Bacterial Infections in Acute-on-Chronic Liver Failure

Lingling Yang; Tianzhou Wu; Jiang Li; Jun Li

doi:10.1055/s-0038-1657751

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2018; 38(02): 121-133
DOI: 10.1055/s-0038-1657751

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Bacterial Infections in Acute-on-Chronic Liver Failure

Authors

Lingling Yang

¹State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Tianzhou Wu

¹State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

²The Infectious Disease Department, The First People's Hospital of Wenling, Wenling, China
Jiang Li

¹State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
Jun Li

¹State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

Abstract

Acute-on-chronic liver failure (ACLF) is a newly recognized clinical syndrome characterized by preexisting chronic liver disease or cirrhosis with organ failure and high 28-day mortality (50–90%). Bacterial infections (BIs) play pivotal roles in the development and progression of ACLF either as a main precipitating event or a specific complication. The main organisms isolated as triggering ACLF are Gram-positive bacteria, followed by Gram-negative bacteria. Spontaneous bacterial peritonitis, pneumonia, urinary tract infections, and skin infections are prevalent infections that trigger and complicate ACLF. Despite appropriate antibiotic treatment, BIs account for poor ACLF outcomes and lead to a worse clinical course and higher intensive care unit admission and short-term mortality. Early diagnosis and novel nonantibiotic methods are highly important for managing BIs. Thus, this review focuses on the epidemiology, prognosis, and diagnosis of and management strategies for BIs in ACLF patients as well as the relationship between BIs and ACLF.

