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DOI: 10.1055/s-0032-1301737
Infectious Complications of Acute and Chronic Liver Disease
Publication History
Publication Date:
23 March 2012 (online)
Abstract
Acute and chronic liver diseases are frequently complicated by infections, which result in increased morbidity and mortality and place an economic burden on health care systems. This review discusses the epidemiology and the impact on prognosis of infections in liver cirrhosis, nonalcoholic fatty liver disease/nonalcoholic steatohepatitis, acute liver failure, and post–liver transplantation. Possible mechanisms for this increased susceptibility are innate immune dysfunction (Kupffer cells, neutrophils, monocytes), genetic predisposition, and intrinsic cellular defects. The causes for innate immune dysfunction may lie in increased gut permeability, the occurrence of endotoxemia, albumin and lipoprotein dysfunction, or toll-like receptor expression. From a clinical viewpoint this article discusses problems in diagnosing infection. Established (vaccination, antibiotic prophylaxis, antiviral prophylaxis, and nutrition) and experimental (probiotic) prophylactic strategies as well as established (antibiotics) and experimental (liver support, albumin, toll-like receptor antagonists) strategies are also reviewed.
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References
- 1 Leon DA, McCambridge J. Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data. Lancet 2006; 367 (9504) 52-56
- 2 Centers for Disease Control and Prevention. Vital and health statistics, Series 13. Average length of stay in short-stay hospitals: demographic factors: United States, 1968. Gordon EW. April 1973. 46 pp. (HSM) 73-1764. PB88-227038. PC A03 MF A01
- 3 Ostapowicz G, Lee WM. Acute hepatic failure: a Western perspective. J Gastroenterol Hepatol 2000; 15 (5) 480-488
- 4 Mansour A, Watson W, Shayani V, Pickleman J. Abdominal operations in patients with cirrhosis: still a major surgical challenge. Surgery 1997; 122 (4) 730-735 , discussion 735–736
- 5 Garcia-Tsao G. Bacterial infections in cirrhosis. Can J Gastroenterol 2004; 18 (6) 405-406
- 6 Aggarwal A, Ong JP, Younossi ZM, Nelson DR, Hoffman-Hogg L, Arroliga AC. Predictors of mortality and resource utilization in cirrhotic patients admitted to the medical ICU. Chest 2001; 119 (5) 1489-1497
- 7 Caly WR, Strauss E. A prospective study of bacterial infections in patients with cirrhosis. J Hepatol 1993; 18 (3) 353-358
- 8 Navasa M, Fernández J, Rodés J. Bacterial infections in liver cirrhosis. Ital J Gastroenterol Hepatol 1999; 31 (7) 616-625
- 9 Borzio M, Salerno F, Piantoni L , et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001; 33 (1) 41-48
- 10 Christou L, Pappas G, Falagas ME. Bacterial infection-related morbidity and mortality in cirrhosis. Am J Gastroenterol 2007; 102 (7) 1510-1517
- 11 Fernández J, Navasa M, Gómez J , et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002; 35 (1) 140-148
- 12 Navasa M, Rodés J. Bacterial infections in cirrhosis. Liver Int 2004; 24 (4) 277-280
- 13 Rimola A, García-Tsao G, Navasa M , et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000; 32 (1) 142-153
- 14 Conn HO. Spontaneous peritonitis and bacteremia in Laennec's cirrhosis caused by enteric organisms: a relatively common but rarely recognized syndrome. Ann Intern Med 1964; 60: 568-580
- 15 Arvaniti V, D’Amico G, Fede G , et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010; 139 (4) 1246-1256, e1–e5
- 16 Nobre SR, Cabral JE, Gomes JJ, Leitão MC. In-hospital mortality in spontaneous bacterial peritonitis: a new predictive model. Eur J Gastroenterol Hepatol 2008; 20 (12) 1176-1181
- 17 Burroughs AK, Rosenstein IJ, Epstein O, Hamilton-Miller JM, Brumfitt W, Sherlock S. Bacteriuria and primary biliary cirrhosis. Gut 1984; 25 (2) 133-137
- 18 O’Donohue J, Workman MR, Rolando N, Yates M, Philpott-Howard J, Williams R. Urinary tract infections in primary biliary cirrhosis and other chronic liver diseases. Eur J Clin Microbiol Infect Dis 1997; 16 (10) 743-746
- 19 Cruz RdeC, Tanajura D, Almeida D, Cruz M, Paraná R. Urinary tract infection in non-hospitalized patients with cirrhosis and no symptoms of urinary tract infection: a case series study. Braz J Infect Dis 2006; 10 (6) 380-383
- 20 Rosa H, Silvério AO, Perini RF, Arruda CB. Bacterial infection in cirrhotic patients and its relationship with alcohol. Am J Gastroenterol 2000; 95 (5) 1290-1293
- 21 Viasus D, Garcia-Vidal C, Castellote J , et al. Community-acquired pneumonia in patients with liver cirrhosis: clinical features, outcomes, and usefulness of severity scores. Medicine (Baltimore) 2011; 90 (2) 110-118
- 22 Chen SY, Tsai CL, Lin CH , et al. Impact of liver cirrhosis on mortality in patients with community-acquired bacteremia. Diagn Microbiol Infect Dis 2009; 64 (2) 124-130
