Pub Date : 2025-12-18DOI: 10.1183/13993003.00070-2025
Stig Holm Ovesen,Søren Helbo Skaarup,Rasmus Aagaard,Nikolaj Raaber,Gitte Boier Tygesen,Thomas Nielsen,Charlotte Møgelvang,Jesper Wamberg,Peter Biesenbach,Christina Brandhof,Danny Yu,Jakob Grønnebæk Rhode,Christian Linde Larsen,Kas Zarandi,Christina Katrin Lehmann,Søren Majgaard Pedersen,Mads Damgaard Mørkenborg,Ronja Leth,Simon Thorgaard-Rasmussen,Philip Uhd,Bo Løfgren,Stefan Posth,Michael Dan Arvig,Bo Martin Bibby,Christian B Laursen,Hans Kirkegaard,Jesper Weile
BACKGROUNDPrevious trials have suggested that point-of-care ultrasound for emergency department (ED) patients with dyspnea increases the proportion of patients discharged within 24 h. We aimed to assess whether this effect could be confirmed.METHODSThis trial was a randomized controlled trial in ten Danish EDs. Adult patients presenting to the ED with dyspnea as the chief complaint were randomized to the addition or omission of focused lung and cardiac ultrasound. The primary outcome was the proportion of patients discharged alive within 24 h. Secondary outcomes included overall hospital length of stay, chest imaging utilization, and 72 h alive and revisit-free.RESULTSAmong 674 patients who were randomized between January 25, 2023, and August 23, 2024, 663 were included in the analysis. The primary outcome occurred in 141 (42.6%) of 331 patients in the intervention group versus 151 (45.5%) of 332 in the control group (risk difference: -2.9; 95% confidence interval: -10.4-4.7; p=0.45). The overall incidence rate of hospital discharges per person-days at risk was 0.28 in the intervention group versus 0.32 in the control group (hazard ratio: 0.93; 95% confidence interval: 0.79-1.08; p=0.35).CONCLUSIONSIn adult ED patients with dyspnea as chief complaint, a point-of-care ultrasound-driven diagnostic pathway did not alter the proportion of patients discharged alive within 24 h or the overall hospital length of stay compared with standard care.
{"title":"A Point-of-Care Ultrasound-Driven Diagnostic Pathway for Emergency Department Patients with Dyspnea: A Randomized Controlled Trial.","authors":"Stig Holm Ovesen,Søren Helbo Skaarup,Rasmus Aagaard,Nikolaj Raaber,Gitte Boier Tygesen,Thomas Nielsen,Charlotte Møgelvang,Jesper Wamberg,Peter Biesenbach,Christina Brandhof,Danny Yu,Jakob Grønnebæk Rhode,Christian Linde Larsen,Kas Zarandi,Christina Katrin Lehmann,Søren Majgaard Pedersen,Mads Damgaard Mørkenborg,Ronja Leth,Simon Thorgaard-Rasmussen,Philip Uhd,Bo Løfgren,Stefan Posth,Michael Dan Arvig,Bo Martin Bibby,Christian B Laursen,Hans Kirkegaard,Jesper Weile","doi":"10.1183/13993003.00070-2025","DOIUrl":"https://doi.org/10.1183/13993003.00070-2025","url":null,"abstract":"BACKGROUNDPrevious trials have suggested that point-of-care ultrasound for emergency department (ED) patients with dyspnea increases the proportion of patients discharged within 24 h. We aimed to assess whether this effect could be confirmed.METHODSThis trial was a randomized controlled trial in ten Danish EDs. Adult patients presenting to the ED with dyspnea as the chief complaint were randomized to the addition or omission of focused lung and cardiac ultrasound. The primary outcome was the proportion of patients discharged alive within 24 h. Secondary outcomes included overall hospital length of stay, chest imaging utilization, and 72 h alive and revisit-free.RESULTSAmong 674 patients who were randomized between January 25, 2023, and August 23, 2024, 663 were included in the analysis. The primary outcome occurred in 141 (42.6%) of 331 patients in the intervention group versus 151 (45.5%) of 332 in the control group (risk difference: -2.9; 95% confidence interval: -10.4-4.7; p=0.45). The overall incidence rate of hospital discharges per person-days at risk was 0.28 in the intervention group versus 0.32 in the control group (hazard ratio: 0.93; 95% confidence interval: 0.79-1.08; p=0.35).CONCLUSIONSIn adult ED patients with dyspnea as chief complaint, a point-of-care ultrasound-driven diagnostic pathway did not alter the proportion of patients discharged alive within 24 h or the overall hospital length of stay compared with standard care.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"82 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDNoonan syndrome (NS) is a RASopathy inherited in an autosomal dominant manner, mainly caused by gain-of-function variants activating the RAS/MAPK signalling pathway. Pulmonary hypertension (PH) may occur in NS, but its mechanisms, clinical characteristics, and outcomes remain poorly defined.METHODSWe analysed data from the French PH Network to characterize the phenotype of NS patients who develop PH, and conducted a systematic analysis of the literature.RESULTSSeven patients were identified from the French PH Network (male/female ratio: 1.1), with a median age at PH diagnosis of 9 years (range 5-21). Genetic analysis revealed five pathogenic variants in PTPN11 and one in SOS1. Associated features included facial dysmorphism, growth retardation, atrial septal defect and pulmonary valve stenosis. Hemodynamics showed severe precapillary PH without acute vasodilator response: mean pulmonary artery pressure 55 mmHg (40-78), cardiac output 3.95 L.min-1 (3.12-4.95) and pulmonary vascular resistance 