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Brüggemann Y, Klöhn M, Wedemeyer H, Steinmann E. Hepatitis E virus: from innate sensing to adaptive immune responses. Nat Rev Gastroenterol Hepatol 2024; 21:710-725. [PMID: 39039260 DOI: 10.1038/s41575-024-00950-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/29/2024] [Indexed: 07/24/2024]
Abstract
Hepatitis E virus (HEV) infections are a major cause of acute viral hepatitis in humans worldwide. In immunocompetent individuals, the majority of HEV infections remain asymptomatic and lead to spontaneous clearance of the virus, and only a minority of individuals with infection (5-16%) experience symptoms of acute viral hepatitis. However, HEV infections can cause up to 30% mortality in pregnant women, become chronic in immunocompromised patients and cause extrahepatic manifestations. A growing body of evidence suggests that the host immune response to infection with different HEV genotypes is a critical determinant of distinct HEV infection outcomes. In this Review, we summarize key components of the innate and adaptive immune responses to HEV, including the underlying immunological mechanisms of HEV associated with acute and chronic liver failure and interactions between T cell and B cell responses. In addition, we discuss the current status of vaccines against HEV and raise outstanding questions regarding the immune responses induced by HEV and treatment of the disease, highlighting areas for future investigation.
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Affiliation(s)
- Yannick Brüggemann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Sites Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.
- German Center for Infection Research (DZIF), External Partner Site, Bochum, Germany.
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Yadav KK, Kenney SP. Hepatitis E virus immunosuppressed animal models. BMC Infect Dis 2024; 24:965. [PMID: 39266958 PMCID: PMC11395946 DOI: 10.1186/s12879-024-09870-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/03/2024] [Indexed: 09/14/2024] Open
Abstract
Hepatitis E virus (HEV) is an important emerging pathogen producing significant morbidity in immunosuppressed patients. HEV has been detrimental to solid organ transplant (SOT) patients, cancer patients, and HIV-positive patients, where chronic HEV infections occur. Blood-borne transfusions and multiple cases of chronic HEV infection in transplant patients have been reported in the past few decades, necessitating research on HEV pathogenesis using immunosuppressed animal models. Numerous animal species with unique naturally occurring HEV strains have been found, several of which have the potential to spread to humans and to serve as pathogenesis models. Host immunosuppression leads to viral persistence and chronic HEV infection allows for genetic adaptation to the human host creating new strains with worse disease outcomes. Procedures necessary for SOT often entail blood transfusions placing immunosuppressive patients into a "high risk group" for HEV infection. This scenario requires an appropriate immunosuppressive animal model to understand disease patterns in these patients. Hence, this article reviews the recent advances in the immunosuppressed animal models for chronic HEV infection with emphasis on pathogenesis, immune correlates, and the liver pathology associated with the chronic HEV infections.
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Affiliation(s)
- Kush Kumar Yadav
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA
| | - Scott P Kenney
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA.
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA.
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Solignac J, Boschi C, Pernin V, Fouilloux V, Motte A, Aherfi S, Fabre-Aubrespy M, Legris T, Brunet P, Colson P, Moal V. The question of screening organ donors for hepatitis e virus: a case report of transmission by kidney transplantation in France and a review of the literature. Virol J 2024; 21:136. [PMID: 38867299 PMCID: PMC11167830 DOI: 10.1186/s12985-024-02401-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/28/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Hepatitis E is a potentially serious infection in organ recipients, with an estimated two-thirds of cases becoming chronic, and with a subsequent risk of cirrhosis and death. In Europe, transmission occurs most often through the consumption of raw or undercooked pork, more rarely through blood transfusion, but also after solid organ transplantation. Here we describe a case of Hepatitis E virus (HEV) infection transmitted following kidney transplantation and review the literature describing cases of HEV infection transmitted by solid organ transplantation. CASE PRESENTATION Three weeks after kidney transplantation, the patient presented with an isolated minimal increase in GGT and hepatic cytolysis 6 months later, leading to the diagnosis of genotype 3c hepatitis E, with a plasma viral load of 6.5 log10IU/mL. In retrospect, HEV RNA was detected in the patient's serum from the onset of hepatitis, and in the donor's serum on the day of donation, with 100% identity between the viral sequences, confirming donor-derived HEV infection. Hepatitis E had a chronic course, was treated by ribavirin, and relapsed 10 months after the end of treatment. DISCUSSION Seven cases of transmission of HEV by solid organ transplantation have been described since 2012 without systematic screening for donors, all diagnosed at the chronic infection stage; two patients died. HEV organ donor transmission may be underestimated and there is insufficient focus on immunocompromised patients in whom mild liver function test impairment is potentially related to hepatitis E. However, since HEV infection is potentially severe in these patients, and as evidence accumulates, we believe that systematic screening of organ donors should be implemented for deceased and living donors regardless of liver function abnormalities, as is already the case in the UK and Spain. In January 2024, the French regulatory agency of transplantation has implemented mandatory screening of organ donors for HEV RNA.
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Affiliation(s)
- Justine Solignac
- Centre de Néphrologie Et Transplantation Rénale, Aix Marseille Université, Publique Hôpitaux de Marseille, Hôpital Conception, 147 Boulevard Baille, 13005, Marseille, France
| | - Celine Boschi
- IHU Méditerranée Infection, Publique Hôpitaux de Marseille, 19-21 Boulevard Jean Moulin, 13005, Marseille, France
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France
| | - Vincent Pernin
- Department of Nephrology Dialysis and Kidney Transplantation, Lapeyronie University Hospital, Montpellier, France
- Institute for Regenerative Medicine and Biotherapy (IRMB), Montpellier, France
| | - Virginie Fouilloux
- Department of Congenital and Pediatric Cardiac Surgery, Timone Children's Hospital, Marseille, France
| | - Anne Motte
- IHU Méditerranée Infection, Publique Hôpitaux de Marseille, 19-21 Boulevard Jean Moulin, 13005, Marseille, France
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France
| | - Sarah Aherfi
- IHU Méditerranée Infection, Publique Hôpitaux de Marseille, 19-21 Boulevard Jean Moulin, 13005, Marseille, France
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France
| | - Maxime Fabre-Aubrespy
- Department of Orthopaedic Surgery, Sainte-Marguerite University Hospital, Marseille, France
| | - Tristan Legris
- Centre de Néphrologie Et Transplantation Rénale, Publique Hôpitaux de Marseille, Hôpital Conception, Marseille, France
| | - Philippe Brunet
- Centre de Néphrologie Et Transplantation Rénale, Aix Marseille Université, Publique Hôpitaux de Marseille, Hôpital Conception, 147 Boulevard Baille, 13005, Marseille, France
| | - Philippe Colson
- IHU Méditerranée Infection, Publique Hôpitaux de Marseille, 19-21 Boulevard Jean Moulin, 13005, Marseille, France
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France
| | - Valérie Moal
- Centre de Néphrologie Et Transplantation Rénale, Aix Marseille Université, Publique Hôpitaux de Marseille, Hôpital Conception, 147 Boulevard Baille, 13005, Marseille, France.
- Aix Marseille Université, Institut de Recherche Et Développement, Microbes Evolution Phylogeny and Infections, 27 Boulevard Jean Moulin, 13005, Marseille, France.
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Kim SJ, Moon J. Narrative Review of the Safety of Using Pigs for Xenotransplantation: Characteristics and Diagnostic Methods of Vertical Transmissible Viruses. Biomedicines 2024; 12:1181. [PMID: 38927388 PMCID: PMC11200752 DOI: 10.3390/biomedicines12061181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/22/2024] [Accepted: 05/24/2024] [Indexed: 06/28/2024] Open
Abstract
Amid the deepening imbalance in the supply and demand of allogeneic organs, xenotransplantation can be a practical alternative because it makes an unlimited supply of organs possible. However, to perform xenotransplantation on patients, the source animals to be used must be free from infectious agents. This requires the breeding of animals using assisted reproductive techniques, such as somatic cell nuclear transfer, embryo transfer, and cesarean section, without colostrum derived in designated pathogen-free (DPF) facilities. Most infectious agents can be removed from animals produced via these methods, but several viruses known to pass through the placenta are not easy to remove, even with these methods. Therefore, in this narrative review, we examine the characteristics of several viruses that are important to consider in xenotransplantation due to their ability to cross the placenta, and investigate how these viruses can be detected. This review is intended to help maintain DPF facilities by preventing animals infected with the virus from entering DPF facilities and to help select pigs suitable for xenotransplantation.
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Affiliation(s)
- Su-Jin Kim
- Apures Co., Ltd., 44, Hansan-gil, Cheongbuk-eup, Pyeongtaek-si 17792, Gyeonggi-do, Republic of Korea;
| | - Joonho Moon
- Division of Cardiology, Department of Internal Medicine, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul 03080, Republic of Korea
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León-Janampa N, Boennec N, Le Tilly O, Ereh S, Herbet G, Moreau A, Gatault P, Longuet H, Barbet C, Büchler M, Baron C, Gaudy-Graffin C, Brand D, Marlet J. Relevance of Tacrolimus Trough Concentration and Hepatitis E virus Genetic Changes in Kidney Transplant Recipients With Chronic Hepatitis E. Kidney Int Rep 2024; 9:1333-1342. [PMID: 38707810 PMCID: PMC11069011 DOI: 10.1016/j.ekir.2024.01.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 01/26/2024] [Accepted: 01/29/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction Hepatitis E virus (HEV) can cause chronic infection (≥3 months) and cirrhosis in immunocompromised patients, especially kidney transplant recipients. Low alanine aminotransferase (ALT) levels and high HEV intrahost diversity have previously been associated with evolution toward chronicity in these patients. We hypothesized that additional clinical and viral factors could be associated with the risk of chronic HEV infection. Methods We investigated a series of 27 kidney transplant recipients with HEV infection, including 20 patients with chronic hepatitis E. Results High tacrolimus trough concentration at diagnosis was the most relevant marker associated with chronic hepatitis E (9.2 vs. 6.4 ng/ml, P = 0.04). Most HEV genetic changes selected during HEV infection were compartmentalized between plasma and feces. Conclusion This compartmentalization highlights the diversity and complexity of HEV replication compartments. Tacrolimus trough concentration at diagnosis of HEV infection could allow an early identification of patients at high risk of chronic hepatitis E and guide treatment initiation.
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Affiliation(s)
- Nancy León-Janampa
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | - Natacha Boennec
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | | | - Simon Ereh
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | - Gabriel Herbet
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | - Alain Moreau
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | - Philippe Gatault
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Hélène Longuet
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Christelle Barbet
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Mathias Büchler
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Christophe Baron
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Catherine Gaudy-Graffin
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, Tours, France
| | - Denys Brand
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, Tours, France
| | - Julien Marlet
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, Tours, France
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Luo Q, Chen J, Zhang Y, Xu W, Liu Y, Xie C, Peng L. Viral hepatitis E: Clinical manifestations, treatment, and prevention. LIVER RESEARCH 2024; 8:11-21. [PMID: 39959034 PMCID: PMC11771268 DOI: 10.1016/j.livres.2024.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/17/2023] [Accepted: 01/03/2024] [Indexed: 02/18/2025]
Abstract
Hepatitis E is a globally distributed infection that varies in seroprevalence between developed and developing regions. In the less developed regions of Asia and Africa, a high seropositivity rate has been reported for hepatitis E virus (HEV) antibodies. Although acute hepatitis E is often self-limited and has a favorable prognosis, some populations experience severe manifestations, which may progress to liver failure. Moreover, some immunocompromised patients are at risk of developing chronic HEV infection and cirrhosis. Proactive screening, reducing misdiagnosis, improving patient management, timely antiviral therapy for severe and chronic cases, and vaccination of high-risk groups are important measures to reduce the morbidity of hepatitis E. This review focused on the clinical presentation, management, and prevention of hepatitis E.
