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Peer-reviewedCC BYNature Communications

Pulmonary inflammation in severe pneumonia is characterised by compartmentalised and mechanistically distinct sub-phenotypes

  • Mark Jeffrey1,2
  • Josefin Bartholdson Scott3,2
  • Shyamanova Mazumdar1,4
  • Richard Joseph White3,5,2
  • Ellen E. Higginson3,6,2
  • Mailis Maes3,2
  • Sally Forrest3,7,2
  • Joana Pereira-Dias3,6,8
  • Surendra Parmar9,8
  • Emma Heasman-Hunt9,8
  • Martin D. Curran9,10
  • Petra Polgarova11,10
11 more authors
  • Jurgen Herre12,13
  • Els Wauters14,15,2
  • Diether Lambrechts16,17,2
  • Pierre Van Mol14,16,10
  • Cato Jacobs18,19,2
  • Joost Wauters18,19
  • Emma E. Davenport6
  • Stephen Baker20
  • Gordon Dougan B3,21
  • Vilas Navapurkar11
  • Andrew Conway Morris22,23
23 affiliations
  1. 1Division of Perioperative, Acute, Critical Care and Emergency Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
  2. 2University of Cambridge
  3. 3Cambridge Institute of Therapeutic Immunology & Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, UK
  4. 4Queen Mary University of London
  5. 5European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, UK
  6. 6Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
  7. 7The School of Medicine, University of St Andrews, St Andrews, UK
  8. 8Clinical Microbiology and Public Health Laboratory, UK Health Security Agency, Cambridge
  9. 9Clinical Microbiology and Public Health Laboratory, UK Health Security Agency, Cambridge, UK
  10. 10Addenbrookes Hospital, Cambridge
  11. 11John V Farman Intensive Care Unit, Addenbrooke's Hospital, Cambridge, UK
  12. 12Department of Respiratory Medicine, Addenbrooke's Hospital, Cambridge, UK
  13. 13Wellcome-Sanger Institute, Cambridge
  14. 14Department of Pneumology, University Hospitals Leuven, Leuven, Belgium
  15. 15Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
  16. 16Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
  17. 17VIB Center for Cancer Biology, VIB, Leuven, Belgium
  18. 18Laboratory for Clinical Infectious and Inflammatory Disorders, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
  19. 19Medical Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium
  20. 20A*STAR Infectious Diseases Labs (A*STAR IDL), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
  21. 21Centre for Translational Stem Cell Biology, LKS Faculty of Medicine, Hong Kong University, Hong Kong, China
  22. 22Division of Perioperative, Acute, Critical Care and Emergency Medicine, Department of Medicine, University of Cambridge, Cambridge, UK. [email protected]
  23. 23John V Farman Intensive Care Unit, Addenbrooke's Hospital, Cambridge, UK. [email protected]
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Abstract

Pneumonia is the leading infectious disease killer worldwide and commonly requires admission to critical care. Despite its prevalence, the underpinning biology of severe pneumonia remains incompletely understood. Here we perform multifaceted assessments of bronchoalveolar transcriptome, cytokines, microbiology, and clinical features to biologically characterise a cohort of patients with suspected severe pneumonia. Our data implicate three lung-restricted transcriptionally defined severe pneumonia endotypes (termed 'Pneumotypes' (Pn)). All three Pneumotypes have comparable clinical presentations and severity of respiratory failure but experience divergent outcomes. Pn1, the most common, is characterised by low alveolar cytokines, expanded tolerogenic macrophages and epithelial damage. Pn3 is characterised by immature neutrophil infiltration, IL-6-STAT3 activation and longer duration of mechanical ventilation. Pn2 displays the fastest resolution, exhibiting a balanced immune response and epithelial-endothelial repair signatures. We identify and validate mechanistically distinct phenotypes in the lungs of patients with suspected pneumonia and acute lung injury, implicating targets for personalised therapy.

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Cite

BibTeXRIS
BibTeX
@article{jeffrey2026pulmonary,
  title = {{Pulmonary inflammation in severe pneumonia is characterised by compartmentalised and mechanistically distinct sub-phenotypes}},
  author = {Mark Jeffrey and Josefin Bartholdson Scott and Shyamanova Mazumdar and Richard Joseph White and Ellen E. Higginson and Mailis Maes and Sally Forrest and Joana Pereira-Dias and Surendra Parmar and Emma Heasman-Hunt and Martin D. Curran and Petra Polgarova and Jurgen Herre and Els Wauters and Diether Lambrechts and Pierre Van Mol and Cato Jacobs and Joost Wauters and Emma E. Davenport and Stephen Baker and Gordon Dougan B and Vilas Navapurkar and Andrew Conway Morris},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-74190-x},
  url = {https://doi.org/10.1038/s41467-026-74190-x},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Pulmonary inflammation in severe pneumonia is characterised by compartmentalised and mechanistically distinct sub-phenotypes
AU  - Mark Jeffrey
AU  - Josefin Bartholdson Scott
AU  - Shyamanova Mazumdar
AU  - Richard Joseph White
AU  - Ellen E. Higginson
AU  - Mailis Maes
AU  - Sally Forrest
AU  - Joana Pereira-Dias
AU  - Surendra Parmar
AU  - Emma Heasman-Hunt
AU  - Martin D. Curran
AU  - Petra Polgarova
AU  - Jurgen Herre
AU  - Els Wauters
AU  - Diether Lambrechts
AU  - Pierre Van Mol
AU  - Cato Jacobs
AU  - Joost Wauters
AU  - Emma E. Davenport
AU  - Stephen Baker
AU  - Gordon Dougan B
AU  - Vilas Navapurkar
AU  - Andrew Conway Morris
PY  - 2026
DA  - 2026/06/23
JO  - Nature Communications
DO  - 10.1038/s41467-026-74190-x
UR  - https://doi.org/10.1038/s41467-026-74190-x
AB  - Pneumonia is the leading infectious disease killer worldwide and commonly requires admission to critical care. Despite its prevalence, the underpinning biology of severe pneumonia remains incompletely understood. Here we perform multifaceted assessments of bronchoalveolar transcriptome, cytokines, microbiology, and clinical features to biologically characterise a cohort of patients with suspected severe pneumonia. Our data implicate three lung-restricted transcriptionally defined severe pneumonia endotypes (termed 'Pneumotypes' (Pn)). All three Pneumotypes have comparable clinical presentations and severity of respiratory failure but experience divergent outcomes. Pn1, the most common, is characterised by low alveolar cytokines, expanded tolerogenic macrophages and epithelial damage. Pn3 is characterised by immature neutrophil infiltration, IL-6-STAT3 activation and longer duration of mechanical ventilation. Pn2 displays the fastest resolution, exhibiting a balanced immune response and epithelial-endothelial repair signatures. We identify and validate mechanistically distinct phenotypes in the lungs of patients with suspected pneumonia and acute lung injury, implicating targets for personalised therapy.
SN  - 2041-1723
ER  -