Host derived biomarkers of inflammation, apoptosis, and endothelial activation are associated with clinical outcomes in patients with bacteremia and sepsis regardless of microbial etiology

References

• Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001; 29:1303–10; PMID:11445675; http://dx.doi.org/10.1097/00003246-200107000-00002
   PubMed Web of Science ®Google Scholar
• SEER Cancer Stat Fact Sheets [Internet]. [cited 2014 Oct 3]; Available from: http://seer.cancer.gov/statfacts/
   Google Scholar
• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med 2013; 41:580–637; PMID:23353941; http://dx.doi.org/10.1097/CCM.0b013e31827e83af
   PubMed Web of Science ®Google Scholar
• Kimbrell MR, Warshakoon H, Cromer JR, Malladi S, Hood JD, Balakrishna R, Scholdberg TA, David SA. Comparison of the immunostimulatory and proinflammatory activities of candidate Gram-positive endotoxins, lipoteichoic acid, peptidoglycan, and lipopeptides, in murine and human cells. Immunol Lett 2008; 118:132–41; PMID:18468694; http://dx.doi.org/10.1016/j.imlet.2008.03.009
   PubMed Web of Science ®Google Scholar
• Branger J, Knapp S, Weijer S, Leemans JC, Pater JM, Speelman P, Florquin S, van der Poll T. Role of Toll-like receptor 4 in gram-positive and gram-negative pneumonia in mice. Infect Immun 2004; 72:788–94; PMID:14742522; http://dx.doi.org/10.1128/IAI.72.2.788-794.2004
   PubMed Web of Science ®Google Scholar
• Elson G, Dunn-Siegrist I, Daubeuf B, Pugin J. Contribution of Toll-like receptors to the innate immune response to Gram-negative and Gram-positive bacteria. Blood 2007; 109:1574–83; PMID:17038528; http://dx.doi.org/10.1182/blood-2006-06-032961
   PubMed Web of Science ®Google Scholar
• Björk L, Andersson J, Ceska M, Andersson U. Endotoxin and Staphylococcus aureus enterotoxin A induce different patterns of cytokines. Cytokine 1992; 4:513–9; PMID:1292633; http://dx.doi.org/10.1016/1043-4666(92)90013-H
   PubMed Web of Science ®Google Scholar
• McConnell KW, McDunn JE, Clark AT, Dunne WM, Dixon DJ, Turnbull IR, Dipasco PJ, Osberghaus WF, Sherman B, Martin JR, et al. Streptococcus pneumoniae and Pseudomonas aeruginosa pneumonia induce distinct host responses. Crit Care Med 2010; 38:223–41; PMID:19770740; http://dx.doi.org/10.1097/CCM.0b013e3181b4a76b
   PubMed Web of Science ®Google Scholar
• Xu X-J, Tang Y-M, Liao C, Song H, Yang S-L, Xu W-Q, Shi S-W, Zhao N. Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Intensive Care Med 2013; 39:319–26; PMID:23179333; http://dx.doi.org/10.1007/s00134-012-2752-4
   PubMed Web of Science ®Google Scholar
• Abe R, Oda S, Sadahiro T, Nakamura M, Hirayama Y, Tateishi Y, Shinozaki K, Hirasawa H. Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia. Crit Care 2010; 14:R27; PMID:20202204; http://dx.doi.org/10.1186/cc8898
   PubMed Web of Science ®Google Scholar
• Feezor RJ, Oberholzer C, Baker HV, Novick D, Rubinstein M, Moldawer LL, Pribble J, Souza S, Dinarello CA, Ertel W, et al. Molecular characterization of the acute inflammatory response to infections with gram-negative vs. gram-positive bacteria. Infect Immun 2003; 71:5803–13; PMID:14500502; http://dx.doi.org/10.1128/IAI.71.10.5803-5813.2003
   PubMed Web of Science ®Google Scholar
