ERJ Open Research

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.

Rationale: Air trapping in functional areas of the lung is common in chronic obstructive pulmonary disease (COPD). We developed a novel music-based intervention, Engagement of Music for Pulmonary Obstruction With Expiratory Restoration (EMPOWER) aimed at reducing air trapping and functional small airways disease (fSAD) in patients with COPD. Objectives: We conducted a pilot study to assess if air trapping and fSAD in COPD patients are reduced by our targeted EMPOWER music-based singing intervention. Methods: Participants completed four weeks of singing and vocalizing with a board-certified music therapist. Pre- and post-intervention assessments of standard pulmonary function tests (PFTs), and quantitative computed tomography (qCT) lung imaging documented changes in air trapping. Pre- and post-intervention change in psychological and patient-reported outcomes of hope, emotional wellbeing, agency and COPD symptom burden were also obtained. Main Results: All five adult participants with COPD who enrolled completed the study and reported strong interest in continuing with a similar program. Additionally, we observed trends toward improvement in qCT-measured fSAD, six-minute walk distance, and patient-reported symptoms on the COPD Assessment Test. Conclusion: Results of this preliminary study showed improvements in both patient-reported and imaging-indicated respiratory outcomes, suggesting that targeted singing components in music-based interventions such as the EMPOWER intervention may support physiological lung function changes in COPD patients.

IntroductionAlthough 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. MethodsSymptomatic, 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. ResultsOf 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 [≥]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%. ConclusionsHome 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. Key messagesO_LIWhat is already known on this topic: Asthma can be difficult to diagnose, as objective tests may be normal when assessments are performed during periods of minimal or intermittent symptoms. C_LIO_LIWhat this study adds: Our data suggest that home spirometry and FeNO monitoring could be successfully implemented within a diagnostic accuracy trial. Participants were able to perform these tests reliably in the home environment. C_LIO_LIHow this study might affect research, practice or policy: The early findings suggest that home-based physiological monitoring may offer additive diagnostic value beyond standard clinic-based assessments and could reduce reliance on bronchial challenge testing. These results provide a clear rationale for larger diagnostic accuracy trials and for undertaking early health-economic modelling to assess the potential impact on clinical pathways and resource utilisation. C_LI

Background: Olfactory dysfunction (OD) in children remains underdiagnosed and poorly characterised. Despite its known impacts on nutrition, quality of life, safety awareness, and psychosocial development, no standardised diagnostic or management pathway currently exists for paediatric OD. This study aimed to characterise global practice patterns and identify diagnostic and therapeutic challenges unique to paediatric care. Methodology/Principal: A 44-item cross-sectional online survey was distributed to a verified international network of paediatric otolaryngologists across 36 countries via a closed professional platform. The survey assessed five domains: diagnostic practices, management protocols, technology and innovation, education and training, and barriers to effective care. Regional grouping was used to facilitate meaningful statistical comparisons. Categorical variables were evaluated using chi-square tests, with odds ratios and 95% confidence intervals reported for significant findings. Results: Of 351 potential participants, 167 responded (47.6% response rate). Most respondents (83%) reported seeing children with OD, yet 95% saw fewer than ten such patients annually. Psychophysical testing was never performed by 54.8% of respondents, while 88.4% routinely ordered cross-sectional imaging. Testing frequency increased significantly with patient age (Cochran's Q p<0.001). The most common barriers to objective testing were insufficient training (44.3%), time constraints (29.9%), and funding limitations (28.1%). Multidisciplinary collaboration was negligible. Significant regional variation was observed across most practice domains. Conclusions: Paediatric OD care is characterised by functional underinvestigation, fragmented multidisciplinary collaboration, and systemic educational gaps. These findings support urgent development of standardised clinical guidelines, age-appropriate validated assessment tools, and formal interdisciplinary care pathways.

