|
1
|
Baymakova MP, Konaktchieva M, Kunchev M, Popivanov G, Kundurzhiev T, Tsachev I, Mutafchiyski V. First Insight into the Seroprevalence of Hepatitis E Virus and Associated Risk Factors Among Liver Transplant Recipients from Bulgaria. Vector Borne Zoonotic Dis 2025. [PMID: 39943906 DOI: 10.1089/vbz.2024.0101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/19/2025] Open
Abstract
Introduction: Hepatitis E virus (HEV) infection is caused by viruses belonging to the Hepeviridae family. HEV infection can be self-limiting; however, extrahepatic manifestations may be present. The purpose of the current study was to establish the seroprevalence of HEV among Bulgarian liver transplant recipients (LTRs) and to identify associated risk factors. Materials & Methods: The present study was conducted between April 1, 2023, and October 30, 2023, at the Military Medical Academy, Sofia, Bulgaria. All serum samples were tested for anti-HEV IgG/IgM using HEV IgG/IgM enzyme-linked immunosorbent assay on Dia.Pro (Milan, Italy). Each participating LTR completed a detailed paper-based closed-ended questionnaire regarding the associated risk factors for HEV infection. Results: The study included 73 LTRs with a mean age of 47.0 ± 14.0 years. Anti-HEV IgG antibodies were detected in 25 LTRs (34.2%), including 20 males (37.7%) and 5 females (25%). All participants were HEV-IgM negative. HEV seropositivity rates were higher but not statistically significant in LTRs aged >60 years than in those aged <60 years (40% vs. 32.7%). A significant factor by logistic regression was "high level of education" (odds ratio [OR] = 2.917; p = 0.038). Conclusion: To the best of our knowledge, this is the first seroepidemiological HEV study among LTRs from Bulgaria that found a high seroprevalence (34.2%).
Collapse
Affiliation(s)
| | - Marina Konaktchieva
- Department of Gastroenterology and Hepatology, Military Medical Academy, Sofia, Bulgaria
| | - Metodi Kunchev
- Department of Virology, Military Medical Academy, Sofia, Bulgaria
| | - Georgi Popivanov
- Department of Surgery, Military Medical Academy, Sofia, Bulgaria
| | - Todor Kundurzhiev
- Department of Occupational Medicine, Faculty of Public Health, Medical University, Sofia, Bulgaria
| | - Ilia Tsachev
- Department of Microbiology, Infectious and Parasitic Diseases, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria
| | | |
Collapse
|
|
2
|
Yadav KK, Kenney SP. Hepatitis E virus immunosuppressed animal models. BMC Infect Dis 2024; 24:965. [PMID: 39266958 PMCID: PMC11395946 DOI: 10.1186/s12879-024-09870-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/03/2024] [Indexed: 09/14/2024] Open
Abstract
Hepatitis E virus (HEV) is an important emerging pathogen producing significant morbidity in immunosuppressed patients. HEV has been detrimental to solid organ transplant (SOT) patients, cancer patients, and HIV-positive patients, where chronic HEV infections occur. Blood-borne transfusions and multiple cases of chronic HEV infection in transplant patients have been reported in the past few decades, necessitating research on HEV pathogenesis using immunosuppressed animal models. Numerous animal species with unique naturally occurring HEV strains have been found, several of which have the potential to spread to humans and to serve as pathogenesis models. Host immunosuppression leads to viral persistence and chronic HEV infection allows for genetic adaptation to the human host creating new strains with worse disease outcomes. Procedures necessary for SOT often entail blood transfusions placing immunosuppressive patients into a "high risk group" for HEV infection. This scenario requires an appropriate immunosuppressive animal model to understand disease patterns in these patients. Hence, this article reviews the recent advances in the immunosuppressed animal models for chronic HEV infection with emphasis on pathogenesis, immune correlates, and the liver pathology associated with the chronic HEV infections.
Collapse
Affiliation(s)
- Kush Kumar Yadav
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA
| | - Scott P Kenney
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA.
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA.
| |
Collapse
|
|
3
|
Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. S2k-Leitlinie Lebertransplantation der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) und der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV). ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | | |
Collapse
|
|
4
|
Ziersch M, Harms D, Neumair L, Kurreck A, Johne R, Bock CT, Kurreck J. Combining RNA Interference and RIG-I Activation to Inhibit Hepatitis E Virus Replication. Viruses 2024; 16:1378. [PMID: 39339854 PMCID: PMC11435946 DOI: 10.3390/v16091378] [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: 07/15/2024] [Revised: 08/19/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
Hepatitis E virus (HEV) poses a significant global health threat, with an estimated 20 million infections occurring annually. Despite being a self-limiting illness, in most cases, HEV infection can lead to severe outcomes, particularly in pregnant women and individuals with pre-existing liver disease. In the absence of specific antiviral treatments, the exploration of RNAi interference (RNAi) as a targeted strategy provides valuable insights for urgently needed therapeutic interventions against Hepatitis E. We designed small interfering RNAs (siRNAs) against HEV, which target the helicase domain and the open reading frame 3 (ORF3). These target regions will reduce the risk of viral escape through mutations, as they belong to the most conserved regions in the HEV genome. The siRNAs targeting the ORF3 efficiently inhibited viral replication in A549 cells after HEV infection. Importantly, the siRNA was also highly effective at inhibiting HEV in the persistently infected A549 cell line, which provides a suitable model for chronic infection in patients. Furthermore, we showed that a 5' triphosphate modification on the siRNA sense strand activates the RIG-I receptor, a cytoplasmic pattern recognition receptor that recognizes viral RNA. Upon activation, RIG-I triggers a signaling cascade, effectively suppressing HEV replication. This dual-action strategy, combining the activation of the adaptive immune response and the inherent RNAi pathway, inhibits HEV replication successfully and may lead to the development of new therapies.
Collapse
Affiliation(s)
- Mathias Ziersch
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
| | - Dominik Harms
- Department of Infectious Diseases, Division of Viral Gastroenteritis and Hepatitis Pathogens and Enterovirus, Robert Koch Institute, 13353 Berlin, Germany
| | - Lena Neumair
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
| | - Anke Kurreck
- Bioprocess Engineering, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
- BioNukleo GmbH, Ackerstrasse 76, 13355 Berlin, Germany
| | - Reimar Johne
- Department of Biological Safety, German Federal Institute for Risk Assessment, 12277 Berlin, Germany
| | - C-Thomas Bock
- Department of Infectious Diseases, Division of Viral Gastroenteritis and Hepatitis Pathogens and Enterovirus, Robert Koch Institute, 13353 Berlin, Germany
| | - Jens Kurreck
- Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany
| |
Collapse
|
|
5
|
Kanda T, Li TC, Takahashi M, Nagashima S, Primadharsini PP, Kunita S, Sasaki-Tanaka R, Inoue J, Tsuchiya A, Nakamoto S, Abe R, Fujiwara K, Yokosuka O, Suzuki R, Ishii K, Yotsuyanagi H, Okamoto H. Recent advances in hepatitis E virus research and the Japanese clinical practice guidelines for hepatitis E virus infection. Hepatol Res 2024; 54:1-30. [PMID: 38874115 DOI: 10.1111/hepr.14062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/22/2024] [Accepted: 05/09/2024] [Indexed: 06/15/2024]
Abstract
Acute hepatitis E was considered rare until reports emerged affirming the existence of hepatitis E virus (HEV) genotypes 3 and 4 infections in Japan in the early 2000s. Extensive studies by Japanese researchers have highlighted the pivotal role of pigs and wild animals, such as wild boars and deer, as reservoirs for HEV, linking them to zoonotic infections in Japan. Currently, when hepatitis occurs subsequent to the consumption of undercooked or grilled pork, wild boar meat, or offal (including pig liver and intestines), HEV infection should be considered. Following the approval of anti-HEV immunoglobulin A antibody as a diagnostic tool for hepatitis E by Japan's Health Insurance System in 2011, the annual number of diagnosed cases of HEV infection has surged. Notably, the occurrence of post-transfusion hepatitis E promoted nationwide screening of blood products for HEV using nucleic acid amplification tests since 2020. Furthermore, chronic hepatitis E has been observed in immunosuppressed individuals. Considering the significance of hepatitis E, heightened preventive measures are essential. The Japan Agency for Medical Research and Development Hepatitis A and E viruses (HAV and HEV) Study Group, which includes special virologists and hepatologists, held a virtual meeting on February 17, 2024. Discussions encompassed pathogenesis, transmission routes, diagnosis, complications, severity factors, and ongoing and prospective vaccination or treatments for hepatitis E. Rigorous assessment of referenced studies culminated in the formulation of recommendations, which are detailed within this review. This comprehensive review presents recent advancements in HEV research and Japanese clinical practice guidelines for HEV infection.
Collapse
Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Satoshi Kunita
- Center for Experimental Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryuzo Abe
- Department of Emergency Medicine, Oita University, Oita, Japan
| | - Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koji Ishii
- Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| |
Collapse
|
|
6
|
Orosz L, Sárvári KP, Dernovics Á, Rosztóczy A, Megyeri K. Pathogenesis and clinical features of severe hepatitis E virus infection. World J Virol 2024; 13:91580. [PMID: 38984076 PMCID: PMC11229844 DOI: 10.5501/wjv.v13.i2.91580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 06/24/2024] Open
Abstract
The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.
