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1
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Codes L, Zapata R, Mendizabal M, Junior ADMF, Restrepo JC, Schiavon LDL, Malbouisson LMS, Andraus W, Gadano A, Padilla-Machaca PM, Villamil A, Stucchi RSB, Castro-Narro GE, Pages J, Terrabuio DRB, Urzúa A, Pessoa MG, Mainardi V, Pedro R, Imventarza O, Gerona S, Wolff R, Abdala E, Tenorio L, Cerda-Reyes E, Cairo F, Uribe M, Bittencourt PL. Latin American association for the study of the liver (ALEH) guidance on postoperative care after liver transplantation. Ann Hepatol 2025; 30:101899. [PMID: 40057036 DOI: 10.1016/j.aohep.2025.101899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/12/2024] [Accepted: 01/01/2025] [Indexed: 03/16/2025]
Abstract
Liver transplantation (LT) is a well-established therapy for patients with decompensated cirrhosis and early-stage hepatocellular carcinoma. Liver transplantation activity varies sharply across Latin American (LATAM) countries due to differences in resources, expertise, and funding and local attitudes toward organ donation and transplantation. This current guidance of postoperative care after LT is the first position paper of the Latin American Association for the Study of the Liver (ALEH) Special Interest Group (SIG), drawing evidence-based recommendations regarding immediate and long-term postoperative care of LT recipients, taking into consideration their applicability in Latin America.
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Affiliation(s)
- Liana Codes
- Hospital Português, Salvador, Bahia, Brazil; Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil.
| | - Rodrigo Zapata
- Unidad de Trasplante hepático, Clínica Alemana/ Facultad de Medicina, Universidad del Desarrollo, Santiago, Chile.
| | - Manuel Mendizabal
- Unidad de Hepatología y Trasplante de Hígado, Hospital Universitario Austral, Provincia de Buenos Aires, Pilar, Argentina.
| | | | | | | | | | - Wellington Andraus
- Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | | | - P Martin Padilla-Machaca
- Liver Unit, Guillermo Almenara National Hospital, EsSalud, Lima, Perú, and National University of San Marcos, Lima, Perú
| | | | | | - Graciela Elia Castro-Narro
- Unidad de Hepatología y Trasplantes, Hospital Médica Sur, Ciudad de México, México; Servicio de Gastroenterología, Hepatología y Trasplantes, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, México
| | - Josefina Pages
- Unidad de Hepatología y Trasplante de Hígado, Hospital Universitario Austral, Provincia de Buenos Aires, Pilar, Argentina.
| | | | - Alvaro Urzúa
- Hospital Clínico Universidad de Chile, Santiago, Chile.
| | - Mário Guimarães Pessoa
- Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
| | | | - Rodolpho Pedro
- Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Oscar Imventarza
- Hospital Argerich, Hospital Garrahan, Stalyc Representative, Buenos Aires, Argentina
| | - Solange Gerona
- Hospital Central de Las Fuerzas Armadas, Montevideo, Uruguay
| | - Rodrigo Wolff
- Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Edson Abdala
- Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
| | - Laura Tenorio
- Hospital Nacional Edgardo Rebagliati Martins, Lima, Perú
| | - Eira Cerda-Reyes
- Hospital Central Militar, Escuela Militar de Graduados de Sanidad, Ciudad de México, Mexico
| | | | - Mario Uribe
- Hospital Dr. Luis Calvo Mackenna, Santiago, Chile
| | - Paulo Lisboa Bittencourt
- Hospital Português, Salvador, Bahia, Brazil; Escola Bahiana de Medicina e Saúde Pública, Salvador, Bahia, Brazil.
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2
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Ssebyatika G, Dinkelborg K, Ströh LJ, Hinte F, Corneillie L, Hueffner L, Guzman EM, Nankya PL, Plückebaum N, Fehlau L, Garn J, Meyer N, Prallet S, Mehnert AK, Kraft ARM, Verhoye L, Jacobsen C, Steinmann E, Wedemeyer H, Viejo-Borbolla A, Dao Thi VL, Pietschmann T, Lütgehetmann M, Meuleman P, Dandri M, Krey T, Behrendt P. Broadly neutralizing antibodies isolated from HEV convalescents confer protective effects in human liver-chimeric mice. Nat Commun 2025; 16:1995. [PMID: 40011441 DOI: 10.1038/s41467-025-57182-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/12/2025] [Indexed: 02/28/2025] Open
Abstract
Hepatitis E virus (HEV) causes 3.3 million symptomatic cases and 44,000 deaths per year. Chronic infections can arise in immunocompromised individuals, and pregnant women may suffer from fulminant disease as a consequence of HEV infection. Despite these important implications for public health, no specific antiviral treatment has been approved to date. Here, we report combined functional, biochemical, and X-ray crystallographic studies that characterize the human antibody response in convalescent HEV patients. We identified a class of potent and broadly neutralizing human antibodies (bnAbs), targeting a quaternary epitope located at the tip of the HEV capsid protein pORF2 that contains an N-glycosylation motif and is conserved across members of the Hepeviridae. These glycan-sensitive bnAbs specifically recognize the non-glycosylated pORF2 present in infectious particles but not the secreted glycosylated form acting as antibody decoy. Our most potent bnAb protects human liver-chimeric mice from intraperitoneal HEV challenge and co-housing exposure. These results provide insights into the bnAb response to this important emerging pathogen and support the development of glycan-sensitive antibodies to combat HEV infection.
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Affiliation(s)
- George Ssebyatika
- Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany
| | - Katja Dinkelborg
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
- Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
| | - Luisa J Ströh
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Florian Hinte
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Laura Corneillie
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lucas Hueffner
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Elina M Guzman
- Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany
| | - Prossie L Nankya
- Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany
| | - Nina Plückebaum
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Lukas Fehlau
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Jonathan Garn
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Nele Meyer
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Sarah Prallet
- Schaller Research Group, Department of Infectious Diseases, Virology, University Hospital Heidelberg, Center for Integrative Infectious Diseases Research (CIID), 61920, Heidelberg, Germany
| | - Ann-Kathrin Mehnert
- Schaller Research Group, Department of Infectious Diseases, Virology, University Hospital Heidelberg, Center for Integrative Infectious Diseases Research (CIID), 61920, Heidelberg, Germany
| | - Anke R M Kraft
- Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Centre for Individualised Infection Medicine (CiiM), a joint venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
| | - Lieven Verhoye
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Carina Jacobsen
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Abel Viejo-Borbolla
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Viet Loan Dao Thi
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Schaller Research Group, Department of Infectious Diseases, Virology, University Hospital Heidelberg, Center for Integrative Infectious Diseases Research (CIID), 61920, Heidelberg, Germany
| | - Thomas Pietschmann
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Marc Lütgehetmann
- German Center for Infection Research (DZIF), Braunschweig, Germany
- University Medical Center Hamburg-Eppendorf, Institute of Medical Microbiology, Virology and Hygiene, Hamburg, Germany
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Maura Dandri
- German Center for Infection Research (DZIF), Braunschweig, Germany
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Thomas Krey
- Center of Structural and Cell Biology in Medicine, Institute of Biochemistry, University of Luebeck, Luebeck, Germany.
- German Center for Infection Research (DZIF), Braunschweig, Germany.
- Institute of Virology, Hannover Medical School, Hannover, Germany.
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany.
- Centre for Structural Systems Biology (CSSB), Hamburg, Germany.
| | - Patrick Behrendt
- TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School, Hannover, Germany.
- Department of Gastroenterology, Hepatology, Infectious diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
- German Center for Infection Research (DZIF), Braunschweig, Germany.
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3
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He P, Li J, Wang C, Zhang J, Jiang Y, Liu H, Zhao Y, Li Z, Gao Y, Wang Y. Incidence and risk factors of de novo hepatitis E virus infection after receiving liver transplantation. J Med Virol 2024; 96:e29939. [PMID: 39360633 DOI: 10.1002/jmv.29939] [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: 05/21/2024] [Revised: 09/07/2024] [Accepted: 09/17/2024] [Indexed: 10/04/2024]
Abstract
Organ transplant recipients with hepatitis E virus (HEV) infection bears high risk to develop chronic hepatitis, which is generally associated with immunosuppressive therapies. This study aimed to identify the incidence and predictors of de novo HEV infection in patients after receiving transplantation. We performed a large retrospective study to investigate the prevalence of anti-HEV at baseline, incidence of de novo HEV infection after transplantation, and the risk factors of HEV infection among patients with liver transplant in China. A total of 407 liver transplant recipients were examined for the presence of anti-HEV immunoglobulin G, IgM antibodies, and HEV RNA in serum. Basal indexes in individuals with evidence of post-transplant HEV infection were compared with those without evidence of that, and risk factors associated with HEV infection were assessed. The prevalence of anti-HEV at pretransplant in liver transplant recipients was 25.8% (105/407). Serum-negative conversion occurred in 34 (32.38%) of 105 liver transplant patients. Sixty-five out of 302 patients had de novo HEV infection after transplantation, with a cumulative incidence of 42.74% during follow-up. After transplantation, HEV infection was associated with liver failure (p = 0.012), hypoproteinemia (p = 0.030) and higher level of r-glutamyl transferase (GGT) (p = 0.022) before transplantation. Graft rejection (OR = 0.075; p = 0.045) was negatively associated with serum-negative conversion in patients who had positive anti-HEV antibody before transplantation. The incidence of de novo HEV infection after transplantation were higher in China. Liver failure, hypoproteinemia, and GGT elevation may be associated with HEV infection after liver transplantation. This study suggests that prevention and control of HEV infection after liver transplantation should be paid attention in patients bearing these risk factors.
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Affiliation(s)
- Ping He
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jialei Li
- Medical School of Nanjing University, Nanjing, China
| | - Chen Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Jiayue Zhang
- School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huaian, China
| | - Yiyun Jiang
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Hongyang Liu
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yao Zhao
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Zhiwei Li
- Department of Hepato-Biliary Surgery, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China
| | - Yinjie Gao
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yijin Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
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4
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Turlewicz-Podbielska H, Ruszkowski JJ, Wojciechowski J, Pomorska-Mól M. No evidence of hepatitis E virus (HEV) infection among pet cats and dogs, and low seroprevalence of hepatitis E virus among pet rabbits in Poland. Vet Res Commun 2024; 48:597-602. [PMID: 37740104 PMCID: PMC10811079 DOI: 10.1007/s11259-023-10223-w] [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: 07/10/2023] [Accepted: 09/19/2023] [Indexed: 09/24/2023]
Abstract
The seroprevalence of Paslahepevirus balayani genotype 3 (hepatitis E virus genotype 3 - HEV-3; Hepeviridae family, genus Paslahepevirus) in pet cats, dogs and rabbits was evaluated. Samples from cats and dogs were collected from three veterinary practices from various parts of Poland: Poznan (wielkopolskie voivodeship), Przemysl (podkarpackie voivodeship) and Lublin (lubelskie voivodeship). Samples from rabbits were collected in Poznan. In total, serum samples from 90 cats, 82 dogs and 71 rabbits were selected and tested for specific anti-HEV-3 immunoglobulin (IgG) antibodies using a commercial ELISA test. Pathogen seroprevalence among rabbits was calculated at a 95% confidence interval (CI) for each gender, age (up to 12 months, 1-3 years, 4-7 years and over 8 years), symptoms group (healthy, gastrointestinal disorders, other disorders) and compared with a chi-squared test. No anti-HEV-3 IgG antibodies were detected in any of the samples from cats and dogs. Anti-HEV-3 IgG antibodies were detected in 2.82% of the serum samples from rabbits (2/71; 95% CI: 0.78-9.70). No significant correlations between seropositivity and gender, age, and symptoms (p > 0.05) were observed in rabbits. Our findings indicate that pet rabbits in Poland are exposed to HEV-3, develop humoral response due to infection and might constitute a source for HEV-3 transmission to humans.
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Affiliation(s)
- Hanna Turlewicz-Podbielska
- Department of Preclinical Sciences and Infectious Diseases, Faculty of Veterinary Medicine and Animals Sciences, Poznan University of Life Sciences, Wolynska 35, 60‑637, Poznan, Poland
| | - Jakub Jędrzej Ruszkowski
- Department of Animal Anatomy, Faculty of Veterinary Medicine and Animals Sciences, Poznan University of Life Sciences, Wojska Polskiego 71C, 60‑625, Poznan, Poland
| | | | - Małgorzata Pomorska-Mól
- Department of Preclinical Sciences and Infectious Diseases, Faculty of Veterinary Medicine and Animals Sciences, Poznan University of Life Sciences, Wolynska 35, 60‑637, Poznan, Poland.
