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1
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Schwarz M, Mozayani B, Trauner M, Stättermayer AF. Chronic hepatitis E in a patient after chimeric antigen receptor-T-cell treatment for diffuse large B-cell lymphoma and rapid progression towards decompensated liver cirrhosis. Br J Haematol 2024. [PMID: 39506930 DOI: 10.1111/bjh.19892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024]
Affiliation(s)
- Michael Schwarz
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Behrang Mozayani
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Albert Friedrich Stättermayer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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2
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He P, Li J, Wang C, Zhang J, Jiang Y, Liu H, Zhao Y, Li Z, Gao Y, Wang Y. Incidence and risk factors of de novo hepatitis E virus infection after receiving liver transplantation. J Med Virol 2024; 96:e29939. [PMID: 39360633 DOI: 10.1002/jmv.29939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/07/2024] [Accepted: 09/17/2024] [Indexed: 10/04/2024]
Abstract
Organ transplant recipients with hepatitis E virus (HEV) infection bears high risk to develop chronic hepatitis, which is generally associated with immunosuppressive therapies. This study aimed to identify the incidence and predictors of de novo HEV infection in patients after receiving transplantation. We performed a large retrospective study to investigate the prevalence of anti-HEV at baseline, incidence of de novo HEV infection after transplantation, and the risk factors of HEV infection among patients with liver transplant in China. A total of 407 liver transplant recipients were examined for the presence of anti-HEV immunoglobulin G, IgM antibodies, and HEV RNA in serum. Basal indexes in individuals with evidence of post-transplant HEV infection were compared with those without evidence of that, and risk factors associated with HEV infection were assessed. The prevalence of anti-HEV at pretransplant in liver transplant recipients was 25.8% (105/407). Serum-negative conversion occurred in 34 (32.38%) of 105 liver transplant patients. Sixty-five out of 302 patients had de novo HEV infection after transplantation, with a cumulative incidence of 42.74% during follow-up. After transplantation, HEV infection was associated with liver failure (p = 0.012), hypoproteinemia (p = 0.030) and higher level of r-glutamyl transferase (GGT) (p = 0.022) before transplantation. Graft rejection (OR = 0.075; p = 0.045) was negatively associated with serum-negative conversion in patients who had positive anti-HEV antibody before transplantation. The incidence of de novo HEV infection after transplantation were higher in China. Liver failure, hypoproteinemia, and GGT elevation may be associated with HEV infection after liver transplantation. This study suggests that prevention and control of HEV infection after liver transplantation should be paid attention in patients bearing these risk factors.
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Affiliation(s)
- Ping He
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Jialei Li
- Medical School of Nanjing University, Nanjing, China
| | - Chen Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Jiayue Zhang
- School of Pharmacy, Jiangsu Food & Pharmaceutical Science College, Huaian, China
| | - Yiyun Jiang
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Hongyang Liu
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yao Zhao
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Zhiwei Li
- Department of Hepato-Biliary Surgery, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China
| | - Yinjie Gao
- Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Yijin Wang
- Department of Pharmacology, Joint Laboratory of Guangdong-Hong Kong Universities for Vascular Homeostasis and Diseases, School of Medicine, Southern University of Science and Technology, Shenzhen, China
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3
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Yadav KK, Kenney SP. Hepatitis E virus immunosuppressed animal models. BMC Infect Dis 2024; 24:965. [PMID: 39266958 PMCID: PMC11395946 DOI: 10.1186/s12879-024-09870-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/03/2024] [Indexed: 09/14/2024] Open
Abstract
Hepatitis E virus (HEV) is an important emerging pathogen producing significant morbidity in immunosuppressed patients. HEV has been detrimental to solid organ transplant (SOT) patients, cancer patients, and HIV-positive patients, where chronic HEV infections occur. Blood-borne transfusions and multiple cases of chronic HEV infection in transplant patients have been reported in the past few decades, necessitating research on HEV pathogenesis using immunosuppressed animal models. Numerous animal species with unique naturally occurring HEV strains have been found, several of which have the potential to spread to humans and to serve as pathogenesis models. Host immunosuppression leads to viral persistence and chronic HEV infection allows for genetic adaptation to the human host creating new strains with worse disease outcomes. Procedures necessary for SOT often entail blood transfusions placing immunosuppressive patients into a "high risk group" for HEV infection. This scenario requires an appropriate immunosuppressive animal model to understand disease patterns in these patients. Hence, this article reviews the recent advances in the immunosuppressed animal models for chronic HEV infection with emphasis on pathogenesis, immune correlates, and the liver pathology associated with the chronic HEV infections.
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Affiliation(s)
- Kush Kumar Yadav
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA
| | - Scott P Kenney
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA.
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA.
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Deigin V, Linkova N, Vinogradova J, Vinogradov D, Polyakova V, Medvedev D, Krasichkov A, Volpina O. The First Reciprocal Activities of Chiral Peptide Pharmaceuticals: Thymogen and Thymodepressin, as Examples. Int J Mol Sci 2024; 25:5042. [PMID: 38732260 PMCID: PMC11084461 DOI: 10.3390/ijms25095042] [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: 03/15/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024] Open
Abstract
Peptides show high promise in the targeting and intracellular delivery of next-generation biotherapeutics. The main limitation is peptides' susceptibility to proteolysis in biological systems. Numerous strategies have been developed to overcome this challenge by chemically enhancing the resistance to proteolysis. In nature, amino acids, except glycine, are found in L- and D-enantiomers. The change from one form to the other will change the primary structure of polypeptides and proteins and may affect their function and biological activity. Given the inherent chiral nature of biological systems and their high enantiomeric selectivity, there is rising interest in manipulating the chirality of polypeptides to enhance their biomolecular interactions. In this review, we discuss the first examples of up-and-down homeostasis regulation by two enantiomeric drugs: immunostimulant Thymogen (L-Glu-L-Trp) and immunosuppressor Thymodepressin (D-Glu(D-Trp)). This study shows the perspective of exploring chirality to remove the chiral wall between L- and D-biomolecules. The selected clinical result will be discussed.
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Affiliation(s)
- Vladislav Deigin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St., 16/10, Moscow 117997, Russia; (V.D.); (O.V.)
| | - Natalia Linkova
- St. Petersburg Research Institute of Phthisiopulmonology, Ligovskii Prospect, 2-4, St. Petersburg 191036, Russia;
- St. Petersburg Institute of Bioregulation and Gerontology, 3 Dynamo Ave., St. Petersburg 197110, Russia
| | - Julia Vinogradova
- The Department of Hospital Therapy No. 2, I.M. Sechenov First Moscow State Medical University, 8 Trubetskaya Str., Building 2, Moscow 119991, Russia; (J.V.); (D.V.)
| | - Dmitrii Vinogradov
- The Department of Hospital Therapy No. 2, I.M. Sechenov First Moscow State Medical University, 8 Trubetskaya Str., Building 2, Moscow 119991, Russia; (J.V.); (D.V.)
| | - Victoria Polyakova
- St. Petersburg Research Institute of Phthisiopulmonology, Ligovskii Prospect, 2-4, St. Petersburg 191036, Russia;
- St. Petersburg Institute of Bioregulation and Gerontology, 3 Dynamo Ave., St. Petersburg 197110, Russia
| | - Dmitrii Medvedev
- St. Petersburg Institute of Bioregulation and Gerontology, 3 Dynamo Ave., St. Petersburg 197110, Russia
- The Department of Social Rehabilitation and Occupational Therapy of the St. Petersburg Medical and Social Institute, Kondratievsky St., 72A, St. Petersburg 195271, Russia
| | - Alexander Krasichkov
- Department of Radio Engineering Systems, Saint Petersburg Electrotechnical University ‘LETI’, St. Petersburg 197376, Russia
| | - Olga Volpina
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St., 16/10, Moscow 117997, Russia; (V.D.); (O.V.)
