Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis

Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival.Patients407 patients with ACLF and 235 patients with acute decompensation (AD).Results152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%).ConclusionBacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.

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Macrophages in Chronic Liver Failure: Diversity, Plasticity and Therapeutic Targeting

Frontiers in Immunology ◽

10.3389/fimmu.2021.661182 ◽

2021 ◽

Vol 12 ◽

Author(s):

Arjuna Singanayagam ◽

Evangelos Triantafyllou

Keyword(s):

Liver Failure ◽

Bacterial Infections ◽

Cell Activation ◽

Immune Cell ◽

Cell Damage ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Bacterial Peritonitis ◽

Disease States ◽

Macrophage Populations

Chronic liver injury results in immune-driven progressive fibrosis, with risk of cirrhosis development and impact on morbidity and mortality. Persistent liver cell damage and death causes immune cell activation and inflammation. Patients with advanced cirrhosis additionally experience pathological bacterial translocation, exposure to microbial products and chronic engagement of the immune system. Bacterial infections have a high incidence in cirrhosis, with spontaneous bacterial peritonitis being the most common, while the subsequent systemic inflammation, organ failure and immune dysregulation increase the mortality risk. Tissue-resident and recruited macrophages play a central part in the development of inflammation and fibrosis progression. In the liver, adipose tissue, peritoneum and intestines, diverse macrophage populations exhibit great phenotypic and functional plasticity determined by their ontogeny, epigenetic programming and local microenvironment. These changes can, at different times, promote or ameliorate disease states and therefore represent potential targets for macrophage-directed therapies. In this review, we discuss the evidence for macrophage phenotypic and functional alterations in tissue compartments during the development and progression of chronic liver failure in different aetiologies and highlight the potential of macrophage modulation as a therapeutic strategy for liver disease.

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Assessment of Sepsis-3 criteria and quick SOFA in patients with cirrhosis and bacterial infections

Gut ◽

10.1136/gutjnl-2017-314324 ◽

2017 ◽

Vol 67 (10) ◽

pp. 1892-1899 ◽

Cited By ~ 36

Author(s):

Salvatore Piano ◽

Michele Bartoletti ◽

Marta Tonon ◽

Maurizio Baldassarre ◽

Giada Chies ◽

...

Keyword(s):

Hospital Mortality ◽

Liver Failure ◽

Bacterial Infections ◽

Fungal Infections ◽

Chronic Liver ◽

Population Increase ◽

Chronic Liver Failure ◽

Reactive Protein ◽

Acute Decompensation ◽

Sirs Criteria

IntroductionPatients with cirrhosis have a high risk of sepsis, which confers a poor prognosis. The systemic inflammatory response syndrome (SIRS) criteria have several limitations in cirrhosis. Recently, new criteria for sepsis (Sepsis-3) have been suggested in the general population (increase of Sequential Organ Failure Assessment (SOFA) ≥2 points from baseline). Outside the intensive care unit (ICU), the quick SOFA (qSOFA (at least two among alteration in mental status, systolic blood pressure ≤100 mm Hg or respiratory rate ≥22/min)) was suggested to screen for sepsis. These criteria have never been evaluated in patients with cirrhosis. The aim of the study was to assess the ability of Sepsis-3 criteria in predicting in-hospital mortality in patients with cirrhosis and bacterial/fungal infections.Methods259 consecutive patients with cirrhosis and bacterial/fungal infections were prospectively included. Demographic, laboratory and microbiological data were collected at diagnosis of infection. Baseline SOFA was assessed using preadmission data. Patients were followed up until death, liver transplantation or discharge. Findings were externally validated (197 patients).ResultsSepsis-3 and qSOFA had significantly greater discrimination for in-hospital mortality (area under the receiver operating characteristic (AUROC)=0.784 and 0.732, respectively) than SIRS (AUROC=0.606) (p<0.01 for both). Similar results were observed in the validation cohort. Sepsis-3 (subdistribution HR (sHR)=5.47; p=0.006), qSOFA (sHR=1.99; p=0.020), Chronic Liver Failure Consortium Acute Decompensation score (sHR=1.05; p=0.001) and C reactive protein (sHR=1.01;p=0.034) were found to be independent predictors of in-hospital mortality. Patients with Sepsis-3 had higher incidence of acute-on-chronic liver failure, septic shock and transfer to ICU than those without Sepsis-3.ConclusionsSepsis-3 criteria are more accurate than SIRS criteria in predicting the severity of infections in patients with cirrhosis. qSOFA is a useful bedside tool to assess risk for worse outcomes in these patients. Patients with Sepsis-3 and positive qSOFA deserve more intensive management and strict surveillance.