Collapse
Affiliation(s)
- László Orosz
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Károly Péter Sárvári
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - András Rosztóczy
- Department of Internal Medicine, Division of Gastroenterology, University of Szeged, Szeged 6725, Csongrád-Csanád, Hungary
| | - Klára Megyeri
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| |
Collapse
|
|
7
|
Paronetto O, Allioux C, Diméglio C, Lobjois L, Jeanne N, Ranger N, Boineau J, Pucelle M, Demmou S, Abravanel F, Chapuy-Regaud S, Izopet J, Lhomme S. Characterization of virus‒host recombinant variants of the hepatitis E virus. J Virol 2024; 98:e0029524. [PMID: 38712945 PMCID: PMC11237545 DOI: 10.1128/jvi.00295-24] [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: 02/13/2024] [Accepted: 04/09/2024] [Indexed: 05/08/2024] Open
Abstract
Hepatitis E virus is a single-strand, positive-sense RNA virus that can lead to chronic infection in immunocompromised patients. Virus-host recombinant variants (VHRVs) have been described in such patients. These variants integrate part of human genes into the polyproline-rich region that could introduce new post-translational modifications (PTMs), such as ubiquitination. The aim of this study was to characterize the replication capacity of different VHRVs, namely, RNF19A, ZNF787, KIF1B, EEF1A1, RNA18, RPS17, and RPL6. We used a plasmid encoding the Kernow strain, in which the fragment encoding the S17 insertion was deleted (Kernow p6 delS17) or replaced by fragments encoding the different insertions. The HEV RNA concentrations in the supernatants and the HepG2/C3A cell lysates were determined via RT-qPCR. The capsid protein ORF2 was immunostained. The effect of ribavirin was also assessed. The HEV RNA concentrations in the supernatants and the cell lysates were higher for the variants harboring the RNF19A, ZNF787, KIF1B, RPS17, and EEF1A1 insertions than for the Kernow p6 del S17, while it was not with RNA18 or RPL6 fragments. The number of ORF2 foci was higher for RNF19A, ZNF787, KIF1B, and RPS17 than for Kernow p6 del S17. VHRVs with replicative advantages were less sensitive to the antiviral effect of ribavirin. No difference in PTMs was found between VHRVs with a replicative advantage and those without. In conclusion, our study showed that insertions did not systematically confer a replicative advantage in vitro. Further studies are needed to determine the mechanisms underlying the differences in replicative capacity. IMPORTANCE Hepatitis E virus (HEV) is a major cause of viral hepatitis. HEV can lead to chronic infection in immunocompromised patients. Ribavirin treatment is currently used to treat such chronic infections. Recently, seven virus-host recombinant viruses were characterized in immunocompromised patients. These viruses have incorporated a portion of a human gene fragment into their genome. We studied the consequences of these insertions on the replication capacity. We found that these inserted fragments could enhance virus replication for five of the seven recombinant variants. We also showed that the recombinant variants with replicative advantages were less sensitive to ribavirin in vitro. Finally, we found that the mechanisms leading to such a replicative advantage do not seem to rely on the post-translational modifications introduced by the human gene fragment that could have modified the function of the viral protein. The mechanisms involved in improving the replication of such recombinant viruses remain to be explored.
Collapse
Affiliation(s)
- Olivia Paronetto
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Claire Allioux
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Chloé Diméglio
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Lhorane Lobjois
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Nicolas Jeanne
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Noémie Ranger
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Jérôme Boineau
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Mélanie Pucelle
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Sofia Demmou
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Florence Abravanel
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Sabine Chapuy-Regaud
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Jacques Izopet
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| | - Sébastien Lhomme
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), UMR 5051 (CNRS), UMR 1291 (INSERM), Université Toulouse III-Paul Sabatier, Toulouse, France
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, Toulouse, France
| |
Collapse
|
|
8
|
Sottil P, Lhomme S, Saune K, El Hayani S, Oliveira-Mendes K, Peron JM, Kamar N, Izopet J, Abravanel F. Evaluation of an automated platform for the detection of HEV RNA in plasma and stool. J Virol Methods 2024; 327:114920. [PMID: 38574772 DOI: 10.1016/j.jviromet.2024.114920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/14/2024] [Accepted: 03/24/2024] [Indexed: 04/06/2024]
Abstract
INTRODUCTION We evaluated the performance of the automated Altostar HEV RNA platform for detecting HEV RNA. METHODS AND RESULTS Clinical performance was determined by testing 81 plasma samples and 10 fecal samples manually quantified previously with the Realstar RT-PCR assay using the Magnapure instrument for extraction. The assays were concordant for 79/81 plasma samples (97.5%) and 10/10 (100%) fecal samples. The two plasma samples that tested negative with the Altostar assay had a very low HEV RNA concentration (1.6 and 1.4 log10 IU/ml). Quantitative results obtained with the automated platform and the manual workflow were highly correlated (ρ= 0.98, p<0.01). The intra-run and inter-run standard deviation were 0.09 IU/ml and 0.13 IU/ml respectively. The assay was linear from 2 to 6 log IU/ml. The limit of detection determined by Probit analysis with the WHO HEV RNA standard was 7.6 [95% CI: 4.4-52.5] IU/ml. CONCLUSIONS The Altostar platform enables highly accurate testing for the detection of HEV RNA in stool and the quantification of HEV RNA in plasma. This allowed us to shorten turnaround times and to save time for the technical staff.
Collapse
Affiliation(s)
- Pauline Sottil
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, National Reference Center for Hepatitis E, Toulouse 31300, France
| | - Sébastien Lhomme
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, National Reference Center for Hepatitis E, Toulouse 31300, France; Inserm UMR 1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France
| | - Karine Saune
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, National Reference Center for Hepatitis E, Toulouse 31300, France; Inserm UMR 1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France
| | - Soheil El Hayani
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, National Reference Center for Hepatitis E, Toulouse 31300, France
| | - Kévin Oliveira-Mendes
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, National Reference Center for Hepatitis E, Toulouse 31300, France
| | - Jean-Marie Peron
- CHU Toulouse, Hôpital Purpan, Département de Gastroentérologie, 31300, France
| | - Nassim Kamar
- CHU Toulouse, Hôpital Rangueil, Département de Néphrologie, Dialyse et Transplantation multi-organe, 31300, France
| | - Jacques Izopet
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, National Reference Center for Hepatitis E, Toulouse 31300, France; Inserm UMR 1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France
| | - Florence Abravanel
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, National Reference Center for Hepatitis E, Toulouse 31300, France; Inserm UMR 1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France.
| |
Collapse
|
|
9
|
León-Janampa N, Boennec N, Le Tilly O, Ereh S, Herbet G, Moreau A, Gatault P, Longuet H, Barbet C, Büchler M, Baron C, Gaudy-Graffin C, Brand D, Marlet J. Relevance of Tacrolimus Trough Concentration and Hepatitis E virus Genetic Changes in Kidney Transplant Recipients With Chronic Hepatitis E. Kidney Int Rep 2024; 9:1333-1342. [PMID: 38707810 PMCID: PMC11069011 DOI: 10.1016/j.ekir.2024.01.054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 01/26/2024] [Accepted: 01/29/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction Hepatitis E virus (HEV) can cause chronic infection (≥3 months) and cirrhosis in immunocompromised patients, especially kidney transplant recipients. Low alanine aminotransferase (ALT) levels and high HEV intrahost diversity have previously been associated with evolution toward chronicity in these patients. We hypothesized that additional clinical and viral factors could be associated with the risk of chronic HEV infection. Methods We investigated a series of 27 kidney transplant recipients with HEV infection, including 20 patients with chronic hepatitis E. Results High tacrolimus trough concentration at diagnosis was the most relevant marker associated with chronic hepatitis E (9.2 vs. 6.4 ng/ml, P = 0.04). Most HEV genetic changes selected during HEV infection were compartmentalized between plasma and feces. Conclusion This compartmentalization highlights the diversity and complexity of HEV replication compartments. Tacrolimus trough concentration at diagnosis of HEV infection could allow an early identification of patients at high risk of chronic hepatitis E and guide treatment initiation.
Collapse
Affiliation(s)
- Nancy León-Janampa
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | - Natacha Boennec
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | | | - Simon Ereh
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | - Gabriel Herbet
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | - Alain Moreau
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
| | - Philippe Gatault
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Hélène Longuet
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Christelle Barbet
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Mathias Büchler
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Christophe Baron
- Transplantation rénale – Immunologie clinique, CHRU de Tours, Tours, France
| | - Catherine Gaudy-Graffin
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, Tours, France
| | - Denys Brand
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, Tours, France
| | - Julien Marlet
- INSERM U1259 MAVIVH, Université de Tours et CHRU de Tours, Tours, France
- Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, Tours, France
| |
Collapse
|
|
10
|
Bezerra KC, Vieira CMAG, de Oliveira-Filho EF, Reis CRS, Oriá RB. Susceptibility of solid organ transplant recipients to viral pathogens with zoonotic potential: A mini-review. Braz J Infect Dis 2024; 28:103742. [PMID: 38670166 PMCID: PMC11078645 DOI: 10.1016/j.bjid.2024.103742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 02/28/2024] [Accepted: 04/14/2024] [Indexed: 04/28/2024] Open
Abstract
A substantial number of zoonotic diseases are caused by viral pathogens, representing a significant menace to public health, particularly to susceptible populations, such as pregnant women, the elderly, and immunocompromised individuals. Individuals who have undergone solid organ transplantation frequently experience immunosuppression, to prevent organ rejection, and, thus are more prone to opportunistic infections. Furthermore, the reactivation of dormant viruses can threaten transplant recipients and organ viability. This mini-review examines the up-to-date literature covering potential zoonotic and organ rejection-relevant viruses in solid organ transplant recipients. A comprehensive list of viruses with zoonotic potential is highlighted and the most important clinical outcomes in patients undergoing transplantation are described. Moreover, this mini-review calls attention to complex multifactorial events predisposing viral coinfections and the need for continuous health surveillance and research to understand better viral pathogens' transmission and pathophysiology dynamics in transplanted individuals.
Collapse
Affiliation(s)
- Karine C Bezerra
- Universidade Federal do Ceará, Faculdade de Medicina, Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, Fortaleza, CE, Brazil
| | - Carlos Meton A G Vieira
- Universidade Federal do Ceará, Faculdade de Medicina, Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, Fortaleza, CE, Brazil
| | | | - Christian Robson S Reis
- Fundação Oswaldo Cruz, Instituto Aggeu Magalhães, Departamento de Microbiologia, Recife, PE, Brazil
| | - Reinaldo B Oriá
- Universidade Federal do Ceará, Faculdade de Medicina, Laboratório da Biologia da Cicatrização, Ontogenia e Nutrição de Tecidos, Fortaleza, CE, Brazil.
| |
Collapse
|
|
11
|
León-Janampa N, Caballero-Posadas I, Barc C, Darrouzain F, Moreau A, Guinoiseau T, Gatault P, Fleurot I, Riou M, Pinard A, Pezant J, Rossignol C, Gaudy-Graffin C, Brand D, Marlet J. A pig model of chronic hepatitis E displaying persistent viremia and a downregulation of innate immune responses in the liver. Hepatol Commun 2023; 7:e0274. [PMID: 37938097 PMCID: PMC10635601 DOI: 10.1097/hc9.0000000000000274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 06/27/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) is a zoonotic virus transmitted by pig meat and responsible for chronic hepatitis E in immunocompromised patients. It has proved challenging to reproduce this disease in its natural reservoir. We therefore aimed to develop a pig model of chronic hepatitis E to improve the characterization of this disease. METHODS Ten pigs were treated with a tacrolimus-based regimen and intravenously inoculated with HEV. Tacrolimus trough concentration, HEV viremia, viral diversity, innate immune responses, liver histology, clinical disease and biochemical markers were monitored for 11 weeks post-infection (p.i.). RESULTS HEV viremia persisted for 11 weeks p.i. HEV RNA was detected in the liver, small intestine, and colon at necropsy. Histological analysis revealed liver inflammation and fibrosis. Several mutations selected in the HEV genome were associated with compartmentalization in the feces and intestinal tissues, consistent with the hypothesis of extrahepatic replication in the digestive tract. Antiviral responses were characterized by a downregulation of IFN pathways in the liver, despite an upregulation of RIG-I and ISGs in the blood and liver. CONCLUSIONS We developed a pig model of chronic hepatitis E that reproduced the major hallmarks of this disease. This model revealed a compartmentalization of HEV genomes in the digestive tract and a downregulation of innate immune responses in the liver. These original features highlight the relevance of our model for studies of the pathogenesis of chronic hepatitis E and for validating future treatments.
