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

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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Predictors of mortality among patients with compensated and decompensated liver cirrhosis: the role of bacterial infections and infection-related acute-on-chronic liver failure

Scandinavian Journal of Gastroenterology ◽

10.3109/00365521.2015.1017834 ◽

2015 ◽

Vol 50 (7) ◽

pp. 875-883 ◽

Cited By ~ 25

Author(s):

Konstantina Sargenti ◽

Hanne Prytz ◽

Emma Nilsson ◽

Evangelos Kalaitzakis

Keyword(s):

Liver Cirrhosis ◽

Liver Failure ◽

Bacterial Infections ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Decompensated Liver Cirrhosis ◽

Predictors Of Mortality

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Applicability of the Chronic Liver Failure-Consortium score in patients with cirrhosis and bacterial infections: a single-clinic experience

GASTROENTEROLOGY ◽

10.22141/2308-2097.55.4.2021.247915 ◽

2021 ◽

Vol 55 (4) ◽

pp. 239-245

Author(s):

D.I. Haurylenka ◽

N.N. Silivontchik

Keyword(s):

Liver Failure ◽

Bacterial Infections ◽

Serum Bilirubin Level ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Acute Decompensation ◽

Clinic Experience ◽

Cirrhotic Patients ◽

The City ◽

Number Needed To Harm

Background. The frequency and characteristics of acute-on-chronic liver failure (ACLF) are reported in numerous articles from different countries. The aim of the study was to assess the cirrhosis decompensation in patients with bacterial infections based on the Chronic Liver Failure-Consortium (CLIF-C) score in one of the city clinics in Belarus. Materials and methods. The patients underwent laboratory and instrumental studies during the hospitalization. The assessment of the syndrome of acute-on-chronic liver failure was performed using the CLIF-C score. Bacterial infections were diagnosed on the basis of standard criteria. Results. The study included 151 cirrhotic patients, 87 males and 64 females. Median age was 55 years (Q1 = 43; Q3 = 61). Cirrhosis was predominantly due to alcohol addiction — 83 patients (55 %). ACLF was diagnosed in 44 of 151 patients with cirrhosis (29.1 %; 95% confidence interval (CI) 22.0–37.1). Bacterial infections were detected in 67 people (44.4 %; 95% CI 36.3–52.7). Most often patients had liver failure that was detected by an increase in serum bilirubin level. Among individuals with upper gastrointestinal bleedings, number needed to harm for developing ACLF was 3.3 (95% CI 2.2–4.4). The risk of developing ACLF grade 2 and 3 in cirrhotic patients with infections was 8.2, with 95% CI 1.0–69.6 (number needed to harm was 12.9; 95% CI 10.7–15.0). Bacterial infections increase the risk of acute decompensation in patients with cirrhosis (odds ratio = 2.0, p = 0.048). Conclusions. The CLIF-C score is quite applicable in our cohort of patients with cirrhosis.

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Bacterial infections with and without acute-on-chronic liver failure in patients with cirrhosis and acute decompensation: Risk factors and outcome

Digestive and Liver Disease ◽

10.1016/j.dld.2018.01.021 ◽

2018 ◽

Vol 50 (1) ◽

pp. 10 ◽

Cited By ~ 1

Author(s):

M. Bartoletti ◽

M. Baldassarre ◽

M. Domenicali ◽

R. Lewis ◽

M. Giannella ◽

...

Keyword(s):

Risk Factors ◽

Liver Failure ◽

Bacterial Infections ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Acute Decompensation

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Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe

Journal of Hepatology ◽

10.1016/j.jhep.2018.10.027 ◽

2019 ◽

Vol 70 (3) ◽

pp. 398-411 ◽

Cited By ~ 61

Author(s):

Javier Fernández ◽

Verónica Prado ◽

Jonel Trebicka ◽

Alex Amoros ◽

Thierry Gustot ◽

...

Keyword(s):

Liver Failure ◽

Bacterial Infections ◽

Multidrug Resistant ◽

Chronic Liver ◽

Decompensated Cirrhosis ◽

Chronic Liver Failure

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

Gut ◽

10.1136/gutjnl-2017-314240 ◽

2017 ◽

Vol 67 (10) ◽

pp. 1870-1880 ◽

Cited By ~ 131

Author(s):

Javier Fernández ◽

Juan Acevedo ◽

Reiner Wiest ◽

Thierry Gustot ◽

Alex Amoros ◽

...

Keyword(s):

Liver Failure ◽

Systemic Inflammation ◽

Bacterial Infections ◽

Clinical Course ◽

Fungal Infections ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Bacterial Peritonitis ◽

Probability Of Survival

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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Clinical characteristics and 28-d outcomes of bacterial infections in patients with hepatitis B virus-related acute-on-chronic liver failure

World Journal of Clinical Cases ◽

10.12998/wjcc.v8.i6.1042 ◽

2020 ◽

Vol 8 (6) ◽

pp. 1042-1055 ◽

Cited By ~ 1

Author(s):

Chen Li ◽

Hai-Bin Su ◽

Xiao-Yan Liu ◽

Jin-Hua Hu

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Liver Failure ◽

Bacterial Infections ◽

Clinical Characteristics ◽

Chronic Liver ◽

Chronic Liver Failure ◽

B Virus

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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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Role of Infections in Acute-on-Chronic Liver Failure

Digestive Diseases ◽

10.1159/000375356 ◽

2015 ◽

Vol 33 (4) ◽

pp. 577-581 ◽

Cited By ~ 10

Author(s):

Richard Moreau

Keyword(s):

Liver Failure ◽

Immune Suppression ◽

Bacterial Infections ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Prolonged Stay ◽

Major Mechanism ◽

Risk Of Death ◽

Increased Risk ◽

Organ Failures

Patients with cirrhosis are prone to developing bacterial infections. Moreover, bacterial infection is the most common identifiable trigger of acute-on-chronic liver failure (ACLF), which is characterized by organ failures and a high risk of death. There is evidence of an excessive immune response of the host as a major mechanism leading to the development of organ failures in patients with cirrhosis. However, a role for direct tissue damage caused by bacterial toxins and virulence factors cannot be excluded. Failed tolerance mechanisms may also contribute to organ failures, although the involved mechanisms are unclear. A proportion of patients with infection-related ACLF have a prolonged stay in the intensive care unit. These patients have immune suppression, increased risk of superinfection and poor outcome. Immune suppression might be a consequence of the first infection episode that has led patients to be admitted to hospital.

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