Biomarkers of sepsis

James D Faix, James D Faix

Abstract

Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate's effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high.

Figures

Figure 1.
Figure 1.
Sepsis may be divided into two phases. Following infection, a hyper-inflammatory phase is characterized by SIRS. This may resolve or the patient may progress to what is called severe sepsis. During this phase, there is evidence of CARS with immunosuppression and multiple organ dysfunction. This may also resolve, especially with appropriate support, but it often leads to death.
Figure 2.
Figure 2.
Sepsis begins with either infection or tissue injury. PAMPs from invading organisms or DAMPs from injured tissue cells (or both) are recognized by macrophage receptors such as the TLRs. This results in the production of pro-inflammatory cytokines such as TNF, IL-1β and IL-6 and chemokines such as IL-8 and MCP-1. IL-6 stimulates the liver to produce CRP and complement proteins. Many cells in the body also produce PCT in response to both infection and injury.
Figure 3.
Figure 3.
Activated inflammatory cells up-regulate a number of proteins which may be detected as biomarkers of sepsis, either on the cell surface or as soluble forms in plasma. (a) An unstimulated PMN; (b) a stimulated PMN with darker (“toxic”) granules and a Dohle body (arrow); (c) frequently utilized biomarkers of sepsis related to PMNs include CD64, the soluble forms of TREM-1 and CD11b, and HBP. (d) Frequently utilized biomarkers of sepsis related to macrophages or monocytes include the soluble forms of CD14 (which facilitates recognition of bacterial lipopolysaccharides) and the receptor for RAGE.
Figure 4.
Figure 4.
There is significant evidence that patients with severe sepsis have defective adaptive immunity. Macrophages (or monocytes) may lose expression of the Class II MHC proteins which display foreign peptide to the TCR. However, more importantly, T-cells upregulate expression of CTLA-4, an alternative ligand for the co-stimulator B7 on the antigen-presenting cell. Instead of providing co-stimulation and activation of the T-cell, which would occur if B7 interacted with CD28, interaction with CTLA-4 results in T-cell unresponsiveness and, eventually, death by apoptosis.
Figure 5.
Figure 5.
An alternative model for the progression of sepsis to severe sepsis proposes that the CARS begins while the pro-inflammatory SIRS is still present. Understanding the interplay of these opposing features may help investigators discover the pathogenesis of the organ dysfunction that occurs in patients who develop severe sepsis (and die).

References

    1. Levy MM, Dellinger RP, Townsend SR, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med. 2010;36:222–31.
    1. Hall MJ, Williams SN, DeFrances CJ, Golosinsky A. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. National Center for Health Statistics Data Brief No. 62. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Jun. 2011. Available from: [last accessed 2 Jan 2013]
    1. Wang HE, Shapiro NI, Angus DC, Yealy DM. National estimates of severe sepsis in United States emergency departments. Crit Care Med. 2007;35:1928–36.
    1. Ulevitch RJ, Tobias PS. Recognition of gram-negative bacteria and endotoxin by the innate immune system. Curr Opin Immunol. 1999;11:19–22.
    1. Kumar H, Kawai T, Akira S. Pathogen recognition by the innate immune system. Int Rev Immunol. 2011;30:16–34.
    1. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20:864–74.
    1. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250–6.
    1. Balk R, Roger C. Bone, MD and the evolving paradigms of sepsis. Contrib Microbiol. 2011;17:1–11.
    1. Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest. 1997;112:235–43.
    1. Choileain NN, Redmond HP. The immunological consequences of injury. Surgeon. 2006;4:23–31.
    1. Chung LP, Waterer GW. Genetic predisposition to respiratory infection and sepsis. Crit Rev Clin Lab Sci. 2011;48:250–68.
    1. Bone RC, Fisher JC Jr, Clemmer TP, et al. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Eng J Med. 1987;317:653–8.
    1. Karzai W, Oberhoffer M, Meier-Hellmann A, Reinhart K. Procalcitonin: a new indicator of the systemic response to severe infections. Infection. 1997;25:329–34.
    1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Eng J Med. 2001;345:1368–77.
    1. Christaki E, Anyfanti P, Opal SM. Immunomodulatory therapy for sepsis: an update. Expert Rev Anti Infect Ther. 2011;9:1013–33.
    1. Ghezzi P, Cerami A. Tumor necrosis factor as a pharmacological target. Methods Mol Med. 2004;98:1–8.
    1. Qui P, Cui X, Barochia A, Li Y, et al. The evolving experience with therapeutic TNF inhibition in sepsis: considering the potential influence of risk of death. Expert Opin Investig Drugs. 2011;20:1555–64.