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Shrestha A, Basnet S, Kc S. Subclinical hepatitis E virus genotype 1 infection: The concept of "dynamic human reservoir". World J Hepatol 2024; 16:506-510. [PMID: 38689746 PMCID: PMC11056895 DOI: 10.4254/wjh.v16.i4.506] [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: 12/28/2023] [Revised: 02/22/2024] [Accepted: 03/28/2024] [Indexed: 04/24/2024] Open
Abstract
Hepatitis E virus (HEV) is hyperendemic in South Asia and Africa accounting for half of total Global HEV burden. There are eight genotypes of HEV. Among them, the four common ones known to infect humans, genotypes 1 and 2 are prevalent in the developing world and genotypes 3 and 4 are causing challenge in the industrialized world. Asymptomatic HEV viremia in the general population, especially among blood donors, has been reported in the literature worldwide. The clinical implications related to this asymptomatic viremia are unclear and need further exploration. Detection of viremia due to HEV genotype 1 infection, apparently among healthy blood donors is also reported without much knowledge about its infection rate. Similarly, while HEV genotype 3 is known to be transmitted via blood transfusion in humans and has been subjected to screening in many European nations, instances of transmission have also been documented albeit without significant clinical consequences. Epidemiology of HEV genotype 1 in endemic areas often show waxing and waning pattern. Occasional sporadic occurrence of HEV infection interrupted by outbreaks have been frequently seen. In absence of known animal reservoir, where HEV exists in between outbreak is a mystery that needs further exploration. However, occurrence of asymptomatic HEV viremia due to HEV genotype 1 during epidemiologically quiescent period may explain that this phenomenon may act as a dynamic reservoir. Since HEV genotype 1 infection cannot cause chronicity, subclinical transient infection and transmission of virus might be the reason it sustains in interepidemic period. This might be the similar phenomenon with SARS COVID-19 corona virus infection which is circulating worldwide in distinct phases with peaks and plateaus despite vaccination against it. In view of existing evidence, we propose the concept of "Dynamic Human Reservoir." Quiescent subclinical infection of HEV without any clinical consequences and subsequent transmission may contribute to the existence of the virus in a community. The potential for transmitting HEV infection by asymptomatic HEV infected individuals by fecal shedding of virus has not been reported in literature. This missing link may be a key to Pandora's box in understanding epidemiology of HEV infection in genotype 1 predominant region.
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Affiliation(s)
- Ananta Shrestha
- Department of Hepatology, Alka Hospital, Kathmandu 44600, Nepal
| | - Suresh Basnet
- Department of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, United States
| | - Sudhamshu Kc
- Department of Hepatology, National Academy of Medical Sciences, Kathmandu 44600, Nepal.
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Alexandrova R, Tsachev I, Kirov P, Abudalleh A, Hristov H, Zhivkova T, Dyakova L, Baymakova M. Hepatitis E Virus (HEV) Infection Among Immunocompromised Individuals: A Brief Narrative Review. Infect Drug Resist 2024; 17:1021-1040. [PMID: 38505248 PMCID: PMC10948336 DOI: 10.2147/idr.s449221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 02/21/2024] [Indexed: 03/21/2024] Open
Abstract
Hepatitis E virus (HEV) is a single-stranded positive-sense RNA virus that belongs to Hepeviridae family. HEV is the most common cause of acute viral hepatitis worldwide. According to the World Health Organization (WHO), there are estimated 20 million HEV infections worldwide every year, leading to estimated 3.3 million symptomatic cases of HEV infection. The WHO estimates that HEV infection caused approximately 44,000 deaths in 2015, which represents 3.3% of mortality rates due to viral hepatitis. In low-income (LI) countries and lower-middle-income (LMI) countries, HEV is a waterborne infection induced by HEV genotype (gt) 1 and HEV gt 2 that cause large outbreaks and affect young individuals with a high mortality rate in pregnant women from South Asian countries and patients with liver diseases. HEV gt 3, HEV gt 4, and HEV gt 7 are responsible for sporadic infections with zoonotic transmission mainly through the consumption of raw or undercooked meat from different animals. Acute HEV infection is relatively asymptomatic or mild clinical form, in rare cases the disease can be moderate/severe clinical forms and result in fulminant hepatitis or acute liver failure (ALF). Furthermore, HEV infection is associated with extrahepatic manifestations, including renal and neurological clinical signs and symptoms. Pregnant women, infants, older people, immunocompromised individuals, patients with comorbidities, and workers who come into close contact with HEV-infected animals are recognized as major risk groups for severe clinical form of HEV infection and fatal outcome. Chronic HEV infection can occur in immunocompromised individuals with the possibility of progression to cirrhosis.
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Affiliation(s)
- Radostina Alexandrova
- Department of Pathology, Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Ilia Tsachev
- Department of Microbiology, Infectious and Parasitic Diseases, Faculty of Veterinary Medicine, Trakia University, Stara Zagora, Bulgaria
| | - Plamen Kirov
- Department of Pathology, Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Abedulkadir Abudalleh
- Department of Pathology, Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Hristo Hristov
- Department of Pathology, Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Tanya Zhivkova
- Department of Pathology, Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Lora Dyakova
- Department of Synaptic Signaling and Communication, Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - Magdalena Baymakova
- Department of Infectious Diseases, Military Medical Academy, Sofia, Bulgaria
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Songtanin B, Molehin AJ, Brittan K, Manatsathit W, Nugent K. Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations. Viruses 2023; 15:1389. [PMID: 37376687 DOI: 10.3390/v15061389] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are four main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route. Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans via undercooked meat. Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients. The majority of patients with HEV infection are asymptomatic and usually have spontaneous viral clearance without treatment. However, infection in immunocompromised individuals can lead to chronic HEV infection. Both acute and chronic HEV infections can have extrahepatic manifestations. No specific treatment is required for acute HEV infection, no treatment has been approved in chronic infection, and no HEV vaccine has been approved by the (United States) Food and Drug Administration. This review focuses on the molecular virology (HEV life cycle, genotypes, model systems, zoonosis), pathogenesis, clinical manifestation, and treatment of chronic HEV infection, especially in immunocompromised patients, to provide clinicians a better understanding of the global distribution of these infections and the significant effect they can have on immunocompromised patients.
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Affiliation(s)
- Busara Songtanin
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Adebayo J Molehin
- Department of Microbiology & Immunology, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA
| | - Kevin Brittan
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Wuttiporn Manatsathit
- Department of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
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Zhang F, Xu LD, Zhang Q, Wang A, Yu X, Liu S, Chen C, Wu S, Jin J, Lin A, Neculai D, Zhao B, Feng XH, Liang T, Xu P, Huang YW. Targeting proteostasis of the HEV replicase to combat infection in preclinical models. J Hepatol 2023; 78:704-716. [PMID: 36574921 DOI: 10.1016/j.jhep.2022.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 11/15/2022] [Accepted: 12/06/2022] [Indexed: 12/25/2022]
Abstract
BACKGROUND & AIMS Appropriate treatment options are lacking for hepatitis E virus (HEV)-infected pregnant women and immunocompromised individuals. Thus, we aimed to identify efficient anti-HEV drugs through high-throughput screening, validate them in vitro and in vivo (in a preclinical animal study), and elucidate their underlying antiviral mechanism of action. METHODS Using appropriate cellular and rodent HEV infection models, we studied a critical pathway for host-HEV interactions and performed a preclinical study of the corresponding antivirals, which target proteostasis of the HEV replicase. RESULTS We found 17 inhibitors that target HEV-HSP90 interactions by unbiased compound library screening on human hepatocytes harboring an HEV replicon. Inhibitors of HSP90 (iHSP90) markedly suppressed HEV replication with efficacy exceeding that of conventional antivirals (IFNα and ribavirin) in vitro. Mechanistically, iHSP90 treatment released the viral replicase ORF1 protein from the ORF1-HSP90 complex and triggered rapid ubiquitin/proteasome-mediated degradation of ORF1, resulting in abrogated HEV replication. Furthermore, a preclinical trial in a Mongolian gerbil HEV infection model showed this novel anti-HEV strategy to be safe, efficient, and able to prevent HEV-induced liver damage. CONCLUSIONS In this study, we uncover a proteostatic pathway that is critical for host-HEV interactions and we provide a foundation from which to translate this new understanding of the HEV life cycle into clinically promising antivirals. IMPACT AND IMPLICATIONS Appropriate treatment options for hepatitis E virus (HEV)-infected pregnant women and immunocompromised patients are lacking; hence, there is an urgent need for safe and effective HEV-specific therapies. This study identified new antivirals (inhibitors of HSP90) that significantly limit HEV infection by targeting the viral replicase for degradation. Moreover, these anti-HEV drugs were validated in an HEV rodent model and were found to be safe and efficient for prevention of HEV-induced liver injury in preclinical experiments. Our findings substantially promote the understanding of HEV pathobiology and pave the way for antiviral development.
