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Hyperinflammation and Mediators of Immune Suppression in Critical Illness

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Annual Update in Intensive Care and Emergency Medicine 2013

Part of the book series: Annual Update in Intensive Care and Emergency Medicine ((AUICEM))

Abstract

Critical illness, constituting an acute illness or injury resulting in organ dysfunction and failure, is associated with a profound, systemic activation of the immune system and inflammation-mediated organ damage [1]. However, critically ill patients also suffer a high rate of nosocomial infection with secondary sepsis being a common cause of death [2]. This high prevalence of secondary infections argues for the influence of an immune suppression that may, at first glance, appear paradoxical in light of the pro-inflammatory nature of many critical illnesses. Although immune cell hypo-function has been noted in clinical and experimental critical illnesses, the mediators of these effects remain poorly defined. This review will present the recent evidence accumulating for the role of pro-inflammatory mediators in driving immune dysfunction, and how this insight may, in part, explain the apparent paradox of immune suppression occurring in a patient with manifestations of hyperinflammation [3].

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References

  1. Adibconquy M, Cavaillon J (2007) Stress molecules in sepsis and systemic inflammatory response syndrome. FEBS Lett 581:3723–3733

    Article  CAS  Google Scholar 

  2. Vincent JL, Bihari DJ, Suter P et al (1995) The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 274:639–644

    Article  PubMed  CAS  Google Scholar 

  3. Ward PA (2011) Immunosuppression in sepsis. JAMA 306:2618–2619

    Article  PubMed  CAS  Google Scholar 

  4. Pellizzer G, Mantoan P, Timillero L et al (2008) Prevalence and risk factors for nosocomial infections in hospitals of the Veneto region, north-eastern Italy. Infection 36:112–119

    Article  PubMed  CAS  Google Scholar 

  5. Vincent JL, Rello J, Marshall J et al (2009) International study of the prevalence and outcomes of infection in intensive care units. JAMA 302:2323–2329

    Article  PubMed  CAS  Google Scholar 

  6. The GIMEMA Investigators (1991) Prevention of bacterial infection in neutropenic patients with hematologic malignancies. A randomized, multicenter trial comparing norfloxacin with ciprofloxacin. Ann Intern Med 115:7–12

    Google Scholar 

  7. Chastre J, Fagon J (2002) Ventilator-associated pneumonia. Am J Respr Crit Care Med 165:867–903

    Article  Google Scholar 

  8. Sakamoto Y, Mashiko K, Matsumoto H, Hara Y, Kutsukata N, Yokota H (2010) Systemic inflammatory response syndrome score at admission predicts injury severity, organ damage and serum neutrophil elastase production in trauma patients. J Nihon Med Sch 77:138–144

    Article  Google Scholar 

  9. Miyaoka K, Iwase M, Suzuki R et al (2005) Clinical evaluation of circulating interleukin-6 and interleukin-10 levels after surgery-induced inflammation. J Surg Res 125:144–150

    Article  PubMed  CAS  Google Scholar 

  10. Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leuk Biol 81:1–5

    Article  CAS  Google Scholar 

  11. Bone RC (1996) Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 24:1125–1128

    Article  PubMed  CAS  Google Scholar 

  12. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150

    Article  PubMed  CAS  Google Scholar 

  13. Morris AC, Kefala K, Wilkinson TS et al (2009) C5a mediates peripheral blood neutrophil dysfunction in critically ill patients. Am J Respir Crit Care Med 180:19–28

    Article  CAS  Google Scholar 

  14. Morris AC, Brittan M, Wilkinson TS et al (2011) C5a-mediated neutrophil phagocytic dysfunction is RhoA-dependent and predicts nosocomial infection in critically ill patients. Blood 117:5178–5188

    Article  PubMed  CAS  Google Scholar 

  15. Döcke W, Randow F, Syrbe U et al (1997) Monocyte deactivation in septic patients: restoration by IFN-gamma treatment. Nat Med 3:678–681

    Article  PubMed  Google Scholar 

  16. Flohé SB, Agrawal H, Flohé S, Rani M, Bangen JM, Schade FU (2008) Diversity of interferon gamma and granulocyte-macrophage colony-stimulating factor in restoring immune dysfunction of dendritic cells and macrophages during polymicrobial sepsis. Mol Med 14:247–256

    Article  PubMed  Google Scholar 

  17. Yanagawa Y, Onoe K (2007) Enhanced IL-10 production by TLR4- and TLR2-primed dendritic cells upon TLR restimulation. J Immunol 178:6173–6180

