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Anti-cytokine and anti-inflammatory therapies for the treatment of severe sepsis: progress and pitfalls

Published online by Cambridge University Press:  07 March 2007

Douglas J. Minnich  and
Lyle L. Moldawer
Douglas J. Minnich
Affiliation:
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA
Lyle L. Moldawer*
Affiliation:
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA
*
Corresponding author: Dr Lyle L. Moldawer, fax +1 352 265 0676, [email protected]
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Abstract

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The medical care of patients with sepsis or severe inflammatory response syndromes has seen tremendous technological advancements in recent years; yet, several clinical studies with anti-cytokine therapies targetted to this population have met with disappointing results. Four primary factors have been identified that represent potential pitfalls involving the use of biological response modifiers in critically-ill patients. First, the physiological response in the stressed patient is complex. Redundancy within this system may not allow a single intervention to produce a clinical response. Second, the critically-ill patient population is heterogenous and important factors including the age of the patient, associated co-morbidities, the nature of the original injury and the presence or absence of an ongoing injury can modulate the effectiveness of a specific therapy. Third, the timing of the therapeutic intervention can be difficult to standardize among patients and can often produce differing results. A greater understanding of the physiological response to injury has shown that there are both proinflammatory and anti-inflammatory processes ongoing simultaneously. Determining the optimal time to intervene within this framework can be problematic. Fourth, the presence of genetic polymorphisms within the general population has identified subsets of individuals who may have different physiological responses to similar stresses. The relative proportions of patients with these polymorphisms within clinical trials may affect outcome and data analysis. Thus, a better understanding of these issues will result in improvement of the experimental design of clinical trials involving anti-cytokine therapies and critically-ill patients. Avoidance of these pitfalls will enhance the quality and utility of outcomes research in this subset of patients.

Keywords

Clinical trialsCritical careSepsisGenetic polymorphism
Type
Nutrition Society Symposium: Nutrition and metabolism in critical care
Information
Proceedings of the Nutrition Society , Volume 63 , Issue 3 , August 2004 , pp. 437 - 441
Copyright
Copyright © The Nutrition Society 2004

