Journal Article

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

Mazumdar, Shyamanova, Maes, Mailis, Bartholdson Scott, Josefin, Davenport, Emma E., Navapurkar, Vilas, Herre, Jurgen, Dougan, Gordon, Polgarova, Petra, Parmar, Surendra, Van Mol, Pierre, Jacobs, Cato, Forrest, Sally, Pereira-Dias, Joana, Conway Morris, Andrew, White, Richard J., Wauters, Els, Curran, Martin D., Lambrechts, Diether, Jeffrey, Mark, Wauters, Joost, Baker, Stephen, Higginson, Ellen, Heasman-Hunt, Emma

2026

Overview

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. Analysis of cell samples from pneumonia patients may indicate specific phenotypes associated with disease. Here the authors use a multi-omics approach to analyse transcriptional pneumotypes in severe pneumonia showing different features and inflammatory profiles in these different groups including differences in neutrophil phenotypes and cytokine responses.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/91 / 631/250/2502 / 631/250/255 / 631/250/347 / 692/308/575 / 692/699/1785/3193 / Acute Lung Injury - genetics / Acute Lung Injury - immunology / Acute Lung Injury - pathology / Alveoli / Body mass index / Bronchoalveolar Lavage Fluid / Bronchus / Cell activation / Cellular biology / Cytokines / Cytokines - metabolism / Extubation / Female / Genes / Hospitals / Humanities and Social Sciences / Humans / Illnesses / Immune response / Infections / Infectious diseases / Inflammation / Injury analysis / Interleukin-6 - immunology / Interleukin-6 - metabolism / Lavage / Leukocytes (neutrophilic) / Lung - immunology / Lung - metabolism / Lung - pathology / Lungs / Macrophages / Male / Mechanical ventilation / Microbiology / Mortality / multidisciplinary / Neutrophil Infiltration / Neutrophils / Neutrophils - immunology / Patients / Phenotype / Phenotypes / Pneumonia / Pneumonia - genetics / Pneumonia - immunology / Pneumonia - microbiology / Pneumonia - pathology / Respiratory distress syndrome / Respiratory failure / Science / Science (multidisciplinary) / Stat3 protein / STAT3 Transcription Factor - metabolism / Transcriptome / Transcriptomes