Detection of In Vivo Inflammasome Activation for Predicting Sepsis Mortality
Jing Cui, Stephanie Oehrl, Fareed Ahmad, Thorsten Brenner, Florian Uhle, Christian Nußhag, Christoph Rupp, Felix Funck, Stefan Meisel, Markus A. Weigand, Christian Morath, Knut Schäkel
Abstract
Sepsis is a severe life-threatening syndrome caused by dysregulated host responses to infection. Biomarkers that allow for monitoring the patient’s immune status are needed. Recently, a flow cytometry-based detection of in vivo inflammasome activation by formation of cytoplasmic aggregates of ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) has been proposed. Here we report on the frequency of ASC-speck + leukocytes correlating with the survival of sepsis. 25 patients with sepsis were sampled consecutively for 7 days. Blood, serum samples and patient data were collected according to the guidelines of the PredARRT-Sep-Trial. Flow cytometric analysis was performed on fresh whole blood samples to investigate the formation of ASC-specks in leukocyte subsets. Serum samples were analyzed for production of IL-1ß, IL-18 and additional inflammatory markers. ASC-speck formation was found to be increased in leukocytes from sepsis patients compared to healthy donor controls. The absolute number of ASC-speck + neutrophils peaked on day 1. For monocytes, the highest percentage and maximum absolute number of ASC-speck + cells were detected on day 6 and day 7. Inflammatory cytokines were elevated on day 1 and declined thereafter, with exception of IL-18. Survival analysis showed that patients with lower absolute numbers of ASC-speck + monocytes (<1,650 cells/ml) on day 6 had a lower probability to survive, with a hazard ratio (HR) of 10.178. Thus, the frequency of ASC-speck + monocytes on day 6 after onset of sepsis may serve to identify patients at risk of death from sepsis.