Gene heterogeneity of hepatitis B virus isolates from patients with severe hepatitis B

BACKGROUND: The pathogenesis of severe hepatitis B remains unknown. Reports have indicated that hepatitis B virus (HBV) mutations are important factors in the pathogenesis of this disease. This study was to investigate the genetic heterogeneity of HBV strains from serum samples of patients with fulminant hepatitis B. METHODS: Full-length HBV genomes from 4 patients with severe hepatitis B were cloned and sequenced to observe mutations in every open reading-frame ( ORF). Serum samples of another 25 patients with severe hepatitis B, 30 patients with chronic hepatitis B, and 25 HBV carriers were collected for sequencing and comparison of mutations in preS2, preC and core promoter regions. RESULTS: Of 4 HBV full-length genome sequences, 3 had a G to A mutation at nucleotide A1896 in the preC region and 1 had double mutations of T1762-A1764 in the core promoter region. The 4 sequences showed mutations in the known B or T cell epitopes of the preS2 and C regions. For the other 3 groups, more mutations were seen in the preS2 region in the HBV isolates from the patients with severe hepatitis B than those from the patients with chronic hepatitis B and HBV carriers (P <0.01). There was a significant difference of mutations in the T cell epitope region of preS2 between the patients with severe hepatitis B and those with chronic hepatitis B or HBV carriers (P <0.01). In the preC and core promoter regions, the mutation frequencies of T1653 and C1753 were 48.0% and 24.0% respectively in the patients with severe hepatitis B, but none of these mutations were observed in the patients with chronic hepatitis B group or HBV carriers (P <0.01). The mutation frequency of T1762-A1764 was 76.0% in the patients with severe hepatitis B, 40.0% in the patients with chronic hepatitis B (P <0. 01) , and 16. 0% in the HBV carriers ( P < 0. 01). There was a significant difference in A1896 mutation between the patients with severe hepatitis B and the patients with chronic hepatitis B (P < 0. 05 ) or the HBV carriers (P<0.05). CONCLUSION: Our observations suggest that the accumulation and persistence of high frequency mutations or complex mutations may be associated with the development and deterioration of HBV infection.

Short-term entecavir therapy of chronic severe hepatitis B

BACKGROUND: Chronic severe hepatitis B patients often have limited survival. This investigation aimed to evaluate the short-term effects of nucleoside analog therapy on chronic severe hepatitis B. METHODS: We retrospectively, randomly collected the data of 129 chronic severe hepatitis B patients: 55 were treated with entecavir, and the remaining 74 were not treated with nucleoside analogues. RESULTS: No significant difference in short-term survival rate was found between the group treated with entecavir and that treated without nucleoside analogues. Although entecavir greatly reduced HBV replication in different periods of therapy (P<0.001), the model for end-stage liver disease (MELD) score and liver function (alanine aminotransferase, albumin, bilirubin, prothrombin time) showed no significant change. No significant differences were found in MELD scores and liver function in patients with different HBV DNA levels (<= 10(4) copies/ml, >10(4) to <10(6) copies/ml, >= 10(6) copies/ml). Nor correlation was observed between HBV DNA levels and MELD scores in different periods of therapy (P>0.05). The HBV DNA levels of patients who survived for over 3 months or less than 3 months were not significantly different either. However, the MELD score and parameters of liver function (albumin, bilirubin, prothrombin time) were different between the two groups (P<0.05). CONCLUSION: These results suggest that short-term suppression of HBV replication may not slow down the progression of liver failure in patients with chronic severe hepatitis B.

Prognostic factors for chronic severe hepatitis and construction of a prognostic model