Collapse
Affiliation(s)
- Nancy León-Janampa
- INSERM U1259 MAVIVH, Tours University and Tours University Hospital, Tours, France
| | | | - Céline Barc
- UE-1277 Platform for Experimentation on Infectious Diseases, INRAe, Nouzilly, France
| | - François Darrouzain
- Department of Pharmacology and Toxicology, Tours University Hospital, Tours, France
| | - Alain Moreau
- INSERM U1259 MAVIVH, Tours University and Tours University Hospital, Tours, France
| | - Thibault Guinoiseau
- Department of Bacteriology-Virology-Hygiene, Tours University Hospital, Tours, France
| | - Philippe Gatault
- Department of Nephrology and Transplantation, Tours University Hospital, Tours, France
- EA4245, University of Tours, Tours, France
| | | | - Mickaël Riou
- UE-1277 Platform for Experimentation on Infectious Diseases, INRAe, Nouzilly, France
| | - Anne Pinard
- UE-1277 Platform for Experimentation on Infectious Diseases, INRAe, Nouzilly, France
| | - Jérémy Pezant
- UE-1277 Platform for Experimentation on Infectious Diseases, INRAe, Nouzilly, France
| | | | - Catherine Gaudy-Graffin
- INSERM U1259 MAVIVH, Tours University and Tours University Hospital, Tours, France
- Department of Bacteriology-Virology-Hygiene, Tours University Hospital, Tours, France
| | - Denys Brand
- INSERM U1259 MAVIVH, Tours University and Tours University Hospital, Tours, France
- Department of Bacteriology-Virology-Hygiene, Tours University Hospital, Tours, France
| | - Julien Marlet
- INSERM U1259 MAVIVH, Tours University and Tours University Hospital, Tours, France
- Department of Bacteriology-Virology-Hygiene, Tours University Hospital, Tours, France
| |
Collapse
|
|
12
|
Ushiro-Lumb I, Forsythe J, Haywood B, Geoghegan C, Maddox V, Ijaz S, Manas D, Thorburn D. Impact of Hepatitis E Virus Screening in the UK Deceased Organ Donor Population. Transpl Int 2023; 36:11673. [PMID: 37727381 PMCID: PMC10505649 DOI: 10.3389/ti.2023.11673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Accepted: 08/10/2023] [Indexed: 09/21/2023]
Abstract
Universal Hepatitis E Virus (HEV) screening of deceased organ donors was implemented by the UK national organ procurement organisation in October 2017. Donor testing for HEV infection is done post-transplant; detection of HEV ribonucleic acid (RNA) in donor plasma is therefore not a contra-indication for organ donation, with the result being used to inform recipient management. Immediate post-transplant detection of donor HEV viraemia triggers notification to transplant centres. Follow up of liver and kidney recipients has shown that transmission through solid organs is very efficient, particularly through liver grafts, as expected; no other organ types were transplanted in this cohort. Although donors with higher plasma viral load (VL > 103 IU/mL) were invariably associated with recipient infection, transmission was also documented at lower VL levels. Knowledge of donor HEV status has led to identification of transmission of infection via solid organ grafts followed by close patient monitoring and informed clinical management decisions. The purpose of this strategy is to allow early detection of infection and recurrence and treatment to circumvent the risk of accelerated liver damage from chronic HEV infection due to undiagnosed, inadvertent donor-derived transmission of infection.
Collapse
Affiliation(s)
- Ines Ushiro-Lumb
- Organ and Tissue Donation and Transplantation, NHS Blood and Transplant, London, United Kingdom
- UK Health Security Agency (UKHSA), London, United Kingdom
- Microbiology Services Laboratory, NHS Blood and Transplant, London, United Kingdom
| | - John Forsythe
- Organ and Tissue Donation and Transplantation, NHS Blood and Transplant, London, United Kingdom
| | - Becky Haywood
- UK Health Security Agency (UKHSA), London, United Kingdom
| | | | - Victoria Maddox
- Microbiology Services Laboratory, NHS Blood and Transplant, London, United Kingdom
| | - Samreen Ijaz
- UK Health Security Agency (UKHSA), London, United Kingdom
| | - Derek Manas
- Organ and Tissue Donation and Transplantation, NHS Blood and Transplant, London, United Kingdom
| | - Douglas Thorburn
- Organ and Tissue Donation and Transplantation, NHS Blood and Transplant, London, United Kingdom
| |
Collapse
|
|
13
|
Kosuta I, Ostojic A, Vujaklija Brajkovic A, Babel J, Simunov B, Sremac M, Mrzljak A. Shifting perspectives in liver diseases after kidney transplantation. World J Hepatol 2023; 15:883-896. [PMID: 37547033 PMCID: PMC10401415 DOI: 10.4254/wjh.v15.i7.883] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/15/2023] [Accepted: 06/06/2023] [Indexed: 07/21/2023] Open
Abstract
Liver diseases after kidney transplantation range from mild biochemical abnormalities to severe hepatitis or cirrhosis. The causes are diverse and mainly associated with hepatotropic viruses, drug toxicity and metabolic disorders. Over the past decade, the aetiology of liver disease in kidney recipients has changed significantly. These relates to the use of direct-acting antiviral agents against hepatitis C virus, the increasing availability of vaccination against hepatitis B and a better understanding of drug-induced hepatotoxicity. In addition, the emergence of the severe acute respiratory syndrome coronavirus 2 pandemic has brought new challenges to kidney recipients. This review aims to provide healthcare professionals with a comprehensive understanding of recent advances in the management of liver complications in kidney recipients and to enable them to make informed decisions regarding the risks and impact of liver disease in this population.
Collapse
Affiliation(s)
- Iva Kosuta
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Ana Ostojic
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Ana Vujaklija Brajkovic
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| | - Jaksa Babel
- Department of Intensive Care Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Bojana Simunov
- Department of Nephrology, University Hospital Merkur, Zagreb 10000, Croatia
| | - Maja Sremac
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, Liver Transplant Center, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia
| |
Collapse
|
|
14
|
Franz A, Reuken PA, Guliyeva S, Rose M, Boden K, Stallmach A, Bruns T. Early ribavirin for hepatitis E virus infection in patients receiving immunosuppressive therapy: a retrospective, observational study. J Int Med Res 2023; 51:3000605231187941. [PMID: 37523153 PMCID: PMC10392516 DOI: 10.1177/03000605231187941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/01/2023] Open
Abstract
OBJECTIVE Hepatitis E virus (HEV) infections are common, self-limiting causes of acute viral hepatitis. This study aimed to analyze hepatic injury, viremia, and chronicity rates in patients with acute HEV infection receiving immunosuppressive (IS) therapy taking into account ribavirin treatment. METHODS In this retrospective, single-center, observational study, we analyzed the disease course of 25 non-cirrhotic patients receiving IS therapy who were diagnosed with acute HEV viremia. Forty-four patients with acute HEV viremia without IS therapy were controls. RESULTS Demographics, symptoms at presentation, and extrahepatic manifestations were not different between patients with and without IS therapy, but liver injury at presentation was less severe in patients with IS therapy. Among the patients with IS therapy, 18 (72%) received ribavirin for a median of 56 days. Sustained viral clearance was observed in 21 patients with IS therapy, whereas 3 patients relapsed after ribavirin, and 1 patient had viral persistence. Among patients with sustained viral clearance, there was a longer duration of viremia in patients with IS therapy than in those without. CONCLUSIONS In this cohort of non-cirrhotic patient with IS, early treatment with ribavirin for acute HEV infection did not improve viral clearance rates, but may have shortened the duration of viremia.
Collapse
Affiliation(s)
- Anika Franz
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Sura Guliyeva
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Michael Rose
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany
| | - Katharina Boden
- Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany
- Dianovis GmbH, Greiz, Germany
| | - Andreas Stallmach
- Department of Internal Medicine IV, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| |
Collapse
|
|
15
|
Wu E, Koch N, Bachmann F, Schulz M, Seelow E, Weber U, Waiser J, Halleck F, Faber M, Bock CT, Eckardt KU, Budde K, Hofmann J, Nickel P, Choi M. Risk Factors for Hepatitis E Virus Infection and Eating Habits in Kidney Transplant Recipients. Pathogens 2023; 12:850. [PMID: 37375540 DOI: 10.3390/pathogens12060850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/13/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
There is a significant risk for ongoing and treatment-resistant courses of hepatitis E virus (HEV) infection in patients after solid organ transplantation. The aim of this study was to identify risk factors for the development of hepatitis E, including the dietary habits of patients. We conducted a retrospective single-center study with 59 adult kidney and combined kidney transplant recipients who were diagnosed with HEV infection between 2013 and 2020. The outcomes of HEV infections were analyzed during a median follow-up of 4.3 years. Patients were compared with a control cohort of 251 transplant patients with elevated liver enzymes but without evidence of an HEV infection. Patients' alimentary exposures during the time before disease onset or diagnosis were assessed. Previous intense immunosuppression, especially treatment with high-dose steroids and rituximab, was a significant risk factor to acquire hepatitis E after solid organ transplantation. Only 11 out of 59 (18.6%) patients reached remission without further ribavirin (RBV) treatment. A total of 48 patients were treated with RBV, of which 19 patients (39.6%) had either viral rebounds after the end of treatment or did not reach viral clearance at all. Higher age (>60 years) and a BMI ≤ 20 kg/m2 were risk factors for RBV treatment failure. Deterioration in kidney function with a drop in eGFR (p = 0.046) and a rise in proteinuria was more common in patients with persistent hepatitis E viremia. HEV infection was associated with the consumption of undercooked pork or pork products prior to infection. Patients also reported processing raw meat with bare hands at home more frequently than the controls. Overall, we showed that the intensity of immunosuppression, higher age, a low BMI and the consumption of undercooked pork meat correlated with the development of hepatitis E.
Collapse
Affiliation(s)
- Eva Wu
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Nadine Koch
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Friederike Bachmann
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Marten Schulz
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Evelyn Seelow
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Ulrike Weber
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Johannes Waiser
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Mirko Faber
- Department of Infectious Disease Epidemiology, Robert Koch-Institute, 13353 Berlin, Germany
| | - Claus-Thomas Bock
- Department of Infectious Diseases, Robert Koch-Institute, 13353 Berlin, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Jörg Hofmann
- Institute of Virology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Institute of Health, and German Centre for Infection Research (DZIF), Partner Site Charité, 13353 Berlin, Germany
- Labor Berlin, Charité-Vivantes GmbH, 13353 Berlin, Germany
| | - Peter Nickel
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| | - Mira Choi
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 13353 Berlin, Germany
| |
Collapse
|
|
16
|
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.