    PubMed  CAS  Google Scholar 

  18. Heidecke CD, Hensler T, Weighardt H et al (1999) Selective defects of T lymphocyte function in patients with lethal intraabdominal infection. Am J Surg 178:288–292

    Article  PubMed  CAS  Google Scholar 

  19. Mohr A, Polz J, Martin EM (2012) Sepsis leads to a reduced antigen-specific primary antibody response. Eur J Immunol 42:341–352

    Article  PubMed  CAS  Google Scholar 

  20. Souza-Fonseca-Guimaraes F, Parlato M, Fitting C, Cavaillon JM, Adib-Conquy M (2012) NK cell tolerance to TLR agonists mediated by regulatory T cells after polymicrobial sepsis. J Immunol 15:5850–5858

    Article  Google Scholar 

  21. Meisel C, Schefold JC, Pschowski R et al (2009) Granulocyte-Macrophage Colony-stimulating Factor to Reverse Sepsis-associated Immunosuppression: A Double-Blind, Randomized, Placebo-controlled Multicenter Trial. Am J Respir Crit Care Med 180:640–648

    Article  PubMed  CAS  Google Scholar 

  22. Venet F, Chung CS, Monneret G et al (2008) Regulatory T cell populations in sepsis and trauma. J Leuk Biol 83:523–535

    Article  CAS  Google Scholar 

  23. Lukaszewicz AC, Grienay M, Resche-Rigon M et al (2009) Monocytic HLA-DR expression in intensive care patients: interest for prognosis and secondary infection prediction. Crit Care Med 37:2746–2752

    Article  PubMed  CAS  Google Scholar 

  24. Danikas DD, Karakantza M, Theodorou GL, Sakellaropoulos GC, Gogos CA (2008) Prognostic value of phagocytic activity of neutrophils and monocytes in sepsis. Correlation to CD64 and CD14 antigen expression. Clin Exp Immunol 154:87–97

    Article  PubMed  CAS  Google Scholar 

  25. Arraes SM, Freitas MS, da Silva SV et al (2006) Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation. Blood 108:2906–2913

    Article  PubMed  CAS  Google Scholar 

  26. Ward PA (2004) The dark side of C5a in sepsis. Nat Rev Immunol 4:133–142

    Article  PubMed  CAS  Google Scholar 

  27. Huber-Lang M, Younkin EM, Sarma JV et al (2002) Complement-induced impairment of innate immunity during sepsis. J Immunol 169:3223–3231

    PubMed  CAS  Google Scholar 

  28. Boomer JS, To K, Chang KC et al (2011) Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 21:2594–2605

    Article  Google Scholar 

  29. Osuchowski MF, Welch K, Siddiqui J, Remick DG (2006) Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J Immunol 177:1967–1974

    PubMed  CAS  Google Scholar 

  30. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF (2006) Neutrophils in development of multiple organ failure in sepsis. Lancet 368:157–169

    Article  PubMed  CAS  Google Scholar 

  31. Muller Kobold A, Tulleken JE, Zijlstra JG et al (2000) Leukocyte activation in sepsis; correlations with disease state and mortality. Intensive Care Med 26:883–892

    Article  PubMed  CAS  Google Scholar 

  32. Rosenbloom AJ, Pinsky MR, Napolitano C et al (1999) Suppression of cytokine-mediated beta2-integrin activation on circulating neutrophils in critically ill patients. J Leuk Biol 66:83–89

    CAS  Google Scholar 

  33. Ertel W, Jarrar D, Jochum M et al (1994) Enhanced release of elastase is not concomitant with increased secretion of granulocyte-activating cytokines in whole blood from patients with sepsis. Arch Surg 129:90–97

    Article  PubMed  CAS  Google Scholar 

  34. Nuijens JH, Abbink JJ, Wachtfogel YT et al (1992) Plasma elastase alpha 1-antitrypsin and lactoferrin in sepsis: evidence for neutrophils as mediators in fatal sepsis. J Lab Clin Med 119:159–168

    PubMed  CAS  Google Scholar 

  35. Kothari N, Keshari RS, Bogra J et al (2011) Increased myeloperoxidase enzyme activity in plasma is an indicator of inflammation and onset of sepsis. J Crit Care 26:435.e1– 435.e7

    Article  CAS  Google Scholar 

  36. Morris AC, Kefala K, Wilkinson TS et al (2010) Diagnostic importance of pulmonary interleukin-1 beta and interleukin-8 in ventilator-associated pneumonia. Thorax 65:201–207

