Respiratory Research

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.

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are phenotypically divergent disorders arising from similar exposures (including cigarette smoke). Differences in DNA methylation may drive the exposed lung towards COPD vs. IPF. To characterize differential methylation in COPD and IPF lung tissue relative to controls, we conducted epigenome-wide association studies of COPD and IPF in lung tissue from the Lung Tissue Research Consortium (N=1029), adjusting for age, sex, smoke exposure, ancestry, estimated cell type composition, and plate. "Switch probes" were defined as CpGs differentially methylated in COPD vs. control and IPF vs. control in opposite directions. Gaussian graphical models were used to mine network properties of switch probes. Differential methylation of genes related to COPD/IPF in the literature was assessed. Switch probe methylation was compared with previously reported gene expression to identify multi-omic switches. We found 13,313 CpGs were associated with COPD and 43,359 with IPF (3,163 overlapping). We identified 1,091 switch CpGs enriched for endocytosis, glycosphingolipid biosynthesis, and pathways in cancer. 24 genes exhibited multi-omic switch behavior, many related to lipid metabolism (ACSL1; FASN; LPCAT1; MED27; NCOR2). LPCAT1 is of particular interest due to its role in maintaining phosphatidylcholine, the majority component of surfactant. Further related to surfactant, we observed strong divergent methylation and expression of ATP11A, which facilitates endocytosis of surfactant lipids. CONCLUSIONS Our findings suggest multi-omic switch-like regulation may underlie differential COPD/IPF etiology. Future investigation of LPCAT1 and ATP11A could provide new mechanistic understanding and therapeutic avenues.

Chronic obstructive pulmonary disease (COPD) is a debilitating and progressive lung disease that affects millions of people worldwide. There is a continuing clinical need to characterize COPD at the molecular level to be able to identify the multi-omic biomarkers of its pathogenesis and to enable more accurate diagnoses and more effective treatment. We used Multi-Omics Factor Analysis (MOFA) to jointly analyze genomic, blood transcriptomic, and plasma proteomic data collected from 1,872 participants in the Genetic Epidemiology of COPD study who had moderate to very severe COPD. Five latent factors identified by MOFA were associated with COPD-related lung function, chest computed tomography (CT) imaging, and blood count phenotypes, as well as all-cause mortality. The top genetic, transcriptomic and proteomic contributors to these latent factors were also individually associated with COPD-related outcomes. Moreover, factor loadings and expression levels of top omic drivers helped distinguish between patient subgroups. Quantitative trait loci analysis of a latent factor that was jointly driven by transcriptomics and proteomics revealed potential common genetic control of gene expression and protein abundance. Polygenic risk scores derived from a genomics-driven latent factor were associated with chest CT imaging and lung function phenotypes, and these associations were replicated in an independent COPD cohort. Together, our results suggest the potential of integrative omic approaches to identify the major axes of heterogeneity in COPD and uncover the multi-omic interplay between the contributors to each axis.

BackgroundCYFRA 21-1, a cytokeratin-19 fragment, is a validated serum biomarker for non-small cell lung cancer (NSCLC). However, most studies rely on single time-point measurements, limiting its specificity in differentiating malignancy from benign pulmonary conditions. Inspired by the clinical utility of serial PSA measurements in prostate cancer, we investigated whether longitudinal trends in CYFRA 21-1 could enhance diagnostic and monitoring capabilities in patients with pulmonary nodules Methods and FindingsWe analyzed 132 patients with pulmonary nodules, including 41 with lung cancer and 91 with benign diagnoses. CYFRA 21-1 levels were measured serially using electrochemiluminescence assays. Longitudinal trends were assessed using linear mixed-effects models to estimate biomarker trajectories. Subgroup analyses examined differences between benign, untreated cancer, and post-treatment cancer groups, as well as within-patient changes in a subset of 16 cancer patients with both pre- and post-surgical measurements. Log-transformed data were used for the analysis. At baseline, CYFRA 21-1 levels were significantly higher in malignant versus benign nodules. Over time, CYFRA trajectories diverged: benign cases showed slight increases, whereas cancer patients exhibited greater biomarker volatility. In treated cancer patients, trend of CYFRA levels on the natural log scale decline from -0.00137 pre-surgery to - 0.00263 to post-surgery, and both cancer groups showed significantly higher absolute slopes than the benign group (p < 0.05). While pre- vs post-treatment slope differences did not reach significance (p = 0.211), the general pattern indicated that CYFRA 21-1 is a dynamic marker responsive to tumor presence and removal. ConclusionsCYFRA 21-1 exhibits substantial within-patient variability over time, with trajectories that reflect disease state and treatment. These findings suggest that longitudinal monitoring of CYFRA 21-1--analogous to PSA velocity in prostate cancer-- may offer improved diagnostic and prognostic insight in the evaluation of pulmonary nodules. Further studies in larger cohorts are warranted to validate these findings and explore clinical implementation of CYFRA trajectory analysis.

Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza and SARS-COV-2 driven pneumonia. Our analysis revealed highly pneumonia type specific proteomic signatures, including COVID-19 specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V-domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry driven autoantibody profiling in two independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.

Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where deficiency of the TGF/BMP pathways have causal roles in hereditary and idiopathic forms. It is an attractive candidate for therapeutic intervention but there is an unmet need for clinically-relevant and practical biomarkers that can measure target engagement. A major challenge has been the inaccessibility of lung tissue in disease for molecular profiling. Here we explore the surrogate capacity of peripheral blood BMP pathway-specific markers. We demonstrate that BMPR-II in flow cytometrically characterised white blood cell subsets is reduced in a proportion of patients, however proteomic analysis demonstrates pleiotropic alterations of TGF{beta}/BMP modulators. Downstream BMPR-II canonical and non-canonical signalling is impacted and measurable in whole blood. We present discovery and international replication cohorts for a transcriptomic BMPR-II signalling signature. The composite biomarker panel is repeatable, reproducible, longitudinally stable and expressed in correlated gene modules in PAH which associate with clinical outcomes. The assay performance characteristics of the biomarker panel make it feasible for early phase, target engagement clinical trials and an adaptive three arm study of two pre- clinically validated modulators of BMPR-II is underway. One Sentence SummaryThe first demonstration of clinically-relevant BMP biomarker panels validated in international populations of patients with PAH.

Acute respiratory failure causes millions of deaths worldwide each year, highlighting the need for a better understanding of its pathophysiology and approaches to identify treatment-responsive subphenotypes of patients. Although subphenotypes of acute respiratory failure have been described using peripheral blood biomarkers, it remains unclear whether lung-specific molecular profiles can define biologically and clinically meaningful subphenotypes. In this study, we identified four distinct subphenotypes based on the measurement of twenty-five soluble proteins in alveolar fluid collected from 466 patients with acute respiratory failure. Forty-eight of these participants also underwent immunophenotyping by spectral flow cytometry to characterize immune cell populations. Twenty-eight-day mortality was significantly different across the four subphenotypes. The subphenotype with lowest mortality (12.7%) showed elevated levels of soluble PD-L1, enrichment of T cell-related chemokines, and the highest proportion of memory CD8+ T cells. A subphenotype characterized by globally low soluble protein levels and higher proportions of exhausted T cell subsets had a mortality rate of 22.1% despite relatively moderate illness severity. The subphenotype with the highest mortality (29.4%) exhibited increased pyrogenic and neutrophil-associated alveolar mediators. Severity of respiratory failure varied markedly between subphenotypes, while non-pulmonary organ failures were similar across groups. We developed a parsimonious classifier to predict subphenotypes in two additional cohorts totaling 122 patients. The clinical differences between the subphenotypes were similar across cohorts, although associations with mortality were not detected in the smaller validation cohorts. These findings identify novel subphenotypes of acute respiratory failure and support integrating lung-specific molecular measures into future studies to advance precision-medicine approaches. One Sentence SummaryThis study identifies novel subphenotypes of acute respiratory failure that exhibit highly distinct immune signatures and associations with clinical outcomes.

