Expert Consensus on the Prevention and Treatment of Chronic Hepatitis B in Children

The aim of this consensus is to standardize the prevention, diagnosis, and treatment of chronic hepatitis B in children and to achieve the goal of “eliminating viral hepatitis as a major public health threat by 2030” issued by the World Health Organization. Formulated by organized experts of the Chinese Society of Infectious Diseases and Chinese Society of Hepatology, Chinese Medical Association;Group of Infectious Diseases, Chinese Pediatric Society, Chinese Medical Association;and the National Clinical Research Center for Infectious Diseases (Beijing), the consensus provides the latest evidence and recommendations for the prevention, diagnosis, and treatment of chronic hepatitis B in children.

Safety,immunogenicity and protective effect of sequential vaccination with inactivated and recombinant protein COVID-19 vaccine in the elderly:a prospective longitudinal study

The safety and efficacy of COVID-19 vaccines in the elderly,a high-risk group for severe COVID-19 infection,have not been fully understood.To clarify these issues,this prospective study followed up 157 elderly and 73 young participants for 16 months and compared the safety,immunogenicity,and efficacy of two doses of the inactivated vaccine BBIBP-CorV followed by a booster dose of the recombinant protein vaccine ZF2001.The results showed that this vaccination protocol was safe and tolerable in the elderly.After administering two doses of the BBIBP-CorV,the positivity rates and titers of neutralizing and anti-RBD antibodies in the elderly were significantly lower than those in the young individuals.After the ZF2001 booster dose,the antibody-positive rates in the elderly were comparable to those in the young;however,the antibody titers remained lower.Gender,age,and underlying diseases were independently associated with vaccine immunogenicity in elderly individuals.The pseudovirus neutralization assay showed that,compared with those after receiving two doses of BBIBP-CorV priming,some participants obtained immunological protection against BA.5 and BF.7 after receiving the ZF2001 booster.Breakthrough infection symptoms last longer in the infected elderly and pre-infection antibody titers were negatively associated with the severity of post-infection symptoms.The antibody levels in the elderly increased significantly after breakthrough infection but were still lower than those in the young.Our data suggest that multiple booster vaccinations at short intervals to maintain high antibody levels may be an effective strategy for protecting the elderly against COVID-19.

Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients

B cells play an important role in the clearance of hepatitis B virus （HBV） and protection against reinfection. However, the functional characteristics of these cells that are associated with the outcome of chronic HBV infection remain unknown. We comprehensively investigated the frequency, phenotype, and function of peripheral B-cell subsets from CHB patients in different phases： immune tolerance （IT）, immune activation （IA）, immune clearance （IC）, responders with HBsAg seroconversion （resolved patients, RP）, and healthy controls （HC）. IA patients displayed lower percentages of peripheral blood memory B cells compared with the other groups. Overall polyclonal activation of B cells, indicated by higher levels of activation markers and secretion of IgG and IgM, was observed in IA patients. This B-cell hyperactivation could be induced by increased IFN-a and soluble CD40 ligands in IA patients. Notably, the expression of the co-stimulator molecule CD80 and serum HBsAb and the frequency of HBsAg-specific B cells were significantly decreased in IT, IA, and IC patients compared with HC subjects. More importantly, the B-cell hyperactivation, co-stimulatory molecule downregulation and HBsAg-specific B-cell impairment were reversed in RP patients. The reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients.

