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Publications

Journal Article Ahead of print

PubMed: 42025308 DOI: 10.1183/13993003.00113-2026

Pleural fluid neutrophil extracellular traps are associated with disease severity and risk of one-year mortality in pleural infection. An observational, international, multicohort study (TORPIDS-3).

Eur Respir J

Authors: Julia Y Chu, Samuel Hollins, Alguili Elsheikh, Stephen Gerry, Nikita Manoharan, Tryfon Zarganes-Tzitzikas, Yinzhou Feng, Elie Antoun, Eihab O Bedawi, John P Corcoran, Amy Gilmour, Federico Mei, Federica Monaco, Marco Tomasetti, Argyrios Tzouvelekis, Electra Koulousousa, Fotios Sampsonas, Malvika Bhatnagar, Ellice Z Chen, Paul E Brennan, Tao Dong, Ian D Pavord, Yuanlin Song, James D Chalmers, Julian C Knight, Najib M Rahman, Nikolaos I Kanellakis

Affiliations

  • Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Laboratory of Respiratory Translational Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Oxford Centre for Respiratory Medicine, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
  • Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
  • Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, University of Oxford, Oxford, UK.
  • Alzheimer's Research UK Oxford Drug Discovery Institute, Centre for Medicines Discovery, Nuffield Department of Medicine Research Building, University of Oxford, Oxford, UK.
  • Centre for Translational Immunology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
  • Respiratory Disease Unit, Department of Internal Medicine, University Hospital, Ancona, Italy.
  • Department of Biomedical Sciences and Public Health, Polytechnic University of Marche, Ancona, Italy.
  • Occupational Medicine, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
  • Respiratory Department, Patras University Hospital, University of Patras, Patras, Greece.
  • Pulmonary Critical Care and Sleep Medicine Department, Yale School of Medicine, New Haven, USA.
  • MRC Translational Immune Discovery Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Respiratory Medicine Unit, Oxford NIHR Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • Shanghai Key Laboratory of Lung Inflammation and Injury, Shanghai Respiratory Research Institute, Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
  • Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • These authors contributed equally to this work.
  • National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
  • Chinese Academy of Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

Abstract

BACKGROUND

Influx of large numbers of neutrophils is characteristic of pleural infection; however, neutrophil behaviour is understudied. We designed an observational multicohort study with the aims to discover and validate the association between neutrophil extracellular traps (NETs), disease severity, one-year survival, and the extent of sonographic septations.

METHODS

We analysed five independent datasets across three countries. The PILOT cohort (UK, n=215) was used as a discovery cohort for the association of NETs with disease severity with validation in four independent cohorts across three countries (UK, Greece, Italy, n=100). The PILOT cohort was further analysed to assess the association of NETs with one-year survival and the development and extent of sonographic septations. A separate cohort (the Oxford-Osler cohort, UK, n=30) was used to assess the relationship between NETs and the need for intrapleural enzyme therapy (IET) as rescue treatment.

RESULTS

A ten-unit increase in NETs was associated with 13% higher odds of being into a higher RAPID Score group (OR=1.13, 95% CI: 1.02-1.27, p=0.02), and this association remained robust in the independent validation cohort (OR=1.29, 95% CI: 1.11-1.40, p=0.0005). A ten-unit increase in NETs was also associated with a 15% higher risk of one-year mortality (HR=1.15, 95% CI: 1.01-1.32, p=0.04) independent of the RAPID Score, and a 17% higher likelihood of sonographic septations (OR=1.17, 95% CI: 1.01-1.37, p=0.04). Citrullinated fibrin was associated with septation severity (OR=1.10, 95% CI: 1.04-1.16, p=0.00005).

CONCLUSIONS

Pleural fluid NETs are a biomarker of disease severity and one-year mortality, in pleural infection. Future studies are required to assess the combination of NET-targeting strategies in combination with existing treatments.

MeSH

Mortality, Respiration, Neutrophils, Therapeutics, Extracellular Traps, Infections