Chronic infections in cystic fibrosis (CF) emerge from gradual ecological transitions in the airway microbiome, yet early predictive markers remain poorly defined. We developed a new autoencoder-based framework that outperforms read-based or metagenome-assembled genome-based analyses at capturing the continuum from health-associated commensals to pathogen-dominated, antibiotic-tolerant communities. This improvement is achieved by integrating taxonomic and functional data from 127 sputum and bronchoalveolar lavage metagenomes from 64 people with CF into latent "Clusters of Phylogeny and Functions" (COPFs). Coupled with gradient-boosted random forests, COPFs predicted Pseudomonas aeruginosa colonisation, multidrug resistance, and impending infection up to a year before clinical detection. The multidrug-resistant P. aeruginosa signature showed the same resistance-mechanism evolution as found in laboratory experiments. The inclusion of eukaryotic markers revealed persistent Aspergillus fumigatus signatures even during culture-negative intervals. Applying our South Australian-trained model to over 1,000 global metagenomes from 22 independent CF datasets, we achieved 94% accuracy in predicting P. aeruginosa status across platforms and geographies, validating the models universal utility. Our results demonstrate that combining datasets with deep learning reveals conserved ecological and metabolic mechanisms in disease progression, transforming metagenomics into a predictive framework for managing chronic infections.

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.

BackgroundInterstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD), share similar features that complicate diagnosis. Tumor markers are often elevated in ILD, yet their diagnostic utility remains unclear. MethodsThis retrospective study included ILD patients hospitalized between 2018 and 2025. Serum levels of alpha-fetoprotein, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 199, CA125, CA153, neuron-specific enolase (NSE), and cytokeratin 19 fragment (CYFRA 21-1) were analyzed. Arterial blood gases and erythrocyte sedimentation rates (ESRs) were also collected. Statistical analyses involved the Kruskal-Wallis test, Dunns post hoc test, Spearmans correlation, logistic regression, and receiver operating characteristic (ROC) curve analysis. ResultsCEA, CA199, and CA125 levels varied significantly among ILD subtypes (all p < 0.05). NSE differed among CTD-ILD subgroups (p = 0.0409). In IPF, CEA and NSE correlated inversely with PaO2 (r = -0.1556, p = 0.0380; r = -0.2205, p = 0.0031). In CTD-ILD, NSE correlated negatively with PaCO2 (r = -0.1811, p = 0.016), and CYFRA 21-1 with PaO2 (r = -0.1999, p = 0.0078). A diagnostic model incorporating CEA, CA199, sex, age, smoking, PaO2, and ESR differentiated IPF from CTD-ILD with an AUC of 0.833 (95% CI: 0.790-0.876), showing 73.6% sensitivity and 82.4% specificity at a cutoff of 0.569, outperforming single markers. ConclusionCEA, CA199, and CA125 aid in distinguishing ILD subtypes, while CEA, NSE, and CYFRA 21-1 correlate with impaired gas exchange. The combined clinical and biomarker model demonstrated superior performance in discriminating IPF from CTD-ILD, highlighting its clinical potential.

AbstractO_ST_ABSRationaleC_ST_ABSIdiopathic pulmonary fibrosis (IPF) is an age-related disorder with common and rare genetic risk factors. It is unknown if the effects of PF genetic risk factors differ by chronologic age. ObjectivesTo assess age-specific effects of genetic risk factors in PF patients and their relatives. MethodsWe identified common and rare genetic risk factors using a Columbia whole genome sequencing (WGS) cohort (777 IPF, 2905 controls) and replicated findings using Trans-Omics for Precision Medicine (TOPMed, 1148 IPF, 5202 controls). We assessed age-stratified genetic risk of IPF and assessed for interaction with age across a range of cutoffs. We analyzed 313 FPF pedigrees and compared age-specific prevalence of interstitial lung disease in relatives stratified by proband genetic risk factors. Measurements and Main ResultsAdjusted odds of disease from MUC5B SNP increase with age, while odds of disease from rare variants decrease with age. The magnitude of the interaction term between age and both genetic variables was greatest in younger individuals. There were significant interactions between age <55 and the MUC5B SNP (discovery pinteraction=0.01; replication pinteraction<0.0001) and rare variants (discovery pinteraction<0.0001; replication pinteraction=0.03). Pedigree analysis showed more prevalent disease especially in younger relatives in FPF families with rare variants versus without (p<0.0001). ConclusionsAge modifies the effects of genetic risk factors in IPF. Rare variants confer greater risk in younger individuals whereas the MUC5B SNP confers greater risk in older individuals. Relatives of FPF patients with rare variants exhibit earlier prevalent disease, which has implications for preclinical disease screening.