基于血清学指标的联合模型诊断代偿期肝硬化轻微型肝性脑病的价值

目的探讨血清学指标对代偿期肝硬化轻微型肝性脑病(MHE)的诊断价值,构建基于血清学指标的联合模型并评估其对MHE的诊断价值。方法前瞻性、多中心研究。选取2021年10月至2022年8月来自我国15个省(自治区、直辖市)的23家医院就诊的代偿期肝硬化患者263例。收集患者临床资料及实验室检查结果,并计算终末期肝病模型(MELD)评分。使用基线血氨测量值/正常参考值上限(AMM-ULN)集中校正各中心血氨测量结果,以我国《肝硬化肝性脑病诊疗指南》标准,数字连接试验-A、数字符号试验均异常作为诊断MHE的标准。基于R语言caret包将患者随机(7∶3)分为训练集(n=185)和验证集(n=78)。通过Logistic回归构建诊断MHE的联合模型;受试者工作特征曲线下面积(AUC)、Hosmer-Lemeshow拟合优度检验及校准曲线图评估诊断性能,并用Bootstrap法(n=200)进行内部验证;Delong检验比较AUC之间的差异。结果训练集中,MHE占37.8%(70/185),MHE组AMM-ULN、白蛋白、血小板、碱性磷酸酶、国际标准化比值、终末期肝病模型评分以及教育年限与无MHE组比较,差异有统计学意义(P均<0.05)。多因素Logistic回归分析显示,AMM-ULN(OR=1.78,95%CI 1.05~3.14,P=0.038)和MELD评分(OR=1.11,95%CI 1.04~1.20,P=0.002)是MHE的独立危险因素,AUC分别为0.663和0.625。联合AMM-ULN、MELD评分和教育年限的联合模型诊断MHE的AUC为0.755,特异度和敏感度分别为85.2%和55.7%。Hosmer-Lemeshow拟合优度检验表明模型具有较好的校准度(P=0.733),联合模型内部验证AUC为0.752。Delong检验显示联合模型诊断效能优于单独使用血氨(P=0.020)和MELD评分(P=0.003)。验证集中,联合模型诊断MHE的AUC为0.794,Hosmer-Lemeshow拟合优度检验显示有较好的校准度(P=0.841)。结论基于AMM-ULN、MELD评分和教育年限的联合模型可提高对MHE的诊断价值。

Clinical Epidemiology,Illness Profiles,and the Implication of COVID-19 Before and After the Nationwide Omicron Outbreak During the Winter of 2022

China.In this study,we aimed to investigate the clinical characteristics and outcomes of patients with coronavirus disease 2019(COVID-19)in the Beijing region.Methods:In this retrospective study,we enrolled inpatients admitted for COVID-19 in the Fifth Medical Center of Chinese PLA General Hospital in Beijing between November 10,2022,and January 30,2023.Demographic and clinical features and treatment outcomeswere comprehensively analyzed.We used logistic regression and linear regression analyses to explore the risk factors associated with disease severity and time of nucleic acid conversion,respectively.Results:A total of 1010 hospitalized patients with COVID-19 were enrolled.The median age was 43.0 years(interquartile range,28.0–63.0),and patients aged<60 years and≥60 years comprised 71.2%and 28.8%of total included patients,respectively.The clinical classification of mild(74.6%,753/1010),moderate(21.0%,212/1010),severe(2.7%,27/1010),and unidentified(1.8%,18/1010)was separately recorded;1005 patients were discharged,and 5 patients died in the hospital.The outbreak of the emerging epidemic witnessed an evident increase in the proportion of moderate(42.9%vs.16.4%)and severe(10.3%vs.1.1%)cases after December 7,2022.Patients with a moderate/severe classification had higher levels of procalcitonin,IL-6,serum ferritin,C-reactive protein,lactic dehydrogenase,serum urea nitrogen,and D-dimer and lower counts of CD4+T,CD8+T,and B cells(all P<0.001).Multivariable regression analysis revealed that increased odds of disease severity were associated with the following factors:age≥60 years,IL-6>7 pg/mL,lactic dehydrogenase level>245 U/L,cough,and fever at admission.Age≥80 years and chronic lung diseasewere independent risk factors in the nonmild group in elderly patients.In addition,the duration for nucleic acid to turn negativewas approximately 5.0 d(interquartile range,3.0–7.0).Prolonged time of nucleic acid conversion was associated with age≥60 years,serum urea nitrogen level>8.2 mmol/L,neutrophil count>7×10^(9)/L,and the presence of a chronic lung disease or carcinoma.Finally,unvaccinated patients accounted for 37.3%of enrolled patients;children and the elder people accounted for approximately half of that.The univariable analysis found that booster doses reduced disease severity and shortened the time of nucleic acid conversion in elderly patients.Conclusions:The outbreak ofOmicron rapidly increased the number of patientswith COVID-19 in Beijing.In elderly patients,booster doses may reduce disease severity and shorten the time of nucleic acid conversion.Healthcare systems should be optimized before an emerging epidemic outbreak.