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Pires H, Cardoso L, Lopes AP, Fontes MDC, Santos-Silva S, Matos M, Pintado C, Figueira L, Matos AC, Mesquita JR, Coelho AC. Prevalence and Risk Factors for Hepatitis E Virus in Wild Boar and Red Deer in Portugal. Microorganisms 2023; 11:2576. [PMID: 37894234 PMCID: PMC10609178 DOI: 10.3390/microorganisms11102576] [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: 08/28/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Hepatitis E virus (HEV) is a zoonotic foodborne virus with an annual infection prevalence of 20 million human cases, which seriously affects public health and economic development in both developed and developing countries. To better understand the epidemiology of HEV in Central Portugal, a cross-sectional study was conducted from 2016 to 2023 with sera samples from wild ungulates. The seroprevalence and risk factors for HEV seropositivity were evaluated in the present study. Specifically, antibodies against HEV were determined by a commercial enzyme-linked immune-sorbent assay (ELISA). Our results show that in the 650 sera samples collected from 298 wild red deer and 352 wild boars in Portugal, 9.1% red deer and 1.7% wild boar were positive for antibodies to HEV. Regarding age, the seropositivity in juvenile wild ungulates was 1.3%, whereas it was 7.2% in adults. Logistic regression models investigated risk factors for seropositivity. The odds of being seropositive was 3.6 times higher in adults than in juveniles, and the risk was 4.2 times higher in red deer than in wild boar. Both wild ungulate species were exposed to HEV. The higher seroprevalence in red deer suggests that this species may make a major contribution to the ecology of HEV in Central Portugal. Further research is needed to understand how wildlife affects the epidemiology of HEV infections in Portugal.
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Affiliation(s)
- Humberto Pires
- Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal; (H.P.); (C.P.); (A.C.M.)
| | - Luís Cardoso
- Animal and Veterinary Research Centre (CECAV), Department of Veterinary Sciences, University of Trás-os-Montes e Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (L.C.); (A.P.L.); (M.d.C.F.)
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 5000-801 Vila Real, Portugal
| | - Ana Patrícia Lopes
- Animal and Veterinary Research Centre (CECAV), Department of Veterinary Sciences, University of Trás-os-Montes e Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (L.C.); (A.P.L.); (M.d.C.F.)
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 5000-801 Vila Real, Portugal
| | - Maria da Conceição Fontes
- Animal and Veterinary Research Centre (CECAV), Department of Veterinary Sciences, University of Trás-os-Montes e Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (L.C.); (A.P.L.); (M.d.C.F.)
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 5000-801 Vila Real, Portugal
| | - Sérgio Santos-Silva
- School of Medicine and Biomedical Sciences (ICBAS), Porto University, 4050-313 Porto, Portugal; (S.S.-S.); (J.R.M.)
| | - Manuela Matos
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes e Alto Douro (UTAD), 5000-801 Vila Real, Portugal;
| | - Cristina Pintado
- Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal; (H.P.); (C.P.); (A.C.M.)
- Research Center for Natural Resources, Environment and Society, Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal;
- Quality of Life in the Rural World (Q-RURAL), Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal
| | - Luís Figueira
- Research Center for Natural Resources, Environment and Society, Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal;
- Quality of Life in the Rural World (Q-RURAL), Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal
| | - Ana Cristina Matos
- Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal; (H.P.); (C.P.); (A.C.M.)
- Research Center for Natural Resources, Environment and Society, Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal;
- Quality of Life in the Rural World (Q-RURAL), Polytechnic Institute of Castelo Branco, 6001-909 Castelo Branco, Portugal
| | - João Rodrigo Mesquita
- School of Medicine and Biomedical Sciences (ICBAS), Porto University, 4050-313 Porto, Portugal; (S.S.-S.); (J.R.M.)
- Epidemiology Research Unit (EPIUnit), Instituto de Saúde Pública da Universidade do Porto, 4050-600 Porto, Portugal
- Laboratório Para a Investigação Integrativa e Translacional em Saúde Populacional (ITR), 4050-600 Porto, Portugal
| | - Ana Cláudia Coelho
- Animal and Veterinary Research Centre (CECAV), Department of Veterinary Sciences, University of Trás-os-Montes e Alto Douro (UTAD), 5000-801 Vila Real, Portugal; (L.C.); (A.P.L.); (M.d.C.F.)
- Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), 5000-801 Vila Real, Portugal
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Takakusagi S, Kakizaki S, Takagi H. The Diagnosis, Pathophysiology, and Treatment of Chronic Hepatitis E Virus Infection-A Condition Affecting Immunocompromised Patients. Microorganisms 2023; 11:1303. [PMID: 37317277 DOI: 10.3390/microorganisms11051303] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/01/2023] [Accepted: 05/13/2023] [Indexed: 06/16/2023] Open
Abstract
Hepatitis E is a zoonosis caused by hepatitis E virus (HEV), which was first discovered 40 years ago. Twenty million HEV infections worldwide are estimated each year. Most hepatitis E cases are self-limiting acute hepatitis, but the virus has been recognized to cause chronic hepatitis. Following the first case report of chronic hepatitis E (CHE) in a transplant recipient, CHE has recently been identified as associated with chronic liver damage induced by HEV genotypes 3, 4, and 7-usually in immunocompromised patients such as transplant recipients. In addition, patients infected with HIV and those receiving chemotherapy for malignancy, along with patients with rheumatic disease and COVID-19, have recently been reported as having CHE. CHE can be easily misdiagnosed by usual diagnostic methods of antibody response, such as anti-HEV IgM or IgA, because of the low antibody response in the immunosuppressive condition. HEV RNA should be evaluated in these patients, and appropriate treatments-such as ribavirin-should be given to prevent progression to liver cirrhosis or liver failure. While still rare, cases of CHE in immunocompetent patients have been reported, and care must be taken not to overlook these instances. Herein, we conduct an overview of hepatitis E, including recent research developments and management of CHE, in order to improve our understanding of such cases. The early diagnosis and treatment of CHE should be performed to decrease instances of hepatitis-virus-related deaths around the world.
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Affiliation(s)
- Satoshi Takakusagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka 375-0024, Gunma, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, 36 Takamatsu-cho, Takasaki 370-0829, Gunma, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka 375-0024, Gunma, Japan
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7
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Geng Y, Shi T, Wang Y. Transmission of Hepatitis E Virus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:73-92. [PMID: 37223860 DOI: 10.1007/978-981-99-1304-6_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Transmission of hepatitis E virus (HEV) occurs predominantly by the fecal-oral route. Large epidemics of hepatitis E in the developing countries of Asia and Africa are waterborne and spread through contaminated drinking water. The reservoir of HEV in developed countries is believed to be in animals with zoonotic transmission to humans, possibly through direct contact or the consumption of undercooked contaminated meat. And HEV transmission through blood transfusion, organ transplantation, and vertical transmission has been reported.
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Affiliation(s)
- Yansheng Geng
- Key Laboratory of Public Health Safety of Hebei Province, School of Public Health, Hebei University, Baoding, China
| | - Tengfei Shi
- Key Laboratory of Public Health Safety of Hebei Province, School of Public Health, Hebei University, Baoding, China
| | - Youchun Wang
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, China.
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8
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Hepatitis E Virus Infection, a Risk for Liver Transplant Recipients in Sweden. Transplant Direct 2022; 8:e1409. [PMID: 36398195 PMCID: PMC9666183 DOI: 10.1097/txd.0000000000001409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/08/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
Following exposure to hepatitis E virus (HEV), liver transplant (LT) recipients have an increased risk of developing chronic infection, which may rapidly progress to severe liver damage if not treated. The prevalence of HEV infection after LT is unclear and likely varies geographically. The aim of this study was to investigate the prevalence of acute and chronic HEV infection among LT recipients in an HEV endemic region.
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9
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Markakis GE, Papatheodoridis GV, Cholongitas E. Epidemiology and treatment of hepatitis E in the liver transplantation setting: A literature review. J Viral Hepat 2022; 29:698-718. [PMID: 35644040 DOI: 10.1111/jvh.13709] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 02/01/2022] [Accepted: 05/10/2022] [Indexed: 12/09/2022]
Abstract
Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing countries, but it can also take a chronic course especially in immunocompromised patients. Its epidemiology after liver transplantation (LT) is hard to assess and treatment options are still explored. Between 2009 and 2020, literature reporting HEV prevalence and treatment in LT recipients was searched and a synthesis was attempted. Sixteen studies reported HEV prevalence in consecutive LT patients: HEV RNA positivity ranged between 0%-1.4% and 0%-7.7% for Western and Eastern cohorts, respectively. In studies published between 2009-2014 and 2015-2020, HEV RNA positivity ranged between 0.35%-1.3% (all European) and 0%-7.7% (European: 0%-1.4%), respectively. Five studies evaluated HEV prevalence in LT recipients with abnormal liver enzymes: HEV RNA positivity was 2.9% in studies published between 2009 and 2014 and from 3.5% to 20% in studies published between 2015 and 2020. Twenty-seven studies reported HEV treatment in LT recipients: sustained virologic response was achieved in 15% by immunosuppression reduction alone and in 83% of cases by ribavirin regiments. Chronic HEV infection is affecting LT recipients, mostly those with abnormal liver enzymes and in Eastern countries. HEV diagnoses should be based on PCR techniques. Successful treatment can be achieved with ribavirin in most cases.
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Affiliation(s)
- George E Markakis
- Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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10
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Vij M, Rammohan A, Rela M. Long-term liver allograft fibrosis: A review with emphasis on idiopathic post-transplant hepatitis and chronic antibody mediated rejection. World J Hepatol 2022; 14:1541-1549. [PMID: 36157865 PMCID: PMC9453462 DOI: 10.4254/wjh.v14.i8.1541] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 07/08/2022] [Accepted: 08/16/2022] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation (LT) is a life-saving surgical procedure and the current standard of care for most patients with end stage liver disease. With improvements in organ preservation techniques, perioperative care, and immunosuppression, there is better patient and graft survival following LT, and assessment of the liver allograft in long-term survivors is becoming increasingly important. Recurrent or de novo viral or autoimmune injury remains the most common causes of chronic hepatitis and fibrosis following liver transplantation in adults. However, no obvious cause can be identified in many adults with controlled recurrent disease and the majority of pediatric LT recipients, as they have been transplanted for non-recurrent liver diseases. Serial surveillance liver biopsies post LT have been evaluated in several adult and pediatric centers to identify long-term pathological changes. Pathological findings are frequently present in liver biopsies obtained after a year post LT. The significance of these findings is uncertain as many of these are seen in protocol liver biopsies from patients with clinically good allograft function and normal liver chemistry parameters. This narrative review summaries the factors predisposing to long-term liver allograft fibrosis, highlighting the putative role of idiopathic post-LT hepatitis and chronic antibody mediated rejection in its pathogenesis.
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr. Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver disease and Transplantation, Dr. Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver disease and Transplantation, Dr. Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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11
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Carter M, Solsrud K, Yeddula S, Fitzmaurice MG, Singh A, Nagai S, Jafri SM. Hepatitis E Diagnosis and Management After Liver, Kidney, or Heart Transplant: A Single-Center Experience. Transplant Proc 2022; 54:1737-1741. [PMID: 35907694 DOI: 10.1016/j.transproceed.2022.04.025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 03/04/2022] [Accepted: 04/13/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Transplant-related hepatitis E virus (HEV) infection is a rarely recognized phenomenon with significant clinical importance given its potential to result in chronic hepatitis posttransplant. METHODS We retrospectively evaluated HEV diagnosis and treatment after liver, kidney, and heart transplant in a single center. We identified patients diagnosed with HEV by serologic testing and evaluated their treatment regimens. RESULTS Fifteen transplant recipients (12 liver, 2 kidney, and 1 heart) presented with elevated liver enzymes and were positive for HEV IgM antibody. Liver enzymes normalized in 4 patients after being treated with ribavirin. One of the 4 patients had 2 recurrences with positive HEV RNA results following ribavirin treatment but recovered after 12 months of ribavirin therapy. After treatment with reduction in immunosuppression without antiviral treatment, 6 of 8 patients' liver enzymes normalized. One of these patients died of acute pancreatitis 2 months after testing positive for HEV IgM antibody. CONCLUSIONS The potential for complications related to active HEV infections in transplant recipients necessitates prompt diagnosis and treatment to prevent irreversible damage. Diagnosis with HEV reverse transcriptase-polymerase chain reaction should follow a positive HEV IgM antibody test. This manuscript provides evidence that ribavirin antiviral therapy and reducing immunosuppression are effective treatments for HEV infections in liver, kidney, and heart transplant recipients, which has not been sufficiently investigated in the population of the United States. Larger multicenter studies are needed to confirm the risks and benefits of using ribavirin antiviral therapy as first-line therapy of HEV posttransplant.