BACKGROUND: Chronic severe hepatitis is a serious illness with a high mortality rate. Discussion of prognostic judgment criteria for chronic severe hepatitis is of great value in clinical guidance. This study was designed to investigate the clinical and laboratory indices affecting the prognosis of chronic severe hepatitis and construct a prognostic model. METHODS: The clinical and laboratory indices of 213 patients with chronic severe hepatitis within 24 hours after diagnosis were analyzed retrospectively. Death or survival was limited to within 3 months after diagnosis. RESULTS: The mortality of all patients was 47.42%. Compared with the survival group, the age, basis of hepatocirrhosis, infection, degree of hepatic encephalopathy (HE) and the levels of total bilirubin (TBil), total cholesterol (CHO), cholinesterase (CHE), blood urea nitrogen (BUN), blood creatinine (Cr), blood sodium ion (Na), peripheral blood leukocytes (WBC), alpha-fetoprotein (AFP), international normalized ratio (INR) of blood coagulation and prothrombin time (PT) were significantly different in the group who died, but the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and hemoglobin (HGB) were not different between the two groups. At the same time, a regression model, Logit (P)=1.573xAge+1.338xHE-1.608xCHO+0.011xCr-0.109xNa+1.298xINR+11.057, was constructed by logistic regression analysis and the prognostic value of the model was higher than that of the MELD score. CONCLUSIONS: Multivariate analysis excels univariate anlysis in the prognosis of chronic severe hepatitis, and the regression model is of significant value in the prognosis of this disease.

The MELD scoring system for predicting prognosis in patients with severe hepatitis after plasma exchange treatment

BACKGROUND: Hepatic failure caused by severe hepatitis is a clinical syndrome where the major liver functions, particularly detoxification, synthetic functions, and metabolic regulation are impaired to different degrees, and may result in major life-threatening complications such as hepatic encephalopathy, ascites, jaundice, cholestasis, bleeding and hepatorenal syndrome. Plasma exchange (PE) has been found useful in treating patients with fulminant hepatic failure by removing hepatic toxins and replacement of clotting factors, so PE treatment has temporary supportive effects on liver failure caused by severe viral hepatitis. in this study, our aim was to predict the prognosis of patients with severe hepatitis after PE treatment using the end-stage liver disease (MELD) scoring system. METHODS: Two hundred and twenty patients were randomly divided into PE and control groups, and the MELD score was calculated for each patient according to the original formula. The efficacy of PE was assessed by mortality or improvement in biochemical parameters and MELD score. RESULTS: The levels of total bilirubin and international normalised ratio (INR) in patients whose MELD scores were between 30 and 39 were lower than those before PE treatment, as those in patients whose MELD scores were 40 or higher. The mortality of patients in the PE group with MELD scores from 30 to 39 was 50.0%, while it was 83.3% in the control group (P<0.01). The mortality of patients with MELD scores higher than 40 was 90.0% in the PE group and 98.0% in the control group (P>0.05). CONCLUSIONS: PE treatment can decrease the serum total bilirubin level and INR and MELD score of patients with severe hepatitis and improve liver function. Compared with the control group, PE can significantly decrease the mortality of patients with MELD scores from 30 to 39, but has no effect in patients with MELD scores of 40 or higher.

Operative timing of liver transplantation for patients with severe hepatitis

BACKGROUND: Fulminant hepatic failure manifests a rapid onset, serious complications, and a high mortality, but still there is a possibility of recovery. Once the patient is able to pass a crisis, the liver is able to regenerate completely and regain its normal function. Therefore it is of vital importance to determine the eligible timing for transplantation. Premature surgery might result in a loss of the chance of internal medical treatment and misuse of liver resources, whereas delayed surgery might increase the difficulty of treatment in the preoperative period and the possibility of complications and medical expense, which eventually result in decreased rate of success and survival. This problem remains worldwide how to choose the optional timing of operation. METHODS: Thirty-six patients with severe hepatitis were treated by orthotopic liver transplantation. The distribution of MELD scores in these patients was: 10-19 in 8 patients, 20-29 in 10, 30-39 in 11, and 40 in 7. They were divided into two groups: MELD score <30 and MELD score >= 30. Parameters (1-year survival rate, complications, preoperative use of artificial liver, operative time, volume of bleeding and blood transfusion, and average hospital costs) were examined as prognostic factors after liver transplantation. RESULTS: The I-year survival rate of the MELD score <30 group was higher than that of the >= 30 group (77.8% and 33.3%, P=0.007), and the rate of complications in the <30 group was lower (P=0.012). There were no differences in the timing of artificial liver treatment, operative time, operative hemorrhage, and transfusion between the two groups (P=0.742). But the average daily hospital cost in the MELD score >= 30 group was higher (P=0.008). CONCLUSION: This study shows that when the MELD score is <30 it may be the optimal time to perform liver transplantation for patients with severe hepatitis.