13 WU (10-15.3). Computed tomography of the chest identified perivascular ground-glass opacities, mediastinal infiltration, dilated bronchial arteries, distal pulmonary vascular tortuosity and possible arteriovenous shunts. Five patients were treated with drugs approved for PAH. Three patients died and one underwent lung transplantation. Explanted lungs revealed plexiform lesions associated with diffuse lymphangiectasia. Twelve additional cases from the literature included seven with precapillary PH, four with postcapillary PH due to cardiomyopathy, and one without RHC.CONCLUSIONPrecapillary and postcapillary PH may complicate the course of NS, potentially in association with congenital heart defects and multisystem manifestations. Further studies are needed to better delineate the phenotype of PH in patients with NS.
{"title":"Pulmonary hypertension in patients with Noonan syndrome.","authors":"Julien Grynblat,Mathieu Farges,Pascal Magro,Laurent Savale,Maria-Rosa Ghigna,Julia Tagmouti,Xavier Jais,Athénaïs Boucly,Marilyne Levy,Fabrice Antigny,Olivier Meyrignac,Stanislas Lyonnet,Helene Cavé,Romain Nicolle,Sylvain Marchand-Adam,Olivier Sitbon,Florence Coulet,Marc Humbert,Damien Bonnet,David Montani","doi":"10.1183/13993003.01796-2025","DOIUrl":"https://doi.org/10.1183/13993003.01796-2025","url":null,"abstract":"BACKGROUNDNoonan syndrome (NS) is a RASopathy inherited in an autosomal dominant manner, mainly caused by gain-of-function variants activating the RAS/MAPK signalling pathway. Pulmonary hypertension (PH) may occur in NS, but its mechanisms, clinical characteristics, and outcomes remain poorly defined.METHODSWe analysed data from the French PH Network to characterize the phenotype of NS patients who develop PH, and conducted a systematic analysis of the literature.RESULTSSeven patients were identified from the French PH Network (male/female ratio: 1.1), with a median age at PH diagnosis of 9 years (range 5-21). Genetic analysis revealed five pathogenic variants in PTPN11 and one in SOS1. Associated features included facial dysmorphism, growth retardation, atrial septal defect and pulmonary valve stenosis. Hemodynamics showed severe precapillary PH without acute vasodilator response: mean pulmonary artery pressure 55 mmHg (40-78), cardiac output 3.95 L.min-1 (3.12-4.95) and pulmonary vascular resistance 13 WU (10-15.3). Computed tomography of the chest identified perivascular ground-glass opacities, mediastinal infiltration, dilated bronchial arteries, distal pulmonary vascular tortuosity and possible arteriovenous shunts. Five patients were treated with drugs approved for PAH. Three patients died and one underwent lung transplantation. Explanted lungs revealed plexiform lesions associated with diffuse lymphangiectasia. Twelve additional cases from the literature included seven with precapillary PH, four with postcapillary PH due to cardiomyopathy, and one without RHC.CONCLUSIONPrecapillary and postcapillary PH may complicate the course of NS, potentially in association with congenital heart defects and multisystem manifestations. Further studies are needed to better delineate the phenotype of PH in patients with NS.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"116 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1183/13993003.01112-2025
Moisés Selman,Ivette Buendia-Roldan,Annie Pardo
Idiopathic Pulmonary Fibrosis (IPF) is a progressive disease of unknown etiology, characterized by a radiological and/or morphological pattern of usual interstitial pneumonia. Its diagnosis is challenging, and disease progression is often variable and unpredictable. In recent years the introduction of Artificial Intelligence (AI), particularly machine-learning (ML) and deep-learning (DL) models, has shown the potential to improve the diagnosis, prognosis, and therapeutic strategies for IPF. As part of DL, convolutional neural network, enhance the accuracy of high-resolution computed tomography analysis, facilitating early and precise diagnosis. Likewise, predictive ML and DL models are being developed using clinical, morphological, transcriptional and imaging data to assess disease progression and stratify patients by risk, thereby improving prognosis evaluation. Furthermore, AI-driven drug discovery may optimize treatment strategies by identifying novel therapeutic targets, as recently demonstrated with the discovery of an NCK-interacting kinase inhibitor with strong antifibrotic properties. However, several challenges hamper widespread clinical integration and real-life implementation, including data heterogeneity, model interpretability, and the need for robust validation through large-scale, multicenter studies. Future research should prioritize the development of standardized models of AI in large cohorts of IPF patients, combining clinical, imaging, morphologic, multiomics and other data, and enhance model transparency to strengthen clinical confidence. With continued advancements, AI holds potential to improve IPF management, enabling early diagnosis, individualized prognosis, and targeted therapy, all aimed at improving patient outcomes. In this review, we explore the evolving role of AI in IPF management, its potential to support clinical decisions, and the challenges to its clinical integration.