Collapse
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
| |
Collapse
|
|
17
|
Gabrielli F, Alberti F, Russo C, Cursaro C, Seferi H, Margotti M, Andreone P. Treatment Options for Hepatitis A and E: A Non-Systematic Review. Viruses 2023; 15:v15051080. [PMID: 37243166 DOI: 10.3390/v15051080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 04/27/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
Hepatitis A and hepatitis E are relatively common causes of liver disease. Both viruses are mainly transmitted through the faecal-oral route and, consequently, most outbreaks occur in countries with poor sanitation. An important role of the immune response as the driver of liver injury is also shared by the two pathogens. For both the hepatitis A (HAV) and hepatitis E (HEV) viruses, the clinical manifestations of infection mainly consist of an acute disease with mild liver injury, which results in clinical and laboratory alterations that are self-limiting in most cases. However, severe acute disease or chronic, long-lasting manifestations may occur in vulnerable patients, such as pregnant women, immunocompromised individuals or those with pre-existing liver disease. Specifically, HAV infection rarely results in fulminant hepatitis, prolonged cholestasis, relapsing hepatitis and possibly autoimmune hepatitis triggered by the viral infection. Less common manifestations of HEV include extrahepatic disease, acute liver failure and chronic HEV infection with persistent viraemia. In this paper, we conduct a non-systematic review of the available literature to provide a comprehensive understanding of the state of the art. Treatment mainly consists of supportive measures, while the available evidence for aetiological treatment and additional agents in severe disease is limited in quantity and quality. However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results.
Collapse
Affiliation(s)
- Filippo Gabrielli
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Department of Surgical Sciences, University of Bologna, 40126 Bologna, Italy
| | - Francesco Alberti
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Cristina Russo
- Postgraduate School of Internal Medicine, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Carmela Cursaro
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Hajrie Seferi
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Marzia Margotti
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Pietro Andreone
- Internal and Metabolic Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, AOU di Modena, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41126 Modena, Italy
- Postgraduate School of Allergology and Clinical Immunology, University of Modena and Reggio Emilia, 41126 Modena, Italy
| |
Collapse
|
|
18
|
de Oliveira JM, dos Santos DRL, Pinto MA. Hepatitis E Virus Research in Brazil: Looking Back and Forwards. Viruses 2023; 15:548. [PMID: 36851763 PMCID: PMC9965705 DOI: 10.3390/v15020548] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/03/2023] [Accepted: 02/06/2023] [Indexed: 02/19/2023] Open
Abstract
Hepatitis E virus (HEV) has emerged as a public health concern in Brazil. From the first identification and characterization of porcine and human HEV-3 strains in the 2000s, new HEV subtypes have been identified from animal, human, and environmental isolates. As new potential animal reservoirs have emerged, there is a need to compile evidence on the zoonotic dissemination of the virus in animal hosts and the environment. The increasing amount of seroprevalence data on sampled and randomly selected populations must be systematically retrieved, interpreted, and considered under the One Health concept. This review focused on HEV seroprevalence data in distinct animal reservoirs and human populations reported in the last two decades. Furthermore, the expertise with experimental infection models using non-human primates may provide new insights into HEV pathogenesis, prevention, and environmental surveillance.
Collapse
Affiliation(s)
- Jaqueline Mendes de Oliveira
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, Brazil
| | | | - Marcelo Alves Pinto
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, Brazil
| |
Collapse
|
|
19
|
Abravanel F, Lhomme S, Marion O, Péron JM, Kamar N, Izopet J. Diagnostic and management strategies for chronic hepatitis E infection. Expert Rev Anti Infect Ther 2023; 21:143-148. [PMID: 36625025 DOI: 10.1080/14787210.2023.2166932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
INTRODUCTION Hepatitis E Virus (HEV) was initially thought to cause only acute infections, but the discovery of chronic hepatitis E in immunocompromised patients has profoundly changed our understanding of the virus. AREAS COVERED We describe the physiopathology, diagnosis, and clinical management of chronic HEV infection. The virus can persist in nearly two-thirds of immunosuppressed patients. Reducing immunosuppression is the first immunomodulatory strategy to cure chronic hepatitis E. But this may not always be feasible or effective. Ribavirin monotherapy for 3 months has been recommended as first-line treatment for chronically infected patients. Ribavirin is around 80% effective at eradicating HEV in retrospective studies. Apart from ribavirin, interferon has been successfully used in liver transplants recipients, but if the patient does not respond, no other alternative drug is available. The vaccine available to prevent HEV infection is one available only in China. EXPERT OPINION HEV infection is a major concern in immunocompromised patients. But the therapeutic arsenal is limited to ribavirin and interferon. Both produce several side effects and new drugs are urgently needed. Moreover, preventive strategies to limit HEV transmission and/or evolution to a chronic infection are also required.
Collapse
Affiliation(s)
- Florence Abravanel
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France
| | - Sébastien Lhomme
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France
| | - Olivier Marion
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France.,CHU Toulouse, Hôpital Rangueil, département de Néphrologie et transplantation d'organe, Toulouse, France
| | - Jean Marie Péron
- CHU Toulouse, Hôpital Rangueil, département de Gastroentérologie, Toulouse, France
| | - Nassim Kamar
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Rangueil, département de Néphrologie et transplantation d'organe, Toulouse, France
| | - Jacques Izopet
- Inserm UMR 1291 - CNRS UMR5051, Université Toulouse III, Toulouse, France.,CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France
| |
Collapse
|
|
20
|
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.
Collapse
|
|
21
|
Unmet Needs for the Treatment of Chronic Hepatitis E Virus Infection in Immunocompromised Patients. Viruses 2022; 14:v14102116. [PMID: 36298671 PMCID: PMC9611326 DOI: 10.3390/v14102116] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/20/2022] [Accepted: 09/22/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatitis E virus (HEV) is the most prevalent hepatitis virus worldwide. Genotypes 3 (HEV3) and 4 (HEV4) as well as rat HEV can lead to chronic hepatitis E and cirrhosis in immunosuppressed patients. Within the last decade, several options for treating chronic hepatitis have been developed and have achieved a sustained virological response. However, there are still unmet needs such as optimizing immunosuppression to allow HEV clearance with or without ribavirin, as well as alternative therapies to ribavirin that are discussed in this paper.
Collapse
|
|
22
|
Li M, Wang Y, Li K, Lan H, Zhou C. Characterization of highly expressed novel hub genes in hepatitis E virus chronicity in rabbits: a bioinformatics and experimental analysis. BMC Vet Res 2022; 18:239. [PMID: 35739587 PMCID: PMC9219159 DOI: 10.1186/s12917-022-03337-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/06/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hepatitis E virus (HEV), which is the leading cause of acute viral hepatitis worldwide, usually causes self-limited infections in common individuals. However, it can lead to chronic infection in immunocompromised individuals and its mechanisms remain unclear. Rabbits are the natural host of HEV, and chronic HEV infections have been observed in rabbits. Therefore, we aimed to investigate potential key genes in HEV chronicity process in rabbits. In this study, both bioinformatics and experimental analysis were performed to deepen the understanding of hub genes in HEV chronic infection in rabbits. RESULTS Ninety-four candidate differentially expressed genes (DEGs) and the pathways they enriched were identified to be related with HEV chronicity. A total of 10 hub genes were found by protein-protein interaction (PPI) network construction. Rabbits of group P (n = 4) which showed symptoms of chronic HEV infection were selected to be compared with HEV negative rabbits (group N, n = 6). By detecting the identified hub genes in groups P and N by real-time PCR, we found that the expressions of MX1, OAS2 and IFI44 were significantly higher in group P (P < 0.05). CONCLUSIONS In this work, we presented that MX1, OAS2 and IFI44 were significantly upregulated in HEV chronic infected rabbits, indicating that they may be involved in the pathogenesis of HEV chronicity.
Collapse
Affiliation(s)
- Manyu Li
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, 2 Tiantanxili Rd, Dongcheng District, 100050, Beijing, China.
| | - Yan Wang
- First Clinical Medical College, Shanxi Medical University, Taiyuan, China
| | - Kejian Li
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, 2 Tiantanxili Rd, Dongcheng District, 100050, Beijing, China
| | - Haiyun Lan
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, 2 Tiantanxili Rd, Dongcheng District, 100050, Beijing, China
| | - Cheng Zhou
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, 2 Tiantanxili Rd, Dongcheng District, 100050, Beijing, China.
| |
Collapse
|
|
23
|
Nagra N, Kozarek RA, Burman BE. Therapeutic Advances in Viral Hepatitis A-E. Adv Ther 2022; 39:1524-1552. [PMID: 35220557 DOI: 10.1007/s12325-022-02070-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/31/2022] [Indexed: 11/25/2022]
Abstract
Viral hepatitis remains a significant global health problem. All forms of viral hepatitis A through E (A-E) can lead to acute symptomatic infection, while hepatitis B and C can lead to chronic infection associated with significant morbidity and mortality related to progression to cirrhosis, end-stage-liver disease, and liver cancer. Viral hepatitis occurs worldwide, though certain regions are disproportionately affected. We now, remarkably, have highly effective curative regimens for hepatitis C, and safe and tolerable medications to suppress hepatitis B activity, and to prevent liver damage and slow disease progression. We have effective vaccines for hepatitis A and B which provide long-lasting immunity, while improved sanitation and awareness can curb outbreaks of hepatitis A and E. However, more effective and available preventive and curative strategies are needed to achieve global eradication of viral hepatitis. This review provides an overview of the epidemiology, transmission, diagnosis, and clinical features of each viral hepatitis with a primary focus on current and future therapeutic and curative options.