Model for end-stage liver disease-sodium predicts prognosis in patients with chronic severe hepatitis B

Background Serum sodium predicts prognosis in chronic severe hepatitis B and may improve the prognostic accuracy of the model for end-stage liver disease （MELD） score, but the available information is limited. The present study was undertaken to study the clinical use of the serum sodium incorporated MELD （MELD-Na） and assess its validity by the concordance （c）-statistics in predicting the prognosis of the patient with chronic severe hepatitis B.Methods A total of 426 adult patients with a diagnosis of chronic severe hepatitis B between January 1, 2007, and December 31, 2007 at a single center were studied. The scores of serum sodium, MELD, MELD-Na, and ΔMELD-Na （ΔMELD-Na=MELD-Na at 14 days after medical treatment -MELD-Na score on admission） of the patients with chronic severe hepatitis B were calculated. The 3-month mortality in the patients was measured, and the validity of the models was determined by means of the concordance （c） statistics.Results The average MELD, MELD-Na scores of survival group were 25.70±5.08 and 26.60±6.90, and those of dead group were 35.60±6.78 and 42.80±9.57 on admission. There was a significant difference in MELD and MELD-Na between the survival and dead groups （P 〈0.01）. The average △MELD-Na score of the survival group was -0.97±3.51, and that of the dead group was 3.45±2.38 at 2 weeks after the treatment. There was a significant difference in △MELD-Na between the survival and dead groups （P 〈0.01）. The areas under the receiver-operating characteristic curves of Na, MELD and MELD-Na for the occurrence of death in 3 months were 0.742, 0.875 and 0.922. The 3-month mortality of the MELD-Na scores group 〈25, 25-30, 31-34, 35-40 and 〉40 were 2.0%, 5.4%, 35.4%, 53.8 % and 86.9%, respectively. There was a significant difference in the 3-month mortality between the five groups （P 〈0.05）. The 3-month mortality of the △MELD-Na〉0 group was 65.9%, and that of the △MELD-Na ≤0 group was 15.8%; there was a significant difference in the 3-month mortality between the two groups （P 〈0.05）.Conclusions MELD-Na score is a valid model to predict the 3-month mortality in patients with chronic severe hepatitis B. △MELD-Na is a clinically useful parameter for predicting the therapeutic effect of chronic severe hepatitis B.

Clinical Observation on the Treatment of Chronic Severe Hepatitis B by Retention Enema with Huchang Jiedu Decoction(护肠解毒汤)

Objective： To observe the efficacy of retention enema with Huchang Jiedu Decoction （护肠解毒汤, HJD） in treating chronic severe hepatitis B （CSHB）. Methods： Sixty patients of CSHB were equally randomized into the treated group and the control group. Both groups were treated with conventional integrative medicine, but to patients in the treated group, retention enema with HJD was given in addition, once every day for 3 weeks. The dominant symptoms, physical signs, and related biochemical indices, as well as the incidence of complications in patients before and after treatment, were observed. Results： Good therapeutic effects were shown in the treated group, with a total effective rate better than that in the control group （83.3% versus 60.0%, P〈0.05）, superior in terms of lowering alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, total bilirubin （TBil）, globulin （GIb）, and endotoxin （ET） levels and increasing prothrombin activity （PTA）, total cholesterol （TC）, and calcium （Ca） levels, as well as eliminating ascites and preventing hepatic encephalopathy （P〈0.05）; especially in treating middle/early stage patients with Chinese medicine syndrome differentiated as water-toxin accumulation pattern. Conclusion： Retention enema with HJD is surely effective in treating CSHB, and its primary mechanism may be related to the mitigation of enterogenous endotoxemia.

Effect of medical ozone therapy on renal blood flow and renal function of patients with chronic severe hepatitis