{"title":"Artificial Intelligence in Idiopathic Pulmonary Fibrosis: Advances, Challenges, and Future Directions.","authors":"Moisés Selman,Ivette Buendia-Roldan,Annie Pardo","doi":"10.1183/13993003.01112-2025","DOIUrl":"https://doi.org/10.1183/13993003.01112-2025","url":null,"abstract":"Idiopathic Pulmonary Fibrosis (IPF) is a progressive disease of unknown etiology, characterized by a radiological and/or morphological pattern of usual interstitial pneumonia. Its diagnosis is challenging, and disease progression is often variable and unpredictable. In recent years the introduction of Artificial Intelligence (AI), particularly machine-learning (ML) and deep-learning (DL) models, has shown the potential to improve the diagnosis, prognosis, and therapeutic strategies for IPF. As part of DL, convolutional neural network, enhance the accuracy of high-resolution computed tomography analysis, facilitating early and precise diagnosis. Likewise, predictive ML and DL models are being developed using clinical, morphological, transcriptional and imaging data to assess disease progression and stratify patients by risk, thereby improving prognosis evaluation. Furthermore, AI-driven drug discovery may optimize treatment strategies by identifying novel therapeutic targets, as recently demonstrated with the discovery of an NCK-interacting kinase inhibitor with strong antifibrotic properties. However, several challenges hamper widespread clinical integration and real-life implementation, including data heterogeneity, model interpretability, and the need for robust validation through large-scale, multicenter studies. Future research should prioritize the development of standardized models of AI in large cohorts of IPF patients, combining clinical, imaging, morphologic, multiomics and other data, and enhance model transparency to strengthen clinical confidence. With continued advancements, AI holds potential to improve IPF management, enabling early diagnosis, individualized prognosis, and targeted therapy, all aimed at improving patient outcomes. In this review, we explore the evolving role of AI in IPF management, its potential to support clinical decisions, and the challenges to its clinical integration.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"22 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1183/13993003.01133-2025
Laurens J Ceulemans,Christelle M Vandervelde,Stephanie Everaerts,Christophe Dooms,Hannelore Geysen,Marianne Fontaine,Sofian Bouneb,Arne Neyrinck,Paul De Leyn,Wim Janssens,Walter Weder
OBJECTIVEA quarter of a century after NETT, lung volume reduction surgery (LVRS) remains an underused procedure with the notion of high mortality and morbidity, mainly recommended for upper lobe predominant heterogeneous emphysema. With advances in patient selection, minimally invasive surgery and improved recovery, this perception may be outdated. This study evaluates five-year single-centre outcome, including patients beyond traditional NETT criteria (non-upper lobe and non-heterogeneous morphology).METHODSThis prospective study included all consecutive LVRS procedures (08/2019-07/2024). Surgical, functional and quality of life outcomes (COPD assessment test (CAT) and St. Georgés Respiratory Questionnaire (SGRQ)) were analysed at 3 and 6 months, and then annually up to 3 years. Subanalysis compared markedly versus non-markedly heterogeneous morphology, and isolated versus non-isolated upper lobe disease.RESULTSA total of 223 procedures were performed in 191 patients with baseline median FEV1: 31%pred (IQR 27-37), RV 219%pred (203-250), 6MWD 358 m (291-439), CAT 22 (18-25) and SGRQ 62 (48-71). Thirty-day mortality was 0.5% (n=1). Hospital stay was 7 days (4-10); prolonged air leak occurred in 17.9%, infection in 2.2%. At 3 years (n=42/191), FEV1 improved to 38%pred (29-48), RV to 173%pred (148-199), CAT to 20 (17-24), and SGRQ to 55 (39-68), all statistically significant. Morphology was non-markedly heterogeneous in 57.6% and non-isolated upper lobe in 56%, with no significant difference in morbidity.CONCLUSIONSThis study demonstrates that LVRS performed in a specialised centre results in exceptionally low mortality, morbidity and meaningful clinical and functional improvement, supporting broader indications beyond classical NETT criteria.