Prevalence and risk factors for minimal hepatic encephalopathy in cirrhotic patients with different etiologies

Aims:Minimal hepatic encephalopathy(MHE)significantly affects the prognosis of patients with cirrhosis.This study was performed to determine whether there is a difference in the prevalence of MHE among patients with cirrhosis of different etiologies and whether the etiology directly influences the occurrence of MHE.Methods:This multicenter,cross-sectional study enrolled 1879 patients with confirmed cirrhosis at 40 hospitals from October 25,2021,to January 10,2023(Trial registration:https://clinicaltrials.gov/[NCT05140837]).The patients'demographics,etiologies of cirrhosis,and laboratory test results were collected.The psychometric hepatic encephalopathy score(PHES)was determined in all patients to screen for MHE.Multivariate logistic analyses were performed to identify the risk factors for MHE.Results:In total,736 patients with cirrhosis were analyzed.The prevalence of MHE was 42.0%(n=309).The primary etiology among all patients was hepatitis B virus(HBV)-related cirrhosis(71.9%[529/736]).The prevalence of MHE was significantly higher in patients with alcoholic cirrhosis(57.1%[40/70])than in those with HBV-related cirrhosis(40.6%[215/529],p=0.009)or hepatitis C virus(HCV)-related cirrhosis(38.2%[26/68],p=0.026).Age(odds ratio[OR],1.042;95%confidence interval[CI],1.024-1.059;p<0.001),duration of education(OR,0.935;95%CI,0.899-0.971;p=0.001),etiology(OR,1.740;95%CI,1.028-2.945;p=0.039),and high MELD-Na scores(OR,1.038;95%CI,1.009-1.067;p=0.009)were independent risk factors for MHE.When patients with cirrhosis of different etiologies were analyzed separately,the results showed that age(OR,1.035;95%CI,1.014-1.057;p=0.001)and duration of education(OR,0.924;95%CI,0.883-0.966;p=0.001)were risk factors for MHE among patients with HBV-related cirrhosis,whereas age(OR,1.138;95%CI,1.033-1.254;p=0.009)and creatinine concentration(OR,16.487;95%CI,1.113-244.160;p=0.042)were risk factors for MHE in patients with HCV-related cirrhosis.No risk factors for MHE were found in patients with autoimmune cirrhosis.For patients with alcoholic cirrhosis,the platelet count(OR,1.014;95%CI,1.000-1.027;p=0.045)was a risk factor for MHE.The PHES subtest results were inconsistent among patients who had MHE with cirrhosis of different etiologies.Patients with HBV-related cirrhosis performed better on Number Connection Test B and the serial dotting test than those with alcoholic cirrhosis(p=0.007 and p<0.001),better on Number Connection Test B than those with HCV-related cirrhosis(p=0.020),and better on the line tracing test than those with autoimmune cirrhosis(p=0.037).Conclusion:The etiology of cirrhosis affected the prevalence of MHE and risk factors for MHE.The domains of major cognitive impairment varied among patients with cirrhosis of different etiologies.Further studies are required to verify these findings.

Effect of Methylprednisolone on Mortality and Clinical Courses in Patients with Severe CoVID-19: A Propensity Score Matching Analysis

