[Research progress on hepatitis E virus-related liver failure].

Hepatitis E virus (HEV) is one of the important causes of acute viral hepatitis worldwide, and its incidence rate is increasing year by year. HEV infection can lead to acute, subacute, or acute-on-chronic liver failure with a high mortality rate among some particular patient population, who are pregnant women, older, chronic liver diseases like chronic hepatitis B and cirrhosis, or immunocompromised. The clinical characteristics of HEV infection, the pathogenesis of HEV-related liver failure, and the progress in diagnosis and treatment will be elaborated upon in this article from these three aspects in order to improve clinicians' ability to identify and prevent HEV-related liver failure and its clinical outcomes.

Transfusion-transmission of hepatitis E virus through red blood cell transfusion but not through platelet concentrates: A case report from Spain.

BACKGROUND: Few cases of transfusion-transmitted hepatitis E virus (HEV) have been published in Spain. Here, we describe a well-characterized lookback investigation of a transfusion-transmitted HEV case at the Community Centre for Blood and Tissues of Asturias (Spain). CASE REPORT: A female patient with chronic myeloid leukemia underwent an allogeneic bone marrow transplant in March 2019 and showed alterations in liver function shortly afterwards. This patient received blood components from 30 different donors in the 3 months before the transplant. Frozen plasma samples from these donations were investigated for the presence of HEV-RNA. One frequent donor was identified as asymptomatic HEV RNA-positive at the time of his whole blood donation. The investigation revealed that this donor's plasma unit, originally intended for the fractionation industry, had a viral RNA concentration of 1.9 × 104 copies/mL. HEV RNA was detected initially in the index patient who received the red cell concentrate from this donor 25 days after the transfusion. HEV RNA isolated from both donor and recipient were identified as subtype 3f. The recipient of platelet concentrate (PC), treated with a riboflavin-based pathogen reduction technology (PRT) was not infected, being negative for the presence of HEV IgM, IgG, and HEV RNA before and after the transfusion. CONCLUSION: This case study shows that HEV was transmitted through red cell transfusion to a recipient, while the patient who received riboflavin/UV light treated PC did not develop signs of infection. A causal relationship between PRT treatment of the PC and the non-transmission of HEV remains to be established.

Hepatitis aguda per virus de l’hepatitis E / Hepatitis aguda por virus de la hepatitis E / Acute hepatitis by Hepatitis E virus

Introducció. L’hepatitis aguda és un procés necroinflamatoridel fetge causat per una noxa puntual. Analíticament esmanifesta per un augment de les transaminases i la presentació clínica pot ser variable (de formes subclíniques a insuficiència hepàtica aguda). L’estudi d’hepatitis inclouproves per valorar el grau d’alteració fisiològica i per identificar-ne l’etiologia. La causa més freqüent són les infeccions víriques.Cas clínic. Pacient de 8 anys amb família originària delPakistan, d’on retorna poc abans d’iniciar la clínica. Presenta abdominàlgia, diarrea, febre, colúria i acòlia. En l’exploració física destaca icterícia mucocutània, esplenomegàlia i hepatomegàlia lleus. L’analítica presenta augmentde transaminases i bilirubina directa. S’ingressa per a estudi i tractament simptomàtic. En les serologies s’obté unresultat positiu a virus d’hepatitis E.Comentaris. El virus de l’hepatitis E (VHE) és un virus RNAque pertany a la família Herpesviridae. La caracteritzaciómolecular ha permès identificar-ne quatre genotips: HVE1i HVE2 infecten únicament humans i són predominants enpaïsos en vies de desenvolupament. HVE3 i HVE4 infectentambé altres mamífers. Són responsables dels casos esporàdics a escala mundial. La majoria d’infeccions sónasimptomàtiques en pacients immunocompetents, però demés risc en pacients immunodeprimits pel risc més alt de cronificació. (AU)