Collapse
Affiliation(s)
- Navroop Nagra
- Department of Gastroenterology, University of Louisville, Louisville, KY, 40202, USA
| | - Richard A Kozarek
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA
| | - Blaire E Burman
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA.
| |
Collapse
|
|
24
|
Damiris K, Aghaie Meybodi M, Niazi M, Pyrsopoulos N. Hepatitis E in immunocompromised individuals. World J Hepatol 2022; 14:482-494. [PMID: 35582299 PMCID: PMC9055194 DOI: 10.4254/wjh.v14.i3.482] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/15/2021] [Accepted: 02/13/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) originally identified as a cause of acute icteric hepatitis in developing countries has grown to be a cause of zoonotic viral hepatitis in developed countries such as the United States. While there are eight identified genotypes to date, genotype 1 (HEV1), HEV2, HEV3, HEV4 are the most common to infect humans. HEV1 and HEV2 are most common in developing countries including Latina America, Africa and Asia, and are commonly transmitted through contaminated water supplies leading to regional outbreaks. In contrast HEV3 and HEV4 circulate freely in many mammalian animals and can lead to occasional transmission to humans through fecal contamination or consumption of undercooked meat. The incidence and prevalence of HEV in the United States is undetermined given the absence of FDA approved serological assays and the lack of commercially available testing. In majority of cases, HEV infection is a self-limiting hepatitis requiring only symptomatic treatment. However, this is not the case in immunocompromised individuals, including those that have undergone solid organ or stem cell transplantation. In this subset of patients, chronic infection can be life threatening as hepatic insult can lead to inflammation and fibrosis with subsequent cirrhosis and death. The need for re-transplantation as a result of post-transplant hepatitis is of great concern. In addition, there have been many reported incidents of extrahepatic manifestations, for which the exact mechanisms remain to be elucidated. The cornerstone of treatment in immunocompromised solid organ transplant recipients is reduction of immunosuppressive therapies, while attempting to minimize the risk of organ rejection. Subsequent treatment options include ribavirin, and pegylated interferon alpha in those who have demonstrated ribavirin resistance. Further investigation assessing safety and efficacy of anti-viral therapy is imperative given the rising global health burden. Given this concern, vaccination has been approved in China with other investigations underway throughout the world. In this review we introduce the epidemiology, diagnosis, clinical manifestations, and treatment of HEV, with emphasis on immunocompromised individuals in the United States.
Collapse
Affiliation(s)
- Konstantinos Damiris
- Department of Medicine, Rutgers - New Jersey Medical School, Newark, NJ 07103, United States
| | - Mohamad Aghaie Meybodi
- Department of Medicine, Rutgers - New Jersey Medical School, Newark, NJ 07103, United States
| | - Mumtaz Niazi
- Department of Medicine - Gastroenterology and Hepatology, Rutgers - New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Department of Medicine - Gastroenterology and Hepatology, Rutgers - New Jersey Medical School, Newark, NJ 07103, United States
| |
Collapse
|
|
25
|
Leoni S, Casabianca A, Biagioni B, Serio I. Viral hepatitis: Innovations and expectations. World J Gastroenterol 2022; 28:517-531. [PMID: 35316960 PMCID: PMC8905017 DOI: 10.3748/wjg.v28.i5.517] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/14/2021] [Accepted: 01/17/2022] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is a significant health problem worldwide, associated with morbidity and mortality. Hepatitis B, C, D, and occasionally E viruses (HBV, HCV, HDV, and HEV) can evolve in chronic infections, whereas hepatitis A virus (HAV) frequently produces acute self-limiting hepatitis. In the last years, different studies have been performed to introduce new antiviral therapies. The most important goal in the treatment of viral hepatitis is to avoid chronic liver disease and complications. This review analyzes currently available therapies, in particular for viruses associated with chronic liver disease. The focus is especially on HBV and HCV therapies, investigating new drugs already introduced in clinical practice and clinical trials. We also describe new entry inhibitors, developed for the treatment of chronic HDV and HBV and currently available treatments for HEV. The last drugs introduced have shown important efficacy in HCV, with achievable target HCV elimination by 2030. Concurrently, renewed interest in curative HBV therapies has been registered; current nucleotide/ nucleoside analogs positively impact liver-related complications, ensuring high safety and tolerability. Novel approaches to HBV cure are based on new antivirals, targeting different steps of the HBV life cycle and immune modulators. The improved knowledge of the HDV life cycle has facilitated the development of some direct-acting agents, as bulevirtide, the first drug conditionally approved in Europe for HDV associated compensated liver disease. Further studies are required to identify a new therapeutic approach in hepatitis E, especially in immunosuppressed patients.
Collapse
Affiliation(s)
- Simona Leoni
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Alberto Casabianca
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Benedetta Biagioni
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Ilaria Serio
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| |
Collapse
|
|
26
|
Cheung CKM, Wong SH, Law AWH, Law MF. Transfusion-transmitted hepatitis E: What we know so far? World J Gastroenterol 2022; 28:47-75. [PMID: 35125819 PMCID: PMC8793017 DOI: 10.3748/wjg.v28.i1.47] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 07/16/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) is a major cause of viral hepatitis globally. There is growing concern about transfusion-transmitted HEV (TT-HEV) as an emerging global health problem. HEV can potentially result in chronic infection in immunocompromised patients, leading to a higher risk of liver cirrhosis and even death. Between 0.0013% and 0.281% of asymptomatic blood donors around the world have HEV viremia, and 0.27% to 60.5% have anti-HEV immunoglobulin G. HEV is infectious even at very low blood concentrations of the virus. Immunosuppressed patients who develop persistent hepatitis E infection should have their immunosuppressant regimen reduced; ribavirin may be considered as treatment. Pegylated interferon can be considered in those who are refractory or intolerant to ribavirin. Sofosbuvir, a nucleotide analog, showed modest antiviral activity in some clinical studies but sustained viral response was not achieved. Therefore, rescue treatment remains an unmet need. The need for HEV screening of all blood donations remains controversial. Universal screening has been adopted in some countries after consideration of risk and resource availability. Various pathogen reduction methods have also been proposed to reduce the risk of TT-HEV. Future studies are needed to define the incidence of transmission through transfusion, their clinical features, outcomes and prognosis.
Collapse
Affiliation(s)
| | - Sunny Hei Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong 852, China
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore
| | | | - Man Fai Law
- Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
| |
Collapse
|
|
27
|
Lhomme S, Abravanel F, Cintas P, Izopet J. Hepatitis E Virus Infection: Neurological Manifestations and Pathophysiology. Pathogens 2021; 10:pathogens10121582. [PMID: 34959537 PMCID: PMC8705630 DOI: 10.3390/pathogens10121582] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) is the first cause of viral hepatitis in the world. While the water-borne HEV genotypes 1 and 2 are found in developing countries, HEV genotypes 3 and 4 are endemic in developed countries due to the existence of animal reservoirs, especially swine. An HEV infection produces many extra-hepatic manifestations in addition to liver symptoms, especially neurological disorders. The most common are neuralgic amyotrophy or Parsonage–Turner syndrome, Guillain–Barré syndrome, myelitis, and encephalitis. The pathophysiology of the neurological injuries due to HEV remains uncertain. The immune response to the virus probably plays a role, but direct virus neurotropism could also contribute to the pathophysiology. This review describes the main neurological manifestations and their possible pathogenic mechanisms.
Collapse
Affiliation(s)
- Sébastien Lhomme
- Infinity, Université Toulouse, CNRS, INSERM, UPS, 31300 Toulouse, France; (F.A.); (J.I.)
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France
- Correspondence: ; Tel.: +33-(0)-5-67-69-04-24
| | - Florence Abravanel
- Infinity, Université Toulouse, CNRS, INSERM, UPS, 31300 Toulouse, France; (F.A.); (J.I.)
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France
| | - Pascal Cintas
- Service de Neurologie, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France;
| | - Jacques Izopet
- Infinity, Université Toulouse, CNRS, INSERM, UPS, 31300 Toulouse, France; (F.A.); (J.I.)
- Laboratoire de Virologie, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France
| |
Collapse
|
|
28
|
Serological Evidence of Hepatitis E Virus Infection in Semi-Domesticated Eurasian Tundra Reindeer ( Rangifer tarandus tarandus) in Norway. Pathogens 2021; 10:pathogens10121542. [PMID: 34959497 PMCID: PMC8709481 DOI: 10.3390/pathogens10121542] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 01/23/2023] Open
Abstract
Hepatitis E virus (HEV) is a common cause of viral hepatitis in humans. In developing countries, HEV-infections seem to be mainly associated with pigs, but other animal species may be involved in viral transmission. Recently, anti-HEV antibodies were detected in Norwegian wild reindeer. Here, we investigated anti-HEV seroprevalence in Norwegian semi-domesticated reindeer, animals in closer contact with humans than their wild counterparts. Blood samples (n = 516) were obtained from eight reindeer herds during the period 2013–2017 and analysed with a commercial enzyme-linked immunosorbent assay designed for detecting anti-HEV antibodies in livestock. Antibodies were found in all herds and for all sampling seasons. The overall seroprevalence was 15.7% (81/516), with adults showing a slightly higher seroprevalence (18.0%, 46/256) than calves (13.5%, 35/260, p = 0.11). The seroprevalence was not influenced by gender or latitude, and there was no temporal trend (p > 0.15). A positive association between the presence of anti-HEV antibodies and antibodies against alphaherpesvirus and pestivirus, detected in a previous screening, was found (p < 0.05). We conclude that Norwegian semi-domesticated reindeer are exposed to HEV or an antigenically similar virus. Whether the virus is affecting reindeer health or infects humans and poses a threat for human health remains unknown and warrants further investigations.
Collapse
|
|
29
|
Torre P, Aglitti A, Masarone M, Persico M. Viral hepatitis: Milestones, unresolved issues, and future goals. World J Gastroenterol 2021; 27:4603-4638. [PMID: 34366625 PMCID: PMC8326259 DOI: 10.3748/wjg.v27.i28.4603] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
In this review the current overall knowledge on hepatitis A, B, C, D, and E will be discussed. These diseases are all characterized by liver inflammation but have significant differences in distribution, transmission routes, and outcomes. Hepatitis B virus and hepatitis C virus are transmitted by exposure to infected blood, and in addition to acute infection, they can cause chronic hepatitis, which in turn can evolve into cirrhosis. It is estimated that more than 300 million people suffer from chronic hepatitis B or C worldwide. Hepatitis D virus, which is also transmitted by blood, only affects hepatitis B virus infected people, and this dual infection results in worse liver-related outcomes. Hepatitis A and E spread via the fecal-oral route, which corresponds mainly to the ingestion of food or water contaminated with infected stools. However, in developed countries hepatitis E is predominantly a zoonosis. Although hepatitis A virus and hepatitis E virus are usually responsible for a self-limiting hepatitis, a serious, rarely fatal illness is also possible, and in immunosuppressed patients, such as organ transplant recipients, hepatitis E virus infection can become chronic. The description of goals achieved, unresolved issues, and the latest research on this topic may make it possible to speculate on future scenarios in the world of viral hepatitis.