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Affiliation(s)
- Qiumin Luo
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jia Chen
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yeqiong Zhang
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenxiong Xu
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ying Liu
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Chan Xie
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Liang Peng
- Department of Infectious Disease, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Viral agents (2nd section). Transfusion 2024; 64 Suppl 1:S19-S207. [PMID: 38394038 DOI: 10.1111/trf.17630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 12/02/2023] [Indexed: 02/25/2024]
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Schäfer G, Lübke R, Degen O, Mader M, Scheiter R, Wolski A, Addo MM, Schulze Zur Wiesch J, Pischke S. Lack of evidence of acute HEV infections as a sexually transmitted disease: Data from a German cohort of PrEP users. Braz J Infect Dis 2024; 28:103720. [PMID: 38365184 PMCID: PMC10885309 DOI: 10.1016/j.bjid.2024.103720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 12/26/2023] [Accepted: 01/24/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND While the sexual transmissibility of HAV in MSM has been extensively described, the potential for sexual transmission of HEV has not been definitively established. Although HEV has been detected in the ejaculate of chronically infected men, studies among MSM PrEP users in France did not observe an elevated anti-HEV seroprevalence as an indicator of increased exposure risk by sexual intercourse. PATIENTS AND METHODS A total of 111 unselected PrEP users and 111 age- and sex-matched blood donors were tested for anti-HEV IgG, IgM and HEV (PCR). Of the participants 79/111 (71 %) responded to a questionnaire covering topics as sexual preferences, previous sexually transmitted diseases, profession, food consumption, and pet ownership. RESULTS The anti-HEV IgG seroprevalence in PrEP users (22 %) did not differ significantly from the rate in controls (17 %). While one PrEP user and three controls tested positive for anti-HEV IgM, all PrEP users and controls tested PCR negative. CONCLUSION In immunocompetent individuals with frequent changes of sexual partners, the epidemiology of Hepatitis E Virus does not significantly involve the sexual transmission route.
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Affiliation(s)
- Guido Schäfer
- ICH Hamburg, Hamburg, Germany; Ambulanzentrum des UKE, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rabea Lübke
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Olaf Degen
- Ambulanzentrum des UKE, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maria Mader
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Robin Scheiter
- Ambulanzentrum des UKE, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Annika Wolski
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Marylyn M Addo
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, Hamburg, Germany
| | - Julian Schulze Zur Wiesch
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, Hamburg, Germany
| | - Sven Pischke
- First Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, Hamburg, Germany.
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Biswas S, Shalimar. Liver Transplantation for Acute Liver Failure- Indication, Prioritization, Timing, and Referral. J Clin Exp Hepatol 2023; 13:820-834. [PMID: 37693253 PMCID: PMC10483009 DOI: 10.1016/j.jceh.2023.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 01/17/2023] [Indexed: 09/12/2023] Open
Abstract
Acute liver failure (ALF) is a major success story in gastroenterology, with improvements in critical care and liver transplant resulting in significant improvements in patient outcomes in the current era compared to the dismal survival rates in the pretransplant era. However, the ever-increasing list of transplant candidates and limited organ pool makes judicious patient selection and organ use mandatory to achieve good patient outcomes and prevent organ wastage. Several scoring systems exist to facilitate the identification of patients who need a liver transplant and would therefore need an early referral to a specialized liver unit. The timing of the liver transplant is also crucial as transplanting a patient too early would lead to those who would recover spontaneously receiving an organ (wastage), and a late decision might result in the patient becoming unfit for transplant (delisted) or have an advanced disease which would result in poor post-transplant outcomes. The current article reviews the indications and contraindications of liver transplant in ALF patients, the various prognostic scoring systems, etiology-specific outcomes, prioritization and timing of referral.
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Affiliation(s)
- Sagnik Biswas
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences New Delhi, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences New Delhi, India
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Ying D, Niu W, Chen Y, Wang Y, Tian W, Zhang X, Liu C, Wang S, Chen Z, Lin Y, Guo S, Yu Z, Chen X, Fang M, Qiang H, Yin Y, Tang Z, Zheng Z, Fu L, Xia N. Case Report: Chronic hepatitis E virus Infection in an individual without evidence for immune deficiency. Front Immunol 2023; 14:1183859. [PMID: 37404820 PMCID: PMC10315653 DOI: 10.3389/fimmu.2023.1183859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/03/2023] [Indexed: 07/06/2023] Open
Abstract
Chronic hepatitis E virus (HEV) infection occurs mainly in immunosuppressed populations. We describe an investigation of chronic HEV infection of genotype 3a in an individual without evidence for immune deficiency who presented hepatitis with significant HEV viremia and viral shedding. We monitored HEV RNA in plasma and stools, and assessed anti-HEV specific immune responses. The patient was without apparent immunodeficiency based on quantified results of white blood cell, lymphocyte, neutrophilic granulocyte, CD3+ T cell, CD4+ T cell, and CD8+ T cell counts and CD4/CD8 ratio, as well as total serum IgG, IgM, and IgA, which were in the normal range. Despite HEV specific cellular response and strong humoral immunity being observed, viral shedding persisted up to 109 IU/mL. After treatment with ribavirin combined with interferon, the indicators of liver function in the patient returned to normal, accompanied by complete suppression and clearance of HEV. These results indicate that HEV chronicity can also occur in individuals without evidence of immunodeficiency.
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Affiliation(s)
- Dong Ying
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Wenxia Niu
- Department of Infectious Disease, Xiang’an Hospital of Xiamen University, Xiamen, China
| | - Yanling Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yingbin Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Weikun Tian
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xiaoping Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Chang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Siling Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zihao Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yajie Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Shaoqi Guo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zihao Yu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Xiuting Chen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Mujin Fang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
- National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, China
| | - Hongsheng Qiang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Yifan Yin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Zimin Tang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
- National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, China
| | - Zizheng Zheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
| | - Lijuan Fu
- Department of Infectious Disease, Xiang’an Hospital of Xiamen University, Xiamen, China
- Xiamen Quality Control Center of Infectious Diseases, Xiamen, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, China
- National Medical Products Administration (NMPA) Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, China
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11
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Animal Models for Studying Congenital Transmission of Hepatitis E Virus. Microorganisms 2023; 11:microorganisms11030618. [PMID: 36985191 PMCID: PMC10057890 DOI: 10.3390/microorganisms11030618] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
One of the most intriguing issues in the hepatitis E virus (HEV) field is the significant increase in mortality rates of the mother and fetus when infection occurs in the second and third trimesters of gestation. A virus that is normally self-limiting and has a mortality rate of less than one percent in otherwise healthy individuals steeply rises by up to 30% in these pregnant populations. Answering this pivotal question has not been a simple task. HEV, in general, has been a difficult pathogen to understand in the laboratory setting. A historical lack of ability to efficiently propagate the virus in tissue culture models has led to many molecular aspects of the viral lifecycle being understudied. Although great strides have been made in recent years to adapt viruses to cell culture, this field remains behind other viruses that are much easier to replicate efficiently in vitro. Some of the greatest discoveries regarding HEV have come from using animal models for which naturally occurring strains of HEV have been identified, including pigs and chickens, but key limitations have made animal models imperfect for studying all aspects of human HEV infections. In addition to the difficulties working with HEV, pregnancy is a very complicated biological process with an elaborate interplay between many different host systems, including hormones, cardiovascular, kidneys, respiratory, gastrointestinal, epithelial, liver, metabolic, immune, and others. Significant differences between the timing and interplay of these systems are notable between species, and making direct comparisons between animals and humans can be difficult at times. No simple answer exists as to how HEV enhances mortality in pregnant populations. One of the best approaches to studying HEV in pregnancy is likely a combinatorial approach that uses the best combination of emerging in vitro and in vivo systems while accounting for the deficiencies that are present in each model. This review describes many of the current HEV animal model systems and the strengths and weaknesses of each as they apply to HEV pregnancy-associated mortality. We consider factors that are critical to analyzing HEV infection within the host and how, despite no perfect animal model for human pregnancy mortality existing, recent developments in HEV models, both in vitro and in vivo, are advancing our overall understanding of HEV in the pregnant host.
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12
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De Sabato L, Ianiro G, Filipello V, Arnaboldi S, Righi F, Ostanello F, Giammarioli M, Lavazza A, Di Bartolo I. Absence of Hepatitis E Virus (HEV) in Italian Lagomorph Species Sampled between 2019 and 2021. Animals (Basel) 2023; 13:ani13030545. [PMID: 36766433 PMCID: PMC9913390 DOI: 10.3390/ani13030545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
The zoonotic hepatitis E virus genotype 3 (HEV-3) causes most autochthonous human hepatitis E cases in Europe, which are due to the consumption of raw or undercooked food products of animal origin. Pigs and wild boars are considered the main reservoirs of this genotype, while rabbits are the reservoir of a distinct phylogenetic group named HEV-3ra, which is classified within the HEV-3 genotype but in a separate clade. Evidence for the zoonotic potential of HEV-3ra was suggested by its detection in immunocompromised patients in several European countries. HEV-3ra infection was found in farmed and feral rabbit populations worldwide and its circulation was reported in a few European countries, including Italy. Furthermore, Italy is one of the major rabbit meat producers and consumers across Europe, but only a few studies investigated the presence of HEV in this reservoir. The aim of this study was to assess the presence of HEV in 328 Italian hares and 59 farmed rabbits collected in 3 Italian macro-areas (North, North-Central, and South-Central), between 2019 and 2021. For this purpose, liver samples were used to detect HEV RNA using broad-range real-time RT-PCR and nested RT-PCR. Using 28 liver transudates from hares, the ELISA test for anti-HEV IgG detection was also performed. Neither HEV RNA nor anti-HEV antibodies were detected. Further studies will be conducted to assess the HEV presence in Italian lagomorphs to establish the role of this host and the possible risk of transmission for workers with occupational exposure, to pet owners and via food.
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Affiliation(s)
- Luca De Sabato
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
| | - Giovanni Ianiro
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
- Correspondence: (G.I.); (F.O.)
| | - Virginia Filipello
- Department of Food Safety, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia-Romagna “Bruno Ubertini” (IZSLER), Via Antonio Bianchi, 7/9, 25124 Brescia, Italy
| | - Sara Arnaboldi
- Department of Food Safety, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia-Romagna “Bruno Ubertini” (IZSLER), Via Antonio Bianchi, 7/9, 25124 Brescia, Italy
| | - Francesco Righi
- Department of Food Safety, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia-Romagna “Bruno Ubertini” (IZSLER), Via Antonio Bianchi, 7/9, 25124 Brescia, Italy
| | - Fabio Ostanello
- Department of Veterinary Medical Sciences, University of Bologna, Via Tolara di Sopra, 50, 40064 Ozzano dell’ Emilia, Italy
- Correspondence: (G.I.); (F.O.)
| | - Monica Giammarioli
- Istituto Zooprofilattico Sperimentale dell’Umbria e delle Marche “Togo Rosati” (IZSUM), Via Salvemini, 1, 06126 Perugia, Italy
| | - Antonio Lavazza
- Department of Animal Health and Welfare, Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia-Romagna “Bruno Ubertini” (IZSLER), Via Antonio Bianchi, 7/9, 25124 Brescia, Italy
| | - Ilaria Di Bartolo
- Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy
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13
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Abravanel F, Lhomme S, Marion O, Péron JM, Kamar N, Izopet J. Diagnostic and management strategies for chronic hepatitis E infection. Expert Rev Anti Infect Ther 2023; 21:143-148. [PMID: 36625025 DOI: 10.1080/14787210.2023.2166932] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Hepatitis E Virus (HEV) was initially thought to cause only acute infections, but the discovery of chronic hepatitis E in immunocompromised patients has profoundly changed our understanding of the virus. AREAS COVERED We describe the physiopathology, diagnosis, and clinical management of chronic HEV infection. The virus can persist in nearly two-thirds of immunosuppressed patients. Reducing immunosuppression is the first immunomodulatory strategy to cure chronic hepatitis E. But this may not always be feasible or effective. Ribavirin monotherapy for 3 months has been recommended as first-line treatment for chronically infected patients. Ribavirin is around 80% effective at eradicating HEV in retrospective studies. Apart from ribavirin, interferon has been successfully used in liver transplants recipients, but if the patient does not respond, no other alternative drug is available. The vaccine available to prevent HEV infection is one available only in China. EXPERT OPINION HEV infection is a major concern in immunocompromised patients. But the therapeutic arsenal is limited to ribavirin and interferon. Both produce several side effects and new drugs are urgently needed. Moreover, preventive strategies to limit HEV transmission and/or evolution to a chronic infection are also required.