    1. Rice TW, Wheeler AP, Morris PE, et al. Safety and efficacy of affinity-purified, anti-tumor necrosis factor-alpha, ovine fab for injection CytoFab in severe sepsis. Crit Care Med. 2006;34:2271–81.
    1. Cannon JG, Tompkins RG, Gelfand JA, et al. Circulating interleukin-1 and tumor necrosis factor in septic shock and experimental endotoxin fever. J Infect Dis. 1990;161:79–84.
    1. Jooster LA, van de Veerdonk FL, Vonk AG, et al. Differential susceptibility to lethal endtoxinaemia in mice deficient in IL-1α, IL-1β, or IL-1 receptor type I. APMIS. 2010;118:1000–7.
    1. Batfalsky A, Lohr A, Heussen N, et al. Diagnostic value of an interleukin-6 bedside test in term and preterm neonates at the time of clinical suspicion of early- and late-onset bacterial infection. Neonatology. 2012;102:37–44.
    1. Patel RT, Deen KI, Korings D, Warwick J, Keighley MR. Interleukin-6 is a prognostic indicator of outcome in severe intra-abdominal sepsis. Br J Surg. 1994;81:1306–8.
    1. Petilla V, Hynninen M, Takkunen O, et al. Predictive value of procalcitonin and interleukin 6 in critically ill patients with suspected sepsis. Intensive Care Med. 2002;28:1220–5.
    1. Panacek EA, Marshall JC, Albertson TE, et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody Fab’2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004;32:2173–82.
    1. Osuchowski MF, Connett J, Welch K, et al. Stratification is the key: inflammatory biomarkers accurately direct immunomodulatory therapy in experimental sepsis. Crit Care Med. 2009;37:1567–73.
    1. Eliasson M, Egesten A. Antibacterial chemokines: actors in both innate and adaptive immunity. In: Herwald H, Egesten A, editors. Trends in innate immunity. Vol. 15. Basel: Karger; Contrib Microbiol; 2008. pp. 101–17.
    1. Stryjewski GR, Nylen ES, Bell MJ, et al. Interleukin-6, interleukin-8, and a rapid and sensitive assay for calcitonin precursors for the determination of bacterial sepsis in febrile neutropenic children. Pediatr Crit Care Med. 2005;6:129–35.
    1. Bozza FA, Salluh JI, Japiassu AM, et al. Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care. 2007;11:R49.
    1. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Eng J Med. 1999;340:448–54.
    1. Jaye DL, Waites KB. Clinical applications of c-reactive protein in pediatrics. Ped Infect Dis. 1997;16:735–8.
    1. Benzaquen LR, Yu H, Rifai N. High-sensitivity C-reactive protein: an emerging role in cardiovascular risk assessment. Crit Rev Clin Lab Sci. 2002;39:459–97.
    1. Hofer N, Zacharias E, Muller W, Resch B. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology. 2012;102:25–36.
    1. Welsch T, Frommhold K, Hinz U, et al. Persisting elevation of C-reactive protein after pancreatic resections can indicate developing inflammatory complications. Surgery. 2008;143:20–28.
    1. Mauri T, Bellani G, Patroniti N, et al. 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. 2010;36:621–29.
    1. Assicot M, Gendrel D. High serum procalcitonin concentrations in patients with sepsis and infection. Lancet. 1993;341:515–8.
    1. Muller B, White JC, Nylen ES, et al. Ubiquitous expression of the calcitonin-I gene in multiple tissues in response to sepsis. J Clin Endocrinol Metab. 2001;86:396–404.
    1. Tavares E, Minano FJ. Immunoneutralization of the aminoprocalcitonin peptide of procalcitonin protects rats from lethal endotoxaemias: neuroendocrine and systemic studies. Clin Sci. 2010;119:519–34.
    1. O’Grady NP, Barie PS, Bartlett JG, et al. American College of Critical Care Medicine; Infectious Diseases Society of America. Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med. 2008;36:1330–40.
    1. Simon L, Gauvin F, Amre DK, et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis. 2004;39:206–17.
    1. Chirouze C, Schuhmacher H, Rabaud C, et al. Low serum procalcitonin level accurately predicts the absence of bacteremia in adult patients with acute fever. Clin Infect Dis. 2002;35:156–61.