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Affiliation(s)
| | | | - Sirisha Yeddula
- Department of Surgery Transplant, Henry Ford Health Systems, Detroit, Michigan
| | | | - Ashina Singh
- Department of Surgery Transplant, Henry Ford Health Systems, Detroit, Michigan
| | - Shunji Nagai
- Department of Surgery Transplant, Henry Ford Health Systems, Detroit, Michigan
| | - Syed-Mohammed Jafri
- Department of Gastroenterology, Henry Ford Health Systems, Detroit, Michigan
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12
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[Raw meat, lots of problems: rare infection in a patient after mechanical valve replacement and liver transplantation]. Internist (Berl) 2022; 63:658-661. [PMID: 35175370 DOI: 10.1007/s00108-022-01279-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2022] [Indexed: 10/19/2022]
Abstract
We report about a 43-year-old man who presented to the emergency department in septic shock with nonspecific gastrointestinal symptoms. Sonography and computed tomography (CT) could not identify the location of the infection in the patient who had undergone liver transplantation and has a mechanical mitral valve. Blood cultures were positive for Listeria monocytogenes. Transesophageal echocardiography showed prosthetic endocarditis. The findings regressed markedly under ampicillin.
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13
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Velavan TP, Pallerla SR, Johne R, Todt D, Steinmann E, Schemmerer M, Wenzel JJ, Hofmann J, Shih JWK, Wedemeyer H, Bock CT. Hepatitis E: An update on One Health and clinical medicine. Liver Int 2021; 41:1462-1473. [PMID: 33960603 DOI: 10.1111/liv.14912] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 03/09/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022]
Abstract
The hepatitis E virus (HEV) is one of the main causes of acute hepatitis and the de facto global burden is underestimated. HEV-related clinical complications are often undetected and are not considered in the differential diagnosis. Convincing findings from studies suggest that HEV is clinically relevant not only in developing countries but also in industrialized countries. Eight HEV genotypes (HEV-1 to HEV-8) with different human and animal hosts and other HEV-related viruses are in circulation. Transmission routes vary by genotype and location, with large waterborne outbreaks in developing countries and zoonotic food-borne infections in developed countries. An acute infection can be aggravated in pregnant women, organ transplant recipients, patients with pre-existing liver disease and immunosuppressed patients. HEV during pregnancy affects the fetus and newborn with an increased risk of vertical transmission, preterm and stillbirth, neonatal jaundice and miscarriage. Hepatitis E is associated with extrahepatic manifestations that include neurological disorders such as neuralgic amyotrophy, Guillain-Barré syndrome and encephalitis, renal injury and haematological disorders. The risk of transfusion-transmitted HEV is increasingly recognized in Western countries where the risk may be because of a zoonosis. RNA testing of blood components is essential to determine the risk of transfusion-transmitted HEV. There are currently no approved drugs or vaccines for HEV infections. This review focuses on updating the latest developments in zoonoses, screening and diagnostics, drugs in use and under development, and vaccines.
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Affiliation(s)
- Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research, VG-CARE, Hanoi, Vietnam.,Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
| | - Srinivas R Pallerla
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research, VG-CARE, Hanoi, Vietnam
| | - Reimar Johne
- German Federal Institute for Risk Assessment, Berlin, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.,European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mathias Schemmerer
- Institute of Clinical Microbiology and Hygiene, National Consultant Laboratory for HAV and HEV, University Medical Center Regensburg, Regensburg, Germany
| | - Jürgen J Wenzel
- Institute of Clinical Microbiology and Hygiene, National Consultant Laboratory for HAV and HEV, University Medical Center Regensburg, Regensburg, Germany
| | - Jörg Hofmann
- Institute of Virology, Charité Universitätsmedizin Berlin, Labor Berlin-Charité-Vivantes GmbH, Berlin, Germany
| | | | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Partner Hannover-Braunschweig, Braunschweig, Germany
| | - Claus-Thomas Bock
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
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14
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López-Santaella T, Álvarez Y Muñoz T, Medeiros-Domingo M, Moreno-Espinosa S, Consuelo-Sánchez A, Muñoz-Hernández O, Sarmiento-Silva RE, Sotomayor-González A, Trujillo-Ortega ME, García-Hernández ME, Taboada-Ramírez BI, Arenas-Huertero F. Serological and molecular study of Hepatitis E virus in pediatric patients in Mexico. Ann Hepatol 2021; 19:295-301. [PMID: 31899127 DOI: 10.1016/j.aohep.2019.12.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 11/27/2019] [Accepted: 12/04/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Cases of viral hepatitis reported in Mexico are typically identified as hepatitis A, B and C. However, unspecified cases are reported annually. Hepatitis E virus (HEV) is an emergent agent that causes a self-limiting infection that can evolve to chronic in immunosuppressed individuals. In Mexico, HEV genotype 2 is considered endemic, though it's the prevalence is not well known. Therefore, the present study was designed to determine the prevalence of HEV among patients at the "Hospital Infantil de Mexico Federico Gomez". MATERIALS AND METHODS The study included 99 patients, anti-HEV antibody (IgG and IgM) were detected by indirect ELISA and viral genome was identified using RT-PCR technique. Two PCR products of positive cases were sequenced. RESULTS ELISA results were positive in 3% and 6%, for IgG and IgM respectively, 54.5% prevalence was found by PCR. Low lymphocyte count (p<0.05) and malnutrition (p<0.005) were significant factors for high PCR prevalence and could increase the possibility of infection. Two samples were sequenced and confirmed the presence of HEV genotype 3. CONCLUSIONS This report reveals the incidence of HEV in pediatric patients in Mexico. Moreover, the identification of HEV genotype 3 in human samples suggests a potential zoonotic risk that requires further research.
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Affiliation(s)
- Tayde López-Santaella
- Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Ciudad de México, Mexico
| | - Teresa Álvarez Y Muñoz
- Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Ciudad de México, Mexico
| | - Mara Medeiros-Domingo
- Servicio de Nefrología, Hospital Infantil de México Federico Gómez, Ciudad de México, Mexico
| | | | | | - Onofre Muñoz-Hernández
- Dirección de Investigación, Hospital Infantil de México Federico Gómez, Ciudad de México, Mexico
| | - Rosa Elena Sarmiento-Silva
- Departamento de Microbiología e Inmunología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
| | - Alicia Sotomayor-González
- Departamento de Microbiología e Inmunología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - María Elena Trujillo-Ortega
- Departamento de Medicina y Zootecnia de Cerdos, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Montserrat Elemi García-Hernández
- Departamento de Microbiología e Inmunología, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Blanca Itzel Taboada-Ramírez
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Mor. Mexico
| | - Francisco Arenas-Huertero
- Laboratorio de Investigación en Patología Experimental, Hospital Infantil de México Federico Gómez, Ciudad de México, Mexico
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15
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Corman VM, Nagy P, Ostermann S, Arloth J, Liljander A, Barua R, Das Gupta A, Hakimuddin F, Juhasz J, Wernery U, Drosten C. Hepatitis E Virus Genotype 7 RNA and Antibody Kinetics in Naturally Infected Dromedary Calves, United Arab Emirates. Emerg Infect Dis 2021; 26:2214-2217. [PMID: 32818408 PMCID: PMC7454054 DOI: 10.3201/eid2609.191758] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Orthohepevirus A genotype 7 is a novel zoonotic variant of hepatitis E virus. To clarify infection in the animal reservoir, we virologically monitored 11 dromedary dam–calf pairs. All calves became infected during the first 6 months of life and cleared the virus after an average of 2 months. Dams did not become infected.
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16
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de Moraes ACP, Gouvea MG, Ferreira AC, Pinho JRR, de Mello ES, D'Albuquerque LAC, Terrabuio D, Abdala E, Carrilho FJ, Pessoa MG. The impact of hepatitis E infection on hepatic fibrosis in liver transplanted patients for hepatitis C infection. Braz J Infect Dis 2021; 25:101587. [PMID: 34062126 PMCID: PMC9392192 DOI: 10.1016/j.bjid.2021.101587] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 04/06/2021] [Accepted: 04/18/2021] [Indexed: 11/28/2022] Open
Abstract
Hepatitis E Virus (HEV) is an infection known worldwide for its asymptomatic and self-limited course in most cases. Some cases progressing to chronicity have been described in immunosuppressed patients, especially in recipients of solid organ transplants. We evaluated laboratory parameters of HEV infection (HEV RNA, anti-HEV IgM and anti-HEV IgG) through enzyme-linked immunosorbent assay (Elisa), confirmed by immunoblotting, in a cohort of 294 patients who received liver transplants at the HCFMUSP (Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo). Laboratory and demographic data were collected from the entirety of the transplanted population. Hepatic biopsies of 122 patients transplanted due liver failure secondary to hepatitis C (HCV), with or without serological or molecular markers of HEV, were analyzed according to METAVIR score. Out of 24 (8.2%) patients tested positive for anti-HEV IgG, six (2%) were positive for anti-HEV IgM and 17 (5.8%) for HEV RNA. Of the patients transplanted because of HCV infection, 95 (77.8%) had received treatment including ribavirin for at least six months before blood sample collection. Among patients transplanted due to HCV cirrhosis who tested positive for anti-HEV IgG, only three (37.5%) showed fibrosis beyond stage 2, while five (41.7%) of the HEV RNA-positive patients had liver fibrosis beyond stage 2. Overall, the prevalence of HEV in the post-hepatic transplant scenario appears to be low, and, at least histologically, seemingly not harmful. We conclude that, although some studies reported a risk of HEV chronification, patients who had their livers transplanted due to HCV and showed serological or molecular markers of HEV did not have higher levels of fibrosis compared to patients who showed no indications of HEV infection at the time of the analysis.
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Affiliation(s)
| | - Michele Gomes Gouvea
- School of Medicine, Institute of Tropical Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Ariana Carolina Ferreira
- School of Medicine, Institute of Tropical Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - João Renato Rebello Pinho
- School of Medicine, Institute of Tropical Medicine, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Evandro Sobroza de Mello
- School of Medicine, Department of Pathology, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | | | - Debora Terrabuio
- School of Medicine, Hospital das Clínicas (HCFMUSP), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Edson Abdala
- School of Medicine, Hospital das Clínicas (HCFMUSP), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Flair José Carrilho
- School of Medicine, Hospital das Clínicas (HCFMUSP), Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Mário Guimarães Pessoa
- School of Medicine, Hospital das Clínicas (HCFMUSP), Universidade de São Paulo (USP), São Paulo, SP, Brazil
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17
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Oshiro Y, Harada H, Hasegawa K, Akutsu N, Yoshizumi T, Kawagishi N, Nanmoku K, Ichimaru N, Okamura K, Ohira M, Itabashi Y, Fujiyama N, Ide K, Okajima H, Ogawa K, Takagi K, Eguchi H, Shinoda M, Nishida K, Shimazaki J, Shimoda M, Takahashi M, Okamoto H, Suzuki S. Loss of antibodies to hepatitis E virus in organ transplant patients with hepatitis E. Hepatol Res 2021; 51:538-547. [PMID: 33749100 DOI: 10.1111/hepr.13637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 02/10/2021] [Accepted: 03/14/2021] [Indexed: 02/08/2023]
Abstract
AIM Studies regarding changes in antibodies to hepatitis E virus (HEV) after HEV infection in organ transplant patients are limited. This study aimed to clarify HEV infection trends in organ transplant patients who contracted HEV using data from a previous Japanese nationwide survey. METHODS This study was undertaken from 2012 to 2019. Among 4518 liver, heart, and kidney transplant patients, anti-HEV immunoglobulin G (IgG) antibodies were positive in 164; data were collected from 106 of these patients, who consented to participate in the study. In total, 32 liver transplant patients, seven heart transplant patients, and 67 kidney transplant patients from 16 institutions in Japan were examined for IgG, IgM, and IgM antibodies to HEV and the presence of HEV RNA in the serum. The χ2 -test was used to determine the relationship between the early and late postinfection groups in patients with anti-HEV IgG positive-to-negative conversion rates. The Mann-Whitney U-test was used to compare clinical factors. RESULTS Anti-HEV IgG positive-to-negative conversion occurred in 25 (23.6%) of 106 organ transplant patients. Of eight patients with hepatitis E who tested positive for HEV RNA, one (14.0%) had anti-HEV IgG positive-to-negative conversion. Twenty-four (24.5%) of 98 patients negative for HEV RNA had anti-HEV IgG positive-to-negative conversion. CONCLUSIONS This study revealed, for the first time, the changes in HEV antibodies in organ transplant patients. Loss of anti-HEV IgG could often occur unexpectedly in organ transplant patients with previous HEV infection.
