Search

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., (Copyright ©The authors 2025. For reproduction rights and permissions contact permissions@ersnet.org.)

Aim: To elucidate the important cellular and molecular drivers of pulmonary long COVID, we generated a single-cell transcriptomic map of the airway mucosa using bronchial brushings from patients with long COVID who reported persistent pulmonary symptoms., Method: Adults with and without long COVID were recruited from the general community in Greater Vancouver, Canada. The cohort was divided into those with pulmonary long COVID, which was defined as persons with new or worsening respiratory symptoms following ≥12 weeks from their initial acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (n=9); and control subjects defined as SARS-CoV-2 infected persons whose acute respiratory symptoms had fully resolved or individuals who had no history of acute coronavirus disease 2019 (COVID-19) (n=9). These participants underwent bronchoscopy from which a single cell suspension was created from bronchial brush samples and then sequenced., Results: A total of 56 906 cells were recovered for the downstream analysis, with 34 840 cells belonging to the pulmonary long COVID group, which strikingly showed a unique cluster of neutrophils in the pulmonary long COVID group (p<0.05). Ingenuity Pathway Analysis revealed that the neutrophil degranulation pathway was enriched across epithelial cell clusters. Differential gene expression analysis between the pulmonary long COVID and control groups demonstrated upregulation of inflammatory chemokines and epithelial barrier dysfunction across epithelial cell clusters, as well as over-expression of mucin genes across secretory cell clusters., Conclusion: A single-cell transcriptomic landscape of the small airways suggest that neutrophils may play a significant role in mediating the chronic small airway inflammation driving pulmonary symptoms of long COVID., Competing Interests: Conflict of interest: F.V. Geraveli reports grants from MiTACS Accelerate. S. Milne reports payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi Australia, The Limbic Australia and Research Review Australia, support for attending meetings from Sanofi Australia, Chiesi Australia and AstraZeneca, and a leadership role with Thoracic Society of Australia and New Zealand (NSW/ACT). R.L. Eddy reports grants from Michael Smith Health Research BC, Canadian Respiratory Research Network and Natural Sciences and Engineering Research Council Canada, consultancy fees from VIDA Diagnostics Inc., payment or honoraria for lectures, presentations, manuscript writing or educational events from Thorasys Thoracic Medical Systems Inc., and support for attending meetings from Canadian Institutes of Health Research – Institute of Circulatory and Respiratory Health. C. Gilchrist reports grants from Canadian institutes of Health Research. J. Leipsic reports consultancy fees from Heartflow, and stock (or stock options) with Heartflow. J.M. Leung reports support for the present study from Canadian Institutes of Health Research, grants from Canadian Institutes of Health Research and BC Lung Foundation, payment or honoraria for lectures, presentations, manuscript writing or educational events from BC Lung Foundation and University of British Columbia, participation on a data safety monitoring board with Enhance Quality Safety and Patient experience in Chronic Obstructive Pulmonary Disorder (EQuiP COPD), and leadership roles with Canadian Respiratory Research Network and the CanCOLD Study. D.D. Sin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, AstraZeneca and Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board with NHLBI. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Background: Long COVID impacts ∼10% of people diagnosed with coronavirus disease 2019 (COVID-19), yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129 Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID. Therefore, we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes., Methods: COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129 Xe MRI ∼14 months post-acute infection across three centres. Long COVID was defined as persistent dyspnoea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully recovered. 129 Xe MRI ventilation defect percent (VDP) and membrane-to-gas (Mem/Gas), red blood cell-to-membrane (RBC/Mem) and red blood cell-to-gas (RBC/Gas) ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction., Results: We evaluated 135 participants across three centres: 28 COVID-negative (mean±sd age 40±16 years), 34 fully recovered (42±14 years) and 73 long COVID (49±13 years). RBC/Mem (p=0.03) and forced expiratory volume in 1 s (FEV 1 ) (p=0.04) were different between long COVID and COVID-negative; FEV 1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster 1 was the youngest with normal MRI and mild gas trapping; Cluster 2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster 3 had mildly increased Mem/Gas with normal PFTs; and Cluster 4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern., Conclusions: We identified four 129 Xe MRI long COVID phenotypes with distinct characteristics. 129 Xe MRI can dissect pathophysiological heterogeneity of long COVID to enable personalised patient care., Competing Interests: Conflicts of interest: R.L. Eddy reports grants from Michael Smith Health Research BC, Canadian Respiratory Research Network, and Natural Sciences and Engineering Research Council Canada, consulting fees from VIDA Diagnostics Inc., payment or honoraria for lectures from Thorasys Thoracic Medical Systems Inc., support for attending meetings and/or travel from the Canadian Institutes of Health Research – Institute of Circulatory and Respiratory Health, and a leadership or fiduciary role for the Xenon MRI Clinical Trials Consortium (Steering Committee Member). D. Mummy reports consultancy fees from Polarean Imaging Plc. F.V. Gerayeli reports grants from MITACS Accelerate. J.A. Leipsic reports grants from GE Healthcare, consultancy fees and support for attending meetings and/or travel from Heartflow, and owns stock/stock options in Heartflow. J.M. Leung reports grants from the Canadian Institutes of Health Research and BC Lung Foundation, payment or honoraria for lectures, presentations, manuscript writing or educational events from the BC Lung Foundation, participation on a data safety monitoring board or advisory board for Enhance Quality Safety, and Patient Experience in Chronic Obstructive Pulmonary Disorder (EQuiP COPD), and leadership or fiduciary roles for the Canadian Respiratory Research Network and CanCOLD Study. B. Driehuys reports grants from Translating Duke Health (Duke Internal Award), royalties or licenses from Polarean Imaging, a leadership or fiduciary role with Polarean Imaging, and owns stock/stock options in Polarean Imaging. L.G. Que reports grants from Translating Duke Health (Duke Internal Award) and a leadership or fiduciary role as a member of the Xe MRI Consortium. M. Castro reports grants from the NIH, ALA, PCORI, AstraZeneca, Gala Therapeutics, Genentech, GSK, Novartis, Pulmatrix, Sanofi-Aventis, Shionogi and Theravance, consulting fees from Genentech, Teva, Sanofi-Aventis, Merck, Novartis, Arrowhead Pharmaceuticals, Allakos, Amgen, OM Pharma, Pfizer, Pioneering Medicines and GSK, payment or honoraria for lectures, presentations, manuscript writing or educational events from Amgen, AstraZeneca, Genentech, Regeneron, Sanofi-Aventis and Teva, and owns stock/stock options in Aer Therapeutics. D.D. Sin reports payment or honoraria for lectures, presentations, manuscript writing or educational events from GSK, AstraZeneca and Boehringer Ingelheim, and participation on a data safety monitoring board or advisory board for the NHLBI. P.J. Niedbalski reports grants from the Scleroderma Foundation (New Investigator Grant) and American Heart Association (CDA 930177), and consultancy fees, payment or honoraria for lectures, and support for attending meetings and/or travel from Polarean Imaging Plc. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Competing Interests: Conflict of interest: R.L. Eddy has nothing to disclose. Conflict of interest: G. Parraga has nothing to disclose.