Background Medical ozone therapy system was reported to have certain effects on the treatment of severe hepatitis, but its mechanism is not very clear. One of the causes of death of severe hepatitis is complication of renal damage or hepatorenal syndrome. The present study aimed to observe effects of medical ozone therapy system on plasma renin activity （PRA）, angiotensin II （All）, aldosterone （ALD）, renal blood flow and renal function of patients with chronic severe hepatitis and explore mechanisms of medical ozone therapy in the treatment of severe hepatitis. Methods Eighty-five cases with chronic severe hepatitis were randomly divided into ozone therapy group （43 cases） and control group （42 cases）. The patients in the ozone therapy group were treated with basic treatments plus ozone therapy system. Basic autohemotherapy was used. One hundred milliliter venous blood was drawn from each patient, and was mixed with 100 ml （35 pg/ml） medical ozone and then was returned the blood to the patient intravenously, once every other day for 20 days. Only the basic treatments were given to the control group. PRA, All, ALD, renal blood flow and damage to renal function of the two groups before treatment and 20 days after treatment were compared. Survival rates were also compared. Results Twenty days after the treatment, in ozone therapy group, PRA was （1.31±0.12） ng.m^-1.h^1, All （111.25±17.35） pg/ml, ALD （251.31±22.60） pg/ml, which decreased significantly compared with those before treatment （PRA （2.23±0.13） ng.ml^-1.h^-1, All （155.18±19.13） pg/ml, ALD （405.31±29.88） pg/ml, t=4.67-14.23, P 〈0.01 ）, also lower than those of control group 20 days after the treatment （PRA （2.02±0.11） ng.ml^-1.h^-1, All （162.21±15.32） pg/ml, ALD （401.20±35.02） pg/ml, t=4.97-15.61, P 〈0.01）; renal blood flow was （175.15±28.20） ml/min, which increased compared with that before the treatment （（125.68±21.25） ml/min） and was higher than that of control group 20 days after the treatment （（128.59±23.15） ml/min, t=4.78, 4.61, P 〈0.01）. Renal damage occurred in 2 cases （5%） in ozone therapy group, less than that in control group （9 cases, 21%） （X^2=5.295, P 〈0.05）. Thirty-three cases （77%） in ozone therapy group vs. 16 cases （38%） in control group survived （X^2=12.993, P 〈0.01 ）. Conclusions Basic treatment plus medical ozone therapy for patients with chronic severe hepatitis could decrease PRA, All and ALD levels significantly increase renal blood flow, prevent renal damage to certain extent and improve survival rate of the patients.

Assessment of prognosis and curative effect in patients with chronic severe hepatitis using the model for end-stage liver disease scores

Severe hepatitis is the most severe liver disease, with poor prognosis and high mortality. We explored the practical use of the model for end-stage liver disease （MELD） on clinical and the molecular adsorbents recirculating system （MARS） on chronic severe hepatitis to predict the short-term prognosis of patients with chronic severe hepatitis using the MELD score and the curative effect of MARS treatment.

Diagnosis and Clinical Management of Acute Severe Hepatitis of Unknown Origin: Operational Recommendation of Peking Union Medical College Hospital

Around 450 cases of acute severe hepatitis of unknown origin in children have been reported in 21 countries and region globally since April 2022,which has exceeded the past annual incidences of related regions,and has aroused wide concern.Affected patients were predominantly children under 16years of age,presented with symptoms of acute hepatitis with markedly elevated liver enzymes,and had been ruled out of common viral infections such as hepatitis A,B,C,D,and E.Similar cases have not been reported in China yet.However,considering that the severe acute hepatitis has involved worldwide areas,still with unknown origin,and incidences of severity is relatively high,we formulated this recommendation to standardize diagnosis and treatment of acute severe hepatitis of unknown origin in Peking Union Medical College Hospital,to get fully prepared to the possible public health events.

DETECTION OF PLASMA SOLUBLE INTERLEUKIN－2 RECEPTOR IN PATIENTS WITH SEVERE AND CHRONIC ACTIVE HEPATITIS B

Plasma levels of soluble interleukin-2 receptor (sIL-2R) in patients with chronic active hepatitis B (CAHB) or severe hepatitis B (SHB) were measured quantitatively by 'sandwich' ELISA with monoclonal antibodies in order to explore the change of sIL-2R levels, its clinical significance,and its relation to liver damage. The results showed that the plasma sIL-2R levels in patients with CAHB and SHB were much higher than those in normal controls (P < 0. 01 ), and the level ofplasma sIL-2R in patients with SHB was greatly higher than that in patients with CAHB. These results suggest that there is close relation between plasma level of sIL-2R, the clinical types of hepatitis B,and the severity of liver damage. In addition, there is no significant difference in plasma levels of sIL-2R between acute severe hepatitis B (ASHB), subacute severe hepatitis B (SASHB), and chronic severe hepatitis B (CSHB). No relation was found between sIL-2R level and hepatitis B virusreplication activity.