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Affiliation(s)
- Yukio Oshiro
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
| | - Hiroshi Harada
- Kidney Transplant Surgery, Sapporo City General Hospital, Sapporo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organs and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naotake Akutsu
- Department of Surgery, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Koji Nanmoku
- Department of Renal Surgery and Transplantation, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Naotsugu Ichimaru
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kenichi Okamura
- Department of Cardiovascular Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masahiro Ohira
- Department of Gastroenterology and Metabolism, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - Yoshihiro Itabashi
- Department of Nephrology, School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Nobuhiro Fujiyama
- Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan
| | - Kentaro Ide
- Department of Gastroenterology and Metabolism, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - Hideaki Okajima
- Department of Paediatric Surgery, Kanazawa Medical University, Kahoku, Japan
| | - Kohei Ogawa
- Department of HPB and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kosei Takagi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masahiro Shinoda
- Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Kiyotaka Nishida
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
| | - Jiro Shimazaki
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
| | - Mitsugi Shimoda
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, 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
| | - Shuji Suzuki
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
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18
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Castaneda D, Gonzalez AJ, Alomari M, Tandon K, Zervos XB. From hepatitis A to E: A critical review of viral hepatitis. World J Gastroenterol 2021; 27:1691-1715. [PMID: 33967551 PMCID: PMC8072198 DOI: 10.3748/wjg.v27.i16.1691] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/02/2021] [Accepted: 04/09/2021] [Indexed: 02/06/2023] Open
Abstract
Viral infections affecting the liver have had an important impact on humanity, as they have led to significant morbidity and mortality in patients with acute and chronic infections. Once an unknown etiology, the discovery of the viral agents triggered interest of the scientific community to establish the pathogenesis and diagnostic modalities to identify the affected population. With the rapid scientific and technological advances in the last centuries, controlling and even curing the infections became a possibility, with a large focus on preventive medicine through vaccination. Hence, a comprehensive understanding of hepatitis A, B, C, D and E is required by primary care physicians and gastroenterologists to provide care to these patients. The review article describes the epidemiology, pathogenesis, clinical presentation, diagnostic tools and current medication regimens, with a focus on upcoming treatment options and the role of liver transplantation.
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Affiliation(s)
- Daniel Castaneda
- Digestive Disease Institute, Cleveland Clinic Florida, Weston, FL 33331, United States
| | | | - Mohammad Alomari
- Digestive Disease Institute, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Kanwarpreet Tandon
- Digestive Disease Institute, Cleveland Clinic Florida, Weston, FL 33331, United States
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19
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Hansrivijit P, Trongtorsak A, Puthenpura MM, Boonpheng B, Thongprayoon C, Wijarnpreecha K, Choudhury A, Kaewput W, Mao SA, Mao MA, Jadlowiec CC, Cheungpasitporn W. Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis. World J Gastroenterol 2021; 27:1240-1254. [PMID: 33828397 PMCID: PMC8006097 DOI: 10.3748/wjg.v27.i12.1240] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/17/2021] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) infection is underdiagnosed due to the use of serological assays with low sensitivity. Although most patients with HEV recover completely, HEV infection among patients with pre-existing chronic liver disease and organ-transplant recipients on immunosuppressive therapy can result in decompensated liver disease and death.
AIM To demonstrate the prevalence of HEV infection in solid organ transplant (SOT) recipients.
METHODS We searched Ovid MEDLINE, EMBASE, and the Cochrane Library for eligible articles through October 2020. The inclusion criteria consisted of adult patients with history of SOT. HEV infection is confirmed by either HEV-immunoglobulin G, HEV-immunoglobulin M, or HEV RNA assay.
RESULTS Of 563 citations, a total of 22 studies (n = 4557) were included in this meta-analysis. The pooled estimated prevalence of HEV infection in SOT patients was 20.2% [95% confidence interval (CI): 14.9-26.8]. The pooled estimated prevalence of HEV infection for each organ transplant was as follows: liver (27.2%; 95%CI: 20.0-35.8), kidney (12.8%; 95%CI: 9.3-17.3), heart (12.8%; 95%CI: 9.3-17.3), and lung (5.6%; 95%CI: 1.6-17.9). Comparison across organ transplants demonstrated statistical significance (Q = 16.721, P = 0.002). The subgroup analyses showed that the prevalence of HEV infection among SOT recipients was significantly higher in middle-income countries compared to high-income countries. The pooled estimated prevalence of de novo HEV infection was 5.1% (95%CI: 2.6-9.6) and the pooled estimated prevalence of acute HEV infection was 4.3% (95%CI: 1.9-9.4).
CONCLUSION HEV infection is common in SOT recipients, particularly in middle-income countries. The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants. More studies examining the clinical impacts of HEV infection in SOT recipients, such as graft failure, rejection, and mortality are warranted.
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Affiliation(s)
- Panupong Hansrivijit
- Department of Internal Medicine, UPMC Pinnacle, Harrisburg, PA 17104, United States
| | - Angkawipa Trongtorsak
- Department of Internal Medicine, Amita Health Saint Francis Hospital, Evanston, IL 60202, United States
| | - Max M Puthenpura
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA 19129, United States
| | - Boonphiphop Boonpheng
- David Geffen School of Medicine, University of California, Los Angeles, Division of Nephrology, Los Angeles, CA 90095, United States
| | - Charat Thongprayoon
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Karn Wijarnpreecha
- Department of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, United States
| | - Avishek Choudhury
- School of Systems and Enterprises, Stevens Institute of Technology, Hoboken, NJ 07030, United States
| | - Wisit Kaewput
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok 10400, Thailand
| | - Shennen A Mao
- Department of Transplant Surgery, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Michael A Mao
- Department of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Caroline C Jadlowiec
- Department of Transplant Center, Mayo Clinic, Scottsdale, AZ 85259, United States
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20
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Capai L, Hozé N, Chiaroni J, Gross S, Djoudi R, Charrel R, Izopet J, Bosseur F, Priet S, Cauchemez S, de Lamballerie X, Falchi A, Gallian P. Seroprevalence of hepatitis E virus among blood donors on Corsica, France, 2017. ACTA ACUST UNITED AC 2020; 25. [PMID: 32046820 PMCID: PMC7014670 DOI: 10.2807/1560-7917.es.2020.25.5.1900336] [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] [Indexed: 12/28/2022]
Abstract
Background Hepatitis E virus (HEV) is an emerging zoonotic pathogen and an important cause of acute viral hepatitis in European countries. Corsica Island has been previously identified as a hyperendemic area for HEV. Aim Our aim was to characterise the prevalence and titres of IgG antibodies to HEV among blood donors on Corsica and establish a model of the annual force of infection. Methods Between September 2017 and January 2018, 2,705 blood donations were tested for anti-HEV IgG using the Wantai HEV IgG enzyme immunoassay. Results The overall seroprevalence was 56.1%. In multivariate analysis, seroprevalence was higher in men than in women (60.0% vs 52.2%; p < 0.01), increased with age and was significantly higher among donors born on Corsica (60.6% vs 53.2%; p < 0.01). No significant difference was observed between the five districts of the island. IgG anti-HEV titres were mostly low (70% of positive donors had titres < 3 IU/mL). In Corsican natives, increasing seroprevalence by age could be explained by models capturing a loss of immunity (annual probability of infection: 4.5%; duration of immunity: 55 years) or by age-specific probabilities of infection (3.8% for children, 1.3% for adults). Conclusion We confirmed the high HEV seroprevalence on Corsica and identified three aspects that should be further explored: (i) the epidemiology in those younger than 18 years, (ii) common sources of contamination, in particular drinking water, that may explain the wide exposure of the population, and (iii) the actual protection afforded by the low IgG titres observed and the potential susceptibility to secondary HEV infection.
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Affiliation(s)
- Lisandru Capai
- EA 7310, Laboratoire de Virologie, Université de Corse, Corte, France
| | - Nathanaël Hozé
- Mathematical Modelling of Infectious Diseases Unit, Institut Pasteur, UMR2000, CNRS, Paris, France
| | - Jacques Chiaroni
- Etablissement Français du Sang Provence alpes Côte d'Azur et Corse, Marseille, France
| | - Sylvie Gross
- Etablissement Français du Sang, 93210, La Plaine-Saint-Denis, France
| | - Rachid Djoudi
- Etablissement Français du Sang, 93210, La Plaine-Saint-Denis, France
| | - Rémi Charrel
- Unité des Virus Émergents (UVE): Aix Marseille Univ, IRD 190, INSERM 1207, IHU Méditerranée Infection, Marseille, France
| | - Jacques Izopet
- Institut National de la Santé et de la Recherche Médicale Unité 1043, Université Toulouse III, Toulouse, France.,Laboratoire de Virologie, Institut Fédératif de Biologie, Centre Hospitalier et Universitaire, Toulouse, France
| | - Frédéric Bosseur
- Sciences Pour l'Environnement - UMR CNRS 6134 Université de Corse, Corte, France
| | - Stéphane Priet
- Unité des Virus Émergents (UVE): Aix Marseille Univ, IRD 190, INSERM 1207, IHU Méditerranée Infection, Marseille, France
| | - Simon Cauchemez
- Mathematical Modelling of Infectious Diseases Unit, Institut Pasteur, UMR2000, CNRS, Paris, France
| | - Xavier de Lamballerie
- Unité des Virus Émergents (UVE): Aix Marseille Univ, IRD 190, INSERM 1207, IHU Méditerranée Infection, Marseille, France
| | - Alessandra Falchi
- EA 7310, Laboratoire de Virologie, Université de Corse, Corte, France
| | - Pierre Gallian
- Unité des Virus Émergents (UVE): Aix Marseille Univ, IRD 190, INSERM 1207, IHU Méditerranée Infection, Marseille, France.,Etablissement Français du Sang, 93210, La Plaine-Saint-Denis, France.,Etablissement Français du Sang Provence alpes Côte d'Azur et Corse, Marseille, France
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21
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A Nationwide Survey of Hepatitis E Virus Infection and Chronic Hepatitis in Heart and Kidney Transplant Recipients in Japan. Transplantation 2020; 104:437-444. [PMID: 31205267 PMCID: PMC7004465 DOI: 10.1097/tp.0000000000002801] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Background. Recently, chronic hepatitis E has been reported in solid organ transplant (SOT) recipients in European countries. Previously, we clarified the prevalence of hepatitis E virus (HEV) infection in Japanese liver transplant recipients and identified 2 chronic hepatitis E patients infected by blood transfusion. However, the rate of HEV infection in recipients of SOTs other than liver in Japan remains unclear, so we conducted a nationwide survey to clarify the prevalence of chronic HEV infection in Japanese heart and kidney transplant recipients. Methods. A total of 99 heart and 2526 kidney transplant recipients in 17 hospitals in Japan were examined for the presence of the IgG class of anti-HEV antibodies as well as for serum HEV RNA. Results. The prevalence of anti-HEV IgG among heart and kidney transplant recipients was 7.07% (7/99) and 4.08% (103/2526), respectively. One heart transplant patient (1.01%) and 11 kidney transplant patients (0.44%) were found to be positive for HEV RNA. The HEV isolates from all viremic patients were typed as genotype 3. Four patients developed chronic hepatitis E after transplantation. Three patients were treated with ribavirin; their liver enzymes normalized, and HEV RNA became negative immediately. Sustained virologic response was achieved in all cases. Conclusions. This is the first nationwide survey of HEV infection in Japanese heart and kidney transplant recipients. The prevalence of anti-HEV IgG and HEV RNA in heart and kidney transplant recipients in Japan was lower than that in European countries. Of note, 42% of viremic transplant patients developed chronic hepatitis.
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22
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Cornberg M, Pischke S, Müller T, Behrendt P, Piecha F, Benckert J, Todt D, Steinmann E, Papkalla A, von Karpowitz M, Koch A, Lohse A, Hardtke S, Manns MP, Wedemeyer H. Sofosbuvir monotherapy fails to achieve HEV RNA elimination in patients with chronic hepatitis E - The HepNet SofE pilot study. J Hepatol 2020; 73:696-699. [PMID: 32624195 DOI: 10.1016/j.jhep.2020.05.020] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/06/2020] [Accepted: 05/13/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; Center for Individualised Infection Medicine (CiiM), Hannover, Germany; German Center for Infection Research (DZIF); HepNet Study-House, Hannover, Germany; German Center for Infection Research (DZIF); Partner Site Hannover-Braunschweig, Germany.
| | - Sven Pischke
- I.Medical Clinic and Polyclinic, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany
| | - Tobias Müller
- Department of Gastroenterology and Hepatology, Charité Campus Virchow-Klinikum (CVK), Berlin, Germany
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; German Center for Infection Research (DZIF); Partner Site Hannover-Braunschweig, Germany
| | - Felix Piecha
- I.Medical Clinic and Polyclinic, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Julia Benckert
- Department of Gastroenterology and Hepatology, Charité Campus Virchow-Klinikum (CVK), Berlin, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Armin Papkalla
- Hannover Clinical Trial Center (HCTC-KKS), Hannover, Germany
| | | | - Armin Koch
- Institute for Biometry, Hannover Medical School, Germany
| | - Ansgar Lohse
- I.Medical Clinic and Polyclinic, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; German Center for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Germany
| | - Svenja Hardtke
- German Center for Infection Research (DZIF); HepNet Study-House, Hannover, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; German Center for Infection Research (DZIF); HepNet Study-House, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany; German Center for Infection Research (DZIF); Partner Site Hannover-Braunschweig, Germany.