- 23 Lin JN, Tsai YS, Lai CH , et al. Risk factors for mortality of bacteremic patients in the emergency department. Acad Emerg Med 2009; 16 (8) 749-755
- 24 Linderoth G, Jepsen P, Schønheyder HC, Johnsen SP, Sørensen HT. Short-term prognosis of community-acquired bacteremia in patients with liver cirrhosis or alcoholism: a population-based cohort study. Alcohol Clin Exp Res 2006; 30 (4) 636-641
- 25 Koulaouzidis A, Bhat S, Saeed AA. Spontaneous bacterial peritonitis. World J Gastroenterol 2009; 15 (9) 1042-1049
- 26 Cholongitas E, Papatheodoridis GV, Lahanas A, Xanthaki A, Kontou-Kastellanou C, Archimandritis AJ. Increasing frequency of gram-positive bacteria in spontaneous bacterial peritonitis. Liver Int 2005; 25 (1) 57-61
- 27 Falcone M, Massetti AP, Russo A, Vullo V, Venditti M. Invasive aspergillosis in patients with liver disease. Med Mycol 2011; 49 (4) 406-413
- 28 Mookerjee RP, Stadlbauer V, Lidder S , et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology 2007; 46 (3) 831-840
- 29 D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44 (1) 217-231
- 30 Kamath PS, Kim WR ; Advanced Liver Disease Study Group. The model for end-stage liver disease (MELD). Hepatology 2007; 45 (3) 797-805
- 31 Durand F, Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol 2005; 42 (1, Suppl) S100-S107
- 32 Wehler M, Kokoska J, Reulbach U, Hahn EG, Strauss R. Short-term prognosis in critically ill patients with cirrhosis assessed by prognostic scoring systems. Hepatology 2001; 34 (2) 255-261
- 33 Tsai MH, Peng YS, Lien JM , et al. Multiple organ system failure in critically ill cirrhotic patients: a comparison of two multiple organ dysfunction/failure scoring systems. Digestion 2004; 69 (3) 190-200
- 34 Tsai MH, Chen YC, Ho YP , et al. Organ system failure scoring system can predict hospital mortality in critically ill cirrhotic patients. J Clin Gastroenterol 2003; 37 (3) 251-257
- 35 Chen YC, Tsai MH, Hsu CW , et al. Role of serum creatinine and prognostic scoring systems in assessing hospital mortality in critically ill cirrhotic patients with upper gastrointestinal bleeding. J Nephrol 2003; 16 (4) 558-565
- 36 Vincent JL, Moreno R, Takala J , et al. The SOFA (sepsis-related organ failure assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996; 22 (7) 707-710
- 37 Zauner CA, Apsner RC, Kranz A , et al. Outcome prediction for patients with cirrhosis of the liver in a medical ICU: a comparison of the APACHE scores and liver-specific scoringsystems. Intensive Care Med 1996; 22 (6) 559-563
- 38 Zimmermann M, Busch K, Kuhn S, Zeppezauer M. Endotoxin adsorbent based on immobilized human serum albumin. Clin Chem Lab Med 1999; 37 (3) 373-379
- 39 Singh N, Gayowski T, Wagener MM, Marino IR. Outcome of patients with cirrhosis requiring intensive care unit support: prospective assessment of predictors of mortality. J Gastroenterol 1998; 33 (1) 73-79
- 40 Kress JP, Rubin A, Pohlman AS, Hall JB. Outcomes of critically ill patients denied consideration for liver transplantation. Am J Respir Crit Care Med 2000; 162 (2 Pt 1) 418-423
- 41 Afessa B, Kubilis PS. Upper gastrointestinal bleeding in patients with hepatic cirrhosis: clinical course and mortality prediction. Am J Gastroenterol 2000; 95 (2) 484-489
- 42 Ho YP, Chen YC, Yang C , et al. Outcome prediction for critically ill cirrhotic patients: a comparison of APACHE II and Child-Pugh scoring systems. J Intensive Care Med 2004; 19 (2) 105-110
- 43 Chen YC, Tsai MH, Ho YP , et al. Comparison of the severity of illness scoring systems for critically ill cirrhotic patients with renal failure. Clin Nephrol 2004; 61 (2) 111-118
- 44 Gildea TR, Cook WC, Nelson DR , et al. Predictors of long-term mortality in patients with cirrhosis of the liver admitted to a medical ICU. Chest 2004; 126 (5) 1598-1603
- 45 Rabe C, Schmitz V, Paashaus M , et al. Does intubation really equal death in cirrhotic patients? Factors influencing outcome in patients with liver cirrhosis requiring mechanical ventilation. Intensive Care Med 2004; 30 (8) 1564-1571
- 46 du Cheyron D, Bouchet B, Parienti JJ, Ramakers M, Charbonneau P. The attributable mortality of acute renal failure in critically ill patients with liver cirrhosis. Intensive Care Med 2005; 31 (12) 1693-1699
- 47 Vitalis Z, Altorjay I, Tornai I , et al. Phenotypic polymorphism of haptoglobin: a novel risk factor for the development of infection in liver cirrhosis. Hum Immunol 2011; 72 (4) 348-354
- 48 Younossi ZM, Stepanova M, Afendy M , et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011; 9 (6) 524-530, e1, quiz e60
- 49 Ribeireiro T, Swain J, Sarr M , et al. NAFLD and insulin resistance do not increase the risk of postoperative complications among patients undergoing bariatric surgery—a prospective analysis. Obes Surg 2011; 21 (3) 310-315
