Abstract
Critically ill patients who display a systemic inflammatory response syndrome (SIRS) are prone to develop nosocomial infections. The challenge remains to distinguish as early as possible among SIRS patients those who are developing sepsis. Following a sterile insult, damage-associated molecular patterns (DAMPs) released by damaged tissues and necrotic cells initiate an inflammatory response close to that observed during sepsis. During sepsis, pathogen-associated molecular patterns (PAMPs) trigger the release of host mediators involved in innate immunity and inflammation through identical receptors as DAMPs. In both clinical settings, a compensatory anti-inflammatory response syndrome (CARS) is concomitantly initiated. The exacerbated production of pro- or anti-inflammatory mediators allows their detection in biological fluids and particularly within the bloodstream. Some of these mediators can be used as biomarkers to decipher among the patients those who developed sepsis, and eventually they can be used as prognosis markers. In addition to plasma biomarkers, the analysis of some surface markers on circulating leukocytes or the study of mRNA and miRNA can be helpful. While there is no magic marker, a combination of few biomarkers might offer a high accuracy for diagnosis.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Bone RC, Grodzin CJ, Balk RA (1997) Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 121:235–243
Adib-Conquy M, Cavaillon JM (2009) Compensatory anti-inflammatory response syndrome. Thromb Haemost 101:36–47
Cavaillon JM, Muñoz C, Fitting C, Misset B, Carlet J (1992) Circulating cytokines: the tip of the iceberg ? Circ Shock 38:145–152
Pierrakos C, Vincent JL (2010) Sepsis biomarkers: a review. Crit Care 14:R15
Kumar A, Roberts D, Wood KE, Light B, Parrillo JE et al (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34:1589–1596
Nobre V, Harbarth S, Graf JD, Rohner P, Pugin J (2008) Use of procalcitonin to shorten antibiotic treatment duration in septic patients: a randomized trial. Am J Respir Crit Care Med 177:498–505
Vincent JL, Beumier M (2013) Diagnostic and prognostic markers in sepsis. Expert Rev Anti Infect Ther 11:265–275
Reinhart K, Wiegand-Lohnert C, Grimminger F, Kaul M, Withington S et al (1996) Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study. Crit Care Med 24:733–742
Tillet W, Francis T (1930) Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 52:561–571
McCarty M (1947) The occurrence during acute infection of a protein not normally present in the blood. IV Crystallization of the C-reactive protein. J Exp Med 85:491–498
Osmand AP, Friedenson B, Gewurz H, Painter RH, Hofmann T et al (1977) Characterization of C-reactive protein and the complement subcomponent C1t as homologous proteins displaying cyclic pentameric symmetry (pentraxins). Proc Natl Acad Sci U S A 74:739–743
Meynaar IA, Droog W, Batstra M, Vreede R, Herbrink P (2011) In critically Ill patients, serum procalcitonin is more useful in differentiating between sepsis and SIRS than CRP, Il-6, or LBP. Crit Care Res Pract 2011:594645
Fitting C, Parlato M, Adib-Conquy M, Memain N, Philippart F et al (2012) DNAemia detection by multiplex PCR and biomarkers for infection in systemic inflammatory response syndrome patients. PLoS One 7:e38916
Su L, Han B, Liu C, Liang L, Jiang Z et al (2012) Value of soluble TREM-1, procalcitonin, and C-reactive protein serum levels as biomarkers for detecting bacteremia among sepsis patients with new fever in intensive care units: a prospective cohort study. BMC Infect Dis 12:157
Sierra R, Rello J, Bailen MA, Benitez E, Gordillo A et al (2004) C-reactive protein used as an early indicator of infection in patients with systemic inflammatory response syndrome. Intensive Care Med 30:2038–2045
Meisner M, Tschaikowsky K, Palmaers T, Schmidt J (1999) Comparison of procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations at different SOFA scores during the course of sepsis and MODS. Crit Care 3:45–50
Ohlin A, Bjorkqvist M, Montgomery SM, Schollin J (2010) Clinical signs and CRP values associated with blood culture results in neonates evaluated for suspected sepsis. Acta Paediatr 99:1635–1640
Povoa P, Coelho L, Almeida E, Fernandes A, Mealha R et al (2005) C-reactive protein as a marker of infection in critically ill patients. Clin Microbiol Infect 11:101–108
Tsalik EL, Jaggers LB, Glickman SW, Langley RJ, van Velkinburgh JC et al (2012) Discriminative value of inflammatory biomarkers for suspected sepsis. J Emerg Med 43:97–106
Tschaikowsky K, Hedwig-Geissing M, Schmidt J, Braun GG (2011) Lipopolysaccharide-binding protein for monitoring of postoperative sepsis: complemental to C-reactive protein or redundant? PLoS One 6:e23615
Tschaikowsky K, Hedwig-Geissing M, Braun GG, Radespiel-Troeger M (2011) Predictive value of procalcitonin, interleukin-6, and C-reactive protein for survival in postoperative patients with severe sepsis. J Crit Care 26:54–64
Schmit X, Vincent JL (2008) The time course of blood C-reactive protein concentrations in relation to the response to initial antimicrobial therapy in patients with sepsis. Infection 36:213–219
Boraey N, Sheneef A, Mohammad M, Yousef L (2012) Procalcitonin and C- reactive protein as diagnostic markers of neonatal sepsis. Aust J Basic Appl Sci 6:108–114
Simon L, Gauvin F, Amre DK, Saint-Louis P, Lacroix J (2004) Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 39:206–217
Yu CW, Juan LI, Wu MH, Shen CJ, Wu JY et al (2013) Systematic review and meta-analysis of the diagnostic accuracy of procalcitonin, C-reactive protein and white blood cell count for suspected acute appendicitis. Br J Surg 100:322–329
Yu CW, Juan LI, Hsu SC, Chen CK, Wu CW et al (2013) Role of procalcitonin in the diagnosis of infective endocarditis: a meta-analysis. Am J Emerg Med 31:935–941
Lyu YX, Yu XC, Zhu MY (2013) Comparison of the diagnostic value of procalcitonin and C-reactive protein after hematopoietic stem cell transplantation: a systematic review and meta-analysis. Transpl Infect Dis 15:290–299
Kofoed K, Andersen O, Kronborg G, Tvede M, Petersen J et al (2007) Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study. Crit Care 11:R38
Chan T, Gu F (2011) Early diagnosis of sepsis using serum biomarkers. Expert Rev Mol Diagn 11:487–496
Uhlar CM, Whitehead AS (1999) Serum amyloid A, the major vertebrate acute-phase reactant. Eur J Biochem 265:501–523
Cicarelli DD, Vieira JE, Bensenor FE (2008) Comparison of C-reactive protein and serum amyloid a protein in septic shock patients. Mediators Inflamm 2008:631414
Casl MT, Rogina B, Glojnaric-Spasic I, Minigo H, Planinc-Peraica A et al (1994) The differential diagnostic capacity of serum amyloid A protein between infectious and non-infectious febrile episodes of neutropenic patients with acute leukemia. Leuk Res 18:665–670
Arnon S, Litmanovitz I, Regev RH, Bauer S, Shainkin-Kestenbaum R et al (2007) Serum amyloid A: an early and accurate marker of neonatal early-onset sepsis. J Perinatol 27:297–302
Enguix A, Rey C, Concha A, Medina A, Coto D et al (2001) Comparison of procalcitonin with C-reactive protein and serum amyloid for the early diagnosis of bacterial sepsis in critically ill neonates and children. Intensive Care Med 27:211–215
Ucar B, Yildiz B, Aksit MA, Yarar C, Colak O et al (2008) Serum amyloid A, procalcitonin, tumor necrosis factor-alpha, and interleukin-1beta levels in neonatal late-onset sepsis. Mediators Inflamm 2008:737141
Edgar JD, Gabriel V, Gallimore JR, McMillan SA, Grant J (2010) A prospective study of the sensitivity, specificity and diagnostic performance of soluble intercellular adhesion molecule 1, highly sensitive C-reactive protein, soluble E-selectin and serum amyloid A in the diagnosis of neonatal infection. BMC Pediatr 10:22
Lannergard A, Viberg A, Cars O, Karlsson MO, Sandstrom M et al (2009) The time course of body temperature, serum amyloid A protein, C-reactive protein and interleukin-6 in patients with bacterial infection during the initial 3 days of antibiotic therapy. Scand J Infect Dis 41:663–671
Smith K, Bigham M (2011) Biomarkers in pediatric sepsis. Open Inflamm J 4:24–30
Prucha M, Herold I, Zazula R, Dubska L, Dostal M et al (2003) Significance of lipopolysaccharide-binding protein (an acute phase protein) in monitoring critically ill patients. Crit Care 7:R154–R159
Sakr Y, Burgett U, Nacul FE, Reinhart K, Brunkhorst F (2008) Lipopolysaccharide binding protein in a surgical intensive care unit: a marker of sepsis? Crit Care Med 36:2014–2022
Gaini S, Koldkjaer OG, Pedersen C, Pedersen SS (2006) Procalcitonin, lipopolysaccharide-binding protein, interleukin-6 and C-reactive protein in community-acquired infections and sepsis: a prospective study. Crit Care 10:R53
Watkin RW, Harper LV, Vernallis AB, Lang S, Lambert PA et al (2007) Pro-inflammatory cytokines IL6, TNF-alpha, IL1beta, procalcitonin, lipopolysaccharide binding protein and C-reactive protein in infective endocarditis. J Infect 55:220–225
Albillos A, de-la-Hera A, Alvarez-Mon M (2004) Serum lipopolysaccharide-binding protein prediction of severe bacterial infection in cirrhotic patients with ascites. Lancet 363:1608–1610
Porcel JM, Vives M, Cao G, Bielsa S, Ruiz-Gonzalez A et al (2009) Biomarkers of infection for the differential diagnosis of pleural effusions. Eur Respir J 34:1383–1389
Muller B, Peri G, Doni A, Torri V, Landmann R et al (2001) Circulating levels of the long pentraxin PTX3 correlate with severity of infection in critically ill patients. Crit Care Med 29:1404–1407
Vänskä M, Koivula I, Hamalainen S, Pulkki K, Nousiainen T et al (2011) High pentraxin 3 level predicts septic shock and bacteremia at the onset of febrile neutropenia after intensive chemotherapy of hematologic patients. Haematologica 96:1385–1389
Uusitalo-Seppala R, Huttunen R, Aittoniemi J, Koskinen P, Leino A et al (2013) Pentraxin 3 (PTX3) is associated with severe sepsis and fatal disease in emergency room patients with suspected infection: a prospective cohort study. PLoS One 8:e53661
Mauri T, Bellani G, Patroniti N, Coppadoro A, Peri G et al (2010) Persisting high levels of plasma pentraxin 3 over the first days after severe sepsis and septic shock onset are associated with mortality. Intensive Care Med 36:621–629
Huttunen R, Hurme M, Aittoniemi J, Huhtala H, Vuento R et al (2011) High plasma level of long pentraxin 3 (PTX3) is associated with fatal disease in bacteremic patients: a prospective cohort study. PLoS One 6:e17653
Okorie ON, Dellinger P (2011) Lactate: biomarker and potential therapeutic target. Crit Care Clin 27:299–326
Douzinas EE, Tsidemiadou PD, Pitaridis MT, Andrianakis I, Bobota-Chloraki A et al (1997) The regional production of cytokines and lactate in sepsis-related multiple organ failure. Am J Respir Crit Care Med 155:53–59
Hack CE, Nuijens JH, Strack van Schijndel RJ, Abbink JJ, Eerenberg AJ et al (1990) A model for the interplay of inflammatory mediators in sepsis–a study in 48 patients. Intensive Care Med 16(Suppl 3):S187–S191
Gogos CA, Lekkou A, Papageorgiou O, Siagris D, Skoutelis A et al (2003) Clinical prognostic markers in patients with severe sepsis: a prospective analysis of 139 consecutive cases. J Infect 47:300–306
Trzeciak S, Dellinger RP, Chansky ME, Arnold RC, Schorr C et al (2007) Serum lactate as a predictor of mortality in patients with infection. Intensive Care Med 33:970–977
Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A et al (2004) Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 32:1637–1642
Marty P, Roquilly A, Vallee F, Luzi A, Ferre F et al (2013) Lactate clearance for death prediction in severe sepsis or septic shock patients during the first 24 hours in intensive care unit: an observational study. Ann Intensive Care 3:3
Jeng JC, Jablonski K, Bridgeman A, Jordan MH (2002) Serum lactate, not base deficit, rapidly predicts survival after major burns. Burns 28:161–166
Manikis P, Jankowski S, Zhang H, Kahn RJ, Vincent JL (1995) Correlation of serial blood lactate levels to organ failure and mortality after trauma. Am J Emerg Med 13:619–622
McNelis J, Marini CP, Jurkiewicz A, Szomstein S, Simms HH et al (2001) Prolonged lactate clearance is associated with increased mortality in the surgical intensive care unit. Am J Surg 182:481–485