Keywords

bacterial infections - acute-on-chronic liver failure - prognosis - prophylaxis

Full Text

References

References
1 Fernández J, Navasa M, Gómez J. , et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002; 35 (01) 140-148
2 Bajaj JS, O'Leary JG, Reddy KR. , et al; NACSELD. Second infections independently increase mortality in hospitalized patients with cirrhosis: the North American consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology 2012; 56 (06) 2328-2335
3 Bajaj JS, O'Leary JG, Wong F, Reddy KR, Kamath PS. Bacterial infections in end-stage liver disease: current challenges and future directions. Gut 2012; 61 (08) 1219-1225
4 Fernández J, Acevedo J, Castro M. , et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012; 55 (05) 1551-1561
5 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 (04) 1246-1256 , 1256.e1–1256.e5
6 Nahon P, Lescat M, Layese R. , et al; ANRS CO12 CirVir and Microcir Groups. Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort). Gut 2017; 66 (02) 330-341
7 Bajaj JS, O'Leary JG, Reddy KR. , et al; North American Consortium For The Study Of End-Stage Liver Disease (NACSELD). Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures. Hepatology 2014; 60 (01) 250-256
8 Hernaez R, Solà E, Moreau R, Ginès P. Acute-on-chronic liver failure: an update. Gut 2017; 66 (03) 541-553
9 Moreau R, Jalan R, Gines P. , et al; CANONIC Study Investigators of the EASL–CLIF Consortium. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144 (07) 1426-1437 , 1437.e1–1437.e9
10 Sarin SK, Kedarisetty CK, Abbas Z. , et al; APASL ACLF Working Party. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014. Hepatol Int 2014; 8 (04) 453-471
11 Wu T, Li J, Shao L. , et al; Chinese Group on the Study of Severe Hepatitis B (COSSH). Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure. Gut 2017; ;gutjnl-2017-314641
12 Shi Y, Yang Y, Hu Y. , et al. Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults. Hepatology 2015; 62 (01) 232-242
13 Mücke MM, Rumyantseva T, Mücke VT. , et al. Bacterial infection-triggered acute-on-chronic liver failure is associated with increased mortality. Liver Int 2018; 38 (04) 645-653
14 Fernández J, Acevedo J, Wiest R. , et al; European Foundation for the Study of Chronic Liver Failure. Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis. Gut 2017; ;gutjnl-2017-314240
15 Li H, Chen LY, Zhang NN. , et al. Characteristics, diagnosis and prognosis of acute-on-chronic liver failure in cirrhosis associated to hepatitis B. Sci Rep 2016; 6: 25487
16 Caly WR, Strauss E. A prospective study of bacterial infections in patients with cirrhosis. J Hepatol 1993; 18 (03) 353-358
17 Yoshida H, Hamada T, Inuzuka S, Ueno T, Sata M, Tanikawa K. Bacterial infection in cirrhosis, with and without hepatocellular carcinoma. Am J Gastroenterol 1993; 88 (12) 2067-2071
18 Deschênes M, Villeneuve JP. Risk factors for the development of bacterial infections in hospitalized patients with cirrhosis. Am J Gastroenterol 1999; 94 (08) 2193-2197
19 Thulstrup AM, Sørensen HT, Schønheyder HC, Møller JK, Tage-Jensen U. Population-based study of the risk and short-term prognosis for bacteremia in patients with liver cirrhosis. Clin Infect Dis 2000; 31 (06) 1357-1361
20 Merli M, Lucidi C, Di Gregorio V. , et al. An empirical broad spectrum antibiotic therapy in health-care-associated infections improves survival in patients with cirrhosis: a randomized trial. Hepatology 2016; 63 (05) 1632-1639
21 Fernández J, Bert F, Nicolas-Chanoine MH. The challenges of multi-drug-resistance in hepatology. J Hepatol 2016; 65 (05) 1043-1054
22 Gustot T, Felleiter P, Pickkers P. , et al; EPIC II Group of Investigators. Impact of infection on the prognosis of critically ill cirrhotic patients: results from a large worldwide study. Liver Int 2014; 34 (10) 1496-1503
23 Karvellas CJ, Pink F, McPhail M. , et al. Bacteremia, acute physiology and chronic health evaluation II and modified end stage liver disease are independent predictors of mortality in critically ill nontransplanted patients with acute on chronic liver failure. Crit Care Med 2010; 38 (01) 121-126
24 Sarin SK, Kumar A, Almeida JA. , et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL). Hepatol Int 2009; 3 (01) 269-282
25 Wasmuth HE, Kunz D, Yagmur E. , et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol 2005; 42 (02) 195-201
26 Jalan R, Fernandez J, Wiest R. , et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol 2014; 60 (06) 1310-1324
27 Tandon P, Abraldes JG, Keough A. , et al. Risk of bacterial infection in patients with cirrhosis and acute variceal hemorrhage, based on Child-Pugh class, and effects of antibiotics. Clin Gastroenterol Hepatol 2015; 13 (06) 1189-96.e2