Collapse
Affiliation(s)
- Pietro Torre
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno 84081, Italy
| | - Andrea Aglitti
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno 84081, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno 84081, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Dentistry, “Scuola Medica Salernitana,” University of Salerno, Salerno 84081, Italy
| |
Collapse
|
|
30
|
Gorris M, van der Lecq BM, van Erpecum KJ, de Bruijne J. Treatment for chronic hepatitis E virus infection: A systematic review and meta-analysis. J Viral Hepat 2021; 28:454-463. [PMID: 33301609 PMCID: PMC7898834 DOI: 10.1111/jvh.13456] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/09/2020] [Accepted: 11/23/2020] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus infection can cause chronic hepatitis in immunocompromised patients with significant chance of progressive fibrosis and possibly cirrhosis. The aim of this systematic review was to summarize the efficacy and safety of the various treatment options for chronic hepatitis E. We performed a systematic literature search. The primary outcome measure was a sustained virological response (SVR). Secondary end points were rapid virological response (RVR), relapse rates, side effects and adverse events. Forty-four articles were included with a total of 582 patients. Reduction of immunosuppressive medication induced viral clearance in 55/174 (32%) of the patients. Meta-analysis of 395 patients showed a pooled SVR rate of 78% (95-CI 72%-84%) after ribavirin treatment. Twenty-five per cent of the patients obtained a RVR, whereas a relapse occurred in 18% of the patients. Anaemia during treatment led to dose reduction, use of erythropoietin and/or blood transfusion in 37% of the patients. A second treatment attempt with ribavirin led to a SVR in 39/51 (76%) of the patients. Pegylated interferon-alpha was administered to 13 patients and SVR was obtained in 85%. Two patients (15%) suffered from acute transplant rejection during treatment with interferon. In conclusion, reduction of immunosuppressive medication and treatment with ribavirin is safe, generally well tolerated and induced viral clearance in 32% and 78% of patients, respectively. Therefore, ribavirin should be considered as first treatment step for chronic hepatitis E. Treatment with pegylated interferon-alpha increases the risk of transplant rejection and should therefore be administered with great caution.
Collapse
Affiliation(s)
- Myrte Gorris
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Bernice M. van der Lecq
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Karel J. van Erpecum
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Joep de Bruijne
- Department of Gastroenterology & HepatologyUniversity Medical Center UtrechtUtrechtThe Netherlands
| |
Collapse
|
|
31
|
Sridhar S, Yip CCY, Wu S, Chew NFS, Leung KH, Chan JFW, Zhao PS, Chan WM, Poon RWS, Tsoi HW, Cai JP, Chan HSY, Leung AWS, Tse CWS, Zee JST, Tsang OTY, Cheng VCC, Lau SKP, Woo PCY, Tsang DNC, Yuen KY. Transmission of Rat Hepatitis E Virus Infection to Humans in Hong Kong: A Clinical and Epidemiological Analysis. Hepatology 2021; 73:10-22. [PMID: 31960460 DOI: 10.1002/hep.31138] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 12/23/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Hepatitis E virus (HEV) variants causing human infection predominantly belong to HEV species A (HEV-A). HEV species C genotype 1 (HEV-C1) circulates in rats and is highly divergent from HEV-A. It was previously considered unable to infect humans, but the first case of human HEV-C1 infection was recently discovered in Hong Kong. The aim of this study is to further describe the features of this zoonosis in Hong Kong. APPROACH AND RESULTS We conducted a territory-wide prospective screening study for HEV-C1 infection over a 31-month period. Blood samples from 2,860 patients with abnormal liver function (n = 2,201) or immunosuppressive conditions (n = 659) were screened for HEV-C1 RNA. In addition, 186 captured commensal rats were screened for HEV-C1 RNA. Sequences of human-derived and rat-derived HEV-C1 isolates were compared. Epidemiological and clinical features of HEV-C1 infection were analyzed. HEV-C1 RNA was detected in 6/2,201 (0.27%) patients with hepatitis and 1/659 (0.15%) immunocompromised persons. Including the previously reported case, eight HEV-C1 infections were identified, including five in patients who were immunosuppressed. Three patients had acute hepatitis, four had persistent hepatitis, and one had subclinical infection without hepatitis. One patient died of meningoencephalitis, and HEV-C1 was detected in cerebrospinal fluid. HEV-C1 hepatitis was generally milder than HEV-A hepatitis. HEV-C1 RNA was detected in 7/186 (3.76%) rats. One HEV-C1 isolate obtained from a rat captured near the residences of patients was closely related to the major outbreak strain. CONCLUSIONS HEV-C1 is a cause of hepatitis E in humans in Hong Kong. Immunosuppressed individuals are susceptible to persistent HEV-C1 infection and extrahepatic manifestations. Subclinical HEV-C1 infection threatens blood safety. Tests for HEV-C1 are required in clinical laboratories.
Collapse
Affiliation(s)
- Siddharth Sridhar
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China
| | - Cyril Chik-Yan Yip
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Shusheng Wu
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Nicholas Foo-Siong Chew
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Kit-Hang Leung
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jasper Fuk-Woo Chan
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China
| | - Pyrear Suhui Zhao
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wan-Mui Chan
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Rosana Wing-Shan Poon
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Hoi-Wah Tsoi
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Jian-Piao Cai
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Helen Shuk-Ying Chan
- The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China
| | | | | | | | | | - Vincent Chi-Chung Cheng
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Susanna Kar-Pui Lau
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China.,Tuen Mun Hospital, Hong Kong, China
| | - Patrick Chiu-Yat Woo
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China.,Tuen Mun Hospital, Hong Kong, China
| | | | - Kwok-Yung Yuen
- Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.,State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China.,Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China.,Tuen Mun Hospital, Hong Kong, China
| |
Collapse
|
|
32
|
van den Bogaart L, Cipriano A, Koutsokera A, Manuel O. Understanding rare infections post-lung transplantation. Expert Rev Respir Med 2020; 15:325-338. [PMID: 33106068 DOI: 10.1080/17476348.2021.1843428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Introduction: Lung transplant recipients are at the highest risk of infectious complications among all solid-organ transplant (SOT) recipients. In the current era, many standardized protocols in terms of diagnostic algorithms, prophylaxis, and therapeutic strategies have improved the management of the most common infectious complications. Conversely, diagnosis of rare infections can be particularly challenging and this can delay appropriate treatment.Areas covered: This article will review the epidemiology, clinical presentation, diagnostic and therapeutic management of certain rarely reported viral, fungal, bacterial and parasitic infections in lung transplant recipients.Expert opinion: Once the most frequent infections are excluded, clinical suspicion combined with molecular diagnostic methods such as targeted and broad-spectrum PCRs can allow diagnosis of a rare infection. A multidisciplinary team, including transplant pulmonologists, transplant infectious diseases specialists, microbiologists and pathologists is essential for prompt diagnosis and optimal therapeutic management.
Collapse
Affiliation(s)
- Lorena van den Bogaart
- Infectious Diseases Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland.,Transplantation Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Ana Cipriano
- Infectious Disease Department, Centro Hospitalar Do Porto, Porto, Portugal
| | - Angela Koutsokera
- Division of Pulmonology, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| | - Oriol Manuel
- Infectious Diseases Service, Lausanne University Hospital (CHUV), Lausanne, Switzerland.,Transplantation Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland
| |
Collapse
|
|
33
|
Aslan AT, Balaban HY. Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment. World J Gastroenterol 2020; 26:5543-5560. [PMID: 33071523 PMCID: PMC7545399 DOI: 10.3748/wjg.v26.i37.5543] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/11/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
The hepatitis E virus (HEV) is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s. Globally, it is one of the most frequent causes of acute viral hepatitis. The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus. Among the eight different genotypes identified to date, HEV genotype 1 (HEV1), HEV2, HEV3, and HEV4 are the most frequent genotypes causing infections in humans. HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies. They are also responsible for severe hepatitis in pregnant patients and infants. In contrast, HEV3 and HEV4 are zoonotic, and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals. Their main reservoir is the pig, and they are mostly encountered in developed countries. The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women, infants, older people, immunocompromised individuals, patients with underlying chronic liver diseases, and workers that come into close contact with HEV-infected animals. In the clinical perspective, HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis, acute-on-chronic liver disease, chronic hepatitis, cirrhosis, and liver failure. Although HEV mainly results in acute self-limiting infection, chronic HEV infection may occur among immunocompromised patients (e.g., solid-organ transplant recipients). Additionally, HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade, although the causal link for many of them still needs to be proven. Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. However, ribavirin is contraindicated in pregnant patients, and interferon-alpha cannot be used in most transplant recipients. Therefore, there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirin-resistant HEV. In this review article, a literature search using PubMed and MEDLINE databases was performed, up to March 2020. Only the articles published in English were reviewed.
Collapse
Affiliation(s)
| | - Hatice Yasemin Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
| |
Collapse
|
|
34
|
Thakur V, Ratho RK, Kumar S, Saxena SK, Bora I, Thakur P. Viral Hepatitis E and Chronicity: A Growing Public Health Concern. Front Microbiol 2020; 11:577339. [PMID: 33133046 PMCID: PMC7550462 DOI: 10.3389/fmicb.2020.577339] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatitis E viral infection recently emerges as a global health concern. Over the last decade, the understanding of hepatitis E virus (HEV) had changed with the discovery of new genotypes like genotype-7 and genotype-8 with associated host and mode of infection. Diversification in the mode of hepatitis E infection transmission through blood transfusion, and organ transplants in contrast to classical feco-oral and zoonotic mode is the recent medical concern. The wide spectrum of infection ranging from self-limiting to acute liver failure is now overpowered by HEV genotype-specific chronic infection especially in transplant patients. This concern is further escalated by the extra-hepatic manifestations of HEV targeting the central nervous system (CNS), kidney, heart, and pancreas. However, with the development of advanced efficient cell culture systems and animal models simulating the infection, much clarity toward understanding the pathogenetic mechanism of HEV has been developed. Also this facilitates the development of vaccines research or therapeutics. In this review, we highlight all the novel findings in every aspect of HEV with special emphasis on recently emerging chronic mode of infection with specific diagnosis and treatment regime with an optimistic hope to help virologists and/or liver specialists working in the field of viral hepatitis.
Collapse
Affiliation(s)
- Vikram Thakur
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Radha Kanta Ratho
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Swatantra Kumar
- Centre for Advanced Research, Faculty of Medicine, King George's Medical University, Lucknow, India
| | - Shailendra K Saxena
- Centre for Advanced Research, Faculty of Medicine, King George's Medical University, Lucknow, India
| | - Ishani Bora
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Pryanka Thakur
- Department of Virology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| |
Collapse
|
|
35
|
Lhomme S, Migueres M, Abravanel F, Marion O, Kamar N, Izopet J. Hepatitis E Virus: How It Escapes Host Innate Immunity. Vaccines (Basel) 2020; 8:E422. [PMID: 32731452 PMCID: PMC7564545 DOI: 10.3390/vaccines8030422] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 07/23/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis E virus (HEV) is a leading cause of viral hepatitis in the world. It is usually responsible for acute hepatitis, but can lead to a chronic infection in immunocompromised patients. The host's innate immune response is the first line of defense against a virus infection; there is growing evidence that HEV RNA is recognized by toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), leading to interferon (IFN) production. The IFNs activate interferon-stimulated genes (ISGs) to limit HEV replication and spread. HEV has developed strategies to counteract this antiviral response, by limiting IFN induction and signaling. This review summarizes the advances in our knowledge of intracellular pathogen recognition, interferon and inflammatory response, and the role of virus protein in immune evasion.