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Affiliation(s)
- Florence Abravanel
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France
| | - Sébastien Lhomme
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France
| | - Olivier Marion
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France.,CHU Toulouse, Hôpital Rangueil, département de Néphrologie et transplantation d'organe, Toulouse, France
| | - Jean Marie Péron
- CHU Toulouse, Hôpital Rangueil, département de Gastroentérologie, Toulouse, France
| | - Nassim Kamar
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Rangueil, département de Néphrologie et transplantation d'organe, Toulouse, France
| | - Jacques Izopet
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France
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14
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He Q, Zhang F, Shu J, Li S, Liang Z, Du M, Liu X, Liu T, Li M, Yin X, Pan Q, Lu F, Wang L, Wang L. Immunocompromised rabbit model of chronic HEV reveals liver fibrosis and distinct efficacy of different vaccination strategies. Hepatology 2022; 76:788-802. [PMID: 35278241 DOI: 10.1002/hep.32455] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/17/2022] [Accepted: 03/06/2022] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS HEV infection can lead to chronicity and rapid progression to liver fibrosis and cirrhosis in immunocompromised organ transplant recipients. Robust animal models are urgently needed to study the pathogenesis and test the efficacy of vaccines and antiviral drugs in immunosuppressed settings. APPROACH AND RESULTS Cyclosporin A was used to induce immunosuppression. Rabbits were challenged with genotype 3 or 4 HEV (i.e., the rabbit-derived HEV3 and human-derived HEV3 or HEV4). We assessed HEV markers within 13 weeks post inoculation (wpi) and pathological changes by hematoxylin and eosin and Masson staining at 4, 8, or 13 wpi. Chronic HEV infection was successfully established in immunocompromised rabbits. HEV RNA and/or antigens were detected in the liver, kidney, intestine, urine, and cerebrospinal fluid samples. Chronically infected animals exhibited typical characteristics of liver fibrosis development. Intrahepatic transcriptomic analysis indicated activation of both innate and adaptive immunity. Establishment of HEV chronicity likely contributed to the inhibited T-cell immune response. Ribavirin is effective in clearing HEV infection in immunocompromised rabbits. Most interestingly, vaccination completed before immunosuppression conferred full protection against both HEV3 and HEV4 infections, but vaccination during immunosuppression was only partially protective, and the efficacy did not improve with increased or additional vaccine doses. CONCLUSIONS The immunocompromised rabbit model of both chronic HEV3 and HEV4 infection that was established captured the key features of chronic HEV infection in transplant patients, including liver fibrogenesis, and revealed the distinct effectiveness of vaccination administered before or under immunosuppression. This rabbit model is valuable for understanding the pathogenesis of chronic hepatitis E, as well as for evaluating antiviral agents and vaccines.
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Affiliation(s)
- Qiyu He
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fan Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Jingyi Shu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Shuangshuang Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhaochao Liang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Minghao Du
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xing Liu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Tianxu Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Manyu Li
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xin Yin
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Peking University-Sansure Biotech Joint Laboratory of Molecular Medicine, Peking University, Beijing, China
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15
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Chew N, Situ J, Wu S, Yao W, Sridhar S. Independent Evaluation of Cell Culture Systems for Hepatitis E Virus. Viruses 2022; 14:v14061254. [PMID: 35746725 PMCID: PMC9227121 DOI: 10.3390/v14061254] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 02/04/2023] Open
Abstract
Hepatitis E virus (HEV) infection in humans is primarily caused by genotypes within Paslahepevirus species balayani (HEV-A). Rocahepevirus species ratti (HEV-C1, otherwise known as rat HEV) can also infect humans. HEV grows poorly in cell culture. Recent studies have reported that hyper-confluent cell layers, amphotericin B, MgCl2, progesterone, and dimethyl sulfoxide (DMSO) increase HEV yield in vitro. Here, we describe an independent evaluation of the effectiveness of these modifications in improving the yield of HEV-A genotype 4 (HEV-A4) and HEV-C1 from clinical samples in PLC/PRF/5 cells. We found that amphotericin B, MgCl2, and DMSO increased HEV yield from high-viral-load patient stool samples, while progesterone was not effective. Yield of HEV-C1 was lower than HEV-A4 across all medium conditions, but was boosted by DMSO. HEV-A4 could be maintained for over 18 months in amphotericin B- and MgCl2-containing medium, with the demonstration of viral antigen in supernatants and infected cells. We also evaluated various protocols to remove pseudo-envelopes from cell culture-derived HEV. Treating cell culture supernatant with NP-40 was the most effective. Our findings identify key modifications that boost HEV growth in vitro and illustrate the importance of independent verification of such studies using diverse HEV variants and cell lines.
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Affiliation(s)
- Nicholas Chew
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (N.C.); (J.S.); (S.W.); (W.Y.)
| | - Jianwen Situ
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (N.C.); (J.S.); (S.W.); (W.Y.)
| | - Shusheng Wu
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (N.C.); (J.S.); (S.W.); (W.Y.)
| | - Weiming Yao
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (N.C.); (J.S.); (S.W.); (W.Y.)
| | - Siddharth Sridhar
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; (N.C.); (J.S.); (S.W.); (W.Y.)
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China
- Correspondence: ; Tel.: +852-22552408
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16
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Abstract
Hepatitis E virus (HEV) is a major cause of acute viral hepatitis in humans. A convenient small mammalian model for basic research and antiviral testing is still greatly needed. Although a small rodent, the Mongolian gerbil, was reported to be susceptible to swine genotype-4 HEV infection, whether the previous results were reliable and consistent needs to be validated by using biologically pure HEV stocks or infectious RNA. In this study, we revisited this gerbil infection model for human HEV of genotype 1, 3, or 4 (G1, G3, or G4) by HEV reverse genetics. Gerbils inoculated intrahepatically with capped G3 HEV RNA transcripts or intraperitoneally with infectious G3 cloned HEV produced robust infection, as evidenced by presence of HEV in livers, spleens, and feces for up to 7 weeks post inoculation, seroconversion, and pathological liver lesions. Furthermore, the value of the gerbil model in antiviral testing and type I IFN in host defense was assessed. We demonstrated the effectiveness of peg-IFNα-2a and ribavirin in inhibiting HEV replication in gerbils. By treatment with two molecule inhibitors of TBK1, we also revealed a role of RIG-I like receptor-interferon regulatory factor 3 in host anti-HEV innate immune sensing in this in vivo model. Finally, susceptibility of G4 HEV was demonstrated in intrahepatically inoculated gerbils with infectious HEV RNA transcripts, whereas no evidence for G1 HEV susceptibility was found. The availability of the convenient gerbil model will greatly facilitate HEV-specific antiviral development and assess the mechanism of host immune response during HEV infection. IMPORTANCE HEV infects >20 million people annually, causing acute viral hepatitis as well as chronic hepatitis, neurological diseases, and pregnancy-associated high mortality, which require therapeutic intervention. The HEV antiviral research is largely limited by the lack of a convenient small animal model. Here we revisit the Mongolian gerbil model for three genotypes of human HEV by infectious HEV clones and recognized standards of experimental procedures. Fecal virus shedding, seroconversion, and pathological liver lesions could be detected in HEV-inoculated gerbils. We demonstrate the effectiveness and usefulness of this model in testing antiviral drugs, and in assessing the mechanism of host innate immune response upon HEV infection. This conventional rodent model will aid in future antiviral development and delineating mechanism of host immune response.
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17
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Hepatitis A and E in the Mediterranean: A systematic review. Travel Med Infect Dis 2022; 47:102283. [PMID: 35227863 DOI: 10.1016/j.tmaid.2022.102283] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/05/2022] [Accepted: 02/23/2022] [Indexed: 11/23/2022]
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18
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Ji Y, Li P, Jia Y, Wang X, Zheng Q, Peppelenbosch MP, Ma Z, Pan Q. Estimating the burden and modeling mitigation strategies of pork-related hepatitis E virus foodborne transmission in representative European countries. One Health 2021; 13:100350. [PMID: 34841035 PMCID: PMC8606544 DOI: 10.1016/j.onehlt.2021.100350] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 11/12/2021] [Accepted: 11/16/2021] [Indexed: 01/04/2023] Open
Abstract
Hepatitis E virus (HEV) is an emerging zoonotic pathogen posing global health burden, and the concerns in Europe are tremendously growing. Pigs serve as a main reservoir, contributing to pork-related foodborne transmission. In this study, we aim to specifically simulate this foodborne transmission route and to assess potential interventions. We firstly established a dose-response relationship between the risk of transmission to human and the amount of ingested viruses. We further estimated the incidence of HEV infection specifically attributed to pork-related foodborne transmission in four representative European countries. Finally, we demonstrated a proof-of-concept of mitigating HEV transmission by implementing vaccination in human and pig populations. Our modeling approach bears essential implications for better understanding the transmission of pork-related foodborne HEV and for developing mitigation strategies.
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Affiliation(s)
- Yunpeng Ji
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.,Department of Genetics, Inner Mongolian Maternal and Child Care Hospital, Inner Mongolian, China
| | - Pengfei Li
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Yueqi Jia
- Department of Genetics, Inner Mongolian Maternal and Child Care Hospital, Inner Mongolian, China
| | - Xiaohua Wang
- Department of Genetics, Inner Mongolian Maternal and Child Care Hospital, Inner Mongolian, China
| | - Qinyue Zheng
- School of Management, Shandong Key Laboratory of Social Supernetwork Computation and Decision Simulation, Shandong University, Jinan, China
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Zhongren Ma
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China
| | - Qiuwei Pan
- Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou, China.,Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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19
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Hriskova K, Marosevic D, Belting A, Wenzel JJ, Carl A, Katz K. Epidemiology of Hepatitis E in 2017 in Bavaria, Germany. FOOD AND ENVIRONMENTAL VIROLOGY 2021; 13:337-346. [PMID: 33900549 PMCID: PMC8379136 DOI: 10.1007/s12560-021-09474-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 04/03/2021] [Indexed: 05/04/2023]
Abstract
In the last decade, the number of reported hepatitis E virus (HEV) infections in Germany, including Bavaria, has continued to rise. In order to identify risk factors associated with HEV infection, we investigated notified hepatitis E cases from Bavaria during 2017. The project "Intensified Hepatitis E Surveillance in Bavaria" included interviews with questionnaires, collection and genotyping of stool, serum and food samples. In addition, certain risk factors were examined in a sample comparison with healthy population using univariable analysis and logistic regression. In total, 135 hepatitis E cases from Bavaria were included in the analysis. Mean age for women was 46 (range 20-74) years and 47.5 (range 20-85) for men. 56 of the cases (41.5%) were asymptomatic. Among the symptomatic cases, both men and women were equally affected with symptoms like fever (16.3%), jaundice (18.8%) and upper abdominal pain (28.2%). 145 human samples (serum, stool) and 6 food samples were collected. 15.9% of the human samples (n = 23) were positive for HEV RNA by reverse-transcription quantitative real-time PCR (RT-qPCR). Identified risk factors significantly associated with hepatitis E were sausage consumption with odds ratio 9.6 (CI 1.3-70.1), fish with OR 2.2 (CI 1.1-4.4) and cat ownership with OR 1.9 (CI 1.3-3.0) in multivariable analyses. Further investigation is needed to confirm the role of fish in HEV transmission. Autochthonous HEV genotype 3 is prevalent in Bavaria and there could be more transmission routes contributing to the spread of HEV than previously known. Undercooked meat, offal, sausages, fish, shellfish and contact with animals and pets are possible sources for infection.
