European Respiratory Journal最新文献

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis (BE). Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase, cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in BE, no drug that controls neutrophilic inflammation is licensed for the treatment of BE. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of neutrophil elastase) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in BE pathogenesis, and not just neutrophil elastase. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in BE and improve disease outcomes as a result. Clinical trials for CatC inhibitors in BE have reported positive Phase III results. In this narrative review, we discuss the role of high NSP activity in BE, and how this feature drives the associated morbidity and mortality seen in BE. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the BE lung, summarising clinical trial outcomes, and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in BE.

Background: COPD has high mortality, compounded by comorbid cardiovascular disease. We investigated two electrocardiogram (ECG) markers, Cardiac Infarction Injury Score (CIIS) and P pulmonale, as prognostic tools for adverse cardiopulmonary events in COPD.

Methods: Post hoc analysis of the IMPACT trial. Outcomes included odds (odds ratio [95% confidence intervals]) of adverse cardiopulmonary events stratified by CIIS threshold (<20/≥20) and P pulmonale (baseline). Events included all-cause death, hospitalisation/death, cardiovascular adverse event of special interest (CVAESI), severe COPD exacerbations, and moderate/severe COPD exacerbations. Effects of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus FF/VI or UMEC/VI based on CIIS and P pulmonale were also assessed.

Results: We included 9448 patients. Patients with CIIS ≥20 had greater odds of all-cause death (1.73[1.27-2.37]; p<0.001), hospitalisation/death (1.33[1.17-1.50]; p<0.001), CVAESI (1.27[1.08-1.48]; p<0.005), severe COPD exacerbations (1.41[1.21-1.64]; p<0.001) and moderate/severe COPD exacerbations (1.25[1.13-1.40]; p<0.001) versus CIIS <20. Patients with P pulmonale (versus without) had greater odds of all-cause death (2.25[1.54-3.29]; p<0.001), hospitalisation/death (1.51[1.28-1.79]; p<0.001), severe COPD exacerbations (2.00[1.65-2.41]; p<0.001) and moderate/severe COPD exacerbations (1.25[1.08-1.46]; p<0.001). A combined model demonstrated patients with CIIS ≥20 and P pulmonale had increased risk of all-cause death (3.38[1.23-9.30]; p=0.019), hospitalisation/death (1.61[1.14-2.22]; p=0.004), and rate of severe COPD exacerbations (1.89[1.22-2.91]; p=0.004) and moderate/severe COPD exacerbations (1.25[1.00-1.56]; p=0.046). The risk of all-cause death and CVAESI was reduced with FF/UMEC/VI versus UMEC/VI in patients with CIIS ≥20, but not CIIS <20.

Conclusions: These findings suggest potential clinical relevance of CIIS and P pulmonale as risk indicators for adverse cardiopulmonary events in COPD.

Background: Sensitisation to Aspergillus fumigatus is linked to worse outcomes in patients with chronic obstructive pulmonary disease (COPD), however, its prevalence and clinical implications in domestic (residential) settings remains unknown.

Methods: Individuals with COPD (n=43) recruited in Singapore had their residences prospectively sampled and assessed by shotgun metagenomic sequencing including indoor air, outdoor air, and touch surfaces (total: 126 specimens). The abundance of environmental A. fumigatus and the occurrence of A. fumigatus (Asp f) allergens in the environment were determined and immunological responses to A. fumigatus allergens determined in association with clinical outcomes including exacerbation frequency. Findings were validated in 12 individuals (31 specimens) with COPD in Vancouver, Canada, a climatically different region.

Results: 157 metagenomes from 43 homes were assessed. Eleven and nine separate Aspergillus spp. were identified in Singapore and Vancouver respectively. Despite climatic, temperature, and humidity variation, A. fumigatus was detectable in the environment from both locations. The relative abundance of environmental A. fumigatus was significantly associated with exacerbation frequency in both Singapore (r=0.27, p=0.003) and Vancouver (r=0.49, p=0.01) and individuals with higher Asp f 3 sensitisation responses lived in homes with a greater abundance of environmental Asp f 3 allergens (p=0.037). Patients exposed and sensitised to Asp f 3 allergens demonstrated a higher rate of COPD exacerbations at 1-year follow-up (p=0.021).

Conclusion: Environmental A. fumigatus exposure in the home environment including air and surfaces with resulting sensitisation carries pathogenic potential in individuals with COPD. Targeting domestic A. fumigatus abundance may reduce COPD exacerbations.