    Article  Google Scholar 

  37. Wilkinson TS, Morris AC, Kefala K, et al (2012) Ventilator-associated pneumonia is characterized by excessive release of neutrophil proteases in the lung. Chest (in press)

    Google Scholar 

  38. Rittirsch D, Flierl M, Ward P (2008) Harmful molecular mechanisms in sepsis. Nat Rev Immunol 8:776–787

    Article  PubMed  CAS  Google Scholar 

  39. Gardinali M, Padalino P, Vesconi S et al (1992) Complement activation and polymorphonuclear neutrophil leukocyte elastase in sepsis. Correlation with severity of disease. Arch Surg 127:1219–1224

    Article  PubMed  CAS  Google Scholar 

  40. Oppermann M, Götze O (1994) Plasma clearance of the human C5a anaphylatoxin by binding to leucocyte C5a receptors. Immunology 82:516–521

    PubMed  CAS  Google Scholar 

  41. Fosse E, Pillgram-Larsen J, Svennevig JL et al (1998) Complement activation in injured patients occurs immediately and is dependent on the severity of the trauma. Injury 29:509–514

    Article  PubMed  CAS  Google Scholar 

  42. Kamanova J, Kofronova O, Masin J et al (2008) Adenylate cyclase toxin subverts phagocyte function by RhoA inhibition and unproductive ruffling. J Immunol 181:5587–5597

    PubMed  CAS  Google Scholar 

  43. Zhang Q, Raoof M, Chen Y et al (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104–107

    Article  PubMed  CAS  Google Scholar 

  44. Mookerjee R, Stadlbauer V, Lidder S et al (2007) Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 46:831–840

    Article  PubMed  CAS  Google Scholar 

  45. Cruz DN, Antonelli M, Fumagalli R et al (2009) Early use of polymyxin B hemoperfusion in abdominal septic shock. JAMA 301:2445–2452

    Article  PubMed  CAS  Google Scholar 

  46. Meddows-Taylor S, Pendle S, Tiemessen CT (2001) Altered expression of CD88 and associated impairment of complement 5a-induced neutrophil responses in human immunodeficiency virus type 1-infected patients with and without pulmonary tuberculosis. J Infect Dis 15:662–665

    Article  Google Scholar 

  47. Korzenik JR (2007) Is Crohn’s disease due to defective immunity? Gut 56:2–5

    Article  PubMed  CAS  Google Scholar 

  48. Maisel AS (1994) Beneficial effects of metoprolol treatment in congestive heart failure. Reversal of sympathetic-induced alterations of immunologic function. Circulation 90:1774–1780

    Article  PubMed  CAS  Google Scholar 

  49. Jeschke MG, Norbury WB, Finnerty CC, Branski LK, Herndon DN (2007) Propranolol does not increase inflammation, sepsis, or infectious episodes in severely burned children. J Trauma 62:676–681

    Article  PubMed  CAS  Google Scholar 

  50. Ackland GL, Yao ST, Rudiger A et al (2010) Cardioprotection, attenuated systemic inflammation, and survival benefit of beta1-adrenoceptor blockade in severe sepsis in rats. Crit Care Med 38:388–394

    Article  PubMed  CAS  Google Scholar 

  51. Morris AC (2011) Unravelling the paradox, how inflammation leads to immuno-suppression and secondary infection. Journal of the Intensive Care Society 12:56–57

    Google Scholar 

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Authors and Affiliations

  1. Queen’s Medical Research Institute, Center for Inflammation Research, University of Edinburgh, 47 Little France Crescent, EH16 4TJ, Edinburgh, UK

    A. C. Morris & T. S. Walsh

  2. Institute of Cellular Medicine, Newcastle University, NE2 4HH, Newcastle upon Tyne, UK

    A. J. Simpson

Authors
  1. A. C. Morris
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  2. A. J. Simpson
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  3. T. S. Walsh
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Correspondence to T. S. Walsh .

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Editors and Affiliations

  1. Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium

    Jean-Louis Vincent Prof.

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Morris, A.C., Simpson, A.J., Walsh, T.S. (2013). Hyperinflammation and Mediators of Immune Suppression in Critical Illness. In: Vincent, JL. (eds) Annual Update in Intensive Care and Emergency Medicine 2013. Annual Update in Intensive Care and Emergency Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-35109-9_11

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  • DOI: https://doi.org/10.1007/978-3-642-35109-9_11

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-35108-2

  • Online ISBN: 978-3-642-35109-9

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