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Affiliation(s)
- K Hriskova
- Institute for Medical Information Processing, Biometry and Epidemiology - IBE, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.
- Pettenkofer School of Public Health, Munich, Germany.
| | - D Marosevic
- Bavarian Public Health and Food Safety Authority (LGL), Veterinärstraße 2, 85764, Oberschleißheim, Germany
| | - A Belting
- Bavarian Public Health and Food Safety Authority (LGL), Veterinärstraße 2, 85764, Oberschleißheim, Germany
| | - J J Wenzel
- National Consultant Laboratory for HAV and HEV, Institute of Clinical Microbiology and Hygiene, University Medical Centre Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany
| | - A Carl
- Bavarian Public Health and Food Safety Authority (LGL), Veterinärstraße 2, 85764, Oberschleißheim, Germany
| | - K Katz
- Bavarian Public Health and Food Safety Authority (LGL), Veterinärstraße 2, 85764, Oberschleißheim, Germany
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20
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Genetic Diversity and Epidemiological Significance of Wild Boar HEV-3 Strains Circulating in Poland. Viruses 2021; 13:v13061176. [PMID: 34205456 PMCID: PMC8235543 DOI: 10.3390/v13061176] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 05/24/2021] [Accepted: 06/15/2021] [Indexed: 01/06/2023] Open
Abstract
The wild boar is the most important reservoir of zoonotic HEV-3 strains among different wildlife species. The aim of the study was subtype identification of wild boar HEV-3 strains circulating in Poland. Wild boar liver was used in the study in the form of homogenates prepared from 57 samples positive for HEV in a real-time RT-PCR. These samples were collected from juvenile and adult wild boars hunted in the jurisdictions of different Regional Directorates of State Forests (RDSF) across Poland. Subtype identification of detected HEV strains was based on a phylogenetic analysis of the most conserved HEV ORF2 genome fragment. Out of 57 tested samples, consensus HEV ORF2 sequences of 348 bp were obtained for 45 strains. Nineteen strains were identified and belonged to the HEV gt 3a and 3i subtypes, whereas 26 were not assigned to any virus subtype. HEV gt 3i strains prevailed in the Polish wild boar population, 16 of such were identified, and they were significantly more often observed in the RDSF Katowice area (χ2 = 28.6, p = 0.027 (<0.05)) compared to other regions of the country. Circulation of 3a strains was limited only to the RDSF Gdańsk territory (χ2 = 48, p = 0.000 (<0.05)). The virus strains detected in the Polish population of wild boars representing previously identified HEV subtypes in wild boars, pigs, or humans in Europe are of epidemiological importance for public health.
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21
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Oluremi AS, Opaleye OO, Ogbolu DO, Alli OAT, Ashiru FT, Alaka OO, Suleiman IE, Enitan SS, Adelakun AA, Adediji IO, Olowoyeye EA, Adewumi OO, Ayodele TO, Ogunleke OA. Serological evidence of HIV, Hepatitis B, C, and E viruses among liver disease patients attending tertiary hospitals in Osun State, Nigeria. J Immunoassay Immunochem 2021; 42:69-81. [PMID: 32967530 DOI: 10.1080/15321819.2020.1821214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Hepatitis infection in HIV positive individuals with liver diseases causes high mortality worldwide. HIV worsens the pathological effect of hepatitis viruses and potentiates reactivation of latent hepatitis infections due to reduced immunity. This research therefore aimed to study the occurrence of HIV and hepatitis viruses among liver diseases patients (LVDP) attending tertiary hospitals in Osun State, southwestern Nigeria. A total of 121 LVDP blood samples collected were tested for HIV and Hepatitis B, C, and E using and enzyme linked Immunossorbent assay (ELISA). Data were analyzed using packages within SPSS and P ≤ 0.05 was considered significant. Prevalence of 32.2%, 0.8%, 10.7%, and 18.2% for HBsAg, Anti-HCV, HEV-IgM, and HIV were found respectively. Marital status showed a significant association with HEV-IgM infection (χ2 = 9.869, P = .020). The prevalence of HBsAg, HEV, and HIV among LVDP in Osun State is alarming and health education among the patients and general populace is hereby advocated. High HEV-IgM seroprevalence implies that HEV routine screening should be incorporated into blood screening. Since HEV is associated with unhygienic practice, people should be enlightened on how to improve their living conditions.
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Affiliation(s)
- A S Oluremi
- Department of Medical Laboratory Science, Babcock University, Ilishan Remo, Nigeria
- Department of Medical Microbiology & Parasitology, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - O O Opaleye
- Department of Medical Microbiology & Parasitology, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - D O Ogbolu
- Department of Medical Laboratory Science, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - O A T Alli
- Department of Medical Laboratory Science, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - F T Ashiru
- Department of Medical Laboratory Science, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - O O Alaka
- Department of Medical Microbiology & Parasitology, Obafemi Awolowo University Teaching Hospital Complex, Ile Ife, Nigeria
| | - I E Suleiman
- Department of Chemical Pathology & Immunology, University of Ilorin Teaching Hospital, Ilorin, Nigeria
| | - S S Enitan
- Department of Medical Laboratory Science, Babcock University, Ilishan Remo, Nigeria
| | - A A Adelakun
- Department of Medical Laboratory Science, Babcock University, Ilishan Remo, Nigeria
| | - I O Adediji
- Department of Medical Laboratory Science, Babcock University, Ilishan Remo, Nigeria
| | - E A Olowoyeye
- Department of Basic Medical Sciences, College of Health Sciences & Technology, Ijero Ekiti, Nigeria
| | - O O Adewumi
- PPP Laboratory, University College Hospital, Ibadan, Nigeria
| | - T O Ayodele
- Department of Basic Medical Sciences, College of Health Sciences & Technology, Ijero Ekiti, Nigeria
- Department of Medical Laboratory Science, LAUTECH Teaching Hospital, Osogbo, Nigeria
| | - O A Ogunleke
- Department of Medical Laboratory Science, LAUTECH Teaching Hospital, Osogbo, Nigeria
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22
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Xu LD, Zhang F, Peng L, Luo WT, Chen C, Xu P, Huang YW. Stable Expression of a Hepatitis E Virus (HEV) RNA Replicon in Two Mammalian Cell Lines to Assess Mechanism of Innate Immunity and Antiviral Response. Front Microbiol 2020; 11:603699. [PMID: 33424806 PMCID: PMC7793998 DOI: 10.3389/fmicb.2020.603699] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/13/2020] [Indexed: 12/17/2022] Open
Abstract
Hepatitis E virus (HEV) is one of the major etiological agents responsible for acute hepatitis. Hepatitis E virus does not replicate efficiently in mammalian cell cultures, thus a useful model that mimics persistent HEV replication is needed to dissect the molecular mechanism of pathogenesis. Here we report a genotype-3 HEV RNA replicon expressing an EGFP-Zeocin (EZ) resistant gene (p6-EZ) that persistently self-replicated in cell lines of human (Huh-7-S10-3) or hamster (BHK-21) origin after transfection with in vitro RNA transcripts and subsequent drug screening. Two cell lines, S10-3-EZ and BHK-21-EZ, stably expressed EGFP in the presence of Zeocin during continuous passages. Both genomic and subgenomic HEV RNAs and viral replicase proteins were stably expressed in persistent HEV replicon cells. The values of the cell models in antiviral testing, innate immune RNA sensing and type I IFN in host defense were further demonstrated. We revealed a role of RIG-I like receptor-interferon regulatory factor 3 in host antiviral innate immune sensing during HEV replication. We further demonstrated that treatment with interferon (IFN-α) or ribavirin significantly reduced expression of replicon RNA in a dose-dependent manner. The availability of the models will greatly facilitate HEV-specific antiviral development, and delineate mechanisms of HEV replication.
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Affiliation(s)
- Ling-Dong Xu
- Institute of Preventive Veterinary Science and Key Laboratory of Animal Virology of Ministry of Agriculture, Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Fei Zhang
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Lei Peng
- Institute of Preventive Veterinary Science and Key Laboratory of Animal Virology of Ministry of Agriculture, Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Wen-Ting Luo
- Institute of Preventive Veterinary Science and Key Laboratory of Animal Virology of Ministry of Agriculture, Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Chu Chen
- Institute of Preventive Veterinary Science and Key Laboratory of Animal Virology of Ministry of Agriculture, Department of Veterinary Medicine, Zhejiang University, Hangzhou, China
| | - Pinglong Xu
- MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yao-Wei Huang
- Institute of Preventive Veterinary Science and Key Laboratory of Animal Virology of Ministry of Agriculture, Department of Veterinary Medicine, Zhejiang University, Hangzhou, China.,Zhaoqing Branch Center of Guangdong Laboratory for Lingnan Modern Agricultural Science and Technology, Zhaoqing, China
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23
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Janahi EM, Parkar SFD, Mustafa S, Eisa ZM. Implications of Hepatitis E Virus in Blood Transfusions, Hemodialysis, and Solid Organ Transplants. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:E206. [PMID: 32344807 PMCID: PMC7279256 DOI: 10.3390/medicina56050206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 01/05/2023]
Abstract
Hepatitis E Virus (HEV) is emerging as the primary cause of acute viral hepatitis in humans. The virus is commonly transmitted by the fecal-oral route via contaminated water in endemic regions or through the consumption of inadequately cooked swine products or game meats in industrialized regions. HEV genotypes 1 and 2 are predominantly associated with waterborne transmission in developing countries, whereas HEV3 and HEV4 are mainly zoonotically transmitted in industrialized countries. Seroprevalence in populations determined by detecting anti-HEV antibodies and serum HEV RNA is commonly used to analyze the presence of HEV. Although HEV RNA-based detection is now standardized, there is a lack of agreement between the assaying methods used for gathering seroprevalence data. Since 2004, HEV has been considered as a transmissible infectious agent through blood transfusion. Recent seroprevalence studies in European countries indicate an underestimated risk for blood transfusion and hence warrant testing the blood supply. HEV infection is usually self-limiting and spontaneously cleared. However, in about 60% of recipients of solid organ transplants, HEV progresses to chronic hepatitis. Immunosuppressive drugs such as tacrolimus are a major cause of chronic hepatitis and reducing its dosage results in viral clearance in about 30% of patients. In hemodialysis patients, the parenteral route is implicated as an important mechanism of transmission. In this review, we explore the clinical and epidemiological characteristics of various HEV genotypes in blood donors, hemodialysis patients, and transplant recipients.
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Affiliation(s)
- Essam M. Janahi
- Department of Biology, College of Science, University of Bahrain, Sakhir 32038, Bahrain; (S.F.D.P.); (S.M.)
| | - Saba F. D. Parkar
- Department of Biology, College of Science, University of Bahrain, Sakhir 32038, Bahrain; (S.F.D.P.); (S.M.)
| | - Sakina Mustafa
- Department of Biology, College of Science, University of Bahrain, Sakhir 32038, Bahrain; (S.F.D.P.); (S.M.)
| | - Zaki M. Eisa
- The National Center for Disease Prevention and Control, Jazan 82722-2476, Saudi Arabia;
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24
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Istrate A, Rădulescu AL. A comparison of hepatitis E and A in a teaching hospital in Northwestern Romania. Acute hepatitis E - a mild disease? Med Pharm Rep 2020; 93:30-38. [PMID: 32133444 PMCID: PMC7051815 DOI: 10.15386/mpr-1487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/20/2019] [Accepted: 12/09/2019] [Indexed: 12/13/2022] Open
Abstract
Background and aims The incidence of locally acquired hepatitis E has increased in recent years across Europe. There are only few data on hepatitis E in Romania. The purpose of our research was to describe and compare hepatitis E and hepatitis A in adult patients. Methods We included all consecutive adult patients with hepatitis E and hepatitis A admitted to the Teaching Hospital of Infectious Diseases, Cluj-Napoca, Romania between January 2017 and August 2019. Results Hepatitis E incidence increased in 2018–2019 compared to 2017. The average age in hepatitis E (n=48) patients was 50.6 versus 39.1 years in hepatitis A (n=152, not including 262 minors) and two-thirds of the patients in both groups were men. Compared to hepatitis A, patients with hepatitis E presented significantly less modified AST and ALT, bilirubin, prothrombin index and INR levels. We found more comorbidities in hepatitis E patients adjusted for age and gender. Severe forms were found in 5 (3.3%) hepatitis A patients, compared to 12 (25%) of hepatitis E patients, of which 3 died. Ribavirin treatment was considered in 9 patients with acute-on-chronic hepatitis E, immunosuppression, cancers or neurological manifestations, showing good results. Conclusions We observed an increased number of hepatitis E cases. Although laboratory results were less modified compared to hepatitis A, we found a higher number of severe hepatitis E cases. Ribavirin treatment seems to be beneficial in patients with preexisting conditions.