{"title":"Low mortality and favourable outcome in lung volume reduction surgery for different emphysema morphologies.","authors":"Laurens J Ceulemans,Christelle M Vandervelde,Stephanie Everaerts,Christophe Dooms,Hannelore Geysen,Marianne Fontaine,Sofian Bouneb,Arne Neyrinck,Paul De Leyn,Wim Janssens,Walter Weder","doi":"10.1183/13993003.01133-2025","DOIUrl":"https://doi.org/10.1183/13993003.01133-2025","url":null,"abstract":"OBJECTIVEA quarter of a century after NETT, lung volume reduction surgery (LVRS) remains an underused procedure with the notion of high mortality and morbidity, mainly recommended for upper lobe predominant heterogeneous emphysema. With advances in patient selection, minimally invasive surgery and improved recovery, this perception may be outdated. This study evaluates five-year single-centre outcome, including patients beyond traditional NETT criteria (non-upper lobe and non-heterogeneous morphology).METHODSThis prospective study included all consecutive LVRS procedures (08/2019-07/2024). Surgical, functional and quality of life outcomes (COPD assessment test (CAT) and St. Georgés Respiratory Questionnaire (SGRQ)) were analysed at 3 and 6 months, and then annually up to 3 years. Subanalysis compared markedly versus non-markedly heterogeneous morphology, and isolated versus non-isolated upper lobe disease.RESULTSA total of 223 procedures were performed in 191 patients with baseline median FEV1: 31%pred (IQR 27-37), RV 219%pred (203-250), 6MWD 358 m (291-439), CAT 22 (18-25) and SGRQ 62 (48-71). Thirty-day mortality was 0.5% (n=1). Hospital stay was 7 days (4-10); prolonged air leak occurred in 17.9%, infection in 2.2%. At 3 years (n=42/191), FEV1 improved to 38%pred (29-48), RV to 173%pred (148-199), CAT to 20 (17-24), and SGRQ to 55 (39-68), all statistically significant. Morphology was non-markedly heterogeneous in 57.6% and non-isolated upper lobe in 56%, with no significant difference in morbidity.CONCLUSIONSThis study demonstrates that LVRS performed in a specialised centre results in exceptionally low mortality, morbidity and meaningful clinical and functional improvement, supporting broader indications beyond classical NETT criteria.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"15 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1183/13993003.00492-2025
Debbie Clements,Roya Babaei-Jadidi,Jan Johnson,Suzanne Miller,Niraj Shah,Jannie M B Sand,Diana J Leeming,Lee A Borthwick,Andrew J Fisher,Antoine Dufour,Simon R Johnson
RATIONALELAM is a rare cystic lung disease driven by nodules containing TSC2 -/- "LAM cells" and recruited LAM associated fibroblasts. Although rapamycin reduces lung function loss, some patients continue to decline, meaning additional therapies are needed.OBJECTIVESTo investigate how the LAM nodule environment affects LAM cell proliferation and the response to rapamycin.METHODSProteins altered in advanced LAM were identified using shotgun proteomics and immunohistochemistry in tissue from closely phenotyped patients. Genes associated with rapamycin insensitivity on LAM derived extracellular matrix were identified by RNA sequencing and validated using pharmacologic inhibitors.MEASUREMENTS AND MAIN RESULTSMore advanced disease was associated a greater decline in FEV1 when treated with rapamycin (p=0.005). In advanced LAM, using proteomics analysis, an upregulation of protein clusters comprising extracellular matrix, glucose metabolism and the actin cytoskeleton was identified. RNA sequencing and immunohistochemistry confirmed expression of collagens I and VI in LAM associated fibroblasts and LAM nodules, and increased markers of collagen turnover in patient serum (p=0.0048). Growth of LAM patient-derived cells in vitro was faster on LAM associated fibroblast-derived extracellular matrix (p<0.0001) and incompletely suppressed by rapamycin. RNA sequencing identified upregulation of pathways driving cell cycle control, transcription and metabolism by extracellular matrix. Tractable, pro-proliferative, upregulated genes included CDK7, GAS6, PLAUR and PLAU. Inhibitors of these pathways reduced LAM cell proliferation and enhanced the anti-proliferative effect of rapamycin.CONCLUSIONSExtracellular matrix deposition upregulates the expression of genes which may blunt the response to rapamycin but offer additional therapeutic opportunities for patients with established LAM.