28 Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61 (06) 1385-1396
29 Ramos JM, Vidal I, Bellot P, Gómez-Hurtado I, Zapater P, Such J. Comparison of the in vitro susceptibility of rifaximin versus norfloxacin against multidrug resistant bacteria in a hospital setting. A proof-of-concept study for use in advanced cirrhosis. Gut 2016; 65 (01) 182-183
30 Dam G, Vilstrup H, Watson H, Jepsen P. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology 2016; 64 (04) 1265-1272
31 Fernández J, Tandon P, Mensa J, Garcia-Tsao G. Antibiotic prophylaxis in cirrhosis: Good and bad. Hepatology 2016; 63 (06) 2019-2031
32 Gustot T, Fernandez J, Szabo G. , et al. Sepsis in alcohol-related liver disease. J Hepatol 2017; 67 (05) 1031-1050
33 Louvet A, Wartel F, Castel H. , et al. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology 2009; 137 (02) 541-548
34 Sargenti K, Prytz H, Nilsson E, Bertilsson S, Kalaitzakis E. Bacterial infections in alcoholic and nonalcoholic liver cirrhosis. Eur J Gastroenterol Hepatol 2015; 27 (09) 1080-1086
35 Vergis N, Atkinson SR, Knapp S. , et al. In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, and is associated with high circulating levels of bacterial DNA. Gastroenterology 2017; 152 (05) 1068-1077.e4
36 Thévenot T, Bureau C, Oberti F. , et al. Effect of albumin in cirrhotic patients with infection other than spontaneous bacterial peritonitis. A randomized trial. J Hepatol 2015; 62 (04) 822-830
37 Wong F, O'Leary JG, Reddy KR. , et al; North American Consortium for Study of End-Stage Liver Disease. New consensus definition of acute kidney injury accurately predicts 30-day mortality in patients with cirrhosis and infection. Gastroenterology 2013; 145 (06) 1280-8.e1
38 Plessier A, Denninger MH, Consigny Y. , et al. Coagulation disorders in patients with cirrhosis and severe sepsis. Liver Int 2003; 23 (06) 440-448
39 Merli M, Lucidi C, Pentassuglio I. , et al. Increased risk of cognitive impairment in cirrhotic patients with bacterial infections. J Hepatol 2013; 59 (02) 243-250
40 Singer M, Deutschman CS, Seymour CW. , et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315 (08) 801-810
41 Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe sepsis in cirrhosis. Hepatology 2009; 50 (06) 2022-2033
42 Clària J, Stauber RE, Coenraad MJ. , et al; CANONIC Study Investigators of the EASL-CLIF Consortium and the European Foundation for the Study of Chronic Liver Failure (EF-CLIF). Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure. Hepatology 2016; 64 (04) 1249-1264
43 Grp SCCT; SepNet Critical Care Trials Group. Incidence of severe sepsis and septic shock in German intensive care units: the prospective, multicentrle INSEP study. Intensive Care Med 2016; 42 (12) 1980-1989
44 Twilla JD, Nair SP, Talwar M, Kovalic A, Satapathy SK. Severity of systemic inflammatory response syndrome affects outcomes in decompensated cirrhotics with spontaneous bacterial peritonitis. Am J Gastroenterol 2016; 111 (07) 1043-1045
45 Angeli P, Tonon M, Pilutti C, Morando F, Piano S. Sepsis-induced acute kidney injury in patients with cirrhosis. Hepatol Int 2016; 10 (01) 115-123
46 Galbois A, Bigé N, Pichereau C. , et al. Exploration of skin perfusion in cirrhotic patients with septic shock. J Hepatol 2015; 62 (03) 549-555
47 Jalan R, Stadlbauer V, Sen S, Cheshire L, Chang YM, Mookerjee RP. Role of predisposition, injury, response and organ failure in the prognosis of patients with acute-on-chronic liver failure: a prospective cohort study. Crit Care 2012; 16 (06) R227
48 Michelena J, Altamirano J, Abraldes JG. , et al. Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis. Hepatology 2015; 62 (03) 762-772
49 Katoonizadeh A, Laleman W, Verslype C. , et al. Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study. Gut 2010; 59 (11) 1561-1569
50 Tilg H, Cani PD, Mayer EA. Gut microbiome and liver diseases. Gut 2016; 65 (12) 2035-2044
51 Bajaj JS, Heuman DM, Hylemon PB. , et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol 2014; 60 (05) 940-947
52 Hackstein CP, Assmus LM, Welz M. , et al. Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis. Gut 2017; 66 (03) 507-518
53 Selvapatt N, Singanayagam A, Wendon J, Antoniades CG. Understanding infection susceptibility in patients with acute-on-chronic liver failure. Intensive Care Med 2014; 40 (09) 1363-1366
54 Bernsmeier C, Singanayagam A, Patel VC, Wendon J, Antoniades CG. Immunotherapy in the treatment and prevention of infection in acute-on-chronic liver failure. Immunotherapy 2015; 7 (06) 641-654
55 Bernsmeier C, Triantafyllou E, Brenig R. , et al. CD14⁺CD15^-HLA-DR^- myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure. Gut 2017; ;gutjnl-2017-314184