Bronchopulmonary dysplasia (BPD) in infancy is a risk factor for obstructive lung disease in adults. We hypothesized that adults born preterm and diagnosed with BPD have an altered lung architecture which is correlated to lung function impairment. Individuals from the LUNAPRE cohort (clinicaltrials.gov/ct2/show/NCT02923648) were included: preterm born (gestational week <32) with (n=24) or without (n=23) a previous diagnosis of BPD, full term born with allergic asthma (n=22) and healthy volunteers (n=24). Inspiratory and expiratory HRCT scans were performed and interpreted by two expert reviewers in a blinded manner. Structural changes were scored and quantitative density measurements were analysed automatically using a dedicated post-processing workstation. The HRCT scores were significantly higher in the BPD group compared to the other groups (p<0.001) and had highest numbers in subjects diagnosed with severe BPD. Most common HRCT changes were small peripheral opacities. Hypoattenuation during inspiration was only observed in the BPD group. Architectural distortion was observed in 6/24 BPD and 2/23 premature without BPD. HRCT scores correlated to FEV1 in a negative manner for preterm (p<0.001) and BPD (p<0.05) groups. Oxygen supplementation during the neonatal period correlated with HRCT score in a positive manner for preterm group (p<0.001). No differences in lung density were observed between the groups. Young adults previously diagnosed with BPD have structural changes on CT which correlate with airway obstruction. Severity of BPD at the diagnosis was associated with CT abnormalities in adulthood. HRCT changes in adults with BPD were correlated with spirometry findings.

BackgroundRecent 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. MethodsWe 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. ResultsIn 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. ConclusionFeNO 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.

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.

IntroductionImpaired motile cilia function contributes to many respiratory disorders, but therapies targeting this cellular defect are currently lacking. Personalized airway epithelial models combined with quantitative, complementary ciliary assays can pave the way for the development of such therapies. However, existing airway epithelial cultures often show variable ciliogenesis, and ciliary function is frequently assessed using a single assay that does not capture the phenotypic heterogeneity of ciliary dysfunction. Here, we established a personalized, multi-assay in vitro platform using human nasal epithelial cells (HNECs) to assess ciliary function and therapeutic response, using primary ciliary dyskinesia (PCD) as a model disease. MethodsHNECs from 8 healthy individuals and 13 individuals with PCD carrying distinct disease-associated variants were obtained by nasal brushing. Cells were differentiated under optimized conditions, including {gamma}-secretase/Notch and BMP pathway inhibitors and a low liquid-liquid interface, to generate highly ciliated 2D epithelial cultures. Ciliary function was assessed using ciliary beat frequency, bead transport, and apical-out nasal organoid rotation assays. Therapeutic rescue was assessed in HNECs harboring DNAI1 alterations using DNAI1 mRNA-loaded lipid nanoparticles. ResultsOptimized differentiation yielded reproducibly multiciliated HNEC cultures. The multi-assay platform distinguished healthy from PCD-derived HNECs and revealed individual- and genotype-specific patterns of ciliary dysfunction not captured by a single assay. Basolateral administration of DNAI1 mRNA-loaded lipid nanoparticles resulted in partial, dose-dependent recovery of ciliary function in DNAI1-deficient HNECs. ConclusionThis study establishes a standardized, individual-specific multi-assay nasal epithelial platform for functional phenotyping of motile cilia and preclinical evaluation of emerging therapies, with demonstrated utility in PCD.

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.

Background: The chromosome 1q31 Th2 pathway-associated interval has been linked to asthma, but its phenotype specificity and cross-ancestry architecture remain unclear. Methods: We analyzed African (AFR) and European (EU) ancestry datasets, including 9,965 asthma cases and 37,391 controls of AFR, and 6,074 cases and 116,255 controls of EU ancestry. Imputed dosage-based association analyses were performed for asthma, steroid-dependent asthma (SDA), and non-steroid-dependent asthma, followed by QC-filtered SDA remapping, leave-one-batch-out analysis, cross-ancestry comparison, and functional enrichment. Results: Strong regional association was observed only for SDA. After quality-control (QC) filtering, the SDA signal remained significant in both ancestries, with 2,280 genome-wide significant variants in AFR and 859 in EU. Cross-ancestry comparison identified 3,129 significant variants: 10 shared, 2,270 AFR-specific, and 849 EU-specific. Shared variants showed concordant effects, whereas 237 variants showed nominal heterogeneity. AFR-specific signals included PTPRC variants with larger effects in AFR. Functional enrichment suggested different biological emphases within the same interval: immune and contractile airway-wall biology in AFR, and additional neuroaxonal components in EU. Conclusions: The 1q31 interval is strongly associated with SDA in both AFR and EU populations, and its fine-scale architecture differs by ancestry. These findings highlight population-specific effects within a shared SDA susceptibility interval, with potential implications for population-informed precision medicine in steroid responsiveness and asthma management.