{"title":"Extracellular Matrix Deposition Drives Disease Progression and Reduces Rapamycin Response in LAM.","authors":"Debbie Clements,Roya Babaei-Jadidi,Jan Johnson,Suzanne Miller,Niraj Shah,Jannie M B Sand,Diana J Leeming,Lee A Borthwick,Andrew J Fisher,Antoine Dufour,Simon R Johnson","doi":"10.1183/13993003.00492-2025","DOIUrl":"https://doi.org/10.1183/13993003.00492-2025","url":null,"abstract":"RATIONALELAM is a rare cystic lung disease driven by nodules containing TSC2 -/- \"LAM cells\" and recruited LAM associated fibroblasts. Although rapamycin reduces lung function loss, some patients continue to decline, meaning additional therapies are needed.OBJECTIVESTo investigate how the LAM nodule environment affects LAM cell proliferation and the response to rapamycin.METHODSProteins altered in advanced LAM were identified using shotgun proteomics and immunohistochemistry in tissue from closely phenotyped patients. Genes associated with rapamycin insensitivity on LAM derived extracellular matrix were identified by RNA sequencing and validated using pharmacologic inhibitors.MEASUREMENTS AND MAIN RESULTSMore advanced disease was associated a greater decline in FEV1 when treated with rapamycin (p=0.005). In advanced LAM, using proteomics analysis, an upregulation of protein clusters comprising extracellular matrix, glucose metabolism and the actin cytoskeleton was identified. RNA sequencing and immunohistochemistry confirmed expression of collagens I and VI in LAM associated fibroblasts and LAM nodules, and increased markers of collagen turnover in patient serum (p=0.0048). Growth of LAM patient-derived cells in vitro was faster on LAM associated fibroblast-derived extracellular matrix (p<0.0001) and incompletely suppressed by rapamycin. RNA sequencing identified upregulation of pathways driving cell cycle control, transcription and metabolism by extracellular matrix. Tractable, pro-proliferative, upregulated genes included CDK7, GAS6, PLAUR and PLAU. Inhibitors of these pathways reduced LAM cell proliferation and enhanced the anti-proliferative effect of rapamycin.CONCLUSIONSExtracellular matrix deposition upregulates the expression of genes which may blunt the response to rapamycin but offer additional therapeutic opportunities for patients with established LAM.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"8 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1183/13993003.00804-2025
Theodoros Karampitsakos, Minxue Jia, Bochra Tourki, Zainab Fatima, Bogdan Visinescu, Carole Y Perrot, Tamer Fadli, Amy Zhao, Avraham Unterman, Marc A Schneider, Debabrata Bandyopadhyay, Brenda M Juan-Guardela, Ioannis Vamvakaris, Antje Prasse, Imre Noth, Stephen Liggett, Michael Kreuter, Wonder Drake, Argyris Tzouvelekis, Joe G N Garcia, Erica Herzog, Naftali Kaminski, Panayiotis V Benos, Jose D Herazo-Maya
Background: The association between immune-cell-specific transcriptomic profiles and mortality in IPF is unknown.
Methods: We profiled peripheral blood mononuclear cells (PBMC) by single-cell RNA sequencing (scRNA-seq) and investigated which immune-cell-specific transcriptomic profile predicted IPF outcomes consistently. Prognostic accuracy was investigated in PBMC, Bronchoalveolar Lavage (BAL) and lung tissue. Findings were validated by flow cytometry, analysis of independent scRNA-seq datasets and cellular deconvolution. We investigated the function of this transcriptomic profile and its cellular source in lung tissue (overall sample size:1054, IPF:555, other:499). Connectivity map and LASSO regression were used to identify drug candidates and a subset of genes with prognostic potential, respectively.
Results: A 230-gene-up-score (Pittsburgh-PBMC) from CD14+CD163-HLA-DRlow monocytes predicted mortality in Chicago PBMC cohort (HR: 6.58, 95%CI:2.15-20.13, p=0.001), in BAL pooled analysis (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003) and negatively correlated with Forced Vital Capacity (FVC) in lung tissues (ρ=-0.2, p=0.02). CD14+CD163-HLA-DRlow monocytes were higher in progressive versus stable IPF (12.59%, 95%CI:9.66-16.23, versus 7.61%, 95%CI:6.68-10.21, p=0.014). High risk IPF patients had decreased expression of T-cell co-stimulatory genes (Pittsburgh and Chicago p<0.01). CD14+HLA-DRlow monocytes had higher expression of profibrotic, proangiogenic and chemotactic factors compared to CD14+HLA-DRhi monocytes (p<0.05). The 230-gene-up-score correlated with the SPP1+fibrosis-associated macrophages-gene-score in lung tissues (ρ=0.19, p<2.2e-16). Connectivity map identified drug categories to reverse the 230-gene-signature. A subset of six genes retained predictive performance (pooled PBMC cohorts -HR: 4.79, 95%CI:2.58-8.92, p<0.0001).
