Dataset Information

Circulating microRNAs improve bacterial infection diagnosis and overall survival prediction in acute decompensation of liver cirrhosis.

ABSTRACT: Bacterial infections are the most frequent precipitating event in patients with acute decompensation of cirrhosis (AD) and are associated with high mortality. Early diagnosis is challenging due to cirrhosis-related systemic inflammation. Here we investigated the potential of circulating microRNAs to diagnose bacterial infections and predict survival in cirrhotic patients with AD. High throughput profiling of circulating microRNAs was performed using the Nanostring technology in 57 AD patients and 24 patients with compensated cirrhosis (CC). Circulating miRs profiling showed that: (a) miRs differentially detected in AD vs. CC were mostly down-regulated; (b) a composite score including absolute neutrophil count, C reactive protein and miR-362-3p could diagnose bacterial infection with an excellent performance (AUC of 0.825 [95% CI = 0.671-0.980; p < 0.001]); (c) a composite score including miR-382-5p, miR-592 and MELD-Na improved 6-month survival prediction. Circulating miRs are strongly dysregulated in patients with AD and may help to improve bacterial infection diagnosis and survival prediction.

SUBMITTER: Chouik Y

PROVIDER: S-EPMC10415934 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Circulating microRNAs improve bacterial infection diagnosis and overall survival prediction in acute decompensation of liver cirrhosis.

Chouik Yasmina Y Lebossé Fanny F Plissonnier Marie-Laure ML Lega Jean-Christophe JC Pradat Pierre P Antonini Teresa T Subic Miroslava M Hartig-Lavie Kerstin K Erard Domitille D Villeret François F Guichon Céline C Payancé Audrey A Radenne Sylvie S Rautou Pierre-Emmanuel PE Zoulim Fabien F Levrero Massimo M

iScience 20230720 8

Bacterial infections are the most frequent precipitating event in patients with acute decompensation of cirrhosis (AD) and are associated with high mortality. Early diagnosis is challenging due to cirrhosis-related systemic inflammation. Here we investigated the potential of circulating microRNAs to diagnose bacterial infections and predict survival in cirrhotic patients with AD. High throughput profiling of circulating microRNAs was performed using the Nanostring technology in 57 AD patients an ...[more]

PMID: 37575179

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Project description:Background & Aims: Infectious complications determine the prognosis of cirrhosis patients. Their infection susceptibility relates to the development of immuneparesis, a complex interplay of different immunosuppressive cells and soluble factors. Mechanisms underlying the dynamics of immuneparesis of innate immunity remain inconclusive. We aimed to dissect the heterogeneity of circulating monocyte states in different cirrhosis stages, and pursued the function of selected differentially expressed (DE) genes. Methods: We systematically investigated circulating monocytes in health, compensated and not-acutely decompensated (NAD) cirrhosis using single cell RNA sequencing. Selective genes were confirmed by flow cytometry and diverse functional assays on monocytes ex vivo. Results: We identified seven monocyte clusters. Their abundances varied between cirrhosis stages, confirming previously reported changes i.e. reduction in CD14lowCD16++ and emergence of M-MDSC in advanced stages. DE genes between health and disease and among stages were detected, including for the first time CD52. CD52-expression on monocytes significantly enhanced throughout compensated and NAD cirrhosis. Heretofore the biological significance of CD52-expression on mon enhanced migratory potential, increased cytokine production, but poor T cell activation. Following acute decompensation (AD), CD52 was cleaved by elevated phospholipase C (PLC), and soluble CD52 (sCD52) was detected in the circulation. Inhibition and cleavage of CD52 significantly suppressed monocyte functions ex vivo and in vitro, and the predominance of immunosuppressive CD52low circulating monocytes in patients with AD was associated with infection and low transplant-free survival. Conclusion: CD52 may represent a biologically relevant target for future immunotherapy. Stabilising CD52 may enhance monocyte functions and infection control in the context of cirrhosis, guided by sCD52/PLC as biomarkers indicating immuneparesis.ocytes remained unknown. CD52highCD14+CD16highHLA-DRhigh monocytes in patients with cirrhosis revealed a functional phenotype of active phagocytes with enhanced migratory potential, increased cytokine production, but poor T cell activation. Following acute decompensation (AD), CD52 was cleaved by elevated phospholipase C (PLC), and soluble CD52 (sCD52) was detected in the circulation. Inhibition and cleavage of CD52 significantly suppressed monocyte functions ex vivo and in vitro, and the predominance of immunosuppressive CD52low circulating monocytes in patients with AD was associated with infection and low transplant-free survival. Conclusion: CD52 may represent a biologically relevant target for future immunotherapy. Stabilising CD52 may enhance monocyte functions and infection control in the context of cirrhosis, guided by sCD52/PLC as biomarkers indicating immuneparesis.

