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* Department of Pathology,
Center for Statistical Consultation and Research, University of Michigan Medical School, Ann Arbor, MI 48109; and
Laboratory of Biomedical Science, Institute for Medical Research at North Shore-Long Island Jewish System, Manhasset, NY 11030
Late mortality in septic patients often exceeds the lethality occurring in acute sepsis, yet the immunoinflammatory alterations preceding chronic sepsis mortality are not well defined. We studied plasma cytokine concentrations preceding late septic deaths (days 6–28) in a murine model of sepsis induced by polymicrobial peritonitis. The late prelethal inflammatory response varied from a virtually nonexistent response in three of 14 to a mixed response in eight of 14 mice to the concurrent presence of nearly all measured cytokines, both proinflammatory and anti-inflammatory in three of 14 mice. In responding mice a consistent prelethal surge of plasma MIP-2 (1.6 vs 0.12 ng/ml in survivors; mean values), MCP-1 (2.0 vs 1.3 ng/ml), soluble TNF receptor type I (2.5 vs 0.66 ng/ml), and the IL-1 receptor antagonist (74.5 vs 3.3 ng/ml) was present, although there were infrequent increases in IL-6 (1.9 vs 0.03 ng/ml) and IL-10 (0.12 vs 0.04 ng/ml). For high mobility group box 1, late mortality was signaled by its decrease in plasma levels (591 vs 864 ng/ml). These results demonstrate that impeding mortality in the chronic phase of sepsis may be accurately predicted by plasma biomarkers, providing a mechanistic basis for individualized therapy. The pattern of late prelethal responses suggest that the systemic inflammatory response syndrome to compensatory anti-inflammatory response syndrome transition paradigm fails to follow a simple linear pattern.
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1 This work was supported in part by National Institutes of Health Grant GM 67189.
2 Address correspondence and reprint requests to Dr. Daniel G. Remick at the current address: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, 670 Albany Street, Room 441, Boston, MA 02118. E-mail address: remickd{at}bu.edu
3 Abbreviations used in this paper: SIRS, systemic inflammatory response syndrome; AUC, area under the curve; CARS, compensatory anti-inflammatory response syndrome; CLP, cecal ligation and puncture; HMGB-1, high mobility group box 1; IL-1ra, IL-1 receptor antagonist; MARS, mixed anti-inflammatory response syndrome; ROC, receiver operating characteristic; TNF-SRI, soluble TNF receptor type I; TNF-SRII, TNF receptor type II.
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