• Kinasewitz GT, Yan SB, Basson B, Comp P, Russell JA, Cariou A, Um SL, Utterback B, Laterre PF, Dhainaut JF, et al. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit Care 2004; 8:R82–90; PMID:15025782; http://dx.doi.org/10.1186/cc2459
   PubMed Web of Science ®Google Scholar
• Tang BMP, McLean AS, Dawes IW, Huang SJ, Cowley MJ, Lin RCY. Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients. Crit Care Med 2008; 36:1125–8; PMID:18379237; http://dx.doi.org/10.1097/CCM.0b013e3181692c0b
   PubMed Web of Science ®Google Scholar
• Zahar JR, Timsit JF, Garrouste-Orgeas M, Français A, Vesin A, Vesim A, Descorps-Declere A, Dubois Y, Souweine B, Haouache H, et al. Outcomes in severe sepsis and patients with septic shock: pathogen species and infection sites are not associated with mortality. Crit Care Med 2011; 39:1886–95; PMID:21516036; http://dx.doi.org/10.1097/CCM.0b013e31821b827c
   PubMed Web of Science ®Google Scholar
• Ani C, Farshidpanah S, Bellinghausen Stewart A, Nguyen HB. Variations in organism-specific severe sepsis mortality in the United States: 1999-2008. Crit Care Med 2015; 43:65–77; PMID:25230374; http://dx.doi.org/10.1097/CCM.0000000000000555
   PubMed Web of Science ®Google Scholar
• Osuchowski MF, Welch K, Yang H, Siddiqui J, Remick DG. Chronic sepsis mortality characterized by an individualized inflammatory response. J Immunol 2007; 179:623–30; PMID:17579084; http://dx.doi.org/10.4049/jimmunol.179.1.623
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: tilting toward immunosuppression. Nat Med 2009; 15:496–7; PMID:19424209; http://dx.doi.org/10.1038/nm0509-496
   PubMed Web of Science ®Google Scholar
• Osuchowski MF, Craciun F, Weixelbaumer KM, Duffy ER, Remick DG. Sepsis chronically in MARS: systemic cytokine responses are always mixed regardless of the outcome, magnitude, or phase of sepsis. J Immunol 2012; 189:4648–56; PMID:23008446; http://dx.doi.org/10.4049/jimmunol.1201806
   PubMed Web of Science ®Google Scholar
• Tamayo E, Fernández A, Almansa R, Carrasco E, Heredia M, Lajo C, Goncalves L, Gómez-Herreras JI, de Lejarazu RO, Bermejo-Martin JF. Pro- and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock. Eur Cytokine Netw 2011; 22:82–7; PMID:21628135
   PubMed Web of Science ®Google Scholar
• Hutchins NA, Chung CS, Borgerding JN, Ayala CA, Ayala A. Kupffer cells protect liver sinusoidal endothelial cells from Fas-dependent apoptosis in sepsis by down-regulating gp130. Am J Pathol 2013; 182:742–54; PMID:23306157; http://dx.doi.org/10.1016/j.ajpath.2012.11.023
   PubMed Web of Science ®Google Scholar
• Gais P, Reim D, Jusek G, Rossmann-Bloeck T, Weighardt H, Pfeffer K, Altmayr F, Janssen K-P, Holzmann B. Cutting edge: Divergent cell-specific functions of MyD88 for inflammatory responses and organ injury in septic peritonitis. J Immunol 2012; 188:5833–7; PMID:22586041; http://dx.doi.org/10.4049/jimmunol.1200038
   PubMed Web of Science ®Google Scholar
• Lerolle N, Nochy D, Guérot E, Bruneval P, Fagon JY, Diehl JL, Hill G. Histopathology of septic shock induced acute kidney injury: apoptosis and leukocytic infiltration. Intensive Care Med 2010; 36:471–8; PMID:19924395; http://dx.doi.org/10.1007/s00134-009-1723-x
   PubMed Web of Science ®Google Scholar