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.

Respiratory monitoring in daily-life settings is important for health assessment, yet extracting physiologically interpretable information from breathing signals under natural conditions remains challenging, as breathing is inherently dynamic and strongly modulated by behavior. Here, a portable breathing monitoring device based on a flexible lead zirconate titanate sensor is developed to address this challenge. By exploiting polarity-opposed piezoelectric and pyroelectric responses through sensor orientation, the recorded breathing waveform exhibits a characteristic dual-component structure, consisting of a narrow transient spike followed by a broad quasi-steady peak within each breathing phase. This intrinsic waveform structure enables phase-resolved quantification of how breathing effort is distributed between transient and quasi-steady components during inhalation and exhalation. Pilot measurements in healthy subjects and patients with chronic obstructive pulmonary disease or asthma reveal systematic shifts toward transient-enhanced breathing in patients, providing clearer differentiation than conventional descriptors based on breathing duration or amplitude. By transforming complex breathing dynamics into stable and physiologically meaningful signal components under daily-life conditions, this dual-response sensing approach enables more robust access to function-related changes in natural breathing.

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.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapies and poorly defined cross-tissue immune mechanisms. We performed single-cell RNA sequencing and TCR profiling of paired lung, lymph node, and peripheral blood samples from patients with IPF, combined with functional coculture assays and mouse model. We identified GZMK-high CD8 T cells enriched in fibrotic lungs, displaying inflammatory but low-cytotoxic features. TCR and trajectory analyses indicated that these cells originate from lymph-node CD8_HSPA1A cells and migrate to the lung. Higher GZMKCD8 T-cell levels correlated with impaired lung function and worse outcomes. Mechanistically, GZMK-overexpressing CD8 T cells promoted fibroblast-to-myofibroblast differentiation and proliferation through TGF-{beta}1 signalling, while GZMK inhibition reduced fibroblast activation and collagen deposition. Pharmacological blockade of TGF{beta}R1/ALK4 with TEW suppressed fibroblast activation in vitro and significantly attenuated pulmonary fibrosis in vivo. Together, these findings identify a lymph node-to-lung migration axis of GZMKCD8 T cells that drives fibroblast activation through TGF{beta}R1/ALK4 signalling, highlighting GZMK as a potential biomarker and therapeutic target in IPF.

ObjectivesTo evaluate the efficacy and safety of sitafloxacin-containing regimens versus non-sitafloxacin therapy in patients with nontuberculous mycobacterial (NTM) pulmonary disease, focusing on sputum/BALF conversion rate, time of sputum/BALF culture conversion and radiographic improvement. MethodsThis retrospective cohort study analyzed 149 adults (76 control group vs. 73 sitafloxacin group) with NTM pulmonary disease treated between 2021 to 2024. Inclusion criteria: (1) Sitafloxacin group: [&ge;] 3 months of sitafloxacin-based therapy; (2) Both groups: Confirmed diagnosis of NTM pulmonary disease and age [&ge;] 18 years old. Exclusion criteria: extrapulmonary/disseminated NTM, HIV, active tuberculosis, or incomplete clinical data. Primary endpoint: culture conversion rate and time to culture conversion. Secondary endpoints: radiographic improvement and adverse events (AEs). ResultsThe sitafloxacin group demonstrated significantly higher conversion rate (53.8% vs. 22.1%, P 0.001) and faster culture conversion than the control group without sitafloxacin (median 195 vs. 292 days, P 0.001). Radiographic improvement was more frequent with the sitafloxacin group (54.5% vs. 36.1%, P = 0.046). Compared to the control group, the sitafloxacin group exhibited no significant adverse events. ConclusionsSitafloxacin-based regimens accelerate microbiological clearance and promote radiographic healing in NTM pulmonary disease with good safety, positioning it as a viable drug for improved treatment of NTM infections.

