was most marked in CF (81% vs 56%) and in extrapulmonary restriction (57% vs 37%). With the novel 9-scenario chart, patients from very different diagnostic groups with a "low DLco" due to emphysema, bronchial disease, interstitial damage or incomplete expansion got classified across distinct scenarios, whereas ERS/ATS22 just grouped them together. In conclusion, when "low VA" is evaluated against lung inflation, a differentiation of DLco interpretation can be obtained in various patient groups involving obstruction and/or restriction. This approach can be readily implemented in clinical practice.

BackgroundTBX4 variants are a recognised cause of paediatric pulmonary hypertension (PH), often associated with interstitial lung disease (ILD). Evidence for ILD-directed therapy in this group is lacking. MethodsWe conducted a retrospective study of children ([&le;]18 years) with TBX4-associated PH at a national centre (2001-2025). ILD was defined using ChILD-EU criteria. Patients treated with pulsed intravenous methylprednisolone were assessed for response using ChILD-EU categories. Secondary outcomes included respiratory severity score (RSS), functional class (FC), echocardiographic measures, and NT-proBNP. ResultsOf 21 children, 11 (52%) had ILD; 9 received corticosteroids. Median age at treatment was 0.8 years. A clear or best response occurred in 7/9 (78%). RSS improved in 6/9 (p=0.02), with all children on respiratory support showing partial or complete weaning. Functional class improved in all with FC III/IV at baseline (p=0.02). Right ventricular function improved (TAPSE z-score +1.65, p=0.04), and elevated NT-proBNP normalised. Key clinical milestones included ECMO weaning, transplant delisting, and discontinuation of prostacyclin therapy. No significant adverse effects were observed. Untreated children showed no early improvement. ConclusionsCorticosteroids were associated with meaningful improvements in respiratory and PH outcomes in TBX4-associated PH with ILD. Prospective evaluation is warranted.

BackgroundProgressive pulmonary fibrosis carries poor prognosis despite availability of antifibrotics. Current progression criteria rely on functional decline (FVC [&ge;]10% decline over 6-12 months), which detects disease worsening after significant structural damage. Previous quantitative CT (qCT) methods using fixed Hounsfield unit (HU) thresholds or volume-only measurements have shown inconsistent sensitivity for early progression. We hypothesized that a hybrid approach combining HU thresholding with Z-score normalization would detect qualitative progression (tissue densification) before quantitative territorial expansion. MethodsWe developed a novel hybrid CT analysis method integrating: (1) HU threshold-based fibrosis detection (>-600 HU), (2) Z-score normalization for severity stratification (mild Z=1-2, moderate Z=2-3, severe Z[&ge;]3), and (3) five clinical progression criteria including qualitative worsening ({Delta}Z-score [&ge;]0.5). The method was validated in two ILD patients with serial CT at short intervals (3.5 and 10 months). Automated lung segmentation, fibrosis quantification, and clinical decision support were implemented in Python (scikit-image, SimpleITK, NumPy). ResultsIn the index case (progressive COPD-fibrosis overlap, 3.5-month interval), traditional volume-based analysis showed minimal change (+1 mL, +2%), below significance threshold. However, the hybrid method detected significant qualitative progression: Z-score increased from 2.35 to 2.87 (+0.52 SD, p<0.05 criterion threshold), with emergence of 24 mL new severe fibrosis (Z[&ge;]3). This represented redistribution from mild/moderate to severe categories despite stable total volume. The qualitative progression criterion triggered clinical recommendation for antifibrotic consideration, which volume-only analysis would have missed. In a comparative case (10-month interval), massive quantitative progression (+136 mL, +191.5%) with moderate qualitative component ({Delta}Z +0.24) was detected, demonstrating method sensitivity across extreme progression patterns (pure densification vs dominant territorial expansion). ConclusionsThe hybrid HU-Z-score method overcomes critical limitations of previous qCT approaches by detecting qualitative fibrosis progression (tissue densification) independent of territorial expansion. This enables identification of "Phase 1 progression" (densification) at 3-6 month intervals, earlier than functional criteria (6-12 months) or traditional volumetric CT analysis. The method provides objective, standardized clinical decision support for antifibrotic therapy initiation, addressing a critical gap in progressive fibrosing ILD management. Prospective validation in larger cohorts is warranted to establish optimal {Delta}Z-score thresholds and evaluate impact on clinical outcomes.