• Yagi H, Soto-Gutierrez A, Navarro-Alvarez N, Nahmias Y, Goldwasser Y, Kitagawa Y, Tilles AW, Tompkins RG, Parekkadan B, Yarmush ML. Reactive bone marrow stromal cells attenuate systemic inflammation via sTNFR1. Mol Ther 2010; 18:1857–64; PMID:20664529; http://dx.doi.org/10.1038/mt.2010.155
   PubMed Web of Science ®Google Scholar
• Mohler KM, Torrance DS, Smith CA, Goodwin RG, Stremler KE, Fung VP, Madani H, Widmer MB. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993; 151:1548–61; PMID:8393046
   PubMed Web of Science ®Google Scholar
• Oberholzer A, Souza SM, Tschoeke SK, Oberholzer C, Abouhamze A, Pribble JP, Moldawer LL. Plasma cytokine measurements augment prognostic scores as indicators of outcome in patients with severe sepsis. Shock 2005; 23:488–93; PMID:15897799
   PubMed Web of Science ®Google Scholar
• Gamble JR, Drew J, Trezise L, Underwood A, Parsons M, Kasminkas L, Rudge J, Yancopoulos G, Vadas MA. Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ Res 2000; 87:603–7; PMID:11009566; http://dx.doi.org/10.1161/01.RES.87.7.603
   PubMed Web of Science ®Google Scholar
• Benest AV, Kruse K, Savant S, Thomas M, Laib AM, Loos EK, Fiedler U, Augustin HG. Angiopoietin-2 is critical for cytokine-induced vascular leakage. PLoS One 2013; 8:e70459; PMID:23940579; http://dx.doi.org/10.1371/journal.pone.0070459
   PubMed Web of Science ®Google Scholar
• Ziegler T, Horstkotte J, Schwab C, Pfetsch V, Weinmann K, Dietzel S, Rohwedder I, Hinkel R, Gross L, Lee S, et al. Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. J Clin Invest [Internet] 2013; 123(8):3436–3445
   Google Scholar
• Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE, Jr, Hui JJ, Chang KC, Osborne DF, Freeman BD, Cobb JP, Buchman TG, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001; 166:6952–63; PMID:11359857; http://dx.doi.org/10.4049/jimmunol.166.11.6952
   PubMed Web of Science ®Google Scholar
• Marsik C, Halama T, Cardona F, Wlassits W, Mayr F, Pleiner J, Jilma B. Regulation of Fas (APO-1, CD95) and Fas ligand expression in leukocytes during systemic inflammation in humans. Shock 2003; 20:493–6; PMID:14625471; http://dx.doi.org/10.1097/01.shk.0000097248.97298.ea
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Osmon SB, Chang KC, Wagner TH, Coopersmith CM, Karl IE. Accelerated lymphocyte death in sepsis occurs by both the death receptor and mitochondrial pathways. J Immunol 2005; 174:5110–8; PMID:15814742; http://dx.doi.org/10.4049/jimmunol.174.8.5110
   PubMed Web of Science ®Google Scholar
• De Freitas I, Fernández-Somoza M, Essenfeld-Sekler E, Cardier JE. Serum levels of the apoptosis-associated molecules, tumor necrosis factor-α/tumor necrosis factor type-I receptor and Fas/FasL, in sepsis. Chest 2004; 125:2238–46; http://dx.doi.org/10.1378/chest.125.6.2238
   PubMed Web of Science ®Google Scholar
• Li S, Zhang L, Yao Q, Li L, Dong N, Rong J, Gao W, Ding X, Sun L, Chen X, et al. Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains. Nature 2013; 501:242–6; PMID:23955153; http://dx.doi.org/10.1038/nature12436
   PubMed Web of Science ®Google Scholar
• Paunel-Görgülü A, Flohé S, Scholz M, Windolf J, Lögters T. Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis. Crit Care 2011; 15:R20; PMID:21232130; http://dx.doi.org/10.1186/cc9965
   PubMed Web of Science ®Google Scholar
