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

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. 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. Competing Interest Statement MDC is the inventor on a patent held by the Secretary of State for Health (UK government) EP2788503, which covers some of the genetic sequences used in this study. VN is a founder, director, and shareholder in Cambridge Infection Diagnostics (CID) which is a commercial company aimed at developing molecular diagnostics in infection and antimicrobial and AMR stewardship. ACM and SB are members of the Scientific Advisory Board of CID. ACM has received speaking fees from Boston Scientific, Biomerieux and ThermoFisher. All other authors declare no conflict of interest. Clinical Protocols https://zenodo.org/records/5081880 Funding Statement The study was funded by Addenbrookes Charitable Trust and the NIHR Cambridge Biomedical Resource Centre (Grant 18135 to Professor Dougan). This project is supported by the HealthatInnoHK, Innovation Technology Commission Funding. Dr Conway Morris was supported by a Clinical Research Career Development Fellowship from the Wellcome Trust (WT 2055214/Z/16/Z) and is currently supported by an MRC Clinician Scientist Fellowship (MR/V006118/1). Dr Mark Jeffrey was supported by a Clinical Research Fellowship Award (ACT 900361). Dr Davenport was supported by the Wellcome Trust [220540/Z/20/A]. The funders had no role in the analysis of data or decision to publish. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The prospective study was approved by the Leeds East Research Ethics Committee (17/YH/0286), Cambridge University Hospitals NHS Foundation Trust was the sponsor, and registered with clinicaltrials.gov (NCT03996330). Written informed consent was obtained from patients or proxy assent, with retrospective consent sought from patients who regained capacity whilst in hospital. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Correction of S Parmar name spelling on manuscript version (name correctly spelled on MedRxiv record) Data Availability All data produced in the present study are available upon reasonable request to the authors