Project description:Background & aimsSystemic inflammation is a driver of decompensation in cirrhosis with unclear relevance in the compensated stage. We evaluated inflammation and bacterial translocation markers in compensated cirrhosis and their dynamics in relation to the first decompensation.MethodsThis study is nested within the PREDESCI trial, which investigated non-selective beta-blockers for preventing decompensation in compensated cirrhosis and clinically significant portal hypertension (CSPH: hepatic venous pressure gradient ≥10 mmHg). Blood biomarkers were measured at baseline and at 1 and 2 years in patients who remained compensated and had available samples (n = 164). Values of patients with CSPH were split at each time point by decompensation development in the next time interval after sampling. We also included 54 patients with cirrhosis and subclinical portal hypertension (PH) and 35 controls. We assessed markers of inflammation (interleukin-6 [IL-6], tumor necrosis factor-alpha, von Willebrand factor [vWF], C-reactive protein), macrophage activation (CD14, CD163), intestinal barrier integrity (fatty acid-binding protein [FABP], haptoglobin), and bacterial translocation (lipopolysaccharide [LPS]).ResultsIL-6, CD163, and vWF were higher (p <0.01) at baseline in patients with cirrhosis and CSPH compared to those with subclinical PH and controls. IL-6 increased (p <0.05) at 1 year in patients with CSPH, with a greater rise in those who developed decompensation. CD163 was higher (p <0.01) in patients who decompensated at baseline and 1 and 2 years. FABP was elevated (p <0.01) in patients with CSPH compared to subclinical PH and controls at baseline and 1 year, while haptoglobin was lower (p <0.01). LPS was higher (p <0.01) in patients with CSPH than in those with subclinical PH and controls and increased at 1 year regardless of decompensation development.ConclusionsInflammation and bacterial products are present in the systemic circulation in patients with compensated cirrhosis and CSPH. Progressive inflammation precedes the first decompensation.Impact and implicationsSystemic inflammation drives cirrhosis progression during the decompensated stage, but its role in the compensated stage is unclear. We evaluated biomarkers of systemic inflammation, intestinal barrier integrity and bacterial translocation in patients with compensated cirrhosis and their dynamics in relation to the first decompensation. We demonstrate that low-grade inflammation and bacterial products are present in the systemic circulation in compensated cirrhosis, provided clinically significant portal hypertension has developed. We also show that worsening of systemic inflammation precedes the development of first clinical decompensation.

Project description:Background and aimsPatients with cirrhosis have an increased risk of postoperative mortality for a range of surgeries; however, they are also at risk of postoperative complications such as infection and cirrhosis decompensation. To date, there are no prediction scores that specifically risk stratify patients for these morbidities.MethodsThis was a retrospective study using data of patients with cirrhosis who underwent diverse surgeries in the Veterans Health Administration. Validated algorithms and/or manual adjudication were used to ascertain postoperative decompensation and postoperative infection through 90 days. Multivariable logistic regression was used to evaluate prediction models in derivation and validation sets using variables from the recently-published Veterans Outcomes and Costs Associated with Liver Disease (VOCAL)-Penn cirrhosis surgical risk scores for postoperative mortality. Models were compared with the Mayo risk score, Model for End-stage Liver Disease (MELD)-sodium, and Child-Turcotte-Pugh (CTP) scores.ResultsA total 4712 surgeries were included; patients were predominantly male (97.2 %), white (63.3 %), and with alcohol-related liver disease (35.3 %). Through 90 postoperative days, 8.7 % of patients experienced interval decompensation, and 4.5 % infection. Novel VOCAL-Penn prediction models for decompensation demonstrated good discrimination for interval decompensation (C-statistic 0.762 vs 0.663 Mayo vs 0.603 MELD-sodium vs 0.560 CTP; P < .001); however, discrimination was only fair for postoperative infection (C-statistic 0.666 vs 0.592 Mayo [P = .13] vs 0.502 MELD-sodium [P < .001] vs 0.503 CTP [P < .001]). The model for interval decompensation had excellent calibration in both derivation and validation sets.ConclusionWe report the derivation and internal validation of a novel, parsimonious prediction model for postoperative decompensation in patients with cirrhosis. This score demonstrated superior discrimination and calibration as compared with existing clinical standards, and will be available at www.vocalpennscore.com.

Dataset Information

Circulating microRNAs improve bacterial infection diagnosis and overall survival prediction in acute decompensation of liver cirrhosis.

Publications

Circulating microRNAs improve bacterial infection diagnosis and overall survival prediction in acute decompensation of liver cirrhosis.

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