Chronic hepatitis B (CHB) infection leads to progressive dysfunction and exhaustion of antiviral immune cells, which is a primary obstacle to clinical cure. Although the phenotypic hallmarks of exhausted T cells are well described, the hierarchical trajectory, subset-specific heterogeneity, and underlying mechanisms of exhaustion across the full spectrum of immune cells in the unique hepatic microenvironment remain poorly defined. This review provides a comprehensive and critical synthesis of recent advances in immune exhaustion during CHB. We delineate the common and distinct exhaustion programs among T, B, and natural killer cells, highlighting the pivotal roles of transcription factors and metabolic dysregulation. Furthermore, we critically evaluate the limitations of current evidence and pinpoint critical knowledge gaps, such as the heterogeneity of non-classical exhausted subsets and the liver-resident immune compartment. By framing these findings within a critical and comparative context, this review not only updates our understanding of immune exhaustion but also proposes a roadmap for developing more precise immunotherapies aimed at achieving a functional cure for CHB.

As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

BACKGROUND:The profiles of hepatitis B virus (HBV) integration related to hepatitis B surface antigen (HBsAg) loss remain largely unknown. AIMS:We aimed to delineate the patterns of HBV integration in virally suppressed chronic hepatitis B (CHB) patients and their association with HBsAg loss following antiviral therapy. METHODS:Forty-five patients with paired liver biopsies were randomly selected from the Anchor study for high-throughput viral integration detection. The primary endpoint was HBsAg loss at Week 96. In Group II (pegylated interferon alpha-2b & entecavir), 13 patients achieved HBsAg loss, whereas all patients in Group I (entecavir monotherapy) and 17 in Group II failed to achieve HBsAg loss. RESULTS:At baseline, the level of clonal expansion was positively correlated with the duration of nucleos(t)ide analogue (NUC) treatment, the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, whereas no association was observed with the HBsAg, hepatitis B core-related antigen (HBcrAg), HBV RNA or covalently closed circular DNA (cccDNA) levels. Patients with less than 28 breakpoint types achieved a significantly higher rate of HBsAg loss following Peg-IFN-based therapy at Week 48 and 96, compared to those with more than 28. CONCLUSIONS:The duration of NUC treatment, as well as ALT and AST levels, were associated with the level of clonal expansion in virally-suppressed patients. A lower number of breakpoint types at baseline may be related to a higher HBsAg loss rate following Peg-IFN-based treatment and serve as a useful marker in guiding treatment decision-making (NCT02327416). TRIAL REGISTRATION:The Anchor study is registered at ClinicalTrials.gov, NCT02327416.

Functional cure is considered the advanced treatment goal for patients with chronic hepatitis B (CHB). We aimed to evaluate hepatitis B surface antigen (HBsAg) loss rates after combination treatment of entecavir (ETV) and peginterferon alfa-2b (Peg-IFN) with or without granulocyte–macrophage colony-stimulating factor (GM-CSF). In this randomized controlled trial, virally suppressed patients undergoing nucleos(t)ide analogs with HBsAg < 3000 IU/mL were randomized 1:1:1 to receive either ETV for 96 weeks (E group), or 48 weeks of Peg-IFN + ETV, followed by 48-week Peg-IFN alone (EP group), or 48 weeks of Peg-IFN + ETV + GM-CSF, followed by 48-week Peg-IFN alone (EPG group). The primary outcome is HBsAg loss at week 96. Among 249 patients (81 in E group, 83 in EP group and 85 in EPG group), EP group (30.12