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Affiliation(s)
- Alexandru Istrate
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Epidemiology, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania
| | - Amanda Lelia Rădulescu
- Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Epidemiology, Clinical Hospital of Infectious Diseases, Cluj-Napoca, Romania
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25
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Yrondi A, Salles J, Péron JM, Sporer M, Taib S, Gallini A, Noilhan C, Dimeglio C, Entajan F, Crequy M, Izopet J, Schmitt L. The Prevalence of Hepatitis E in a Patient Cohort Presenting With Addictive Injection Behavior. Front Psychiatry 2019; 10:832. [PMID: 31798477 PMCID: PMC6874121 DOI: 10.3389/fpsyt.2019.00832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Accepted: 10/21/2019] [Indexed: 12/14/2022] Open
Abstract
Introduction: Hepatitis E is the most common cause of acute viral hepatitis worldwide. Seroprevalence is approximately 15% in developed countries, and 22% in France. hepatitis E virus (HEV) can be transmitted via transfusions and therefore possibly intravenous (IV) drug use. Hepatitis E serology is routinely tested in patients who seek medical advice for addictive injection behavior at the addiction treatment, support and prevention unit of Toulouse University Hospital. We assume that hepatitis E is more prevalent in patients presenting with addictive injection behavior than in the general French population. Methods: Hepatitis E serological assays [immunoglobulin M (IgM) and IgG] were carried out for all patients presenting with addictive injection behavior during an initial evaluation. The controls were taken from a cohort of 3,353 blood donors living in southern France and who donated blood during the first 2 weeks of October 2011. Results: We included 52 patients presenting with addictive injection behavior and 103 healthy controls matched for age, sex, and area of residence. We found no difference between patients and controls for the prevalence of hepatitis E: patients vs. healthy controls: positive IgGs: 42.31%, 95% confidence interval (CI) (28.73-56.80%) vs. 43.43%, 95% CI (33.50-53.77%) (p = 0.89) and positive IgMs: 3.85%, 95% CI (0.47-13.22%) vs. 4.85%, 95% CI (0.16-10.97%) (p = 0.57). Conclusion: There was no difference in HEV seroprevalence between IV drug users and the general population, suggesting that the IV route of HEV infection is not significant in this population.
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Affiliation(s)
- Antoine Yrondi
- Service de Psychiatrie et de Psychologie Médicale, Centre Expert Dépression Résistante FondaMental, CHU Toulouse, Hospital Purpan, ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, Toulouse, France
| | - Juliette Salles
- Service de Psychiatrie et de Psychologie Médicale, CHU de Toulouse, Hospital Purpan, Toulouse, France
- CSAPA Maurice Dide, CHU Toulouse, Toulouse, France
| | - Jean Marie Péron
- Service d'Hépatologie, Hôpital Rangueil Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier Toulouse III, Toulouse, France
| | - Marie Sporer
- Service de Psychiatrie et de Psychologie Médicale, CHU de Toulouse, Hospital Purpan, Toulouse, France
| | - Simon Taib
- Service de Psychiatrie et de Psychologie Médicale, CHU Toulouse, Hospital Purpan, ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, Toulouse, France
| | - Adeline Gallini
- UMR1027, INSERM University of Toulouse, Toulouse, France
- Department of Epidemiology and Public Health, Centre Hospitalier Universitaire Toulouse (University Hospital Centre), Toulouse, France
| | - Chloé Noilhan
- Department of Epidemiology and Public Health, Centre Hospitalier Universitaire Toulouse (University Hospital Centre), Toulouse, France
| | - Chloé Dimeglio
- INSERM U1043—CNRS UMR5282—Toulouse University Paul Sabatier, CPTP, Toulouse, France
- CHU de Toulouse, Hôpital Purpan, Laboratoire de Virologie, Toulouse, France
| | | | - Marie Crequy
- CSAPA Maurice Dide, CHU Toulouse, Toulouse, France
| | - Jacques Izopet
- INSERM U1043—CNRS UMR5282—Toulouse University Paul Sabatier, CPTP, Toulouse, France
- CHU de Toulouse, Hôpital Purpan, Laboratoire de Virologie, Toulouse, France
| | - Laurent Schmitt
- Service de Psychiatrie et de Psychologie Médicale, CHU de Toulouse, Hospital Purpan, Toulouse, France
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26
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Heo NY. [Hepatitis E Virus: Epidemiology, Diagnosis, and Management]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 74:130-136. [PMID: 31554028 DOI: 10.4166/kjg.2019.74.3.130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 01/08/2023]
Abstract
The HEV is a known cause of water-borne outbreaks of acute non-A non-B hepatitis in developing countries, which affects young people and may result in high mortality in pregnant women. In recent decades, however, HEV genotypes 3 and 4 have been known as a cause of sporadic zoonotic infections in older males from swine HEV worldwide. Most acute HEV infections are self-limited. On the other hand, in immunosuppressed patients, including solid organ transplant recipients, chronic HEV infections may exist and progress to liver cirrhosis or decompensation. Therefore, physicians need to recognize HEV as a major pathogen for acute and chronic hepatitis of unknown causes and investigate this disease.
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Affiliation(s)
- Nae-Yun Heo
- Division of Gastroenterology, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
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27
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Wenter C, Borena W, Oberhuber G, Graziadei I. Acute liver failure in immunocompetent patients infected with hepatitis E. Wien Klin Wochenschr 2019; 131:442-445. [PMID: 31493102 PMCID: PMC6748887 DOI: 10.1007/s00508-019-01547-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/17/2019] [Indexed: 01/10/2023]
Abstract
In almost all immunocompetent patients an acute hepatitis E virus (HEV) infection is clinically silent with spontaneous viral clearance. So far, only a very small number of severe acute HEV infections have been described. This article reports the case of a 78-year-old immunocompetent, diabetic patient, who presented with a symptomatic acute HEV genotype (GT) 3 infection and that progressed to acute liver failure. After starting with an antiviral therapy with ribavirin, the HEV viral load rapidly decreased with a significant improvement of the laboratory parameters as well as a clinical amelioration of the patient. The treatment was continued for 3 months and led to a complete resolution of this acute fulminant hepatitis E. Although the risk is almost negligible this article clearly demonstrates that an acute liver failure due to HEV should also be considered in immunocompetent patients, especially in older male individuals with diabetes mellitus.
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Affiliation(s)
- Christian Wenter
- Department of Internal Medicine, Academic Teaching Hospital Hall in Tirol, Milserstraße 10, 6060, Hall in Tirol, Austria
| | - Wegene Borena
- Division of Virology, Medical University Innsbruck, Innsbruck, Austria
| | - Georg Oberhuber
- INNPATH, Institute of Pathology, Tirol Kliniken Innsbruck, Innsbruck, Austria
| | - Ivo Graziadei
- Department of Internal Medicine, Academic Teaching Hospital Hall in Tirol, Milserstraße 10, 6060, Hall in Tirol, Austria. .,Medical University Innsbruck, Innsbruck, Austria.
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28
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Walker CM. Adaptive Immune Responses in Hepatitis A Virus and Hepatitis E Virus Infections. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a033472. [PMID: 29844218 DOI: 10.1101/cshperspect.a033472] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Both hepatitis A virus (HAV) and hepatitis E virus (HEV) cause self-limited infections in humans that are preventable by vaccination. Progress in characterizing adaptive immune responses against these enteric hepatitis viruses, and how they contribute to resolution of infection or liver injury, has therefore remained largely frozen for the past two decades. How HAV and HEV infections are so effectively controlled by B- and T-cell immunity, and why they do not have the same propensity to persist as HBV and HCV infections, cannot yet be adequately explained. The objective of this review is to summarize our understanding of the relationship between patterns of virus replication, adaptive immune responses, and acute liver injury in HAV and HEV infections. Gaps in knowledge, and recent studies that challenge long-held concepts of how antibodies and T cells contribute to control and pathogenesis of HAV and HEV infections, are highlighted.
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Affiliation(s)
- Christopher M Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's, Columbus, Ohio 43004
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29
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Kamar N, Pischke S. Acute and Persistent Hepatitis E Virus Genotype 3 and 4 Infection: Clinical Features, Pathogenesis, and Treatment. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a031872. [PMID: 29735575 DOI: 10.1101/cshperspect.a031872] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis E virus (HEV) genotype (gt)3 and 4 infections are prevalent in industrialized and high-income countries. Although most HEV gt3 and gt4 infections are clinically silent, acute infection may be symptomatic in some patients. In persons with underlying liver disease and in elderly men, HEV infections may present as acute or acute-on-chronic liver failure. Chronic hepatitis may develop in immunosuppressed individuals, including transplant recipients, human immunodeficiency virus (HIV)-infected patients, and persons with hematologic malignancy undergoing chemotherapy, and may progress to life-threatening liver cirrhosis. Extrahepatic manifestations of infection may include neurological and renal disease. Although there is no approved specific therapy for the treatment of acute or chronic HEV gt3 or gt4 infection, off-label use of ribavirin appears to be capable of eliminating chronic HEV infection, and may reduce disease severity in patients suffering from acute liver failure.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology and Organ Transplantation, Université Paul Sabatier, Toulouse 31059, France
| | - Sven Pischke
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
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30
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Low EXS, Tripon E, Lim K, Tan PS, Low HC, Dan YY, Lee YM, Muthiah M, Loo WM, Koh CJ, Phyo WW, Pang J, Lim SG, Lee GH. Risk factors for ribavirin treatment failure in Asian organ transplant recipients with chronic hepatitis E infection. World J Hepatol 2019; 11:553-561. [PMID: 31293723 PMCID: PMC6603503 DOI: 10.4254/wjh.v11.i6.553] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 06/11/2019] [Accepted: 06/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) infection is a cause of chronic hepatitis in immunosuppressed patients. Sustained virologic response rates to a 12-wk course of ribavirin therapy were reported to be > 70% in the West. This study describes the outcome of HEV treatment in a transplant center in Singapore. AIM To study the outcome of ribavirin treatment in a series of chronic HEV patients, and the cause of treatment failure. METHODS We studied all of the transplant recipients who were diagnosed with HEV infection between 2012 to 2015. The outcome of therapy and virologic relapse are monitored for three years after the end of therapy. RESULTS Ten transplant recipients (4 liver, 5 kidney, and 1 bone marrow transplantation) with positive HEV RNA were studied. Nine patients received at least 12 wk of ribavirin therapy, and the remaining patient resolved after reducing immunosuppression therapy. Two subjects had prolonged viremia that lasted more than one year, despite continuous ribavirin therapy. Four ribavirin-treated patients (44.4%) had HEV RNA relapse after achieving a virologic response by the end of treatment. The overall failure rate is 66.7%. Being a kidney transplant recipient is the strongest risk factor for not achieving an initial sustained virologic response (0/5 treated, Chi-Square test, P < 0.05). The most common side effect of ribavirin is anemia (100%) (haemoglobin reduction of 3-6.2 g/dL). Seven patients required either a blood transfusion or erythropoietin therapy. CONCLUSION The sustained virologic response rate of 12-wk ribavirin therapy for HEV infection in this Asian series was lower than expected. Kidney transplant recipients had a higher rate of treatment failure due to higher immunosuppression requirements and adverse effects.
