Current Infectious Disease Reports

, Volume 8, Issue 5, pp 351–357 | Cite as

Biomarkers of sepsis



Sepsis is a highly heterogeneous clinical disorder currently characterized almost exclusively by the use of physiologic variables. A burgeoning interest in the potential descriptive role of biomarkers in sepsis holds the promise of transforming the diagnosis from a clinical one to a biologic one, and so permitting better evaluation and use of a spectrum of adjuvant therapies. Biomarkers provide information in one of three domains: diagnosis, prognosis, and monitoring of response to treatment. Their primary prognostic utility, however, is not in forecasting outcome, but in identifying patients who are more likely to benefit from (or be harmed by) a particular intervention. A proposed template for staging sepsis in a manner analogous to systems used in oncology provides a framework for evaluating sepsis biomarkers. The model stratifies patients on the basis of predisposition, insult, response, and organ dysfunction, generating the acronym PIRO. This brief review considers the methodologic basis for biomarker development and validation and situates some emerging sepsis biomarkers within the framework of the PIRO model.


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References and Recommended Reading

  1. 1.
    Bone RC, Balk RA, Cerra FB, et al.: ACCP/SCCM Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992, 101:1644–1655.PubMedGoogle Scholar
  2. 2.
    Matzinger P: The danger model: A renewed sense of self. Science 2002, 296:301–305.PubMedCrossRefGoogle Scholar
  3. 3.
    Rivers E, Nguyen B, Havstad S, et al.: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001, 345:1368–1377.PubMedCrossRefGoogle Scholar
  4. 4.
    Dellinger RP, Carlet JM, Masur H, et al.: Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004, 32:858–873. A comprehensive and evidence-based summary of the current best approaches to the early management of patients with severe sepsis or septic shock.PubMedCrossRefGoogle Scholar
  5. 5.
    Levy MM, Fink MP, Marshall JC, et al.: 2001 SCCM/ ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 2003, 29:530–538.PubMedGoogle Scholar
  6. 6.
    Bernard GR, Vincent J-L, Laterre PF, et al.: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001, 344:699–709.PubMedCrossRefGoogle Scholar
  7. 7.
    Annane D, Sebille V, Charpentier C, et al.: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002, 288:862–871.PubMedCrossRefGoogle Scholar
  8. 8.
    Van den Berghe G, Wouters P, Weekers F, et al.: Intensive insulin therapy in the surgical intensive care unit. N Engl J Med 2001, 345:1359–1367.PubMedCrossRefGoogle Scholar
  9. 9.
    Bone RC, Fisher CJ, Clemmer TP, et al.: Sepsis syndrome: a valid clinical entity. Crit Care Med 1989, 17:389–393.PubMedCrossRefGoogle Scholar
  10. 10.
    Molina R, Barak V, van Dalen A, et al.: Tumor markers in breast cancer—European Group on Tumor Markers recommendations. Tumour Biol 2005, 26:281–293.PubMedCrossRefGoogle Scholar
  11. 11.
    Pritchard KI, Shepherd LE, O’Malley FP, et al.: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 2006, 354:2103–2111.PubMedCrossRefGoogle Scholar
  12. 12.
    Marshall JC, Foster D, Vincent JL, et al.: Diagnostic and prognostic implications of endotoxemia in critical illness: Results of the MEDIC study. J Infect Dis 2004, 190:527–534.PubMedCrossRefGoogle Scholar
  13. 13.
    Marshall JC, Vincent JL, Guyatt G, et al.: Outcome measures for clinical research in sepsis: A report of the 2nd Cambridge Colloquium of the International Sepsis Forum. Crit Care Med 2005, 33:1708–1716.PubMedCrossRefGoogle Scholar
  14. 14.
