Antiviral immunity of severe fever with thrombocytopenia syndrome: current understanding and implications for clinical treatment.

Dabie Banda virus (DBV), a tick-borne pathogen, was first identified in China in 2009 and causes profound symptoms including fever, leukopenia, thrombocytopenia and multi-organ dysfunction, which is known as severe fever with thrombocytopenia syndrome (SFTS). In the last decade, global incidence and mortality of SFTS increased significantly, especially in East Asia. Though previous studies provide understandings of clinical and immunological characteristics of SFTS development, comprehensive insight of antiviral immunity response is still lacking. Here, we intensively discuss the antiviral immune response after DBV infection by integrating previous ex- and in-vivo studies, including innate and adaptive immune responses, anti-viral immune responses and long-term immune characters. A comprehensive overview of potential immune targets for clinical trials is provided as well. However, development of novel strategies for improving the prognosis of the disease remains on challenge. The current review may shed light on the establishment of immunological interventions for the critical disease SFTS.

C-C chemokine receptor 5 is essential for conventional NK cell trafficking and liver injury in a murine hepatitis virus-induced fulminant hepatic failure model.

BACKGROUND: Previous studies have demonstrated that natural killer (NK) cells migrated into the liver from peripheral organs and exerted cytotoxic effects on hepatocytes in virus-induced liver failure. AIM: This study aimed to investigate the potential therapeutic role of chemokine receptors in the migration of NK cells in a murine hepatitis  virus strain 3 (MHV-3)-induced fulminant hepatic failure (MHV-3-FHF) model and its mechanism. RESULTS: By gene array analysis, chemokine (C-C motif) receptor 5 (CCR5) was found to have remarkably elevated expression levels in hepatic NK cells after MHV-3 infection. The number of hepatic CCR5+ conventional NK (cNK) cells increased and peaked at 48 h after MHV-3 infection, while the number of hepatic resident NK (rNK) cells steadily declined. Moreover, the expression of CCR5-related chemokines, including macrophage inflammatory protein (MIP)-1α, MIP-1ß and regulated on activation, normal T-cell expressed and secreted (RANTES) was significantly upregulated in MHV-3-infected hepatocytes. In an in vitro Transwell migration assay, CCR5-blocked splenic cNK cells showed decreased migration towards MHV-3-infected hepatocytes, and inhibition of MIP-1ß or RANTES but not MIP-1α decreased cNK cell migration. Moreover, CCR5 knockout (KO) mice displayed reduced infiltration of hepatic cNK cells after MHV-3 infection, accompanied by attenuated liver injury and improved mouse survival time. Adoptive transfer of cNK cells from wild-type mice into CCR5 KO mice resulted in the abundant accumulation of hepatic cNK cells and aggravated liver injury. Moreover, pharmacological inhibition of CCR5 by maraviroc reduced cNK cell infiltration in the liver and liver injury in the MHV-3-FHF model. CONCLUSION: The CCR5-MIP-1ß/RANTES axis played a critical role in the recruitment of cNK cells to the liver during MHV-3-induced liver injury. Targeted inhibition of CCR5 provides a therapeutic approach to ameliorate liver damage during virus-induced acute liver injury.

Targeting super enhancers for liver disease: a review.

Background: Super enhancers (SEs) refer to the ultralong regions of a gene accompanied by multiple transcription factors and cofactors and strongly drive the expression of cell-type-related genes. Recent studies have demonstrated that SEs play crucial roles in regulating gene expression related to cell cycle progression and transcription. Aberrant activation of SEs is closely related to the occurrence and development of liver disease. Liver disease, especially liver failure and hepatocellular carcinoma (HCC), constitutes a major class of diseases that seriously endanger human health. Currently, therapeutic strategies targeting SEs can dramatically prevent disease progression and improve the prognosis of animal models. The associated new approaches to the treatment of related liver disease are relatively new and need systematic elaboration. Objectives: In this review, we elaborate on the features of SEs and discuss their function in liver disease. Additionally, we review their application prospects in clinical practice in the future. The article would be of interest to hepatologists, molecular biologists, clinicians, and all those concerned with targeted therapy and prognosis of liver disease. Methodology: We searched three bibliographic databases (Web of Science Core Collection, Embase, PubMed) from 01/1981 to 06/2022 for peer-reviewed scientific publications focused on (1) gene treatment of liver disease; (2) current status of SE research; and (3) targeting SEs for liver disease. We included English language original studies only. Results: The number of published studies considering the role of enhancers in liver disease is considerable. Since SEs were just defined in 2013, the corresponding data on SEs are scarce: approximately 50 papers found in bibliographic databases on the correlation between enhancers (or SEs) and liver disease. Remarkably, half of these papers were published in the past three years, indicating the growing interest of the scientific community in this issue. Studies have shown that treatments targeting components of SEs can improve outcomes in liver disease in animal and clinical trials. Conclusions: The treatment of liver disease is facing a bottleneck, and new treatments are needed. Therapeutic regimens targeting SEs have an important role in the treatment of liver disease. However, given the off-target effect of gene therapy and the lack of clinical trials, the available experimental data are still fragmented and controversial.