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23
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Abstract
Viral hepatitis can cause a wide spectrum of clinical presentations from a benign form with minimal or no symptoms to acute liver failure or death. Hepatitis D coinfection and superinfection have distinct clinical courses, with the latter more likely leading to chronic infection. Management of chronic hepatitis D virus is individualized because of the paucity of treatment options and significant side effect profile of currently available treatments. Sporadic cases of hepatitis E caused by contaminated meats are becoming increasingly prevalent in immunocompromised hosts. Human herpesviruses are an important cause of disease also in immunocompromised individuals.
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24
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Hepatitis E virus infection in liver transplant recipients: a descriptive literature review. Eur J Gastroenterol Hepatol 2020; 32:916-922. [PMID: 32091436 DOI: 10.1097/meg.0000000000001682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus infection has been recognized as a rising hepatotropic viral infection in the developing countries but overlooked in the developed countries, due to its lower prevalence. However, hepatitis E virus prevalence is on rise in the liver transplant recipients due to immunosuppression, which needs prompt recognition by healthcare practitioners. Hepatitis E virus infection is commonly believed to be transmitted via an animal host; but in the post-liver transplant patients, it can also be acquired via blood and blood products transfusion and autochthonous route. Previous studies have shown the significance of hepatitis E virus infection in post-liver transplant, as the patients at a high risk of progressing to chronic hepatitis and cirrhosis. Pediatric patients are at higher risk of hepatitis E virus infection post-liver transplant. Specific hepatitis E virus genotypes have the potential for greater severity. The clinical manifestation of hepatitis E virus can also present as extrahepatic features which need high level of suspicion for early recognition and treatment. Treatment options of hepatitis E virus range from immunosuppressive drug minimization, ribavirin therapy to novel direct-acting antiviral regimens. Herein, we aim to explore epidemiology, prevalence, risk factor, diagnosis, and management of hepatitis E virus infection giving special attention to liver transplant recipients.
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25
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Progress in the Production of Virus-Like Particles for Vaccination against Hepatitis E Virus. Viruses 2020; 12:v12080826. [PMID: 32751441 PMCID: PMC7472025 DOI: 10.3390/v12080826] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 07/16/2020] [Accepted: 07/28/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatitis E virus (HEV), a pathogen that causes acute viral hepatitis, is a small icosahedral, quasi-enveloped, positive ssRNA virus. Its genome has three open reading frames (ORFs), with ORF1 and ORF3 encoding for nonstructural and regulatory proteins, respectively, while ORF2 is translated into the structural, capsid protein. ORF2 is most widely used for vaccine development in viral hepatitis. Hepatitis E virus-like particles (VLPs) are potential vaccine candidates against HEV infection. VLPs are composed of capsid subunits mimicking the natural configuration of the native virus but lack the genetic material needed for replication. As a result, VLPs are unable to replicate and cause disease, constituting safe vaccine platforms. Currently, the recombinant VLP-based vaccine Hecolin® against HEV is only licensed in China. Herein, systematic information about the expression of various HEV ORF2 sequences and their ability to form VLPs in different systems is provided.
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26
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Li Y, Long F, Yang C, Hao X, Wu J, Situ J, Chen S, Qian Z, Huang F, Yu W. BALB/c Mouse Is a Potential Animal Model System for Studying Acute and Chronic Genotype 4 Hepatitis E Virus Infection. Front Microbiol 2020; 11:1156. [PMID: 32612582 PMCID: PMC7308725 DOI: 10.3389/fmicb.2020.01156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 05/06/2020] [Indexed: 01/13/2023] Open
Abstract
Hepatitis E virus (HEV) is the main pathogen of hepatitis worldwide. However, its infection biology and pathogenesis remain largely unknown. Suitable small-animal models are required to advance the study of HEV infection. Although an efficient model of genotype 1 (gt1) and gt3 HEV infection has been established in human liver chimeric mice, the infectivity of gt4 HEV infection in mice has not been comprehensively characterized. In this study, immunocompromised BALB/c nude, immunocompetent BALB/c, and C57BL/6 mice were inoculated with either gt3 or gt4 HEV (19 HEV strains, including human, swine, macaque-adapted, and cow HEV strains). Infectivity was identified by viral RNA and antigen detection, inflammation, and histopathological analysis. Then, HEV-infected BALB/c mice were treated with antiviral drugs. Acute HEV infection was established in BALB/c mice inoculated with eight gt4 HEV strains. However, gt3 HEV strains failed to achieve active HEV infection. HEV infection was established in BALB/c nude and regular mice inoculated with gt4 HEV but not in C57BL/6 mice. Gt4 HEV infection resulted in rapid viremia and high titers in feces, sera, and replication sites. HEV infection in mice showed no gender preference. Furthermore, chronic gt4 HEV infection was well imitated in BALB/c mice for 32 weeks and caused liver fibrosis. CONCLUSION BALB/c mice have a great potential for reproducing the process of gt4 HEV infection. The successful establishment of a gt4 HEV small-animal model provides an opportunity to further understand HEV infection biology and zoonotic transmission and develop anti-HEV vaccine.
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Affiliation(s)
- Yunlong Li
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Feiyan Long
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Chenchen Yang
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Xianhui Hao
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Jian Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianwen Situ
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Shuangfeng Chen
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Zhongyao Qian
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Fen Huang
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Wenhai Yu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China
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27
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Ledesma J, Williams D, Stanford FA, Hewitt PE, Zuckerman M, Bansal S, Dhawan A, Mbisa JL, Tedder R, Ijaz S. Resolution by deep sequencing of a dual hepatitis E virus infection transmitted via blood components. J Gen Virol 2020; 100:1491-1500. [PMID: 31592753 DOI: 10.1099/jgv.0.001302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hepatitis E virus (HEV) is a zoonotic infection, with consumption of processed pork products thought to be the major route of transmission in England. The clinical features of HEV infection range from asymptomatic infection to mild hepatitis to fulminant liver failure. Persistent, chronic hepatitis is increasingly recognized in immunocompromised patients. Infection via HEV-containing blood components and organs has been reported and measures to reduce this transmission risk were introduced into the blood service in England in 2016. We report here the sequence and phylogenetic findings from investigations into a transmission event from an HEV-infected donor to two recipients. Phylogenetic analysis of HEV genome sequence fragments obtained by Sanger sequencing showed that, whilst most of the sequences from both recipients' samples grouped with the sequence from the blood donor sample, the relationship of five sequences from recipient 2 were unresolved. Analysis of Illumina short-read deep sequence data demonstrated the presence of two divergent viral populations in the donor's sample that were also present in samples from both recipients. A clear phylogenetic relationship was established, indicating a probable transmission of both populations from the donor to each of the immunocompromised recipients. This study demonstrates the value of the application of new sequencing technologies combined with bioinformatic data analysis when Sanger sequencing is not able to clarify a proper phylogenetic relationship in the investigation of transmission events.
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Affiliation(s)
- Juan Ledesma
- National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Blood Borne and Sexually Transmitted Infections, London, UK.,Antiviral Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK
| | - David Williams
- Bioinformatics, Virus Reference Department, National Infection Service, Public Health England, London, UK
| | - Felicia Adelina Stanford
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK
| | | | - Mark Zuckerman
- South London Specialist Virology Centre, King's College Hospital NHS Foundation Trust, London, UK
| | - Sanjay Bansal
- Paediatric Liver, GI and Nutrition Centre and Mowat Labs, King's College Hospital, London, UK
| | - Anil Dhawan
- Paediatric Liver, GI and Nutrition Centre and Mowat Labs, King's College Hospital, London, UK
| | - Jean Lutamyo Mbisa
- National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Blood Borne and Sexually Transmitted Infections, London, UK.,Antiviral Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK
| | - Richard Tedder
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK
| | - Samreen Ijaz
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK.,National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Blood Borne and Sexually Transmitted Infections, London, UK
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28
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Wallace SJ, Swann R, Donnelly M, Kemp L, Guaci J, Murray A, Spoor J, Lin N, Miller M, Dalton HR, Hussaini SH, Gunson R, Simpson K, Stanley A, Fraser A. Mortality and morbidity of locally acquired hepatitis E in the national Scottish cohort: a multicentre retrospective study. Aliment Pharmacol Ther 2020; 51:974-986. [PMID: 32285976 DOI: 10.1111/apt.15704] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 11/19/2019] [Accepted: 03/09/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV) is the most common acute viral hepatitis in Scotland. Little is known about the burden of morbidity and mortality, which can be high in chronic liver disease or immunocompromised states. AIMS To record the morbidity and mortality of HEV in Scotland. METHODS Demographic, clinical and laboratory data were collected retrospectively from all cases of HEV reported to virology departments across nine NHS health boards, between January 2013 and January 2018. RESULTS Five hundred and eleven cases were included (Mean age 62, 64% male). 58 (11%) cases had pre-existing cirrhosis and 110 (21%) had diabetes. Three hundred and three patients required admission (59%), totalling 2747 inpatient bed days. Seventeen (3.3%) HEV-related deaths were recorded. Factors that predicted mortality included haematological malignancy (OR 51.56, 95% CI 3.40-782.83, P = 0.005), cirrhosis (OR 41.85, 95% CI 2.85-594.16, P = 0.006), higher serum bilirubin (OR 1.01, 95% CI 1.01-1.02, P = 0.011) and chronic HEV infection (OR 0.02, 95% CI 0.02-0.28, P < 0.001). HEV infection affected 35 transplant patients of 106 total immunosuppressed patients (21%). Of these, 25 patients received Ribavirin therapy with a sustained virological remission of 76%. Thirty-five (6.7%) patients developed acute or acute-on-chronic liver failure with two requiring transplant. Thirty-seven (7.2%) patients reported neurological complications with 10 developing neuralgic amyotrophy, 6 Guillain-Barré and 2 encephalitis. Forty-four (8.6%) patients developed acute kidney injury. CONCLUSION In Scotland, HEV causes a significant burden of inpatient admissions, organ failure and death. Cirrhosis and haematological malignancy are significant predictors of mortality. Neurological and renal complications occur in a significant minority.
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Affiliation(s)
| | - Rachael Swann
- Department of Gastroenterology, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Mhairi Donnelly
- Department of Gastroenterology, Royal Infirmary Edinburgh, Edinburgh, UK
| | - Linda Kemp
- Department of Gastroenterology, Ninewells Hospital, Dundee, UK
| | - Julia Guaci
- Department of Gastroenterology, Royal Infirmary Edinburgh, Edinburgh, UK
| | - Aimee Murray
- Department of Gastroenterology, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Johannes Spoor
- Department of Gastroenterology, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Nan Lin
- Department of Mathematics, Physics and Electrical Engineering, Northumbria University, Newcastle, UK
| | - Michael Miller
- Department of Gastroenterology, Ninewells Hospital, Dundee, UK
| | - Harry R Dalton
- Department of Gastroenterology, Royal Cornwall Hospital Trust, Truro, Cornwall, UK
| | - S Hyder Hussaini
- Department of Gastroenterology, Royal Cornwall Hospital Trust, Truro, Cornwall, UK
| | - Rory Gunson
- Department of Virology, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Kenneth Simpson
- Department of Gastroenterology, Royal Infirmary Edinburgh, Edinburgh, UK
| | - Adrian Stanley
- Department of Gastroenterology, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Andrew Fraser
- Department of Gastroenterology, NHS Greater Glasgow and Clyde, Glasgow, UK.,Department of Gastroenterology, Royal Infirmary Edinburgh, Edinburgh, UK
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29
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Whitsett M, Feldman DM, Jacobson I. Hepatitis E Virus Infection in the United States: Current Understanding of the Prevalence and Significance in the Liver Transplant Patient Population and Proposed Diagnostic and Treatment Strategies. Liver Transpl 2020; 26:709-717. [PMID: 32061053 DOI: 10.1002/lt.25732] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 01/28/2020] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV), of the family Herpesviridae, is a virus that infects nearly 20 million people per year throughout the world. HEV is most commonly transmitted via the fecal-oral route and has long been described as a virus that afflicts only those in resource-poor countries. However, HEV has been detected in numerous animal carriers, various food sources, and even in human blood products in resource-rich regions of the world. HEV is of importance in the transplant patient population because of its ability to cause chronic viral infection in these patients can lead to graft loss and cirrhosis. In this review, we discuss the current knowledge of HEV as it pertains to the liver transplant patient population and discuss diagnosis and treatment of this infection.
