European Respiratory Journal最新文献

Pulmonary fibrosis (PF) is the most prevalent and severe form of end-stage interstitial lung disease. Macrophages are crucial players in inflammation-induced PF, but the mechanisms driving macrophage polarization and their specific roles in PF pathogenesis remain poorly understood. Here, we demonstrate that both YAP and TAZ are activated in lung macrophages from patients with PF as well as in mice with bleomycin-induced PF. Myeloid-specific Yap/Taz deletion resulted in reduced recruitment of monocyte-derived alveolar macrophages (Mo-AMs), impaired inflammatory responses, decreased PF, and enhanced alveolar epithelial cell regeneration following bleomycin treatment. Conversely, the expression of a constitutively active YAP mutant (YAP^5SA) exacerbated bleomycin-induced PF by increasing Mo-AM recruitment, elevating expression of proinflammatory and profibrotic markers, and impairing alveolar epithelial cell regeneration. We demonstrate that YAP/TAZ-CCL2 signaling plays a crucial role in bleomycin-induced PF, as blocking CCL2 with a neutralizing antibody effectively abrogated the YAP^5SA-induced recruitment of Mo-AMs, inflammatory and fibrotic responses. Additionally, we reveal that the YAP/TAZ-MBD2-TGFβ1-pSMAD2 signaling axis is crucial not only for profibrotic macrophage polarization but also for their crosstalk with lung fibroblasts, driving the fibroblast-to-myofibroblast transition. Collectively, these findings suggest that targeting aberrant YAP/TAZ activity to modulate inflammatory and fibrotic response could be a promising strategy for the prevention and treatment of PF.

Objective: To compare the effectiveness and safety of tofacitinib (TOF) versus calcineurin inhibitor (CNI) as initial immunosuppressive regimen for anti-melanoma differentiation-associated gene 5-positive dermatomyositis with interstitial lung disease (MDA5+DM-ILD).

Methods: Adult Chinese patients with newly-diagnosed MDA5+DM-ILD (ILD course<3 months) from five tertiary referral centres between April 2014 and January 2023 were included for this retrospective cohort study. The primary effectiveness endpoint was lung transplantation-free survival within 1 year. Propensity score-based inverse probability of treatment weighting (IPTW) was applied for adjustment in this real-world study.

Results: In the eligible cohort, a total of 94 (32.4%) and 105 (46.7%) patients died or underwent lung transplantation within 1 year in the TOF group (n=290) and the CNI group (n=225), respectively. After adjustment by IPTW, patients' lung transplantation-free survival rate within 1 year was significantly higher in the TOF group compared to the CNI group (log-rank p=0.013). Multivariable Cox analysis performed in the IPTW dataset revealed the hazard ratio of TOF versus CNI for 1-year survival was 0.72 (95% CI, 0.56 to 0.94, p=0.013). The adjusted difference of survival rate was 9.3% (95%CI 2.8% to 15.8%). Alternative analytic strategies yielded consistent results in sensitivity analyses. Patients less than 60 years old, without RPILD, or with baseline PaO₂/FiO₂ ≥300 mmHg might benefit more from TOF. Opportunistic infection was the major treatment-related serious adverse event, with generally comparable incidence (42.4% versus 45.3%).

Conclusion: In this large multi-centre cohort study, tofacitinib showed significantly more benefits for 1-year lung transplantation-free survival than calcineurin inhibitors in MDA5+DM-ILD.

Background: Several major risk factors for COPD, such as population ageing, smoking rates and air pollution levels, are rapidly changing, causing inevitable changes in the population burden of COPD. We determined the excess direct costs of COPD and their trend from 2001 to 2020.

Methods: Using administrative health data from British Columbia, Canada, we created a retrospective matched cohort of physician-diagnosed COPD patients and non-COPD individuals. Excess direct medical costs (in 2020 Canadian dollars (CAD)) were estimated by analysing hospital records, outpatient services, medications and community care services. Comorbidity classes were assessed using International Classification of Diseases codes. Excess COPD costs were estimated as the adjusted difference in direct medical costs between the COPD and non-COPD cohorts.

Results: There were 208 554 and 404 703 individuals in the COPD and non-COPD cohorts, respectively (47.8% female; mean baseline age 69.1 and 68.2 years, respectively). Direct medical costs for COPD were CAD 9224 per patient-year compared to CAD 3396 per patient-year for non-COPD, giving rise to excess costs of CAD 5828 (95% CI 5759-5897) per patient-year. Excess costs increased by 48% over the study period. Excess costs due to comorbidities were CAD 3588 (95% CI 3554-3622) per patient-year, with cardiovascular-related conditions alone exceeding the costs attributed to COPD (CAD 1375 versus 904 per patient-year).

Conclusions: Despite multifaceted prevention and management initiatives, COPD-related economic burden is increasing, with the majority of costs due to comorbid conditions. Rising per-patient costs, combined with the flat or increasing prevalence of COPD in many jurisdictions, indicates a significant increase in COPD burden.