Introducción. La hepatitis aguda es un proceso necroinflamatoriodel hígado causado por una noxa puntual. Analíticamente se manifiesta por un aumento de las transaminasas y la presentaciónclínica puede ser variable (de formas subclínicas a insuficienciahepática aguda). El estudio de hepatitis incluye pruebas para valorar el grado de alteración fisiológica y para identificar su etiología. La causa más frecuente son las infecciones víricas.Caso clínico. Paciente de 8 años con familia originaria de Pakistán,de donde vuelve poco antes de iniciar la clínica. Presenta abdominalgia, diarrea, fiebre, coluria y acolia. En la exploración físicadestaca ictericia cutánea-mucosa, esplenomegalia y hepatomegalia leves. En la analítica presenta aumento de transaminasas y bilirrubina directa. Se ingresa para estudio y tratamiento sintomático. En las serologías se obtiene un resultado positivo a virus dela hepatitis E.Comentarios. El virus de la hepatitis E (VHE) es un virus RNA quepertenece a la familia Herpesviridae. La caracterización molecularha permitido identificar cuatro genotipos: HVE1 y HVE2 infectanúnicamente a humanos y son predominantes en países en vías dedesarrollo. HVE3 y HVE4 infectan también a otros mamíferos. Sonresponsables de los casos esporádicos a nivel mundial. La mayoríade infecciones son asintomáticas en pacientes inmunocompetentes, pero de mayor riesgo en pacientes inmunodeprimidos por elmayor riesgo de cronificación. (AU)

Introduction. Acute hepatitis is a necroinflammatory process of theliver caused by isolated noxa. Its laboratory findings are characterized by an increase in liver transaminases, and the clinical presentation may be variable (from subclinical forms to acute liverfailure). The study of hepatitis includes tests to assess the degreeof physiological alteration and to identify its etiology. The mostcommon cause is viral infections.Clinical case. An 8-year-old patient who recently returned from atrip to Pakistan presented with abdominal pain, diarrhea, fever,choluria and acholia. Physical examination revealed mild mucocutaneous jaundice, splenomegaly, and hepatomegaly. Laboratoryevaluation showed an increase in liver transaminases and directbilirubin. He was admitted for diagnostic evaluation and symptomatic treatment. Serology for hepatitis E virus resulted positive.Comments. Hepatitis E virus (HEV) is an RNA virus of the Herpesviridae family. Molecular characterization has identified four genotypes, HVE 1-4. HVE1 and HVE2 infect only humans and are predominant in developing countries, whereas HVE3 and HVE4 alsoinfect other mammals. HVE is responsible for sporadic casesworldwide. Most infections are asymptomatic in immunocompetent patients but risk is higher in immunocompromised patientsdue to increased risk of chronicity. (AU)

Prolonged jaundice in hepatitis-E patients: Going beyond the optics.

Hepatitis E virus (HEV) is an RNA virus that is transmitted faeco-orally. Due to unhygienic living conditions and unsatisfactory treatment of drinking water, it is a major cause of acute viral hepatitis in Pakistan. Hepatitis E infection in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may cause prolonged jaundice resulting in serious complications like, severe haemolysis, acute renal failure, encephalopathy and even demise. Although both these diseases occur frequently in our country there is a dearth of literature on the effect of Hepatitis E infection in G6PD deficient patients, leading to higher rate of complications in such patients. We report the case of a 37 years old male who was referred to our hospital with worsening jaundice. Patient had HEV infection with concomitant G6PD deficiency. This case had a different prospect, since it resulted in prolonged jaundice and severe haemolysis. However the patient's condition improved with conservative management.