BackgroundBronchiectasis is an increasingly recognized structural complication among patients with chronic obstructive pulmonary disease (COPD), yet evidence from Bangladesh remains limited. This study aimed to determine the prevalence, clinical characteristics, radiological patterns, and associated factors of bronchiectasis among COPD patients in tertiary-level hospitals. MethodsA cross-sectional study was conducted among 129 COPD patients regardless of age distribution, all are met GOLD criteria and underwent high-resolution computed tomography (HRCT). Data on sociodemographic, behavioral, clinical, radiological, laboratory, and quality-of-life characteristics were analyzed using descriptive statistics, chi-square tests, t-tests, correlation analyses, and binary logistic regression. ResultsBronchiectasis was detected in 73.6% of COPD patients, with cylindrical bronchiectasis being the most common subtype (48.4%). Patients with bronchiectasis had a significantly longer duration of COPD (7.58 {+/-} 3.36 years vs. 2.51 {+/-} 1.67 years; p < 0.001) and more frequent symptoms, including chronic cough (72.1%), purulent sputum (34.9%), and higher dyspnea grades. Mucus plugging showed a perfect association with bronchiectasis (p = 0.001). Significant predictors of bronchiectasis included rural residence (AOR 5.82; 95% CI 1.34-25.29) and smoking habit (AOR 3.69; 95% CI 1.01-13.49). A weak but significant negative correlation was found between serum albumin and CRP (r = -0.211; p = 0.016), indicating systemic inflammation, while smoking duration was negatively correlated with FEV{square} (r = -0.174; p = 0.048). Quality of life was markedly impaired, with over 70% reporting poor or fair status. ConclusionBronchiectasis is highly prevalent among COPD patients in Bangladesh and is associated with longer disease duration, greater symptom burden, functional impairment, structural lung abnormalities, and poor quality of life. Rural residence, smoking, and mucus plugging emerged as key determinants. Early HRCT-based screening, phenotype-specific management, reduction of biomass and tobacco exposure, and improved rural respiratory care are essential to mitigate disease progression and improve outcomes.

Background and AimsThe prognosis of interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) has not been studied as extensively as IPF. This study aimed to evaluate baseline factors associated with mortality in non-IPF ILD, including demographic characteristics, respiratory function test (RFT), comorbidities, and ILD subtypes. MethodsThis retrospective cohort study analysed prospectively collected data of patients with non-IPF ILD at a single tertiary centre in Malaysia (2010-2023). Patients without baseline RFT or HRCT were excluded. Survival was assessed using Kaplan-Meier analysis, and mortality predictors were identified using Cox regression. ResultsThe mean age was 60 {+/-} 15 years, with a male-to-female ratio of 1:3. Indian ethnicity constituted the largest group (n = 109, 47.6%). The mean baseline forced vital capacity (FVC) was 53.3 {+/-} 21% predicted. An FVC <50% predicted, age [&ge;]50 years at diagnosis, specific ILD subtypes, and ethnicity were independently associated with mortality. Compared with Malays, both Chinese (hazard ratio [HR] 9.86, 95% confidence interval [CI] 1.27-76.89, p = 0.037) and Indians (HR 8.59, 95% CI 1.14-64.69, p = 0.001) were associated with a higher risk of death. Kaplan-Meier analysis demonstrated significant differences in survival across non-IPF ILD subtypes (log-rank p = 0.048), with hypersensitivity pneumonitis showing the poorest prognosis (mean survival 6.1 years). ConclusionEthnicity emerged as an independent prognostic factor for mortality in non-IPF ILD. The underlying mechanisms remain unclear and may reflect differences in genetic variation, cultural factors, or environmental exposures. Larger prospective studies are required to validate these findings.

