Objective Severe early-onset-chronic obstructive pulmonary disease (SEO-COPD) represents the most severe form of COPD that manifests at an earlier age than common COPD. We hypothesise that this is driven by a partially different disease pathogenesis and investigated whether SEO-COPD has a distinct gene and miRNA expression profile.Methods RNA and small RNA sequencing was performed on lung tissue from 18 SEO-COPD, 22 common COPD and 32 non-COPD control subjects. Differential gene expression analysis was performed to identify SEO-COPD-specific genes and miRNA signatures. This was followed by gene set enrichment analysis, pathway enrichment, genome-wide association studies catalog interrogation, expression quantitative trait loci (eQTL) analysis, immunohistochemical validation, mRNA-miRNA integration and cellular deconvolution.Results We identified 105 SEO-COPD specific genes and three SEO-COPD specific miRNAs. Pathway analysis showed enrichment of B-cell-mediated adaptive immunity, chemotaxis and extracellular matrix (ECM) pathways among genes upregulated in SEO-COPD, including the B-cell marker CD79A and ECM component FBLN1 as leading-edge genes. More CD79A-positive infiltrates were observed in SEO-COPD lung tissue compared with control. For 15 SEO-COPD genes, COPD- or lung function-associated single nucleotide polymorphisms were identified, while eQTLs were identified for six SEO-COPD-associated genes. mRNA-miRNA integration identified miR331-3p as a potential regulator of the ECM-related gene expression changes in SEO-COPD.Conclusions The identified lung tissue gene and miRNA expression profiles for SEO-COPD support the presence of a distinct pathogenetic phenotype of SEO-COPD characterised by B-cell-mediated immunity, ECM dysregulation as well as genetic pre-disposition.
Background In recent years, China has experienced declining fine particulate matter (PM2.5) levels but rising ozone (O-3) levels. We aimed to examine the independent and joint associations of long-term exposure to PM2.5 and O-3 with all-cause mortality among patients with lung cancer and to estimate potential survival gains. Methods We included 172 845 lung cancer patients diagnosed in 2003-2022 from the Beijing Cancer Registry. Three-year average pre-diagnosis PM2.5 and O-3 were assigned using the China High Air Pollutants dataset. Cox proportional hazards models were used to estimate associations of PM2.5 and O-3 with mortality. Joint exposure-response patterns were examined using a two-dimensional tensor-product spline and quantified by the multiplicative interaction index. Model-estimated avoided deaths and extended expected lifespan (EEL) were calculated using counterfactual simulations based on 2013 exposure levels. Results Both PM2.5 and O-3 were associated with increased mortality among patients with lung cancer, with HRs of 1.111 for PM2.5 (95% CI 1.083 to 1.140) and 1.117 for O-3 (95% CI 1.070 to 1.166) per 10 mu g/m3 increase. A significant multiplicative interaction was observed between PM(2.5)and O-3, with statistically significant positive interactions mainly occurring at higher O3 concentrations (>105 & micro;g/m3). During 2016-2022, reductions in pre-diagnosis PM2.5 exposure were associated with 13 229 model-estimated avoided deaths and a 7.8-month increase in 5-year EEL. However, O-3 and the PM2.5-O-3 interaction offset approximately 40% of these benefits. Discussion PM2.5 reduction was associated with substantial survival gains among lung cancer patients, but rising O-3 and pollutant interactions partly offset these benefits, supporting coordinated multipollutant control.
Background Antimicrobial resistance (AMR) is a global threat for people with chronic lung infection; however, international AMR epidemiology in bronchiectasis and cystic fibrosis (CF) is poorly characterised. In this study, we retrospectively analyse international longitudinal AMR epidemiology in bronchiectasis and CF. Methods Microbiology data were analysed from 110 323 respiratory samples in 19 143 individuals with bronchiectasis or CF across 11 cities, eight countries, three continents between 2011 and 2024. Longitudinal AMR prevalence, multidrug-resistant (MDR) and extensively drug-resistant (XDR) prevalence and multiple antibiotic resistance (MAR) index were analysed by disease and country. Pilot analysis of concurrent/disjoint resistance in antimicrobial pairs and triplets in regional datasets was performed to inform combination or cyclical antimicrobial choice. Findings Geographic AMR differences were noted across pathogens in bronchiectasis and CF with increased Pseudomonas aeruginosa resistance in central/southern Europe and increased Klebsiella pneumoniae resistance in Hong Kong. MDR burden was high in emergent pathogens Escherichia coli (CF: MDR 32.6%; XDR 12.4%; bronchiectasis: MDR 39.2%; XDR 4.9%) and K. pneumoniae (CF: MDR 22.7%; XDR 15.6%; bronchiectasis: MDR 13.4%; XDR 1.5%). A longitudinal rise in P. aeruginosa AMR was seen in bronchiectasis across four centres for antipseudomonal aminoglycosides (p<0.001; OR/year 1.44; 95% CI 1.24 to 1.67), fluoroquinolones (p=0.002; OR/year 1.13; 95% CI 1.05 to 1.23), cephalosporins (p=0.005; OR/year 1.17; 95% CI 1.05 to 1.30), penicillins with beta-lactamase inhibitor (p=0.02; OR/year 1.18; 95% CI 1.03 to 1.35) and carbapenems (p=0.048; OR/year 1.11; 95% CI 1.00 to 1.23). Rising longitudinal K. pneumoniae AMR was seen for cephalosporins (p=0.01; OR/year 1.32; 95% CI 1.06 to 1.65) and carbapenems (p=0.04; OR/year 1.64; 95% CI 1.03 to 2.62). A significant increase in AMR, as measured by the MAR index, was observed in individuals with residual culture-positive CF receiving triple cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (p<0.001). Strong concurrent resistance was noted in bronchiectasis across regions with geographic variation in disjoint antimicrobial pair resistance. Conclusion We show a significant increasing international AMR burden in bronchiectasis and CF, with geographic variation and persistence post-CFTR modulator therapy.
More than 400 million people have chronic obstructive pulmonary disease (COPD), with exacerbations representing a major health burden. Although the overall incidence of invasive pulmonary aspergillosis (IPA) in patients with COPD with hospitalized exacerbation is only 1% to 4%, certain factors substantially increase this frequency. Risk factors compromising defenses against Aspergillus spp. in COPD patients include systemic or high-dose inhaled corticosteroids; comorbidities including bronchiectasis, diabetes, and cardiovascular disease; and prolonged courses of antibiotics. An international group of experts met to develop criteria for diagnosing IPA based on existing literature and consensus in nonventilated COPD patients. The preliminary diagnostic recommendations were further evaluated by additional experts using the Delphi methodology. A hospitalized exacerbation of COPD with 2 or more of the above clinical risk factors should prompt (1) a computed tomography scan of the chest; (2) sending a respiratory sample (sputum, induced sputum or bronchoscopy sample) for direct microscopy for fungi, high-volume fungal culture, and preferably Aspergillus PCR and, if a bronchoscopy sample is obtained, then also Aspergillus antigen (galactomannan); and (3) a serum sample for galactomannan and Aspergillus IgG. The combination of a high-risk COPD patient, with compatible imaging abnormalities and any 2 positive tests (2 samples or different tests on the same respiratory sample) for Aspergillus is sufficient to establish the diagnosis of IPA with enough confidence to initiate antifungal therapy and/or enroll the patient in a clinical or epidemiological study of IPA in COPD. Additional studies are required to augment performance data for most assays in COPD and validate the proposed diagnostic criteria.