    Cohen J: The detection and interpretation of endotoxemia. Intensive Care Med 2000, 26(Suppl):S51-S56.PubMedCrossRefGoogle Scholar
  15. 15.
    Bates DW, Parsonnet J, Ketchum PA, et al.: Limulus amebocyte lysate assay for detection of endotoxin in patients with sepsis sydrome. Clin Infect Dis 1998, 27:582–591.PubMedGoogle Scholar
  16. 16.
    Hamrahian AH, Oseni TS, Arafah BM: Measurements of serum free cortisol in critically ill patients. N Engl J Med 2004, 350:1629–1638.PubMedCrossRefGoogle Scholar
  17. 17.
    Marshall JC, Vincent JL, Fink MP, et al.: Measures, markers, and mediators: Towards a staging system for clinical sepsis. Crit Care Med 2003, 31:1560–1567. Summarizes the discussions of an expert symposium on biomarkers for sepsis, outlining methodologic principles. The first articulation of the need for a staging system.PubMedCrossRefGoogle Scholar
  18. 18.
    Borgel D, Clauser S, Bornstain C, et al.: Elevated growtharrest-specific protein 6 plasma levels in patients with severe sepsis. Crit Care Med 2006, 34:219–222.PubMedCrossRefGoogle Scholar
  19. 19.
    Lee PS, Drager LR, Stossel TP, et al.: Relationship of plasma gelsolin levels to outcomes in critically ill surgical patients. Ann Surg 2006, 243:399–403.PubMedCrossRefGoogle Scholar
  20. 20.
    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, 32:1637–1642.PubMedCrossRefGoogle Scholar
  21. 21.
    Sorensen TI, Nielsen GG, Andersen PK, Teasdale PW: Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988, 318:727–732.PubMedCrossRefGoogle Scholar
  22. 22.
    Arcaroli J, Fessler MB, Abraham E: Genetic polymorphisms and sepsis. Shock 2005, 24:300–312.PubMedCrossRefGoogle Scholar
  23. 23.
    Poltorak A, He X, Smirnova I, et al.: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: Mutations in the Tlr4 gene. Science 1998, 282:2085–2088.PubMedCrossRefGoogle Scholar
  24. 24.
    Hawn TR, Verbon A, Janer M, et al.: Toll-like receptor 4 polymorphisms are associated with resistance to Legionnaires’ disease. Proc Natl Acad Sci USA 2005, 102:2487–2489.PubMedCrossRefGoogle Scholar
  25. 25.
    Barber RC, Aragaki CC, Rivera-Chavez FA, et al.: TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury. J Med Genet 2004, 41:808–813.PubMedCrossRefGoogle Scholar
  26. 26.
    Mira JP, Cariou A, Grall F, et al.: Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality. JAMA 1999, 282:561–568.PubMedCrossRefGoogle Scholar
  27. 27.
    Appoloni O, Dupont E, Vandercruys M, et al.: Association of tumor necrosis factor-2 allele with plasma tumor necrosis factor-alpha levels and mortality from septic shock. Am J Med 2001, 110:486–488.PubMedCrossRefGoogle Scholar
  28. 28.
    Mugnier B, Balandraud N, Darque A, et al.: Polymorphism at position-308 of the tumor necrosis factor alpha gene influences outcome of infliximab therapy in rheumatoid arthritis. Arthritis Rheum 2003, 48:1849–1852.PubMedCrossRefGoogle Scholar
  29. 29.
    Criswell LA, Lum RF, Turner KN, et al.: The influence of genetic variation in the HLA-DRB1 and LTA-TNF regions on the response to treatment of early rheumatoid arthritis with methotrexate or etanercept. Arthritis Rheum 2004, 50:2750–2756.PubMedCrossRefGoogle Scholar
  30. 30.
    Peters DL, Barber RC, Flood EM, et al.: Methodologic quality and genotyping reproducibility in studies of tumor necrosis factor -308 G-->A single nucleotide polymorphism and bacterial sepsis: implications for studies of complex traits. Crit Care Med 2003, 31:1691–1696.PubMedCrossRefGoogle Scholar
  31. 31.
    Sutherland AM, Walley KR, Manocha S, Russell JA: The association of interleukin 6 haplotype clades with mortality in critically ill adults. Arch Intern Med 2005, 165:75–82. Highly readable and thoughtful introduction to the concept of haplotype clades as a method for grouping polymorphisms.PubMedCrossRefGoogle Scholar