Background & aims: With a drastic increase in the number of chronic hepatitis B (CHB) patients with coexisting nonalcoholic fatty liver disease (NAFLD), there is an urgent need to evaluate antiviral treatment effects in this special population. Methods: CHB patients with hepatic steatosis (CHB + HS) were prospectively recruited with followed-up of 3 years. HS and liver fibrosis were assessed by transient elastography. HS was defined as controlled attenuation parameter (CAP) ≥248 dB/m, and fibrosis progression was defined with ≥1-stage fibrosis increment. Multivariate and propensity score matching (PSM) analysis were used to evaluate antiviral therapy effects on fibrosis progression. Results: In total 212 recruited CHB + HS patients (median age 36 years, median ALT 59 U/L), 49.1% (104/212) received antiviral therapy and 50.9% (108/212) did not. Among patients with antiviral therapy, rates of serum HBV DNA undetectable, HBeAg and HBsAg loss, and ALT normalization at year 3 were 88.5%, 31.0%, 8.7% and 70.2%, respectively. Patients with mild-moderate HS didn't differ patients with severe HS regarding biochemical and virological responses. Antiviral therapy was independently associated with a lower risk of fibrosis progression among the entire cohort (odds ratio 0.473, 95% CI 0.245–0.911, P = 0.025). This finding was further verified by PSM analysis. When stratified by the severity of HS, the antiviral therapy benefits in reducing fibrosis progression were mainly seen in patients with mild-moderate HS. Conclusions: Among CHB + HS patients, long-term antiviral treatment effectively inhibits HBV replication and reduces fibrosis progression. Our findings have implications for the optimal management of this population.

Background: The burden of nonalcoholic fatty liver disease (NAFLD) is growing in patients with chronic hepatitis B (CHB). NAFLD is typically associated with obesity, however, it is increasingly being identified in non-obese patients. This study aimed to investigate disease severity and antiviral response in non-obese patients with CHB with NAFLD (CHB + NAFLD). Methods: A total of 809 patients with CHB + NAFLD were prospectively recruited and followed up for 3 years. NAFLD was diagnosed by transient elastography and defined as controlled attenuation parameter >= 248 dB/m, in the absence of excessive alcohol intake. Obesity status was defined by the Asian body mass index (BMI) cutoff of 25 kg/m(2). Metabolic abnormality was defined by the presence of dyslipidemia, hypertension or diabetes. Fibrosis staging was defined according to the EASL-ALEH guidelines, with fibrosis progression defined as >= 1-stage increment. Results: In the total cohort (median age 40 years, 59.0% antiviral-treated), 33.3% were non-obese. Non-obese patients were less metabolically abnormal than obese patients (60.2% vs 72.0%, P = 0.003). After 3-year follow up, the rate of fibrosis progression was comparable between non-obese and obese patients (17.5% vs 21.9% in the total cohort, P = 0.145; 15.7% vs 14.6% in antiviral-treated cohort with persistent viral suppression, P = 0.795). No significant differences in virological and biochemical responses were observed between non-obese and obese patients (P >0.05 for all). Conclusion: Approximately one third of CHB + NAFLD patients were non-obese. Non-obese patients, while less metabolically abnormal, had a similar risk for fibrosis progression as obese patients. Obesity status did not impact the efficiency of antiviral therapy.

目的:针对核苷经治的慢性乙型肝炎(CHB)患者,采用恩替卡韦(ETV)和聚乙二醇干扰素α-2b(Peg-IFNα-2b)联合序贯的抗病毒治疗方法,分析96周治疗结束时获得临床治愈的CHB患者的临床和病毒学特征.方法:采用多中心前瞻性研究,将122例CHB核苷经治患者,采用恩替卡韦联合聚乙二醇干扰素α-2b联合序贯治疗96周,治疗结束时根据临床疗效分为临床治愈组和非临床治愈组.比较两组患者在96周时HBsAg定量、HBeAg定量、HBV DNA定量、HBV RNA定量的差异.结果:96周治疗结束时,122例使用恩替卡韦和聚乙二醇干扰素α-2b联合序贯治疗的患者,均实现病毒学应答[即转氨酶正常,HBV DNA持续低于检测下限(＜20 IU/ml)],43例患者实现临床治愈,临床治愈率达35.25％.临床治愈组与非临床治愈组在24周(P＜0.001)、48周(P＜0.001)、72周(P＜0.001)及96周(P＜0.001)的HBsAg定量均有显著差异.临床治愈组患者0～24周内HBsAg下降幅度明显高于非临床治愈组患者(2.379 vs 0.715 log 10 IU/ml,P＜0.001).96周时,临床治愈组HBV RNA定量水平显著低于非临床治愈组[(4.229±1.26)vs(4.906±0.93)log10 copies/ml,P=0.010].结论:恩替卡韦和聚乙二醇干扰素联合序贯治疗可显著降低HBV病毒复制水平,提高CHB患者临床治愈率.

