Journal article
Pathogen characteristics are key determinants of distinct host response phenotypes of sepsis
The Journal of clinical investigation, Vol.136(6), 197346
03/16/2026
DOI: 10.1172/JCI197346
PMCID: PMC12987626
PMID: 41837287
Abstract
BACKGROUND. Sepsis encompasses considerable biological and clinical heterogeneity. Previously, 2 phenotypes (“hyperinflammatory” and “hypoinflammatory”) have been consistently identified within sepsis via latent class analysis. These phenotypes differ in their biological features, clinical outcomes, and therapeutic responses to interventions. Prior studies of sepsis heterogeneity have focused primarily on the host response. Here, we investigate the potential influence of the causative pathogen on sepsis heterogeneity and pathobiology.
METHODS. We performed a retrospective observational analysis of 8,280 critically ill patients with sepsis to identify associations between pathogen characteristics and the hyperinflammatory and hypoinflammatory patient phenotypes. We also performed controlled murine and swine modeling of sepsis and lung injury and a secondary analysis of 449 patients enrolled in the EUPHRATES randomized controlled trial.
RESULTS. Pathogen characteristics (pathogen identity, burden, virulence, and anatomic site of infection) were strongly and independently associated with the previously reported phenotypes. In a cohort of critically ill patients with sepsis, infection with gram-negative pathogens, primarily Enterobacterales spp. (e.g., Escherichia coli, Klebsiella pneumoniae), was strongly associated with the hyperinflammatory phenotype. The hyperinflammatory phenotype was also independently associated with increased pathogen burden, virulence, and initial anatomic site of infection. In controlled murine and swine modeling, both the identity and burden of the pathogen provoked key biological features of the hyperinflammatory phenotype. Among patients with sepsis, the prognostic value of lactate clearance varied substantially by phenotype. In a secondary analysis of a randomized trial of polymyxin B hemoadsorption (which removes circulating endotoxin), hypoinflammatory patients experienced worse survival.
CONCLUSIONS. Our results demonstrate the central importance of pathogen features in the clinical and biological heterogeneity of sepsis. Future studies of sepsis pathobiology and heterogeneity should expand their scope beyond the host response, as understanding pathogen-host interactions will be crucial in the development of precision therapeutic strategies to improve patient outcomes.
TRIAL REGISTRATION. EUPHRATES trial NCT01046669.
Details
- Title: Subtitle
- Pathogen characteristics are key determinants of distinct host response phenotypes of sepsis
- Creators
- Rishi Chanderraj - University of MichiganBrian Bartek - Washington University in St. LouisKathleen A. Stringer - University of MichiganMohamad H. Tiba - Environmental Research Institute of MichiganMichael W. Sjoding - University of MichiganYing He - University of MichiganMark Nuppnau - University of MichiganKale S. Bongers - University of IowaMark D. Adame - University of MichiganSunny S. Lou - Washington University in St. LouisV. Eric Kerschberger - Vanderbilt University Medical CenterMatthew M. Churpek - University of Wisconsin–MadisonCarolyn S. Calfee - University of California, San FranciscoSandhya Tripathi - Washington University in St. LouisDebra M. Foster - Iridian Spectral Technologies (Canada)John A. Kellum - University of PittsburghRobert P. Dickson - Environmental Research Institute of MichiganPratik Sinha - Washington University in St. Louis
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.136(6), 197346
- DOI
- 10.1172/JCI197346
- PMID
- 41837287
- PMCID
- PMC12987626
- NLM abbreviation
- J Clin Invest
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Publisher
- American Society for Clinical Investigation
- Grant note
- NIHAnn Arbor VA Medical Center
5P30AG024824, IK2CX002766, R01HL144599, K24HL159247, R01HL158626, R01HL173531, R35GM142992, R35GM145330, R35GM136312, K23HL166880, R35HL140026.This work is the result of NIH funding, in whole or in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central. center dot 5P30AG024824 and IK2CX002766 (RC). center dot R01HL144599, K24HL159247 (RPD). center dot R01HL158626 (MS). center dot R01HL173531, R35GM142992 (PS). center dot K08AR083015 (KSB). center dot R35GM145330 (MC). center dot R35GM136312 (KAS). center dot K23HL166880 (SL). center dot R35HL140026 (CSC). center dot The Ann Arbor VA Medical Center.
- Language
- English
- Date published
- 03/16/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985147204602771
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