- 50 Farhadi A, Gundlapalli S, Shaikh M , et al. Susceptibility to gut leakiness: a possible mechanism for endotoxaemia in non-alcoholic steatohepatitis. Liver Int 2008; 28 (7) 1026-1033
- 51 Day CP, James OF. Steatohepatitis: a tale of two “hits”?. Gastroenterology 1998; 114 (4) 842-845
- 52 Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis. Proc Natl Acad Sci U S A 1997; 94 (6) 2557-2562
- 53 Polson J, Lee WM ; American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 2005; 41 (5) 1179-1197
- 54 Schmidt LE, Larsen FS. Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure. Crit Care Med 2006; 34 (2) 337-343
- 55 Wade J, Rolando N, Philpott-Howard J, Wendon J. Timing and aetiology of bacterial infections in a liver intensive care unit. J Hosp Infect 2003; 53 (2) 144-146
- 56 Antoniades CG, Berry PA, Davies ET , et al. Reduced monocyte HLA-DR expression: a novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure. Hepatology 2006; 44 (1) 34-43
- 57 Rolando N, Gimson A, Wade J, Philpott-Howard J, Casewell M, Williams R. Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology 1993; 17 (2) 196-201
- 58 Vaquero J, Polson J, Chung C , et al. Infection and the progression of hepatic encephalopathy in acute liver failure. Gastroenterology 2003; 125 (3) 755-764
- 59 Rolando N, Philpott-Howard J, Williams R. Bacterial and fungal infection in acute liver failure. Semin Liver Dis 1996; 16 (4) 389-402
- 60 Canalese J, Gove CD, Gimson AE, Wilkinson SP, Wardle EN, Williams R. Reticuloendothelial system and hepatocytic function in fulminant hepatic failure. Gut 1982; 23 (4) 265-269
- 61 Wyke RJ, Yousif-Kadaru AG, Rajkovic IA, Eddleston AL, Williams R. Serum stimulatory activity and polymorphonuclear leucocyte movement in patients with fulminant hepatic failure. Clin Exp Immunol 1982; 50 (2) 442-449
- 62 Clapperton M, Rolando N, Sandoval L, Davies E, Williams R. Neutrophil superoxide and hydrogen peroxide production in patients with acute liver failure. Eur J Clin Invest 1997; 27 (2) 164-168
- 63 Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000; 32 (4 Pt 1) 734-739
- 64 Karvellas CJ, Pink F, McPhail M , et al. Predictors of bacteraemia and mortality in patients with acute liver failure. Intensive Care Med 2009; 35 (8) 1390-1396
- 65 Rolando N, Harvey F, Brahm J , et al. Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients. Hepatology 1990; 11 (1) 49-53
- 66 Cuellar-Rodríguez J, Sierra-Madero JG. [Infections in solid organ transplant recipients]. Rev Invest Clin 2005; 57 (2) 368-380
- 67 Hollenbeak CS, Alfrey EJ, Souba WW. The effect of surgical site infections on outcomes and resource utilization after liver transplantation. Surgery 2001; 130 (2) 388-395
- 68 Merli M, Giusto M, Gentili F , et al. Nutritional status: its influence on the outcome of patients undergoing liver transplantation. Liver Int 2010; 30 (2) 208-214
- 69 Shi SH, Kong HS, Xu J , et al. Multidrug resistant gram-negative bacilli as predominant bacteremic pathogens in liver transplant recipients. Transpl Infect Dis 2009; 11 (5) 405-412
- 70 Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007; 357 (25) 2601-2614
- 71 Sun HY, Cacciarelli TV, Singh N. Impact of pretransplant infections on clinical outcomes of liver transplant recipients. Liver Transpl 2010; 16 (2) 222-228
- 72 Janny S, Bert F, Dondero F , et al. Microbiological findings of culture-positive preservation fluid in liver transplantation. Transpl Infect Dis 2011; 13 (1) 9-14
- 73 Weiss E, Dahmani S, Bert F , et al. Early-onset pneumonia after liver transplantation: microbiological findings and therapeutic consequences. Liver Transpl 2010; 16 (10) 1178-1185
- 74 Wade JJ, Rolando N, Hayllar K, Philpott-Howard J, Casewell MW, Williams R. Bacterial and fungal infections after liver transplantation: an analysis of 284 patients. Hepatology 1995; 21 (5) 1328-1336
- 75 Singh N, Wagener MM, Obman A, Cacciarelli TV, de Vera ME, Gayowski T. Bacteremias in liver transplant recipients: shift toward gram-negative bacteria as predominant pathogens. Liver Transpl 2004; 10 (7) 844-849
- 76 Singh N, Avery RK, Munoz P , et al. Trends in risk profiles for and mortality associated with invasive aspergillosis among liver transplant recipients. Clin Infect Dis 2003; 36 (1) 46-52
- 77 Cockbain AJ, Goldsmith PJ, Gouda M , et al. The impact of postoperative infection on long-term outcomes in liver transplantation. Transplant Proc 2010; 42 (10) 4181-4183
- 78 Aberg F, Mäkisalo H, Höckerstedt K, Isoniemi H. Infectious complications more than 1. year after liver transplantation: a 3-decade nationwide experience. Am J Transplant 2011; 11 (2) 287-295
- 79 Bert F, Galdbart JO, Zarrouk V , et al. Association between nasal carriage of Staphylococcus aureus and infection in liver transplant recipients. Clin Infect Dis 2000; 31 (5) 1295-1299
- 80 Kawecki D, Chmura A, Pacholczyk M , et al. Etiological agents of bacteremia in the early period after liver transplantation. Transplant Proc 2007; 39 (9) 2816-2821
