REVIEW ARTICLE MARTIN MATEOS AND ALBILLOS Sepsis in Patients With Cirrhosis Awaiting Liver Transplantation: New Trends and Management Rosa Martin Mateos and Agustín Albillos Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain Bacterial infections are more frequent and severe in patients with advanced liver disease and, therefore, in liver transplant candidates. The increased risk of infection in these patients parallels the severity of the immune dysfunction associated with cirrhosis, which is related to systemic inflammation and progressive immunodeficiency. Other factors contribute to this risk, such as genetic polymorphisms, proton pump inhibitor overuse, the numerous invasive procedures and hospitalizations these patients go through, or the immunosuppressive effects of malnutrition or alcohol abuse. Bacterial infections have a great impact on disease progression and significantly increase mortality rates before and after liver transplantation. Mechanisms leading to organ failure in sepsis are associated not only with the hemodynamic derangement but also with an excessive inflam- matory response triggered by infection. Furthermore, prophylactic and empirical antibiotic treatment strategies in patients with cirrhosis are being modified according to the growing prevalence of multidrug-resistant bacteria in the past decade. Also, new criteria have been introduced for the diagnosis of sepsis and septic shock. These new definitions have been validated in patients with cirrhosis and show a better accuracy to predict in-hospital mortality than previous criteria based on systemic inflammatory response syndrome. Accurate prophylaxis and early identification and treatment of bacterial infections are key to reducing the burden of sepsis in patients with cirrhosis awaiting liver transplantation. Liver Transplantation 25 1700‒1709 2019 AASLD. Received April 4, 2019; accepted August 6, 2019. Patients with cirrhosis present an increased risk of decreasing, the risk of sepsis-related death has increased developing bacterial infections,(1) which are, in addition, over the past few years (incidence risk ratio, 4.70; 95% more severe than in the general population (estimated confidence interval, 4.61-4.79).(5) Bacterial infections overall mortality of 38%(2) and up to 70% in case of sep- are the most identifiable triggers of acute-on-chronic tic shock versus 10% and 40%, respectively, for a gen- liver failure (ACLF), accounting for 32% of the precipi- eral hospital population).(3,4) Notably, although overall tating events.(6) Spontaneous bacterial peritonitis (SBP) mortality among hospitalized patients with cirrhosis is and urinary tract infections (UTIs) are the most fre- quent type, followed by pneumonia and cellulitis. Several changes in the epidemiology of bacterial Abbreviations: ACLF, acute-on-chronic liver failure; AKI, acute kidney infections have occurred over the past decade. The injury; CAID, cirrhosis-associated immune dysfunction; DAMP, most relevant is the increasing prevalence of mul- damage-associated molecular pattern; EASL, European Association for the Study of the Liver; ESBLE, extended-spectrum ß-lactamase– tidrug-resistant (MDR) bacteria both in Europe (7) (8) producing Enterobacteriaceae; HRS, hepatorenal syndrome; ICU, (29%) and worldwide (34%). MDR pathogens intensive care unit; IV, intravenous; MDR, multidrug-resistant; are resistant to at least 1 agent in 3 or more antimi- NOD2, nucleotide-binding oligomerization domain containing protein 2; PAMP, pathogen-associated molecular pattern; PMN, crobial categories. When bacteria are resistant to at polymorphonuclear leukocyte; PRR, pattern recognition receptor; least 1 agent in all but 2 or fewer antimicrobial cate- qSOFA, quick Sequential Organ Failure Assessment; SBP, spontaneous gories, they are considered extensively drug resistant, bacterial peritonitis; SIRS, systemic inflammatory response syndrome; and when not susceptible to any currently available SOFA, Sequential Organ Failure Assessment; TLR2, toll-like receptor (9) 2; UTI, urinary tract infection; VATS, video-assisted thoracoscopic agent, they are defined as pandrug-resistant bacteria. surgery; VRE, vancomycin-resistant enterococci; WBC, white blood cell. The most common MDR pathogens are extended- spectrum ß-lactamase–producing Enterobacteriaceae 1700 | REVIEW ARTICLE LIVER TraNSPLANTATION, Vol. 25, No. 11, 2019 MARTIN MATEOS AND ALBILLOS (ESBLE; ie, Escherichia coli and Klebsiella pneumoniae), interactions between the gut and the liver. The intes- AmpC ß-lactamase–producing Enterobacteriaceae tinal surface is formed by physical defenses, includ- (ie, Enterobacter