del Portal DA, Shofer F, Mikkelsen ME, Dorsey PJ Jr, Gaieski DF et al (2010) Emergency department lactate is associated with mortality in older adults admitted with and without infections. Acad Emerg Med 17:260–268
Berg S, Brodin B, Hesselvik F, Laurent TC, Maller R (1988) Elevated levels of plasma hyaluronan in septicaemia. Scand J Clin Lab Invest 48:727–732
Sallisalmi M, Tenhunen J, Kultti A, Tammi M, Pettilä V (2013) Plasma hyaluronan and hemorheology in patients with septic shock: a clinical and experimental study. Microcirc, Clin Hemorheol
Yagmur E, Koch A, Haumann M, Kramann R, Trautwein C et al (2012) Hyaluronan serum concentrations are elevated in critically ill patients and associated with disease severity. Clin Biochem 45:82–87
Keel M, Harter L, Reding T, Sun LK, Hersberger M et al (2009) Pancreatic stone protein is highly increased during posttraumatic sepsis and activates neutrophil granulocytes. Crit Care Med 37:1642–1648
Que YA, Delodder F, Guessous I, Graf R, Bain M et al (2012) Pancreatic stone protein as an early biomarker predicting mortality in a prospective cohort of patients with sepsis requiring ICU management. Crit Care 16:R114
Llewelyn MJ, Berger M, Gregory M, Ramaiah R, Taylor AL et al (2013) Sepsis biomarkers in unselected patients on admission to intensive or high-dependency care. Crit Care 17:R60
Gukasjan R, Raptis DA, Schulz HU, Halangk W, Graf R (2013) Pancreatic stone protein predicts outcome in patients with peritonitis in the ICU. Crit Care Med 41:1027–1036
Delogu G, Lo Bosco L, Marandola M, Famularo G, Lenti L et al (1997) Heat shock protein (HSP70) expression in septic patients. J Crit Care 12:188–192
Sonna LA, Hawkins L, Lissauer ME, Maldeis P, Towns M et al (2010) Core temperature correlates with expression of selected stress and immunomodulatory genes in febrile patients with sepsis and noninfectious SIRS. Cell Stress Chaperones 15:55–66
Gupta A, Cooper ZA, Tulapurkar ME, Potla R, Maity T et al (2013) Toll-like receptor agonists and febrile range hyperthermia synergize to induce heat shock protein 70 expression and extracellular release. J Biol Chem 288:2756–2766
Waterer GW, ElBahlawan L, Quasney MW, Zhang Q, Kessler LA et al (2003) Heat shock protein 70-2 + 1267 AA homozygotes have an increased risk of septic shock in adults with community-acquired pneumonia. Crit Care Med 31:1367–1372
Pittet J-F, Lee H, Morabito D, Howard MB, Welch WJ et al (2002) Serum levels of Hsp 72 measured early after trauma correlate with survival. J Trauma 52:611–617
Wheeler DS, Fisher LE Jr, Catravas JD, Jacobs BR, Carcillo JA et al (2005) Extracellular hsp70 levels in children with septic shock. Pediatr Crit Care Med 6:308–311
Gelain DP, De Bittencourt Pasquali MA, Comim MC, Grunwald MS, Ritter C et al (2011) Serum heat shock protein 70 levels, oxidant status, and mortality in sepsis. Shock 35:466–470
Adib-Conquy M, Cavaillon JM (2007) Stress molecules in sepsis and systemic inflammatory response syndrome. FEBS Lett 581:3723–3733
Wheeler DS, Lahni P, Odoms K, Jacobs BR, Carcillo JA et al (2007) Extracellular heat shock protein 60 (Hsp60) levels in children with septic shock. Inflamm Res 56:216–219
Rhodes A, Wort SJ, Thomas H, Collinson P, Bennett ED (2006) Plasma DNA concentration as a predictor of mortality and sepsis in critically ill patients. Crit Care 10:R60
Saukkonen K, Lakkisto P, Pettila V, Varpula M, Karlsson S et al (2008) Cell-free plasma DNA as a predictor of outcome in severe sepsis and septic shock. Clin Chem 54:1000–1007
Margraf S, Logters T, Reipen J, Altrichter J, Scholz M et al (2008) Neutrophil-derived circulating free DNA (cf-DNA/NETs): a potential prognostic marker for posttraumatic development of inflammatory second hit and sepsis. Shock 30:352–358
Moreira VG, Prieto B, Rodriguez JS, Alvarez FV (2010) Usefulness of cell-free plasma DNA, procalcitonin and C-reactive protein as markers of infection in febrile patients. Ann Clin Biochem 47:253–258
Huttunen R, Kuparinen T, Jylhava J, Aittoniemi J, Vuento R et al (2011) Fatal outcome in bacteremia is characterized by high plasma cell free DNA concentration and apoptotic DNA fragmentation: a prospective cohort study. PLoS One 6:e21700
Dwivedi DJ, Toltl LJ, Swystun LL, Pogue J, Liaw KL et al (2012) Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care 16:R151
Kung CT, Hsiao SY, Tsai TC, Su CM, Chang WN et al (2012) Plasma nuclear and mitochondrial DNA levels as predictors of outcome in severe sepsis patients in the emergency room. J Transl Med 10:130
Puskarich MA, Shapiro NI, Trzeciak S, Kline JA, Jones AE (2012) Plasma levels of mitochondrial DNA in patients presenting to the emergency department with sepsis. Shock 38:337–340
Yamanouchi S, Kudo D, Yamada M, Miyagawa N, Furukawa H et al (2013) Plasma mitochondrial DNA levels in patients with trauma and severe sepsis: time course and the association with clinical status. J Crit Care 28(6):1027–31
Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195
Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251
Angus DC, Yang L, Kong L, Kellum JA, Delude RL et al (2007) Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit Care Med 35:1061–1067
Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G et al (2005) Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med 33:564–573
van Zoelen MA, Laterre PF, van Veen SQ, van Till JW, Wittebole X et al (2007) Systemic and local high mobility group box 1 concentrations during severe infection. Crit Care Med 35:2799–2804
Gaini S, Pedersen SS, Koldkaer OG, Pedersen C, Moestrup SK et al (2008) New immunological serum markers in bacteraemia: anti-inflammatory soluble CD163, but not proinflammatory high mobility group-box 1 protein, is related to prognosis. Clin Exp Immunol 151:423–431
Foell D, Wittkowski H, Vogl T, Roth J (2007) S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukoc Biol 81:28–37
van Zoelen MA, Vogl T, Foell D, Van Veen SQ, van Till JW et al (2009) Expression and role of myeloid-related protein-14 in clinical and experimental sepsis. Am J Respir Crit Care Med 180:1098–1106
Terrin G, Passariello A, Manguso F, Salvia G, Rapacciuolo L et al (2011) Serum calprotectin: an antimicrobial peptide as a new marker for the diagnosis of sepsis in very low birth weight newborns. Clin Dev Immunol 2011:291085
Fontaine M, Pachot A, Larue A, Mougin B, Landelle C et al (2009) Delayed increased S100A9 mRNA predicts hospital-acquired infection after septic shock. Crit Care 13:P56
ten Oever J, Giamarellos-Bourboulis EJ, van de Veerdonk FL, Stelma FF, Simon A et al (2013) Circulating galectin-3 in infections and non-infectious inflammatory diseases. Eur J Clin Microbiol Infect Dis 32:1605–1610
Hotchkiss RS, Nicholson DW (2006) Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 6:813–822
Mariano F, Cantaluppi V, Stella M, Romanazzi GM, Assenzio B et al (2008) Circulating plasma factors induce tubular and glomerular alterations in septic burns patients. Crit Care 12:R42
Ertel W, Keel M, Infanger M, Ungethum U, Steckholzer U et al (1998) Circulating mediators in serum of injured patients with septic complications inhibit neutrophil apoptosis through up-regulation of protein-tyrosine phosphorylation. J Trauma 44:767–775, discussion 775-766
Paunel-Gorgulu A, Flohe S, Scholz M, Windolf J, Logters T (2011) Increased serum soluble Fas after major trauma is associated with delayed neutrophil apoptosis and development of sepsis. Crit Care 15:R20
De Freitas I, Fernandez-Somoza M, Essenfeld-Sekler E, Cardier JE (2004) Serum levels of the apoptosis-associated molecules, tumor necrosis factor-alpha/tumor necrosis factor type-I receptor and Fas/FasL, in sepsis. Chest 125:2238–2246
Doughty L, Clark RS, Kaplan SS, Sasser H, Carcillo J (2002) sFas and sFas ligand and pediatric sepsis-induced multiple organ failure syndrome. Pediatr Res 52:922–927
Huttunen R, Syrjanen J, Vuento R, Laine J, Hurme M et al (2012) Apoptosis markers soluble Fas (sFas), Fas Ligand (FasL) and sFas/FasL ratio in patients with bacteremia: a prospective cohort study. J Infect 64:276–281
Moore DJ, Greystoke A, Butt F, Wurthner J, Growcott J et al (2012) A pilot study assessing the prognostic value of CK18 and nDNA biomarkers in severe sepsis patients. Clin Drug Investig 32:179–187
Roth GA, Krenn C, Brunner M, Moser B, Ploder M et al (2004) Elevated serum levels of epithelial cell apoptosis-specific cytokeratin 18 neoepitope m30 in critically ill patients. Shock 22:218–220
Hofer S, Brenner T, Bopp C, Steppan J, Lichtenstern C et al (2009) Cell death serum biomarkers are early predictors for survival in severe septic patients with hepatic dysfunction. Crit Care 13:R93
Haeffner-Cavaillon N, Cavaillon J-M, Ciancioni C, Bacle F, Delons S et al (1989) In vivo induction of interleukin-1 during hemodialysis. Kidney Int 35:1212–1218
Muñoz C, Misset B, Fitting C, Bleriot JP, Carlet J et al (1991) Dissociation between plasma and monocyte-associated cytokines during sepsis. Eur J Immunol 21:2177–2184
Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF et al (2007) Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care 11:R49
Fischer E, Van Zee KJ, Marano MA, Rock CS, Kenney JS et al (1992) Interleukin-1 receptor antagonist circulates in experimental inflammation and in human disease. Blood 79:2196–2200
Rogy MA, Coyle SM, Oldenburg HS, Rock CS, Barie PS et al (1994) Persistently elevated soluble tumor necrosis factor receptor and interleukin-1 receptor antagonist levels in critically ill patients. J Am Coll Surg 178:132–138
van Deuren M, van der Ven-Jongekrijg J, Demacker PN, Bartelink AK, van Dalen R et al (1994) Differential expression of proinflammatory cytokines and their inhibitors during the course of meningococcal infections. J Infect Dis 169:157–161
Gardlund B, Sjölin J, Nilsson A, Roll M, Wickerts CJ et al (1995) Plasma levels of cytokines in primary septic shock in humans: correlation with disease severity. J Infect Dis 172:296–301
Küster H, Weiss M, Willeitner AE, Detlefsen S, Jeremias I et al (1998) Interleukin-1 receptor antagonist and interleukin-6 for early diagnosis of neonatal sepsis 2 days before clinical manifestation. Lancet 352:1271–1277
Marie C, Losser MR, Fitting C, Kermarrec N, Payen D et al (1997) Cytokines and soluble cytokines receptors in pleural effusions from septic and nonseptic patients. Am J Respir Crit Care Med 156:1515–1522
Adrie C, Adib-Conquy M, Laurent I, Monchi M, Vinsonneau C et al (2002) Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis like” syndrome. Circulation 106:562–568
Samson LM, Allen UD, Creery WD, Diaz-Mitoma F, Singh RN (1997) Elevated IL-1ra levels in pediatric sepsis syndrome. J Pediatr 131:587–591
Cruickshank AM, Fraser WD, Burns HJ, Van Damme J, Shenkin A (1990) Response of serum interleukin-6 in patients undergoing elective surgery of varying severity. Clin Sci (Lond) 79:161–165
Naskalski JW, Kusnierz-Cabala B, Panek J, Kedra B (2003) Poly-C specific ribonuclease activity correlates with increased concentrations of IL-6, IL-8 and sTNFR55/sTNFR75 in plasma of patients with acute pancreatitis. J Physiol Pharmacol 54:439–448
Cavaillon JM, Poignet JL, Fitting C, Delons S (1992) Serum interleukin-6 in long-term hemodialyzed patients. Nephron 60:307–313
Hack C, de Groot E, Felt-Bersma R, Nuijens J, Strack Van Schijndel R et al (1989) Increased plasma levels of interleukin-6 in sepsis. Blood 74:1704–1710
Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ et al (1993) Serum cytokine levels in human septic shock. Relation to multiple-system organ failure and mortality. Chest 103:565–575
Rodriguez-Gaspar M, Santolaria F, Jarque-Lopez A, Gonzalez-Reimers E, Milena A et al (2001) Prognostic value of cytokines in SIRS general medical patients. Cytokine 15:232–236
Calandra T, Gerain J, Heumann D, Baumgartner JD, Glauser MP (1991) High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group. Am J Med 91:23–29
Cavaillon JM, Adib-Conquy M, Fitting C, Adrie C, Payen D (2003) Cytokine cascade in sepsis. Scand J Infect Dis 35:535–544
Ortqvist A, Hedlund J, Wretlind B, Carlstrom A, Kalin M (1995) Diagnostic and prognostic value of interleukin-6 and C-reactive protein in community-acquired pneumonia. Scand J Infect Dis 27:457–462