    1. Nakamura A, Wada H, Ikejiri M, et al. Efficacy of procalcitonin in the early diagnosis of bacterial infections in a critical care unit. Shock. 2009;31:586–91.
    1. Riedel S, Melendez JH, An AT, et al. Procalcitonin as a marker for the detection of bacteremia and sepsis in the Emergency Department. Am J Clin Pathol. 2011;135:190–9.
    1. Uzzan B, Cohen R, Nicolas P, et al. Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis. Crit Care Med. 2006;34:1996–2003.
    1. Yu Z, Liu J, Sun Q, et al. The accuracy of the procalcitonin test for the diagnosis of neonatal sepsis: a meta-analysis. Scand J Infect Dis. 2010;42:723–33.
    1. Mann EA, Wood GI, Wade CE. Use of procalcitonin for the detection of sepsis in the critically ill burn patient: a systemic review of the literature. Burns. 2011;37:549–58.
    1. Tang BMP, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for sepsis diagnosis in critically ill patients: systemic review and meta-analysis. Lancet Infect Dis. 2007;7:210–17.
    1. Reinhart K, Brunkhorst FM. Meta-analysis of procalcitonin for sepsis detection. Lancet Infect Dis. 2007;7:500–2.
    1. Becker KL, Snider R, Nylen ES. Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med. 2008;36:941–52.
    1. Billeter A, Turina M, Seifert B, et al. Early serum procalcitonin, interleukin-6, and 24-hour lactate clearance: useful indicators of septic infections in severely traumatized patients. World J Surg. 2009;33:558–66.
    1. Clec’h C, Fosse JP, Karoubi P, et al. Differential diagnostic value of procalcitonin in surgical and medical patients with septic shock. Crit Care Med. 2006;34:102–7.
    1. Brunkhorst FM, Al-Nawas B, Krummenauer F, et al. Procalcitonin, c-reactive protein and APACHE II score for risk evaluation in patients with severe pneumonia. Clin Microbiol Infect. 2002;8:93–100.
    1. Bele N, Darmon M, Coquet I, et al. Diagnostic accuracy of procalcitonin in critically ill immunocompromised patients. BMC Infect Dis. 2011;11:224.
    1. Jensen JU, Hein L, Lundgren B, et al. Procalcitonin and Survival Study PASS Group. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011;39:2048–58.
    1. Jensen JU, Hein L, Lundgren B, et al. Procalcitonin and Survival Study PASS Group. Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomized trial. BMJ Open. 2012;2:e000635.
    1. Scheutz P, Chiappa V, Briel M, Greenwald JL. Procalcitonin algorithms for antibiotic therapy decisions. Arch Intern Med. 2011;171:1322–31.
    1. Schreiber H, Rittirsch D, Flieri M, et al. Complement activation during sepsis in humans. Adv Exp Med Biol. 2006;586:217–26.
    1. Flierl MA, Rittirsch D, Nadeau BA, et al. Functions of the complement components C3 and C5 during sepsis. FASEB J. 2008;22:3483–90.
    1. Yuan J, Gou SJ, Huang J, et al. C5a and its receptors in human anti-neutrophil cytoplasmic antibody ANCA-associated vasculitis. Arthritis Res Ther. 2012;14:R140.
    1. Ward PA. The harmful role of C5a on innate immunity in sepsis. J Innate Immun. 2010;2:439–45.
    1. Yan C, Gao H. New insights for C5a and C5a receptors in sepsis. Front Immunol. 2012;3:368.
    1. Zipursky A, Palko J, Milner R, Akenzua GI. The hematology of bacterial infection in premature infants. Pediatrics. 1976;57:839–53.
    1. Leino L, Sorvajarvi L, Katajisto M, et al. Febrile infection changes the expression of IgG Fc receptors in human neutrophils in vivo. Clin Exp Immunol. 1997;107:37–43.
    1. Cardelli P, Ferraironi M, Amodeo R, et al. Evaluation of neutrophil CD64 expression and procalcitonin as useful markers in early diagnosis of sepsis. Int J Immunopathol Pharmacol. 2008;21:43–49.
    1. Livaditi O, Kotanidou A, Psarra A, et al. Neutrophil CD64 expression and serum IL-8: sensitive early markers of severity and outcome in sepsis. Cytokine. 2006;36:283–90.
    1. Gros A, Roussel M, Sauvadet E, et al. The sensitivity of neutrophil CD64 expression as a biomarker of bacterial infection is low in critically ill patients. Intensive Care Med. 2012;38:445–52.