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Affiliation(s)
- Maureen Whitsett
- Department of Gastroenterology and Hepatology, NYU Langone Health, NYU Grossman School of Medicine, New York University, New York, NY
| | - David M Feldman
- Department of Gastroenterology and Hepatology, NYU Langone Health, NYU Grossman School of Medicine, New York University, New York, NY
| | - Ira Jacobson
- Department of Gastroenterology and Hepatology, NYU Langone Health, NYU Grossman School of Medicine, New York University, New York, NY
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30
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Clinical significance of post-liver transplant hepatitis E seropositivity in high prevalence area of hepatitis E genotype 3: a prospective study. Sci Rep 2020; 10:7352. [PMID: 32355268 PMCID: PMC7192897 DOI: 10.1038/s41598-020-64551-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/15/2020] [Indexed: 12/25/2022] Open
Abstract
High hepatitis E (HEV) seroprevalence has been reported in the general population and in post-liver transplant (LT) cases in several regions, including Thailand, with genotype 3 being a predominant genotype. We hypothesized that HEV might persist at a subclinical level and might pose clinical risks in the post-LT period. We performed a cross-sectional study with 108 post-LT patients and found an IgG seroprevalence of 55.6%. Subsequently, 91 cases without clinical evidence of HEV-related hepatitis were enrolled in 1 year of prospective follow-up to determine clinical status, serologies and serum/feces HEV RNA every 4 months. HEV RNA was detected, indicating subclinical infections in patients with or without seropositivity, with an annual incidence of 7.7%. Our results suggest that subclinical HEV infection exists among LT patients in this high-prevalence area. Thus, clinicians should be aware of the possibility of disease reemergence and HEV viral transmission in LT patients.
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Darstein F, Häuser F, Mittler J, Zimmermann A, Lautem A, Hoppe-Lotichius M, Otto G, Lang H, Galle PR, Zimmermann T. Hepatitis E Is a Rare Finding in Liver Transplant Patients With Chronic Elevated Liver Enzymes and Biopsy-Proven Acute Rejection. Transplant Proc 2020; 52:926-931. [PMID: 32139278 DOI: 10.1016/j.transproceed.2020.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 11/17/2019] [Accepted: 01/22/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND In past decades, liver transplant (LT) patients were not routinely screened for hepatitis E virus (HEV) infection, and thus it might have been misdiagnosed as an acute rejection episode. Our aim was to analyze a real-world cohort of LT patients who presented with at least 1 episode of biopsy-proven acute rejection (BPAR) and suffered from persistent elevated transaminases, to evaluate the frequency of HEV infection misdiagnosed as a rejection episode. METHODS Data from 306 patients transplanted between 1997 and 2017, including 565 liver biopsies, were analyzed. Biopsies from patients suffering from hepatitis C (n = 79; 25.8%) and from patients who presented with a Rejection Activity Index <5 (n = 134; 43.8%) were excluded. A subgroup of 74 patients (with 134 BPAR) with persistently elevated liver enzymes was chosen for further HEV testing. RESULTS Positive HEV IgG was detectable in 18 of 73 patients (24.7%). Positive HEV RNA was diagnosed in 3 of 73 patients with BPAR (4.1%). Patients with HEV infection showed no difference in etiology of the liver disease, type of immunosuppression, or median Rejection Activity Index. CONCLUSION Few HEV infections were misdiagnosed as acute rejection episodes in this real-world cohort. Thus, HEV infection is an infrequent diagnosis in cases with persistent elevated liver enzymes and BPAR after LT.
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Affiliation(s)
- F Darstein
- First Department of Internal Medicine, Gastroenterology and Hepatology, Universitätsmedizin Mainz, Mainz, Germany.
| | - F Häuser
- Institute for Clinical Chemistry and Laboratory Medicine, Universitätsmedizin Mainz, Mainz, Germany
| | - J Mittler
- Department of Hepatobiliary and Transplantation Surgery, Universitätsmedizin Mainz, Mainz, Germany
| | - A Zimmermann
- First Department of Internal Medicine, Gastroenterology and Hepatology, Universitätsmedizin Mainz, Mainz, Germany
| | - A Lautem
- Department of Hepatobiliary and Transplantation Surgery, Universitätsmedizin Mainz, Mainz, Germany
| | - M Hoppe-Lotichius
- Department of Hepatobiliary and Transplantation Surgery, Universitätsmedizin Mainz, Mainz, Germany
| | - G Otto
- Department of Hepatobiliary and Transplantation Surgery, Universitätsmedizin Mainz, Mainz, Germany
| | - H Lang
- Department of Hepatobiliary and Transplantation Surgery, Universitätsmedizin Mainz, Mainz, Germany
| | - P R Galle
- First Department of Internal Medicine, Gastroenterology and Hepatology, Universitätsmedizin Mainz, Mainz, Germany
| | - T Zimmermann
- First Department of Internal Medicine, Gastroenterology and Hepatology, Universitätsmedizin Mainz, Mainz, Germany
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Wallace SJ, Crossan C, Hussaini SH, Dalton HR. Hepatitis E: a largely underestimated, emerging threat. Br J Hosp Med (Lond) 2020; 80:399-404. [PMID: 31283400 DOI: 10.12968/hmed.2019.80.7.399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Hepatitis E virus has two distinct clinical and epidemiological patterns based on the varying genotypes. Genotypes 3 and 4 cause widespread, sporadic infection in high-income countries and are emerging as the most common type of viral hepatitis in much of Europe. These infections carry significant morbidity and mortality in the growing numbers of immunosuppressed patients or in patients with established liver disease. Furthermore the growing extra-hepatic associations of the virus, including neurological and kidney injury, suggest that it may have been misnamed as a 'hepatitis' virus. This review explores current understanding of the epidemiology, virology and clinical presentations of hepatitis E infection and identifies vulnerable patient groups, who are at serious risk from infection. Guidance is offered regarding the diagnosis, treatment and prevention of this growing public health hazard.
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Affiliation(s)
- S J Wallace
- Speciality Registrar, Department of Gastroenterology, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN
| | - C Crossan
- Research Fellow, Department of Life Sciences, Glasgow Caledonian University, Glasgow
| | - S H Hussaini
- Consultant, Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall
| | - H R Dalton
- Retired Consultant, Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall
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Abstract
Chronic HEV infections pose a significant clinical problem in immunocompromised individuals. The lack of an efficient cell culture system has severely limited investigation of the HEV life cycle and the development of effective antivirals. Here we report the establishment of a robust HEV cell culture system in human hepatocytes with viral titers up to 106 FFU/mL. These produced intracellular-derived HEVcc particles demonstrated replication to high viral loads in human liver chimeric mice and were able to efficiently infect primary human as well as porcine hepatocytes. This unique infectious cell culture model provides a powerful tool for the analysis of host–virus interactions that should facilitate the discovery of antiviral drugs for this important zoonotic pathogen. Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and the leading cause for acute viral hepatitis worldwide. The virus is classified as a member of the genus Orthohepevirus A within the Hepeviridae family. Due to the absence of a robust cell culture model for HEV infection, the analysis of the viral life cycle, the development of effective antivirals and a vaccine is severely limited. In this study, we established a protocol based on the HEV genotype 3 p6 (Kernow C-1) and the human hepatoma cell lines HepG2 and HepG2/C3A with different media conditions to produce intracellular HEV cell culture-derived particles (HEVcc) with viral titers between 105 and 106 FFU/mL. Viral titers could be further enhanced by an HEV variant harboring a mutation in the RNA-dependent RNA polymerase. These HEVcc particles were characterized in density gradients and allowed the trans-complementation of subgenomic reporter HEV replicons. In addition, in vitro produced intracellular-derived particles were infectious in liver-humanized mice with high RNA copy numbers detectable in serum and feces. Efficient infection of primary human and swine hepatocytes using the developed protocol could be observed and was inhibited by ribavirin. Finally, RNA sequencing studies of HEV-infected primary human hepatocytes demonstrated a temporally structured transcriptional defense response. In conclusion, this robust cell culture model of HEV infection provides a powerful tool for studying viral–host interactions that should facilitate the discovery of antiviral drugs for this important zoonotic pathogen.
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Beer A, Holzmann H, Pischke S, Behrendt P, Wrba F, Schlue J, Drebber U, Neudert B, Halilbasic E, Kreipe H, Lohse A, Sterneck M, Wedemeyer H, Manns M, Dienes HP. Chronic Hepatitis E is associated with cholangitis. Liver Int 2019; 39:1876-1883. [PMID: 31102493 PMCID: PMC6790616 DOI: 10.1111/liv.14137] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 12/21/2018] [Accepted: 02/06/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Sporadic hepatitis E is an emerging indigenous disease in Europe induced by genotype 3 of the virus. While the disease takes an acute self-limited course in immunocompetent individuals, under immunocompromised conditions chronic hepatitis E might develop. The histology of chronic hepatitis E has not been described in detail systematically. METHODS Liver biopsies from 19 immunosuppressed patients with chronic hepatitis E were collected: 17 were organ transplant recipients, one had a CD4-deficiency and one had received steroid therapy because of ulcerative colitis. Biopsies were processed with standard stains. Evaluation of histologic activity and fibrosis was performed according to Ishak. Additionally, immunohistochemistry with antibodies directed against open reading frame 2 and 3 of the virus was performed and liver biopsies were tested for hepatitis E virus RNA. RESULTS Biochemical data showed an increase in alanine transaminase, aspartate transaminase, gamma-glutamyl transferase and total bilirubin. Histopathology displayed typical features of chronic hepatitis with mild to moderate activity. The number of polymorphonuclear leucocytes was considerably increased and all patients had a florid cholangitis that presented as a destructive form in five of them. Hepatocytes and bile duct epithelia stained positive for hepatitis E virus by immunohistochemistry. CONCLUSIONS Chronic hepatitis E in immunocompromised individuals runs a similar course as hepatitis B and C and shows similar histopathology. However, the presence of destructive cholangitis in some cases accompanied by an increased number of polymorphonuclear leucocytes is markedly different. Immunohistochemically the virus is present in bile duct epithelia, seemingly the cause for cholangitis.
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Affiliation(s)
- Andrea Beer
- Department of PathologyMedical University of ViennaViennaAustria
| | | | | | - Patrick Behrendt
- Department of Gastroenterology, Hepatology and EndocrinologyMedical School of HanoverHanoverGermany
| | - Fritz Wrba
- Department of PathologyMedical University of ViennaViennaAustria
| | - Jerome Schlue
- Institute for PathologyMedical School of HanoverHanoverGermany
| | - Uta Drebber
- Institute of PathologyUniversity Hospital CologneCologneGermany
| | - Barbara Neudert
- Department of PathologyMedical University of ViennaViennaAustria
| | - Emina Halilbasic
- Department of GastroenterologyMedical University of ViennaViennaAustria
| | - Hans Kreipe
- Institute for PathologyMedical School of HanoverHanoverGermany
| | | | | | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and EndocrinologyMedical School of HanoverHanoverGermany
| | - Michael Manns
- Department of Gastroenterology, Hepatology and EndocrinologyMedical School of HanoverHanoverGermany
| | - Hans P. Dienes
- Department of PathologyMedical University of ViennaViennaAustria
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Soon CF, Behrendt P, Todt D, Manns MP, Wedemeyer H, Sällberg Chen M, Cornberg M. Defining virus-specific CD8+ TCR repertoires for therapeutic regeneration of T cells against chronic hepatitis E. J Hepatol 2019; 71:673-684. [PMID: 31203151 DOI: 10.1016/j.jhep.2019.06.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 05/24/2019] [Accepted: 06/05/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Immunosuppressed patients with chronic hepatitis E virus infection (cHEV), who are ineligible or have failed current treatment with off-label ribavirin, are a potential target population for T cell-based therapy. T cell responses are important for viral control. Herein, we aimed to identify human leukocyte antigen (HLA)-A2 restricted HEV-specific CD8+ T cell epitopes and T cell receptors (TCR) targeting these epitopes, as the basis for a redirected TCR treatment approach for patients with cHEV. METHODS HEV genotype 3 overlapping peptide pools were used to screen HEV-specific CD8+ T cell immune responses in HLA-A2+ patients with acute HEV infection and healthy donors, by intracellular cytokine staining. CD8+ T cells targeting the identified epitopes were sorted for sequencing of the TCR repertoires by next generation sequencing. Messenger RNA encoding these TCRs were introduced into lymphocytes of healthy donors and patients with cHEV through TCR redirection. TCR-engineered lymphocytes were evaluated for Dextramer®-binding capacity, target sensitivity and cytotoxicity against peptide-loaded T2 cells. RESULTS HEV-specific responses were observed across open reading frame (ORF)1 and ORF2 of the HEV genome in patients with acute resolving HEV infection. HLA-A2-restricted HEV-specific CD8+ T cell epitopes targeting the HEV RNA helicase and RNA-dependent RNA polymerase were selected for functional studies. Introduction of HEV-specific TCRs into lymphocytes of immunocompetent donors and patients with chronic hepatitis E enabled the lymphocytes to bind HEV Dextramers, secrete multiple cytokines and exert cytotoxicity in a target-specific manner. CONCLUSION We identified TCRs that target HEV-specific CD8+ T cell epitopes, and characterized their immune properties, which may have clinical potential in future T cell-based therapy. LAY SUMMARY Patients who are immunosuppressed are vulnerable to developing chronic liver disease following infection with hepatitis E virus (HEV). To-date, there is no approved therapy for chronic hepatitis E. Interferon-α and ribavirin are off-label treatment options, but their applications are limited by side effects. Thus, immunotherapy, more specifically T cell-based therapy, may be an alternative approach. We designed T cell receptor-engineered T cells that effectively conferred immune cells, taken from patients with chronic hepatitis E, with the ability to recognize virus-specific epitopes and mediate killing of target cells in vitro.