Establishment and validation of a prognostic model for hepatitis B virus­related acute-on-chronic liver failure patients with bacterial infection.

BACKGROUND: Bacterial infection is one of the most frequent complications in acute-on-chronic liver failure (ACLF), which leads to high mortality. However, a specific prognostic model for ACLF patients with bacterial infection has not been well established. AIM: To establish and validate a nomogram for predicting 30-day mortality of hepatitis B virus-related ACLF (HBV-ACLF) patients with bacterial infection. METHODS: A total of 513 ACLF patients for HBV reactivation were enrolled in the prospective cohort, and 224 patients with bacterial infection were for derivation. Independent predictors were identified using multivariate logistic model and then assembled into a nomogram to predict 30-day mortality. The performance of the nomogram was assessed based on its calibration, discrimination and clinical utility in a retrospective cohort of 192 HBV-ACLF patients with bacterial infection. RESULTS: Age, total bilirubin, lactate dehydrogenase, international normalized ratio and soluble interleukin-2 receptor were shown to be independent risk factors for 30-day mortality of HBV-ACLF patients with bacterial infection and the nomogram was constructed. The nomogram showed a good calibration and discrimination in the derivation cohort, with an area under the receiver operating characteristic curve (AUC) of 0.883. Application of the nomogram in the validation cohort also showed a good calibration and discrimination, with the AUC of 0.852. Decision curve analysis confirmed the clinical utility of the nomogram. CONCLUSION: The nomogram was established and validated for predicting 30-day mortality of HBV-ACLF patients with bacterial infection, which may facilitate optimal therapeutic strategies to improve the prognosis of these patients.

Proton Pump Inhibitor Therapy Increases the Risk of Spontaneous Bacterial Peritonitis in Patients with HBV-Related Acute-on-Chronic Liver Failure.

INTRODUCTION: Spontaneous bacterial peritonitis (SBP) is a common infection in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). SBP significantly increases the mortality rate and medical costs. The association between proton pump inhibitor (PPI) use and SBP remains unclear. We conducted a retrospective study to investigate the association between PPI use and SBP in patients with HBV-related ACLF and to explore the risk factors for SBP. METHODS: We compared the SBP incidence between the PPI and non-PPI groups before and after propensity score matching and explored the association between the duration and type of PPI and SBP occurrence. Risk factors for SBP occurrence were determined by univariate and multivariate logistic regression analysis. RESULTS: The SBP incidence was higher in the PPI group than in the non-PPI group before and after propensity score matching. The SBP incidence increased for elevated MELD scores in PPI users. There was a similar SBP incidence in both different types and durations of PPI users. MELD score, old age, male sex, and high WBC count were significant independent risk factors for SBP in PPI users with HBV-related ACLF in the hospital. CONCLUSIONS: PPI therapy increases the risk of SBP development in patients with HBV-related ACLF. MELD score, old age, male sex, and high WBC count could serve as predictors of SBP in PPI users. Caution should be taken regarding PPI use, especially for patients with MELD scores > 30.

Development and Validation of a Clinical Predictive Model for Bacterial Infection in Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

INTRODUCTION: Bacterial infection is one of the most frequent complications in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF), which leads to high mortality. However, a predictive model for bacterial infection in HBV-ACLF has not been well established. This study aimed to establish and validate a predictive model for bacterial infection in two independent patient cohorts. METHODS: Admission data from a prospective cohort of patients with HBV-ACLF without bacterial infection on admission was used for derivation. Bacterial infection development from day 3 to 7 of admission was captured. Independent predictors of bacterial infection development on multivariate logistic regression were used to develop the predictive model. External validation was performed on a separate retrospective cohort. RESULTS: A total of 377 patients were enrolled into the derivation cohort, including 88 patients (23.3%) who developed bacterial infection from day 3 to 7 of admission. On multivariate regression analysis, admission serum globulin (OR 0.862, 95% CI 0.822-0.904; P < 0.001), interleukin-6 (OR 1.023, 95% CI 1.006-1.040; P = 0.009), and C-reactive protein (OR 1.123, 95% CI 1.081-1.166; P < 0.001) levels were independent predictors for the bacterial infection development, which were adopted as parameters of the predictive model (GIC). In the derivation cohort, the area under the curve (AUC) of GIC was 0.861 (95% CI 0.821-0.902). A total of 230 patients were enrolled into the validation cohort, including 57 patients (24.8%) who developed bacterial infection from day 3 to 7 of admission, and the AUC of GIC was 0.836 (95% CI 0.782-0.881). The Hosmer-Lemeshow test showed a good calibration performance of the predictive model in the two cohorts (P = 0.199, P = 0.746). Decision curve analysis confirmed the clinical utility of the predictive model. CONCLUSION: GIC was established and validated for the prediction of bacterial infection development in HBV-ACLF, which may provide a potential auxiliary solution for the primary complication of HBV-ACLF.