Hepatitis aguda por virus E. Presentación de dos casos con evolución clínica diferente / Acute hepatitis due to E virus. Presentation of two cases with different clinical evolution

RESUMEN El virus de la hepatitis E tiene una amplia distribución a nivel mundial. Se presentaron dos casos clínicos en la provincia de Matanzas, con diagnóstico confirmado de hepatitis E mediante la determinación del ARN viral en heces fecales congeladas; a pesar de proceder de áreas de salud distantes, coincidieron en el mismo período de tiempo. El primero de ellos, una gestante asintomática diagnosticada fortuitamente a partir de elevación de enzimas hepáticas de citolisis. Evolucionó satisfactoriamente sin repercusión en su bienestar materno, trasmisión fetal, ni complicaciones perinatales. El segundo, una paciente portadora de síndrome metabólico, con evolución tórpida de su cuadro infeccioso viral, que la llevó a la insuficiencia hepática y a la muerte. Con estos casos se reflejó el amplio espectro de esta enfermedad en cuanto a formas clínicas de presentación y evolución. Se demostró que pueden ocurrir complicaciones en cualquier grupo poblacional, de ahí la importancia de considerarla en el diagnóstico diferencial de las enfermedades infecciosas hepáticas (AU).

ABSTRACT Hepatitis E virus is widely distributed around the world. Two clinical cases occurring in the province of Matanzas were presented, both with diagnosis of E hepatitis confirmed through viral RNA determination in frozen stool; although patients came from faraway health areas, they coincided in the same time period. The first patient, a pregnant asymptomatic woman, was incidentally diagnosed due to an increase of cytolysis liver enzymes. Her evolution was satisfactory without repercussion on maternal wellbeing, fetal transmission, nor perinatal complications. The second patient, a metabolic syndrome carrier, had torpid evolution of a viral infectious disease leading her to liver failure and death. These cases highlighted the wide range of this disease according to its clinical forms of presentation and evolution. It was showed that complications may occur in any population group, in consequence it is important to consider this disease when making the differential diagnosis of liver infectious diseases (AU).

Viral Hepatitis Other than A, B, and C: Evaluation and Management.

Viral hepatitis can cause a wide spectrum of clinical presentations from a benign form with minimal or no symptoms to acute liver failure or death. Hepatitis D coinfection and superinfection have distinct clinical courses, with the latter more likely leading to chronic infection. Management of chronic hepatitis D virus is individualized because of the paucity of treatment options and significant side effect profile of currently available treatments. Sporadic cases of hepatitis E caused by contaminated meats are becoming increasingly prevalent in immunocompromised hosts. Human herpesviruses are an important cause of disease also in immunocompromised individuals.

Management of viral hepatitis A, C, D and E in pregnancy.

Viral hepatitis can cause significant maternal and neonatal morbidity and mortality. Hepatitis A and E mainly present as acute hepatitis during pregnancy, while hepatitis C and D are usually found as chronic infection in pregnant women. Hepatitis A remains self-limiting during pregnancy while hepatitis E has a higher prevalence and manifests with a rigorous course in pregnant women. Screening of hepatitis C during pregnancy and its subsequent management during pregnancy are still a debatable topic. New treatments of hepatitis C and E require further evaluation for use in pregnancy. This review summarizes the prevalence, clinical manifestations, maternal, foetal and neonatal effects, and the management of hepatitis A, C, D and E viral infection during pregnancy.

Hepatitis E Virus Infection in the United States: Current Understanding of the Prevalence and Significance in the Liver Transplant Patient Population and Proposed Diagnostic and Treatment Strategies.

Hepatitis E virus (HEV), of the family Herpesviridae, is a virus that infects nearly 20 million people per year throughout the world. HEV is most commonly transmitted via the fecal-oral route and has long been described as a virus that afflicts only those in resource-poor countries. However, HEV has been detected in numerous animal carriers, various food sources, and even in human blood products in resource-rich regions of the world. HEV is of importance in the transplant patient population because of its ability to cause chronic viral infection in these patients can lead to graft loss and cirrhosis. In this review, we discuss the current knowledge of HEV as it pertains to the liver transplant patient population and discuss diagnosis and treatment of this infection.

Hepatitis E as a cause of adult hospitalization in Bangladesh: Results from an acute jaundice surveillance study in six tertiary hospitals, 2014-2017.