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.

RationaleHeterogeneous alveolar collapse is prevalent in inflammatory lung conditions such as chronic obstructive pulmonary disease, acute respiratory distress syndrome, and pneumonia. Although neutrophil-released proteases contribute to the tissue remodeling that leads to alveolar collapse, how this altered mechanical environment in turn affects neutrophil migration remains largely unexplored. ObjectivesIn this study, we investigate how alveolar collapse and stretch influence neutrophil migration and identify the mechanical and biochemical factors that govern regional migration differences. MethodsWe developed a novel precision-cut lung slice platform that generates collapsed vs non-collapsed regions within the same slice. Neutrophils in both regions were longitudinally imaged for up to 5 hours to quantify motility behavior. Migration mechanisms were probed using migration-related inhibitors, collagenase, and cigarette smoke extract. A crystal ribcage system, which preserves intact alveolar shape and the air-liquid interface, was also used to assess the effects of ventilation on neutrophil migration. ResultsNeutrophil migration was faster in the collapsed region compared to not-collapsed regions. This regional difference was eliminated by Rho-associated protein kinase (ROCK) inhibition, which selectively increased migration speed in the non-collapsed region. The regional difference persisted with the addition of collagenase and cigarette smoke extract, both of which significantly increased the migration speed in both regions. In the crystal ribcage, the preserved air-liquid interface and ventilation together enhanced neutrophil migration compared with a collapsed lung. ConclusionsAlveolar collapse and stretch facilitate neutrophil migration, indicating the role of localized tissue remodeling in driving neutrophil activity and further disease progression.

ObjectiveTo test whether machine learning (ML) models trained on tidal breathing flow time series can discriminate between individuals with and without respiratory disease and predict lung function indices obtained from conventional pulmonary function testing. BackgroundAccurate assessment of respiratory function in infants and young children is challenging because conventional pulmonary function testing requires sophisticated equipment and/or active patient cooperation. Tidal breathing measurements, in contrast, can be obtained non-invasively with little or no patient cooperation and at low cost, yet their clinical utility has been limited. We hypothesized that sufficiently long tidal breathing flow time series contain clinically relevant information that can be extracted using a recurrent neural network known as a long short-term memory (LSTM) network. ApproachWe evaluated LSTM models in two scenarios within the Basel-Bern Infant Lung Development cohort. First, we assessed the ability of a model trained on flow and derived volume time series to detect bronchopulmonary dysplasia (BPD) in 329 infants. Second, we examined whether a model trained on tidal breathing flow alone could predict forced expiratory volume in one second (FEV1) in 135 school-age children. Signals were filtered and normalized prior to model training, and performance was evaluated on held-out test datasets. Main resultsFor BPD detection, the model achieved 97.0% accuracy, 100% specificity, 91.7% sensitivity, 100% precision, and an F1-score of 95.7%. For FEV1 prediction, Bland-Altman analysis showed a mean bias of -0.009 L (95% CI -0.091 to 0.074), with limits of agreement of -0.416 L and 0.399 L. The mean relative prediction error was 13.7%. SignificanceThese findings demonstrate that temporal patterns in tidal breathing flow signals contain diagnostically and functionally relevant information. ML applied to tidal breathing measurements may provide a low-burden, minimal-cooperation approach for early respiratory disease detection and functional assessment across early life stages.