Objective: Gene expression (transcriptomics) studies have revealed potential mechanisms of interstitial lung disease (ILD), yet sample sizes of studies are often limited and between-subtype comparisons are scarce. The aim of this study was to identify and validate consensus transcriptomic signatures of ILD subtypes.

Methods: We performed a systematic review and meta-analysis of fibrotic ILD transcriptomics studies using an individual participant data approach, and included studies examining bulk transcriptomics of human adult ILD samples and excluding those focusing on individual cell populations. Patient-level data and expression matrices were extracted from 43 studies and integrated using a multivariable integrative algorithm to develop ILD classification models.

Results: Using 1459 samples from 24 studies, we identified transcriptomic signatures for idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), idiopathic nonspecific interstitial pneumonia (NSIP), and systemic sclerosis-associated ILD (SSc-ILD) against control samples, which were validated on 308 samples from 8 studies (area under receiver operating curve [AUC]=0.99 [95% CI: 0.99-1.00], HP AUC=0.91 [0.84-0.99], NSIP AUC=0.94 [0.88-0.99], SSc-ILD AUC=0.98 [0.93-1.00]). Significantly, meta-analysis allowed, for the first time, identification of robust lung transcriptomics signatures to discriminate IPF (AUC=0.71 [0.63-0.79]) and HP (AUC=0.76 [0.63-0.89]) from other fibrotic ILDs, and unsupervised learning algorithms identified putative molecular endotypes of ILD associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (D_LCO) % predicted. Transcriptomics signatures were reflective of both cell-specific and disease-specific changes in gene expression.

Conclusion: We present the first systematic review and largest meta-analysis of fibrotic ILD transcriptomics to date, identifying reproducible transcriptomic signatures with clinical relevance.

Background: The role of epigenetic aging in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter ≤2.5 μm (PM_2.5) and neighbourhood disadvantage exposures are associated with accelerated epigenetic aging, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD.

Methods: This multicentre, international, cohort study included patients with fILD from the University of Pittsburgh (UPitt, n=306) and University of British Columbia (UBC, n=170). Five-year PM_2.5 exposures were estimated using satellite-derived models. Neighbourhood disadvantage was calculated using U.S. and Canadian Census-based metrics. Epigenetic age difference (EAD=epigenetic age - chronological age) was calculated using GrimAge analysis of blood DNA methylation data. Linear models assessed associations of exposures with EAD. Cox models assessed associations of EAD with transplant-free survival. Causal mediation analysis evaluated EAD mediation of exposure-survival relationships.

Results: Median epigenetic age was 11.7 years older than chronological age in patients with fILD. In combined cohort analysis, each interquartile range (IQR) PM_2.5 increase was associated with 2.88 years (95%CI 1.39-4.38, p<0.001) increased EAD. In UPitt, each IQR neighbourhood disadvantage increase was associated with 1.16 years (95%CI 0.22-2.09, p=0.02) increased EAD. Increased EAD was associated with worse transplant-free survival (HR=1.17 per 1-year increase EAD, 95%CI 1.10-1.24, p<0.001), with EAD mediating 40% of PM_2.5-survival relationship and 59% of neighbourhood disadvantage-survival relationships. Epigenetic age was also more strongly associated with transplant-free survival than chronological age.

Conclusions: Epigenetic age acceleration is associated with worse survival and mediates adverse exposure impacts in fILD.

Background: Biologics can induce remission in some patients with severe asthma, however, little is known about pre-biologic disease trajectories and their association with outcomes from biological treatment. We aimed to identify long-term trajectories of disease progression in patients initiating biologics and investigate trajectory associations with disease burden and impact on biologic therapy efficacy.

Methods: Patients in the Danish Severe Asthma Registry initiating biologic therapy between 2016-2022 were included and followed retrospectively in prescription databases starting 1995. We performed sequence analysis for inhaled corticosteroid (ICS) treatment intensity over time combined with unsupervised trajectory clustering.

Results: In total, 755 patients were included and three pre-biologic disease trajectories were identified: Chronic severe asthma (26%), Gradual onset severe asthma (35%), Recent, sudden onset severe asthma (39%). Chronic severe asthma patients were older, had the longest disease duration (35 years), the most impaired pulmonary function, the highest comorbidity prevalence and the lowest employment rate. Recent, sudden onset severe asthma patients were younger, had shorter disease duration (5 years), more tobacco exposure and the least impaired lung function. Gradual onset severe asthma had an intermediate burden of disease. The Chronic severe asthma cluster demonstrated the lowest prevalence of remission (17%) compared to the Gradual onset severe asthma (29%) and Recent onset severe asthma (32%) clusters.

Conclusions: Three pre-biologic disease trajectories were identified, with increased disease duration and activity associating with asthma- and comorbidity burden. Early intervention may be key to prevent irreversible adverse outcomes for patients with severe asthma.