Background Whether methylprednisolone therapy can reduce the mortality rate of patients with severe coronavirus disease 2019(COVID-19)remains controversial,and its effects on the length of hospital stay and virus shedding time are also unknown.This retrospective study investigates the previous issues to provide more evidence for methylprednisolone treatment in severe COVID-19.Methods This retrospective study included 563 of 4827 patients with confirmed COVID-19 admitted to Wuhan Huoshenshan Hospital or Wuhan Guanggu Hospital between February 3,2020 and March 30,2020 who met the screening criteria.The participants’epidemiological and demographic data,comorbidities,laboratory test results,treatments,outcomes,and vital clinical time points were extracted from electronic medical records.The primary outcome was in-hospital death,and the secondary outcomes were 2 clinical courses:length from admission to viral clearance and discharge.Univariate and multivariate logistic or linear regression analyses were used to assess the role of methylprednisolone in different outcomes.Propensity score matching was performed to control for confounding factors.Results Of the 563 patients who met the screening criteria and were included in the subsequent analysis,138 were included in the methylprednisolone group and 425 in the nonmethylprednisolone group.The in-hospital death rate between the methylprednisolone and nonmethylprednisolone groups showed a significant difference(23.91%vs.1.65%,P<0.001),which was maintained after propensity score matching(13.98%vs.5.38%,P=0.048).However,univariate logistic analysis in the matched groups showed that methylprednisolone treatment(odds ratio[OR],5.242;95%confidence interval[CI],0.802 to 34.246;P=0.084)was not a risk factor for in-hospital death in severe patients.Further multivariate logistic regression analysis found comorbidities(OR,3.327;95%CI,1.702 to 6.501;P<0.001),lower lymphocyte count(OR,0.076;95%CI,0.012 to 0.461;P=0.005),higher lactate dehydrogenase(LDH)levels(OR,1.008;95%CI,1.003 to 1.013;P=0.002),and anticoagulation therapy(OR,11.187;95%CI,2.459 to 50.900;P=0.002)were associated with in-hospital mortality.Multivariate linear regression analysis in the matched groups showed that methylprednisolone treatment was not a risk factor for a prolonged duration from admission to viral clearance(βValue 0.081;95%CI,−1.012 to 3.657;P=0.265)or discharge(βValue 0.114;95%CI,−0.723 to 6.408;P=0.117).d-dimer(βValue,0.144;95%CI,0.012 to 0.817;P=0.044),LDH(βValue 0.260;95%CI,0.010 to 0.034;P<0.001),and antiviral therapy(βValue 0.220;95%CI,1.373 to 6.263;P=0.002)were associated with a longer length from admission to viral clearance.The lymphocyte count(βValue−0.206;95%CI,−6.248 to−1.197;P=0.004),LDH(βValue 0.231;95%CI,0.012 to 0.048;P=0.001),antiviral therapy(βValue 0.143;95%CI,0.058 to 7.497;P=0.047),and antibacterial therapy(βValue 0.152;95%CI,0.133 to 8.154;P=0.043)were associated with a longer hospitalization duration from admission to discharge.Further stratified analysis revealed that the low daily dose group(≤60 mg/d)and the low total dose group(≤200 mg)had shorter duration from admission to viral clearance(Z=−2.362,P=0.018;Z=−2.010,P=0.044)and a shorter hospital stay(Z=−2.735,P=0.006;Z=−3.858,P<0.001).Conclusions In patients with severe COVID-19,methylprednisolone is safe and does not prolong the duration from admission to viral clearance or discharge.Low-dose,short-term methylprednisolone treatment may be more beneficial in shortening the disease course.

Meta-analysis of the immunogenicity of standard and booster SARS-CoV-2 vaccination in patients with chronic liver disease and post-liver transplantation

Aims:Patients with liver disease may exhibit higher infection rates and mortality rates from coronavirus disease 2019(COVID-19)than healthy individuals,and vaccination against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is an effective prevention strategy.This metaanalysis aimed to assess the effectiveness and safety of SARS-CoV-2 vaccines in patients with chronic liver disease(CLD)and post-liver transplantation(LT).Methods:The PubMed,Embase,and Cochrane databases were searched.A random-effects model meta-analysis was used to determine the seropositivity rates of SARS-CoV-2 antibodies,odds ratio(OR)compared with healthy controls(HC),risk ratio(RR)between the booster and standard vaccination regimen,and the rate of adverse reactions(ADR).Results:In the standard vaccination regimen analysis,17 controlled articles were included for effectiveness analysis,and six articles for ADR analysis.The pooled seropositivity rates of SARS-CoV-2 antibodies in patients with CLD and post-LT were 93.3%(95%confidence interval[CI]:89.0%-97.6%)and 69.1%(95%CI:63.0%-75.3%),respectively.Both rates were lower than those in HC(p<0.001).The differences remained significant after sorting by detection interval,vaccine type,antibody type,or CLD type.LT recipients showed much lower seropositivity rates of antibodies than patients with CLD(69.1%vs.93.3%)or HC(OR:0.055).The pooled total ADR rate of patients was 24.0%(95%CI:16.2%-31.8%).In the booster vaccination regimen analysis,11 prospective studies were enrolled,and the seropositivity rates of antibodies after the booster dose were increased by 27%compared with those of the standard vaccination regimen(RR:1.27,95%CI:1.15-1.41,p<0.001).Conclusion:Patients with CLD and post-LT can gain protection against COVID-19 from standard vaccines,demonstrating a potentially weaker immunogenic response than HC.Booster vaccines can compensate for this deficiency.Therefore,patients with CLD and post-LT should be prioritized for receiving the COVID-19 booster vaccine.

