European Respiratory Journal最新文献

Background: A subset of COPD patients have high levels of eosinophils in the distal airways ("airway eosinophilia").

Objectives: To compare the gene expression of type 2 inflammation in airway epithelial brushings of COPD patients with and without airway eosinophilia and to investigate the changes after inhaled corticosteroids (ICS).

Methods: Post-hoc analyses of the DISARM randomised controlled trial investigated the expression of airway inflammation (type 1, 2, and 17), IL-13, and mast cell gene signatures at baseline and after 12-week ICS treatment. Gene signatures were generated from RNA sequencing of airway epithelial brushings. Airway eosinophilia was defined as eosinophils>1% of the total leukocyte count in bronchoalveolar lavage. Gene set enrichment analyses identified upregulated canonical pathways in airway eosinophilia.

Results: Among 58 COPD patients, 38% had airway eosinophilia at baseline. Patients with airway eosinophilia had more severe airflow obstruction and more radiographic emphysema than the non-eosinophilia group. Patients with airway eosinophilia showed a higher epithelial expression of type 2 airway inflammation and IL-13 and mast cell activation at baseline, but the expression of type 1 and type 17 airway inflammation was similar to patients without airway eosinophilia. The airway eosinophilia group showed an upregulation of canonical pathways related to type 2 immune response and asthma. Treatment with ICS for 12 weeks reduced the epithelial expression of type 2 inflammation and mast cell gene signatures in patients with airway eosinophilia, while this change was not significant in patients without airway eosinophilia.

Conclusions: Airway eosinophilia marks a subset of COPD patients with increased airway epithelial expression of type 2 inflammation and a response to ICS treatment.

Background: Tuberculosis remains the leading cause of death among people with HIV. The aim of this study was to describe the incidence of tuberculosis (TB), explore risk factors and to calculate their population attributable fractions (PAF) in people with HIV across Europe, stratified by region.

Method: Longitudinal study of people with HIV aged>18 years with follow-up from either 1/1/2012, or cohort enrolment, until date of TB diagnosis, last visit, death, or 31/12/2022. Factors associated with TB, in particular antiretroviral therapy status and smoking, were analysed using multivariable Poisson regression.

Results: A total of 38 837 participants with HIV with a median follow-up of 7.7 (4.3-10.4) years. Overall, 306 TB cases were diagnosed during 275 811 person-years of follow-up (PYFU; incidence rate (IR) 1.03/1000 PYFU, 95% CI 0.91-1.11). 3.3% (n=81/2428) participants had incident TB in Eastern Europe (IR 6.13, 4.93-7.62). Overall, the IR decreased from 2.03 (1.53-2.68) in 2012 to 0.44 (0.20-0.97) in 2022. Modifiable risk factors were smoking (adjusted incidence rate ratio 2.94; 95%CI1.62-5.34) and not receiving antiretroviral therapy (versus on; 3.29; 2.36-4.58). A history of TB pre-baseline increased the risk of recurrence (aIRR 7.77; 95%CI 4.09-14.74). The PAF for not receiving antiretroviral therapy was 34.6% in Non-Eastern Europe and 31.2% in Eastern Europe.

Conclusions: TB incidence has been decreasing among people with HIV, but remains more frequent in Eastern Europe. Improvement of antiretroviral therapy-coverage and adherence and a focus on non-communicable disease risk factors such as smoking could reduce the incidence of TB.

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by significant, but poorly understood immune and antibody responses. This study examines the spatial transcriptomes and microenvironmental niches of antibody-producing plasma cells and tertiary lymphoid structures (TLS) in IPF lungs, and the molecular pathways influencing antibody accumulation and pulmonary fibrosis.

Methods: Explant lung tissues from IPF patients and control normal lungs were used for spatial transcriptome assays and validating RNA-scope and immunofluorescence assays. Fibroblasts derived from IPF and control lungs were examined for their capability to attract plasma cells. Neutralizing antibodies were administered to investigate molecules affecting pulmonary plasma cell accumulation and fibrosis in bleomycin-treated mice.