References

Abraham, E (1999) Why immunomodulatory therapies have not worked in sepsis. Intensive Care Medicine 25, 556–566.CrossRefGoogle Scholar
Abraham, E, Anzueto, A, Gutierrez, G, Tessler, S, San Pedro, G, Wunderink, R et al. (1998) Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. NORASEPT II Study Group. Lancet 351, 929–933.CrossRefGoogle ScholarPubMed
Abraham, E, Glauser, MP, Butler, T, Garbino, J, Gelmont, D, Laterre, PF et al. (1997) p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock. A randomized controlled multicenter trial. Ro 45–2081 Study Group. Journal of the American Medical Association 277, 1531–1538.CrossRefGoogle ScholarPubMed
Abraham, E, Wunderink, R, Silverman, H, Perl, TM, Nasraway, S, Levy, H et al. (1995) Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. Journal of the American Medical Association 273, 934–941.CrossRefGoogle ScholarPubMed
Angus, DC, Linde-Zwirble, WT, Clermont, G, Ball, DE, Basson, BR, Ely, EW, Laterre, PF, Vincent, JL, Bernard, G & Van Hout, B (2003) Cost-effectiveness of drotrecogin alfa (activated) in the treatment of severe sepsis. Critical Care Medicine 31, 1–11.CrossRefGoogle ScholarPubMed
Angus, DC, Linde-Zwirble, WT, Lidicker, J, Clermont, G, Carcillo, J & Pinsky, MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Critical Care Medicine 29, 1303–1310.CrossRefGoogle ScholarPubMed
Baue, AE (2000) Multiple organ failure – the discrepancy between our scientific knowledge and understanding and the management of our patients. Langenbecks Archiv für Chirurgie 385, 441–453.CrossRefGoogle ScholarPubMed
Bernard, GR, Vincent, JL, Laterre, PF, LaRosa, SP, Dhainaut, JF, Lopez-Rodriguez, A, Steingrub, JS, Garber, GE, Helterbrand, JD, Ely, EW & Fisher, CJ (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine 344, 699–709.CrossRefGoogle ScholarPubMed
Bone, RC (1996 a) Sir Isaac Newton, sepsis, SIRS, and CARS. Critical Care Medicine 24, 1125–1128.CrossRefGoogle Scholar
Bone, RC (1996 b) Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Critical Care Medicine 24, 163–172.CrossRefGoogle Scholar
Cecil, RL, Goldman, L, Bennett, JC & Drazen, JM (2000) Cecil Textbook of Medicine, vol. 2, pp. 507–511. Philadelphia, PA: W.B. Saunders.Google Scholar
Cohen, J & Carlet, J (1996) INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Critical Care Medicine 24, 1431–1440.CrossRefGoogle ScholarPubMed
Fang, XM, Schroder, S, Hoeft, A & Stuber, F (1999) Comparison of two polymorphisms of the interleukin-1 gene family: interleukin-1 receptor antagonist polymorphism contributes to susceptibility to severe sepsis. Critical Care Medicine 27, 1330–1334.CrossRefGoogle ScholarPubMed
Feezor, RJ & Moldawer, LL (2003) Genetic polymorphisms, functional genomics and the host inflammatory response to injury and inflammation. Nestle Nutrition Workshop Series Clinical Performance Programme, pp. 15–32. Farmington, CT: S. Karger Publishing Inc.Google Scholar
Fischer, E, Marano, MA, Barber, AE, Hudson, A, Lee, K, Rock, CS et al. (1991) Comparison between effects of interleukin-1 alpha administration and sublethal endotoxemia in primates. American Journal of Physiology 261, R442–R452.Google ScholarPubMed
Fischer, E, Marano, MA, Van Zee, KJ, Rock, CS, Hawes, AS, Thompson, WA et al. (1992) Interleukin-1 receptor blockade improves survival and hemodynamic performance in Escherichia coli septic shock, but fails to alter host responses to sublethal endotoxemia. Journal of Clinical Investigation 89, 1551–1557.CrossRefGoogle ScholarPubMed
Fisher, CJ, Agosti, JM, Opal, SM, Lowry, SF, Balk, RA, Sadoff, JC, Abraham, E, Schein, RM, Benjamin, E & Fisher, CJ Jr (1996) Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The Soluble TNF, Receptor Sepsis Study Group. New England Journal of Medicine 334, 1697–1702.CrossRefGoogle ScholarPubMed
Fisher, CJ, Dhainaut, JF, Opal, SM, Pribble, JP, Balk, RA Slotman, GJ et al. (1994 a) Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. Journal of the American Medical Association 271, 1836–1843.CrossRefGoogle ScholarPubMed
Fisher, CJ, Opal, SM, Dhainaut, JF, Stephens, S, Zimmerman, JL, Nightingale, P et al. (1993) Influence of an anti-tumor necrosis factor monoclonal antibody on cytokine levels in patients with sepsis. The CB0006 Sepsis Syndrome Study Group. Critical Care Medicine 21, 318–327.CrossRefGoogle ScholarPubMed
Fisher, CJ, Opal, SM, Lowry, SF, Sadoff, JC, LaBrecque, JF, Donovan, HC et al. (1994 b) Role of interleukin-1 and the therapeutic potential of interleukin-1 receptor antagonist in sepsis. Circulatory Shock 44, 1–8.Google ScholarPubMed