and Citrobacter spp.), carbapene- ing a layer of epithelial cells interconnected by tight mase-producing Enterobacteriaceae (ie, Klebsiella spp., junctions, and functional defenses, such as the mucous E. Coli, and Enterobacter spp.), methicillin-resistant layer. The intestinal barrier displays a unique immune Staphylococcus aureus, and vancomycin-resistant entero- system capable of distinguishing between regular nu- cocci (VRE; ie, Enterococcus faecium). trient flux, self-antigens, a diverse milieu of commen- A higher susceptibility to infections significantly sal bacteria, and invading pathogens. increases morbidity and mortality and, thus, deterio- Cirrhosis is associated with profound alterations rates the quality of life of patients with cirrhosis await- at different levels of the intestinal barrier. Dysbiosis ing liver transplantation. Strategies aimed at improving (reduced abundance of protective bacteria and diagnosis of infection, prophylaxis, and treatment are increased pathogenic species) and bacterial overgrowth therefore needed. This review examines the mecha- are a result of intestinal hypomotility, changes in bile nisms responsible for the high rate of bacterial infec- flow and composition, and impaired intestinal immu- tions in patients with cirrhosis and provides an overview nity. Disruption of the epithelial and vascular intestinal of the key clinical features and prognostic implications barriers enables passage of viable bacteria and patho- of sepsis in patients awaiting liver transplantation. gen-associated molecular patterns (PAMPs) through the vascular and lymphatic routes to the systemic cir- culation. Bacterial translocation is further aggravated Altered Immune Response in sepsis due to alterations in perfusion, vascular tone, and coagulation that lead to a hypoxic microenviron- in Cirrhosis and Sepsis ment of the intestinal tissue. PATHOLOGICAL BACTERIAL CIRRHOSIS-ASSOCIATED IMMUNE TRANSLOCATION DYSFUNCTION The mucosa of the intestine is a highly organized Systemic inflammation due to persistent immune sys- and compartmentalized structure that controls the tem stimulation and progressive immunodeficiency characterize what is known as cirrhosis-associated immune dysfunction (CAID).(1) Immunodeficiency Address reprint requests to Agustín Albillos, M.D., Ph.D., Gastroenterology and Hepatology Department, Hospital Universitario affects cellular and soluble components of the immune Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal system both at the liver and systemically. The abnor- de Investigación Sanitaria, Centro de Investigación Biomédica en malities include the following: Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Carretera de Colmenar Viejo km 9100, 28034 Madrid, 1. Compromise of the immune surveillance function Spain. Telephone: +34 913368592; FAX: +34 913368592; E-mail: of the liver through damage of the reticuloen- [email protected] dothelial system. Supported by grants from the Spanish Ministerio de Ciencia, Innovación 2. Impaired synthesis of innate immunity proteins. y Universidades, Instituto de Salud Carlos III (number PI14/00876), Centro de Investigación Biomédica en Red en Enfermedades Hepáticas 3. Altered functions of circulating and intestinal y Digestivas (CB06/04/0024), and Ministerio de Economía, Industria populations of immune cells (specifically reduced y Competitividad (SAF 2017-86343-R) awarded to Agustín Albillos. chemotaxis and oxidative burst of neutrophils), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas is funded by the Instituto de Salud Carlos III. Grants impaired phagocytic activity of antigen-presenting were cofinanced by the European Development Regional Fund “A way cells, and exhaustion of the adaptive immune to achieve Europe.” response.(1,10) Copyright © 2019 by the American Association for the Study of Liver On the other hand, systemic inflammation is Diseases. prompted by increased intestinal permeability, bac- View this article online at wileyonlinelibrary.com. terial overgrowth, and dysbiosis, which favors trans- DOI 10.1002/lt.25621 location of bacteria and PAMPs. Specific receptors activated by PAMPs (also called pattern recognition Potential conflict of interest: Nothing to report. receptors [PRRs]) amplify proinflammatory signaling. Intracellular molecules released by injured or dead cells REVIEW ARTICLE | 1701 MARTIN MATEOS AND ALBILLOS LIVER TraNSPLANTATION, November 2019 (damage-associated molecular patterns [DAMPs]) are Because the new definition of sepsis requires a base- also recognized by PRRs, and they contribute to per- line calculation of the SOFA score, an