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Affiliation(s)
- Fei Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Ling-Dong Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Qian Zhang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Ailian Wang
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xinyuan Yu
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Shengduo Liu
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Department of Veterinary Medicine, Zhejiang University, Hangzhou, 310058, China
| | - Chu Chen
- Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center (ZJU-HIC), Hangzhou, 310058, China; Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China
| | - Shiying Wu
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Jianping Jin
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Aifu Lin
- MOE Laboratory of Biosystems Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Dante Neculai
- Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, China
| | - Bin Zhao
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China
| | - Xin-Hua Feng
- MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China.
| | - Pinglong Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China; MOE Laboratory of Biosystems Homeostasis & Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China; Department of Veterinary Medicine, Zhejiang University, Hangzhou, 310058, China; Cancer Center, Zhejiang University, Hangzhou, 310058, China.
| | - Yao-Wei Huang
- Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center (ZJU-HIC), Hangzhou, 310058, China; Guangdong Laboratory for Lingnan Modern Agriculture, College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
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You S, Zhu B, Xin S. Clinical Manifestations of Hepatitis E. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:185-197. [PMID: 37223867 DOI: 10.1007/978-981-99-1304-6_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
The clinical manifestations of hepatitis E are similar to those of other types of viral hepatitis. While acute hepatitis E is usually self-limited, pregnant women and chronic liver disease patients suffering from acute hepatitis E usually present with severe clinical manifestations that may develop into fulminant hepatic failure. Chronic HEV infection is typically seen in organ transplant patients; most HEV cases are asymptomatic and rarely display jaundice, fatigue, abdominal pain, fever, fatigue, or ascites. The clinical manifestations of HEV infection in neonates are diverse and have varied clinical signs, biochemistry, and virus-biomarkers. Lastly, the extrahepatic manifestations and complications of hepatitis E are in need of further study.
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Affiliation(s)
- Shaoli You
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Bing Zhu
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shaojie Xin
- Senior Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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Samala N, Wang RY, Auh S, Balla AK, Dakhoul L, Alter HJ, Farci P, Ghabril M, Lucey MR, Rangnekar AS, Reddy KR, Ghany MG. Hepatitis E prevalence and infection in solid-organ transplant recipients in the United States. J Viral Hepat 2022; 29:1134-1142. [PMID: 36036116 DOI: 10.1111/jvh.13739] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/27/2022] [Accepted: 07/19/2022] [Indexed: 12/29/2022]
Abstract
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. An increased risk for HEV infection has been reported in organ-transplant recipients, mainly from Europe. Prospective data on HEV prevalence in the United States (U.S.) organ transplant population are limited. To determine the prevalence and factors associated with HEV infection among solid organ transplant-recipients, we conducted a prospective, cross-sectional, multicentre study among transplant-recipients and age- and organ-matched waitlist patients. Participants answered a risk-exposure questionnaire and were tested for HEV-RNA (in-house PCR), HEV-IgG, and IgM (ELISA, Wantai). Among 456 participants, 224 were transplant-recipients, and 232 were waitlist patients. The mean age was 58 years, 35% female, and 74% White. HEV seroprevalence of the entire cohort was 20.2% and associated with older age (p < 0.0001) and organ transplantation (p = 0.02). The HEV seropositivity was significantly higher among transplant-recipients compared with waitlist patients (24% vs. 16.4%, p = 0.042). Among transplant recipients, relative-risk of being HEV seropositive increased with older age (RR = 3.4 [1.07-10.74] in patients >70 years compared with ≤50 years, p = 0.037); history of graft hepatitis (2.2 [1.27-3.72], p = 0.005); calcineurin inhibitor use (RR = 1.9 [1.03-3.34], p = 0.02); and kidney transplantation (2.4 [1.15-5.16], p = 0.02). HEV-RNA, genotype 3 was detected in only two patients (0.4%), both transplant-recipients. HEV seroprevalence was higher among transplant-recipients than waitlist patients. HEV should be considered in transplant-recipients presenting with graft hepatitis. Detection of HEV-RNA was rare, suggesting that progression to chronic HEV infection is uncommon in transplant-recipients in the U.S.
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Affiliation(s)
- Niharika Samala
- Division of Gastroenterology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Richard Y Wang
- Department of Transfusion Medicine, National Institutes of Health, Bethesda, Maryland, USA
| | - Sungyoung Auh
- Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Abdalla Kara Balla
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - Lara Dakhoul
- Division of Gastroenterology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Harvey J Alter
- Department of Transfusion Medicine, National Institutes of Health, Bethesda, Maryland, USA
| | - Patrizia Farci
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Marwan Ghabril
- Division of Gastroenterology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Michael R Lucey
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Amol S Rangnekar
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, District of Columbia, USA
| | - K Rajender Reddy
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Marc G Ghany
- Liver Disease Branch (LDB), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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11
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Takakusagi S, Takagi H, Yamazaki Y, Kosone T, Nagashima S, Takahashi M, Murata K, Okamoto H. Chronic hepatitis E in an elderly immunocompetent patient who achieved a sustained virologic response with ribavirin treatment. Clin J Gastroenterol 2022; 16:206-215. [PMID: 36403172 DOI: 10.1007/s12328-022-01733-2] [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: 08/23/2022] [Accepted: 11/04/2022] [Indexed: 11/21/2022]
Abstract
A woman in her late 70 s was diagnosed with liver injury at a health examination. Despite treatment with ursodeoxycholic acid at a nearby hospital, her transaminase levels elevated in two peaks. She was transferred to our hospital 77 days after the health examination. She weighed 42 kg and had a low body mass index of 19.8 kg/m2. Viral markers, including immunoglobulin A (IgA) against hepatitis E virus (anti-HEV IgA), were negative. Drug-induced liver injury was negligible. We suspected autoimmune hepatitis because of the patient's female gender and positive antinuclear antibody. However, prednisolone and azathioprine failed to completely improve her hepatitis. On day 643, anti-HEV IgA was re-evaluated and found to be positive. She was diagnosed with autochthonous chronic hepatitis E because the virus strains in the preserved serum on day 77 and the serum on day 643 had identical nucleotide sequences (genotype 3a). Following prednisolone and azathioprine discontinuation, ribavirin (RBV) was administered for 3 months. HEV RNA disappeared and remained negative for more than 6 months after the cessation of RBV. The HEV RNA titer of 6.2 log10 copies/mL on day 77 was unusually high 2.5 months after the onset, suggesting that hepatitis E had already been chronic before immunosuppressive treatment for possible autoimmune hepatitis. After getting married at 23 years old, she had been a housewife and had no comorbidities that might deteriorate her immunity. Chronicity should be kept in mind when encountering HEV infection in elderly and underweight patients.
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Affiliation(s)
- Satoshi Takakusagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan.
| | - Yuichi Yamazaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-Machi, Maebashi, Gunma, 371-8511, Japan
| | - Takashi Kosone
- Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22 Fujioka, Fujioka, Gunma, 375-0024, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Kazumoto Murata
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
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12
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Ghandili S, Lindhauer C, Pischke S, zur Wiesch JS, von Kroge PH, Polywka S, Bokemeyer C, Fiedler W, Kröger N, Ayuk F, Adjallé R, Modemann F. Clinical features of hepatitis E infections in patients with hematologic disorders. Haematologica 2022; 107:2870-2883. [PMID: 35770534 PMCID: PMC9713558 DOI: 10.3324/haematol.2022.280853] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Indexed: 12/14/2022] Open
Abstract
Hepatitis E virus is increasingly being reported to cause chronic infection in immunocompromised patients. However, less is known about patients with an underlying hematologic disease. In particular, the impact of hepatitis E infection on oncological therapy has been poorly described. In this retrospective single-center study, we analyzed 35 hematologic patients with hepatitis E, including 20 patients under active oncological treatment and 15 patients who were in the posttreatment follow-up or under active surveillance. The primary aim was to describe the clinical courses with particular focus on any hepatitis E-related therapy modifications of cancer-directed therapy. In the majority (60%) of patients who were under active oncological treatment, hepatitis E-related therapy modifications were made, and 25% of deaths were due to progression of the hematologic disease. In patients receiving concomitant oncological treatment, no hepatitis Erelated deaths occurred. In contrast, two patients in the follow-up group died from hepatitis E-associated acute-onchronic liver failure. Chronic hepatitis E was observed in 34% of all cases and 43% received ribavirin therapy; of those, 27% achieved a sustained virological response. CD20-directed therapy was the only independent risk factor for developing chronic hepatitis E. We conclude that CD20-directed treatment at any time point is a risk factor for developing chronic hepatitis E. Nevertheless, since mortality from the progression of hematologic disease was higher than hepatitis E-related mortality, we suggest careful case-by-case decisions on modifications of cancer treatment. Patients in the posttreatment follow-up phase may also suffer from severe courses and hepatitis E chronicity occurs as frequently as in patients undergoing active therapy.