Fisher, CJ, Slotman, GJ, Opal, SM, Pribble, JP, Bone, RC, Emmanuel, G, Ng, D, Bloedow, DC, Catalano, MA & Fisher, CJ Jr (1994 c) Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial. The IL-1RA Sepsis Syndrome Study Group. Critical Care Medicine 22, 12–21.CrossRefGoogle Scholar
Fry, DE (2000) Sepsis syndrome. American Surgeon 66, 126–132.CrossRefGoogle ScholarPubMed
Glauser, MP (2000) Pathophysiologic basis of sepsis: considerations for future strategies of intervention. Critical Care Medicine 28, S4–S8.CrossRefGoogle ScholarPubMed
Grau, GE & Maennel, DN (1997) TNF inhibition and sepsis – sounding a cautionary note. Nature Medicine 3, 1193–1195.CrossRefGoogle ScholarPubMed
Hinshaw, LB, Tekamp-Olson, P, Chang, AC, Lee, PA, Taylor, FB, Murray, CK, Peer, GT, Emerson, TE, Passey, RB, Kuo, GC, Taylor, FB Jr & Emerson, TE Jr (1990) Survival of primates in LD100 septic shock following therapy with antibody to tumor necrosis factor (TNF alpha). Circulatory Shock 30, 279–292.Google ScholarPubMed
Hinshaw, LB, Emerson, TE Jr, Taylor, FB Jr, Chang, AC, Duerr, M, Peer, GT et al. (1992) Lethal Staphylococcus aureus -induced shock in primates: prevention of death with anti-TNF antibody. Journal of Trauma 33, 568–573.CrossRefGoogle ScholarPubMed
Huber, TS, Gaines, GC, Welborn, MB, Rosenberg, JJ, Seeger, JM & Moldawer, LL (2000) Anticytokine therapies for acute inflammation and the systemic inflammatory response syndrome: IL-10 and ischemia/reperfusion injury as a new paradigm. Shock 13, 425–434.CrossRefGoogle ScholarPubMed
Ma, P, Chen, D, Pan, J & Du, B (2002) Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients. Critical Care Medicine 30, 1046–1050.CrossRefGoogle ScholarPubMed
Mandell, GL, Douglas, RG, Bennett, JE & Dolin, R (2000) Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, vol. 2, pp. 806–817. Philadelphia, PA: Churchill Livingstone.Google Scholar
Martin, GS, Mannino, DM, Eaton, S & Moss, M (2003) The epidemiology of sepsis in the United States from 1979 through 2000. New England Journal of Medicine 348, 1546–1554.CrossRefGoogle ScholarPubMed
Mira, JP, Cariou, A, Grall, F, Delclaux, C, Losser, MR, Heshmati, F et al. (1999) Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. Journal of the American Medical Association 282, 561–568.CrossRefGoogle ScholarPubMed
Oberholzer, A, Oberholzer, C & Moldawer, LL (2001) Sepsis syndromes: understanding the role of innate and acquired immunity. Shock 16, 83–96.CrossRefGoogle ScholarPubMed
Opal, SM, Fisher, CJ Jr, Dhainaut, JF, Vincent, JL, Brase, R, Lowry, SF et al. (1997) Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Critical Care Medicine 25, 1115–1124.CrossRefGoogle ScholarPubMed
Rosenberg, JJ, Martin, SW, Seely, JE, Kinstler, O, Gaines, GC, Fukuzuka, K et al. (2001) Development of a novel, nonimmunogenic, soluble human TNF receptor type I (sTNFR-I) construct in the baboon. Journal of Applied Physiology 91, 2213–2223.CrossRefGoogle ScholarPubMed
Schluter, B, Raufhake, C, Erren, M, Schotte, H, Kipp, F, Rust, S, Van Aken, H, Assmann, G & Berendes, E (2002) Effect of the interleukin-6 promoter polymorphism (-174?G/C) on the incidence and outcome of sepsis. Critical Care Medicine 30, 32–37.CrossRefGoogle Scholar
Tabrizi, AR, Zehnbauer, BA, Freeman, BD & Buchman, TG (2001) Genetic markers in sepsis. Journal of the American College of Surgery 192, 106–117.CrossRefGoogle ScholarPubMed
Tracey, KJ, Beutler, B, Lowry, SF, Merryweather, J, Wolpe, S, Milsark, IW et al. (1986) Shock and tissue injury induced by recombinant human cachectin. Science 234, 470–474.CrossRefGoogle ScholarPubMed
Tracey, KJ, Fong, Y, Hesse, DG, Manogue, KR, Lee, AT, Kuo, GC, Lowry, SF & Cerami, A (1987 a) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330, 662–664.CrossRefGoogle ScholarPubMed
Tracey, KJ, Lowry, SF, Fahey, TJ 3rd, Albert, JD, Fong, Y, Hesse, D et al. (1987 b) Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surgery Gynecology and Obstetrics 164, 415–422.Google ScholarPubMed
Van Zee, KJ, Moldawer, LL, Oldenburg, HS, Thompson, WA, Stackpole, SA, Montegut, WJ et al. (1996) Protection against lethal Escherichia coli bacteremia in baboons ( Papio anubis ) by pretreatment with a 55-kDa TNF receptor (CD120a)-Ig fusion protein, Ro 45–2081. Journal of Immunology 156, 2221–2230.CrossRefGoogle ScholarPubMed
Wheeler, AP & Bernard, GR (1999) Treating patients with severe sepsis. New England Journal of Medicine 340, 207–214.CrossRefGoogle ScholarPubMed
Zeni, F, Freeman, B & Natanson, C (1997) Anti-inflammatory therapies to treat sepsis and septic shock: a reassessment. Critical Care Medicine 25, 1095–1100.CrossRefGoogle ScholarPubMed