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

多发性骨髓瘤(multiple myeloma,MM)继发系统性淀粉样变性(AL amyloidosis),AL型淀粉样变性患者早期表现隐匿,临床上难以识别及诊断.以硼替佐米为代表的蛋白酶抑制剂联合CD38单抗[达雷妥尤单抗,Daratumumab(DARA)]化疗可效清除患者体内异常浆细胞,降低轻链含量,为后期自体造血干细胞移植奠定基础.华中科技大学同济医学院附属同济医院收治1例MM合并AL型淀粉样变性患者,治疗效果良好,报道如下并进行文献复习.

BACKGROUND & AIMS:Fulminant viral hepatitis (FVH) is a life-threatening disease, but its pathogenesis is not fully understood. Neutrophil extracellular traps (NETs) were an unrecognized link between inflammation and coagulation, which are 2 main features of FVH. Here, we investigated the role and mechanism of NETs in the pathogenesis of FVH.METHODS:A mouse model of FVH was established by murine hepatitis virus strain-3 infection. Liver leukocytes of infected or uninfected mice were used for single-cell RNA sequencing and whole-transcriptome sequencing. NETs depletion was achieved using DNase 1. Acetaminophen was used to establish a mouse model of non-virus-caused acute liver failure. Clinically, NETs-related markers in liver, plasma, and peripheral neutrophils were assessed in patients with hepatitis B virus (HBV)-related acute liver injury.RESULTS:Increased hepatic NETs formation was observed in murine hepatitis virus strain-3-infected mice, but not in acetaminophen-treated mice. NETs depletion improved the liver damage and survival rate in FVH by inhibiting hepatic fibrin deposition and inflammation. An adoptive transfer experiment showed that neutrophil-specific fibrinogen-like protein 2 (FGL2) promoted NETs formation. FGL2 was found to directly interact with mucolipin 3, which regulated calcium influx and initiated autophagy, leading to NETs formation. Clinically, increased plasma NETs level was associated with coagulation dysfunction in patients with HBV acute liver injury. Colocalization of FGL2, NETs, and fibrin in liver was observed in these patients.CONCLUSIONS:NETs aggravated liver injury in FVH by promoting fibrin deposition and inflammation. NETs formation was regulated by the FGL2-mucolipin 3-autophagy axis. Targeting NETs may provide a new strategy for the treatment of FVH.

Abstract Background Follow-up study of coronavirus disease 2019 (COVID-19) survivors has rarely been reported. We aimed to investigate longitudinal changes in the characteristics of COVID-19 survivors after discharge. Methods A total of 594 COVID-19 survivors discharged from Tongji Hospital in Wuhan from February 10 to April 30, 2020 were included and followed up until May 17, 2021. Laboratory and radiological findings, pulmonary function tests, electrocardiogram, symptoms and signs were analyzed. Results 257 (51.2%) patients had at least one symptom at 3 months post-discharge, which decreased to 169 (40.0%) and 138 (28.4%) at 6-month and 12-month visit respectively. During follow-up period, insomnia, chest tightness, and fatigue were the most prevalent symptoms. Most laboratory parameters returned to normal, whereas increased incidence of abnormal liver and renal function and cardiovascular injury was evidenced after discharge. Fibrous stripes (213; 42.4%), pleural thickening and adhesions (188; 37.5%) and enlarged lymph nodes (120; 23.9%) were the most common radiographical findings at 3 months post-discharge. The abnormalities of pulmonary function included obstructive, restrictive, and mixed, which were 5.5%, 4.0%, 0.9% at 6 months post, and 1.9%, 4.7%, 0.2% at 12 months. Electrocardiogram abnormalities occurred in 256 (51.0%) patients at 3 months post-discharge, including arrhythmia, ST-T change and conduction block, which increased to 258 (61.1%) cases at 6-month visit and were maintained at high frequency (242;49.8%) at 12-month visit. Conclusions Physiological, laboratory, radiological, or electrocardiogram abnormalities, particularly those related to renal, cardiovascular, and liver functions are common in patients who recovered from coronavirus disease 2019 (COVID-19) up to 12 months post-discharge.

