To the Editor:

The recent review by Gustot et al.1 did not emphasize the important, common, and frequently lethal phase of illness that is immunoparesis, caused by the compensatory anti-inflammatory response syndrome (CARS). A term coined by Bone et al.,2 CARS describes prolonged elevations in anti-inflammatory mediators and immune dysregulation with defects in both the innate and adaptive immune responses. Studies in patients without cirrhosis have shown that the severity of this phase determines outcome beyond the initial “cytokine storm” associated with the systemic inflammatory response syndrome (SIRS).3, 4

In cirrhosis, it is common for patients to suffer repeated episodes of nosocomial sepsis following an initial episode of infection. Defects in both innate and adaptive5 arms of the immune response have been demonstrated, and there is increasing evidence that monitoring of monocyte function by assessing the expression of antigen presentation apparatus, such as human leukocyte antigen-DR is of prognostic value.6, 7 Early studies in the animal model of cirrhosis have determined that Toll-like receptor expression is up-regulated,8 predisposing the organism to an exaggerated SIRS, followed by an equally exaggerated and prolonged CARS. In the current era, when organ support strategies are capable of allowing patients to weather the “cytokine storm,” we believe further emphasis should be placed on this harmful sequel to severe sepsis.


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  • 1
    Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe sepsis in cirrhosis. Hepatology 2009; 50: 2022-2033.
  • 2
    Bone RC, Grodzin CJ, Balk RA. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997; 112: 235-243.
  • 3
    Tschaikowsky K, Hedwig-Geissing M, Schiele A, Bremer F, Schywalsky M, Schuttler J. Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients. Crit Care Med 2002; 30: 1015-1023.
  • 4
    Monneret G, Finck ME, Venet F, Debard AL, Bohe J, Bienvenu J, et al. The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol Lett 2004; 95: 193-198.
  • 5
    Antoniades CG, Wendon J, Vergani D. Paralysed monocytes in acute on chronic liver disease. J Hepatol 2005; 42: 163-165.
  • 6
    Berres ML, Schnyder B, Yagmur E, Inglis B, Stanzel S, Tischendorf JJ, et al. Longitudinal monocyte human leukocyte antigen-DR expression is a prognostic marker in critically ill patients with decompensated liver cirrhosis. Liver Int 2009; 29: 536-543.
  • 7
    Berry PA, Antoniades CG, Davies ET, Vergani D, Wendon JA. Early trend in monocyte HLA-DR expression predicts 30-day survival in acute-on-chronic liver failure [Abstract]. Hepatology 2006; 44( 4 Suppl.): 442A.
  • 8
    Shah N, Dhar DK, Olde Damink SW, Malago M, Mookerjee RP, Davies N, et al. Role of toll-like receptor 4 in mediating multiorgan failure in cirrhosis as a consequence of a 2nd hit [Abstract]. Hepatology 2009; 50( 4 Suppl.): 445A.