In the absence of reliable data on the burden of hepatitis E virus (HEV) in high endemic countries, we established a hospital-based acute jaundice surveillance program in six tertiary hospitals in Bangladesh to estimate the burden of HEV infection among hospitalized acute jaundice patients aged ≥14 years, identify seasonal and geographic patterns in the prevalence of hepatitis E, and examine factors associated with death. We collected blood specimens from enrolled acute jaundice patients, defined as new onset of either yellow eyes or skin during the past three months of hospital admission, and tested for immunoglobulin M (IgM) antibodies against HEV, HBV and HAV. The enrolled patients were followed up three months after hospital discharge to assess their survival status; pregnant women were followed up three months after their delivery to assess pregnancy outcomes. From December'2014 to September'2017, 1925 patients with acute jaundice were enrolled; 661 (34%) had acute hepatitis E, 48 (8%) had hepatitis A, and 293 (15%) had acute hepatitis B infection. Case fatality among hepatitis E patients was 5% (28/589). Most of the hepatitis E cases were males (74%; 486/661), but case fatality was higher among females-12% (8/68) among pregnant and 8% (7/91) among non-pregnant women. Half of the patients who died with acute hepatitis E had co-infection with HAV or HBV. Of the 62 HEV infected mothers who were alive until the delivery, 9 (15%) had miscarriage/stillbirth, and of those children who were born alive, 19% (10/53) died, all within one week of birth. This study confirms that hepatitis E is the leading cause of acute jaundice, leads to hospitalizations in all regions in Bangladesh, occurs throughout the year, and is associated with considerable morbidity and mortality. Effective control measures should be taken to reduce the risk of HEV infections including improvements in water quality, sanitation and hygiene practices and the introduction of HEV vaccine to high-risk groups.

Clinicopathologic features and pathologic diagnosis of hepatitis E.

Infection with the hepatitis E virus (HEV) is one of the most common causes, if not the most common, of acute hepatitis worldwide. In the last decade, we have learned that, in addition to the endemically and epidemically occurring form of hepatitis E, which is predominantly transmitted by contaminated drinking water and constitutes a significant health problem in resource-poor countries, there is a globally existing form of hepatitis E, which is a zoonosis and as such is primarily transmitted by the consumption of contaminated meat products. Although in most cases hepatitis E is subclinical or mild and self-limiting, pregnant women and patients with liver cirrhosis may have severe, occasionally even fatal disease, and immunocompromised individuals may develop chronic hepatitis E. Considering the substantial global health burden caused by HEV infection, it is surprising how limited our knowledge of hepatitis E pathology still is. In this article, we describe localization studies on HEV infection and discuss their implications for everyday diagnostics. Furthermore, we outline and discuss the spectrum of histologic changes, which can be found in HEV infection in various clinical contexts.

Hepatitis E Virus (HEV)-Specific T Cell Receptor Cross-Recognition: Implications for Immunotherapy.

T cell immunotherapy is a concept developed for the treatment of cancer and infectious diseases, based on cytotoxic T lymphocytes to target tumor- or pathogen-specific antigens. Antigen-specificity of the T cell receptors (TCRs) is an important selection criterion in the developmental design of immunotherapy. However, off-target specificity is a possible autoimmunity concern if the engineered antigen-specific T cells are cross-reacting to self-peptides in-vivo. In our recent work, we identified several hepatitis E virus (HEV)-specific TCRs as potential candidates to be developed into T cell therapy to treat chronic hepatitis E. One of the identified TCRs, targeting a HLA-A2-restricted epitope at the RNA-dependent RNA polymerase (HEV-1527: LLWNTVWNM), possessed a unique multiple glycine motif in the TCR-ß CDR3, which might be a factor inducing cross-reactivity. The aim of our study was to explore if this TCR could cross-recognize self-peptides to underlay autoimmunity. Indeed, we found that this HEV-1527-specific TCR could also cross-recognize an apoptosis-related epitope, Nonmuscle Myosin Heavy Chain 9 (MYH9-478: QLFNHTMFI). While this TCR had dual specificities to both viral epitope and a self-antigen by double Dextramer binding, it was selectively functional against HEV-1527 but not activated against MYH9-478. The consecutive glycine motif in ß chain may be the reason promoting TCR binding promiscuity to recognize a secondary target, thereby facilitating cross-recognition. In conclusion, candidate TCRs for immunotherapy development should be screened for autoimmune potential, especially when the TCRs exhibit unique sequence pattern.