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a rare, fibrotic lung disease with poor prognosis, usually affecting adults which most commonly occurs idiopathically. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological symptoms. Detailed description of pulmonary manifestations with late-onset presentation have not been reported. MethodsWe describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy and respiratory chain enzyme activity assays were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing (WGS) data. ResultsAll patients (ages 5-36) presented with progressive dyspnea, weight loss and some with spontaneous pneumothoraces. Chest computed tomography and lung biopsies showed features of PPFE. Biallelic pathogenic DGUOK variants were identified in all patients, seven of them carry an unreported intronic variant leading to mtDNA depletion. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells and intermediate cells as their precursor localized at the fibrotic edge. Mitochondrial alterations were identified by electron microscopy. ConclusionPPFE in children and young adults is associated with DGUOK-related mitochondriopathy. For the first time, we demonstrate Aberrant Basaloid cells in pediatric fibrotic lung tissue. Since pulmonary involvement may be underrecognized or misinterpreted and the clinical presentation may not always be typical of a mitochondriopathy, we recommend genetic testing in all patients with PPFE of unknown origin.

Background: Smell testing is increasingly recognized as essential in rhinology practice but remains underutilized because of time constraints and limited clinical resources. This study aimed to evaluate the performance (test-retest reliability, accuracy and test completion time) of a self-administered, digital version of SMELL-RS, a non-semantic test of olfactory resolution (SMELL-R) and sensitivity (SMELL-S). Methodology: We performed a test-retest reliability study in a tertiary care facility. We enrolled 100 subjects with and without smell dysfunction. The primary outcome measures were two replicates of olfactory test scores (SMELL-RS composite score, SMELL-R score, SMELL-S score). The secondary outcome measures were Sniffin Sticks score, test completion time, patient demographics, and other clinical characteristics (clinical symptoms, etiologies). Results: The SMELL-RS composite score was reliable (ICC=0.71; p<0.0001) and correlated with the Sniffin Sticks composite score (r=0.68; p<0.0001). Different etiologies have different magnitudes of smell loss as revealed by the SMELL-RS score. SMELL-S reduces misdiagnosis associated with Sniffin Sticks threshold tests. The average completion time of the olfactory resolution test (SMELL-R) was on average 5.9 minutes (SD=1.9), while the average completion time of the olfactory sensitivity test (SMELL-S) was 5.5 minutes (SD=2.7). This is two to three times faster than the corresponding Sniffin Sticks tests. Conclusions: SMELL-RS is a rapid, fully automated, reliable, and accurate olfactory test suitable for self-administration in a clinical setting.

BackgroundChronic obstructive pulmonary disease (COPD) is a chronic lung condition characterised by accelerated lung aging. Extracellular vesicles (EVs), which can be categorised into large EVs (LEVs) and small EVs (SEVs), may play a critical role in intercellular communication. They contribute to the pathogenesis of COPD by transporting and transferring microRNAs (miRNAs). This study profiles cells and EV-associated miRNAs from both healthy and COPD small airway (SA)-epithelial cells and SA-fibroblasts and identifies the biological pathways associated with these miRNAs. MethodsEVs were isolated from conditioned media of healthy and COPD SA-epithelial cells and SA-fibroblasts, both at baseline and following H2O2 exposure. MiRNAs were extracted from cells and EVs and analysed by small RNA (smRNA) sequencing. ResultsSmRNA sequencing of COPD SA-epithelial cells and EVs revealed that four miRNAs were upregulated and fourteen were downregulated in the cells compared to healthy controls. COPD LEVs displayed nine upregulated and ten downregulated miRNAs, while SEVs showed ten upregulated and eleven downregulated miRNAs. Only one miRNA consistently upregulated in COPD SA-epithelial cells, LEVs, and SEVs. The various differentially expressed miRNAs were primarily associated with cellular senescence pathways. In SA-fibroblasts 39 miRNAs were upregulated in COPD compared to healthy cells. 14 miRNAs were upregulated in COPD LEVs and 11 downregulated, whereas SEVs exhibited twenty upregulated and eleven downregulated miRNAs. Overlap was limited, with only three miRNAs consistently upregulated in SA-fibroblasts and EVs. These miRNAs were linked to pathways related to fibrosis and cellular senescence. Furthermore, oxidative stress alters the miRNA profiles detected in cells and EVs differently between cells from healthy individuals and COPD patients. ConclusionsCOPD alters miRNA signatures in cells and their EVs, with limited overlap between compartments. These COPD-associated miRNAs are enriched in pathways driving cellular senescence and fibrosis, suggesting a potential role in disease progression.