Waage A, Brandtzaeg P, Halstensen A, Kierulf P, Espevik T (1989) The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin-6, interleukin-1, and fatal outcome. J Exp Med 169:333–338
Casey LC, Balk RA, Bone RC (1993) Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann Intern Med 119:771–778
Friedland JS, Porter JC, Daryanani S, Bland JM, Screaton NJ et al (1996) Plasma proinflammatory cytokine concentrations, acute physiology and chronic health evaluation (APACHE) III scores and survival in patients in an intensive care unit. Crit Care Med 24:1775–1781
Riche FC, Cholley BP, Panis YH, Laisne MJ, Briard CG et al (2000) Inflammatory cytokine response in patients with septic shock secondary to generalized peritonitis. Crit Care Med 28:433–437
Suarez-Santamaria M, Santolaria F, Perez-Ramirez A, Aleman-Valls MR, Martinez-Riera A et al (2010) Prognostic value of inflammatory markers (notably cytokines and procalcitonin), nutritional assessment, and organ function in patients with sepsis. Eur Cytokine Netw 21:19–26
Buck C, Bundschu J, Gallati H, Bartmann P, Pohlandt F (1994) Interleukin-6: a sensitive parameter for the early diagnosis of neonatal bacterial infection. Pediatrics 93:54–58
Messer J, Eyer D, Donato L, Gallati H, Matis J et al (1996) Evaluation of interleukin-6 and soluble receptors of tumor necrosis factor for early diagnosis of neonatal infection. J Pediatr 129:574–580
Strait RT, Kelly KJ, Kurup VP (1999) Tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 levels in febrile, young children with and without occult bacteremia. Pediatrics 104:1321–1326
Urbonas V, Eidukaite A, Tamuliene I (2012) The diagnostic value of interleukin-6 and interleukin-8 for early prediction of bacteremia and sepsis in children with febrile neutropenia and cancer. J Pediatr Hematol Oncol 34:122–127
Groeneveld AB, Bossink AW, van Mierlo GJ, Hack CE (2001) Circulating inflammatory mediators in patients with fever: predicting bloodstream infection. Clin Diagn Lab Immunol 8:1189–1195
Sander M, von Heymann C, von Dossow V, Spaethe C, Konertz WF et al (2006) Increased interleukin-6 after cardiac surgery predicts infection. Anesth Analg 102:1623–1629
Giannoudis PV, Smith MR, Evans RT, Bellamy MC, Guillou PJ (1998) Serum CRP and IL-6 levels after trauma. Not predictive of septic complications in 31 patients. Acta Orthop Scand 69:184–188
Rintala E, Pulkki K, Mertsola J, Nevalainen T, Nikoskelainen J (1995) Endotoxin, interleukin-6 and phospholipase-A2 as markers of sepsis in patients with hematological malignancies. Scand J Infect Dis 27:39–43
Jekarl DW, Lee SY, Lee J, Park YJ, Kim Y et al (2013) Procalcitonin as a diagnostic marker and IL-6 as a prognostic marker for sepsis. Diagn Microbiol Infect Dis 75:342–347
Marchant A, Devière J, Byl B, De Groote D, Vincent J et al (1994) Interleukin-10 production during septicaemia. Lancet 343:707–708
Glynn P, Coakley R, Kilgallen I, Murphy N, O’Neill S (1999) Circulating interleukin 6 and interleukin 10 in community acquired pneumonia. Thorax 54:51–55
Lehmann AK, Halstensen A, Sornes S, Rokke O, Waage A (1995) High levbels of interleukin-10 in serum are associated with fatality in meningococcal disease. Infect Immun 63:2109–2112
Gogos CA, Drosou E, Bassaris HP, Skoutelis A (2000) Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 181:176–180
van Dissel JT, van Langevelde P, Westendorp RGJ, Kwappenberg K, Frolich M (1998) Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 351:950–953
Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM et al (2007) Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 167:1655–1663
van Deuren M, van Der Ven-Jongekrijg H, Baterlink AKN, van Dalen R, Sauerwein RW et al (1995) Correlation between proinflammatory cytokines and antiinflammatory mediators and the severity of disease in meningococcal infections. J Infect Dis 172:433–439
Gomez-Jimenez J, Martin MC, Sauri R, Segura RM, Esteban F et al (1995) Interleukin-10 and the monocyte/macrophage-induced inflammatory response in septic shock. J Infect Dis 171:472–475
Riordan FA, Marzouk O, Thomson AP, Sills JA, Hart CA (1996) Proinflammatory and anti-inflammatory cytokines in meningococcal disease. Arch Dis Child 75:453–454
Tamayo E, Fernandez A, Almansa R, Carrasco E, Heredia M et al (2011) Pro- and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock. Eur Cytokine Netw 22:82–87
Cavaillon J-M, Adib-Conquy M, Cloëz-Tayarani I, Fitting C (2001) Immunodepression in sepsis and SIRS assessed by ex vivo cytokine production is not a generalized phenomenon : a review. J Endotoxin Res 7:85–93
Matera G, Puccio R, Giancotti A, Quirino A, Pulicari MC et al (2013) Impact of interleukin-10, soluble CD25 and interferon-gamma on the prognosis and early diagnosis of bacteremic systemic inflammatory response syndrome: a prospective observational study. Crit Care 17:R64
Presterl E, Staudinger T, Pettermann M, Lassnigg A, Burgmann H et al (1997) Cytokine profile and correlation to the APACHE III and MPM II scores in patients with sepsis. Am J Respir Crit Care Med 156:825–832
Vedrine C, Caraion C, Lambert C, Genin C (2004) Cytometric bead assay of cytokines in sepsis: a clinical evaluation. Cytometry B Clin Cytom 60:14–22
Mera S, Tatulescu D, Cismaru C, Bondor C, Slavcovici A et al (2010) Multiplex cytokine profiling in patients with sepsis. APMIS 119:155–163
Emmanuilidis K, Weighardt H, Matevossian E, Heidecke CD, Ulm K et al (2002) Differential regulation of systemic IL-18 and IL-12 release during postoperative sepsis: high serum IL-18 as an early predictive indicator of lethal outcome. Shock 18:301–305
Wu HP, Chen CK, Chung K, Tseng JC, Hua CC et al (2009) Serial cytokine levels in patients with severe sepsis. Inflamm Res 58:385–393
Lavoie PM, Huang Q, Jolette E, Whalen M, Nuyt AM et al (2010) Profound lack of interleukin (IL)-12/IL-23p40 in neonates born early in gestation is associated with an increased risk of sepsis. J Infect Dis 202:1754–1763
Zeerleder S, Hack CE, Caliezi C, van Mierlo G, Eerenberg-Belmer A et al (2005) Activated cytotoxic T cells and NK cells in severe sepsis and septic shock and their role in multiple organ dysfunction. Clin Immunol 116:158–165
Lauw FN, Simpson AJH, Prins JM, Smith MD, Kurimoto M et al (1999) Elevated plasma concentrations of interferon (IFN) and the IFN-inducing cytokines interleukin (IL)18, IL-12, and IL-15 in severe melioidosis. J Infect Dis 180:1878–1885
Grobmyer SR, Lin E, Lowry SF, Rivadeneira DE, Potter S et al (2000) Elevation of IL-18 in human sepsis. J Clin Immunol 20:212–215
Oberholzer A, Steckholzer U, Kurimoto M, Trentz O, Ertel W (2001) Interleukin-18 plasma levels are increased in patients with sepsis compared to severely injured patients. Shock 16:411–414
Zaki MES, Elgendy MY, El-Mashad NB, Farahat ME (2007) IL-18 level correlates with development of sepsis in surgical patients. Immunol Invest 36:403–411
Mommsen P, Frink M, Pape HC, van Griensven M, Probst C et al (2009) Elevated systemic IL-18 and neopterin levels are associated with posttraumatic complications among patients with multiple injuries: a prospective cohort study. Injury 40:528–534
Waage A, Halstensen A, Espevik T (1987) Association between tumor necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet i: 355–357
Girardin E, Grau G, Dayer J, Roux-Lombard P, Lambert P (1988) Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 319:397–400
de Groote MA, Martin MA, Densen P, Pfaller MA, Wenzel RP (1989) Plasma tumor necrosis factor levels in patients with presumed sepsis. Results in those treated with antilipid A antibody vs placebo [see comments]. JAMA 262:249–251
Offner F, Philippé J, Vogelaers D, Colardyn F, Baele G et al (1990) Serum tumor necrosis factor levels in patients with infectious diseases and septic shock. J Lab Clin Med 116:100–105
Calandra T, Baumgartner JD, Grau GE, Wu MM, Lambert PH et al (1990) Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-a, and interferon-g in the serum of patients with septic shock. J Infect Dis 161:982–987
Calandra T, Echtenacher B, Le Roy D, Pugin J, Metz CN et al (2000) Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 6:164–170
Emonts M, Sweep FC, Grebenchtchikov N, Geurts-Moespot A, Knaup M et al (2007) Association between high levels of blood macrophage migration inhibitory factor, inappropriate adrenal response, and early death in patients with severe sepsis. Clin Infect Dis 44:1321–1328
Maxime V, Fitting C, Annane D, Cavaillon J-M (2005) Corticoids normalize leukocyte production of macrophage migration inhibitory factor in septic shock. J Infect Dis 191:138–144
Leaver SK, MacCallum NS, Pingle V, Hacking MB, Quinlan GJ et al (2010) Increased plasma thioredoxin levels in patients with sepsis: positive association with macrophage migration inhibitory factor. Intensive Care Med 36:336–341
Grieb G, Simons D, Piatkowski A, Bernhagen J, Steffens G et al (2010) Macrophage migration inhibitory factor-A potential diagnostic tool in severe burn injuries? Burns 36:335–342
Gessler P, Kirchmann N, Kientsch-Engel R, Haas N, Lasch P et al (1993) Serum concentrations of granulocyte colony-stimulating factor in healthy term and preterm neonates and in those with various diseases including bacterial infections. Blood 82:3177–3182
Pauksen K, Elfman L, Ulfgren AK, Venge P (1994) Serum levels of granulocyte-colony stimulating factor (G-CSF) in bacterial and viral infections, and in atypical pneumonia. Br J Haematol 88:256–260
Fischer JE, Benn A, Harbarth S, Nadal D, Fanconi S (2002) Diagnostic accuracy of G-CSF, IL-8, and IL-1ra in critically ill children with suspected infection. Intensive Care Med 28:1324–1331
Tanaka H, Ishikawa K, Nishino M, Shimazu T, Yoshioka T (1996) Changes in granulocyte colony-stimulating factor concentration in patients with trauma and sepsis. J Trauma 40:718–725, discussion 725-716
Kragsbjerg P, Jones I, Vikerfors T, Holmberg H (1995) Diagnostic value of blood cytokine concentrations in acute pneumonia. Thorax 50:1253–1257
Presneill JJ, Waring PM, Layton JE, Maher DW, Cebon J et al (2000) Plasma granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in critical illness including sepsis and septic shock: relation to disease severity, multiple organ dysfunction, and mortality. Crit Care Med 28:2344–2354
Torre D, Tambini R, Manfredi M, Mangani V, Livi P et al (2003) Circulating levels of granulocyte macrophage colony-stimulating factor in patients with the systemic inflammatory response syndrome. J Infect 47:296–299
Waring P, Wycherley K, Cary D, Nicola N, Metcalf D (1992) Leukemia inhibitory factor levels are elevated in septic shock and various inflammatory body fluids. J Clin Invest 90:2031–2037
Villers D, Dao T, Nguyen JM, Bironneau E, Godard A et al (1995) Increased plasma levels of human interleukin for DA1a cells/leukemia inhibitory factor in sepsis correlate with shock and poor prognosis. J Infect Dis 171:232–236
Guillet C, Fourcin M, Chevalier S, Pouplard A, Gascan H (1995) ELISA detection of circulating levels of LIF, OSM and CNTF in septic shock. Ann N Y Acad Sci 762:407–412
Collighan N, Giannoudis PV, Kourgeraki O, Perry SL, Guillou PJ et al (2004) Interleukin 13 and inflammatory markers in human sepsis. Br J Surg 91:762–768
Wong HR, Cvijanovich NZ, Hall M, Allen GL, Thomas NJ et al (2012) Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. Crit Care 16:R213
Lee KA, Gong MN (2011) Pre-B-cell colony-enhancing factor and its clinical correlates with acute lung injury and sepsis. Chest 140:382–390
Bjerre A, Brusletto B, Hoiby EA, Kierulf P, Brandtzaeg P (2004) Plasma interferon-gamma and interleukin-10 concentrations in systemic meningococcal disease compared with severe systemic Gram-positive septic shock. Crit Care Med 32:433–438
van der Flier M, van Leeuwen HJ, van Kessel KP, Kimpen JL, Hoepelman AI et al (2005) Plasma vascular endothelial growth factor in severe sepsis. Shock 23:35–38
Socha LA, Gowardman J, Silva D, Correcha M, Petrosky N (2006) Elevation in interleukin 13 levels in patients diagnosed with systemic inflammatory response syndrome. Intensive Care Med 32:244–250