Lymphocyte-to-white blood cell ratio is associated with outcome in patients with hepatitis B virus-related acute-on-chronic liver failure

BACKGROUND The lymphocyte-to-white blood cell ratio(LWR)is a blood marker of the systemic inflammatory response.The prognostic value of LWR in patients with hepatitis B virus-associated acute-on-chronic liver failure(HBV-ACLF)remains unclear.AIM To explore whether LWR could stratify the risk of poor outcomes in HBV-ACLF patients.METHODS This study was conducted by recruiting 330 patients with HBV-ACLF at the Department of Gastroenterology in a large tertiary hospital.Patients were divided into survivor and non-survivor groups according to their 28-d prognosis.The independent risk factors for 28-d mortality were calculated by univariate and multivariate Cox regression analyses.Patients were divided into low-and high-LWR groups according to the cutoff values.Kaplan-Meier analysis was performed according to the level of LWR.RESULTS During the 28-d follow-up time,135 patients died,and the mortality rate was 40.90%.The LWR level in non-surviving patients was significantly decreased compared to that in surviving patients.A lower LWR level was an independent risk factor for poor 28-d outcomes(hazard ratio=0.052,95%confidence interval:0.005-0.535).The LWR level was significantly negatively correlated with the Child-Turcotte-Pugh,model for end-stage liver disease,and Chinese Group on the Study of Severe Hepatitis B-ACLF II scores.In addition,the 28-d mortality was higher for patients with LWR<0.11 than for those with LWR≥0.11.CONCLUSION LWR may serve as a simple and useful tool for stratifying the risk of poor 28-d outcomes in HBVACLF patients.

Liver regeneration as treatment target for severe alcoholic hepatitis

Severe alcoholic hepatitis(AH)is a distinct entity in the spectrum of alcoholrelated liver disease,with limited treatment options and high mortality.Supportive medical care with corticosteroids in selected patients is the only currently available treatment option,often with poor outcomes.Based on the insights into the pathogenetic mechanisms of AH,which are mostly obtained from animal studies,several new treatment options are being explored.Studies have implicated impaired and deranged liver regeneration processes as one of the culprit mechanisms and a potential therapeutic target.Acknowledging evidence for the beneficial effects of granulocyte colony-stimulating factor(G-CSF)on liver regeneration and immunomodulation in animal models,several human studies investigated its role in the treatment of advanced alcohol-related liver disease and AH.Contrary to the previously published studies suggesting benefits of G-CSF in the outcomes of patients with severe AH,these effects were not confirmed by a recently published multicenter randomized trial,suggesting that other options should rather be pursued.Stem cell transplantation represents another option for improving liver regeneration,but evidence for its efficacy in patients with severe AH and advanced alcohol-related liver disease is still very scarce and unconvincing,with established lack of efficacy in patients with compensated cirrhosis.In this review,we summarize the current knowledge on the pathogenesis and experimental therapies targeting liver regeneration.The lack of high-quality studies and evidence is a major obstacle in further treatment development.New insights into the pathogenesis of not only liver injury,but also liver regeneration processes are mandatory for the development of new treatment options.A reliable experimental model of the pathogenesis of AH and processes involved in liver recovery is still missing,and data obtained from animal studies are essential for future research.

Antiviral therapy with nucleos(t)ide analogues for severe chronic hepatitis B

To the Editor:I read the paper by Chen et al[1]with great interest.The authors performed a retrospective study to evaluate the short-term efficacy of antiviral therapy with

Nursing of Artificial Liver Support System in the Treatment of Severe

Objective:Research on nursing method of artificial liver support system applied in severe hepatitis patients.Methods:Selected 50 severe hepatitis patients in our hospital during the period of January 2018 and January 2019,observed and analyzed the clinical intervention effect of all treated by artificial liver support system cooperating with related nursing methods.Results:After the treatment,the clinical symptoms and abdominal distension of the patients were relieved,whose spirit took a turn for the better and the jaundice subsided.Among these patients,68%got improved enough to be released,26.00%gave up for financial concerns and 6.00%died.Before and after treatment,the patients’PT and INR,APTT,TT improved obviously,and the difference were quite a lot(P<0.05),while ALT and ALB showed few without any statistical significance(P>0.05).Conclusion:During the treatment and intervention of severe hepatitis patients with artificial liver support system,effective nursing interventions are needed,mainly including completely preoperative,intraoperative and postoperative care so as to ensure the treatment effect and promote the recovery of intervention,which has remarkable significance to clinical development.

