We appreciate the comments of Berry et al. who emphasize the fact that our review article focused on the early phase of sepsis (i.e., “cytokine storm”) and did not pay sufficient attention to the second phase of sepsis (i.e., “immune paralysis”, which may be lethal).1 It should be noted that there is a substantial amount of data regarding the early phase of sepsis in patients or animals with cirrhosis. Many patients with cirrhosis admitted for severe sepsis die within the first hours.2, 3 At the onset of bacterial infection, circulating levels of proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are higher in patients with cirrhosis than in patients who do not have cirrhosis.4 Experiments performed in immune cells from noninfected patients with cirrhosis show a defect in the production of anti-inflammatory IL-10 during the first hours of ex vivo exposure to lipopolysaccharide.5 Among patients with cirrhosis and spontaneous bacterial peritonitis, renal failure develops in those who have the highest levels of TNF-α and IL-6 in the blood and ascites.6 Hyperproduction of TNF-α plays a major role in the development of liver injury in a model of lipopolysaccharide-induced sepsis in cirrhotic rats.7 On the other hand, the second phase of sepsis-induced “immune paralysis” is less documented in patients with cirrhosis. Available data are often preliminary and all were obtained in patients with cirrhosis and acute-on-chronic liver failure due to different causes (gastrointestinal bleeding, infections).8-10 In other words, studies are needed to specifically investigate “immune paralysis” in patients with cirrhosis and sepsis. We agree with Berry et al. that this may lead to new therapeutic strategies aimed at improving the prognosis in those patients with cirrhosis admitted for sepsis who reach the second phase of “immune paralysis”.
Thierry Gustot M.D., Ph.D.* , Richard Moreau M.D.* , * INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Clichy/Paris, France, Liver Unit, Beaujon Hospital, Clichy, and Université Denis Diderot–Paris VII, Paris, France, Department of Gastroenterology, Erasme Hospital Université Libre de Bruxelles, Brussels, Belgium