BackgroundThough a normal forced vital capacity (FVC) is typically thought to imply the absence of restriction, recent data suggest that restriction may in fact be common among patients with normal spirometry. However, the clinical significance of restriction with normal spirometry is unknown. Research QuestionWhat clinical characteristics and outcomes are associated with restriction with normal spirometry? Study Design and MethodsWe interpreted pulmonary function tests (PFTs) with both static and dynamic lung volume measurements performed between 2012 and 2025 at four pulmonary diagnostic labs. We used multivariable logistic regression to identify clinical characteristics associated with restriction among patients with normal spirometry and used a Cox proportional hazards model to assess the association of restriction with survival, adjusting for age, sex, forced expiratory volume in 1 second (FEV1) z-score, FVC z-score, and FEV1/FVC z-score. ResultsWe interpreted 83,886 PFTs from 47,597 patients (mean age 58.8 years, 59.8% female, 63.6% White). The prevalence of restriction among patients with normal spirometry was 25.7% Restriction with normal spirometry was more likely in older patients (adjusted odds ratio [aOR] 1.01 per year, 95% CI 1.01-1.01), in non-White patients (aOR 1.33, 95% CI 1.26-1.41), and in patients with a diagnosis (aOR 3.65, 95% CI 3.43-3.88) or radiographic evidence (aOR 3.02, 95% CI 2.79-3.28) of interstitial lung disease (ILD). Restriction with normal spirometry was less likely among female patients (aOR 0.64, 95% CI 0.60-0.67), and patients with a diagnosis (0.74, 95% CI 0.67-0.82) or radiographic evidence (aOR 0.81, 95% CI 0.73-0.89) of chronic obstructive pulmonary disease. Restriction with normal spirometry was associated with increased all-cause mortality (adjusted hazard ratio 1.45, 95% CI 1.34-1.57) as compared to normal spirometry without restriction. InterpretationRestriction with normal spirometry is associated with ILD and with decreased survival. Clinically significant ventilatory impairments are common in patients with normal spirometry.

BackgroundQuality of life (QoL), the highest prioritised outcome by children with bronchiectasis and their parents, is a patient-reported outcome measure increasingly considered essential when evaluating health and interventions. Despite this, there are no validated instruments that specifically measure QoL related to bronchiectasis in children. We aimed to develop and validate a new bronchiectasis child-specific parent-proxy QoL instrument (BC-QoL). MethodsWe developed a draft 44-item BC-QoL and subsequently conducted a prospective cohort study where 142 parents completed draft BC-QoL and six other measures: two validated cough scores, parent-proxy childrens acute cough-specific QoL, depression, anxiety and stress 21-item scale, RAND-36 and paediatric QoL (PedsQLTM4.0) to assess the convergent and discriminant validity of the BC-QoL. The questionnaires were completed over three weeks at different phases of their childs illness (stable state, exacerbation and/or recovery). Responses were analysed using psychometric and clinical impact techniques to reduce items and determine the instruments reliability and validity. Minimally important difference (MID) was also calculated. ResultsThe final 23-item BC-QoL instrument with its three domains (emotional, physical, social well-being) demonstrated high split half reliability (0.95), Cronbachs alpha (0.97), repeatability (intraclass coefficient=0.74, 95%CI 0.62-0.82), validity and responsiveness. BC-QoLs domains significantly correlated with that of PedsQLTM4.0 (Spearman correlations: emotional=0.43, social=0.41, physical=0.47). BC-QoLs MID ranged from 0.74 to 1.32. ConclusionBC-QoL, the first bronchiectasis child-specific QoL instrument, has evidence demonstrating its validity and reliability, and can be used to evaluate the impact and effectiveness of interventions and better understand the disease burden in children with bronchiectasis.