Conclusions: The transcriptome of CD14+CD163-HLA-DRlow monocytes is associated with increased mortality in patients with IPF. Its reversal should be investigated as a precision-based therapy in IPF.
{"title":"The transcriptome of CD14<sup>+</sup>CD163<sup>-</sup>HLA-DR<sup>low</sup> monocytes predicts mortality in Idiopathic Pulmonary Fibrosis.","authors":"Theodoros Karampitsakos, Minxue Jia, Bochra Tourki, Zainab Fatima, Bogdan Visinescu, Carole Y Perrot, Tamer Fadli, Amy Zhao, Avraham Unterman, Marc A Schneider, Debabrata Bandyopadhyay, Brenda M Juan-Guardela, Ioannis Vamvakaris, Antje Prasse, Imre Noth, Stephen Liggett, Michael Kreuter, Wonder Drake, Argyris Tzouvelekis, Joe G N Garcia, Erica Herzog, Naftali Kaminski, Panayiotis V Benos, Jose D Herazo-Maya","doi":"10.1183/13993003.00804-2025","DOIUrl":"10.1183/13993003.00804-2025","url":null,"abstract":"<p><strong>Background: </strong>The association between immune-cell-specific transcriptomic profiles and mortality in IPF is unknown.</p><p><strong>Methods: </strong>We profiled peripheral blood mononuclear cells (PBMC) by single-cell RNA sequencing (scRNA-seq) and investigated which immune-cell-specific transcriptomic profile predicted IPF outcomes consistently. Prognostic accuracy was investigated in PBMC, Bronchoalveolar Lavage (BAL) and lung tissue. Findings were validated by flow cytometry, analysis of independent scRNA-seq datasets and cellular deconvolution. We investigated the function of this transcriptomic profile and its cellular source in lung tissue (overall sample size:1054, IPF:555, other:499). Connectivity map and LASSO regression were used to identify drug candidates and a subset of genes with prognostic potential, respectively.</p><p><strong>Results: </strong>A 230-gene-up-score (Pittsburgh-PBMC) from CD14<sup>+</sup>CD163<sup>-</sup>HLA-DR<sup>low</sup> monocytes predicted mortality in Chicago PBMC cohort (HR: 6.58, 95%CI:2.15-20.13, p=0.001), in BAL pooled analysis (HR: 2.20, 95%CI: 1.44-3.37, p=0.0003) and negatively correlated with Forced Vital Capacity (FVC) in lung tissues (ρ=-0.2, p=0.02). CD14<sup>+</sup>CD163<sup>-</sup>HLA-DR<sup>low</sup> monocytes were higher in progressive <i>versus</i> stable IPF (12.59%, 95%CI:9.66-16.23, <i>versus</i> 7.61%, 95%CI:6.68-10.21, p=0.014). High risk IPF patients had decreased expression of T-cell co-stimulatory genes (Pittsburgh and Chicago p<0.01). CD14<sup>+</sup>HLA-DR<sup>low</sup> monocytes had higher expression of profibrotic, proangiogenic and chemotactic factors compared to CD14<sup>+</sup>HLA-DR<sup>hi</sup> monocytes (p<0.05). The 230-gene-up-score correlated with the SPP1<sup>+</sup>fibrosis-associated macrophages-gene-score in lung tissues (ρ=0.19, p<2.2e<sup>-</sup>16). Connectivity map identified drug categories to reverse the 230-gene-signature. A subset of six genes retained predictive performance (pooled PBMC cohorts -HR: 4.79, 95%CI:2.58-8.92, p<0.0001).</p><p><strong>Conclusions: </strong>The transcriptome of CD14<sup>+</sup>CD163<sup>-</sup>HLA-DR<sup>low</sup> monocytes is associated with increased mortality in patients with IPF. Its reversal should be investigated as a precision-based therapy in IPF.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1183/13993003.01171-2025
Anna Borrelli,Arianna Venturini,Daniela Guidone,Martina De Santis,Enza Montemitro,Federico Alghisi,Fabiana Ciciriello,Luis J V Galietta
Loss of CFTR chloride channel function is the basic defect in cystic fibrosis (CF), a genetic disease that particularly affects the respiratory system, with bacterial infection and severe inflammation. People with CF carrying the most frequent mutation (F508del) or many types of missense mutations can be efficiently treated with drugs, named correctors and potentiators, that improve CFTR protein processing and channel activity. These treatments are ineffective on nonsense mutations that lead to nonsense-mediated RNA decay (NMD) and CFTR protein truncation. We tested the efficacy of a triple combination of small molecules including the readthrough agent ELX-02, the CFTR corrector VX-809, and the eRF3A degrader CC-90009, on cultured airway epithelia from patients carrying the G542X mutation. The treatment resulted in a significant but relatively modest (three-fold) increase in CFTR function. Importantly, the efficacy of the triple drug combination was greatly amplified under inflammatory conditions, i.e. by exposing the epithelia to IL-4 (15-fold increase) or to IL-17A/TNF-α (9-fold increase). Similar effects were also found in epithelia with the W1282X mutation. The large rescue of CFTR function under inflammatory conditions was paralleled by the appearance of full-length CFTR protein and by the increase in CFTR mRNA. The effect of inflammatory stimuli could be mediated by enhanced translational readthrough and/or reduced NMD. Our results suggest that rescue of CFTR with nonsense mutations could be more effective than expected in vivo Our findings may also lead to the identification of novel targets to correct the effect of nonsense mutations in CF and other genetic diseases.