Friedland J, Suputtamongkol Y, Remick D, Chaowagul W, Strieter R et al (1992) Prolonged elevation of interleukin-8 and interleukin-6 concentrations in plasma and of leukocyte interleukin-8 m-RNA levels during septicemic and localized Pseudomonas pseudomallei infection. Infect Immun 60:2402–2408
Hack C, Hart M, Strack van Schijndel R, Eerenberg A, Nuijens J et al (1992) Interleukin-8 in sepsis: relation to shock and inflammatory mediators. Infect Immun 60:2835–2842
Bossink AW, Paemen L, Jansen PM, Hack CE, Thijs LG et al (1995) Plasma levels of the chemokines monocyte chemotactic proteins-1 and -2 are elevated in human sepsis. Blood 86:3841–3847
Endo S, Inada K, Ceska M, Takakuwa T, Yamada Y et al (1995) Plasma interleukin 8 and polymorphonuclear leukocyte elastase concentrations in patients with septic shock. J Inflamm 45:136–142
Marty C, Misset B, Tamion F, Fitting C, Carlet J et al (1994) Circulating interleukin-8 concentrations in patients with multiple organ failure of septic and nonseptic origin. Crit Care Med 22:673–679
Fujishima S, Sasaki J, Shinozawa Y, Takuma K, Kimura H et al (1996) Serum MIP-1 alpha and IL-8 in septic patients. Intensive Care Med 22:1169–1175
Livaditi O, Kotanidou A, Psarra A, Dimopoulou I, Sotiropoulou C et al (2006) Neutrophil CD64 expression and serum IL-8: sensitive early markers of severity and outcome in sepsis. Cytokine 36:283–290
Wong HR, Cvijanovich N, Wheeler DS, Bigham MT, Monaco M et al (2008) Interleukin-8 as a stratification tool for interventional trials involving pediatric septic shock. Am J Respir Crit Care Med 178:276–282
de Bont ES, Vellenga E, Swaanenburg JC, Fidler V, Visser-van Brummen PJ et al (1999) Plasma IL-8 and IL-6 levels can be used to define a group with low risk of septicaemia among cancer patients with fever and neutropenia. Br J Haematol 107:375–380
Lin KJ, Lin J, Hanasawa K, Tani T, Kodama M (2000) Interleukin-8 as a predictor of the severity of bacteremia and infectious disease. Shock 14:95–100
Tromp YH, Daenen SM, Sluiter WJ, Vellenga E (2009) The predictive value of interleukin-8 (IL-8) in hospitalised patients with fever and chemotherapy-induced neutropenia. Eur J Cancer 45:596–600
Santolaya ME, Alvarez AM, Aviles CL, Becker A, King A et al (2008) Predictors of severe sepsis not clinically apparent during the first twenty-four hours of hospitalization in children with cancer, neutropenia, and fever: a prospective, multicenter trial. Pediatr Infect Dis J 27:538–543
Kurt AN, Aygun AD, Godekmerdan A, Kurt A, Dogan Y et al (2007) Serum IL-1beta, IL-6, IL-8, and TNF-alpha levels in early diagnosis and management of neonatal sepsis. Mediators Inflamm 2007:31397
Marie C, Fitting C, Cheval C, Losser MR, Carlet J et al (1997) Presence of high levels of leukocyte-associated interleukin-8 upon cell activation and in patients with sepsis syndrome. Infect Immun 65:865–871
Steinbach G, Bolke E, Schulte am Esch J, Peiper M, Zant R et al (2007) Comparison of whole blood interleukin-8 and plasma interleukin-8 as a predictor for sepsis in postoperative patients. Clin Chim Acta 378:117–121
Lvovschi V, Arnaud L, Parizot C, Freund Y, Juillien G et al (2011) Cytokine profiles in sepsis have limited relevance for stratifying patients in the emergency department: a prospective observational study. PLoS One 6:e28870
Santana Reyes C, Garcia-Munoz F, Reyes D, Gonzalez G, Dominguez C et al (2003) Role of cytokines (interleukin-1beta, 6, 8, tumour necrosis factor-alpha, and soluble receptor of interleukin-2) and C-reactive protein in the diagnosis of neonatal sepsis. Acta Paediatr 92:221–227
Franz AR, Bauer K, Schalk A, Garland SM, Bowman ED et al (2004) Measurement of interleukin 8 in combination with C-reactive protein reduced unnecessary antibiotic therapy in newborn infants: a multicenter, randomized, controlled trial. Pediatrics 114:1–8
Ng PC, Li K, Chui KM, Leung TF, Wong RP et al (2007) IP-10 is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants. Pediatr Res 61:93–98
Olszyna DP, Prins JM, Dekkers PEP, De Jonge E, Speelman P et al (1999) Sequential measurements of chemokines in urosepsis and experimental endotoxemia. J Clin Immunol 19:399–405
Moller AS, Bjerre A, Brusletto B, Joo GB, Brandtzaeg P et al (2005) Chemokine patterns in meningococcal disease. J Infect Dis 191:768–775
Vermont CL, Hazelzet JA, de Kleijn ED, van den Dobbelsteen GP, de Groot R (2006) CC and CXC chemokine levels in children with meningococcal sepsis accurately predict mortality and disease severity. Crit Care 10:R33
Andaluz-Ojeda D, Bobillo F, Iglesias V, Almansa R, Rico L et al (2012) A combined score of pro- and anti-inflammatory interleukins improves mortality prediction in severe sepsis. Cytokine 57:332–336
El-Maghraby SM, Moneer MM, Ismail MM, Shalaby LM, El-Mahallawy HA (2007) The diagnostic value of C-reactive protein, interleukin-8, and monocyte chemotactic protein in risk stratification of febrile neutropenic children with hematologic malignancies. J Pediatr Hematol Oncol 29:131–136
Nowak JE, Wheeler DS, Harmon KK, Wong HR (2010) Admission chemokine (C-C motif) ligand 4 levels predict survival in pediatric septic shock. Pediatr Crit Care Med 11:213–216
Schall TJ, Jongstra J, Dyer BJ, Jorgensen J, Clayberger C et al (1988) A human T cell-specific molecule is a member of a new gene family. J Immunol 141:1018–1025
Carrol ED, Thomson AP, Mobbs KJ, Hart CA (2000) The role of RANTES in meningococcal disease. J Infect Dis 182:363–366
Ellis M, al-Ramadi B, Hedstrom U, Alizadeh H, Shammas V et al (2005) Invasive fungal infections are associated with severe depletion of circulating RANTES. J Med Microbiol 54:1017–1022
John CC, Opika-Opoka R, Byarugaba J, Idro R, Boivin MJ (2006) Low levels of RANTES are associated with mortality in children with cerebral malaria. J Infect Dis 194:837–845
Shouman B, Badr R (2010) Regulated on activation, normal T cell expressed and secreted and tumor necrosis factor-alpha in septic neonates. J Perinatol 30:192–196
Ellis M, al-Ramadi B, Hedstrom U, Frampton C, Alizadeh H et al (2005) Significance of the CC chemokine RANTES in patients with haematological malignancy: results from a prospective observational study. Br J Haematol 128:482–489
Ng PC, Li K, Leung TF, Wong RP, Li G et al (2006) Early prediction of sepsis-induced disseminated intravascular coagulation with interleukin-10, interleukin-6, and RANTES in preterm infants. Clin Chem 52:1181–1189
Bas S, Gauthier BR, Spenato U, Stingelin S, Gabay C (2004) CD14 is an acute-phase protein. J Immunol 172:4470–4479
Endo S, Inada K, Kasai T, Takakuwa T, Nakae H et al (1994) Soluble CD14 (sCD14) levels in patients with multiple organ failure (MOF). Res Commun Chem Pathol Pharmacol 84:17–25
Landmann R, Zimmerli W, Sansano S, Link S, Hahn A et al (1995) Increased circulating soluble CD14 is associated with high mortality in gram-negative septic shock. J Infect Dis 171:639–644
Burgmann H, Winkler S, Locker GJ, Presterl E, Laczika K et al (1996) Increased serum concentration of soluble CD14 is a prognostic marker in gram-positive sepsis. Clin Immunol Immunopathol 80:307–310
Berner R, Furll B, Stelter F, Drose J, Muller HP et al (2002) Elevated levels of lipopolysaccharide-binding protein and soluble CD14 in plasma in neonatal early-onset sepsis. Clin Diagn Lab Immunol 9:440–445
Blanco A, Solis G, Arranz E, Coto GD, Ramos A et al (1996) Serum levels of CD14 in neonatal sepsis by gram-positive and gram-negative bacteria. Acta Paediatr 85:728–732
Pavcnik-Arnol M, Hojker S, Derganc M (2007) Lipopolysaccharide-binding protein, lipopolysaccharide, and soluble CD14 in sepsis of critically ill neonates and children. Intensive Care Med 33:1025–1032
Chalupa P, Beran O, Herwald H, Kasprikova N, Holub M (2011) Evaluation of potential biomarkers for the discrimination of bacterial and viral infections. Infection 39:411–417
Carrillo EH, Gordon L, Goode E, Davis E, Polk HC Jr (2001) Early elevation of soluble CD14 may help identify trauma patients at high risk for infection. J Trauma 50:810–816
Yaegashi Y, Shirakawa K, Sato N, Suzuki Y, Kojika M et al (2005) Evaluation of a newly identified soluble CD14 subtype as a marker for sepsis. J Infect Chemother 11:234–238
Urbonas V, Eidukaite A, Tamuliene I (2013) The predictive value of soluble biomarkers (CD14 subtype, interleukin-2 receptor, human leucocyte antigen-G) and procalcitonin in the detection of bacteremia and sepsis in pediatric oncology patients with chemotherapy-induced febrile neutropenia. Cytokine 62:34–37
Pugin J, Stern-Voeffray S, Daubeuf B, Matthay MA, Elson G et al (2004) Soluble MD-2 activity in plasma from patients with severe sepsis and septic shock. Blood 104:4071–4079
Tissieres P, Dunn-Siegrist I, Schappi M, Elson G, Comte R et al (2008) Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria. Blood 111:2122–2131
Brunner M, Krenn C, Roth G, Moser B, Dworschak M et al (2004) Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med 30:1468–1473
Hoogerwerf JJ, Tanck MW, van Zoelen MA, Wittebole X, Laterre PF et al (2010) Soluble ST2 plasma concentrations predict mortality in severe sepsis. Intensive Care Med 36:630–637
Takala A, Jousela I, Jansson SE, Olkkola KT, Takkunen O et al (1999) Markers of systemic inflammation predicting organ failure in community-acquired septic shock. Clin Sci (Lond) 97:529–538
Fleischhack G, Kambeck I, Cipic D, Hasan C, Bode U (2000) Procalcitonin in paediatric cancer patients: its diagnostic relevance is superior to that of C-reactive protein, interleukin 6, interleukin 8, soluble interleukin 2 receptor and soluble tumour necrosis factor receptor II. Br J Haematol 111:1093–1102
Saito K, Wagatsuma T, Toyama H, Ejima Y, Hoshi K et al (2008) Sepsis is characterized by the increases in percentages of circulating CD4 + CD25+ regulatory T cells and plasma levels of soluble CD25. Tohoku J Exp Med 216:61–68
Moller HJ, Moestrup SK, Weis N, Wejse C, Nielsen H et al (2006) Macrophage serum markers in pneumococcal bacteremia: prediction of survival by soluble CD163. Crit Care Med 34:2561–2566
Gaini S, Koldkjaer OG, Pedersen SS, Pedersen C, Moestrup SK et al (2006) Soluble haemoglobin scavenger receptor (sCD163) in patients with suspected community-acquired infections. APMIS 114:103–111
Schaer DJ, Schleiffenbaum B, Kurrer M, Imhof A, Bachli E et al (2005) Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J Haematol 74:6–10
Feng L, Zhou X, Su LX, Feng D, Jia YH et al (2012) Clinical significance of soluble hemoglobin scavenger receptor CD163 (sCD163) in sepsis, a prospective study. PLoS One 7:e38400
Evans TJ, Moyes D, Carpenter A, Martin R, Loetscher H et al (1994) Protective effect of 55 but not 75 kD soluble tumor necrosis factor receptor-immunoglobulin G fusion proteins in animal model of gram negative sepsis. J Exp Med 180:2173–2179
Girardin E, Roux-Lombard P, Grau GE, Suter P, Gallati H et al (1992) Imbalance between tumour necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia. Immunology 76:20–23
Ertel W, Scholl FA, Gallati H, Bonaccio M, Schildberg FW et al (1994) Increased release of soluble tumor necrosis factor receptors into blood during clinical sepsis. Arch Surg 129:1330–1336, discussion 1336-1337
van der Poll T, Jansen J, van Leenen D, von der Mohlen M, Levi M et al (1993) Release of soluble receptors for tumor necrosis factor in clinical sepsis and experimental endotoxemia. J Infect Dis 168:955–960
Froon AH, Bemelmans MH, Greve JW, van der Linden CJ, Buurman WA (1994) Increased plasma concentrations of soluble tumor necrosis factor receptors in sepsis syndrome: correlation with plasma creatinine values. Crit Care Med 22:803–809
de Pablo R, Monserrat J, Reyes E, Diaz-Martin D, Rodriguez Zapata M et al (2011) Mortality in patients with septic shock correlates with anti-inflammatory but not proinflammatory immunomodulatory molecules. J Intensive Care Med 26:125–132
Pilz G, Fraunberger P, Appel R, Kreuzer E, Werdan K et al (1996) Early prediction of outcome in score-identified, postcardiac surgical patients at high risk for sepsis, using soluble tumor necrosis factor receptor-p55 concentrations. Crit Care Med 24:596–600
Zhang B, Huang YH, Chen Y, Yang Y, Hao ZL et al (1998) Plasma tumor necrosis factor-alpha, its soluble receptors and interleukin-1beta levels in critically burned patients. Burns 24:599–603