Collapse
Affiliation(s)
- Sébastien Lhomme
- National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (M.M.); (F.A.); (J.I.)
- INSERM UMR1043, CNRS UMR5282, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France; (O.M.); (N.K.)
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Marion Migueres
- National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (M.M.); (F.A.); (J.I.)
- INSERM UMR1043, CNRS UMR5282, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France; (O.M.); (N.K.)
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Florence Abravanel
- National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (M.M.); (F.A.); (J.I.)
- INSERM UMR1043, CNRS UMR5282, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France; (O.M.); (N.K.)
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Olivier Marion
- INSERM UMR1043, CNRS UMR5282, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France; (O.M.); (N.K.)
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, 31400 Toulouse, France
| | - Nassim Kamar
- INSERM UMR1043, CNRS UMR5282, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France; (O.M.); (N.K.)
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, 31400 Toulouse, France
| | - Jacques Izopet
- National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (M.M.); (F.A.); (J.I.)
- INSERM UMR1043, CNRS UMR5282, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France; (O.M.); (N.K.)
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| |
Collapse
|
|
36
|
Abstract
BACKGROUND Hepatitis E virus (HEV) generally causes self-limiting viral hepatitis. However, in pregnant women, HEV infection can be severe and has been associated with up to 30% mortality in the third trimester. Additionally, HEV infection in pregnancy is also associated with high rates of preterm labor and vertical transmission. MAIN BODY HEV is now recognized as a global health problem in both developing and industrialized countries. HEV can be transmitted via the fecal-oral route, zoonotic route, and blood transfusion route. An altered immune status, hormonal levels, and viral factors may be related to the severity of the disease. Currently, no established treatment is available for HEV in pregnant women. A Chinese vaccine has been demonstrated to be protective against HEV in the general population and seems to be safe in pregnancy; however, its safety and efficacy in a large population of pregnant women remain to be determined. CONCLUSION This review summarizes the current knowledge about HEV infection during pregnancy and focuses on the epidemiology, clinical manifestations, mechanisms underlying severe liver injury, and management and prevention of HEV infection during pregnancy. Considering that HEV infection during pregnancy may result in poor outcomes, screening for and monitoring HEV infection early in pregnancy should be taken into account. In addition, a better understanding of the pathogenesis will help to develop potential treatment strategies targeting HEV infection in pregnancy.
Collapse
Affiliation(s)
- Chunchen Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China
| | - Xiaoxue Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China
| | - Jianbo Xia
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China.
| |
Collapse
|
|
37
|
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.
Collapse
|
|
38
|
Hepatitis E: an expanding epidemic with a range of complications. Clin Microbiol Infect 2020; 26:828-832. [PMID: 32251845 DOI: 10.1016/j.cmi.2020.03.039] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 03/30/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV) is a common cause of viral hepatitis worldwide. Previously considered a disease of the developing world, it is increasingly recognized that locally acquired HEV infection is common in industrialized countries. OBJECTIVES The aim was to highlight the changing epidemiology of HEV infection, particularly in the developed world, and inform clinicians of the diverse clinical presentations and extra-hepatic complications associated with the virus. SOURCES References for this review were identified through searches of MEDLINE/PubMed, and Google Scholar, up to January 2020. Searches were restricted to articles published in English. CONTENT Hepatitis E virus is an under-recognized, emerging pathogen with important implications for public health in both the developing and developed world. The number of cases reported in resource-rich settings is increasing, in part due to improved case ascertainment but also as a result of increased incidence in some countries. The reasons behind these epidemiological shifts are not currently known. Chronic HEV infection has been reported in immunocompromised patients. A range of extra-hepatic manifestations have also been reported, most notably neurological and renal complications. There is evidence to suggest a causal link with Guillain-Barré syndrome, neuralgic amyotrophy and encephalitis/myelitis. Glomerular disease has been reported in the context of both acute and chronic infection. IMPLICATIONS HEV should be included in non-invasive liver screens and considered in the differentials for patients presenting with alanine aminotransferase elevation, suspected drug-induced liver injury or decompensated liver disease. Any patients with acute neurological injury and deranged liver function should be tested for hepatitis E, and all patients presenting with Guillain-Barré syndrome or neuralgic amyotrophy should be tested regardless of liver enzymes. Immunocompromised patients with persistently raised liver enzymes should be tested with molecular techniques and offered annual routine screening.
Collapse
|
|
39
|
Specific circulating microRNAs during hepatitis E infection can serve as indicator for chronic hepatitis E. Sci Rep 2020; 10:5337. [PMID: 32210284 PMCID: PMC7093451 DOI: 10.1038/s41598-020-62159-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Accepted: 03/10/2020] [Indexed: 12/20/2022] Open
Abstract
Hepatitis E virus (HEV) genotypes 3 and 4 (HEV-3, HEV-4) infections are an emerging public health issue in industrialized countries. HEV-3 and −4 are usually self-limiting but can progress to chronic hepatitis E in immunocompromised individuals. The molecular mechanisms involved in persistent infections are poorly understood. Micro RNAs (miRNAs) can regulate viral pathogenesis and can serve as novel disease biomarkers. We aimed to explore the modulation of serum miRNAs in patients with acute (AHE) and chronic (CHE) hepatitis E. Both AHE- and CHE-patients exhibited high viral loads (median 3.23E + 05 IU/mL and 2.11E + 06 IU/mL, respectively) with HEV-3c being the predominant HEV-genotype. Expression analysis of liver-specific serum miRNAs was performed using real-time PCR. miR-99a-5p, miR-122-5p, and miR-125b-5p were upregulated in AHE (4.70–5.28 fold) and CHE patients (2.28–6.34 fold), compared to HEV-negative controls. Notably, miR-192-5p was increased 2.57 fold while miR-125b-5p was decreased 0.35 fold in CHE but not in AHE patients. Furthermore, decreased miR-122-5p expression significantly correlates with reduced liver transaminases in CHE patients. To our knowledge, this marks the first investigation concerning the regulation of circulating liver-specific miRNAs in acute and chronic HEV infections. We found that miR-125b-5p, miR-192-5p, and miR-99a-5p may prove useful in the diagnosis of chronic hepatitis E.
Collapse
|
|
40
|
Four-year long (2014-2017) clinical and laboratory surveillance of hepatitis E virus infections using combined antibody, molecular, antigen and avidity detection methods: Increasing incidence and chronic HEV case in Hungary. J Clin Virol 2020; 124:104284. [DOI: 10.1016/j.jcv.2020.104284] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 01/15/2020] [Accepted: 01/27/2020] [Indexed: 12/12/2022]
|
|
41
|
Lhomme S, Marion O, Abravanel F, Izopet J, Kamar N. Clinical Manifestations, Pathogenesis and Treatment of Hepatitis E Virus Infections. J Clin Med 2020; 9:E331. [PMID: 31991629 PMCID: PMC7073673 DOI: 10.3390/jcm9020331] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/14/2020] [Accepted: 01/22/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis throughout the world. Most infections are acute but they can become chronic in immunocompromised patients, such as solid organ transplant patients, patients with hematologic malignancy undergoing chemotherapy and those with a human immunodeficiency virus (HIV) infection. Extra-hepatic manifestations, especially neurological and renal diseases, have also been described. To date, four main genotypes of HEV (HEV1-4) were described. HEV1 and HEV2 only infect humans, while HEV3 and HEV4 can infect both humans and animals, like pigs, wild boar, deer and rabbits. The real epidemiology of HEV has been underestimated because most infections are asymptomatic. This review focuses on the recent advances in our understanding of the pathophysiology of acute HEV infections, including severe hepatitis in patients with pre-existing liver disease and pregnant women. It also examines the mechanisms leading to chronic infection in immunocompromised patients and extra-hepatic manifestations. Acute infections are usually self-limiting and do not require antiviral treatment. Conversely, a chronic HEV infection can be cleared by decreasing the dose of immunosuppressive drugs or by treating with ribavirin for 3 months. Nevertheless, new drugs are needed for those cases in which ribavirin treatment fails.
Collapse
Affiliation(s)
- Sébastien Lhomme
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Olivier Marion
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, 31400 Toulouse, France
| | - Florence Abravanel
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Jacques Izopet
- Virology Laboratory, National Reference Center for Hepatitis E Virus, Toulouse Purpan University Hospital, 31300 Toulouse, France; (F.A.); (J.I.)
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
| | - Nassim Kamar
- INSERM UMR1043, Center for Pathophysiology of Toulouse Purpan, 31300 Toulouse, France;
- Université Toulouse III Paul Sabatier, 31330 Toulouse, France
- Department of Nephrology and Organs Transplantation, Toulouse Rangueil University Hospital, 31400 Toulouse, France
| |
Collapse
|
|
42
|
Mainardi V, Gerona S, Ardao G, Ferreira N, Ramírez G, Arbiza J, Mirazo S. Locally Acquired Chronic Hepatitis E Followed by Epstein-Barr Virus Reactivation and Burkitt Lymphoma as a Suspected Extrahepatic Manifestation in a Liver Transplant Recipient. AMERICAN JOURNAL OF CASE REPORTS 2019; 20:1016-1021. [PMID: 31302664 PMCID: PMC6647622 DOI: 10.12659/ajcr.916253] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing regions. In high-income countries, hepatitis E is an emergent zoonotic disease of increasing concern. Clinically, the infection is usually acute and self-limited in immunocompetent individuals, although rare chronic cases in immunocompromised patients have been reported. Both acute and chronic infections have been recently associated with several extrahepatic manifestations, including neurological and hematological disorders. CASE REPORT A case of autochthonous chronic HEV infection in a liver-transplanted man from a non-endemic country is presented. Phylogenetic analysis revealed a swine origin of the HEV human infection. Chronic hepatitis E was treated with a 9-week course of ribavirin, after which viral clearance was achieved. Subsequently, the patient developed a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoma. At the time of lymphoma diagnosis, the patient had shown a strong reactivation of Epstein-Barr virus (EBV) infection. After additional antiviral ganciclovir therapy and chemotherapy, the patient had a complete recovery with no sequelae. CONCLUSIONS The differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by appropriate nucleic acid techniques (NATs). Cases of HEV infection with an atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.