56 Appenrodt B, Grünhage F, Gentemann MG, Thyssen L, Sauerbruch T, Lammert F. Nucleotide-binding oligomerization domain containing 2 (NOD2) variants are genetic risk factors for death and spontaneous bacterial peritonitis in liver cirrhosis. Hepatology 2010; 51 (04) 1327-1333
57 Senkerikova R, de Mare-Bredemeijer E, Frankova S. , et al. Genetic variation in TNFA predicts protection from severe bacterial infections in patients with end-stage liver disease awaiting liver transplantation. J Hepatol 2014; 60 (04) 773-781
58 Bernsmeier C, Pop OT, Singanayagam A. , et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology 2015; 148 (03) 603-615.e14
59 Choudhury A, Kumar M, Sharma BC. , et al; APASL ACLF working party. Systemic inflammatory response syndrome in acute-on-chronic liver failure: relevance of ‘golden window’: a prospective study. J Gastroenterol Hepatol 2017; 32 (12) 1989-1997
60 Merli M, Lucidi C, Giannelli V. , et al. Cirrhotic patients are at risk for health care-associated bacterial infections. Clin Gastroenterol Hepatol 2010; 8 (11) 979-985
61 European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010; 53 (03) 397-417
62 Mandell LA, Wunderink RG, Waterer GW. Community-acquired pneumonia. N Engl J Med 2015; 372 (03) 293-294
63 Boaretti M, Castellani F, Merli M, Lucidi C, Lleo MM. Presence of multiple bacterial markers in clinical samples might be useful for presumptive diagnosis of infection in cirrhotic patients with culture-negative reports. Eur J Clin Microbiol Infect Dis 2016; 35 (03) 433-441
64 Papp M, Vitalis Z, Altorjay I. , et al. Acute phase proteins in the diagnosis and prediction of cirrhosis associated bacterial infections. Liver Int 2012; 32 (04) 603-611
65 Lin KH, Wang FL, Wu MS. , et al. Serum procalcitonin and C-reactive protein levels as markers of bacterial infection in patients with liver cirrhosis: a systematic review and meta-analysis. Diagn Microbiol Infect Dis 2014; 80 (01) 72-78
66 Parsi MA, Saadeh SN, Zein NN. , et al. Ascitic fluid lactoferrin for diagnosis of spontaneous bacterial peritonitis. Gastroenterology 2008; 135 (03) 803-807
67 Enomoto H, Inoue S, Matsuhisa A. , et al. Development of a new in situ hybridization method for the detection of global bacterial DNA to provide early evidence of a bacterial infection in spontaneous bacterial peritonitis. J Hepatol 2012; 56 (01) 85-94
68 Papp M, Sipeki N, Vitalis Z. , et al. High prevalence of IgA class anti-neutrophil cytoplasmic antibodies (ANCA) is associated with increased risk of bacterial infection in patients with cirrhosis. J Hepatol 2013; 59 (03) 457-466
69 Tornai T, Vitalis Z, Sipeki N. , et al. Macrophage activation marker, soluble CD163, is an independent predictor of short-term mortality in patients with cirrhosis and bacterial infection. Liver Int 2016; 36 (11) 1628-1638
70 Wu Y, Wang M, Zhu Y, Lin S. Serum interleukin-6 in the diagnosis of bacterial infection in cirrhotic patients: A meta-analysis. Medicine (Baltimore) 2016; 95 (41) e5127
71 Xin J, Ding W, Hao S. , et al. Serum macrophage inflammatory protein 3α levels predict the severity of HBV-related acute-on-chronic liver failure. Gut 2016; 65 (02) 355-357
72 Kang DK, Ali MM, Zhang K. , et al. Rapid detection of single bacteria in unprocessed blood using Integrated Comprehensive Droplet Digital Detection. Nat Commun 2014; 5: 5427
73 Shen H, Wang J, Liu H. , et al. Rapid and selective detection of pathogenic bacteria in bloodstream infections with aptamer-based recognition. ACS Appl Mater Interfaces 2016; 8 (30) 19371-19378
74 Cao Z, Lu X, Li Z. , et al. The role of bacterial infection (BI) in decompensated cirrhosis patients with or without acute-on-chronic liver failure (ACLF). J Hepatol 2017; 66: S344-S344
75 Fernández J, Gustot T. Management of bacterial infections in cirrhosis. J Hepatol 2012; 56 (Suppl. 01) S1-S12
76 Fernández J, Navasa M, Planas R. , et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007; 133 (03) 818-824
77 Ginés P, Rimola A, Planas R. , et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 1990; 12 (4 Pt 1): 716-724
78 Fernández J, Ruiz del Arbol L, Gómez C. , et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006; 131 (04) 1049-1056 , quiz 1285
79 Terg R, Fassio E, Guevara M. , et al. Ciprofloxacin in primary prophylaxis of spontaneous bacterial peritonitis: a randomized, placebo-controlled study. J Hepatol 2008; 48 (05) 774-779
80 Lontos S, Gow PJ, Vaughan RB, Angus PW. Norfloxacin and trimethoprim-sulfamethoxazole therapy have similar efficacy in prevention of spontaneous bacterial peritonitis. J Gastroenterol Hepatol 2008; 23 (02) 252-255
81 Lontos S, Shelton E, Angus PW. , et al. A randomized controlled study of trimethoprim-sulfamethoxazole versus norfloxacin for the prevention of infection in cirrhotic patients. J Dig Dis 2014; 15 (05) 260-267
