Inflammatory phenotypes in severe pneumonia: clinical evidence to mouse models for precision therapeutics
Abstract
Rationale: Hyperinflammatory and hypoinflammatory phenotypes previously identified in sepsis and acute respiratory distress syndrome may enable precision therapies, but their clinical relevance and translational modeling in severe pneumonia remain incompletely characterized.
Objectives: To examine biomarker-defined hyperinflammatory and hypoinflammatory phenotypes in critically ill patients with pneumonia (pulmonary sepsis), test whether the biomarkers that define these phenotypes identify subgroups and outcomes in a mouse model of bacterial pneumonia, and determine whether the mouse phenotypes respond differently to therapeutic interventions.
Methods: We performed latent class analysis (LCA) in a cohort of 548 ICU patients with pulmonary sepsis to identify inflammatory phenotypes and test the association of these phenotypes with clinical outcomes using validated classifier models. We developed a mouse model of pneumococcal pneumonia that recapitulated key aspects of these phenotypes and tested responses to dexamethasone and IL-6 receptor blockade.
Measurements and Main Results: Two phenotypes were identified in patients with pulmonary sepsis: a hyperinflammatory phenotype with more lung injury and increased mortality, and a hypoinflammatory phenotype with more favorable outcomes. Despite uniform pathogen exposure and baseline conditions, LCA identified 2 phenotypes in the mice with divergent trajectories (lung injury and mortality). Therapeutic benefit from anti-inflammatory interventions was observed exclusively in the more inflamed mice.
Conclusions: By integrating clinical data from human studies and experimental findings in a clinically relevant mouse model, this study provides a translational framework for developing phenotype-targeted therapies for critical illness, with the goal of improving patient outcomes.
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BibTeX
@article{taenaka2026inflammatory,
title = {{Inflammatory phenotypes in severe pneumonia: clinical evidence to mouse models for precision therapeutics}},
author = {Hiroki Taenaka and Bruno Evrard and Mazharul Maishan and Ruriko Watanabe and Narges Alipanah-Lechner and Sidney A Carrillo and Aartik Sarma and Natasha Spottiswoode and Kathryn M Sullivan and Melanie F Weingart and Hanjing Zhuo and Angelika Ringor and Carolyn Leroux and Olivia Chao and Chelsea Lin and Emma Schmiege and Taarini Hariharan and Liam Magee and Andrew Willmore and Suzanna Chak and Deanna Lee and Kim Bardillon and Carolyn Hendrickson and Jeffrey E Gotts and Charles R Langelier and Carolyn S Calfee and Michael A Matthay},
journal = {American Journal of Respiratory and Critical Care Medicine},
year = {2026},
month = jul,
doi = {10.1093/ajrccm/aamag402},
url = {https://doi.org/10.1093/ajrccm/aamag402},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Inflammatory phenotypes in severe pneumonia: clinical evidence to mouse models for precision therapeutics
AU - Hiroki Taenaka
AU - Bruno Evrard
AU - Mazharul Maishan
AU - Ruriko Watanabe
AU - Narges Alipanah-Lechner
AU - Sidney A Carrillo
AU - Aartik Sarma
AU - Natasha Spottiswoode
AU - Kathryn M Sullivan
AU - Melanie F Weingart
AU - Hanjing Zhuo
AU - Angelika Ringor
AU - Carolyn Leroux
AU - Olivia Chao
AU - Chelsea Lin
AU - Emma Schmiege
AU - Taarini Hariharan
AU - Liam Magee
AU - Andrew Willmore
AU - Suzanna Chak
AU - Deanna Lee
AU - Kim Bardillon
AU - Carolyn Hendrickson
AU - Jeffrey E Gotts
AU - Charles R Langelier
AU - Carolyn S Calfee
AU - Michael A Matthay
PY - 2026
DA - 2026/07/31
JO - American Journal of Respiratory and Critical Care Medicine
DO - 10.1093/ajrccm/aamag402
UR - https://doi.org/10.1093/ajrccm/aamag402
AB - Rationale: Hyperinflammatory and hypoinflammatory phenotypes previously identified in sepsis and acute respiratory distress syndrome may enable precision therapies, but their clinical relevance and translational modeling in severe pneumonia remain incompletely characterized. Objectives: To examine biomarker-defined hyperinflammatory and hypoinflammatory phenotypes in critically ill patients with pneumonia (pulmonary sepsis), test whether the biomarkers that define these phenotypes identify subgroups and outcomes in a mouse model of bacterial pneumonia, and determine whether the mouse phenotypes respond differently to therapeutic interventions. Methods: We performed latent class analysis (LCA) in a cohort of 548 ICU patients with pulmonary sepsis to identify inflammatory phenotypes and test the association of these phenotypes with clinical outcomes using validated classifier models. We developed a mouse model of pneumococcal pneumonia that recapitulated key aspects of these phenotypes and tested responses to dexamethasone and IL-6 receptor blockade. Measurements and Main Results: Two phenotypes were identified in patients with pulmonary sepsis: a hyperinflammatory phenotype with more lung injury and increased mortality, and a hypoinflammatory phenotype with more favorable outcomes. Despite uniform pathogen exposure and baseline conditions, LCA identified 2 phenotypes in the mice with divergent trajectories (lung injury and mortality). Therapeutic benefit from anti-inflammatory interventions was observed exclusively in the more inflamed mice. Conclusions: By integrating clinical data from human studies and experimental findings in a clinically relevant mouse model, this study provides a translational framework for developing phenotype-targeted therapies for critical illness, with the goal of improving patient outcomes.
SN - 1073-449X
SN - 1535-4970
ER -