el-Barbary M, Khabar KS (2002) Soluble tumor necrosis factor receptor p55 predicts cytokinemia and systemic inflammatory response after cardiopulmonary bypass. Crit Care Med 30:1712–1716
Spielmann S, Kerner T, Ahlers O, Keh D, Gerlach M et al (2001) Early detection of increased tumour necrosis factor alpha (TNFalpha) and soluble TNF receptor protein plasma levels after trauma reveals associations with the clinical course. Acta Anaesthesiol Scand 45:364–370
Hou YQ, Xu P, Zhang M, Han D, Peng L et al (2012) Serum decoy receptor 3, a potential new biomarker for sepsis. Clin Chim Acta 413:744–748
Chen CY, Yang KY, Chen MY, Chen HY, Lin MT et al (2009) Decoy receptor 3 levels in peripheral blood predict outcomes of acute respiratory distress syndrome. Am J Respir Crit Care Med 180:751–760
Cowley HC, Heney D, Gearing AJ, Hemingway I, Webster NR (1994) Increased circulating adhesion molecule concentrations in patients with the systemic inflammatory response syndrome: a prospective cohort study. Crit Care Med 22:651–657
Boldt J, Wollbruck M, Kuhn D, Linke LC, Hempelmann G (1995) Do plasma levels of circulating soluble adhesion molecules differ between surviving and nonsurviving critically ill patients? Chest 107:787–792
Froon AH, Bonten MJ, Gaillard CA, Greve JW, Dentener MA et al (1998) Prediction of clinical severity and outcome of ventilator-associated pneumonia. Comparison of simplified acute physiology score with systemic inflammatory mediators. Am J Respir Crit Care Med 158:1026–1031
Hein OV, Misterek K, Tessmann JP, van Dossow V, Krimphove M et al (2005) Time course of endothelial damage in septic shock: prediction of outcome. Crit Care 9:R323–R330
Sessler CN, Windsor AC, Schwartz M, Watson L, Fisher BJ et al (1995) Circulating ICAM-1 is increased in septic shock. Am J Respir Crit Care Med 151:1420–1427
Shapiro NI, Schuetz P, Yano K, Sorasaki M, Parikh SM et al (2010) The association of endothelial cell signaling, severity of illness, and organ dysfunction in sepsis. Crit Care 14:R182
Boldt J, Muller M, Kuhn D, Linke LC, Hempelmann G (1996) Circulating adhesion molecules in the critically ill: a comparison between trauma and sepsis patients. Intensive Care Med 22:122–128
Leone M, Boutiere B, Camoin-Jau L, Albanese J, Horschowsky N et al (2002) Systemic endothelial activation is greater in septic than in traumatic-hemorrhagic shock but does not correlate with endothelial activation in skin biopsies. Crit Care Med 30:808–814
Cummings CJ, Sessler CN, Beall LD, Fisher BJ, Best AM et al (1997) Soluble E-selectin levels in sepsis and critical illness. Correlation with infection and hemodynamic dysfunction. Am J Respir Crit Care Med 156:431–437
Kayal S, Jais JP, Aguini N, Chaudiere J, Labrousse J (1998) Elevated circulating E-selectin, intercellular adhesion molecule 1, and von Willebrand factor in patients with severe infection. Am J Respir Crit Care Med 157:776–784
Schuetz P, Jones AE, Aird WC, Shapiro NI (2011) Endothelial cell activation in emergency department patients with sepsis-related and non-sepsis-related hypotension. Shock 36:104–108
de Pablo R, Monserrat J, Reyes E, Diaz D, Rodriguez-Zapata M et al (2013) Circulating sICAM-1 and sE-Selectin as biomarker of infection and prognosis in patients with systemic inflammatory response syndrome. Eur J Intern Med 24:132–138
Dollner H, Vatten L, Austgulen R (2001) Early diagnostic markers for neonatal sepsis: comparing C-reactive protein, interleukin-6, soluble tumour necrosis factor receptors and soluble adhesion molecules. J Clin Epidemiol 54:1251–1257
Geppert A, Zorn G, Karth GD, Haumer M, Gwechenberger M et al (2000) Soluble selectins and the systemic inflammatory response syndrome after successful cardiopulmonary resuscitation. Crit Care Med 28:2360–2365
Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S et al (2006) Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 12:235–239
Parikh SM, Mammoto T, Schultz A, Yuan HT, Christiani D et al (2006) Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 3:e46
Orfanos SE, Kotanidou A, Glynos C, Athanasiou C, Tsigkos S et al (2007) Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators. Crit Care Med 35:199–206
Siner JM, Bhandari V, Engle KM, Elias JA, Siegel MD (2009) Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis. Shock 31:348–353
David S, Mukherjee A, Ghosh CC, Yano M, Khankin EV et al (2012) Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis*. Crit Care Med 40:3034–3041
Davis JS, Yeo TW, Piera KA, Woodberry T, Celermajer DS et al (2010) Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivity. Crit Care 14:R89
Kumpers P, Lukasz A, David S, Horn R, Hafer C et al (2008) Excess circulating angiopoietin-2 is a strong predictor of mortality in critically ill medical patients. Crit Care 12:R147
Giuliano JS Jr, Lahni PM, Harmon K, Wong HR, Doughty LA et al (2007) Admission angiopoietin levels in children with septic shock. Shock 28:650–654
Agrawal A, Matthay MA, Kangelaris KN, Stein J, Chu JC et al (2013) Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med 187:736–742
Ganter MT, Cohen MJ, Brohi K, Chesebro BB, Staudenmayer KL et al (2008) Angiopoietin-2, marker and mediator of endothelial activation with prognostic significance early after trauma? Ann Surg 247:320–326
Kranidioti H, Orfanos SE, Vaki I, Kotanidou A, Raftogiannis M et al (2009) Angiopoietin-2 is increased in septic shock: evidence for the existence of a circulating factor stimulating its release from human monocytes. Immunol Lett 125:65–71
van der Heijden M, van Nieuw Amerongen GP, van Hinsbergh VW, Groeneveld AB (2010) The interaction of soluble Tie2 with angiopoietins and pulmonary vascular permeability in septic and nonseptic critically ill patients. Shock 33:263–268
Jesmin S, Wada T, Gando S, Sultana SS, Zaedi S (2013) The dynamics of angiogenic factors and their soluble receptors in relation to organ dysfunction in disseminated intravascular coagulation associated with sepsis. Inflammation 36:186–196
Pickkers P, Sprong T, Eijk L, Hoeven H, Smits P et al (2005) Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability. Shock 24:508–512
Karlsson S, Pettila V, Tenhunen J, Lund V, Hovilehto S et al (2008) Vascular endothelial growth factor in severe sepsis and septic shock. Anesth Analg 106:1820–1826
Yang KY, Liu KT, Chen YC, Chen CS, Lee YC et al (2011) Plasma soluble vascular endothelial growth factor receptor-1 levels predict outcomes of pneumonia-related septic shock patients: a prospective observational study. Crit Care 15:R11
Hamalainen S, Juutilainen A, Matinlauri I, Kuittinen T, Ruokonen E et al (2009) Serum vascular endothelial growth factor in adult haematological patients with neutropenic fever: a comparison with C-reactive protein. Eur J Haematol 83:251–257
Pittet JF, Morel DR, Hemsen A, Gunning K, Lacroix JS et al (1991) Elevated plasma endothelin-1 concentrations are associated with the severity of illness in patients with sepsis. Ann Surg 213:261–264
Takakuwa T, Endo S, Nakae H, Kikichi M, Suzuki T et al (1994) Plasma levels of TNF-alpha, endothelin-1 and thrombomodulin in patients with sepsis. Res Commun Chem Pathol Pharmacol 84:261–269
Nakae H, Endo S, Inada K, Yamada Y, Takakuwa T et al (1996) Plasma levels of endothelin-1 and thrombomodulin in burn patients. Burns 22:594–597
Tschaikowsky K, Sagner S, Lehnert N, Kaul M, Ritter J (2000) Endothelin in septic patients: effects on cardiovascular and renal function and its relationship to proinflammatory cytokines. Crit Care Med 28:1854–1860
Schuetz P, Christ-Crain M, Morgenthaler NG, Struck J, Bergmann A et al (2007) Circulating precursor levels of endothelin-1 and adrenomedullin, two endothelium-derived, counteracting substances, in sepsis. Endothelium 14:345–351
Figueras-Aloy J, Gomez L, Rodriguez-Miguelez JM, Jordan Y, Salvia MD et al (2003) Plasma nitrite/nitrate and endothelin-1 concentrations in neonatal sepsis. Acta Paediatr 92:582–587
Hirata Y, Mitaka C, Sato K, Nagura T, Tsunoda Y et al (1996) Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis. J Clin Endocrinol Metab 81:1449–1453
Nishio K, Akai Y, Murao Y, Doi N, Ueda S et al (1997) Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock. Crit Care Med 25:953–957
Ehlenz K, Koch B, Preuss P, Simon B, Koop I et al (1997) High levels of circulating adrenomedullin in severe illness: correlation with C-reactive protein and evidence against the adrenal medulla as site of origin. Exp Clin Endocrinol Diabetes 105:156–162
Ueda S, Nishio K, Minamino N, Kubo A, Akai Y et al (1999) Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. Am J Respir Crit Care Med 160:132–136
Chen YX, Li CS (2013) Prognostic value of adrenomedullin in septic patients in the ED. Am J Emerg Med 31:1017–1021
Oncel MY, Dilmen U, Erdeve O, Ozdemir R, Calisici E et al (2012) Proadrenomedullin as a prognostic marker in neonatal sepsis. Pediatr Res 72:507–512
Al Shuaibi M, Bahu RR, Chaftari AM, Al Wohoush I, Shomali W et al (2013) Pro-adrenomedullin as a novel biomarker for predicting infections and response to antimicrobials in febrile patients with hematologic malignancies. Clin Infect Dis 56:943–950
Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A et al (2005) Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care 9:R816–R824
Guignant C, Voirin N, Venet F, Poitevin F, Malcus C et al (2009) Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients. Intensive Care Med 35:1859–1867
Scherpereel A, Depontieu F, Grigoriu B, Cavestri B, Tsicopoulos A et al (2006) Endocan, a new endothelial marker in human sepsis. Crit Care Med 34:532–537
De Freitas CN, Legendre B, Parmentier E, Scherpereel A, Tsicopoulos A et al (2013) Identification of a 14 kDa endocan fragment generated by cathepsin G, a novel circulating biomarker in patients with sepsis. J Pharm Biomed Anal 78–79:45–51
Linder A, Christensson B, Herwald H, Bjorck L, Akesson P (2009) Heparin-binding protein: an early marker of circulatory failure in sepsis. Clin Infect Dis 49:1044–1050
Borgel D, Clauser S, Bornstain C, Bieche I, Bissery A et al (2006) Elevated growth-arrest-specific protein 6 plasma levels in patients with severe sepsis. Crit Care Med 34:219–222
Ekman C, Linder A, Akesson P, Dahlback B (2010) Plasma concentrations of Gas6 (growth arrest specific protein 6) and its soluble tyrosine kinase receptor sAxl in sepsis and systemic inflammatory response syndromes. Crit Care 14:R158
Duswald KH, Jochum M, Schramm W, Fritz H (1985) Released granulocytic elastase: an indicator of pathobiochemical alterations in septicemia after abdominal surgery. Surgery 98:892–899
Tanaka H, Sugimoto H, Yoshioka T, Sugimoto T (1991) Role of granulocyte elastase in tissue injury in patients with septic shock complicated by multiple-organ failure. Ann Surg 213:81–85
Gardinali M, Padalino P, Vesconi S, Calcagno A, Ciappellano S et al (1992) Complement activation and polymorphonuclear neutrophil leukocyte elastase in sepsis. Correlation with severity of disease. Arch Surg 127:1219–1224
Bossink AW, Groeneveld AB, Thijs LG (1999) Prediction of microbial infection and mortality in medical patients with fever: plasma procalcitonin, neutrophilic elastase-alpha1-antitrypsin, and lactoferrin compared with clinical variables. Clin Infect Dis 29:398–407
Selberg O, Hecker H, Martin M, Klos A, Bautsch W et al (2000) Discrimination of sepsis and systemic inflammatory response syndrome by determination of circulating plasma concentrations of procalcitonin, protein complement 3a, and interleukin-6. Crit Care Med 28:2793–2798
Basu RK, Standage SW, Cvijanovich NZ, Allen GL, Thomas NJ et al (2011) Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray. Crit Care 15:R273
Hoffmann U, Bertsch T, Dvortsak E, Liebetrau C, Lang S et al (2006) Matrix-metalloproteinases and their inhibitors are elevated in severe sepsis: prognostic value of TIMP-1 in severe sepsis. Scand J Infect Dis 38:867–872
Lorente L, Martin MM, Labarta L, Diaz C, Sole-Violan J et al (2009) Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis. Crit Care 13:R158
Gaddnas FP, Sutinen MM, Koskela M, Tervahartiala T, Sorsa T et al (2010) Matrix-metalloproteinase-2, -8 and -9 in serum and skin blister fluid in patients with severe sepsis. Crit Care 14:R49
Yazdan-Ashoori P, Liaw P, Toltl L, Webb B, Kilmer G et al (2011) Elevated plasma matrix metalloproteinases and their tissue inhibitors in patients with severe sepsis. J Crit Care 26:556–565