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Affiliation(s)
- Susanne Ghandili
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf,*SG and CL contributed equally as co-first authors
| | - Cecilia Lindhauer
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf,*SG and CL contributed equally as co-first authors
| | - Sven Pischke
- The I. Department of Internal Medicine, Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf
| | - Julian Schulze zur Wiesch
- The I. Department of Internal Medicine, Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf
| | - Philipp H. von Kroge
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf
| | - Susanne Polywka
- The Institute of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf
| | - Carsten Bokemeyer
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
| | - Walter Fiedler
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf
| | - Nicolaus Kröger
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf and
| | - Francis Ayuk
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf and
| | - Raissa Adjallé
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf and ,RA and FM contributed equally as co-last authors
| | - Franziska Modemann
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf,Mildred Scheel Cancer Career Center, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,RA and FM contributed equally as co-last authors
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13
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Cross-Species Transmission of Rabbit Hepatitis E Virus to Pigs and Evaluation of the Protection of a Virus-like Particle Vaccine against Rabbit Hepatitis E Virus Infection in Pigs. Vaccines (Basel) 2022; 10:vaccines10071053. [PMID: 35891218 PMCID: PMC9320745 DOI: 10.3390/vaccines10071053] [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: 05/26/2022] [Revised: 06/21/2022] [Accepted: 06/26/2022] [Indexed: 11/28/2022] Open
Abstract
We investigated the cross-species transmission of rabbit hepatitis E virus (rb HEV) to pigs and evaluated the cross-protection of a swine (sw) HEV-3 virus-like particle (VLP) vaccine against rb HEV infection in pigs. Twelve 4-week-old conventional pigs were divided into negative control (n = 3), positive control (rb HEV-infected, n = 4), and vaccinated (vaccinated and rb HEV-challenged, n = 5) groups. The vaccine was administered at weeks 0 and 2, and viral challenge was conducted at week 4. Serum HEV RNA, anti-HEV antibody, cytokine, and liver enzyme levels were determined. Histopathological lesions were examined in abdominal organs. Viral RNA was detected and increased anti-HEV antibody and alanine aminotransferase (ALT) levels were observed in positive control pigs; liver fibrosis, inflammatory cell infiltration in the lamina propria of the small intestine and shortened small intestine villi were also observed. In vaccinated pigs, anti-HEV antibody and Th1 cytokine level elevations were observed after the second vaccination; viral RNA was not detected, and ALT level elevations were not observed. The results verified the cross-species transmission of rb HEV to pigs and cross-protection of the sw HEV-3 VLP vaccine against rb HEV infection in pigs. This vaccine may be used for cross-protection against HEV infection in other species.
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14
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Ahmed Z, Shetty A, Victor DW, Kodali S. Viral hepatitis: A narrative review of hepatitis A–E. World J Meta-Anal 2022; 10:99-121. [DOI: 10.13105/wjma.v10.i3.99] [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: 02/16/2022] [Revised: 04/27/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis continues to be a major health concern leading to hepatic decompensation ranging from acute hepatitis to cirrhosis and hepatocellular carcinoma. The hepatic and extrahepatic manifestations are not only debilitating but also associated with a significant economic burden. Over the last two decades, the field of virology has made significant breakthroughs leading to a better understanding of the pathophysiology of viral hepatitis, which in turn has led to new therapeutic options. The advent of direct-acting antiviral agents changed the landscape of hepatitis C virus (HCV) therapy, and new drugs are in the pipeline for chronic hepatitis B virus (HBV) treatment. There has also been a significant emphasis on screening and surveillance programs, widespread availability of vaccines, and linkage of care. Despite these efforts, significant gaps persist in care, and there is a pressing need for increased collaboration and teamwork across the globe to achieve a reduction of disease burden and elimination of HBV and HCV.
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Affiliation(s)
- Zunirah Ahmed
- Division of Gastroenterology and Hepatology, Underwood Center for Digestive Disorders, Houston Methodist Hospital, Houston, TX 77030, United States
| | - Akshay Shetty
- Department of Gastroenterology and Hepatology, University of California, Los Angeles, CA 90095, United States
| | - David W Victor
- Department of Hepatology, J C Walter Jr Transplant Center, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Weill Cornell Medical College, Houston, TX 77030, United States
| | - Sudha Kodali
- Department of Hepatology, J C Walter Jr Transplant Center, Sherrie and Alan Conover Center for Liver Disease and Transplantation, Weill Cornell Medical College, Houston, TX 77030, United States
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15
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Gupta J, Irfan M, Ramgir N, Muthe KP, Debnath AK, Ansari S, Gandhi J, Ranjith-Kumar CT, Surjit M. Antiviral Activity of Zinc Oxide Nanoparticles and Tetrapods Against the Hepatitis E and Hepatitis C Viruses. Front Microbiol 2022; 13:881595. [PMID: 35814711 PMCID: PMC9260229 DOI: 10.3389/fmicb.2022.881595] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/17/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatitis E virus (HEV) causes an acute, self-limiting hepatitis. The disease takes a severe form in pregnant women, leading to around 30% mortality. Zinc is an essential micronutrient that plays a crucial role in multiple cellular processes. Our earlier findings demonstrated the antiviral activity of zinc salts against HEV infection. Zinc oxide (ZnO) and its nanostructures have attracted marked interest due to their unique characteristics. Here we synthesized ZnO nanoparticles [ZnO(NP)] and tetrapod-shaped ZnO nanoparticles [ZnO(TP)] and evaluated their antiviral activity. Both ZnO(NP) and ZnO(TP) displayed potent antiviral activity against hepatitis E and hepatitis C viruses, with the latter being more effective. Measurement of cell viability and intracellular reactive oxygen species levels revealed that both ZnO(NP) and ZnO(TP) are noncytotoxic to the cells even at significantly higher doses, compared to a conventional zinc salt (ZnSO4). Our study paves the way for evaluation of the potential therapeutic benefit of ZnO(TP) against HEV and HCV.
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Affiliation(s)
- Jyoti Gupta
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - Minnah Irfan
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Niranjan Ramgir
- Technical Physics Division, Bhabha Atomic Research Center, Mumbai, India
| | - K. P. Muthe
- Technical Physics Division, Bhabha Atomic Research Center, Mumbai, India
| | - A. K. Debnath
- Technical Physics Division, Bhabha Atomic Research Center, Mumbai, India
| | - Shabnam Ansari
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - Jaya Gandhi
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - C. T. Ranjith-Kumar
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Milan Surjit
- Virology Laboratory, Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
- *Correspondence: Milan Surjit
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16
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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: 12] [Impact Index Per Article: 4.0] [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.
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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
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17
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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: 12] [Impact Index Per Article: 4.0] [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.
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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
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18
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Immunosuppressive Drugs. ENCYCLOPEDIA OF INFECTION AND IMMUNITY 2022. [PMCID: PMC8987166 DOI: 10.1016/b978-0-12-818731-9.00068-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Immunosuppressant is a class of medicines that inhibit or decrease the intensity of the immune response in the body. Most of these medications are used to allow the body less likely to resist a transplanted organ. In solid organ transplantation, immunosuppressive agents are needed for the activation of early-stage immunosuppression, the management of late-stage immunosuppression or for the maintenance of organ rejection. The emergence of novel agents and improvements in immunosuppression regimens after transplantation are significant factors leading to this progress. However, these drugs also increase the risk of infection, cancers and specific adverse side effects specific to each agent in patients particularly in pregnant women and fertility issues. Corona virus disease being hot topic of debate is has given positive outcome to immunosuppressive drugs however need more attention in future. Transplant centers across the world utilize multiple immunosuppression protocols; nevertheless, each patient can require an individually formulated immunosuppression regimen to manage the advantages and possible damage of treatment thus eliminating the likelihood of their primary disease recurrence.