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19:a phase 1 clinical trial

No effective drug treatments are available for coronavirus disease 2019(COVID-19).Host-directed therapies targeting the underlying aberrant immune responses leading to pulmonary tissue damage,death,or long-term functional disability in survivors require clinical evaluation.We performed a parallel assigned controlled,non-randomized,phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells(UC-MSCs)infusions in the treatment of patients with moderate and severe COVID-19 pulmonary disease.The study enrolled 18 hospitalized patients with COVID-19(n=9 for each group).The treatment group received three cycles of intravenous infusion of UC-MSCs(3×107 cells per infusion)on days 0,3,and 6.Both groups received standard COVID-treatment regimens.Adverse events,duration of clinical symptoms,laboratory parameters,length of hospitalization,serial chest computed tomography(CT)images,the PaO2/FiO2 ratio,dynamics of cytokines,and IgG and IgM anti-SARS-CoV-2 antibodies were analyzed.No serious UC-MSCs infusion-associated adverse events were observed.Two patients receiving UC-MSCs developed transient facial flushing and fever,and one patient developed transient hypoxia at 12 h post UC-MSCs transfusion.Mechanical ventilation was required in one patient in the treatment group compared with four in the control group.All patients recovered and were discharged.Our data show that intravenous UC-MSCs infusion in patients with moderate and severe COVID-19 is safe and well tolerated.Phase 2/3 randomized,controlled,double-blinded trials with long-term follow-up are needed to evaluate the therapeutic use of UC-MSCs to reduce deaths and improve long-term treatment outcomes in patients with serious COVID-19.

Effect of methylprednisolone therapy on hospital stay and viral clearance in patients with moderate COVID-19

Background:The benefits and harms of methylprednisolone treatment in patients with moderate coronavirus disease 2019(COVID-19)remain controversial.In this study,we investigated the effect of methylprednisolone on mortality rate,viral clearance,and hospitalization stay in patients with moderate COVID-19.Methods:This retrospective study included 4827 patients admitted to Wuhan Huoshenshan and Wuhan Guanggu hospitals from February to March 2020 diagnosed with COVID-19 pneumonia.The participants’epidemiological and demographic data,comorbidities,laboratory test results,treatments,outcomes,and vital clinical time points were extracted from electronic medical records.The primary outcome was in-hospital death;secondary outcomes were time from admission to viral clearance and hospital stay.Univariate and multivariate logistic or linear regression analysis were used to assess the roles of methylprednisolone in different outcomes.The propensity score matching(PSM)method was used to control for confounding factors.Results:A total of 1320 patients were included in this study,of whom 100 received methylprednisolone.Overall,in-hospital mortality was 0.91%(12/1320);the 12 patients who died were all in the methylprednisolone group,though multivariate logistic regression analysis showed methylprednisolone treatment was not a risk factor for in-hospital death in moderate patients before or after adjustment for confounders by PSM.Methylprednisolone treatment was correlated with longer length from admission to viral clearance time and hospital stay before and after adjustment for confounders.Conclusions:Methylprednisolone therapy was not associated with increased in-hospital mortality but with delayed viral clearance and extended hospital stay in moderate COVID-19 patients.

Legionella sainthelensi Pneumonia with Abdominal Symptoms as Prominent Manifestations:A Case Report

Fewstudies have reported Legionella sainthelensi infection.This infection primarily presents with respiratorymanifestations.Here,we report an immunocompromised patient with cavitary pneumonia caused by L.sainthelensi who mainly had abdominal symptoms.The timely administration of moxifloxacin provided clinical improvement and resolution of symptoms.To our knowledge,this is one of the rare cases of L.sainthelensi infection presenting uniquelywith abdominal distension and liver function impairment butwithout obvious respiratory symptoms.