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Affiliation(s)
- En Xian Sarah Low
- Department of Medicine, Ng Teng Fong General Hospital, National University Health System, Singapore 609606, Singapore
| | - Edhel Tripon
- Centre for Liver Disease Management and Transplant of Medical City, Manila 1605, Philippines
| | - Kieron Lim
- Mount Elizabeth Medical Centre, Singapore 228510, Singapore
| | - Poh Seng Tan
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - How Cheng Low
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Yin Mei Lee
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Wai Mun Loo
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Calvin Jianyi Koh
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Wah Wah Phyo
- Department of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - JunXiong Pang
- Centre for Infectious Disease Epidemiology and Research, National University of Singapore, Singapore 117549, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Guan-Huei Lee
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore.
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31
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Hepatitis E Virus Infection in Blood Donors and Risk to Patients in the United States and Canada. Transfus Med Rev 2019; 33:139-145. [PMID: 31324552 DOI: 10.1016/j.tmrv.2019.05.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/16/2019] [Accepted: 05/26/2019] [Indexed: 12/20/2022]
Abstract
Hepatitis E virus (HEV) is the most common cause of acute hepatitis worldwide including large water-borne outbreaks, zoonotic infections and transfusion transmissions. Several countries have initiated or are considering blood donor screening in response to high HEV-RNA donation prevalence leading to transfusion-transmission risk. Because HEV transmission is more common through food sources, the efficacy of blood donor screening alone may be limited. HEV-nucleic acids in 101 489 blood donations in the United States and Canada were studied. A risk-based decision-making framework was used to evaluate the quantitative risks and cost-benefit of HEV-blood donation screening in Canada comparing three scenarios: no screening, screening blood for all transfused patients or screening blood for only those at greatest risk. HEV-RNA prevalence in the United States was one per 16 908 (95% confidence interval [CI], 1:5786-1:81987), whereas Canadian HEV-RNA prevalence was one per 4615 (95% CI, 1:2579-1:9244). Although 4-fold greater, Canadian HEV-RNA prevalence was not significantly higher than in the United States. Viral loads ranged from 20 to 3080 international units per mL; all successfully typed infections were genotype 3. No HEV-RNA false-positive donations were identified for 100 percent specificity. Without donation screening, heart and lung transplant recipients had the greatest HEV-infection risk (1:366962) versus kidney transplant recipients with the lowest (1:2.8 million) at costs of $225 546 to $561 810 per quality-adjusted life-year (QALY) gained for partial or universal screening, respectively. Higher cost per QALY would be expected in the United States. Thus, HEV prevalence in North America is lower than in countries performing blood donation screening, and if implemented, is projected to be costly under any scenario.
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32
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Lhomme S, Legrand-Abravanel F, Kamar N, Izopet J. Screening, diagnosis and risks associated with Hepatitis E virus infection. Expert Rev Anti Infect Ther 2019; 17:403-418. [DOI: 10.1080/14787210.2019.1613889] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Sébastien Lhomme
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Florence Legrand-Abravanel
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Nassim Kamar
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
- Department of Nephrology and Organs Transplantation, CHU Rangueil, Toulouse, France
| | - Jacques Izopet
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
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Hepatitis E virus: reasons for emergence in humans. Curr Opin Virol 2018; 34:10-17. [PMID: 30497051 DOI: 10.1016/j.coviro.2018.11.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/08/2018] [Accepted: 11/13/2018] [Indexed: 12/11/2022]
Abstract
Hepatitis E virus (HEV) infects both humans and other animal species. Recently, we have seen a steady increase in autochthonous cases of human HEV infection in certain areas especially in Europe, and large outbreaks in several African countries among the displaced population. This mini-review critically analyzes potential host, environmental, and viral factors that may be associated with the emergence of hepatitis E in humans. The existence of numerous HEV reservoir animals such as pig, deer and rabbit results in human exposure to infected animals via direct contact or through animal meat consumption. Contamination of drinking, irrigation and coastal water by animal and human wastes lead to emergence of endemic cases in industrialized countries and outbreaks in displaced communities especially in war-torn countries.
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An Update on the Clinicopathologic Features and Pathologic Diagnosis of Hepatitis E in Liver Specimens. Adv Anat Pathol 2018; 25:273-281. [PMID: 29697415 DOI: 10.1097/pap.0000000000000195] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Infection with the hepatitis E virus (HEV) is globally seen a leading cause of hepatitis. Now increasingly recognized also in industrialized countries, hepatitis E constitutes a significant health problem worldwide. The patient's immune status determines the clinical course and histopathology of hepatitis E. In immunocompetent patients, hepatitis E usually follows an asymptomatic or subclinical course, but may also present with acute hepatitis. In contrast, immunocompromised patients may develop chronic hepatitis, and patients with preexisting liver diseases are at risk for liver decompensation with potentially fatal outcome. Whereas pathologists only occasionally encounter liver biopsies from immunocompetent individuals with hepatitis E, they are more likely exposed to biopsies from patients with preexisting liver disease or immunocompromised individuals. Histopathologic hallmarks of hepatitis E in immunocompetent patients comprise lobular disarray, lobular, and portal inflammation, as well as hepatocyte necrosis of varying extend and regeneration. Thus, it is similar to acute non-E viral hepatitis, yet further differential diagnoses include autoimmune hepatitis and drug-induced liver injury. Histopathologic findings of hepatitis E in preexisting liver disease are determined by the underlying pathology, but may be more severe. Histopathologic presentation of hepatitis E in immunocompromised patients is highly variable, ranging from minimal active hepatitis to chronic hepatitis with severe activity and progressive fibrosis. Taken together, the variability of the histologic features depending on the clinical context and the overlap with other liver diseases make the histopathologic diagnosis of hepatitis E challenging. Immunohistochemistry for HEV open reading frame 2 protein and molecular testing for HEV RNA are useful tissue-based ancillary tools.
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Fenaux H, Chassaing M, Berger S, Jeulin H, Gentilhomme A, Bensenane M, Bronowicki J, Gantzer C, Bertrand I, Schvoerer E. Molecular features of Hepatitis E Virus circulation in environmental and human samples. J Clin Virol 2018; 103:63-70. [PMID: 29656087 DOI: 10.1016/j.jcv.2018.04.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 03/20/2018] [Accepted: 04/03/2018] [Indexed: 12/20/2022]
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36
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Dalton HR, Kamar N, Baylis SA, Moradpour D, Wedemeyer H, Negro F. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018; 68:1256-1271. [PMID: 29609832 DOI: 10.1016/j.jhep.2018.03.005] [Citation(s) in RCA: 434] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 03/09/2018] [Indexed: 02/08/2023]
Abstract
Infection with hepatitis E virus (HEV) is a significant cause of morbidity and mortality, representing an important global health problem. Our understanding of HEV has changed completely over the past decade. Previously, HEV was thought to be limited to certain developing countries. We now know that HEV is endemic in most high-income countries and is largely a zoonotic infection. Given the paradigm shift in our understanding of zoonotic HEV and that locally acquired HEV is now the commonest cause of acute viral hepatitis in many European countries, the focus of these Clinical Practice Guidelines will be on HEV genotype 3 (and 4).
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A nationwide retrospective study on prevalence of hepatitis E virus infection in Italian blood donors. BLOOD TRANSFUSION = TRASFUSIONE DEL SANGUE 2018; 16:413-421. [PMID: 29757135 DOI: 10.2450/2018.0033-18] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 04/10/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND In Europe, hepatitis E virus (HEV) infection is mainly a food-borne zoonosis, but it can also be transmitted by blood transfusion. It is usually a mild and self-limited infection. However, immunocompromised persons, who are also those more likely to undergo blood transfusions, may develop chronic hepatitis and often cirrhosis. Since this is a potential threat to blood safety, we aimed to investigate HEV prevalence in Italian blood donors. MATERIALS AND METHODS We used plasma donations collected during 2015-2016 by blood services (BS) scattered throughout the Italian regions and intended for the production of plasma-derived medicines. Plasma samples were tested for IgG and IgM anti-HEV and for HEV RNA using validated assays. Data concerning donor's age and sex, and the location of the BS were collected. RESULTS A total of 10,011 plasma samples were tested. Overall IgG and IgM prevalence rates were 8.7 and 0.4%, respectively. No sample was HEV RNA-positive. IgG prevalence was significantly higher in males and in donors aged 44 years and over. IgG prevalence differed greatly according to region. Overall regional rates over 15% were found in Abruzzo and in Sardinia, and rates of 10-15% were found in Lazio, Umbria and the Marche. Considering IgG prevalence according to the province where the BS was located, rates over 30% were found in Sardinia and Abruzzo. Age, sex and donor's region of residence were independently associated with IgG positivity. BS location produced significant heterogeneity on prevalence rates within the regions. DISCUSSION The detected IgG rate of 8.7% in this study represents one of the lowest seroprevalence rates reported among blood donors in Europe. Particularly high prevalence rates in some regions and provinces may be explained by local eating habits and/or intensive environmental HEV contamination. Before considering the introduction of HEV RNA screening for blood donations in Italy, further important issues should be addressed and prospective incidence and reliable cost-benefit studies are needed.
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Zafrullah M, Zhang X, Tran C, Nguyen M, Kamili S, Purdy MA, Stramer SL. Disparities in detection of antibodies against hepatitis E virus in US blood donor samples using commercial assays. Transfusion 2018. [PMID: 29520800 DOI: 10.1111/trf.14553] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Reported hepatitis E virus (HEV) antibody assay performance characteristics are variable. Using a subset of surplus US blood donation samples, we compared assays for detecting anti-HEV immunoglobulin M (Ig)M and IgG or total anti-HEV antibodies. STUDY DESIGN AND METHODS Samples from 5040 random blood donations, all HEV-RNA negative, collected primarily in the midwestern United States in 2015 were tested for anti-HEV IgM and IgG or total anti-HEV using assays manufactured by Diagnostic Systems, Wantai, and MP Biomedicals. RESULTS Overall, the percentage of detection for anti-HEV IgG and total anti-HEV was 11.4%, and for anti-HEV IgM was 1.8%. Nine samples were reactive for anti-HEV IgM by all assays, giving a recent infection rate of 0.18%. Anti-HEV IgG/total anti-HEV detection rates increased with age. Interassay agreement was higher among the IgG anti-HEV/total anti-HEV assays (84%) than the IgM assays (22%). Regression analyses of signal-to-cutoff ratios from IgG/total antibody assay were heteroskedastic, indicating no constant variance among these assays, suggesting they may detect different epitopes or were affected by waning or less avid antibodies in the US donor population. CONCLUSIONS Although similar percentages of IgG anti-HEV/total anti-HEV detection were observed across the three commercial assays, each assay detected a unique sample subpopulation and was heteroskedastic when compared pairwise. Discordance was higher among anti-HEV IgM assays, but a recent HEV infection rate of at least 0.18% was estimated based on assay concordance.