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19
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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.
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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
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20
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Kunkel J, Schott E. Rheumatologie und Hepatologie
interdisziplinär. AKTUEL RHEUMATOL 2021. [DOI: 10.1055/a-1626-8710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
ZusammenfassungRheumatologische und hepatologische Erkrankungen haben einige
Überschneidungen, die für Behandler aus beiden Disziplinen
relevant sind. In dieser Übersicht wird ein Schlaglicht auf 2
Erkrankungen geworfen, die sich an der Schnittstelle befinden: Arthropathie bei
Hämochromatose und Systemische Sklerose bei Primär
Biliärer Cholangitis. Daneben werden hepatologische Fragestellungen bei
rheumatologischer Therapie beleuchtet.
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Affiliation(s)
- Jan Kunkel
- Klinik für Innere Medizin II, HELIOS Klinikum Emil von Behring
Berlin-Zehlendorf, Berlin, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II, HELIOS Klinikum Emil von Behring
Berlin-Zehlendorf, Berlin, Deutschland
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21
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Sari G, Mulders CE, Zhu J, van Oord GW, Feng Z, Kreeft‐Voermans JJ, Boonstra A, Vanwolleghem T. Treatment induced clearance of hepatitis E viruses by interferon-lambda in liver-humanized mice. Liver Int 2021; 41:2866-2873. [PMID: 34392598 PMCID: PMC9291846 DOI: 10.1111/liv.15033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/02/2021] [Accepted: 07/28/2021] [Indexed: 01/05/2023]
Abstract
BACKGROUND Hepatitis E viruses (HEV) are an underestimated global cause of enterically transmitted viral hepatitis, which may persist in immunocompromised hosts, posing a risk for progressive liver fibrosis with limited treatment options. We previously established liver-humanized mice as a model for chronic HEV infections, which can be cleared by a 2-week pegylated (peg)-Interferon(IFN)α treatment course. However, severe side effects may hamper the use of IFNα in immunocompromised transplant recipient patients. IFNλ may be a valuable alternative, as its receptor is less ubiquitously expressed. AIMS In this study, we assess the in vitro and in vivo potency of pegIFNλ to induce innate immune signalling in liver cells and to clear a persistent HEV infection in liver-humanized mice. METHODS & RESULTS We found that human liver cells expressed the IFNλ receptor (IFNLR1) and are responsive to pegIFNλ. Treatment with pegIFNλ of liver-humanized mice persistently infected with HEV genotype 3 showed that pegIFNλ was well tolerated. Dose escalation studies showed that although HEV was not cleared at pegIFNλ doses up to 0.12 mg/kg for a maximum of 8 weeks, a dose of 0.3 mg/kg pegIFNλ treatment resulted in complete clearance of HEV antigen and HEV RNA from the liver in 8 out of 9 liver-humanized mice. CONCLUSIONS PegIFNλ is well tolerated in mice and leads to clearance of a persistent HEV infection in liver-humanized mice.
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Affiliation(s)
- Gulce Sari
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Claudia E. Mulders
- Department of ViroscienceErasmus University Medical CenterRotterdamThe Netherlands
| | - Jingting Zhu
- Center for Vaccines and ImmunityThe Research Institute at Nationwide Children’s HospitalColumbusOhioUSA
| | - Gertine W. van Oord
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Zongdi Feng
- Center for Vaccines and ImmunityThe Research Institute at Nationwide Children’s HospitalColumbusOhioUSA,Department of PediatricsThe Ohio State University College of MedicineColumbusOhioUSA
| | | | - Andre Boonstra
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands
| | - Thomas Vanwolleghem
- Department of Gastroenterology and HepatologyErasmus University Medical CenterRotterdamThe Netherlands,Laboratory of Experimental Medicine and PediatricsFaculty of Medicine and Health SciencesUniversity of AntwerpAntwerpBelgium,Department of Gastroenterology and HepatologyAntwerp University HospitalAntwerpBelgium
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Klöhn M, Schrader JA, Brüggemann Y, Todt D, Steinmann E. Beyond the Usual Suspects: Hepatitis E Virus and Its Implications in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:5867. [PMID: 34831021 PMCID: PMC8616277 DOI: 10.3390/cancers13225867] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/16/2021] [Accepted: 11/19/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus infections are the leading cause of viral hepatitis in humans, contributing to an estimated 3.3 million symptomatic cases and almost 44,000 deaths annually. Recently, HEV infections have been found to result in chronic liver infection and cirrhosis in severely immunocompromised patients, suggesting the possibility of HEV-induced hepatocarcinogenesis. While HEV-associated formation of HCC has rarely been reported, the expansion of HEV's clinical spectrum and the increasing evidence of chronic HEV infections raise questions about the connection between HEV and HCC. The present review summarizes current clinical evidence of the relationship between HEV and HCC and discusses mechanisms of virus-induced HCC development with regard to HEV pathogenesis. We further elucidate why the development of HEV-induced hepatocellular carcinoma has so rarely been observed and provide an outlook on possible experimental set-ups to study the relationship between HEV and HCC formation.
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Affiliation(s)
- Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Jil Alexandra Schrader
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Yannick Brüggemann
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
- European Virus Bioinformatics Center (EVBC), 07743 Jena, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
- German Centre for Infection Research (DZIF), External Partner Site, 44801 Bochum, Germany
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23
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Kupke P, Werner JM. Hepatitis E Virus Infection-Immune Responses to an Underestimated Global Threat. Cells 2021; 10:cells10092281. [PMID: 34571931 PMCID: PMC8468229 DOI: 10.3390/cells10092281] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/23/2021] [Accepted: 08/30/2021] [Indexed: 12/19/2022] Open
Abstract
Infection with the hepatitis E virus (HEV) is one of the main ubiquitous causes for developing an acute hepatitis. Moreover, chronification plays a predominant role in immunocompromised patients such as transplant recipients with more frequent severe courses. Unfortunately, besides reduction of immunosuppression and off-label use of ribavirin or pegylated interferon alfa, there is currently no specific anti-viral treatment to prevent disease progression. So far, research on involved immune mechanisms induced by HEV is limited. It is very difficult to collect clinical samples especially from the early phase of infection since this is often asymptomatic. Nevertheless, it is certain that the outcome of HEV-infected patients correlates with the strength of the proceeding immune response. Several lymphoid cells have been identified in contributing either to disease progression or achieving sustained virologic response. In particular, a sufficient immune control by both CD4+ and CD8+ T cells is necessary to prevent chronic viral replication. Especially the mechanisms underlying fulminant courses are poorly understood. However, liver biopsies indicate the involvement of cytotoxic T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat.
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24
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Wu J, Ling B, Guo N, Zhai G, Li M, Guo Y. Immunological Manifestations of Hepatitis E-Associated Acute and Chronic Liver Failure and Its Regulatory Mechanisms. Front Med (Lausanne) 2021; 8:725993. [PMID: 34434948 PMCID: PMC8380956 DOI: 10.3389/fmed.2021.725993] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis E virus (HEV) is a common cause of viral hepatitis in developing countries, most commonly transmitted through the fecal-oral route. The virus is mainly of genotypes (GT) 1 and GT2 genotypes, and patients usually show symptoms of acute hepatitis. Due to the rising trend of HEV serological prevalence in global population, HEV has become an important public health problem in developed countries. Severe hepatitis caused by HEV includes acute and chronic liver failure (ACLF). ACLF frequently occurs in developed countries and is caused by overlapping chronic liver diseases of HEV with genotypes GT3 and GT4. Because the onset of hepatitis E is closely associated with immunity, it is critical to understand the immunological mechanism of hepatitis E associated with acute and chronic liver failure (HEV-ACLF). This review discusses the immunological manifestations and mechanisms of HEV-ACLF, intrahepatic immune microenvironment and treatment, and raises outstanding questions about the immunological mechanism and treatment of the disease.