Background Genetic studies to date are yet to define the major portion of the genetic risk for adult-onset pulmonary fibrosis (PF). Further the dearth of knowledge of clinically actionable variants for PF is hampering efforts to implement genetic testing to aid early diagnosis and improve disease management. Here we evaluated the contribution of rare and common variants to PF in cohorts with and without a family history of PF. Method Whole genome sequencing (WGS) was performed in a familial cohort comprising PF cases and their family members (85 individuals representing 55 families); and 122 cases from the Australian IPF Registry (AIPFR) with and without a self-reported family history of PF. WGS data were interrogated for rare potentially PF-causing variants in 33 genes previously associated with PF. Variants that were rare and predicted to be likely causative were formally curated using the American College of Medical Genetics and Association for Molecular Pathology (ACMG-AMP) guidelines. Additionally, to examine the common risk variant contribution, a weighted polygenic risk score (PRS) was generated using 16 previously IPF-associated common SNPs. PRS were generated from WGS for the 85 clinically confirmed familial cases and 122 AIPFR cases. In the remaining 202 AIPFR cases, PRS were generated from TaqMan genotyping data. Results Interrogation of WGS generated from 207 individuals with PF revealed multiple rare putative pathogenic variants in both familial and AIPFR cohorts. Formal curation revealed pathogenic (P) or likely pathogenic (LP) variants confirmed in TERT or RTEL1 in four families (7.3%) with the majority of remaining variants classified as variants of uncertain significance (VUS; 12.7%) in seven additional families. Amongst AIPFR participants, four variants met the threshold for classification as P/LP variants (3.3%), with a further six individuals found to harbour VUS following curation (4.9%). Overall weighted PRS did not differ significantly between individuals with familial PF or with no reported family history. However, PRS in all patient groups were significantly elevated compared with population controls. Conclusion VUS remain the major portion of rare variants identified in known PF -related genes. For ~80% individuals with a confirmed family history no potentially causative variants were identified in known PF related genes nor was there evidence that a high burden of common variants contributed to risk in these families. Similarly, we found no evidence that a high burden of common variants contributes to a significant proportion of risk PF in those individuals with no reported family history.

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.

AimCystic fibrosis (CF) care has been transformed by CFTR modulator therapies, yet most efficacy data arise from clinical trials with restrictive eligibility criteria. Real-world registry data can capture treatment outcomes in broader, more diverse patient populations. We used the Cystic Fibrosis Foundation Patient Registry (CFFPR) data to evaluate longitudinal clinical outcomes, and care benchmarking at a single Adult CF Program Center over a decade. MethodsA retrospective, descriptive analysis of CFFPR data (2011-2022) was performed to assess trends in modulator use, lung function (ppFEV1), body mass index (BMI), respiratory microbiology, and pulmonary exacerbations (PEx). Comparative Effectiveness Research (CER) methods were applied to compare outcomes across peak modulator eras: pre-modulator (2011), ivacaftor (2015), mixed-modulator (2019), and elexacaftor/tezacaftor/ivacaftor (ELE/TEZ/IVA) (2021). Program-level outcomes were benchmarked against national network metrics to assess adherence to guideline-based care. ResultsOver ten years, median ppFEV1 improved from 63.4% (2011) to 78.8% (2021), and BMI increased from 22.3 to 24.8 kg/m2. The proportion of adults experiencing more than one PEx annually declined from 39.7% to 19.5%, while Pseudomonas aeruginosa (P.a.) culture positivity decreased from 79% to 47%. ELE/TEZ/IVA therapy was associated with greatest clinical improvements. Program-level performance remained comparable to national network benchmarks, reflecting high adherence to standard care metrics. ConclusionRegistry-based CER provides valuable real-world insights into CF care effectiveness and quality improvement. This decade-long analysis demonstrates significant clinical gains associated with modulator therapies and highlights the importance of patient registries in monitoring outcomes, benchmarking care, and informing global CF care models and standards for rare disease management. Key Messages{square} Real-world registry data enables decade-long evaluation of CFTR modulator effectiveness. {square}Elexacaftor/tezacaftor/ivacaftor demonstrates the greatest clinical benefit among modulator therapies. {square}Benchmarking Adult CF Program performance against the Network of Adult CF Programs facilitates quality improvement and standard care guideline adherence. {square}Patient registries provide insights for personalized care, program-level decision-making, and international standards for rare disease management.

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.