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Affiliation(s)
- Mohammad Zafrullah
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Xiugen Zhang
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Coleen Tran
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia.,MiMex, Marietta, Georgia
| | - Megan Nguyen
- American Red Cross, Gaithersburg, Maryland.,US Food and Drug Administration, Silver Spring, Maryland
| | - Saleem Kamili
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Michael A Purdy
- Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia
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De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacol Res 2018; 130:308-315. [PMID: 29499270 DOI: 10.1016/j.phrs.2018.02.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 02/06/2018] [Accepted: 02/26/2018] [Indexed: 12/22/2022]
Abstract
Hepatitis E virus (HEV) is the most common cause of viral hepatitis worldwide. Genotypes 1 and 2 (GT1 and GT2) are mainly present in developing countries, while GT3 and GT4 are prevalent in developed and high-income countries. In the majority of cases, HEV causes a self-limiting hepatitis. GT3 and GT4 can be responsible for a chronic hepatitis that can lead to cirrhosis in immunocompromized patients, i.e. solid-organ- and stem-cell-transplant-patients, human immunodeficiency virus-infected patients, and patients receiving chemotherapy or immunotherapy. HEV has also been associated with extra-hepatic manifestations such as neurologic disorders (Guillain-Barré Syndrome and neuralgic amyotrophy) and kidney disease. In patients with chronic hepatitis, reduction of immunosuppression, when possible, is the first therapeutic option. In the remaining patients, ribavirin therapy has been shown to very efficient for treating HEV infection leading to a sustained virological response in nearly 80-85% of patients. However, the mechanism of action of ribavirin in this setting is still unknown, as is the impact of HEV RNA polymerase mutations. There are unmet needs with regard to the treatment of chronic HEV with ribavirin. These include the optimal dosing and duration of treatment, and the potential beneficial effects of therapeutic drug monitoring on the virological response and the incidence of side effects. In the present review, we will provide an overview of HEV epidemiology, its mode of transmission and clinical manifestations, as well as its treatment by ribavirin with a focus on the drug's pharmacokinetics and dosing.
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Affiliation(s)
- Brenda C M De Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Rotterdam Transplant Group, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Internal Medicine, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France.
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Lhomme S, Bardiaux L, Abravanel F, Gallian P, Kamar N, Izopet J. Hepatitis E Virus Infection in Solid Organ Transplant Recipients, France. Emerg Infect Dis 2018; 23:353-356. [PMID: 28098552 PMCID: PMC5324811 DOI: 10.3201/eid2302.161094] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The rate of transfusion-transmitted hepatitis E virus (HEV) in transplant recipients is unknown. We identified 60 HEV-positive solid organ transplant patients and retrospectively assessed their blood transfusions for HEV. Seven of 60 patients received transfusions; 3 received HEV-positive blood products. Transfusion is not the major route of infection in this population.
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Nicolini LA, Zappulo E, Viscoli C, Mikulska M. Management of chronic viral hepatitis in the hematological patient. Expert Rev Anti Infect Ther 2018; 16:227-241. [PMID: 29415584 DOI: 10.1080/14787210.2018.1438264] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Infection with HBV and HCV represents a growing challenge in the management of patients with hematological malignancies. Recently, hepatitis E (HEV) was recognized as an endemic infection in developed countries and as an emerging health problem in immunocompromised patients. Areas covered: We reviewed the current knowledge on the impact of chronic viral hepatitis in the hematological setting. Epidemiological features, screening strategies and indications for treatment and monitoring have been explored and commented. Expert commentary: Knowing patient's complete HBV serostatus is mandatory in order to choose between treatment, prophylaxis or a pre-emptive approach. Recent guidelines favor treatment with high barrier molecules in all patients with chronic HBV infection and long lasting prophylaxis with those with inactive or resolved one. With regard to HCV, the new direct-acting antiviral agents have been safely administered in the hematological setting. Their use as first-line single treatment in indolent lymphomas, and combined with chemotherapy in aggressive ones, should be considered. Due to the existing risk of chronic HEV infection in the immunocompromised, screening with serum HEV-RNA should be performed in case of signs and symptoms indicative of hepatitis. In the event of HEV infection, reduction of immunosuppression and, if not feasible or unsuccessful, ribavirin treatment should be prescribed.
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Affiliation(s)
- Laura Ambra Nicolini
- a Infectious Diseases Unit, Department of Health Science (DISSAL), Ospedale Policlinico San Martino, IRCCS per l'Oncologia , University of Genoa , Genoa , Italy
| | - Emanuela Zappulo
- a Infectious Diseases Unit, Department of Health Science (DISSAL), Ospedale Policlinico San Martino, IRCCS per l'Oncologia , University of Genoa , Genoa , Italy.,b Division of Infectious Diseases, Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Claudio Viscoli
- a Infectious Diseases Unit, Department of Health Science (DISSAL), Ospedale Policlinico San Martino, IRCCS per l'Oncologia , University of Genoa , Genoa , Italy
| | - Malgorzata Mikulska
- a Infectious Diseases Unit, Department of Health Science (DISSAL), Ospedale Policlinico San Martino, IRCCS per l'Oncologia , University of Genoa , Genoa , Italy
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Cook N, D'Agostino M, Johne R. Potential Approaches to Assess the Infectivity of Hepatitis E Virus in Pork Products: A Review. FOOD AND ENVIRONMENTAL VIROLOGY 2017; 9:243-255. [PMID: 28470455 DOI: 10.1007/s12560-017-9303-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 04/26/2017] [Indexed: 05/04/2023]
Abstract
The zoonotic transmission of hepatitis E, caused by the hepatitis E virus (HEV), is an emerging issue. HEV appears common in pigs (although infected pigs do not show clinical signs), and evidence suggests that a number of hepatitis E cases have been associated with the consumption of undercooked pork meat and products. Little information is available on whether cooking can eliminate HEV, since there is currently no robust method for measuring its infectivity. HEV infectivity can be clearly demonstrated by monitoring for signs of infection (e.g., shedding of virus) in an animal model. However, this approach has several disadvantages, such as lack of reproducibility and unsuitability for performing large numbers of tests, high costs, and not least ethical considerations. Growth in cell culture can unambiguously show that a virus is infectious and has the potential for replication, without the disadvantages of using animals. Large numbers of tests can also be performed, which can make the results more amenable to statistical interpretation. However, no HEV cell culture system has been shown to be applicable to all HEV strains, none has been standardized, and few studies have demonstrated their use for measurement of HEV infectivity in food samples. Nonetheless, cell culture remains the most promising approach, and the main recommendation of this review is that there should be an extensive research effort to develop and validate a cell culture-based method for assessing HEV infectivity in pork products. Systems comprising promising cell lines and HEV strains which can grow well in cell culture should be tested to select an assay for effective and reliable measurement of HEV infectivity over a wide range of virus concentrations. The assay should then be harnessed to a procedure which can extract HEV from pork products, to produce a method suitable for further use. The method can then be used to determine the effect of heat or other elimination processes on HEV in pork meat and products, or to assess whether HEV detected in any surveyed foodstuffs is infectious and therefore poses a risk to public health.
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Affiliation(s)
- Nigel Cook
- Fera Science Ltd., Sand Hutton, York, YO41 1LZ, UK.
- Jorvik Food and Environmental Virology Ltd., York, UK.
| | - Martin D'Agostino
- Fera Science Ltd., Sand Hutton, York, YO41 1LZ, UK
- Campden BRI, Chipping Campden, UK
| | - Reimar Johne
- German Federal Institute for Risk Assessment, Berlin, Germany
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Passos-Castilho AM, Reinaldo MR, Sena AD, Granato CFH. High prevalence of hepatitis E virus antibodies in Sao Paulo, Southeastern Brazil: analysis of a group of blood donors representative of the general population. Braz J Infect Dis 2017; 21:535-539. [PMID: 28606414 PMCID: PMC9425471 DOI: 10.1016/j.bjid.2017.05.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 04/24/2017] [Accepted: 05/11/2017] [Indexed: 12/12/2022] Open
Affiliation(s)
| | | | - Anne de Sena
- Division of Infectious Diseases, Federal University of Sao Paulo, Sao Paulo, SP, Brazil; Fleury SA Group, Sao Paulo, SP, Brazil
| | - Celso F H Granato
- Division of Infectious Diseases, Federal University of Sao Paulo, Sao Paulo, SP, Brazil; Fleury SA Group, Sao Paulo, SP, Brazil
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44
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Fang SY, Han H. Hepatitis E viral infection in solid organ transplant patients. Curr Opin Organ Transplant 2017; 22:351-355. [DOI: 10.1097/mot.0000000000000432] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Pandolfi R, Ramos de Almeida D, Alves Pinto M, Kreutz LC, Frandoloso R. In house ELISA based on recombinant ORF2 protein underline high prevalence of IgG anti-hepatitis E virus amongst blood donors in south Brazil. PLoS One 2017; 12:e0176409. [PMID: 28486512 PMCID: PMC5423711 DOI: 10.1371/journal.pone.0176409] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 04/09/2017] [Indexed: 01/19/2023] Open
Abstract
Hepatitis E Virus (HEV) is a zoonotic pathogen responsible for causing acute hepatitis in human, especially in developing countries. Diagnosis of HEV usually relies on the detection of antibodies mostly by enzyme-linked immunosorbent assay (ELISA). In the present study, we designed a new indirect ELISA (iELISA) based on a short recombinant peptide derived from the capsid protein (ORF2p) and demonstrated its potential for detecting human IgG against HEV genotype 3. The best polystyrene plate (Maxisorp®), optimal ORF2p coating antigen concentration (0,67μg/well) and primary antibody dilution (1:100) were determined. This iELISA showed a sensitivity of 91.4% and specificity of 95.9%. The comparison of our in house iELISA with a commercial assay (RecomWell, Mikrogen®) showed 94.25% of agreement and a kappa index of 0.88. The ORF2 recombinant ELISA was used to screen 780 blood donors for anti-HEV IgG and we found that 314 (40,25%) of these donors were IgG positive. This high prevalence of antibodies suggests, for the first time, that the Southern Brazil region might be endemic to Hepatitis E Virus genotype 3.
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Affiliation(s)
- Rafael Pandolfi
- Laboratório de Microbiologia e Imunologia Avançada, Faculdade de Agronomia e Medicina Veterinária, Universidade de Passo Fundo, Passo Fundo, Rio Grande do Sul, Brazil
| | - Denise Ramos de Almeida
- Laboratório de Microbiologia e Imunologia Avançada, Faculdade de Agronomia e Medicina Veterinária, Universidade de Passo Fundo, Passo Fundo, Rio Grande do Sul, Brazil
| | - Marcelo Alves Pinto
- Laboratório de Desenvolvimento Tecnológico em Virologia/IOC - Fundação Instituto Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Luiz Carlos Kreutz
- Laboratório de Microbiologia e Imunologia Avançada, Faculdade de Agronomia e Medicina Veterinária, Universidade de Passo Fundo, Passo Fundo, Rio Grande do Sul, Brazil
| | - Rafael Frandoloso
- Laboratório de Microbiologia e Imunologia Avançada, Faculdade de Agronomia e Medicina Veterinária, Universidade de Passo Fundo, Passo Fundo, Rio Grande do Sul, Brazil
- * E-mail:
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Pischke S, Hartl J, Pas SD, Lohse AW, Jacobs BC, Van der Eijk AA. Hepatitis E virus: Infection beyond the liver? J Hepatol 2017; 66:1082-1095. [PMID: 27913223 DOI: 10.1016/j.jhep.2016.11.016] [Citation(s) in RCA: 175] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Revised: 11/13/2016] [Accepted: 11/20/2016] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV) infections are not limited to the liver but may also affect other organs. Several diseases, including Guillain-Barré syndrome, neuralgic amyotrophy, glomerulonephritis, cryoglobulinemia, pancreatitis, lymphoma, thrombopenia, meningitis, thyroiditis and myocarditis have been observed in the context of hepatitis E. To date, the definite pathophysiological links between HEV and extrahepatic manifestations are not yet established. However, it is suggested that HEV infection might be causative based on serological studies, case series, in vitro data and animal models. In particular, neuronal and renal diseases as well as pancreatitis seem to be caused by HEV, while a causative relationship between HEV and other diseases is more doubtful. Either direct cytopathic tissue damage by extrahepatic replication, or immunological processes induced by an overwhelming host immune response, are possible origins of HEV-associated extrahepatic manifestations. Hepatologists should be aware of the possibility that acute or chronically HEV-infected patients could develop extrahepatic manifestations. Neurologists, nephrologists, rheumatologists and other groups of physicians should consider HEV infection as a potential differential diagnosis when observing one of the diseases described in this review. Ribavirin and steroids have been used in small groups of patients with extrahepatic manifestations of HEV, but the efficacy of these drugs still needs to be verified by large, multicenter studies. This article comprehensively reviews the published literature regarding HEV and extrahepatic manifestations. We discuss the probability of specific extrahepatic diseases being caused by previous or ongoing HEV infection, and summarize the published knowledge about antiviral treatment in extrahepatic disorders.