- 81 Singh N, Husain S ; AST Infectious Diseases Community of Practice. Invasive aspergillosis in solid organ transplant recipients. Am J Transplant 2009; 9 (Suppl) (4) S180-S191
- 82 Bonham CA, Dominguez EA, Fukui MB , et al. Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management. Transplantation 1998; 66 (12) 1596-1604
- 83 Cazzaniga M, Dionigi E, Gobbo G, Fioretti A, Monti V, Salerno F. The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome. J Hepatol 2009; 51 (3) 475-482
- 84 Thabut D, Massard J, Gangloff A , et al. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology 2007; 46 (6) 1872-1882
- 85 Larcher VF, Wyke RJ, Mowat AP, Williams R. Bacterial and fungal infection in children with fulminant hepatic failure: possible role of opsonisation and complement deficiency. Gut 1982; 23 (12) 1037-1043
- 86 Leithead JA, Ferguson JW, Bates CM , et al. The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure. Gut 2009; 58 (3) 443-449
- 87 Miyake Y, Iwasaki Y, Terada R, Takaguchi K, Sakaguchi K, Shiratori Y. Systemic inflammatory response syndrome strongly affects the prognosis of patients with fulminant hepatitis B. J Gastroenterol 2007; 42 (6) 485-492
- 88 Rayes N, Seehofer D, Hansen S , et al. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation 2002; 74 (1) 123-127
- 89 Rayes N, Seehofer D, Theruvath T , et al. Supply of pre- and probiotics reduces bacterial infection rates after liver transplantation—a randomized, double-blind trial. Am J Transplant 2005; 5 (1) 125-130
- 90 Ashare A, Stanford C, Hancock P , et al. Chronic liver disease impairs bacterial clearance in a human model of induced bacteremia. Clin Transl Sci 2009; 2 (3) 199-205
- 91 Hines IN, Wheeler MD. Recent advances in alcoholic liver disease, III: Role of the innate immune response in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol 2004; 287 (2) G310-G314
- 92 Jeong WI, Gao B. Innate immunity and alcoholic liver fibrosis. J Gastroenterol Hepatol 2008; 23 (Suppl) (1) S112-S118
- 93 Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation, and variceal bleeding in cirrhosis. Gut 2005; 54 (4) 556-563
- 94 Rimola A, Soto R, Bory F, Arroyo V, Piera C, Rodes J. Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis. Hepatology 1984; 4 (1) 53-58
- 95 Ueno M. [Endotoxemia and its compensatory mechanisms in experimental liver cirrhosis]. Nippon Shokakibyo Gakkai Zasshi 1990; 87 (8) 1692-1700
- 96 Abdala E, Baía CE, Mies S , et al. Bacterial translocation during liver transplantation: a randomized trial comparing conventional with venovenous bypass vs. piggyback methods. Liver Transpl 2007; 13 (4) 488-496
- 97 von Frankenberg M, Golling M, Mehrabi A, Nentwich H, Klar E, Kraus TW. Donor pretreatment with gadolinium chloride improves early graft function and survival after porcine liver transplantation. Transpl Int 2003; 16 (11) 806-813
- 98 Ashare A, Monick MM, Powers LS, Yarovinsky T, Hunninghake GW. Severe bacteremia results in a loss of hepatic bacterial clearance. Am J Respir Crit Care Med 2006; 173 (6) 644-652
- 99 Jaeschke H, Hasegawa T. Role of neutrophils in acute inflammatory liver injury. Liver Int 2006; 26 (8) 912-919
- 100 Rajkovic IA, Williams R. Mechanisms of abnormalities in host defences against bacterial infection in liver disease. Clin Sci (Lond) 1985; 68 (3) 247-253
- 101 Kirsch R, Woodburne VE, Shephard EG, Kirsch RE. Patients with stable uncomplicated cirrhosis have normal neutrophil function. J Gastroenterol Hepatol 2000; 15 (11) 1298-1306
- 102 Fiuza C, Salcedo M, Clemente G, Tellado JM. In vivo neutrophil dysfunction in cirrhotic patients with advanced liver disease. J Infect Dis 2000; 182 (2) 526-533
- 103 Parlesak A, Schäfer C, Paulus SB, Hammes S, Diedrich JP, Bode C. Phagocytosis and production of reactive oxygen species by peripheral blood phagocytes in patients with different stages of alcohol-induced liver disease: effect of acute exposure to low ethanol concentrations. Alcohol Clin Exp Res 2003; 27 (3) 503-508
- 104 Garcia-González M, Boixeda D, Herrero D, Burgaleta C. Effect of granulocyte-macrophage colony-stimulating factor on leukocyte function in cirrhosis. Gastroenterology 1993; 105 (2) 527-531
- 105 Taïeb J, Mathurin P, Elbim C , et al. Blood neutrophil functions and cytokine release in severe alcoholic hepatitis: effect of corticosteroids. J Hepatol 2000; 32 (4) 579-586
- 106 Stanley AJ, MacGregor IR, Dillon JF, Bouchier IA, Hayes PC. Neutrophil activation in chronic liver disease. Eur J Gastroenterol Hepatol 1996; 8 (2) 135-138
- 107 Condliffe AM, Kitchen E, Chilvers ER. Neutrophil priming: pathophysiological consequences and underlying mechanisms. Clin Sci (Lond) 1998; 94 (5) 461-471
- 108 Urbaschek R, McCuskey RS, Rudi V , et al. Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease. Alcohol Clin Exp Res 2001; 25 (2) 261-268
