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

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. We performed multifaceted assessments of bronchoalveolar transcriptome, cytokines, microbiology, and clinical features to biologically dissect a cohort of patients with suspected severe pneumonia. Our data revealed three lung-restricted transcriptionally defined severe pneumonia endotypes (termed Pneumotypes (Pn)). All three Pneumotypes had comparable clinical presentations and severity of respiratory failure but critically had divergent outcomes. Pn1, the most common, was characterised by low alveolar cytokines, expanded tolerogenic macrophages and epithelial damage. Pn3 was characterised by neutrophil-monocyte infiltration, IL-6-STAT3 activation and longer duration of mechanical ventilation. Pn2 displayed the fastest resolution, exhibiting a balanced immune response and epithelial-endothelial repair signatures. Our work has identified mechanistically distinct phenotypes in the lungs of patients with suspected pneumonia and acute lung injury, providing new targets for personalised therapy.