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Affiliation(s)
- Sven Pischke
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
| | - Johannes Hartl
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Suzan D Pas
- Department of Viroscience, Erasmus MC University Medical Center Rotterdam, Netherlands
| | - Ansgar W Lohse
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Bart C Jacobs
- Department of Neurology and Immunology, Erasmus MC University Medical Center Rotterdam, Netherlands
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Yamazaki Y, Naganuma A, Arai Y, Takeuchi S, Kobayashi T, Takakusagi S, Hatanaka T, Hoshino T, Namikawa M, Hashizume H, Takizawa D, Ohyama T, Suzuki H, Horiguchi N, Takagi H, Sato K, Kakizaki S, Kusano M, Nagashima S, Takahashi M, Okamoto H, Yamada M. Clinical and virological features of acute hepatitis E in Gunma prefecture, Japan between 2004 and 2015. Hepatol Res 2017; 47:435-445. [PMID: 27322051 DOI: 10.1111/hepr.12765] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 06/13/2016] [Accepted: 06/14/2016] [Indexed: 12/13/2022]
Abstract
AIM To evaluate the clinical and virological features of acute hepatitis E (AH-E) in Gunma prefecture and focus on the hepatitis E virus (HEV) infection in immunocompromised patients. METHODS A total of 30 patients with AH-E diagnosed at our Gunma University Hospital, and located in 3-39-15 Showa-machi, Maebashi, Gunma 371-8511 Japan, and its affiliated hospitals from 2004 to 2015, were studied. We evaluated the detailed medical histories, laboratory examinations and virological features of these participants. RESULTS Of the 30 patients, 21 patients were men, with a median age of 61 years. Three of these patients had a history of recent oversea travel. A total of 14 patients had eaten raw or undercooked meat/viscera from animals, and two patients had contracted transfusion-transmitted AH-E. Eight patients were immunocompromised, including those with hematological disease, cancer receiving systemic chemotherapy and kidney transplant or connective tissue disease undergoing immunosuppressive medications. The alanine aminotransferase and total bilirubin levels were more significantly reduced in these immunocompromised patients than in the non-immunocompromised patients. Severe thrombocytopenia, an extra-hepatic manifestation of AH-E, occurred in one case. Among the 22 HEV strains whose subgenotype was determined, two were imported strains (1a and 1f), and 11 strains formed four distinct phylogenetic clusters within subgenotype 3b. The remaining nine strains differed from each other by 9.8-22.4%, and were classified into four subgenotypes (3a, 3b, 3e and 3f). CONCLUSION Markedly divergent HEV strains (3a, 3b, 3e and 3f) were found to circulate in Gunma. Although immunosuppression appears to play a crucial role in establishing chronic sequels, AH-E in eight immunocompromised patients, including transfusion-transmitted HEV infection in two patients, did not become chronic.
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Affiliation(s)
- Yuichi Yamazaki
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
- Department of Internal Medicine, Kiryu Kosei General Hospital Kiryu, Japan
| | - Yosuke Arai
- Department of Internal Medicine, Kiryu Kosei General Hospital Kiryu, Japan
| | - Suguru Takeuchi
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Takeshi Kobayashi
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Satoshi Takakusagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital Fujioka, Japan
| | - Takeshi Hatanaka
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Takashi Hoshino
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Masashi Namikawa
- Department of Internal Medicine, Kiryu Kosei General Hospital Kiryu, Japan
| | - Hiroaki Hashizume
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Daichi Takizawa
- Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan
| | - Tatsuya Ohyama
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hideyuki Suzuki
- Department of Internal Medicine, Haramachi Red Cross Hospital, Higashiagatsuma, Japan
| | - Norio Horiguchi
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
- Department of Gastroenterology and Hepatology, Kusunoki Hospital Fujioka, Japan
| | - Ken Sato
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
- Department of Internal Medicine, Heisei Hidaka Clinic, Takasaki, Japan
| | - Satoru Kakizaki
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Motoyasu Kusano
- Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Masanobu Yamada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Japan
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48
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Gardinali NR, Guimarães JR, Melgaço JG, Kevorkian YB, Bottino FDO, Vieira YR, da Silva ACDA, Pinto DP, da Fonseca LB, Vilhena LS, Uiechi E, da Silva MCC, Moran J, Marchevsky RS, Cruz OG, Otonel RAA, Alfieri AA, de Oliveira JM, Gaspar AMC, Pinto MA. Cynomolgus monkeys are successfully and persistently infected with hepatitis E virus genotype 3 (HEV-3) after long-term immunosuppressive therapy. PLoS One 2017; 12:e0174070. [PMID: 28328941 PMCID: PMC5362194 DOI: 10.1371/journal.pone.0174070] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 03/02/2017] [Indexed: 01/19/2023] Open
Abstract
Epidemiological studies found that hepatitis E virus genotype 3 (HEV-3) infection was associated with chronic hepatitis and cirrhosis in immunocompromised patients. Our study aimed to investigate the relationship between the host immunosuppressive status and the occurrence of HEV-related chronic hepatitis. Here we describe a successful experimental study, using cynomolgus monkeys previously treated with tacrolimus, a potent calcineurin inhibitor immunosuppressant, and infected with a Brazilian HEV-3 strain isolated from naturally infected pigs. HEV infected monkeys were followed up during 160 days post infection (dpi) by clinical signs; virological, biochemical and haematological parameters; and liver histopathology. The tacrolimus blood levels were monitored throughout the experiment. Immunosuppression was confirmed by clinical and laboratorial findings, such as: moderate weight loss, alopecia, and herpes virus opportunistic infection. In this study, chronic HEV infection was characterized by the mild increase of liver enzymes serum levels; persistent RNA viremia and viral faecal shedding; and liver histopathology. Three out of four immunosuppressed monkeys showed recurrent HEV RNA detection in liver samples, evident hepatocellular ballooning degeneration, mild to severe macro and microvesicular steatosis (zone 1), scattered hepatocellular apoptosis, and lobular focal inflammation. At 69 dpi, liver biopsies of all infected monkeys revealed evident ballooning degeneration (zone 3), discrete hepatocellular apoptosis, and at most mild portal and intra-acinar focal inflammation. At 160 dpi, the three chronically HEV infected monkeys showed microscopic features (piecemeal necrosis) corresponding to chronic hepatitis in absence of fibrosis and cirrhosis in liver parenchyma. Within 4-months follow up, the tacrolimus-immunosuppressed cynomolgus monkeys infected with a Brazilian swine HEV-3 strain exhibited more severe hepatic lesions progressing to chronic hepatitis without liver fibrosis, similarly as shown in tacrolimus-immunosuppressed solid organ transplant (SOT) recipients. The cause-effect relationship between HEV infection and tacrolimus treatment was confirmed in this experiment.
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Affiliation(s)
- Noemi Rovaris Gardinali
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
- * E-mail:
| | - Juliana Rodrigues Guimarães
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Juliana Gil Melgaço
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Yohan Britto Kevorkian
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Fernanda de Oliveira Bottino
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Yasmine Rangel Vieira
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Aline Campos de Azevedo da Silva
- Serviço de Equivalência e Farmacocinética –SEFAR, Vice-Presidência de Produção e Inovação em Saúde–VPPIS, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Douglas Pereira Pinto
- Serviço de Equivalência e Farmacocinética –SEFAR, Vice-Presidência de Produção e Inovação em Saúde–VPPIS, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Laís Bastos da Fonseca
- Serviço de Equivalência e Farmacocinética –SEFAR, Vice-Presidência de Produção e Inovação em Saúde–VPPIS, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Leandro Schiavo Vilhena
- Serviço de Equivalência e Farmacocinética –SEFAR, Vice-Presidência de Produção e Inovação em Saúde–VPPIS, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | - Maria Cristina Carlan da Silva
- Laboratório de Biologia Molecular de Patógenos (Virologia Molecular), Centro de Ciências Naturais e Humanas-CCNH, Universidade Federal do ABC-UFABC, São Bernardo do Campo, São Paulo, Brazil
| | - Julio Moran
- Dr. Julio Moran Laboratories, Ebmatingen, Zurich, Switzerland
| | - Renato Sérgio Marchevsky
- Laboratório de Neurovirulência, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | | | | | - Amauri Alcindo Alfieri
- Laboratório de Virologia Animal, Departamento de Medicina Veterinária Preventiva Universidade Estadual de Londrina, Paraná, Brazil
| | - Jaqueline Mendes de Oliveira
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Ana Maria Coimbra Gaspar
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Marcelo Alves Pinto
- Laboratório de Desenvolvimento Tecnológico em Virologia, Oswaldo Cruz, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
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49
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Vollmer T, Diekmann J, Eberhardt M, Knabbe C, Dreier J. Hepatitis E in blood donors: investigation of the natural course of asymptomatic infection, Germany, 2011. ACTA ACUST UNITED AC 2017; 21:30332. [PMID: 27608433 PMCID: PMC5015460 DOI: 10.2807/1560-7917.es.2016.21.35.30332] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 02/16/2016] [Indexed: 12/16/2022]
Abstract
Asymptomatic hepatitis E virus (HEV) infections have been found in blood donors from various European countries, but the natural course is rarely specified. Here, we compared the progression of HEV viraemia, serostatus and liver-specific enzymes in 10 blood donors with clinically asymptomatic genotype 3 HEV infection, measuring HEV RNA concentrations, plasma concentrations of alanine/aspartate aminotransferase, glutamate dehydrogenase and bilirubin and anti-HEV IgA, IgM and IgG antibodies. RNA concentrations ranged from 77.2 to 2.19×105 IU/mL, with viraemia lasting from less than 10 to 52 days. Donors showed a typical progression of a recent HEV infection but differed in the first detection of anti-HEV IgA, IgM and IgG and seropositivity of the antibody classes. The diagnostic window between HEV RNA detection and first occurrence of anti-HEV antibodies ranged from eight to 48 days, depending on the serological assay used. The progression of laboratory parameters of asymptomatic HEV infection was largely comparable to the progression of symptomatic HEV infection, but only four of 10 donors showed elevated liver-specific parameters. Our results help elucidate the risk of transfusion-associated HEV infection and provide a basis for development of screening strategies. The diagnostic window illustrates that infectious blood donors can be efficiently identified only by RNA screening.
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Affiliation(s)
- Tanja Vollmer
- Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein- Westfalen, Universitätsklinik der Ruhr-Universität Bochum, Bad Oeynhausen, Germany
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50
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Pourbaix A, Ouali N, Soussan P, Roque Afonso AM, Péraldi MN, Rondeau E, Peltier J. Evidence of hepatitis E virus transmission by renal graft. Transpl Infect Dis 2017; 19. [PMID: 27775205 DOI: 10.1111/tid.12624] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 04/26/2016] [Accepted: 09/09/2016] [Indexed: 01/20/2023]
Abstract
Hepatitis E virus (HEV) can cause chronic infection among immunocompromised patients, especially solid organ transplant recipients, and can evolve to cirrhosis. Several modes of transmission are known. Here we describe the first two cases, to our knowledge, of HEV infection transmitted by a kidney graft from the same infected donor that led to chronic hepatitis. Consequently, systematic screening of donors by HEV serology and HEV RNA detection by polymerase chain reaction, particularly in endemic regions, should be considered.
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Affiliation(s)
- Annabelle Pourbaix
- Department of Renal ICU and Kidney Transplantation, Tenon Hospital, Paris, France
| | - Nacera Ouali
- Department of Renal ICU and Kidney Transplantation, Tenon Hospital, Paris, France
| | | | | | | | - Eric Rondeau
- Department of Renal ICU and Kidney Transplantation, Tenon Hospital, Paris, France
| | - Julie Peltier
- Department of Renal ICU and Kidney Transplantation, Tenon Hospital, Paris, France
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