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Authors: Chloé Albert Vega 1 2Guy Oriol 3 4François Bartolo 3 5Jonathan Lopez 6Alexandre Pachot 4Thomas Rimmelé 7 8Fabienne Venet 7 9Véronique Leray 8Guillaume Monneret 7 9Benjamin Delwarde 8Karen Brengel-Pesce 3 4Julien Textoris 4 7 8François Mallet # 3 4 7Sophie Trouillet-Assant # 3 10

Abstract: The complexity of sepsis pathophysiology hinders patient management and therapeutic decisions. In this proof-of-concept study we characterised the underlying host immune response alterations using a standardised immune functional assay (IFA) in order to stratify a sepsis population. In septic shock patients, ex vivo LPS and SEB stimulations modulated, respectively, 5.3% (1/19) and 57.1% (12/21) of the pathways modulated in healthy volunteers (HV), highlighting deeper alterations induced by LPS than by SEB. SEB-based clustering, identified 3 severity-based groups of septic patients significantly different regarding mHLA-DR expression and TNFα level post-LPS, as well as 28-day mortality, and nosocomial infections. Combining the results from two independent cohorts gathering 20 HV and 60 patients, 1 cluster grouped all HV with 12% of patients. The second cluster grouped 42% of patients and contained all non-survivors. The third cluster grouped 46% of patients, including 78% of those with nosocomial infections. The molecular features of these clusters indicated a distinctive contribution of previously described genes defining a “healthy-immune response” and a “sepsis-related host response”. The third cluster was characterised by potential immune recovery that underlines the possible added value of SEB-based IFA to capture the sepsis immune response and contribute to personalised management.

Conflict of interest statement: CAV, GO, AP, KBP, JT and FM are employed by the in-vitro diagnostic company bioMérieux. FB is employed in a services company specialised in the management of data-related projects, Soladis. CAV, FM, STA and FB are co-inventors in one patent application. This does not alter the authors’ adherence to all the Scientific Reports policies on sharing data and materials. JL, TR, FV, VL, GM and BD declare no conflict of interest.

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