82 Yan K, Garcia-Tsao G. Novel prevention strategies for bacterial infections in cirrhosis. Expert Opin Pharmacother 2016; 17 (05) 689-701
83 Wiest R, Albillos A, Trauner M, Bajaj JS, Jalan R. Targeting the gut-liver axis in liver disease. J Hepatol 2017; 67 (05) 1084-1103
84 Riordan SM, Williams R. The intestinal flora and bacterial infection in cirrhosis. J Hepatol 2006; 45 (05) 744-757
85 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 (06) 945-951
86 Bajaj JS, Heuman DM, Hylemon PB. , et al. Randomised clinical trial: Lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis. Aliment Pharmacol Ther 2014; 39 (10) 1113-1125
87 Meiphani A, Ramesh M, Salgia R. Successful outcomes of fecal microbiota transplantation in patients with chronic liver disease. Hepatology 2016; 64 (Suppl. 01) 1016A-1017A
88 Bajaj JS, Kassam Z, Fagan A. , et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology 2017; 66 (06) 1727-1738
89 Merli M, Lucidi C, Di Gregorio V. , et al. The chronic use of beta-blockers and proton pump inhibitors may affect the rate of bacterial infections in cirrhosis. Liver Int 2015; 35 (02) 362-369
90 Úbeda M, Lario M, Muñoz L. , et al. Obeticholic acid reduces bacterial translocation and inhibits intestinal inflammation in cirrhotic rats. J Hepatol 2016; 64 (05) 1049-1057
91 Madsen BS, Havelund T, Krag A. Targeting the gut-liver axis in cirrhosis: antibiotics and non-selective β-blockers. Adv Ther 2013; 30 (07) 659-670
92 Mookerjee RP, Pavesi M, Thomsen KL. , et al; CANONIC Study Investigators of the EASL-CLIF Consortium. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol 2016; 64 (03) 574-582
93 de Franchis R. Baveno VI Faculty. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol 2015; 63 (03) 743-752
94 Kalambokis GN, Baltayiannis G, Christou L, Christodoulou D. Red signs and not severity of cirrhosis should determine non-selective β-blocker treatment in Child-Pugh C cirrhosis with small varices: increased risk of hepatorenal syndrome and death beyond 6 months of propranolol use. Gut 2016; 65 (07) 1228-1230
95 Madsen BS, Nielsen KF, Fialla AD, Krag A. Keep the sick from harm in spontaneous bacterial peritonitis: dose of beta blockers matters. J Hepatol 2016; 64 (06) 1455-1456
96 Horvath A, Leber B, Schmerboeck B. , et al. Randomised clinical trial: the effects of a multispecies probiotic vs. placebo on innate immune function, bacterial translocation and gut permeability in patients with cirrhosis. Aliment Pharmacol Ther 2016; 44 (09) 926-935
97 Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology 2013; 58 (05) 1836-1846
98 Gustot T. Beneficial role of G-CSF in acute-on-chronic liver failure: effects on liver regeneration, inflammation/immunoparalysis or both?. Liver Int 2014; 34 (04) 484-486
99 Khanam A, Trehanpati N, Garg V. , et al. Altered frequencies of dendritic cells and IFN-gamma-secreting T cells with granulocyte colony-stimulating factor (G-CSF) therapy in acute-on- chronic liver failure. Liver Int 2014; 34 (04) 505-513
100 Kedarisetty CK, Anand L, Bhardwaj A. , et al. Combination of granulocyte colony-stimulating factor and erythropoietin improves outcomes of patients with decompensated cirrhosis. Gastroenterology 2015; 148 (07) 1362-70.e7
101 Anty R, Tonohouan M, Ferrari-Panaia P. , et al. Low levels of 25-hydroxy vitamin D are independently associated with the risk of bacterial infection in cirrhotic patients. Clin Transl Gastroenterol 2014; 5: e56
102 Anty R, Anstee QM, Gual P, Tran A. Prophylaxis of bacterial infections in cirrhosis: is an optimal 25-OH vitamin D level required?. J Hepatol 2014; 61 (04) 965-966
103 Ariza X, Castellote J, Lora-Tamayo J. , et al. Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous bacterial peritonitis. J Hepatol 2012; 56 (04) 825-832
104 Ison MG. Empiric treatment of nosocomial spontaneous bacterial peritonitis: one size does not fit all. Hepatology 2016; 63 (04) 1083-1085
105 Bartoletti M, Giannella M, Caraceni P. , et al. Epidemiology and outcomes of bloodstream infection in patients with cirrhosis. J Hepatol 2014; 61 (01) 51-58
106 Sargenti K, Prytz H, Strand A, Nilsson E, Kalaitzakis E. Healthcare-associated and nosocomial bacterial infections in cirrhosis: predictors and impact on outcome. Liver Int 2015; 35 (02) 391-400
107 Piano S, Fasolato S, Salinas F. , et al. The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: results of a randomized, controlled clinical trial. Hepatology 2016; 63 (04) 1299-1309
108 Jalan R, Yurdaydin C, Bajaj JS. , et al; World Gastroenterology Organization Working Party. Toward an improved definition of acute-on-chronic liver failure. Gastroenterology 2014; 147 (01) 4-10