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Affiliation(s)
- Jian Wu
- Department of Clinical Laboratory, Gusu School, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
| | - Bai Ling
- Department of Pharmacy, The First People's Hospital of Yancheng City, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, China
| | - Naizhou Guo
- Department of Clinical Laboratory, The First People's Hospital of Yancheng City, The Yancheng Clinical College of Xuzhou Medical University, Yancheng, China
| | - Guanghua Zhai
- Department of Clinical Laboratory, Gusu School, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
| | - Meifen Li
- Department of Clinical Laboratory, Gusu School, Suzhou Municipal Hospital, The Affiliated Suzhou Hospital of Nanjing Medical University, Nanjing Medical University, Suzhou, China
| | - Yurong Guo
- Department of Laboratory Medicine, Yancheng Hospital of Traditional Chinese Medicine, Affiliated to Nanjing University of Traditional Chinese Medicine, Yancheng, China
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25
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Oshiro Y, Harada H, Hasegawa K, Akutsu N, Yoshizumi T, Kawagishi N, Nanmoku K, Ichimaru N, Okamura K, Ohira M, Itabashi Y, Fujiyama N, Ide K, Okajima H, Ogawa K, Takagi K, Eguchi H, Shinoda M, Nishida K, Shimazaki J, Shimoda M, Takahashi M, Okamoto H, Suzuki S. Loss of antibodies to hepatitis E virus in organ transplant patients with hepatitis E. Hepatol Res 2021; 51:538-547. [PMID: 33749100 DOI: 10.1111/hepr.13637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 02/10/2021] [Accepted: 03/14/2021] [Indexed: 02/08/2023]
Abstract
AIM Studies regarding changes in antibodies to hepatitis E virus (HEV) after HEV infection in organ transplant patients are limited. This study aimed to clarify HEV infection trends in organ transplant patients who contracted HEV using data from a previous Japanese nationwide survey. METHODS This study was undertaken from 2012 to 2019. Among 4518 liver, heart, and kidney transplant patients, anti-HEV immunoglobulin G (IgG) antibodies were positive in 164; data were collected from 106 of these patients, who consented to participate in the study. In total, 32 liver transplant patients, seven heart transplant patients, and 67 kidney transplant patients from 16 institutions in Japan were examined for IgG, IgM, and IgM antibodies to HEV and the presence of HEV RNA in the serum. The χ2 -test was used to determine the relationship between the early and late postinfection groups in patients with anti-HEV IgG positive-to-negative conversion rates. The Mann-Whitney U-test was used to compare clinical factors. RESULTS Anti-HEV IgG positive-to-negative conversion occurred in 25 (23.6%) of 106 organ transplant patients. Of eight patients with hepatitis E who tested positive for HEV RNA, one (14.0%) had anti-HEV IgG positive-to-negative conversion. Twenty-four (24.5%) of 98 patients negative for HEV RNA had anti-HEV IgG positive-to-negative conversion. CONCLUSIONS This study revealed, for the first time, the changes in HEV antibodies in organ transplant patients. Loss of anti-HEV IgG could often occur unexpectedly in organ transplant patients with previous HEV infection.
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Affiliation(s)
- Yukio Oshiro
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
| | - Hiroshi Harada
- Kidney Transplant Surgery, Sapporo City General Hospital, Sapporo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Artificial Organs and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naotake Akutsu
- Department of Surgery, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Koji Nanmoku
- Department of Renal Surgery and Transplantation, Jichi Medical University Hospital, Shimotsuke, Japan
| | - Naotsugu Ichimaru
- Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kenichi Okamura
- Department of Cardiovascular Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masahiro Ohira
- Department of Gastroenterology and Metabolism, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - Yoshihiro Itabashi
- Department of Nephrology, School of Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Nobuhiro Fujiyama
- Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, Japan
| | - Kentaro Ide
- Department of Gastroenterology and Metabolism, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - Hideaki Okajima
- Department of Paediatric Surgery, Kanazawa Medical University, Kahoku, Japan
| | - Kohei Ogawa
- Department of HPB and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kosei Takagi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masahiro Shinoda
- Department of Surgery, School of Medicine, Keio University, Tokyo, Japan
| | - Kiyotaka Nishida
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
| | - Jiro Shimazaki
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
| | - Mitsugi Shimoda
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Japan
| | - Shuji Suzuki
- Department of Gastroenterological Surgery, Tokyo Medical University Ibaraki Medical Center, Ami, Japan
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26
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Pellerin M, Hirchaud E, Blanchard Y, Pavio N, Doceul V. Characterization of a Cell Culture System of Persistent Hepatitis E Virus Infection in the Human HepaRG Hepatic Cell Line. Viruses 2021; 13:406. [PMID: 33806591 PMCID: PMC8001476 DOI: 10.3390/v13030406] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/19/2021] [Accepted: 02/26/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis E virus (HEV) is considered as an emerging global health problem. In most cases, hepatitis E is a self-limiting disease and the virus is cleared spontaneously without the need of antiviral therapy. However, immunocompromised individuals can develop chronic infection and liver fibrosis that can progress rapidly to cirrhosis and liver failure. The lack of efficient and relevant cell culture system and animal models has limited our understanding of the biology of HEV and the development of effective drugs for chronic cases. In the present study, we developed a model of persistent HEV infection in human hepatocytes in which HEV replicates efficiently. This HEV cell culture system is based on differentiated HepaRG cells infected with an isolate of HEV-3 derived from a patient suffering from acute hepatitis E. Efficient replication was maintained for several weeks to several months as well as after seven successive passages on HepaRG naïve cells. Moreover, after six passages onto HepaRG, we found that the virus was still infectious after oral inoculation into pigs. We also showed that ribavirin had an inhibitory effect on HEV replication in HepaRG. In conclusion, this system represents a relevant and efficient in vitro model of HEV replication that could be useful to study HEV biology and identify effective antiviral drugs against chronic HEV infection.
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Affiliation(s)
- Marie Pellerin
- UMR 1161 Virologie, INRAE, ANSES, Ecole Nationale Vétérinaire d’Alfort, Université Paris-Est, 94700 Maisons-Alfort, France; (M.P.); (N.P.)
| | - Edouard Hirchaud
- Agence Nationale de Sécurité Sanitaire, De L’environnement et du Travail (ANSES), Laboratory of Ploufragan-Plouzané-Niort, Viral Genetic and Biosafety (GVB) Unit, 22440 Ploufragan, France; (E.H.); (Y.B.)
| | - Yannick Blanchard
- Agence Nationale de Sécurité Sanitaire, De L’environnement et du Travail (ANSES), Laboratory of Ploufragan-Plouzané-Niort, Viral Genetic and Biosafety (GVB) Unit, 22440 Ploufragan, France; (E.H.); (Y.B.)
| | - Nicole Pavio
- UMR 1161 Virologie, INRAE, ANSES, Ecole Nationale Vétérinaire d’Alfort, Université Paris-Est, 94700 Maisons-Alfort, France; (M.P.); (N.P.)
| | - Virginie Doceul
- UMR 1161 Virologie, INRAE, ANSES, Ecole Nationale Vétérinaire d’Alfort, Université Paris-Est, 94700 Maisons-Alfort, France; (M.P.); (N.P.)
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27
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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.
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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
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28
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Hepatitis E virus infection in liver transplant recipients: a descriptive literature review. Eur J Gastroenterol Hepatol 2020; 32:916-922. [PMID: 32091436 DOI: 10.1097/meg.0000000000001682] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus infection has been recognized as a rising hepatotropic viral infection in the developing countries but overlooked in the developed countries, due to its lower prevalence. However, hepatitis E virus prevalence is on rise in the liver transplant recipients due to immunosuppression, which needs prompt recognition by healthcare practitioners. Hepatitis E virus infection is commonly believed to be transmitted via an animal host; but in the post-liver transplant patients, it can also be acquired via blood and blood products transfusion and autochthonous route. Previous studies have shown the significance of hepatitis E virus infection in post-liver transplant, as the patients at a high risk of progressing to chronic hepatitis and cirrhosis. Pediatric patients are at higher risk of hepatitis E virus infection post-liver transplant. Specific hepatitis E virus genotypes have the potential for greater severity. The clinical manifestation of hepatitis E virus can also present as extrahepatic features which need high level of suspicion for early recognition and treatment. Treatment options of hepatitis E virus range from immunosuppressive drug minimization, ribavirin therapy to novel direct-acting antiviral regimens. Herein, we aim to explore epidemiology, prevalence, risk factor, diagnosis, and management of hepatitis E virus infection giving special attention to liver transplant recipients.