  32. 32.
    Engle LJ, Simpson CL, Landers JE: Using high-throughput SNP technologies to study cancer. Oncogene 2006, 25:1594–1601.PubMedCrossRefGoogle Scholar
  33. 33.
    Assicot M, Gendrel D, Carsin H, et al.: High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 1993, 341:515–518.PubMedCrossRefGoogle Scholar
  34. 34.
    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, 39:206–217. A systematic review of very extensive literature on the diagnostic performance of procalcitonin.PubMedCrossRefGoogle Scholar
  35. 35.
    Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al.: Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004, 363:600–607.PubMedCrossRefGoogle Scholar
  36. 36.
    Christ-Crain M, Stolz D, Bingisser R, et al.: Procalcitonin-Guidance of Antibiotic Therapy in Community-Acquired Pneumonia—A Randomized Trial. Am J Respir Crit Care Med 2006, Epub ahead of print. Randomized trial showing the potential role of a validated biomrker in clinical decision-making in critically ill patients.Google Scholar
  37. 37.
    Gibot S, Cravoisy A, Levy B, et al.: Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia. N Engl J Med 2004, 350:451–458.PubMedCrossRefGoogle Scholar
  38. 38.
    Determann RM, Millo JL, Gibot S, et al.: Serial changes in soluble triggering receptor expressed on myeloid cells in the lung during development of ventilator-associated pneumonia. Intensive Care Med 2005, 31:1495–1500.PubMedCrossRefGoogle Scholar
  39. 39.
    Chopin N, Floccard B, Sobas F, et al.: Activated partial thromboplastin time waveform analysis: A new tool to detect infection? Crit Care Med 2006, Epub ahead of print.Google Scholar
  40. 40.
    Panacek EA, Kaul M: IL-6 as a marker of excessive TNFalpha activity in sepsis. Sepsis 1999, 3:65–73.CrossRefGoogle Scholar
  41. 41.
    Panacek EA, Marshall JC, Albertson TE, et al.: Efficacy and safety of the monoclonal anti-TNF antibody F(ab’)2 fragment afelimomab in patients with severe sepsis stratified by IL-6 level. Crit Care Med 2004, 32:2173–2182.PubMedGoogle Scholar
  42. 42.
    Annane D, Sebille V, Troche G, et al.: A 3-level prognostic classi.cation in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 2000, 283:1038–1045.PubMedCrossRefGoogle Scholar
  43. 43.
    Van den Berghe G, Wilmer A, Hermans G, et al.: Intensive insulin therapy in the medical ICU. N Engl J Med 2006, 354:449–461.PubMedCrossRefGoogle Scholar
  44. 44.
    Docke WD, Randow F, Syrbe U, et al.: Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nature Med 1997, 3:678–681.PubMedCrossRefGoogle Scholar
  45. 45.
    Marshall JC, Cook DJ, Christou NV, et al.: Multiple organ dysfunction score: A reliable descriptor of a complex clinical outcome. Crit Care Med 1995, 23:1638–1652.PubMedCrossRefGoogle Scholar
  46. 46.
    Vincent JL, Moreno R, Takala J, et al.: The sepsis-related organ failure assessment (SOFA) score to describe organ dysfunction/failure. Intensive Care Med 1996, 22:707–710.PubMedGoogle Scholar
  47. 47.
    Le Gall JR, Klar J, Lemeshow S, et al.: The logistic organ dysfunction system. JAMA 1996, 276:802–810.PubMedCrossRefGoogle Scholar
  48. 48.
    Nakatani T, Spolter L, Kobayashi K: Arterial ketone body ratio as a parameter of hepatic mitochondrial redox state during and after hemorrhagic shock. World J Surg 1995, 194:592–596.CrossRefGoogle Scholar
  49. 49.
    Hotchkiss RS, Swanson PE, Freeman BD, et al.: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999, 27:1230–1251.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2006

Authors and Affiliations

  1. 1.St. Michael’s HospitalTorontoCanada

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