Objective: Cell death leading to circulating nucleosomes and histones is a critical step in the pathogenesis of sepsis and contributes to lethality. Activated protein C was demonstrated to attenuate the harmful effects of histones. The objective of this retrospective study was to evaluate whether nucleosomes correlate with the severity of the inflammatory response and mortality in children suffering from severe meningococcal sepsis. Furthermore, we wanted to study the effects of infusion of protein C on nucleosome levels in children with septic purpura.
Design: Retrospective analysis of nucleosome levels in children suffering from meningococcal sepsis treated with either placebo or protein C.
Setting: Pediatric intensive care unit of a tertiary care university center.
Patients: In a randomized, placebo-controlled study, either protein C or placebo was administered to 38 children suffering from meningococcal sepsis. Nucleosome levels have been measured retrospectively in these 38 children suffering from meningococcal sepsis.
Measurements and Main Results: Twenty-eight children were treated with protein C and 10 received placebo. Nucleosome levels were significantly higher in nonsurvivors (n = 9) at any time point measured as compared to survivors (n = 29). Nucleosome levels significantly correlated with organ dysfunction scores, cytokines, and parameters for coagulation. Patients treated with protein C had significantly higher activated protein C levels than children receiving placebo. We could not find a clear effect of activated protein C on nucleosome levels in these patients.
Conclusion: Circulating nucleosomes correlated with the severity of the inflammatory response and were associated with mortality in children suffering from meningococcal sepsis. We show that protein C administration does not decrease nucleosome levels in these patients.
From the Department of Immunopathology (SZ, FS), Sanquin Research at CLB and Landsteiner Laboratory of the AMC, Amsterdam, The Netherlands; Department of Hematology (SZ), Academic Medical Center, Amsterdam, The Netherlands; Department of Pediatrics (ME, EDdK, JAH), Division of Pediatric Intensive Care, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Immunology (ME), Erasmus MC, University Medical Center, Rotterdam, The Netherlands; Cardiovascular Biology Research Program (CTE), Oklahoma Medical Research Foundation, Oklahoma, OK; Baxter BioScience (KV), Vienna, Austria; Division of Dermatology and Internal Medicine (CEH), University Medical Center, Utrecht, The Netherlands.
Supported, in part, by a grant from Baxter Bioscience, Vienna, Austria, in 2000. Dr. Zeerleder is supported by an unrestricted grant of Viropharma, and this work was supported by a grant of the Landsteiner Foundation for Blood Transfusion Research (LSBR 0817).
Dr. Esmon is a consultant for Portola, Bayer, and Artisan; received honoraria from Bayer and has stock options with Portola. He has pending patents on histones for therapeutic use and biomarkers for prognosis and monoclonal antibodies against activated protein C. He also received funding from HHMI. The remaining authors have not disclosed any potential conflicts of interest.
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