Results: Human IPF lungs exhibited a remarkably widespread distribution of plasma cells and local antibodies in the fibrotic regions, disseminating from plasma cell-generating TLS. Novel mural cells wrapped the vessels in TLS regions, expressing CCR7 ligands that attracted T cells into TLS to promote plasma cell generation. Distinct IPF-associated fibroblasts further secreted CXCL12, providing an extramedullary niche to foster the dissemination and accumulation of plasma cells in the fibrotic regions. Neutralization of CCR7 ligands or CXCL12 reduced plasma cell and local antibody accumulation in the lungs of bleomycin-treated mice, leading to reduced TGFβ concentrations and alleviated pulmonary fibrosis.

Conclusions: Plasma cells and local antibodies are widely distributed in the fibrotic regions of IPF lungs. Distinct subsets of IPF-associated mural cells and fibroblasts promote pathological plasma cell and antibody accumulation. These findings have potential implications for strategies aimed at targeting immune and antibody responses to combat IPF.

Background: Sleep apnoea specific heart rate response (ΔHR) has been identified as a promising biomarker for stratifying cardiovascular (CV) risk, and predicting positive airway pressure (PAP) benefit in obstructive sleep apnoea (OSA). However, the need for prior manual scoring of respiratory events potentially limits the accessibility and reproducibility of ΔHR. We aimed to evaluate the association of pulse rate response to oxygen desaturations automatically derived from pulse oximetry (ΔHR_oxi) with CV risk in OSA.

Methods: ΔHR_oxi and ΔHR were measured in OSA patients from the IRSR Pays de la Loire Sleep Cohort (PLSC; n=5,002) and the HypnoLaus cohort (n=1,307). The primary outcome was major adverse CV events (MACEs), a composite of mortality, stroke, and cardiac diseases. Cox regressions analyses were conducted to evaluate the association of ΔHR_oxi and ΔHR categorized into low, midrange and high categories, with MACEs.

Results: MACEs occured in 768 patients from PLSC and 87 patients from HypnoLaus (median follow-up: 8.0 and 7.5 years respectively). Multivariable Cox models showed that subjects with high ΔHR_oxi (vs midrange) had higher risk of MACEs in PLSC (hazard ratio, HR: 1.42 [95% CI:1.18-1.71]) and HypnoLaus (HR: 1.72 [1.03-2.87]). Similar findings were observed for high ΔHR. Among 2,718 patients from PLSC treated with PAP, the association of PAP adherence (PAP use ≥4 h/night, vs non adherence) with MACEs was modified by baseline ΔHR and ΔHR_oxi (p for interaction<0.05).

Conclusions: ΔHR_oxi could constitute a reliable and easy to measure biomarker for stratifying CV risk and predicting CV benefit of PAP in OSA.

Background: Identification of COPD disease-causing genes is an important tool for understanding why COPD develops, who is at highest COPD risk, and how new COPD treatments can be developed. Previous COPD genetic studies have identified a highly significant genetic association near nephronectin (NPNT), a gene involved in tissue repair, but the biological mechanisms underlying this association are unknown.

Methods: Splicing quantitative trait locus analysis (sQTL) was performed to identify common genetic variants that alter RNA splicing in lung tissues. These lung sQTL signals were compared to COPD genetic association results near the NPNT gene using colocalization analysis to determine whether genetic risk for COPD in this region may act through altered splicing. Long read sequencing characterized COPD-associated splicing events at isoform-level resolution, and in silico protein structural analysis identified likely functional effects of this alternative splicing.