The Clinical Perspective on Hepatitis E.

Every year, there are an estimated 20 million hepatitis E virus (HEV) infections worldwide, leading to an estimated 3.3 million symptomatic cases of hepatitis E. HEV is largely circulating in the west and is associated with several hepatic and extrahepatic diseases. HEV Genotype 1 and 2 infections are waterborne and causative for epidemics in the tropics, while genotype 3 and 4 infections are zoonotic diseases and are mainly transmitted by ingestion of undercooked pork in industrialized nations. The clinical course of these infections differs: genotype 1 and 2 infection can cause acute illness and can lead to acute liver failure (ALF) or acute on chronic liver failure (ACLF) with a high mortality rate of 20% in pregnant women. In contrast, the majority of HEV GT-3 and -4 infections have a clinically asymptomatic course and only rarely lead to acute on chronic liver failure in elderly or patients with underlying liver disease. Immunosuppressed individuals infected with genotype 3 or 4 may develop chronic hepatitis E, which then can lead to life-threatening cirrhosis. Furthermore, several extra-hepatic manifestations affecting various organs have been associated with ongoing or previous HEV infections but the causal link for many of them still needs to be proven. There is no approved specific therapy for the treatment of acute or chronic HEV GT-3 or -4 infections but off-label use of ribavirin has been demonstrated to be safe and effective in the majority of patients. However, in approximately 15% of chronically HEV infected patients, cure is not possible.

Hepatitis E and Allogeneic Hematopoietic Stem Cell Transplantation: A French Nationwide SFGM-TC Retrospective Study.

Usually self-limited, hepatitis E virus (HEV) infection may evolve to chronicity and cirrhosis in immunosuppressed patients. HEV infection has been described in solid-organ transplantation and hematology patients, but for allogeneic hematopoietic stem cell transplant (alloHSCT) recipients, only small cohorts are available. This retrospective nationwide multi-center series aimed to describe HEV diagnostic practices in alloHSCT French centers, and the course of infection in the context of alloHSCT. Twenty-nine out of 37 centers participated. HEV search in case of liver function tests (LFT) abnormalities was never performed in 24% of centers, occasionally in 55%, and systematically in 21%. Twenty-five cases of active HEV infection were diagnosed in seven centers, all because of LFT abnormalities, by blood nucleic acid testing. HEV infection was diagnosed in three patients before alloHSCT; HEV infection did not influence transplantation planning, and resolved spontaneously before or after alloHSCT. Twenty-two patients were diagnosed a median of 283 days after alloHSCT. Nine patients (41%) had spontaneous viral clearance, mostly after immunosuppressive treatment decrease. Thirteen patients (59%) received ribavirin, with sustained viral clearance in 11/12 evaluable patients. We observed three HEV recurrences but no HEV-related death or liver failure, nor evolution to cirrhosis.

The Interplay between Host Innate Immunity and Hepatitis E Virus.

Hepatitis E virus (HEV) infection represents an emerging global health issue, whereas the clinical outcomes vary dramatically among different populations. The host innate immune system provides a first-line defense against the infection, but dysregulation may partially contribute to severe pathogenesis. A growing body of evidence has indicated the active response of the host innate immunity to HEV infection both in experimental models and in patients. In turn, HEV has developed sophisticated strategies to counteract the host immune system. In this review, we aim to comprehensively decipher the processes of pathogen recognition, interferon, and inflammatory responses, and the involvement of innate immune cells in HEV infection. We further discuss their implications in understanding the pathogenic mechanisms and developing antiviral therapies.

[Epidemiological analysis of viral hepatitis E in China, 2004-2017].