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29
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Zhang W, Ami Y, Suzaki Y, Doan YH, Jirintai S, Takahashi M, Okamoto H, Takeda N, Muramatsu M, Li TC. Persistent infection with a rabbit hepatitis E virus created by a reverse genetics system. Transbound Emerg Dis 2020; 68:615-625. [PMID: 32649803 DOI: 10.1111/tbed.13723] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/24/2020] [Accepted: 07/06/2020] [Indexed: 12/12/2022]
Abstract
Rabbit hepatitis E virus (HEV) is a novel zoonotic infectious agent. Although a cell culture system to grow the virus has been established, there is currently no reverse genetics system for generating the virus. In this study, capped genomic rabbit HEV RNAs generated by in vitro transcription were transfected into PLC/PRF/5 cells, and the recovered viruses were subsequently passaged in the cells. The cell culture supernatant was capable of infecting rabbits negative for anti-HEV antibody by intravenous and oral inoculation, indicating that rabbit HEV generated by the reverse genetics system is infectious. Genome-wide analyses indicated that no nucleotide sequence change occurred in the virus genomes that were recovered from the cell culture supernatant after transfection and passaged one time or in the virus genomes recovered from faecal specimens of the infected rabbits. Ribavirin, a broad-spectrum anti-viral inhibitor, efficiently abrogated virus replication ex vivo and transiently suppressed the virus growth in the virus-infected rabbits, suggesting that this reagent is a candidate for therapeutic treatment. In addition, transmission of rabbit HEV to rabbits caused persistent infection, suggesting that the virus-infected rabbit could be an animal model for virus-induced hepatitis. The infectious rabbit HEV produced by a reverse genetics system would be useful to elucidate the mechanisms of HEV replication and the pathogenesis of viral hepatitis.
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Affiliation(s)
- Wenjing Zhang
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yasushi Ami
- Division of Experimental Animals Research, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yuriko Suzaki
- Division of Experimental Animals Research, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yen Hai Doan
- Department of Environmental Parasitology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Suljid Jirintai
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke-Shi, Japan
| | - Naokazu Takeda
- Research Institute for Microbial Diseases, Osaka University, Suita, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
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30
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Kar P, Karna R. A Review of the Diagnosis and Management of Hepatitis E. CURRENT TREATMENT OPTIONS IN INFECTIOUS DISEASES 2020; 12:310-320. [PMID: 32837339 PMCID: PMC7366488 DOI: 10.1007/s40506-020-00235-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Purpose of review We aim to provide the readers an up-to-date knowledge of the structure, epidemiology, and transmission followed by a detailed discussion on testing, diagnostics and management of hepatitis E virus infection. We have also included a comprehensive review of hepatitis E in pregnancy. Recent findings European Association for the Study of the Liver established clinical practice guidelines for testing and treatment of suspected hepatitis E virus infections in 2018. Evidence suggests chronic hepatitis E may follow a course similar to hepatitis B/C with progression to cirrhosis and possibly hepatocellular carcinoma in immunocompromised patients. Summary Hepatitis E virus is the most common cause of acute viral hepatitis worldwide. A combination of serology and nucleic acid amplification testing is the recommended strategy for suspected patients. Ribavirin therapy for a period of 3 months is the drug of choice for severe acute hepatitis, acute-on chronic liver failure, and chronic infections from hepatitis E virus in immunocompromised patients who are unresponsive to decreased immunosuppression. PEGylated interferon α can be used for ribavirin-resistant liver transplant patients with chronic hepatitis E. Further research in therapeutic options is essential considering the stormy course of hepatitis E infection during pregnancy and teratogenicity of all available options.
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Affiliation(s)
- P. Kar
- Department of Gastroenterology and Hepatology, Max Super Specialty Hospital,Ghaziabad, Delhi, New Delhi 110017 India
| | - R. Karna
- Maulana Azad Medical College & Lok Nayak Hospital, Bahadurshah Zafar Road, New Delhi, India
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31
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Synthetic Peptides Containing Three Neutralizing Epitopes of Genotype 4 Swine Hepatitis E Virus ORF2 induced Protection against Swine HEV Infection in Rabbit. Vaccines (Basel) 2020; 8:vaccines8020178. [PMID: 32294910 PMCID: PMC7348971 DOI: 10.3390/vaccines8020178] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/05/2020] [Accepted: 04/09/2020] [Indexed: 12/12/2022] Open
Abstract
Genotype 4 hepatitis E virus (HEV) is a zoonotic pathogen transmitted to humans through food and water. Previously, three genotype 4 swine HEV ORF2 peptides (407EPTV410, 410VKLYTS415, and 458PSRPF462) were identified as epitopes of virus-neutralizing monoclonal antibodies that partially blocked rabbit infection with swine HEV. Here, individual and tandem fused peptides were synthesized, conjugated to keyhole limpet hemocyanin (KLH), then evaluated for immunoprotection of rabbits against swine HEV infection. Forty New Zealand White rabbits were randomly assigned to eight groups; groups 1 thru 5 received three immunizations with EPTV-KLH, VKLYTS-KLH, PSRPF-KLH, EPTVKLYTS-KLH, or EPTVKLYTSPSRPF-KLH, respectively; group 6 received truncated swine HEV ORF2 protein (sp239), and group 7 received phosphate-buffered saline. After an intravenous swine HEV challenge, all group 7 rabbits exhibited viremia and fecal virus shedding by 2–4 weeks post challenge (wpc), seroconversion by 4–9 wpc, elevated alanine aminotransferase (ALT) at 2 wpc, and severe liver lymphocytic venous periphlebitis. Only 1–2 rabbits/group in groups 1–4 exhibited delayed viremia, fecal shedding, seroconversion, increased ALT levels, and slight liver lymphocytic venous periphlebitis; groups 5–6 showed no pathogenic effects. Collectively, these results demonstrate that immunization with a polypeptide containing three genotype 4 HEV ORF2 neutralizing epitopes completely protected rabbits against swine HEV infection.
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32
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Swartling L, Nordén R, Samuelsson E, Boriskina K, Valentini D, Westin J, Norder H, Sparrelid E, Ljungman P. Hepatitis E virus is an infrequent but potentially serious infection in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2020; 55:1255-1263. [PMID: 32071417 DOI: 10.1038/s41409-020-0823-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/27/2020] [Accepted: 01/30/2020] [Indexed: 01/05/2023]
Abstract
Hepatitis E virus (HEV) can cause chronic infection and liver cirrhosis in immunocompromised individuals. The frequency and clinical importance of HEV was studied retrospectively in a cohort of 236 Swedish allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In blood samples collected at 6 months after HSCT, HEV RNA was identified in 8/236 (3.4%) patients, and 11/236 (4.7%) patients had detectable anti-HEV IgG and/or IgM, eight of whom were HEV RNA negative. Two of the patients with positive HEV RNA died with ongoing signs of hepatitis: one of acute liver and multiple organ failure, the other of unrelated causes. The remaining six patients with HEV RNA had cleared the infection at 7-24 (median 8.5) months after HSCT. HEV infection was associated with elevated alanine aminotransferase at 6 months after HSCT (OR 15, 1.3-174, p = 0.03). Active graft-versus-host disease of the liver at 6 months after HSCT was present in 3/8 (38%) patients with HEV RNA, but was not significantly associated with HEV infection. In conclusion, HEV infection is an important differential diagnosis in patients with elevated liver enzymes after HSCT. Although spontaneous clearance was common, the clinical course may be severe.
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Affiliation(s)
- Lisa Swartling
- Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden. .,Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Rickard Nordén
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.,Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ebba Samuelsson
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.,Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Ksenia Boriskina
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Davide Valentini
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Johan Westin
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Infectious Diseases, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden
| | - Heléne Norder
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden.,Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Elda Sparrelid
- Division of Infectious Diseases, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Per Ljungman
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.,Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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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.