Results: An established COPD genetic risk variant, rs34712979_A, creates a cryptic splice acceptor site that causes four separate splicing changes im NPNT. The only of these splicing changes that was associated with COPD phenotypes involved a cassette exon (exon 3). Long read RNA sequencing demonstrated that the COPD risk allele causes a shift in isoform usage away from the dominant NPNT Isoform B precursor, which excludes exon 3, to the Isoform A precursor which splices-in exon 3. Alpha-fold protein structural analysis reveals that inclusion of this exon disrupts an EGF-like functional domain in NPNT.

Conclusion: Genetic variants in the nephronectin (NPNT) gene increase COPD risk by changing RNA splicing of NPNT in the lung.

Background: SOTERIA (NCT04796337) is an ongoing open-label study evaluating long-term safety, tolerability, and efficacy of sotatercept in participants with pulmonary arterial hypertension (PAH).

Methods: Eligible adults with PAH on stable background therapy who completed a prior sotatercept study without early discontinuation were enrolled. Participants received subcutaneous sotatercept (≤0.7 mg·kg^-1 Q3W). Safety and tolerability (primary objective) were assessed by adverse events (AEs), vital signs, and laboratory assessments. Efficacy (secondary objective) was assessed by 6-minute walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, WHO functional class (FC), clinical worsening events, and simplified French risk score (SFRS). The data cutoff date was 08NOV2023.

Results: Altogether, 426 participants were included in the analyses. Mean (sd) duration of exposure to sotatercept and follow-up in SOTERIA was 448.6 (172.93) days (range 21-923 days; 523 patient-years). Of 426 participants, 387 (90.8%) experienced AEs, 15 (3.5%) discontinued treatment, 129 (30.3%) had serious AEs, and 11 (2.6%) had serious AEs related to treatment. There were 12 deaths (2.8%). Among AEs of interest, epistaxis (22.1%) and telangiectasia (16.9%) were the most frequently reported individual events. Twenty-two (5.2%) participants had serious bleeding events, including 2 (0.5%) with serious bleeding leading to death (not related to treatment by investigator judgment). Improvements in 6MWD, NT-proBNP, WHO FC, and SFRS achieved from baseline of SOTERIA were largely maintained at one year, including in the placebo-crossed group.

Conclusion: Interim results of SOTERIA support the favorable benefit-risk of add-on sotatercept treatment in adults with PAH. Follow-up reports from this study will provide additional information on benefit/risk.

Objective: Post-COVID syndrome involves prolonged symptoms with multi-system and functional impairment lasting at least 12 weeks after acute COVID-19. We aimed to determine the efficacy of exercise-based rehabilitation interventions, either face-to-face or remote, compared to usual care in individuals experiencing Post-COVID syndrome following a hospitalisation of acute COVID-19.

Design: This single-blind randomised controlled trial compared two COVID exercise-based rehabilitation interventions (face-to-face or remote) to usual care in participants with Post-COVID syndrome following a hospitalisation. The interventions were either a face-to-face or remote eight-week program of individually prescribed exercise and education. The primary outcome was the change in Incremental Shuttle Walking Test (ISWT) following eight weeks of intervention (either face-to-face or remote) compared to usual care. Other secondary outcomes were measured including health related quality of life (HRQoL), and exploratory outcomes included lymphocyte immunotyping.

Results: 181 participants (55% male, mean [sd] age 59 [12] years, length of hospital stay 12 [19] days) were randomised. There was an improvement in the ISWT distance following face-to-face rehabilitation (mean 52 [95% CI 19 to 85]m, p=0·002) and remote rehabilitation (mean 34 [95% CI 1 to 66]m, p=0·047) compared to usual care alone. There were no differences between groups for HRQoL of self-reported symptoms. Analysis of immune markers revealed significant increases in naïve and memory CD8+ T cells following face-to-face rehabilitation versus usual care alone (p<0·001, n=31).

Conclusion: Exercise-based rehabilitation improved short-term exercise capacity in Post-COVID syndrome following an acute hospitalisation and showed potential for beneficial immunomodulatory effects.