Lauhio A, Hastbacka J, Pettila V, Tervahartiala T, Karlsson S et al (2011) Serum MMP-8, -9 and TIMP-1 in sepsis: high serum levels of MMP-8 and TIMP-1 are associated with fatal outcome in a multicentre, prospective cohort study. Hypothetical impact of tetracyclines. Pharmacol Res 64:590–594
Tressel SL, Kaneider NC, Kasuda S, Foley C, Koukos G et al (2011) A matrix metalloprotease-PAR1 system regulates vascular integrity, systemic inflammation and death in sepsis. EMBO Mol Med 3:370–384
Punyadeera C, Schneider EM, Schaffer D, Hsu HY, Joos TO et al (2010) A biomarker panel to discriminate between systemic inflammatory response syndrome and sepsis and sepsis severity. J Emerg Trauma Shock 3:26–35
Vadas P (1984) Elevated plasma phospholipase A2 levels: correlation with the hemodynamic and pulmonary changes in gram-negative septic shock. J Lab Clin Med 104:873–881
Rintala EM, Nevalainen TJ (1993) Group II phospholipase A2 in sera of febrile patients with microbiologically or clinically documented infections. Clin Infect Dis 17:864–870
Takakuwa T, Endo S, Nakae H, Suzuki T, Inada K et al (1994) Relationships between plasma levels of type-II phospholipase A2, PAF-acetylhydrolase, leukotriene B4, complements, endothelin-1, and thrombomodulin in patients with sepsis. Res Commun Chem Pathol Pharmacol 84:271–281
Nyman KM, Uhl W, Forsstrom J, Buchler M, Beger HG et al (1996) Serum phospholipase A2 in patients with multiple organ failure. J Surg Res 60:7–14
Sorensen J, Kald B, Tagesson C, Lindahl M (1994) Platelet-activating factor and phospholipase A2 in patients with septic shock and trauma. Intensive Care Med 20:555–561
Endo S, Inada K, Nakae H, Takakuwa T, Yamada Y et al (1995) Plasma levels of type II phospholipase A2 and cytokines in patients with sepsis. Res Commun Mol Pathol Pharmacol 90:413–421
Yamada Y, Endo S, Kamei Y, Minato T, Yokoyama M et al (1998) Plasma levels of type II phospholipase A2 and nitrite/nitrate in patients with burns. Burns 24:513–517
Schrama AJ, de Beaufort AJ, Poorthuis BJ, Berger HM, Walther FJ (2008) Secretory phospholipase A(2) in newborn infants with sepsis. J Perinatol 28:291–296
Uusitalo-Seppala R, Peuravuori H, Koskinen P, Vahlberg T, Rintala EM (2012) Role of plasma bactericidal/permeability-increasing protein, group IIA phospholipase A(2), C-reactive protein, and white blood cell count in the early detection of severe sepsis in the emergency department. Scand J Infect Dis 44:697–704
Hattori N, Oda S, Sadahiro T, Nakamura M, Abe R et al (2009) YKL-40 identified by proteomic analysis as a biomarker of sepsis. Shock 32:393–400
Wittenhagen P, Kronborg G, Weis N, Nielsen H, Obel N et al (2004) The plasma level of soluble urokinase receptor is elevated in patients with Streptococcus pneumoniae bacteraemia and predicts mortality. Clin Microbiol Infect 10:409–415
Kornblit B, Hellemann D, Munthe-Fog L, Bonde J, Strom JJ et al (2013) Plasma YKL-40 and CHI3L1 in systemic inflammation and sepsis-experience from two prospective cohorts. Immunobiology 218:1227–1234
Accardo-Palumbo A, D’Amelio L, Pileri D, D’Arpa N, Mogavero R et al (2010) Reduction of plasma granzyme A correlates with severity of sepsis in burn patients. Burns 36:811–818
Lauw FN, Simpson AJ, Hack CE, Prins JM, Wolbink AM et al (2000) Soluble granzymes are released during human endotoxemia and in patients with severe infection due to gram-negative bacteria. J Infect Dis 182:206–213
Cohen J (2002) The immunopathogenesis of sepsis. Nature 420:885–891
Wilson RF, Farag A, Mammen EF, Fujii Y (1989) Sepsis and antithrombin III, prekallikrein, and fibronectin levels in surgical patients. Am Surg 55:450–456
Leithauser B, Matthias FR, Nicolai U, Voss R (1996) Hemostatic abnormalities and the severity of illness in patients at the onset of clinically defined sepsis. Possible indication of the degree of endothelial cell activation? Intensive Care Med 22:631–636
Sakr Y, Reinhart K, Hagel S, Kientopf M, Brunkhorst F (2007) Antithrombin levels, morbidity, and mortality in a surgical intensive care unit. Anesth Analg 105:715–723
Wilson RF, Mammen EF, Tyburski JG, Warsow KM, Kubinec SM (1996) Antithrombin levels related to infections and outcome. J Trauma 40:384–387
Iba T, Kidokoro A, Fukunaga M, Sugiyama K, Sawada T et al (2005) Association between the severity of sepsis and the changes in hemostatic molecular markers and vascular endothelial damage markers. Shock 23:25–29
Kinasewitz GT, Yan SB, Basson B, Comp P, Russell JA et al (2004) Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit Care 8:R82–R90
Pettila V, Pentti J, Pettila M, Takkunen O, Jousela I (2002) Predictive value of antithrombin III and serum C-reactive protein concentration in critically ill patients with suspected sepsis. Crit Care Med 30:271–275
Okabayashi K, Wada H, Ohta S, Shiku H, Nobori T et al (2004) Hemostatic markers and the sepsis-related organ failure assessment score in patients with disseminated intravascular coagulation in an intensive care unit. Am J Hematol 76:225–229
Reade MC, Yende S, D’Angelo G, Kong L, Kellum JA et al (2009) Differences in immune response may explain lower survival among older men with pneumonia. Crit Care Med 37:1655–1662
Lauterbach R, Pawlik D, Radziszewska R, Wozniak J, Rytlewski K (2006) Plasma antithrombin III and protein C levels in early recognition of late-onset sepsis in newborns. Eur J Pediatr 165:585–589
Ostrowski SR, Berg RM, Windelov NA, Meyer MA, Plovsing RR et al (2013) Coagulopathy, catecholamines, and biomarkers of endothelial damage in experimental human endotoxemia and in patients with severe sepsis: a prospective study. J Crit Care 28:586–596
Fisher CJ Jr, Yan SB (2000) Protein C levels as a prognostic indicator of outcome in sepsis and related diseases. Crit Care Med 28:S49–S56
Macias WL, Nelson DR (2004) Severe protein C deficiency predicts early death in severe sepsis. Crit Care Med 32:S223–S228
Gutovitz S, Papa L, Jimenez E, Falk J, Wieman L et al (2011) Protein C as an early biomarker to distinguish pneumonia from sepsis. J Crit Care 26(330):e339–312
Asakura H, Ontachi Y, Mizutani T, Kato M, Ito T et al (2001) Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation. Eur J Haematol 67:170–175
Borgel D, Bornstain C, Reitsma PH, Lerolle N, Gandrille S et al (2007) A comparative study of the protein C pathway in septic and nonseptic patients with organ failure. Am J Respir Crit Care Med 176:878–885
Shaw AD, Vail GM, Haney DJ, Xie J, Williams MD (2011) Severe protein C deficiency is associated with organ dysfunction in patients with severe sepsis. J Crit Care 26:539–545
Shapiro NI, Trzeciak S, Hollander JE, Birkhahn R, Otero R et al (2009) A prospective, multicenter derivation of a biomarker panel to assess risk of organ dysfunction, shock, and death in emergency department patients with suspected sepsis. Crit Care Med 37:96–104
Iba T, Yagi Y, Kidokoro A, Fukunaga M, Fukunaga T (1995) Increased plasma levels of soluble thrombomodulin in patients with sepsis and organ failure. Surg Today 25:585–590
Boldt J, Wollbruck T, Sonneborn S, Welters A, Hempelmann G (1995) Thrombomodulin in intensive care patients. Intensive Care Med 21:645–650
Boldt J, Papsdorf M, Rothe A, Kumle B, Piper S (2000) Changes of the hemostatic network in critically ill patients–is there a difference between sepsis, trauma, and neurosurgery patients? Crit Care Med 28:445–450
Ikegami K, Suzuki Y, Yukioka T, Matsuda H, Shimazaki S (1998) Endothelial cell injury, as quantified by the soluble thrombomodulin level, predicts sepsis/multiple organ dysfunction syndrome after blunt trauma. J Trauma 44:789–794, discussion 794-785
Lin SM, Wang YM, Lin HC, Lee KY, Huang CD et al (2008) Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med 36:683–689
Kato T, Sakai T, Kato M, Hagihara M, Hasegawa T et al (2013) Recombinant human soluble thrombomodulin administration improves sepsis-induced disseminated intravascular coagulation and mortality: a retrospective cohort study. Thromb J 11:3
Pralong G, Calandra T, Glauser MP, Schellekens J, Verhoef J et al (1989) Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 61:459–462
Brandtzaeg P, Joo GB, Brusletto B, Kierulf P (1990) Plasminogen activator inhibitor 1 and 2, alpha-2-antiplasmin, plasminogen, and endotoxin levels in systemic meningococcal disease. Thromb Res 57:271–278
Madoiwa S, Nunomiya S, Ono T, Shintani Y, Ohmori T et al (2006) Plasminogen activator inhibitor 1 promotes a poor prognosis in sepsis-induced disseminated intravascular coagulation. Int J Hematol 84:398–405
Gando S, Nakanishi Y, Tedo I (1995) Cytokines and plasminogen activator inhibitor-1 in posttrauma disseminated intravascular coagulation: relationship to multiple organ dysfunction syndrome. Crit Care Med 23:1835–1842
Dofferhoff AS, Bom VJ, de Vries-Hospers HG, van Ingen J, Meer J et al (1992) Patterns of cytokines, plasma endotoxin, plasminogen activator inhibitor, and acute-phase proteins during the treatment of severe sepsis in humans. Crit Care Med 20:185–192
Kruithof E, Calandra T, Pralong G, Heumann D, Gerain J et al (1993) Evolution of plasminogen-activator inhibitor type-1 in patients with septic shock - correlation with cytokine concentrations. Fibrinolysis 7:117–121
Menges T, Hermans PW, Little SG, Langefeld T, Boning O et al (2001) Plasminogen-activator-inhibitor-1 4G/5G promoter polymorphism and prognosis of severely injured patients. Lancet 357:1096–1097
Garcia-Segarra G, Espinosa G, Tassies D, Oriola J, Aibar J et al (2007) Increased mortality in septic shock with the 4G/4G genotype of plasminogen activator inhibitor 1 in patients of white descent. Intensive Care Med 33:1354–1362
Robbie LA, Dummer S, Booth NA, Adey GD, Bennett B (2000) Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. Br J Haematol 109:342–348
Bagge L, Haglund O, Wallin R, Borg T, Modig J (1989) Differences in coagulation and fibrinolysis after traumatic and septic shock in man. Scand J Clin Lab Invest 49:63–72
Rubin DB, Wiener-Kronish JP, Murray JF, Green DR, Turner J et al (1990) Elevated von Willebrand factor antigen is an early plasma predictor of acute lung injury in nonpulmonary sepsis syndrome. J Clin Invest 86:474–480
Ware LB, Eisner MD, Thompson BT, Parsons PE, Matthay MA (2004) Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 170:766–772
Claus RA, Bockmeyer CL, Budde U, Kentouche K, Sossdorf M et al (2009) Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure. Thromb Haemost 101:239–247
Christeff N, Benassayag C, Carli-Vielle C, Carli A, Nunez EA (1988) Elevated oestrogen and reduced testosterone levels in the serum of male septic shock patients. J Steroid Biochem 29:435–440
Fourrier F, Jallot A, Leclerc L, Jourdain M, Racadot A et al (1994) Sex steroid hormones in circulatory shock, sepsis syndrome, and septic shock. Circ Shock 43:171–178
Luppa P, Munker R, Nagel D, Weber M, Engelhardt D (1991) Serum androgens in intensive-care patients: correlations with clinical findings. Clin Endocrinol (Oxf) 34:305–310
May AK, Dossett LA, Norris PR, Hansen EN, Dorsett RC et al (2008) Estradiol is associated with mortality in critically ill trauma and surgical patients. Crit Care Med 36:62–68
Baue AE, Gunther B, Hartl W, Ackenheil M, Heberer G (1984) Altered hormonal activity in severely ill patients after injury or sepsis. Arch Surg 119:1125–1132
Bornstein SR, Licinio J, Tauchnitz R, Engelmann L, Negrao AB et al (1998) Plasma leptin levels are increased in survivors of acute sepsis: associated loss of diurnal rhythm, in cortisol and leptin secretion. J Clin Endocrinol Metab 83:280–283
Arnalich F, Lopez J, Codoceo R, Jim nez M, Madero R et al (1999) Relationship of plasma leptin to plasma cytokines and human survival in sepsis and septic shock. J Infect Dis 180:908–911
Langouche L, Vander Perre S, Frystyk J, Flyvbjerg A, Hansen TK et al (2009) Adiponectin, retinol-binding protein 4, and leptin in protracted critical illness of pulmonary origin. Crit Care 13:R112
Koch A, Weiskirchen R, Zimmermann HW, Sanson E, Trautwein C et al (2010) Relevance of serum leptin and leptin-receptor concentrations in critically ill patients. Mediators Inflamm 2010