- 109 Etheredge EE, Spitzer JA. Chronic endotoxemia reversibly alters respiratory burst activity of circulating neutrophils. J Surg Res 1993; 55 (3) 261-268
- 110 Böhmer RH, Trinkle LS, Staneck JL. Dose effects of LPS on neutrophils in a whole blood flow cytometric assay of phagocytosis and oxidative burst. Cytometry 1992; 13 (5) 525-531
- 111 Glauser MP, Zanetti G, Baumgartner JD, Cohen J. Septic shock: pathogenesis. Lancet 1991; 338 (8769) 732-736
- 112 Tsujimoto H, Ono S, Majima T , et al. Neutrophil elastase, MIP-2, and TLR-4 expression during human and experimental sepsis. Shock 2005; 23 (1) 39-44
- 113 Leber B, Mayrhauser U, Rybczynski M, Stadlbauer V. Innate immune dysfunction in acute and chronic liver disease. Wien Klin Wochenschr 2009; 121 (23-24) 732-744
- 114 Hassner A, Kletter Y, Shlag D, Yedvab M, Aronson M, Shibolet S. Impaired monocyte function in liver cirrhosis. Br Med J (Clin Res Ed) 1981; 282 (6272) 1262-1263
- 115 Xing T, Li L, Cao H, Huang J. Altered immune function of monocytes in different stages of patients with acute on chronic liver failure. Clin Exp Immunol 2007; 147 (1) 184-188
- 116 Ertel W, Kremer JP, Kenney J , et al. Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood 1995; 85 (5) 1341-1347
- 117 Guarner-Argente C, Sánchez E, Vidal S , et al. Toll-like receptor 4 D299G polymorphism and the incidence of infections in cirrhotic patients. Aliment Pharmacol Ther 2010; 31 (11) 1192-1199
- 118 Nischalke HD, Berger C, Aldenhoff K , et al. Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis. J Hepatol 2011; 55 (5) 1010-1016
- 119 Ledesma Castaño F, Echevarria Vierna S, Lozano Polo JL, Oloriz Rivas R, Alvarez Moreno C, Pons Romero F. Interleukin-1 in alcoholic cirrhosis of the liver: the influence of nutrition. Eur J Clin Nutr 1992; 46 (7) 527-533
- 120 Gomez F, Ruiz P, Schreiber AD. Impaired function of macrophage Fc gamma receptors and bacterial infection in alcoholic cirrhosis. N Engl J Med 1994; 331 (17) 1122-1128
- 121 Ono Y, Watanabe T, Matsumoto K, Ito T, Kunii O, Goldstein E. Opsonophagocytic dysfunction in patients with liver cirrhosis and low responses to tumor necrosis factor-alpha and lipopolysaccharide in patients’ blood. J Infect Chemother 2004; 10 (4) 200-207
- 122 Akalin HE, Laleli Y, Telatar H. Serum bactericidal and opsonic activities in patients with non-alcoholic cirrhosis. Q J Med 1985; 56 (220) 431-437
- 123 Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005; 41 (3) 422-433
- 124 Petrasek J, Mandrekar P, Szabo G. Toll-like receptors in the pathogenesis of alcoholic liver disease. Gastroenterol Res Pract 2010; 201
- 125 Thalheimer U, De Iorio F, Capra F , et al. Altered intestinal function precedes the appearance of bacterial DNA in serum and ascites in patients with cirrhosis: a pilot study. Eur J Gastroenterol Hepatol 2010; 22 (10) 1228-1234
- 126 Kalaitzakis E, Johansson JE, Bjarnason I, Björnsson E. Intestinal permeability in cirrhotic patients with and without ascites. Scand J Gastroenterol 2006; 41 (3) 326-330
- 127 Zuckerman MJ, Buchwald D, Watts MT. Intestinal permeability to 51Cr-EDTA in patients on chronic ambulatory peritoneal dialysis. Nephron 1994; 68 (3) 408-409
- 128 Pascual S, Such J, Esteban A , et al. Intestinal permeability is increased in patients with advanced cirrhosis. Hepatogastroenterology 2003; 50 (53) 1482-1486
- 129 Campillo B, Pernet P, Bories PN, Richardet JP, Devanlay M, Aussel C. Intestinal permeability in liver cirrhosis: relationship with severe septic complications. Eur J Gastroenterol Hepatol 1999; 11 (7) 755-759
- 130 Ruan P, Gong ZJ, Zhang QR. Changes of plasma D(-)-lactate, diamine oxidase and endotoxin in patients with liver cirrhosis. Hepatobiliary Pancreat Dis Int 2004; 3 (1) 58-61
- 131 Chang CS, Chen GH, Lien HC, Yeh HZ. Small intestine dysmotility and bacterial overgrowth in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1998; 28 (5) 1187-1190
- 132 Morencos FC, de las Heras Castaño G, Martín Ramos L, López Arias MJ, Ledesma F, Pons Romero F. Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Dig Dis Sci 1995; 40 (6) 1252-1256
- 133 Such J, Francés R, Muñoz C , et al. Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology 2002; 36 (1) 135-141
- 134 Such J, Muñoz C, Zapater P, Pérez-Mateo M. Bacterial DNA induces a proinflammatory immune response in patients with decompensated cirrhosis. Gut 2005; 54 (10) 1500 , author reply 1500
- 135 Alexander C, Rietschel ET. Bacterial lipopolysaccharides and innate immunity. J Endotoxin Res 2001; 7 (3) 167-202
- 136 Hurley JC. Endotoxemia: methods of detection and clinical correlates. Clin Microbiol Rev 1995; 8 (2) 268-292
- 137 Hoek JB. Endotoxin and alcoholic liver disease: tolerance and susceptibility. Hepatology 1999; 29 (5) 1602-1604
- 138 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 (3) 527-534
