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Multiplexed Plasma Immune Mediator Signatures Can Differentiate Sepsis and SIRS Patients
*Laura A Cahill1, *Kiyoshi Itagaki2, *Woon-Yong Kwon2, *Charlotte H Kirk2, *Brian Joughin3, *Michael B Yaffe2, *Leo E Otterbein2, *Nathan I Shapiro2, *James A Lederer1, Carl J Hauser2
1Brigham and Womens Medical Center, Boston, MA;2Beth Israel Deaconess Medical Center, Boston, MA;3Massachusetts Institute of Technology, Cambridge, MA

OBJECTIVES: Both sepsis and tissue injury release ‘danger signals’ thereby inducing SIRS. This makes discriminating infective from sterile SIRS difficult in surgical patients. Developing rapid diagnostic biomarker assays could help limit unnecessary antibiotic use and improve outcomes.
METHODS: We surveyed 76 cytokines in conditioned media from human blood mononuclear cells exposed to bacteria or sterile mitochondrial danger signals (mtDAMPs). Using those findings, we created a multiplex assay for 30 “analytes of interest.” We then assayed repository plasmas prospectively collected from patients presenting with a) bacteremia; b) septic shock (SIRS, SBP<90); c) “severe sepsis” (SIRS plus organ failure, usually oliguria) or d) trauma patients (ISS>15 with known circulating mtDAMPs). ER patients discharged without identified pathology were designated “Controls” (n=12/group).
RESULTS: Patterns defining innate immune mediator environmental deviation from normal were readily identified (see heatmap). Bacteremic patients had plasma immune environments similar to septic shock patients without positive blood cultures. “Severe sepsis” patients had plasma immune environments very similar to traumatic SIRS. IL-6, IL-8, IL-10, IL-1RA, CCL22, FLT3L, G-CSF and TGFβ all showed robust predictive power in discriminating between various groups via 5-15 fold differences in concentration (P-values <0.05 to 10-11).
CONCLUSIONS: Multiplex assays can define plasma environmental mediator patterns that distinguish populations with septic and sterile SIRS from normal controls and from each other. Large prospective studies are indicated to validate, operationalize and streamline this approach.


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