Collapse
Affiliation(s)
- Victoria Mainardi
- National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay
| | - Solange Gerona
- National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay
| | - Gonzalo Ardao
- National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay
| | - Noelia Ferreira
- National Liver Transplant Program, Central Hospital of the Armed Forces, Montevideo, Uruguay
| | - Gabriel Ramírez
- Virology Section, Science Faculty, University of the Republic, Montevideo, Uruguay
| | - Juan Arbiza
- Virology Section, Science Faculty, University of the Republic, Montevideo, Uruguay
| | - Santiago Mirazo
- Virology Section, Science Faculty, University of the Republic, Montevideo, Uruguay
| |
Collapse
|
|
43
|
Horvatits T, Schulze Zur Wiesch J, Lütgehetmann M, Lohse AW, Pischke S. The Clinical Perspective on Hepatitis E. Viruses 2019; 11:E617. [PMID: 31284447 PMCID: PMC6669652 DOI: 10.3390/v11070617] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/26/2019] [Accepted: 07/03/2019] [Indexed: 12/17/2022] Open
Abstract
Every year, there are an estimated 20 million hepatitis E virus (HEV) infections worldwide, leading to an estimated 3.3 million symptomatic cases of hepatitis E. HEV is largely circulating in the west and is associated with several hepatic and extrahepatic diseases. HEV Genotype 1 and 2 infections are waterborne and causative for epidemics in the tropics, while genotype 3 and 4 infections are zoonotic diseases and are mainly transmitted by ingestion of undercooked pork in industrialized nations. The clinical course of these infections differs: genotype 1 and 2 infection can cause acute illness and can lead to acute liver failure (ALF) or acute on chronic liver failure (ACLF) with a high mortality rate of 20% in pregnant women. In contrast, the majority of HEV GT-3 and -4 infections have a clinically asymptomatic course and only rarely lead to acute on chronic liver failure in elderly or patients with underlying liver disease. Immunosuppressed individuals infected with genotype 3 or 4 may develop chronic hepatitis E, which then can lead to life-threatening cirrhosis. Furthermore, several extra-hepatic manifestations affecting various organs have been associated with ongoing or previous HEV infections but the causal link for many of them still needs to be proven. There is no approved specific therapy for the treatment of acute or chronic HEV GT-3 or -4 infections but off-label use of ribavirin has been demonstrated to be safe and effective in the majority of patients. However, in approximately 15% of chronically HEV infected patients, cure is not possible.
Collapse
Affiliation(s)
- Thomas Horvatits
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Julian Schulze Zur Wiesch
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Marc Lütgehetmann
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
- Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Sven Pischke
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany.
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany.
| |
Collapse
|
|
44
|
Kamar N, Pischke S. Acute and Persistent Hepatitis E Virus Genotype 3 and 4 Infection: Clinical Features, Pathogenesis, and Treatment. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a031872. [PMID: 29735575 DOI: 10.1101/cshperspect.a031872] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hepatitis E virus (HEV) genotype (gt)3 and 4 infections are prevalent in industrialized and high-income countries. Although most HEV gt3 and gt4 infections are clinically silent, acute infection may be symptomatic in some patients. In persons with underlying liver disease and in elderly men, HEV infections may present as acute or acute-on-chronic liver failure. Chronic hepatitis may develop in immunosuppressed individuals, including transplant recipients, human immunodeficiency virus (HIV)-infected patients, and persons with hematologic malignancy undergoing chemotherapy, and may progress to life-threatening liver cirrhosis. Extrahepatic manifestations of infection may include neurological and renal disease. Although there is no approved specific therapy for the treatment of acute or chronic HEV gt3 or gt4 infection, off-label use of ribavirin appears to be capable of eliminating chronic HEV infection, and may reduce disease severity in patients suffering from acute liver failure.
Collapse
Affiliation(s)
- Nassim Kamar
- Department of Nephrology and Organ Transplantation, Université Paul Sabatier, Toulouse 31059, France
| | - Sven Pischke
- Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
| |
Collapse
|
|
45
|
Low EXS, Tripon E, Lim K, Tan PS, Low HC, Dan YY, Lee YM, Muthiah M, Loo WM, Koh CJ, Phyo WW, Pang J, Lim SG, Lee GH. Risk factors for ribavirin treatment failure in Asian organ transplant recipients with chronic hepatitis E infection. World J Hepatol 2019; 11:553-561. [PMID: 31293723 PMCID: PMC6603503 DOI: 10.4254/wjh.v11.i6.553] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 06/11/2019] [Accepted: 06/17/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) infection is a cause of chronic hepatitis in immunosuppressed patients. Sustained virologic response rates to a 12-wk course of ribavirin therapy were reported to be > 70% in the West. This study describes the outcome of HEV treatment in a transplant center in Singapore.
AIM To study the outcome of ribavirin treatment in a series of chronic HEV patients, and the cause of treatment failure.
METHODS We studied all of the transplant recipients who were diagnosed with HEV infection between 2012 to 2015. The outcome of therapy and virologic relapse are monitored for three years after the end of therapy.
RESULTS Ten transplant recipients (4 liver, 5 kidney, and 1 bone marrow transplantation) with positive HEV RNA were studied. Nine patients received at least 12 wk of ribavirin therapy, and the remaining patient resolved after reducing immunosuppression therapy. Two subjects had prolonged viremia that lasted more than one year, despite continuous ribavirin therapy. Four ribavirin-treated patients (44.4%) had HEV RNA relapse after achieving a virologic response by the end of treatment. The overall failure rate is 66.7%. Being a kidney transplant recipient is the strongest risk factor for not achieving an initial sustained virologic response (0/5 treated, Chi-Square test, P < 0.05). The most common side effect of ribavirin is anemia (100%) (haemoglobin reduction of 3-6.2 g/dL). Seven patients required either a blood transfusion or erythropoietin therapy.
CONCLUSION The sustained virologic response rate of 12-wk ribavirin therapy for HEV infection in this Asian series was lower than expected. Kidney transplant recipients had a higher rate of treatment failure due to higher immunosuppression requirements and adverse effects.
Collapse
Affiliation(s)
- En Xian Sarah Low
- Department of Medicine, Ng Teng Fong General Hospital, National University Health System, Singapore 609606, Singapore
| | - Edhel Tripon
- Centre for Liver Disease Management and Transplant of Medical City, Manila 1605, Philippines
| | - Kieron Lim
- Mount Elizabeth Medical Centre, Singapore 228510, Singapore
| | - Poh Seng Tan
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - How Cheng Low
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Yock Young Dan
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Yin Mei Lee
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Mark Muthiah
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Wai Mun Loo
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Calvin Jianyi Koh
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
| | - Wah Wah Phyo
- Department of Medicine, National University of Singapore, Singapore 119077, Singapore
| | - JunXiong Pang
- Centre for Infectious Disease Epidemiology and Research, National University of Singapore, Singapore 117549, Singapore
| | - Seng Gee Lim
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Guan-Huei Lee
- Division of Gastroenterology and Hepatology, National University Health System, Singapore 119228, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| |
Collapse
|
|
46
|
Abstract
Many microbes, toxins, autoimmune diseases, and neoplastic diseases may cause liver inflammation; however, 5 viruses whose main pathogenesis is liver disease are referred to as hepatitis A, B, C, D, and E viruses. These viruses cause a significant burden of global illness. With the exception of hepatitis A virus, all may cause chronic infection potentially leading to cirrhosis and hepatocellular carcinoma. Excellent serologic and nucleic acid detection methods are available for determining the precise cause and, in some cases, the duration of infection. Diagnostics are critical for identifying individuals needing treatment and for monitoring the treatment success.
Collapse
Affiliation(s)
- Kunatum Prasidthrathsint
- Division of Infectious Diseases, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Division of Clinical Microbiology, Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; University of Iowa Hospitals and Clinics, SW54, GH, 200 Hawkins Drive, Iowa City, IA 52242, USA; Medicine and Research Services, Iowa City Veterans Administration Health Care Center, Iowa City, IA, USA
| | - Jack T Stapleton
- Division of Infectious Diseases, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; University of Iowa Hospitals and Clinics, SW54, GH, 200 Hawkins Drive, Iowa City, IA 52242, USA; Medicine and Research Services, Iowa City Veterans Administration Health Care Center, Iowa City, IA, USA.
| |
Collapse
|
|
47
|
Lhomme S, Legrand-Abravanel F, Kamar N, Izopet J. Screening, diagnosis and risks associated with Hepatitis E virus infection. Expert Rev Anti Infect Ther 2019; 17:403-418. [DOI: 10.1080/14787210.2019.1613889] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Sébastien Lhomme
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Florence Legrand-Abravanel
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Nassim Kamar
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
- Department of Nephrology and Organs Transplantation, CHU Rangueil, Toulouse, France
| | - Jacques Izopet
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| |
Collapse
|
|
48
|
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
| |
Collapse
|
|
49
|
Sridhar S, Cheng VCC, Wong SC, Yip CCY, Wu S, Lo AWI, Leung KH, Mak WWN, Cai J, Li X, Chan JFW, Lau SKP, Woo PCY, Lai WM, Kwan TH, Au TWK, Lo CM, Wong SCY, Yuen KY. Donor-Derived Genotype 4 Hepatitis E Virus Infection, Hong Kong, China, 2018. Emerg Infect Dis 2019; 25:425-433. [PMID: 30789146 PMCID: PMC6390757 DOI: 10.3201/eid2503.181563] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hepatitis E virus (HEV) genotype 4 (HEV-4) is an emerging cause of acute hepatitis in China. Less is known about the clinical characteristics and natural history of HEV-4 than HEV genotype 3 infections in immunocompromised patients. We report transmission of HEV-4 from a deceased organ donor to 5 transplant recipients. The donor had been viremic but HEV IgM and IgG seronegative, and liver function test results were within reference ranges. After a mean of 52 days after transplantation, hepatitis developed in all 5 recipients; in the liver graft recipient, disease was severe and with progressive portal hypertension. Despite reduced immunosuppression, all HEV-4 infections progressed to persistent hepatitis. Four patients received ribavirin and showed evidence of response after 2 months. This study highlights the role of organ donation in HEV transmission, provides additional data on the natural history of HEV-4 infection, and points out differences between genotype 3 and 4 infections in immunocompromised patients.
Collapse
|
|
50
|
Chronic Hepatitis E in Rheumatology and Internal Medicine Patients: A Retrospective Multicenter European Cohort Study. Viruses 2019; 11:v11020186. [PMID: 30813268 PMCID: PMC6410237 DOI: 10.3390/v11020186] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/04/2019] [Accepted: 02/19/2019] [Indexed: 12/23/2022] Open
Abstract
Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim–Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids (n = 2), mycophenolate mofetil/prednisone (n = 1), and sirolimus/prednisone (n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection.
Collapse
|