• Aleksandra Leligdowicz, Jack Kamm, Katrina Kalantar, Alejandra Jauregui, Kathryn Vessel, Saharai Caldera, Paula Hayakawa Serpa, Jason Abbott, Xiaohui Fang, Xiaoli Tian, Arun Prakash, Kirsten Neudoerffer Kangelaris, Kathleen D Liu, Carolyn S Calfee, Charles Langelier, and Michael A Matthay.
• Cardiovascular Research Institute, University of California-San Francisco, San Francisco, California.
• Shock. 2022 Jun 1; 57 (6): 180190180-190.

BackgroundLimited studies have functionally evaluated the heterogeneity in early ex vivo immune responses during sepsis. Our aim was to characterize early sepsis ex vivo functional immune response heterogeneity by studying whole blood endotoxin responses and derive a transcriptional metric of ex vivo endotoxin response.MethodsBlood collected within 24 h of hospital presentation from 40 septic patients was divided into two fractions and incubated with media (unstimulated) or endotoxin. Supernatants and cells were isolated, and responses measured using: supernatant cytokines, lung endothelial permeability after supernatant exposure, and RNA expression. A transcriptomic signature was derived in unstimulated cells to predict the ex vivo endotoxin response. The signature was tested in a separate cohort of 191 septic patients to evaluate for association with clinical outcome. Plasma biomarkers were quantified to measure in vivo host inflammation.ResultsEx vivo response to endotoxin varied and was unrelated to immunosuppression, white blood cell count, or the causative pathogen. Thirty-five percent of patients demonstrated a minimal response to endotoxin, suggesting early immunosuppression. High ex vivo cytokine production by stimulated blood cells correlated with increased in vitro pulmonary endothelial cell permeability and was associated with attenuated in vivo host inflammation. A four-gene signature of endotoxin response detectable without the need for a functional assay was identified. When tested in a separate cohort of septic patients, its expression was inversely associated with hospital mortality.ConclusionsAn attenuated ex vivo endotoxin response in early sepsis is associated with greater host in vivo inflammation and a worse clinical outcome.Copyright © 2022 by the Shock Society.

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