    1. Gibot S, Bene MC, Noel R, et al. Combination biomarkers to diagnose sepsis in the critically ill patient. Am J Respir Crit Care Med. 2012;186:65–71.
    1. Elghetany M, Davis B. Impact of preanalytical variables on granulocytic surface antigen expression: a review. Cytometry. 2005;65:1–5.
    1. Streimish I, Bizzarro M, Northrup V, et al. Neutrophil CD64 as a diagnostic marker in neonatal sepsis. Pediatr Infect Dis J. 2012;31:777–81.
    1. Genel F, Atlihan F, Gulez N, et al. Evaluation of adhesion molecules CD64, CD11b and CD62L in neutrophils and monocytes of peripheral blood for early diagnosis of neonatal infection. World J Pediatr. 2012;8:72–5.
    1. Bouchon A, Facchetti F, Weigand MA, et al. TREM-1 amplifies inflammation and is a crucial mediator of septic shock. Nature. 2001;410:1103–7.
    1. Bopp C, Hofer S, Bouchon A, et al. Soluble TREM-1 is not suitable for distinguishing between systemic inflammatory response syndrome and sepsis survivors and nonsurvivors in the early stage of acute inflammation. Eur J Anaesthesiol. 2009;26:504–7.
    1. Jeong SJ, Song YG, Kim CO, et al. Measurement of plasma sTREM-1 in patients with severe sepsis receiving early goal-directed therapy and evaluation of its usefulness. Shock. 2012;37:574–8.
    1. Gautam N, Olofsson AM, Herwald H, et al. Heparin-binding protein HBP/CAP37: a missing link in neutrophil-evoked alteration of vascular permeability. Nat Med. 2001;7:1123–27.
    1. Linder A, Christensson B, Herwald H, et al. Heparin-binding protein: an early marker of circulatory failure in sepsis. Clin Infect Dis. 2009;49:1044–50.
    1. van Zoelen MAD, Achouti A, van der Poll T. The role of receptor for advanced glycation endproducts RAGE in infection. Crit Care. 2011;15:208.
    1. Bopp C, Hofer S, Weitz J, et al. sRAGE is elevated in septic patients and associated with patient outcome. J Surg Res. 2008;147:79–83.
    1. Narvaez-Rivera RM, Rendon A, Salinas-Carmona MC, Rosas-Taraco AG. Soluble RAGE as a severity marker in community acquired pneumonia associated sepsis. BMC Infect Dis. 2012;12:15.
    1. Jabaudon M, Futier E, Roszyk L, et al. Soluble form of the receptor for advanced glycation end products is a marker of acute lung injury but not of severe sepsis in critically ill patients. Crit Care Med. 2011;39:480–8.
    1. Gutsmann T, Mueller M, Carroll SF, et al. Dual role of lipopolysaccharide LPS-binding protein in neutralization of LPS and enhancement of LPS-induced activation of mononuclear cells. Infect Immun. 2001;69:6942–50.
    1. Sakr Y, Burgett U, Nacul FE, et al. Lipopolysaccharide-binding protein in a surgical intensive care unit: a marker of sepsis? Crit Care Med. 2008;36:2014–22.
    1. Endo S, Suzuki Y, Takahashi G, et al. Usefulness of presepsin in the diagnosis of sepsis in a multicenter prospective study. J Infect Chemother. 2012;18:891–7.
    1. Shozushima T, Takahashi G, Matsumoto M, et al. Usefulness of presepsin sCD14-ST measurements as a marker for the diagnosis and severity of sepsis that satisfied diagnostic criteria for systemic inflammatory response syndrome. J Infect Chemother. 2011;17:764–9.
    1. Jones GR, Lowes JA. The systemic inflammatory response syndrome as a predictor of bacteremia and outcome from sepsis. QJM. 1996;89:515–22.
    1. Dark PM, Dean P, Warhurst G. Bench-to-bedside review: the promise of rapid infection diagnosis during sepsis using polymerase chain reaction-based pathogen detection. Crit Care. 2009;13:217.
    1. Bloos F, Hinder F, Becker K, et al. A multicenter trial to compare blood culture with polymerase chain reaction in severe human sepsis. Intensive Care Med. 2010;36:241–7.
    1. Pletz MW, Wellinghausen N, Welte T. Will polymerase chain reaction PCR-based diagnostics improve outcome in septic patients? A clinical view. Intensive Care Med. 2011;37:1069–76.