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Affiliation(s)
- Chai Fen Soon
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Patrick Behrendt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, Germany
| | - Daniel Todt
- Department for Molecular and Medical Virology, Ruhr-Universität Bochum, Bochum, Germany
| | - Michael Peter Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Department of Gastroenterology and Hepatology, University Clinic Essen, Essen, Germany
| | - Margaret Sällberg Chen
- Department of Dental Medicine and Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Shanghai Tenth People's Hospital, Tongji University, Shanghai, China
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Germany; Centre for Individualised Infection Medicine (CIIM), Hannover, Germany; Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany.
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Chronic Hepatitis E Virus Infection during Lymphoplasmacytic Lymphoma and Ibrutinib Treatment. Pathogens 2019; 8:pathogens8030129. [PMID: 31443360 PMCID: PMC6789582 DOI: 10.3390/pathogens8030129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/16/2019] [Accepted: 08/17/2019] [Indexed: 12/25/2022] Open
Abstract
Hepatitis E virus (HEV) is an increasingly recognised pathogen, affecting several hundred thousand individuals in western countries each year. Importantly, the majority of immunocompromised individuals are not able to clear HEV but develop a chronic course of infection. In the case of lymphoma, which is an inherent immunosuppressive disease per se, chemotherapy can even further exacerbate the immunosuppressive status. As the mechanism of HEV chronification is barely understood, it is important to gain knowledge about the influence of chemotherapeutic drugs on the HEV replication cycle to guide rational clinical management of HEV infection in such patients. In this case report, a 70 year old man was diagnosed with lymphoplasmacytic lymphoma. As we observed the occurrence of chronic HEV after treatment with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in vivo, we investigated the influence of BTK signaling and ibrutinib treatment in the HEV replication cycle in vitro. First, we detected an HEV-induced mobilisation of BTK in human liver cells during HEV replication. A moderate antiviral effect against HEV replicating isolates including genotypes 1 and 3 was observed, suggesting that ibrutinib did not support HEV replication in a direct manner. Combinatory treatments of ibrutinib with ribavirin indicated that ibrutinib did not influence the antiviral effect of ribavirin. Taken together, chemotherapy targeting cellular factors for the treatment of lymphomas may be a neglected risk factor for the chronification of HEV. For ibrutinib, despite the upregulation of its target BTK during HEV replication, we observed neither a proviral effect on HEV replication nor an influence on the antiviral effect of ribavirin, suggesting that the chronification of HEV may be favoured by its immunosuppressive effect.
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37
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Te H, Doucette K. Viral hepatitis: Guidelines by the American Society of Transplantation Infectious Disease Community of Practice. Clin Transplant 2019; 33:e13514. [DOI: 10.1111/ctr.13514] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 02/12/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Helen Te
- Center for Liver Diseases, Section of Gastroenterology, Hepatology and Nutrition University of Chicago Medicine Chicago Illinois
| | - Karen Doucette
- Division of Infectious Diseases University of Alberta Edmonton Alberta Canada
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38
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Meta-Analysis of Human IgG anti-HEV Seroprevalence in Industrialized Countries and a Review of Literature. Viruses 2019; 11:v11010084. [PMID: 30669517 PMCID: PMC6357031 DOI: 10.3390/v11010084] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/16/2019] [Accepted: 01/18/2019] [Indexed: 12/11/2022] Open
Abstract
Although Hepatitis E is increasingly described as a major cause of liver disease in industrialized countries, the epidemiology is far from being fully elucidated. We provide here a comprehensive review of documented clusters of cases, and of serological studies conducted in populations with distinct types of exposure. Seroprevalence rates range from <5% to >50% depending on the countries and the groups of population. Such discrepancies can be attributed to the type of serological assay used, but this solves only a part of the problem. We performed a meta-analysis of studies performed with the broadly used Wantai HEV-IgG ELISA and found striking differences that remain difficult to understand with the current knowledge of transmission pathways.
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40
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Fischer SA. Is This Organ Donor Safe?: Donor-Derived Infections in Solid Organ Transplantation. Infect Dis Clin North Am 2018; 32:495-506. [PMID: 30146019 DOI: 10.1016/j.idc.2018.04.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Infection is an inevitable complication of solid organ transplantation. Unrecognized infection may be transmitted from a donor and result in disseminated disease in the immunosuppressed host. Recent outbreaks of deceased donor-derived infections resulting in high rates of mortality and severe morbidity have emphasized the need to be cautious in using donors with possible meningoencephalitis. Screening of organ donors for potential transmissible infections is paramount to improving transplantation outcomes.
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Affiliation(s)
- Staci A Fischer
- The Warren Alpert Medical School of Brown University, 222 Richmond Street, Providence, RI 02903, USA; Accreditation Council for Graduate Medical Education, 401 North Michigan Avenue, Suite 2000, Chicago, IL 60611, USA.
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41
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Fischer SA. Is This Organ Donor Safe?: Donor-Derived Infections in Solid Organ Transplantation. Surg Clin North Am 2018; 99:117-128. [PMID: 30471737 DOI: 10.1016/j.suc.2018.09.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Infection is an inevitable complication of solid organ transplantation. Unrecognized infection may be transmitted from a donor and result in disseminated disease in the immunosuppressed host. Recent outbreaks of deceased donor-derived infections resulting in high rates of mortality and severe morbidity have emphasized the need to be cautious in using donors with possible meningoencephalitis. Screening of organ donors for potential transmissible infections is paramount to improving transplantation outcomes.
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Affiliation(s)
- Staci A Fischer
- The Warren Alpert Medical School of Brown University, 222 Richmond Street, Providence, RI 02903, USA; Accreditation Council for Graduate Medical Education, 401 North Michigan Avenue, Suite 2000, Chicago, IL 60611, USA.
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Todt D, Meister TL, Steinmann E. Hepatitis E virus treatment and ribavirin therapy: viral mechanisms of nonresponse. Curr Opin Virol 2018; 32:80-87. [PMID: 30384328 DOI: 10.1016/j.coviro.2018.10.001] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 09/27/2018] [Accepted: 10/04/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV) can cause chronic infections in immunosuppressed patients with adverse clinical outcomes. Intervention strategies are limited with ribavirin (RBV) being the only main therapeutic option as off-label drug. Recent reports on RBV monotherapy failures show a coherence with the presence of certain single nucleotide variants (SNVs) and in-frame insertions in the hypervariable region of open reading frame 1 in the HEV genome. Importantly, some of the alterations were present in the viral population as minor variant before RBV administration. Individualized infection medicine by early detection of emerging viral variants in patients could improve treatment outcome and prognosis.
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Affiliation(s)
- Daniel Todt
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany
| | - Toni Luise Meister
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr-University Bochum, Bochum, Germany.
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43
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Cella E, Golkocheva-Markova E, Sagnelli C, Scolamacchia V, Bruni R, Villano U, Ciccaglione AR, Equestre M, Sagnelli E, Angeletti S, Ciccozzi M. Human hepatitis E virus circulation in Bulgaria: Deep Bayesian phylogenetic analysis for viral spread control in the country. J Med Virol 2018; 91:132-138. [PMID: 30168583 DOI: 10.1002/jmv.25296] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 07/07/2018] [Indexed: 12/23/2022]
Abstract
Hepatitis E virus (HEV) infection in Bulgaria is endemic, as demonstrated by the seroprevalence of antibody against the virus in the general population and by the high prevalence of clinical cases registered. In this study, a deep Bayesian phylogenetic analysis has been performed to provide information on the genetic diversity and the spread of HEV genotypes in Bulgaria. Three different data sets of HEV virus was built for genotyping by the maximum likelihood method, for evolutionary rate estimated by Bayesian Markov Chain Monte Carlo approach, for demographic history investigation and for selective pressure analysis. The evolutionary rate for genotype 3e, was 351 × 10-3 substitution/site/year (95% highest posterior density [95% HPD]: 145 × 10 -3 -575 × 10 -3 ). The root of the time to the most recent common ancestor of the Bayesian maximum clade credibility tree of HEV 3e genotype corresponded to 1965 (HPD 95% 1949-1994). The Bulgarian sequences mainly clustered in the main clade (clade A). The monophyletic clade included all Bulgarian genotype 3e sequences. The demographic history showed a slight growth from 1995 to 2000, followed by a sort of bottleneck in 2010s, a peak in 2011 and a new growth to 2015. Selection pressure analysis did not show sites under positive pressure but 64 statistically significant sites under negative selection. Molecular epidemiological surveillance by Bayesian phylogeny of HEV virus can contribute to trace the way of human infection after contact with swine source directly or heating meat improving public health control.
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Affiliation(s)
- Eleonora Cella
- Unit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, Rome, Italy
| | - Elitsa Golkocheva-Markova
- NRL of Viral Hepatitis, Virology Department, National Center of Infectious and Parasitic Diseases (NCIPD), Sofia, Bulgaria
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Vittoria Scolamacchia
- Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, Rome, Italy
| | - Roberto Bruni
- Viral Hepatitis and Oncovirus and Retrovirus Diseases Unit, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Umbertina Villano
- Viral Hepatitis and Oncovirus and Retrovirus Diseases Unit, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Anna Rita Ciccaglione
- Viral Hepatitis and Oncovirus and Retrovirus Diseases Unit, Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Michele Equestre
- Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Silvia Angeletti
- Unit of Clinical Laboratory Science, University Campus Bio-Medico of Rome, Rome, Italy
| | - Massimo Ciccozzi
- Unit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, Rome, Italy
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Hardtke S, Rocco R, Ogata J, Braga S, Barbosa M, Wranke A, Doi E, da Cunha D, Maluf E, Wedemeyer H, Muzzillo D. Risk factors and seroprevalence of hepatitis E evaluated in frozen-serum samples (2002-2003) of pregnant women compared with female blood donors in a Southern region of Brazil. J Med Virol 2018; 90:1856-1862. [DOI: 10.1002/jmv.25274] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 07/07/2018] [Indexed: 12/28/2022]
Affiliation(s)
- S. Hardtke
- Department of Gastroenterology, Hepatology and Endocrinology; Hannover Medical School; Hannover Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig; Hannover Germany
| | - R. Rocco
- Department of Internal Medicine; Clinics Hospital, Federal University of Paraná; Curitiba Brazil
| | - J. Ogata
- Department of Internal Medicine; Clinics Hospital, Federal University of Paraná; Curitiba Brazil
| | - S. Braga
- Department of Internal Medicine; Clinics Hospital, Federal University of Paraná; Curitiba Brazil
| | - M. Barbosa
- Department of Internal Medicine; Clinics Hospital, Federal University of Paraná; Curitiba Brazil
| | - A. Wranke
- Department of Gastroenterology, Hepatology and Endocrinology; Hannover Medical School; Hannover Germany
| | - E. Doi
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig; Hannover Germany
| | - D. da Cunha
- Serology Lab, Clinics Hospital, Federal University of Paraná; Curitiba Brazil
| | - E. Maluf
- Department of Internal Medicine; Clinics Hospital, Federal University of Paraná; Curitiba Brazil
| | - H. Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology; Hannover Medical School; Hannover Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig; Hannover Germany
| | - D. Muzzillo
- Department of Internal Medicine; Clinics Hospital, Federal University of Paraná; Curitiba Brazil
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Allaire M, Bazille C, Selves J, Salamé E, Altieri M. Hepatitis E virus infection mimicking acute graft rejection in a liver transplant recipient. Clin Res Hepatol Gastroenterol 2018; 42:e68-e71. [PMID: 29650438 DOI: 10.1016/j.clinre.2017.12.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/08/2017] [Accepted: 12/22/2017] [Indexed: 02/06/2023]
Abstract
INTRODUCTION In liver transplant (LT) patients, hepatitis E virus (HEV) can lead to acute liver failure, chronic hepatitis and graft cirrhosis. Few data on graft rejection associated with HEV are available and are subject to discussion. CASE REPORT Here we report the case of a 58-year-old male patient who underwent LT in July 2015 for cirrhosis due to NASH and chronic alcohol intake complicated by hepatocellular carcinoma. LT was performed with a deceased donor isogroup and a mismatch CMV (donor+ and recipient-). HEV serology was negative before LT. In February 2016, we noted abnormal liver function, with increased transaminases and cholestasis parameters, without functional complaints. The patient was immunosuppressed by tacrolimus (4mg) and everolimus (2mg). Abdominal ultrasound was normal and liver biopsy showed signs of acute rejection (Banff score 6/9). We dispensed 500mg of methylprednisolone before obtaining positive serological results for HEV genotype 3 infection. Ribavirin (1,200mg per day) for 3 months was started, leading to rapid improvement in liver tests. Viral load became negative one month later. To date, the patient is under LP 5mg tacrolimus with normal liver tests. CONCLUSION We describe a case of HEV genotype 3 infection mimicking acute cellular rejection, with a favorable outcome due to ribavirin treatment. As intensive immunosuppressive therapy administered for graft rejection may promote viral replication and worsen liver damage, potential HEV infection must be considered in cases of pathological signs of acute cellular rejection, in order to avoid chronic graft hepatitis, cirrhosis and liver decompensation.
