Rethinking Sepsis: New Insights from Gene Expression Profiling Studies

  • B. M. Tang
  • S. J. Huang
  • A. S. McLean


Critically ill patients encompass an enormously heterogeneous population and, as such, therapeutic interventions, including drug therapy, can produce multiple outcomes in different patient subgroups. For example, researchers not only look for an ‘average effect’ of a drug on a typical patient, but also seek to understand individual variability. The presence of variability impacts significantly on the success of clinical trials and failure to identify this variability can result in the clinical trial being under-powdered to detect a treatment effect. For clinicians, failure to recognize variability can result in unintended toxicity or excessive harm in certain patients. Hence, understanding variability is critically important in both research and clinical practice.


Septic Shock Severe Sepsis Septic Patient Gene Regulatory Network Sepsis Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Laterre PF (2007) Clinical trials in severe sepsis with drotrecogin alfa (activated). Crit Care 11 (Suppl 5):S5CrossRefGoogle Scholar
  2. 2.
    Ely EW, Laterre P-F, Angus D, et al (2003) Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 31: 12–19CrossRefPubMedGoogle Scholar
  3. 3.
    Carlet J, Cohen J, Calandra T, Opal S, Masur H (2008) Sepsis: Time to reconsider the concept. Crit Care Med 36: 1–3CrossRefGoogle Scholar
  4. 4.
    Levy M, Fink M, Marshall J, et al (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31: 1250–1256CrossRefPubMedGoogle Scholar
  5. 5.
    Marshall J, Vincent J-L, Fink MP, et al (2003) Measures, markers, and mediators: towards a staging system for clinical sepsis. Crit Care Med 31: 1560–1567CrossRefPubMedGoogle Scholar
  6. 6.
    Macias WL, Nelson D, Williams M, Garg R, Janes J, Sashegyi A (2005) Lack of evidence for qualitative treatment by disease severity interactions in clinical studies of severe sepsis. Crit Care 9: R607–622CrossRefPubMedGoogle Scholar
  7. 7.
    Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C (2004) Meta-analysis: The effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 141: 47–56PubMedGoogle Scholar
  8. 8.
    Macias W, Vallet B, Bernard GR, et al (2004) Sources of variability on the estimate of treatment effect in the PROWESS trial: implications for the design and conduct of future studies in severe sepsis. Crit Care Med 32: 2385–2391CrossRefPubMedGoogle Scholar
  9. 9.
    Dear J, Yasuda H, Hu X, et al (2006) Sepsis-induced organ failure is mediated by different pathways in the kidney and liver: acute renal failure is dependent on MyD88 but not renal cell apoptosis. Kidney Int 69: 832–836CrossRefPubMedGoogle Scholar
  10. 10.
    Annane D, Bellissant E, Cavaillon J (2005) Septic shock. Lancet 365: 63–78CrossRefPubMedGoogle Scholar
  11. 11.
    Marshall J (2003) Such stuff as dreams are made on: mediator-directed therapy in sepsis. Nat Rev Drug Discov 2: 391–405CrossRefPubMedGoogle Scholar
  12. 12.
    Holmes CL, Russell JA, Walley KR (2003) Genetic polymorphisms in sepsis and septic shock: role in prognosis and potential for therapy. Chest 124: 1103–1115CrossRefPubMedGoogle Scholar
  13. 13.
    Nguyen A, Yaffe M (2003) Proteomics and systems biology approaches to signal transduction in sepsis. Crit Care Med 31: S1–S6CrossRefPubMedGoogle Scholar
  14. 14.
    Tang B, McLean A, Dawes I, Huang S, Lin R (2008) Gene-expression profiling of peripheral blood mononuclear cells in sepsis. Crit Care Med (in press)Google Scholar
  15. 15.
    Tang B, McLean A, Dawes I, Huang S, Lin R (2007) The use of gene-expression profiling to identify candidate genes in human sepsis. Am J Respir Crit Care Med 176: 676–684CrossRefPubMedGoogle Scholar
  16. 16.
    Tang B, McLean A, Dawes I, Huang S, Cowley M, Lin R (2008) Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients. Crit Care Med 36: 1125–1128CrossRefPubMedGoogle Scholar
  17. 17.
    Calandra T, Cohen J (2005) The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med 33: 1538–1548CrossRefPubMedGoogle Scholar
  18. 18.
    Abraham E, Matthay M, Dinarello C, et al (2000) Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: Time for a reevaluation. Critical Care Medicine 28: 232–235CrossRefPubMedGoogle Scholar
  19. 19.
    Calvano SE, Xiao W, Richards DR, et al (2005) A network-based analysis of systemic inflammation in humans. Nature 437: 1032–1037CrossRefPubMedGoogle Scholar
  20. 20.
    Ramilo O, Allman W, Chung W, et al (2007) Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 109: 2066–2077CrossRefPubMedGoogle Scholar
  21. 21.
    McDunn J, Husain K, Polpitiya A, et al (2008) Plasticity of the systemic inflammatory response to actue infection during critical illness: development of the riboleukogram. PlosOne 3: e1564Google Scholar
  22. 22.
    Prucha M, Ruryk A, Boriss H, Moller E, Zazula R, Russwurm S (2004) Expression profiling: toward an application in sepsis diagnostics. Shock 22: 29–33CrossRefPubMedGoogle Scholar
  23. 23.
    Shanley TP, Cvijanovich N, Lin R, et al (2007) Genome-level longitudinal expression of signaling pathways and gene networks in pediatric septic shock. Mol Med 13: 495–508CrossRefPubMedGoogle Scholar
  24. 24.
    Johnson S, Lissauer M, Bochicchio G, Moore R, Cross A, Scalea T (2007) Gene expression profiles differentiate between sterile SIRS and early sepsis. Ann Surg 245: 611–621CrossRefPubMedGoogle Scholar
  25. 25.
    Hotchkiss R, Karl I (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348: 138–150CrossRefPubMedGoogle Scholar
  26. 26.
    Monneret G, Venet F, Pachot A, Lepape A (2008) Monitoring immune dysfunction in the septic patient: a new skin for the old ceremony. Mol Med 14: 64–78CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • B. M. Tang
    • 1
  • S. J. Huang
    • 1
  • A. S. McLean
    • 1
  1. 1.Department of Intensive Care Nepean Clinical SchoolUniversity of SydneySydneyAustralia

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