Hillenbrand A, Knippschild U, Weiss M, Schrezenmeier H, Henne-Bruns D et al (2010) Sepsis induced changes of adipokines and cytokines - septic patients compared to morbidly obese patients. BMC Surg 10:26
Yousef AA, Amr YM, Suliman GA (2010) The diagnostic value of serum leptin monitoring and its correlation with tumor necrosis factor-alpha in critically ill patients: a prospective observational study. Crit Care 14:R33
Jochberger S, Morgenthaler NG, Mayr VD, Luckner G, Wenzel V et al (2006) Copeptin and arginine vasopressin concentrations in critically ill patients. J Clin Endocrinol Metab 91:4381–4386
Lee JH, Chan YH, Lai OF, Puthucheary J (2013) Vasopressin and copeptin levels in children with sepsis and septic shock. Intensive Care Med 39:747–753
Seligman R, Papassotiriou J, Morgenthaler NG, Meisner M, Teixeira PJ (2008) Copeptin, a novel prognostic biomarker in ventilator-associated pneumonia. Crit Care 12:R11
Muller B, Morgenthaler N, Stolz D, Schuetz P, Muller C et al (2007) Circulating levels of copeptin, a novel biomarker, in lower respiratory tract infections. Eur J Clin Invest 37:145–152
Purhonen AK, Vanska M, Hamalainen S, Pulkki K, Lehtikangas M et al (2012) Plasma copeptin in the assessment of febrile neutropenia. Peptides 36:129–132
Morgenthaler NG, Struck J, Christ-Crain M, Bergmann A, Muller B (2005) Pro-atrial natriuretic peptide is a prognostic marker in sepsis, similar to the APACHE II score: an observational study. Crit Care 9:R37–R45
Ueda S, Nishio K, Akai Y, Fukushima H, Ueyama T et al (2006) Prognostic value of increased plasma levels of brain natriuretic peptide in patients with septic shock. Shock 26:134–139
Witthaut R, Busch C, Fraunberger P, Walli A, Seidel D et al (2003) Plasma atrial natriuretic peptide and brain natriuretic peptide are increased in septic shock: impact of interleukin-6 and sepsis-associated left ventricular dysfunction. Intensive Care Med 29:1696–1702
Brueckmann M, Huhle G, Lang S, Haase KK, Bertsch T et al (2005) Prognostic value of plasma N-terminal pro-brain natriuretic peptide in patients with severe sepsis. Circulation 112:527–534
Charpentier J, Luyt CE, Fulla Y, Vinsonneau C, Cariou A et al (2004) Brain natriuretic peptide: a marker of myocardial dysfunction and prognosis during severe sepsis. Crit Care Med 32:660–665
Varpula M, Pulkki K, Karlsson S, Ruokonen E, Pettila V (2007) Predictive value of N-terminal pro-brain natriuretic peptide in severe sepsis and septic shock. Crit Care Med 35:1277–1283
Kerbaul F, Giorgi R, Oddoze C, Collart F, Guidon C et al (2004) High concentrations of N-BNP are related to non-infectious severe SIRS associated with cardiovascular dysfunction occurring after off-pump coronary artery surgery. Br J Anaesth 93:639–644
McLean AS, Huang SJ, Hyams S, Poh G, Nalos M et al (2007) Prognostic values of B-type natriuretic peptide in severe sepsis and septic shock. Crit Care Med 35:1019–1026
Post F, Weilemann LS, Messow CM, Sinning C, Munzel T (2008) B-type natriuretic peptide as a marker for sepsis-induced myocardial depression in intensive care patients. Crit Care Med 36:3030–3037
Pirracchio R, Deye N, Lukaszewicz AC, Mebazaa A, Cholley B et al (2008) Impaired plasma B-type natriuretic peptide clearance in human septic shock. Crit Care Med 36:2542–2546
Kandil E, Burack J, Sawas A, Bibawy H, Schwartzman A et al (2008) B-type natriuretic peptide: a biomarker for the diagnosis and risk stratification of patients with septic shock. Arch Surg 143:242–246, discussion 246
Chen Y, Li C (2009) Prognostic significance of brain natriuretic peptide obtained in the ED in patients with SIRS or sepsis. Am J Emerg Med 27:701–706
Perman SM, Chang AM, Hollander JE, Gaieski DF, Trzeciak S et al (2011) Relationship between B-type natriuretic peptide and adverse outcome in patients with clinical evidence of sepsis presenting to the emergency department. Acad Emerg Med 18:219–222
Hama N, Itoh H, Shirakami G, Suga S, Komatsu Y et al (1994) Detection of C-type natriuretic peptide in human circulation and marked increase of plasma CNP level in septic shock patients. Biochem Biophys Res Commun 198:1177–1182
Bahrami S, Pelinka L, Khadem A, Maitzen S, Hawa G et al (2010) Circulating NT-proCNP predicts sepsis in multiple-traumatized patients without traumatic brain injury. Crit Care Med 38:161–166
Koch A, Voigt S, Sanson E, Duckers H, Horn A et al (2011) Prognostic value of circulating amino-terminal pro-C-type natriuretic peptide in critically ill patients. Crit Care 15:R45
Rubli E, Bussard S, Frei E, Lundsgaard-Hansen P, Pappova E (1983) Plasma fibronectin and associated variables in surgical intensive care patients. Ann Surg 197:310–317
Ekindjian OG, Marien M, Wassermann D, Bruxelle J, Cazalet C et al (1984) Plasma fibronectin time course in burned patients: influence of sepsis. J Trauma 24:214–219
Blanco A, Guisasola JA, Solis P, Bachiller R, Gonzalez H (1990) Fibronectin in meningococcal sepsis. Correlation with antithrombin III and protein C. Acta Paediatr Scand 79:73–76
Ruiz Martin G, Prieto Prieto J, Veiga de Cabo J, Gomez Lus L, Barberan J et al (2004) Plasma fibronectin as a marker of sepsis. Int J Infect Dis 8:236–243
Glattard E, Welters ID, Lavaux T, Muller AH, Laux A et al (2010) Endogenous morphine levels are increased in sepsis: a partial implication of neutrophils. PLoS One 5:e8791
Sakr Y, Reinhart K, Bloos F, Marx G, Russwurm S et al (2007) Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure. Br J Anaesth 98:775–784
Vaschetto R, Nicola S, Olivieri C, Boggio E, Piccolella F et al (2008) Serum levels of osteopontin are increased in SIRS and sepsis. Intensive Care Med 34:2176–2184
Wang H, Cheng B, Chen Q, Wu S, Lv C et al (2008) Time course of plasma gelsolin concentrations during severe sepsis in critically ill surgical patients. Crit Care 12:R106
Stove S, Welte T, Wagner TO, Kola A, Klos A et al (1996) Circulating complement proteins in patients with sepsis or systemic inflammatory response syndrome. Clin Diagn Lab Immunol 3:175–183
Wolk K, Döcke WD, von Baehr V, Volk HD, Sabat R (2000) Impaired antigen presentation by human monocytes during endotoxin tolerance. Blood 96(1):218–223
Cavaillon JM, Adib-Conquy M (2006) Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care 10:233
Hershman MJ, Cheadle WG, Wellhausen SR, Davidon P, Polk HC (1990) Monocyte HLA-DR antigen expression characterizes clinical outcome in the trauma patients. Br J Surg 77:204–207
Kim OY, Monsel A, Bertrand M, Coriat P, Cavaillon JM et al (2010) Differential down-regulation of HLA-DR on monocyte subpopulations during systemic inflammation. Crit Care 14:R61
Fumeaux T, Pugin J (2002) Role of interleukin-10 in the intracellular sequestration of human leukocyte antigen-DR in monocytes during septic shock. Am J Respir Crit Care Med 166:1475–1482
Le Tulzo Y, Pangault C, Amiot L, Guilloux V, Tribut O et al (2004) Monocyte human leukocyte antigen-DR transcriptional downregulation by cortisol during septic shock. Am J Respir Crit Care Med 169:1144–1151
Ditschkowski M, Kreuzfelder E, Rebmann V, Ferencik S, Majetschak M et al (1999) HLA-DR expression and soluble HLA-DR levels in septic patients after trauma. Ann Surg 229:246–254
Tschaikowsky K, Hedwig-Geissing M, Schiele A, Bremer F, Schywalsky M et al (2002) Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients. Crit Care Med 30:1015–1023
Perry SE, Mostafa SM, Wenstone R, Shenkin A, McLaughlin PJ (2003) Is low monocyte HLA-DR expression helpful to predict outcome in severe sepsis? Intensive Care Med 29:1245–1252
Muehlstedt SG, Lyte M, Rodriguez JL (2002) Increased IL-10 production and HLA-DR suppression in the lungs of injured patients precede the development of nosocomial pneumonia. Shock 17:443–450
Cheadle WG, Hershman MJ, Wellhausen SR, Polk HC Jr (1991) HLA-DR antigen expression on peripheral blood monocytes correlates with surgical infection. Am J Surg 161:639–645
van den Berk JM, Oldenburger RH, van den Berg AP, Klompmaker IJ, Mesander G et al (1997) Low HLA-DR expression on monocytes as a prognostic marker for bacterial sepsis after liver transplantation. Transplantation 63:1846–1848
Satoh A, Miura T, Satoh K, Masamune A, Yamagiwa T et al (2002) Human leukocyte antigen-DR expression on peripheral monocytes as a predictive marker of sepsis during acute pancreatitis. Pancreas 25:245–250
Venet F, Tissot S, Debard AL, Faudot C, Crampe C et al (2007) Decreased monocyte human leukocyte antigen-DR expression after severe burn injury: correlation with severity and secondary septic shock. Crit Care Med 35:1910–1917
Strohmeyer JC, Blume C, Meisel C, Doecke WD, Hummel M et al (2003) Standardized immune monitoring for the prediction of infections after cardiopulmonary bypass surgery in risk patients. Cytometry B Clin Cytom 53:54–62
Monneret G, Lepape A, Voirin N, Bohe J, Venet F et al (2006) Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med 32:1175–1183
Lukaszewicz AC, Grienay M, Resche-Rigon M, Pirracchio R, Faivre V et al (2009) Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med 37:2746–2752
Cheron A, Floccard B, Allaouchiche B, Guignant C, Poitevin F et al (2010) Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after major trauma. Crit Care 14:R208
Landelle C, Lepape A, Voirin N, Tognet E, Venet F et al (2010) Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med 36:1859–1866
Medzhitov R, Preston-Hurlburt P, Janeway CA (1997) A human homologue of the Drosophila Toll protein signals activation of adaptative immunity. Nature 388:394–397
Wittebole X, Coyle SM, Kumar A, Goshima M, Lowry SF et al (2005) Expression of tumour necrosis factor receptor and Toll-like receptor 2 and 4 on peripheral blood leucocytes of human volunteers after endotoxin challenge: a comparison of flow cytometric light scatter and immunofluorescence gating. Clin Exp Immunol 141:99–106
Harter L, Mica L, Stocker R, Trentz O, Keel M (2004) Increased expression of toll-like receptor-2 and -4 on leukocytes from patients with sepsis. Shock 22:403–409
Brandl K, Gluck T, Huber C, Salzberger B, Falk W et al (2005) TLR-4 surface display on human monocytes is increased in septic patients. Eur J Med Res 10:319–324
Tsujimoto H, Ono S, Majima T, Efron PA, Kinoshita M et al (2006) Differential toll-like receptor expression after ex vivo lipopolysaccharide exposure in patients with sepsis and following surgical stress. Clin Immunol 119:180–187
Tsujimoto H, Ono S, Majima T, Kawarabayashi N, Takayama E et al (2005) Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis. Shock 23:39–44
Viemann D, Dubbel G, Schleifenbaum S, Harms E, Sorg C et al (2005) Expression of toll-like receptors in neonatal sepsis. Pediatr Res 58:654–659
Ono S, Tsujimoto H, Hiraki S, Takahata R, Kinoshita M et al (2005) Sex differences in cytokine production and surface antigen expression of peripheral blood mononuclear cells after surgery. Am J Surg 190:439–444
Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J et al (2002) Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 169:4697–4701
Armstrong L, Medford AR, Hunter KJ, Uppington KM, Millar AB (2004) Differential expression of Toll-like receptor (TLR)-2 and TLR-4 on monocytes in human sepsis. Clin Exp Immunol 136:312–319
Martins PS, Brunialti MK, Martos LS, Machado FR, Assuncao MS et al (2008) Expression of cell surface receptors and oxidative metabolism modulation in the clinical continuum of sepsis. Crit Care 12:R25
Adib-Conquy M, Moine P, Asehnoune K, Edouard A, Espevik T et al (2003) Toll-like receptor-mediated tumor necrosis factor and interleukin-10 production differ during systemic inflammation. Am J Respir Crit Care Med 168:158–164
Souza-Fonseca-Guimaraes F, Parlato M, Philippart F, Misset B, Cavaillon JM et al (2012) Toll-like receptors expression and interferon-gamma production by NK cells in human sepsis. Crit Care 16:R206
Brunialti MK, Martins PS, Barbosa de Carvalho H, Machado FR, Barbosa LM et al (2006) TLR2, TLR4, CD14, CD11B, and CD11C expressions on monocytes surface and cytokine production in patients with sepsis, severe sepsis, and septic shock. Shock 25:351–357
Aalto H, Takala A, Kautiainen H, Siitonen S, Repo H (2007) Monocyte CD14 and soluble CD14 in predicting mortality of patients with severe community acquired infection. Scand J Infect Dis 39:596–603