{"title":"Rescue of the CFTR chloride channel with nonsense mutations is markedly improved under inflammatory conditions.","authors":"Anna Borrelli,Arianna Venturini,Daniela Guidone,Martina De Santis,Enza Montemitro,Federico Alghisi,Fabiana Ciciriello,Luis J V Galietta","doi":"10.1183/13993003.01171-2025","DOIUrl":"https://doi.org/10.1183/13993003.01171-2025","url":null,"abstract":"Loss of CFTR chloride channel function is the basic defect in cystic fibrosis (CF), a genetic disease that particularly affects the respiratory system, with bacterial infection and severe inflammation. People with CF carrying the most frequent mutation (F508del) or many types of missense mutations can be efficiently treated with drugs, named correctors and potentiators, that improve CFTR protein processing and channel activity. These treatments are ineffective on nonsense mutations that lead to nonsense-mediated RNA decay (NMD) and CFTR protein truncation. We tested the efficacy of a triple combination of small molecules including the readthrough agent ELX-02, the CFTR corrector VX-809, and the eRF3A degrader CC-90009, on cultured airway epithelia from patients carrying the G542X mutation. The treatment resulted in a significant but relatively modest (three-fold) increase in CFTR function. Importantly, the efficacy of the triple drug combination was greatly amplified under inflammatory conditions, i.e. by exposing the epithelia to IL-4 (15-fold increase) or to IL-17A/TNF-α (9-fold increase). Similar effects were also found in epithelia with the W1282X mutation. The large rescue of CFTR function under inflammatory conditions was paralleled by the appearance of full-length CFTR protein and by the increase in CFTR mRNA. The effect of inflammatory stimuli could be mediated by enhanced translational readthrough and/or reduced NMD. Our results suggest that rescue of CFTR with nonsense mutations could be more effective than expected in vivo Our findings may also lead to the identification of novel targets to correct the effect of nonsense mutations in CF and other genetic diseases.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"8 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-11DOI: 10.1183/13993003.01435-2025
Nicole M Robertson,Arun K Sharma,Mingling Yang,Santa K Das,Trishul Siddharthan,Suzanne L Pollard,Natalie A Rykiel,Patricia Alupo,Oscar Flores-Flores,Bruce Kirenga,Ram K Chandyo,Shumonta A Quaderi,Laxman Shrestha,Robert A Wise,John R Hurst,William Checkley,
BACKGROUNDChronic bronchitis affects up to 40% of individuals with COPD and may serve as an early predictor of the disease and development of COPD. We investigated the prevalence, risk factors, and clinical outcomes associated with chronic bronchitis in three low- and middle-income countries (LMICs).METHODSWe conducted a population-based study of adults aged ≥40 years in Bhaktapur (Nepal), Lima (Peru), and Nakaseke (Uganda). Chronic bronchitis was defined as a productive cough several days per week for over four weeks. Multivariable log-binomial regression identified risk factors and outcomes associated with chronic bronchitis.RESULTSAmong 9664 participants (mean age 56.2 years, 51.0% male, 66.9% ever smokers), chronic bronchitis prevalence was 9.7%, with 31.5% of those also having COPD. Significant risk factors included older age (adjusted RR=1.54 per 19.8 years, 95% CI 1.4-1.7), male sex (1.18, 1.05-1.34), prior tuberculosis (1.45, 1.14-1.83), prior asthma diagnosis (2.11, 1.84-2.42), pack-years of tobacco use (1.16 per 10 pack-years, 1.14-1.18), family history of chronic respiratory diseases (1.69, 1.50-1.91), second-hand smoke exposure (1.45, 1.28-1.64), lower socioeconomic status quartile (1.22,1.07-1.39), and indoor biomass exposure (1.45, 1.13-1.64). Participants with chronic bronchitis experienced more breathlessness, worse respiratory health (higher St. George's Respiratory Questionnaire scores), and higher hospitalization rates (all p<0.001).CONCLUSIONSChronic bronchitis is common in LMIC settings and is associated with multiple modifiable risk factors, including second-hand smoke, biomass exposure, and prior respiratory disease. Addressing these factors may reduce disease burden and improve quality of life.