Plasma perfusion combined with plasma exchange in chronic hepatitis B-related acute-on-chronic liver failure patients.

BACKGROUND AND AIMS: Artificial liver support systems (ALSS) have been shown to significantly reduce mortality in patients with acute-on-chronic liver failure (ACLF). However, the characteristics of patients who would benefit most from ALSS treatment are poorly understood. This study aimed to delineate the indicators for ALSS and evaluate the effectiveness of plasma perfusion combined with plasma exchange (PP + PE) in patients with hepatitis B virus-related ACLF (HBV-ACLF). METHODS: A total of 898 patients with HBV-ACLF in a single center were enrolled retrospectively. Propensity score matching (PSM) was used in case-paired analysis. Hepatic or extra-hepatic organ failures were defined by Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) criteria. Complications included ascites, infection, hepatopulmonary syndrome, hepatorenal syndrome, hepatic encephalopathy and upper gastrointestinal bleeding. Numbers of organ failures or complications were used for risk stratification. RESULTS: Among all patients, 418 patients received standard medical therapy (SMT) and 480 received PP + PE plus SMT. After one-to-one paired PSM within the two groups without risk stratification, 293 pairs were enrolled. The PP + PE group displayed significantly lower mortality risk in both 28- and 90-day observation durations. When stratified, patients with two or more organ failures or complications from the PP + PE group showed greater decrease in mortality risk. Moreover, PP + PE treatment significantly increased the resolution of organ failures and complications and ameliorated the development of new organ failures and complications. CONCLUSIONS: PP + PE treatment significantly reversed organ failures and ameliorated the development of new organ failures and complications, thus reducing mortality risk of patients with HBV-ACLF.

Complications constitute a major risk factor for mortality in hepatitis B virus-related acute-on-chronic liver failure patients: a multi-national study from the Asia-Pacific region.

BACKGROUND AND AIM: Cirrhosis is a controversial determinant of mortality in HBV-related acute-on-chronic liver failure (HBV-ACLF). The present study aimed to explore the effects of cirrhosis and the associated risk factors, especially its complications, on the outcome of HBV-ACLF. METHODS: A prospective-retrospective cohort of 985 patients was identified from the APASL-ACLF Research Consortium (AARC) database and the Chinese Study Group. Complications of ACLF (ascites, infection, hepatorenal syndrome, hepatic encephalopathy, upper gastrointestinal bleeding) as well as cirrhosis and the current main prognostic models were measured for their predictive ability for 28- or 90-day mortality. RESULTS: A total of 709 patients with HBV-ACLF as defined by the AARC criteria were enrolled. Among these HBV-ACLF patients, the cirrhotic group showed significantly higher mortality and complications than the non-cirrhotic group. A total of 36.1% and 40.1% of patients met the European Association for the Study of Liver (EASL)-Chronic Liver Failure consortium (CLIF-C) criteria in the non-cirrhotic and cirrhotic groups, respectively; these patients had significantly higher rates of mortality and complications than those who did not satisfy the CLIF-C criteria. Furthermore, among patients who did not meet the CLIF-C criteria, the cirrhotic group exhibited higher mortality and complication rates than the non-cirrhotic group, without significant differences in organ failure. The Tongji prognostic predictor model score (TPPMs), which set the number of complications as one of the determinants, showed comparable or superior ability to the Chinese Group on the Study of Severe Hepatitis B-ACLF score (COSSH-ACLFs), APASL-ACLF Research Consortium score (AARC-ACLFs), CLIF-C organ failure score (CLIF-C OFs), CLIF-C-ACLF score (CLIF-C-ACLFs), Model for End-Stage Liver Disease score (MELDs) and MELD-sodium score (MELD-Nas) in HBV-ACLF patients, especially in cirrhotic HBV--ACLF patients. Patients with two (OR 4.70, 1.88) or three (OR 8.27, 2.65) complications had a significantly higher risk of 28- or 90-day mortality, respectively. CONCLUSION: The presence of complications is a major risk factor for mortality in HBV-ACLF patients. TPPM possesses high predictive ability in HBV-ACLF patients, especially in cirrhotic HBV-ACLF patients.