Schaaf B, Luitjens K, Goldmann T, van Bremen T, Sayk F et al (2009) Mortality in human sepsis is associated with downregulation of Toll-like receptor 2 and CD14 expression on blood monocytes. Diagn Pathol 4:12
Monneret G, Debard AL, Venet F, Bohe J, Hequet O et al (2003) Marked elevation of human circulating CD4 + CD25+ regulatory T cells in sepsis-induced immunoparalysis. Crit Care Med 31:2068–2071
Venet F, Pachot A, Debard AL, Bohe J, Bienvenu J et al (2004) Increased percentage of CD4 + CD25+ regulatory T cells during septic shock is due to the decrease of CD4 + CD25- lymphocytes. Crit Care Med 32:2329–2331
Venet F, Chung CS, Kherouf H, Geeraert A, Malcus C et al (2009) Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients. Intensive Care Med 35:678–686
Hein F, Massin F, Cravoisy-Popovic A, Barraud D, Levy B et al (2010) The relationship between CD4 + CD25 + CD127- regulatory T cells and inflammatory response and outcome during shock states. Crit Care 14:R19
Leng FY, Liu JL, Liu ZJ, Yin JY, Qu HP (2013) Increased proportion of CD4(+)CD25(+)Foxp3(+) regulatory T cells during early-stage sepsis in ICU patients. J Microbiol Immunol Infect 46:338–344
Sugimoto K, Galle C, Preiser JC, Creteur J, Vincent JL et al (2003) Monocyte CD40 expression in severe sepsis. Shock 19:24–27
Nolan A, Weiden M, Kelly A, Hoshino Y, Hoshino S et al (2008) CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis. Am J Respir Crit Care Med 177:301–308
Katsuura M, Shimizu Y, Akiba K, Kanazawa C, Mitsui T et al (1998) CD48 expression on leukocytes in infectious diseases: flow cytometric analysis of surface antigen. Acta Paediatr Jpn 40:580–585
Lewis SM, Treacher DF, Bergmeier L, Brain SD, Chambers DJ et al (2009) Plasma from patients with sepsis up-regulates the expression of CD49d and CD64 on blood neutrophils. Am J Respir Cell Mol Biol 40:724–732
Bhandari V, Wang C, Rinder C, Rinder H (2008) Hematologic profile of sepsis in neonates: neutrophil CD64 as a diagnostic marker. Pediatrics 121:129–134
Groselj-Grenc M, Ihan A, Pavcnik-Arnol M, Kopitar AN, Gmeiner-Stopar T et al (2009) Neutrophil and monocyte CD64 indexes, lipopolysaccharide-binding protein, procalcitonin and C-reactive protein in sepsis of critically ill neonates and children. Intensive Care Med 35:1950–1958
Streimish I, Bizzarro M, Northrup V, Wang C, Renna S et al (2014) Neutrophil CD64 with Hematologic Criteria for Diagnosis of Neonatal Sepsis. Am J Perinatol 31:21–30
Cardelli P, Ferraironi M, Amodeo R, Tabacco F, De Blasi RA et al (2008) Evaluation of neutrophil CD64 expression and procalcitonin as useful markers in early diagnosis of sepsis. Int J Immunopathol Pharmacol 21:43–49
Gibot S, Bene MC, Noel R, Massin F, Guy J et al (2012) Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med 186:65–71
Gros A, Roussel M, Sauvadet E, Gacouin A, Marque S et al (2012) The sensitivity of neutrophil CD64 expression as a biomarker of bacterial infection is low in critically ill patients. Intensive Care Med 38:445–452
Dimoula A, Pradier O, Kassengera Z, Dalcomune D, Turkan H et al (2014) Serial determinations of neutrophil CD64 expression for the diagnosis and monitoring of sepsis in critically ill patients. Clin Infect Dis 58(6):820–9
Schwulst SJ, Muenzer JT, Chang KC, Brahmbhatt TS, Coopersmith CM et al (2008) Lymphocyte phenotyping to distinguish septic from nonseptic critical illness. J Am Coll Surg 206:335–342
Roger PM, Hyvernat H, Ticchioni M, Kumar G, Dellamonica J et al (2012) The early phase of human sepsis is characterized by a combination of apoptosis and proliferation of T cells. J Crit Care 27:384–393
de Pablo R, Monserrat J, Torrijos C, Martin M, Prieto A et al (2012) The predictive role of early activation of natural killer cells in septic shock. Crit Care 16:413
Bouchon A, Facchetti F, Weigand MA, Colonna M (2001) TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature 410:1103–1107
Gibot S, Le Renard PE, Bollaert PE, Kolopp-Sarda MN, Bene MC et al (2005) Surface triggering receptor expressed on myeloid cells 1 expression patterns in septic shock. Intensive Care Med 31:594–597
Ferat-Osorio E, Esquivel-Callejas N, Wong-Baeza I, Aduna-Vicente R, Arriaga-Pizano L et al (2008) The increased expression of TREM-1 on monocytes is associated with infectious and noninfectious inflammatory processes. J Surg Res 150:110–117
Poukoulidou T, Spyridaki A, Mihailidou I, Kopterides P, Pistiki A et al (2011) TREM-1 expression on neutrophils and monocytes of septic patients: relation to the underlying infection and the implicated pathogen. BMC Infect Dis 11:309
Pachot A, Lepape A, Vey S, Bienvenu J, Mougin B et al (2006) Systemic transcriptional analysis in survivor and non-survivor septic shock patients: a preliminary study. Immunol Lett 106:63–71
Pachot A, Cazalis MA, Venet F, Turrel F, Faudot C et al (2008) Decreased expression of the fractalkine receptor CX3CR1 on circulating monocytes as new feature of sepsis-induced immunosuppression. J Immunol 180:6421–6429
Huang X, Venet F, Wang YL, Lepape A, Yuan Z et al (2009) PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A 106:6303–6308
Guignant C, Lepape A, Huang X, Kherouf H, Denis L et al (2011) Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care 15:R99
Zhang Y, Li J, Lou J, Zhou Y, Bo L et al (2011) Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care 15:R70
Monaghan SF, Thakkar RK, Tran ML, Huang X, Cioffi WG et al (2012) Programmed death 1 expression as a marker for immune and physiological dysfunction in the critically ill surgical patient. Shock 38:117–122
Shubin NJ, Monaghan SF, Heffernan DS, Chung CS, Ayala A (2013) B and T lymphocyte attenuator expression on CD4+ T-cells associates with sepsis and subsequent infections in ICU patients. Crit Care 17:R276
Hauser CJ, Lagoo S, Lagoo A, Hale E, Hardy KJ et al (1995) Human peripheral mononuclear cells do not show proinflammatory patterns of cytokine transcription in early trauma: a preliminary report. Shock 4:247–250
Ramilo O, Allman W, Chung W, Mejias A, Ardura M et al (2007) Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109:2066–2077
Tang BM, McLean AS, Dawes IW, Huang SJ, Cowley MJ et al (2008) Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients. Crit Care Med 36:1125–1128
Johnson SB, Lissauer M, Bochicchio GV, Moore R, Cross AS et al (2007) Gene expression profiles differentiate between sterile SIRS and early sepsis. Ann Surg 245:611–621
Tang BM, McLean AS, Dawes IW, Huang SJ, Lin RC (2009) Gene-expression profiling of peripheral blood mononuclear cells in sepsis. Crit Care Med 37:882–888
Wong HR, Cvijanovich N, Allen GL, Lin R, Anas N et al (2009) Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit Care Med 37:1558–1566
Tang BM, McLean AS, Dawes IW, Huang SJ, Lin RC (2007) The use of gene-expression profiling to identify candidate genes in human sepsis. Am J Respir Crit Care Med 176:676–684
Hinrichs C, Kotsch K, Buchwald S, Habicher M, Saak N et al (2010) Perioperative gene expression analysis for prediction of postoperative sepsis. Clin Chem 56:613–622
Bauer M, Giamarellos-Bourboulis E, Kortgen A, Möller E, Felsmann K, et al. (submitted) A transcriptomic biomarker to quantify systemic inflammation of sepsis
Wynn JL, Cvijanovich NZ, Allen GL, Thomas NJ, Freishtat RJ et al (2011) The influence of developmental age on the early transcriptomic response of children with septic shock. Mol Med 17:1146–1156
Tang BM, Huang SJ, McLean AS (2010) Genome-wide transcription profiling of human sepsis: a systematic review. Crit Care 14:R237
Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233
Taganov KD, Boldin MP, Chang KJ, Baltimore D (2006) NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A 103:12481–12486
Nahid MA, Pauley KM, Satoh M, Chan EK (2009) miR-146a is critical for endotoxin-induced tolerance: implication in innate immunity. J Biol Chem 284:34590–34599
Rossato M, Curtale G, Tamassia N, Castellucci M, Mori L et al (2012) IL-10-induced microRNA-187 negatively regulates TNF-alpha, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci U S A 109:E3101–E3110
Wang JF, Yu ML, Yu G, Bian JJ, Deng XM et al (2010) Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun 394:184–188
Wang L, Wang HC, Chen C, Zeng J, Wang Q et al (2013) Differential expression of plasma miR-146a in sepsis patients compared with non-sepsis-SIRS patients. Exp Ther Med 5:1101–1104
Wang H, Zhang P, Chen W, Feng D, Jia Y et al (2012) Serum microRNA signatures identified by Solexa sequencing predict sepsis patients’ mortality: a prospective observational study. PLoS One 7:e38885
Wang H, Zhang P, Chen W, Feng D, Jia Y et al (2012) Evidence for serum miR-15a and miR-16 levels as biomarkers that distinguish sepsis from systemic inflammatory response syndrome in human subjects. Clin Chem Lab Med 50:1423–1428
Schmidt WM, Spiel AO, Jilma B, Wolzt M, Muller M (2009) In vivo profile of the human leukocyte microRNA response to endotoxemia. Biochem Biophys Res Commun 380:437–441
Vasilescu C, Rossi S, Shimizu M, Tudor S, Veronese A et al (2009) MicroRNA fingerprints identify miR-150 as a plasma prognostic marker in patients with sepsis. PLoS One 4:e7405
Ma Y, Vilanova D, Atalar K, Delfour O, Edgeworth J et al (2013) Genome-wide sequencing of cellular microRNAs identifies a combinatorial expression signature diagnostic of sepsis. PLoS One 8:e75918
Roderburg C, Luedde M, Vargas Cardenas D, Vucur M, Scholten D et al (2013) Circulating microRNA-150 serum levels predict survival in patients with critical illness and sepsis. PLoS One 8:e54612
Tacke F, Roderburg C, Benz F, Cardenas DV, Luedde M et al (2014) Levels of circulating miR-133a are elevated in sepsis and predict mortality in critically ill patients. Crit Care Med 42(5):1096–104
Hurr H, Hawley HB, Czachor JS, Markert RJ, McCarthy MC (1999) APACHE II and ISS scores as predictors of nosocomial infections in trauma patients. Am J Infect Control 27:79–83
Angeletti S, Battistoni F, Fioravanti M, Bernardini S, Dicuonzo G (2013) Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis diagnosis. Clin Chem Lab Med 51:1059–1067
Casserly B, Read R, Levy MM (2011) Multimarker panels in sepsis. Crit Care Clin 27:391–405
Waage A, Espevik T, Lamvik J (1986) Detection of tumour necrosis factor-like cytotoxicity in serum from patients with septicaemia but not from untreated cancer patients. Scand J Immunol 24(6):739–743
Marchant A, Devière J, Byl B, De Groote D, Vincent JL et al (1994) Interleukin-10 production during septicaemia. Lancet 343(8899):707–708
Waring PM, Presneill J, Maher DW, Layton JE, Cebon J et al (1995) Differential alterations in plasma colony-stimulating factor concentrations in meningococcaemia. Clin Exp Immunol 102(3):501–506
DiPiro JT, Howdieshell TR, Goddard JK, Callaway DB, Hamilton RG et al (1995) Association of interleukin-4 plasma levels with traumatic injury and clinical course. Arch Surg 130(11):1159–1162
Zeni F, Vindimian M, Pain P, Gery P, Tardy B et al (1995) Antiinflammatory and proinflammatory cytokines in patients with severe sepsis. J Infect Dis 172(4):1171–1172
Marie C, Cavaillon JM, Losser MR (1996) Elevated levels of circulating transforming growth factor-beta 1 in patients with the sepsis syndrome. Ann Intern Med 125(6):520–521
Sriskandan S, Moyes D, Cohen J (1996) Detection of circulating bacterial superantigen and lymphotoxin-alpha in patients with streptococcal toxic-shock syndrome. Lancet 348(9037):1315–1316
Bingold TM, Ziesché E, Scheller B, Sadik CD, Franck K et al (2010) Interleukin-22 detected in patients with abdominal sepsis. Shock 34(4):337–340
Kasai T, Inada K, Takakuwa T, Yamada Y, Inoue Y et al (1997) Anti-inflammatory cytokine levels in patients with septic shock. Res Commun Mol Pathol Pharmacol 98(1):34–42
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this protocol
Cite this protocol
Parlato, M., Cavaillon, JM. (2015). Host Response Biomarkers in the Diagnosis of Sepsis: A General Overview. In: Mancini, N. (eds) Sepsis. Methods in Molecular Biology, vol 1237. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1776-1_15
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1776-1_15
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-1775-4
Online ISBN: 978-1-4939-1776-1
eBook Packages: Springer Protocols