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Bacterial Infections in Acute-on-Chronic Liver Failure

Seminars in Liver Disease ◽

10.1055/s-0038-1657751 ◽

2018 ◽

Vol 38 (02) ◽

pp. 121-133 ◽

Cited By ~ 8

Author(s):

Lingling Yang ◽

Tianzhou Wu ◽

Jiang Li ◽

Jun Li

Keyword(s):

Liver Failure ◽

Bacterial Infections ◽

Management Strategies ◽

Clinical Syndrome ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Bacterial Peritonitis ◽

Specific Complication ◽

Short Term Mortality ◽

Tract Infections

AbstractAcute-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.

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Characterizing bacterial infections in acute-on-chronic liver failure among patients with cirrhosis from nonalcoholic steatohepatitis

Journal of Hepatology ◽

10.1016/j.jhep.2021.04.006 ◽

2021 ◽

Author(s):

Vinay Sundaram

Keyword(s):

Liver Failure ◽

Nonalcoholic Steatohepatitis ◽

Bacterial Infections ◽

Chronic Liver ◽

Chronic Liver Failure

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P476 SHORT-TERM (28-DAY) CLINICAL COURSE AND TRANSPLANT-FREE MORTALITY IN ACUTE ON CHRONIC LIVER FAILURE (ACLF); EVIDENCE FOR REVERSIBILITY OF ACLF (A STUDY FROM THE CANONIC DATABASE)

Journal of Hepatology ◽

10.1016/s0168-8278(14)60638-3 ◽

2014 ◽

Vol 60 (1) ◽

pp. S228 ◽

Cited By ~ 9

Author(s):

T. Gustot ◽

J. Fernandez ◽

E. Garcia ◽

P. Ginès ◽

R. Moreau ◽

...

Keyword(s):

Liver Failure ◽

Clinical Course ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Short Term

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Systemic inflammation is associated with increased intrahepatic resistance and mortality in alcohol-related acute-on-chronic liver failure

Liver International ◽

10.1111/liv.12559 ◽

2014 ◽

Vol 35 (3) ◽

pp. 724-734 ◽

Cited By ~ 57

Author(s):

Gautam Mehta ◽

Rajeshwar P Mookerjee ◽

Vikram Sharma ◽

Rajiv Jalan

Keyword(s):

Liver Failure ◽

Systemic Inflammation ◽

Chronic Liver ◽

Chronic Liver Failure

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Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity

Gut ◽

10.1136/gutjnl-2018-316888 ◽

2018 ◽

Vol 68 (10) ◽

pp. 1872-1883 ◽

Cited By ~ 16

Author(s):

Hannelie Korf ◽

Johannie du Plessis ◽

Jos van Pelt ◽

Sofie De Groote ◽

David Cassiman ◽

...

Keyword(s):

Glutamine Synthetase ◽

Liver Failure ◽

Bacterial Infections ◽

Chronic Liver ◽

Decompensated Cirrhosis ◽

Chronic Liver Failure ◽

Phenotypic Characterisation ◽

Severity Scores ◽

Aclf Patient

ObjectiveAcute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity.DesignFollowing phenotypic characterisation, we performed RNA sequencing on CD14+CD16− monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function.ResultsMonocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14+CD16− monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores.ConclusionIn ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.

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