- 139 McCuskey RS, Urbaschek R, Urbaschek B. The microcirculation during endotoxemia. Cardiovasc Res 1996; 32 (4) 752-763
- 140 Bode C, Kugler V, Bode JC. Endotoxemia in patients with alcoholic and non-alcoholic cirrhosis and in subjects with no evidence of chronic liver disease following acute alcohol excess. J Hepatol 1987; 4 (1) 8-14
- 141 Fujimoto M, Uemura M, Nakatani Y , et al. Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance. Alcohol Clin Exp Res 2000; 24 (4, Suppl) 48S-54S
- 142 Fukui H. Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure. Alcohol Clin Exp Res 2005; 29 (11, Suppl) 172S-179S
- 143 Nakatani Y, Fukui H, Kitano H , et al. Endotoxin clearance and its relation to hepatic and renal disturbances in rats with liver cirrhosis. Liver 2001; 21 (1) 64-70
- 144 Enomoto N, Ikejima K, Bradford B , et al. Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin. Gastroenterology 1998; 115 (2) 443-451
- 145 Schenker S, Bay MK. Alcohol and endotoxin: another path to alcoholic liver injury?. Alcohol Clin Exp Res 1995; 19 (5) 1364-1366
- 146 Bauer TM, Schwacha H, Steinbrückner B , et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol 2002; 97 (9) 2364-2370
- 147 Han DW. Intestinal endotoxemia as a pathogenetic mechanism in liver failure. World J Gastroenterol 2002; 8 (6) 961-965
- 148 Lin RS, Lee FY, Lee SD , et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol 1995; 22 (2) 165-172
- 149 Fukui H, Tsujita S, Matsumoto M , et al. Endotoxin inactivating action of plasma in patients with liver cirrhosis. Liver 1995; 15 (2) 104-109
- 150 Galbois A, Thabut D, Tazi KA , et al. Ex vivo effects of high-density lipoprotein exposure on the lipopolysaccharide-induced inflammatory response in patients with severe cirrhosis. Hepatology 2009; 49 (1) 175-184
- 151 Hoekstra M, Korporaal SJ, Li Z, Zhao Y, Van Eck M, Van Berkel TJ. Plasma lipoproteins are required for both basal and stress-induced adrenal glucocorticoid synthesis and protection against endotoxemia in mice. Am J Physiol Endocrinol Metab 2010; 299 (6) E1038-E1043
- 152 Tsai MH, Peng YS, Chen YC , et al. Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis. J Hepatol 2009; 50 (5) 906-915
- 153 Gioannini TL, Zhang D, Teghanemt A, Weiss JP. An essential role for albumin in the interaction of endotoxin with lipopolysaccharide-binding protein and sCD14 and resultant cell activation. J Biol Chem 2002; 277 (49) 47818-47825
- 154 David SA, Balaram P, Mathan VI. Characterization of the interaction of lipid A and lipopolysaccharide with human serum albumin: implications for an endotoxin carrier function for albumin. J Endotoxin Res 1995; 2: 99-106
- 155 Jalan R, Schnurr K, Mookerjee RP , et al. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Hepatology 2009; 50 (2) 555-564
- 156 Klammt S, Mitzner S, Stange J , et al. Albumin-binding function is reduced in patients with decompensated cirrhosis and correlates inversely with severity of liver disease assessed by model for end-stage liver disease. Eur J Gastroenterol Hepatol 2007; 19 (3) 257-263
- 157 Oettl K, Stadlbauer V, Petter F , et al. Oxidative damage of albumin in advanced liver disease. Biochim Biophys Acta 2008; 1782 (7-8) 469-473
- 158 Kouoh F, Gressier B, Luyckx M , et al. Antioxidant properties of albumin: effect on oxidative metabolism of human neutrophil granulocytes. Farmaco 1999; 54 (10) 695-699
- 159 Anraku M, Yamasaki K, Maruyama T, Kragh-Hansen U, Otagiri M. Effect of oxidative stress on the structure and function of human serum albumin. Pharm Res 2001; 18 (5) 632-639
- 160 Fernández J, Monteagudo J, Bargallo X , et al. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 2005; 42 (3) 627-634
- 161 Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R ; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350 (22) 2247-2256
- 162 Ballmer PE, Walshe D, McNurlan MA, Watson H, Brunt PW, Garlick PJ. Albumin synthesis rates in cirrhosis: correlation with Child-Turcotte classification. Hepatology 1993; 18 (2) 292-297
- 163 Barle H, Januszkiewicz A, Hållström L , et al. Albumin synthesis in humans increases immediately following the administration of endotoxin. Clin Sci (Lond) 2002; 103 (5) 525-531
- 164 Wang XY, Li WQ, Lu J, Li N, Li JS. Lipopolysaccharide decreasing albumin expression in rat hepatocytes. Hepatobiliary Pancreat Dis Int 2005; 4 (3) 410-415
- 165 Wang XY, Li WQ, Lu J, Li N, Li JS. [Mechanism of reduction of albumin expression induced by lipopolysaccharide in rat hepatocytes]. Chin Med J (Engl) 2005; 118 (20) 1695-1702
- 166 Ruot B, Béchereau F, Bayle G, Breuillé D, Obled C. The response of liver albumin synthesis to infection in rats varies with the phase of the inflammatory process. Clin Sci (Lond) 2002; 102 (1) 107-114
- 167 Hayashi T, Era S, Kawai K , et al. Observation for redox state of human serum and aqueous humor albumin from patients with senile cataract. Pathophysiology 2000; 6: 237-243