Evidence suggests that interferon alpha (IFNα) plays an essential role in decreasing the HBsAg quantification and elevating the rate of clinical cure in chronic hepatitis B (CHB). However, the mechanisms underlying the effects of the exosomes on the expression of host genes in IFNα treatment remain unclear.CHB patients with IFNα treatment were divided into responders and non-responders according to the degree of HBsAg decline. Through microRNA sequencing and a series of molecular biology methods, the key microRNAs in serum exosomes associated with clinical antiviral response of Peg-IFNα treatment in nucleotide analogue-treated CHB patients were investigated. The roles of exosomal miRNAs on the IFNα signal pathway were explored in macrophages.MicroRNA sequencing and RT-qPCR assays confirmed six distinctly declined miRNAs in serum exosomes of responders at week 12 compared with levels at baseline. Exosomes with declined miR27b-3p in the serum of Peg-IFNα-treated responders activated phosphorylation of interferon regulatory factor 3/7 (IRF3/7) in IFNα synthesis pathway in macrophages. However, miR27b-3p overexpression in HepAD38 cells suppressed IFNα synthesis in macrophages, resulting in insufficient ability to eliminate HBV, whereas the inhibitory effect could be blocked by inhibitors of exosomes release. Luciferase assay showed miR-27b-3p directly suppressed retinoic acid-inducible gene I (RIG-I) and TANK-binding kinase 1 (TBK1) expressions, and these effects could be abrogated in mutation experiments.In IFNα treatment, exosomes with declined miR-27b-3p triggered activation of RIG-I/TBK1 signalling in macrophages against HBV. Serum exosomal miR-27-3p might represent a potential biomarker for patients with CHB.

Recently, more and more attention has been paid on adult hemophagocytic lymphohistiocytosis (HLH), a disease with complicated symptoms and high mortality. In order to analyze the clinical characteristics and prediction risk factors of mortality, we designed a retrospective study with 1-year follow-up and included 155 patients admitted to Tongji Hospital diagnosed as HLH. One hundred seven patients formed the training cohort for nomogram development, and 48 patients formed the validation cohort to confirm the model’s performance. All patients’ clinical characteristics, laboratory results, medical records, and prognosis were analyzed. Among all the 107 patients in the training cohort, 46 were male and 61 were female, with the median age of 49.0 (IQR 31.0–63.0). The 1-year mortality rate was 43.9% (47/107) and 45.8% (22/48) in the training and validation cohort, respectively. And further multivariate logistic regression analysis in the training cohort showed that male (odds ratio 5.534, 95% CI 1.507–20.318, p = 0.010), altered mental status (11.876, 1.882–74.947, p = 0.008), serum ferritin ≥ 31,381 μg/L (8.273, 1.855–36.883, p = 0.006), and IL-6 ≥ 18.59 pg/mL (19.446, 1.527–247.642, p = 0.022) were independent risk factor of mortality. A nomogram included the four prediction factors mentioned above was also tabled to help clinicians evaluate the probability of poor outcome. Area under the receiver operating characteristic curve (AUROC) analysis, calibration curves, and decision curve analysis (DCA) certify the accuracy and the clinical usefulness of the nomogram. Our research reveals that male, altered mental status, serum ferritin ≥ 31,381 µg/L, and IL-6 ≥ 18.59 pg/mL are four independent predictors for poor prognosis. Doctors should pay more attention to patients with altered mental status, high serum ferritin, and IL-6 level, who have a higher risk of death.