    1. Romaschin AD, Harris DM, Ribeiro MB, et al. A rapid assay of endotoxin in whole blood using autologous neutrophil-dependent chemiluminescence. J Immunol Methods. 1998;212:169–85.
    1. Marshall JC, Foster D, Vincent JL, et al. MEDIC study. Diagnostic and prognostic implications of endotoxemia in critical illness: results of the MEDIC study. J Infect Dis. 2004;190:527–34.
    1. Yaguchi A, Yuzawa J, Klein DJ, et al. Combining intermediate levels of the Endotoxin Activity Assay EAA with other biomarkers in the assessment of patients with sepsis: results of an observational study. Crit Care. 2012;16:R88.
    1. Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, et al. Persistent elevation of high mobility group box-1 protein HMGB1 in patients with severe sepsis and septic shock. Crit Care Med. 2005;33:564–73.
    1. Karlsson S, Pettila V, Tenhunen J, et al. HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis. Intensive Care Med. 2008;34:1046–53.
    1. van Zoelen MAD, Vogl T, Foell D, et al. Expression and role of myeloid-related protein-14 in clinical and experimental sepsis. Am J Respir Crit Care Med. 2009;180:1098–106.
    1. Tschaikowsky K, Hedwig-Geissing M, Schiele A, et al. Coincidence of pro- and anti-inflammatory responses in the early phase of 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. 2002;30:1015–23.
    1. Cheron A, Floccard B, Allaouchiche B, et al. Lack of recovery in monocyte human leukocyte antigen-DR expression is independently associated with the development of sepsis after trauma. Crit Care. 2010;14:R208.
    1. Monneret G, Lepape A, Voirin N, et al. Persisting low monocyte human leukocyte antigen-DR expression predicts mortality in septic shock. Intensive Care Med. 2006;32:1175–83.
    1. Landelle C, Lepape A, Voirin N, et al. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010;36:1810–2.
    1. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol. 2001;166:6952–63.
    1. Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306:2594–605.
    1. Roger PM, Hyvernat H, Breittmayer JP, et al. Enhanced T-cell apoptosis in human septic shock is associated with alteration of the costimulatory pathway. Eur J Clin Microbiol Infect Dis. 2009;28:575–84.
    1. Zhang Y, Li J, Zhou Y, et al. Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care. 2011;15:R70.
    1. Kessel A, Bamberger E, Masalha M, Toubi E. The role of regulatory T cells in human sepsis. J Autoimmun. 2009;32:211–15.
    1. Monneret G, Finck ME, Venet F, et al. The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol Lett. 2004;95:193–8.
    1. Guignant C, Lepape A, Huang X, et al. Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients. Crit Care. 2011;15:R99.
    1. Urbonas V, Eidukaite A, Tamuliene I. Increased interleukin-10 levels correlate with bacteremia and sepsis in febrile neutropenia pediatric oncology patients. Cytokine. 2012;57:313–5.
    1. Zeitoun AAH, Gad SS, Attia FM, et al. Evaluation of neutrophilic CD64, interleukin 10 and procalcitonin as diagnostic markers of early- and late-onset neonatal sepsis. Scand J Infect Dis. 2010;42:299–305.
    1. de Pablo R, Monserrat J, Reyes E, et al. Sepsis-induced acute respiratory distress syndrome with fatal outcome is associated to increased serum transforming growth factor beta-1 levels. Eur J Intern Med. 2011;23:358–62.
    1. Toffaletti JG. Blood lactate: biochemistry, laboratory methods, and clinical interpretation. Crit Rev Clin Lab Sci. 1991;28:253–68.
    1. Garrabou G, Moren C, Lopez S, et al. The effects of sepsis on mitochondria. J Infect Dis. 2012;205:392–400.
    1. Hernandez G, Bruhn A, Castro R, et al. Persistent sepsis-induced hypotension without hyperlactatemia: a distinct clinical and physiological profile within the spectrum of septic shock. Crit Care Res Pract. 2012;preprint:536852.
    1. Mikkelsen ME, Miltiades AN, Gaieski DF, et al. Serum lactate is associated with mortality in severe sepsis independent of organ failure or shock. Crit Care Med. 2009;37:1670–7.
    1. Wacharasint P, Nakada TA, Boyd JH, et al. Normal-range blood lactate concentration in septic shock is prognostic and predictive. Shock. 2012;38:4–10.
    1. Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med. 2004;32:1637–42.