- 168 Hughes WL, Dintzis HM. Crystallization of the mercury dimers of human and bovine mercaptalbumin. J Biol Chem 1964; 239: 845-849
- 169 Peters T. All About Albumin: Biochemistry, Genetics, and Medical Applications. San Diego, CA: Academic; 1996
- 170 Oettl K, Stauber RE. Physiological and pathological changes in the redox state of human serum albumin critically influence its binding properties. Br J Pharmacol 2007; 151 (5) 580-590
- 171 El Kebir D, József L, Filep JG. Neutrophil recognition of bacterial DNA and Toll-like receptor 9-dependent and -independent regulation of neutrophil function. Arch Immunol Ther Exp (Warsz) 2008; 56 (1) 41-53
- 172 Leifer CA, Kennedy MN, Mazzoni A, Lee C, Kruhlak MJ, Segal DM. TLR9 is localized in the endoplasmic reticulum prior to stimulation. J Immunol 2004; 173 (2) 1179-1183
- 173 Broad A, Jones DE, Kirby JA. Toll-like receptor (TLR) response tolerance: a key physiological “damage limitation” effect and an important potential opportunity for therapy. Curr Med Chem 2006; 13 (21) 2487-2502
- 174 Latz E, Schoenemeyer A, Visintin A , et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 2004; 5 (2) 190-198
- 175 Sabroe I, Prince LR, Jones EC , et al. Selective roles for Toll-like receptor (TLR)2 and TLR4 in the regulation of neutrophil activation and life span. J Immunol 2003; 170 (10) 5268-5275
- 176 Stadlbauer V, Mookerjee RP, Wright GA , et al. Role of Toll-like receptors 2, 4, and 9 in mediating neutrophil dysfunction in alcoholic hepatitis. Am J Physiol Gastrointest Liver Physiol 2009; 296 (1) G15-G22
- 177 Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. J Gastroenterol Hepatol 2009; 24 (6) 943-954
- 178 Testro AG, Gow PJ, Angus PW , et al. Effects of antibiotics on expression and function of Toll-like receptors 2 and 4 on mononuclear cells in patients with advanced cirrhosis. J Hepatol 2010; 52 (2) 199-205
- 179 Manigold T, Böcker U, Hanck C , et al. Differential expression of toll-like receptors 2 and 4 in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2003; 15 (3) 275-282
- 180 Riordan SM, Skinner N, Nagree A , et al. Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis. Hepatology 2003; 37 (5) 1154-1164
- 181 Francés R, Zapater P, González-Navajas JM , et al. Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology 2008; 47 (3) 978-985
- 182 Castellote J, Girbau A, Maisterra S, Charhi N, Ballester R, Xiol X. Spontaneous bacterial peritonitis and bacterascites prevalence in asymptomatic cirrhotic outpatients undergoing large-volume paracentesis. J Gastroenterol Hepatol 2008; 23 (2) 256-259
- 183 Wong F, Bernardi M, Balk R , et al; International Ascites Club. Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club. Gut 2005; 54 (5) 718-725
- 184 Silvestre JP, Coelho LM, Póvoa PM. Impact of fulminant hepatic failure in C-reactive protein?. J Crit Care 2010; 25 (4) 657 , e7–e12
- 185 Bota DP, Van Nuffelen M, Zakariah AN, Vincent JL. Serum levels of C-reactive protein and procalcitonin in critically ill patients with cirrhosis of the liver. J Lab Clin Med 2005; 146 (6) 347-351
- 186 Elefsiniotis IS, Petrocheilou A, Scarmeas N , et al. Serum procalcitonin levels in chronic hepatitis C patients under pegylated interferon-alpha plus ribavirin treatment. J Clin Virol 2006; 37 (4) 329-331
- 187 Vento S, Garofano T, Renzini C , et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998; 338 (5) 286-290
- 188 Keeffe EB. Hepatitis A and B superimposed on chronic liver disease: vaccine-preventable diseases. Trans Am Clin Climatol Assoc 2006; 117: 227-237 , discussion 237–238
- 189 Kumar M, Herrera JL. Importance of hepatitis vaccination in patients with chronic liver disease. South Med J 2010; 103 (12) 1223-1231
- 190 Fiore AE, Uyeki TM, Broder K , et al; Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep 2010; 59 (RR-8) 1-62
- 191 Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep 2010; 59 (34) 1102-1106
- 192 Impfausschuss. Impfplan 2011 Österreich Evidenz-basierte Empfehlungen des Obersten Sanitätsrates. 12. October 2010
- 193 Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, Soares-Weiser K, Uribe M. Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding. Cochrane Database Syst Rev 2010; (9) CD002907
- 194 Runyon BA ; AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009; 49 (6) 2087-2107
- 195 Cohen MJ, Sahar T, Benenson S, Elinav E, Brezis M, Soares-Weiser K. Antibiotic prophylaxis for spontaneous bacterial peritonitis in cirrhotic patients with ascites, without gastro-intestinal bleeding. Cochrane Database Syst Rev 2009; (2) CD004791
- 196 European Association For The Study Of The Liver. EASL clinical practice guidelines: management of chronic hepatitis B. J Hepatol 2009; 50 (2) 227-242