Objective: To analyze the changing epidemiological characteristics of hepatitis E cases in China, in order to promote in preventing and controlling hepatitis E. Methods: Data of hepatitis E and outbreaks reported through national notifiable diseases reporting system were analyzed from 2004 to 2017, but data of Hongkong, Macau and Taiwan were not included. Data of hepatitis E were divided into three phases as 2004-2007, 2008-2011 and 2012-2017, representing eight years before, four years before and years after the postmarketing of hepatitis E vaccine. Linear regression was used for analyzing the trend of hepatitis E, improved muster method was used for analyzing the seasonal intensity. Results: From 2004 to 2017, 329 519 hepatitis E cases were reported and the annual incidence were increasing from 1.27/100 000 to 2.10/100 000 (t=6.87, P<0.001). The concentrations of hepatitis E during 2004-2007, 2008-2011 and 2012-2017 were 17.43, 16.06, 11.17, respectively, with low seasonal intensity. Number of cases reported by Jiangsu, Guangdong and Zhejiang accounted for 31.54% of national cases. The incidence were lower in central (1.45/100 000) and western (1.11/100 000) region than that in eastern region (2.67/100 000), but were increasing continuously. There was an increasing trend of incidence with growing ages (t=7.85, P<0.001). The incidence was higher than 2/100 000 among cases aged ≥40, and was the highest (5.22/100 000) in the age group of 65-69 years old. Farmers, retired persons, houseworkers and unemployees accounted for 67.46% of total cases. A total of 7 outbreaks were reported, among which 3 were in nursing homes. Conclusion: The incidence of hepatitis E in central and western regions were increasing continuously and the surveillance should be strengthened. There was higher risk among middle-aged population, farmers and nursing homes, so strategy for immunization among those population was in great need.

Clinical presentations of Hepatitis E: A clinical review with representative case histories.

Hepatitis E virus (HEV) typically causes an acute, self-limiting hepatitis and is among the commonest cause of such presentations. Hepatitis E viral infection is also increasingly recognized as a cause of chronic hepatitis amongst the immunocompromised, particularly amongst solid organ transplant recipients. Chronic HEV infection remains an underdiagnosed disease and chronic infection can lead to rapidly progressive liver fibrosis and cirrhosis. This review examines current understanding of the HEV. We illustrate typical clinical presentations, management strategies [(based upon guidelines from both the British Transplant Society (BTS) and European Association for the study of liver (EASL)] and outcomes of HEV infection in different cohorts of patients by highlighting select transplant and non-transplant patient cases, from one of the largest tertiary Hepatology centres in Europe.

Absence of Persistent Hepatitis E Virus Infection in Antibody-Deficient Patients Is Associated With Transfer of Antigen-Neutralizing Antibodies From Immunoglobulin Products.

Background: Persistent hepatitis E virus (HEV) infection is described in a number of immunosuppressive conditions. We aimed to determine the risk of persistent HEV infection in patients with primary or secondary antibody deficiency. Methods: Two hundred forty-five antibody-deficient patients receiving regular immunoglobulin replacement therapy were tested for HEV RNA and anti-HEV immunoglobulin G (IgG). Immunoglobulin products and plasma specimens obtained from 9 antibody-deficient patients before and after intravenous immunoglobulin (IVIG) therapy, 5 recently treated patients with persistent HEV infection, and 5 healthy patients recovered from acute HEV infection were analyzed for anti-HEV IgG and for antibody reacting with HEV antigen. Results: No antibody-deficient patient had detectable plasma HEV RNA. Anti-HEV IgG was detected in 38.8% of patients. All 10 immunoglobulin products tested contained anti-HEV capable of neutralizing HEV antigen. Plasma samples collected following IVIG infusion therapy demonstrated a higher anti-HEV IgG level and neutralizing activity, compared with samples collected before IVIG therapy. Neutralizing activity was similar to that in healthy patients with recent acute HEV infection. Conclusion: The risk of persistent HEV infection in patients with antibody deficiency appears extremely low. This may be due to passive seroprotection afforded by the ubiquitous presence of anti-HEV in immunoglobulin replacement products.