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Affiliation(s)
- M Allaire
- Service d'hépato-gastroentérologie, CHU Côte-de-Nacre, Caen, France.
| | - C Bazille
- Service d'anatomopathologie, CHU Côte-de-Nacre, Caen, France
| | - J Selves
- Service d'anatomie et cytologie pathologiques, institut universitaire du cancer de Toulouse, Toulouse, France
| | - E Salamé
- Service de chirurgie digestive, CHU Tours, Tours, France
| | - M Altieri
- Service d'hépato-gastroentérologie, CHU Côte-de-Nacre, Caen, France
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Transmission of Hepatitis E Virus With Plasma Exchange in Kidney Transplant Recipients. Transplantation 2018; 102:1351-1357. [PMID: 29561324 DOI: 10.1097/tp.0000000000002185] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Reekie I, Irish D, Ijaz S, Fox T, Bharucha T, Griffiths P, Thorburn D, Harber M, MacKinnon S, Sekhar M. Hepatitis E infection in stem cell and solid organ transplantpatients: A cross-sectional study: The importance of HEV RNA screening in peri-transplant period. J Clin Virol 2018; 107:1-5. [PMID: 30099145 DOI: 10.1016/j.jcv.2018.07.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 07/19/2018] [Accepted: 07/27/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hepatitis E Virus (HEV) is a common cause of acute viral hepatitis worldwide. Typically associated with a self-limiting illness, infection may persist in immunosuppressed populations with significant morbidity and mortality. Based on clinical data published world-wide, UK blood safety guidance recommends the universal screening for HEV RNA of blood donors and donors of tissue, organs and stem cells. OBJECTIVES This cross-sectional study aimed to determine the point prevalence of HEV viraemia and clinical course of viraemic patients in the peri-transplant period in solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) recipients transplanted over a 3-year period (2013-2015). STUDY DESIGN Nucleic acid extracts of whole blood from patients undergoing SOT or HSCT were tested by an in-house real-time reverse-transcriptase polymerase chain reaction assay for HEV RNA. Samples were tested at baseline (time of transplant), 30, 60 and 90 days post-transplant. RESULTS 870 patients (259 HSCT, 262 liver and 349 kidney transplant) were included with 2554 samples meeting the inclusion criteria. No kidney transplant patients had HEV viraemia at time of testing. One HSCT and three liver transplant patients were found to be HEV RNA positive. Overall this represented 0.46% of the patients testing positive for HEV viraemia. CONCLUSIONS Prevalence of HEV viraemia in SOT and HSCT patients in U.K. although higher than in the general population is low at baseline and remains low throughout the early post-transplant phase. Clearance of viraemia can be maintained despite ongoing immunosuppression. Prospective U.K. studies are necessary to inform screening policies in this population.
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Affiliation(s)
- Ian Reekie
- Royal Free Hospital NHS Foundation Trust, London, UK.
| | - Dianne Irish
- Royal Free Hospital NHS Foundation Trust, London, UK
| | | | - Thomas Fox
- Royal Free Hospital NHS Foundation Trust, London, UK
| | | | | | | | - Mark Harber
- Royal Free Hospital NHS Foundation Trust, London, UK
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Sotomayor-González A, Trujillo-Ortega ME, Taboada-Ramírez BI, Sandoval-Jaime C, Sarmiento-Silva RE. Phylogenetic Analysis and Characterization of the Complete Hepatitis E Virus Genome (Zoonotic Genotype 3) in Swine Samples from Mexico. Viruses 2018; 10:v10080391. [PMID: 30049969 PMCID: PMC6115897 DOI: 10.3390/v10080391] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 07/21/2018] [Accepted: 07/23/2018] [Indexed: 12/22/2022] Open
Abstract
Hepatitis E virus (HEV) is an emerging public health problem with an estimated 20 million infections each year. In Mexico, Orthohepevirus A, genotype 2, has been reported in humans, but genotype 3 has only been reported in swine (zoonotic). No diagnostic tests are publicly available in Mexico, and only partial sequences have been reported from swine samples. Hence, research is necessary to determine circulating strains, understand the features and dynamics of infection on pig farms, determine how to implement surveillance programs, and to assess public health risks. In this study, a next-generation sequencing (NGS) approach was applied to obtain a complete genome of swine HEV. Liver, feces, and bile samples were taken at slaughterhouses and a farm in Mexico. RT-PCR was used to determine positive samples and confirmed by Sanger sequencing. Of the 64 slaughterhouse samples, one bile sample was positive (B1r) (1.56%). Of 21 sample pools from farm animals, 14 were positive (66.66%), representing all stages of production. A complete sequence strain MXCDg3_B1c|_2016 was obtained from the bile of a domestic swine in the fattening stage. In addition, two partial sequences—MXCDg3_H2cons|_2016 (1473 nt) and MXCDg3_C3Acons|_2016 (4777 nt)—were obtained from sampled farm animals. Comparison with all reported genome HEV sequences showed similarity to genotype 3 subgenotype a (G3a), which has been previously reported in acute cases of human hepatitis in the US, Colombia, China, and Japan.
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Affiliation(s)
- Alicia Sotomayor-González
- Laboratory of Virology, Microbiology and Immunology Department, Veterinary Medicine and Husbandry Faculty, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico.
| | - María E Trujillo-Ortega
- Academic Council of the Biological, Chemical and Medical Sciences, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico.
- Swine Medicine and Husbandry Department, Veterinary Medicine and Husbandry Faculty, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico.
| | - Blanca I Taboada-Ramírez
- Biotechnology Institute (IBT), National Autonomous University of Mexico (UNAM), Cuernavaca 62209, Morelos, Mexico.
| | - Carlos Sandoval-Jaime
- Biotechnology Institute (IBT), National Autonomous University of Mexico (UNAM), Cuernavaca 62209, Morelos, Mexico.
| | - Rosa E Sarmiento-Silva
- Laboratory of Virology, Microbiology and Immunology Department, Veterinary Medicine and Husbandry Faculty, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico.
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Todt D, Moeller N, Praditya D, Kinast V, Friesland M, Engelmann M, Verhoye L, Sayed IM, Behrendt P, Dao Thi VL, Meuleman P, Steinmann E. The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo. Antiviral Res 2018; 157:151-158. [PMID: 30036559 PMCID: PMC7113770 DOI: 10.1016/j.antiviral.2018.07.010] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 04/19/2018] [Accepted: 07/17/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV) is the causative agent of hepatitis E in humans and a member of the genus Orthohepevirus in the family Hepeviridae. HEV infections are the common cause of acute hepatitis but can also take chronic courses. Ribavirin is the treatment of choice for most patients and type I interferon (IFN) has been evaluated in a few infected transplantation patients in vivo. However, no effective and specific treatments against HEV infections are currently available. In this study, we evaluated the natural compound silvestrol, isolated from the plant Aglaia foveolata, and known for its specific inhibition of the DEAD-box RNA helicase eIF4A in state-of-the-art HEV experimental model systems. Silvestrol blocked HEV replication of different subgenomic replicons in a dose-dependent manner at low nanomolar concentrations and acted additive to ribavirin (RBV). In addition, HEV p6-based full length replication and production of infectious particles was reduced in the presence of silvestrol. A pangenotypic effect of the compound was further demonstrated with primary isolates from four different human genotypes in HEV infection experiments of hepatocyte-like cells derived from human embryonic and induced pluripotent stem cells. In vivo, HEV RNA levels rapidly declined in the feces of treated mice while no effect was observed in the vehicle treated control animals. In conclusion, silvestrol could be identified as pangenotypic HEV replication inhibitor in vitro with additive effect to RBV and further demonstrated high potency in vivo. The compound therefore may be considered in future treatment strategies of chronic hepatitis E in immunocompromised patients.
The natural compound silvestrol is a potent inhibitor of HEV replication. HEV infection of laboratory and primary isolates could be inhibited by silvestrol. Silvestrol demonstrated high potency in human liver chimeric mice. Targeting translation initiation could be a novel antiviral strategy for the treatment of chronic hepatitis E.
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Affiliation(s)
- Daniel Todt
- Ruhr-University Bochum, Faculty of Medicine, Department of Molecular and Medical Virology, Germany; Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany
| | - Nora Moeller
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany
| | - Dimas Praditya
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany
| | - Volker Kinast
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany
| | - Martina Friesland
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany
| | - Michael Engelmann
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany
| | - Lieven Verhoye
- Laboratory of Liver Infectious Diseases, Department of Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium
| | - Ibrahim M Sayed
- Laboratory of Liver Infectious Diseases, Department of Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium; Microbiology and Immunology Department, Faculty of Medicine, Assuit University, Assuit, Egypt
| | - Patrick Behrendt
- Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
| | - Viet Loan Dao Thi
- Department of Virology, University Hospital, Heidelberg, Germany; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Clinical Chemistry, Microbiology and Immunology, Center for Vaccinology, Ghent University, Ghent, Belgium
| | - Eike Steinmann
- Ruhr-University Bochum, Faculty of Medicine, Department of Molecular and Medical Virology, Germany; Institute for Experimental Virology, TWINCORE Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Feodor-Lynen-Str. 7, 30625, Hannover, Germany.
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50
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Abstract
Hepatitis E virus (HEV) is a well-known cause of acute hepatitis. Immunocompromised subjects, including liver transplant recipients, are considered to be at risk for HEV infection, which occasionally follows a chronic course. The diagnosis of HEV infection in these patients must be based on HEV RNA testing, as serology has variable performance. The aim of this study was to assess the prevalence of HEV infection in liver transplant recipients in Greece by means of HEV RNA testing. Liver transplant recipients followed in the sole transplant centre in Greece were prospectively included. HEV RNA was detected by real-time RT-PCR. Positive samples were further analysed using a nested reverse transcription RT-PCR kit, which amplifies a 137-nucleotide sequence within the ORF2/ORF3 overlapping region to detect the HEV genotype and perform phylogenetic analysis. The mean age of the included patients (n = 76) was 54 years. The most common indication for liver transplantation was viral hepatitis (57%). The majority of the patients (75%) received a calcineurin inhibitor as part of their immunosuppressive regimen and had normal liver enzymes. HEV RNA was found positive in only 1/76 (1.3%) patient. Phylogenetic analysis showed that the sequence clustered into the HEV genotype 3 clade. This patient experienced an acute hepatitis flare, which nonetheless did not become chronic. The prevalence of HEV infection in liver transplant recipients in Greece is similar (1.3%) to that reported previously in other countries. Transplant physicians should be aware of this condition and its associated consequences.
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