Artificial intelligence and machine learning could support drug development for hepatitis A virus internal ribosomal entry sites

Hepatitis A virus(HAV)infection is still an important health issue worldwide.Although several effective HAV vaccines are available,it is difficult to perform universal vaccination in certain countries.Therefore,it may be better to develop antivirals against HAV for the prevention of severe hepatitis A.We found that several drugs potentially inhibit HAV internal ribosomal entry site-dependent translation and HAV replication.Artificial intelligence and machine learning could also support screening of anti-HAV drugs,using drug repositioning and drug rescue approaches.

A scoring model for predicting the prognosis of severe viral hepatitis

The prognosis of patients with severe viral hepatitis is concerned byclinicians, patients and their relatives. Many factors may influence on the prognosis of patientswith this disease. Many studies on the prognosis of severe viral hepatitis by multiple logisticregression analysis have shown generally consistent results. Previouly we established a scoringmodel of severe viral hepatitis (SMSVH) by logistic regression analysis. The aim of this study wasto estimate prospectively the 6-month survival rate of patients with severe viral hepatitis usingSMSVH.

Severe acute hepatitis of unknown causes in children–Current findings,questions,opinions,and recommendations,a mini-review

Since October 2021 in Alabama,the United States,and March 2022 in central Scotland,the United Kingdom,the number of cases of severe acute hepatitis of unknown etiology/causes in children was found to increase,and the total number of cases has reached 920 worldwide by June 22 this year,45 cases(5%)required liver transplantation,and 18 cases(2%)died according to World Health Organization(WHO).To understand the basic characteristics of this disease/syndrome,a literature search was performed at PubMed,websites of WHO,UK Health Security Agency,and US and European Centers for Disease Control and Prevention,and more than 20 reports were enrolled as references for this review.The main clinical manifestations are anorexia,vomiting,fatigue,jaundice,and so forth.Most of the cases seemed to have a self-limited course of the disease,about 6%of cases may develop life-threatening acute liver failure.The disease seems to be transmissible from person to person.Human adenovirus was detected in up to 75%of cases,but this virus seems not to be the only and major etiologic agent,other cofactors probably are involved.Researchers proposed many hypotheses concerning the etiology and pathogenesis,and many important works and studies are ongoing.This mini-review is aimed at summarizing,reviewing,and further understanding the characteristics of the disease,raising some clinically relevant questions,and trying to discuss some questions that may be related to the treatment of the disease for consideration.

Expert symposium on severe acute hepatitis of unknown cause in children,a paradigm of exchanges and sharing between Chinese and Western medicine professionals

Recently,cases of severe acute hepatitis of unknown cause(SAHUC)in children have suddenly increased in the United States,the United Kingdom,and other countries.In order to understand the progress in the diagnosis and treatment of this disease,and to prepare for the relevant plans in advance,the“Expert Symposium on the Severe Acute Hepatitis of Unknown Cause in Children”was successfully held on May 13,2022,online organized by Beijing Children's Hospital(BCH),Capital Medical University,Beijing Institute of Pediatrics Integrated Chinese and Western Medicine,Futang Research Center of Pediatric Development,and Branch of Hepatobiliary Diseases,China Association of Chinese Medicine.More than 9200 people watched the meeting online.Professors Yan Hu,Yan Yang,and Jing Hao,from the Department of Traditional Chinese Medicine(TCM),BCH,Capital Medical University,hosted the symposium.

Trained innate immunity and human adenovirus infection as a novel mechanism linked to the severe acute hepatitis of unknown origin in children during the COVID‐19 pandemic

1|OUTBREAK OF SEVERE ACUTE HEPATITIS OF UNKNOWN ORIGIN IN CHILDREN Severe acute hepatitis of unknown origin in children was first reported by the United Kingdom to the World Health Organization on April 5,2022.Subsequently,650 probable cases were reported worldwide by May 26,2022,1 and four patients were analyzed after reviewing the clinical records of a children's hospital in Alabama since October 1,2021.2 Although most patients recovered,the disease progressed to acute liver failure in several patients,who further required liver transplantation;thus,additional research is required to determine the disease pathogenesis.