• Ventetuolo CE, Levy MM. Biomarkers: diagnosis and risk assessment in sepsis. Clin Chest Med 2008; 29:591–603, vii; PMID:18954695; http://dx.doi.org/10.1016/j.ccm.2008.07.001
   PubMed Web of Science ®Google Scholar
• Jordana-Lluch E, Giménez M, Quesada MD, Rivaya B, Marcó C, Domínguez MJ, Arméstar F, Martró E, Ausina V. Evaluation of the Broad-Range PCR/ESI-MS technology in blood specimens for the molecular diagnosis of bloodstream infections. PLoS One 2015; 10:e0140865; PMID:26474394; http://dx.doi.org/10.1371/journal.pone.0140865
   PubMed Web of Science ®Google Scholar
• Haag H, Locher F, Nolte O. Molecular diagnosis of microbial aetiologies using SepsiTestTM in the daily routine of a diagnostic laboratory. Diagn Microbiol Infect Dis 2013; 76:413–8; PMID:23747029; http://dx.doi.org/10.1016/j.diagmicrobio.2013.04.027
   PubMed Web of Science ®Google Scholar
• Glavan BJ, Holden TD, Goss CH, Black RA, Neff MJ, Nathens AB, Martin TR, Wurfel MM. ARDSnet Investigators. Genetic variation in the FAS gene and associations with acute lung injury. Am J Respir Crit Care Med 2011; 183:356–63; PMID:20813889; http://dx.doi.org/10.1164/rccm.201003-0351OC
   PubMed Web of Science ®Google Scholar
• Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 2008; 36:309–32; PMID:18538699; http://dx.doi.org/10.1016/j.ajic.2008.03.002
   PubMed Web of Science ®Google Scholar
• Hirakata Y, Furuya N, Iwata M, Kashitani F, Ishikawa M, Yumoto S, Yasui K, Endoh H, Marui A, Kaku M, et al. Assessment of clinical significance of positive blood cultures of relatively low-virulence isolates. J Med Microbiol 1996; 44:195–8; PMID:8636936; http://dx.doi.org/10.1099/00222615-44-3-195
   PubMed Web of Science ®Google Scholar
• Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250–6; PMID:12682500; http://dx.doi.org/10.1097/01.CCM.0000050454.01978.3B
   PubMed Web of Science ®Google Scholar
• Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, Bastos PG, Sirio CA, Murphy DJ, Lotring T, Damiano A. The APACHE III prognostic system. Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991; 100:1619–36; PMID:1959406; http://dx.doi.org/10.1378/chest.100.6.1619
   PubMed Web of Science ®Google Scholar
• Opal SM, Garber GE, LaRosa SP, Maki DG, Freebairn RC, Kinasewitz GT, Dhainaut JF, Yan SB, Williams MD, Graham DE, et al. Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated). Clin Infect Dis 2003; 37:50–8; PMID:12830408; http://dx.doi.org/10.1086/375593
   PubMed Web of Science ®Google Scholar
• Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27:1230–51; PMID:10446814; http://dx.doi.org/10.1097/00003246-199907000-00002
   PubMed Web of Science ®Google Scholar
• Huttunen R, Syrjänen J, Vuento R, Laine J, Hurme M, Aittoniemi J. Apoptosis markers soluble Fas (sFas), Fas Ligand (FasL) and sFas/FasL ratio in patients with bacteremia: a prospective cohort study. J Infect 2012; 64:276–81; PMID:22207003; http://dx.doi.org/10.1016/j.jinf.2011.12.006
   PubMed Web of Science ®Google Scholar
• Mikacenic C, Hahn WO, Price BL, Harju-Baker S, Katz R, Kain KC, Himmelfarb J, Liles WC, Wurfel MM. Biomarkers of Endothelial Activation Are Associated with Poor Outcome in Critical Illness. PLoS One 2015; 10:e0141251; PMID:26492036; http://dx.doi.org/10.1371/journal.pone.0141251
   PubMedGoogle Scholar