- 197 Lok AS, McMahon BJ ; Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: update of recommendations. Hepatology 2004; 39 (3) 857-861
- 198 Vilstrup H. Cirrhosis and bacterial infections. Rom J Gastroenterol 2003; 12 (4) 297-302
- 199 Nakamura I, Ochiai K, Imawari M. Phagocytic function of neutrophils of patients with decompensated liver cirrhosis is restored by oral supplementation of branched-chain amino acids. Hepatol Res 2004; 29 (4) 207-211
- 200 Abou-Assi SG, Mihas AA, Gavis EA , et al. Safety of an immune-enhancing nutrition supplement in cirrhotic patients with history of encephalopathy. JPEN J Parenter Enteral Nutr 2006; 30 (2) 91-96
- 201 Jarchum I, Pamer EG. Regulation of innate and adaptive immunity by the commensal microbiota. Curr Opin Immunol 2011; 23 (3) 353-360
- 202 Fedorak RN. Understanding why probiotic therapies can be effective in treating IBD. J Clin Gastroenterol 2008; 42 (Suppl 3, Pt 1) S111-S115
- 203 Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005; 41 (3) 422-433
- 204 Riordan SM, Williams R. The intestinal flora and bacterial infection in cirrhosis. J Hepatol 2006; 45 (5) 744-757
- 205 An H, Xu H, Yu Y , et al. Up-regulation of TLR9 gene expression by LPS in mouse macrophages via activation of NF-kappaB, ERK and p38 MAPK signal pathways. Immunol Lett 2002; 81 (3) 165-169
- 206 Dbouk N, McGuire BM. Hepatic encephalopathy: a review of its pathophysiology and treatment. Curr Treat Options Gastroenterol 2006; 9 (6) 464-474
- 207 Lirussi F, Mastropasqua E, Orando S, Orlando R. Probiotics for non-alcoholic fatty liver disease and/or steatohepatitis. Cochrane Database Syst Rev 2007; (1) CD005165
- 208 D'Souza AL, Rajkumar C, Cooke J, Bulpitt CJ. Probiotics in prevention of antibiotic associated diarrhoea: meta-analysis. BMJ 2002; 324 (7350) 1361
- 209 Cremonini F, Di Caro S, Nista EC , et al. Meta-analysis: the effect of probiotic administration on antibiotic-associated diarrhoea. Aliment Pharmacol Ther 2002; 16 (8) 1461-1467
- 210 McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101 (4) 812-822
- 211 Isakow W, Morrow LE, Kollef MH. Probiotics for preventing and treating nosocomial infections: review of current evidence and recommendations. Chest 2007; 132 (1) 286-294
- 212 Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J Hepatol 2008; 48 (6) 945-951
- 213 Lata J, Novotný I, Príbramská V , et al. The effect of probiotics on gut flora, level of endotoxin and Child-Pugh score in cirrhotic patients: results of a double-blind randomized study. Eur J Gastroenterol Hepatol 2007; 19 (12) 1111-1113
- 214 Eguchi S, Takatsuki M, Hidaka M, Soyama A, Ichikawa T, Kanematsu T. Perioperative synbiotic treatment to prevent infectious complications in patients after elective living donor liver transplantation: a prospective randomized study. Am J Surg 2011; 201 (4) 498-502
- 215 Chavez-Tapia NC, Soares-Weiser K, Brezis M, Leibovici L. Antibiotics for spontaneous bacterial peritonitis in cirrhotic patients. Cochrane Database Syst Rev 2009; (1) CD002232
- 216 Acevedo JG, Fernandez J, Castro M , et al. Current efficacy of recommended empirical antibiotic therapy in patients with cirrhosis and bacterial infection [abstract 6]. Opening and general session 1 2009;Apr 23, 2009;
- 217 Hassanein TI, Schade RR, Hepburn IS. Acute-on-chronic liver failure: extracorporeal liver assist devices. Curr Opin Crit Care 2011; 17 (2) 195-203
- 218 Stadlbauer V, Krisper P, Aigner R , et al. Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure. Crit Care 2006; 10 (6) R169
- 219 Doria C, Marino IR. Bacteremia using the molecular adsorbent recirculating system in patients bridged to liver transplantation. Exp Clin Transplant 2005; 3 (1) 289-292
- 220 Davies N, Proven A, Leckie P , et al. The development and testing of the UCL liver support device (UCL-ARSeNEL): improvement of survival in paracetamol-induced acute liver failure pigs [abstract]. Hepatology 2010; 52: 1616
- 221 Oettl K, Stadlbauer V, Krisper P, Stauber RE. Effect of extracorporeal liver support by molecular adsorbents recirculating system and Prometheus on redox state of albumin in acute-on-chronic liver failure. Ther Apher Dial 2009; 13 (5) 431-436
- 222 Oettl K, Marsche G. Redox state of human serum albumin in terms of cysteine-34 in health and disease. Methods Enzymol 2010; 474: 181-195
- 223 Klammt S, Koball S, Hickstein H , et al. Increase of octanoate concentrations during extracorporeal albumin dialysis treatments. Ther Apher Dial 2009; 13 (5) 437-443
- 224 Pradere JP, Troeger JS, Dapito DH, Mencin AA, Schwabe RF. Toll-like receptor 4 and hepatic fibrogenesis. Semin Liver Dis 2010; 30 (3) 232-244
- 225 Rice TW, Wheeler AP, Bernard GR , et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med 2010; 38 (8) 1685-1694
- 226 Tidswell M, Tillis W, Larosa SP , et al; Eritoran Sepsis Study Group. Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med 2010; 38 (1) 72-83