背景：慢性支气管炎影响多达40%的慢性阻塞性肺病患者，可能是慢性阻塞性肺病发病和发展的早期预测因子。我们调查了三个低收入和中等收入国家（LMICs）慢性支气管炎的患病率、危险因素和临床结果。方法我们在巴克塔普尔（尼泊尔）、利马（秘鲁）和Nakaseke（乌干达）进行了一项基于人群的研究，研究对象为年龄≥40岁的成年人。慢性支气管炎被定义为每周咳嗽几天，持续4周以上。多变量对数二项回归确定了与慢性支气管炎相关的危险因素和结局。结果9664名参与者（平均年龄56.2岁，51.0%为男性，66.9%曾经吸烟），慢性支气管炎患病率为9.7%，其中31.5%同时患有COPD。显著危险因素包括年龄较大（校正后RR=1.54 / 19.8年，95% CI 1.4-1.7）、男性（1.18,1.05-1.34）、既往结核病（1.45,1.14-1.83）、既往哮喘诊断（2.11,1.84-2.42）、烟草使用包年（1.16 / 10包年，1.14-1.18）、慢性呼吸系统疾病家族史（1.69,1.50-1.91）、二手烟暴露（1.45,1.28-1.64）、较低社会经济地位四分位数（1.22,1.07-1.39）和室内生物质暴露（1.45,1.13-1.64）。慢性支气管炎患者呼吸困难、呼吸系统健康状况更差（圣乔治呼吸问卷得分更高）、住院率更高（均p<0.001）。结论慢性支气管炎在低收入人群中很常见，并与多种可改变的危险因素有关，包括二手烟、生物质暴露和既往呼吸道疾病。解决这些因素可以减轻疾病负担，提高生活质量。
{"title":"A multi-country cohort study evaluating the prevalence, risk factors, lung function and clinical outcomes of chronic bronchitis in low- and middle-income countries.","authors":"Nicole M Robertson,Arun K Sharma,Mingling Yang,Santa K Das,Trishul Siddharthan,Suzanne L Pollard,Natalie A Rykiel,Patricia Alupo,Oscar Flores-Flores,Bruce Kirenga,Ram K Chandyo,Shumonta A Quaderi,Laxman Shrestha,Robert A Wise,John R Hurst,William Checkley, ","doi":"10.1183/13993003.01435-2025","DOIUrl":"https://doi.org/10.1183/13993003.01435-2025","url":null,"abstract":"BACKGROUNDChronic bronchitis affects up to 40% of individuals with COPD and may serve as an early predictor of the disease and development of COPD. We investigated the prevalence, risk factors, and clinical outcomes associated with chronic bronchitis in three low- and middle-income countries (LMICs).METHODSWe conducted a population-based study of adults aged ≥40 years in Bhaktapur (Nepal), Lima (Peru), and Nakaseke (Uganda). Chronic bronchitis was defined as a productive cough several days per week for over four weeks. Multivariable log-binomial regression identified risk factors and outcomes associated with chronic bronchitis.RESULTSAmong 9664 participants (mean age 56.2 years, 51.0% male, 66.9% ever smokers), chronic bronchitis prevalence was 9.7%, with 31.5% of those also having COPD. Significant risk factors included older age (adjusted RR=1.54 per 19.8 years, 95% CI 1.4-1.7), male sex (1.18, 1.05-1.34), prior tuberculosis (1.45, 1.14-1.83), prior asthma diagnosis (2.11, 1.84-2.42), pack-years of tobacco use (1.16 per 10 pack-years, 1.14-1.18), family history of chronic respiratory diseases (1.69, 1.50-1.91), second-hand smoke exposure (1.45, 1.28-1.64), lower socioeconomic status quartile (1.22,1.07-1.39), and indoor biomass exposure (1.45, 1.13-1.64). Participants with chronic bronchitis experienced more breathlessness, worse respiratory health (higher St. George's Respiratory Questionnaire scores), and higher hospitalization rates (all p<0.001).CONCLUSIONSChronic bronchitis is common in LMIC settings and is associated with multiple modifiable risk factors, including second-hand smoke, biomass exposure, and prior respiratory disease. Addressing these factors may reduce disease burden and improve quality of life.","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":"45 1","pages":""},"PeriodicalIF":24.3,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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