    1. Arnold RC, Shapiro NI, Jones AE, et al. Emergency Medicine Shock Research Network EMShockNet Investigators. Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock. 2009;32:35–9.
    1. Jones AE, Shapiro NI, Trzeciak S, et al. Emergency Medicine Shock Research Network EMShockNet Investigators. Lactate clearance vs. central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010;303:739–46.
    1. Puskarich MA, Trzeciak S, Shapiro MI, et al. Emergency Medicine Shock Research Network EMSHOCKNET. Prognostic value and agreement of achieving lactate clearance or central venous oxygen saturation goals during early sepsis resuscitation. Acad Emerg Med. 2012;19:252–8.
    1. Paulus P, Jennewein C, Zacharowski K. Biomarkers of endothelial dysfunction: can they help us deciphering systemic inflammation and sepsis? Biomarkers. 2011;16:S11–21.
    1. Esmon CT. Interactions between the innate immune and blood coagulation systems. Trends Immunol. 2004;25:536–42.
    1. Hook KM, Abrams CS. The loss of homeostasis in hemostasis: new approaches in treating and understanding acute disseminated intravascular coagulation in critically ill patients. Clin Transl Sci. 2012;5:85–92.
    1. Voves C, Wuillemin WA, Zeerleder S. International Society on Thrombosis and Hemostasis score for overt disseminated intravascular coagulation predicts organ dysfunction and fatality in sepsis patients. Blood Coagul Fibrinolysis. 2006;17:445–51.
    1. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, et al. Pathogenesis of sepsis. Ann Rev Pathol Mech Dis. 2011;6:19–48.
    1. Ranieri VM, Thompson BT, Barie PS, et al. PROWESS-SHOCK Study Group. Drotrecogin alfa activated in adults with septic shock. N Eng J Med. 2012;366:2055–64.
    1. Cocucci E, Racchetti G, Meldolesi J. Shedding vesicles: artefacts no more. Trends Cell Biol. 2009;19:43–51.
    1. Meziani F, Delabranche X, Asfar P, Toti F. Bench-to-bedside review: circulating microparticles – a new player in sepsis? Crit Care. 2010;14:R236.
    1. Kofoed K, Andersen O, Kronborg G, et al. Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage 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. 2007;11:R38.
    1. Shapiro NI, Trzeciak S, Hollander JE, et al. 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. 2009;37:96–104.
    1. Osuchowski MF, Welch K, Siddiqui J, Remick DG. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol. 2006;177:1967–74.
    1. Kellum JA, Kong L, Fink MP, et al. GenIMS Investigators. Understanding the inflammatory cytokine response in pneumonia and sepsis. Arch Intern Med. 2007;167:1655–63.
    1. Tamayo E, Fernandez A, Almansa R, et al. Pro- and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock. Eur Cytokine Netw. 2011;22:82–7.
    1. Wu JF, Ma J, Chen J, et al. Changes of monocyte human leukocyte antigen-DR expression as a reliable predictor of mortality in severe sepsis. Crit Care. 2011;15:R220.
    1. Tang BMP, McLean AS, Dawes IW, et al. The use of gene-expression profiling to identify candidate genes in human sepsis. Am J Respir Care Med. 2007;176:676–84.
    1. Wong HR, Cvijanovich N, Allen GL, et al. Genomics of Pediatric SIRS/Septic Shock Investigators. Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit Care Med. 2009;27:1558–66.
    1. van der Poll T, van Deventer SJH. Cytokines and anticytokines in the pathogenesis of sepsis. Infect Dis Clin North Am. 1999;13:413–26.
    1. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Eng J Med. 2003;348:138–50.
    1. Andaluz-Ojeda D, Bobillo F, Iglesias V, et al. A combined score of pro- and anti-inflammatory interleukins improves mortality prediction in severe sepsis. Cytokine. 2012;57:332–6.
    1. Gouel-Cheron A, Allaouchiche B, Guignant C, et al. AzuRea Group. Early interleukin-6 and slope of monocyte human leukocyte antigen-DR: a powerful association to predict the development of sepsis after major trauma. PLoS ONE. 2012;7:e33095.
    1. Dwyer J. An infection, unnoticed, turns unstoppable. New York Times. 2012. July 12:A15–6. Available from: [last accessed 26 Feb 2013]
    1. Huang DT, Weissfeld LA, Kellum JA, et al. GenIMS Investigators. Risk prediction with procalcitonin and clinical rules in community-acquired pneumonia. Ann Emerg Med. 2008;52:48–52.

Source: PubMed

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