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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
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Rituximab-Containing Treatment Regimens May Imply a Long-Term Risk for Difficult-To-Treat Chronic Hepatitis E. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17010341. [PMID: 31947836 PMCID: PMC6982013 DOI: 10.3390/ijerph17010341] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/23/2019] [Accepted: 12/31/2019] [Indexed: 02/05/2023]
Abstract
Hepatitis E virus (HEV) infection is an emerging disease in industrialized countries which is usually characterized by a self-limited course. However, there is an increased risk of HEV persistence in immunocompromised risk populations, comprising patients following solid organ transplantation or hematological malignancies. Recently, chronic HEV infection following rituximab-containing treatment regimens has been described. Here we report five patients with chronic hepatitis E after prior rituximab therapy for various indications. We determined the immunological characteristics of these patients and analyzed the development of ribavirin (RBV) treatment failure-associated mutations in the HEV genome. One patient became chronically HEV-infected 110 months after administration of rituximab (RTX). Immunological characterization revealed that all patients exhibited significant hypogammaglobulinemia and CD4+ T cell lymphopenia. One patient permanently cleared HEV following weight-based ribavirin treatment while three patients failed to reach a sustained virological response. In depth mutational analysis confirmed the presence of specific mutations associated with RBV treatment failure in these patients. Our cases indicate that rituximab-containing treatment regimens might imply a relevant risk for persistent HEV infection even years after the last rituximab application. Moreover, we provide further evidence to prior observations suggesting that chronically HEV infected patients following RTX-containing treatment regimens might be difficult to treat.
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Han SH, Park BJ, Ahn HS, Kim YH, Go HJ, Lee JB, Park SY, Song CS, Lee SW, Choi YK, Choi IS. Cross-Species Transmission of Swine Hepatitis E Virus Genotype 3 to Rabbits. Viruses 2020; 12:v12010053. [PMID: 31906555 PMCID: PMC7019366 DOI: 10.3390/v12010053] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/30/2019] [Accepted: 12/31/2019] [Indexed: 12/22/2022] Open
Abstract
Hepatitis E virus (HEV) is a quasi-enveloped, positive-sense single stranded RNA virus. HEV continually expands the host ranges across animal species. In this study, the possibility of cross-species infection with swine HEV-3 was investigated using rabbits. A total of fourteen 8-week old, specific pathogen-free rabbits were divided into three experimental groups. Four rabbits were used as negative controls, four rabbits were infected with rabbit HEV as positive controls, and six rabbits were inoculated with swine HEV-3. HEV RNA were detected from serum and fecal samples after viral challenge. The levels of anti-HEV antibodies, pro-inflammatory cytokines (IL-1, IL-6, TNF-α and IFN-α), and liver enzymes (alanine and aspartate aminotransferases) were determined in serum samples. Histopathological lesions were examined in liver tissues. Viral RNA and anti-HEV antibodies were identified in rabbits inoculated with swine HEV-3 demonstrating positive infectivity of the virus. However, pro-inflammatory cytokine and liver enzyme levels in serum were not significantly elevated, and only mild inflammatory lesions were detected in the liver tissues of rabbits infected with swine HEV-3. These results suggest that swine HEV-3 can engage in cross-species transmission to rabbits, but causes only mild inflammation of the liver.
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Affiliation(s)
- Sang-Hoon Han
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Byung-Joo Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Hee-Seop Ahn
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Yong-Hyun Kim
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Hyeon-Jeong Go
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Joong-Bok Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Seung-Yong Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Chang-Seon Song
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Sang-Won Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
| | - Yang-Kyu Choi
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea;
| | - In-Soo Choi
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Korea; (S.-H.H.); (B.-J.P.); (H.-S.A.); (Y.-H.K.); (H.-J.G.); (J.-B.L.); (S.-Y.P.); (C.-S.S.); (S.-W.L.)
- Correspondence: ; Tel.: +82-2-2049-6055
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Hepatitis E virus infections in Europe. J Clin Virol 2019; 120:20-26. [PMID: 31536936 DOI: 10.1016/j.jcv.2019.09.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 09/06/2019] [Indexed: 12/11/2022]
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Park BJ, Ahn HS, Han SH, Go HJ, Lee JB, Park SY, Song CS, Lee SW, Paik HJ, Choi YK, Choi IS. Evaluation of the protective effects of a nanogel-based vaccine against rabbit hepatitis E virus. Vaccine 2019; 37:5972-5978. [PMID: 31455586 DOI: 10.1016/j.vaccine.2019.08.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/03/2019] [Accepted: 08/17/2019] [Indexed: 12/13/2022]
Abstract
Infection with hepatitis E virus (HEV) has raised serious public health concerns worldwide. In this study, a nanogel-based vaccine encapsulating the capsid protein of rabbit HEV was developed and its protective efficacy was compared with a subunit vaccine. A total of 23 rabbits were divided into 5 groups: (1) negative control (n = 4), (2) positive control (n = 4), (3) nanogel control (n = 5), (4) nanogel vaccine (n = 5), and (5) subunit vaccine (n = 5). Rabbits were vaccinated two times, at weeks 0 and 1, with nanogel and subunit vaccines, respectively, and challenged with rabbit HEV at week 4. By week 11, rabbits vaccinated with the nanogel vaccine produced higher antibodies than those vaccinated with the subunit vaccine. Fecal viral shedding and viremia were identified in rabbits of the positive and nanogel control groups at weeks 6-10. However, there was no viral shedding and viremia in rabbits immunized with both the nanogel and subunit vaccines. Alanine aminotransferase and aspartate aminotransferase levels were not elevated in any rabbit. However, histopathological examination revealed much less hepatic inflammation in rabbits of the nanogel vaccine group compared to the positive and nanogel control groups. Significant increases in IL-12 and IFN-γlevels were identified from rabbits immunized with the nanogel vaccine. Collectively, these results indicate that the newly developed nanogel vaccine induced sufficient immunity leading to complete protection from HEV infection in rabbits. Application of this vaccine should be considered as a preventive measure against HEV infection in other animal species and humans.
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Affiliation(s)
- Byung-Joo Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hee-Seop Ahn
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Sang-Hoon Han
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hyeon-Jeong Go
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Joong-Bok Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Seung-Yong Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Chang-Seon Song
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Sang-Won Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hyun-Jong Paik
- Department of Polymer Science and Engineering, Pusan National University, San 30 Jangjeon 2-dong Geumjeong-gu, Busan 609-735, Republic of Korea
| | - Yang-Kyu Choi
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - In-Soo Choi
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
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Li TC, Wakita T. Small Animal Models of Hepatitis E Virus Infection. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a032581. [PMID: 29735581 DOI: 10.1101/cshperspect.a032581] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Novel hepeviruses have been recovered from many different animal species in recent years, increasing the diversity known to exist among the Hepeviridae, which now include two genera, Piscihepevirus and Orthohepevirus Multiple viral genotypes in the Orthohepevirus A species are able to replicate and cause acute hepatitis E in humans, and thus represent an important public health problem in industrialized as well as developing countries. Although hepatitis E virus (HEV) infections typically result in acute and self-limited hepatitis, immunocompromised and transplant patients are vulnerable to prolonged infections and to chronic hepatitis. Cell culture systems have been established for several HEV strains and offer new opportunities for the study of HEV biology. Similarly, a variety of new small animal models have been developed, using either nonhuman hepeviruses in their cognate hosts as surrogates for human HEV, or human HEV infection of immunodeficient mice with chimeric livers engrafted with human hepatocytes. These new models provide several advantages over previous nonhuman primate models of hepatitis E infection and will facilitate studies of pathogenicity, cross-species infection, mechanisms of virus replication, and vaccine and antiviral agent development. This article reviews the current understanding of small animal models for HEV.
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Affiliation(s)
- Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
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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.
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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
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40
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Aggarwal R, Goel A. Natural History, Clinical Manifestations, and Pathogenesis of Hepatitis E Virus Genotype 1 and 2 Infections. Cold Spring Harb Perspect Med 2019; 9:a032136. [PMID: 29735580 PMCID: PMC6601454 DOI: 10.1101/cshperspect.a032136] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Infection with genotype 1 or 2 hepatitis E virus (HEV) results primarily from human-to-human transmission through the fecal-oral route in low-resource countries. It presents primarily as "acute viral hepatitis" syndrome, usually a self-limiting illness. A few cases progress to acute liver failure, a serious illness with high fatality. Clinical disease is infrequent among children. Infection during pregnancy is associated with a higher risk of symptomatic disease, severe liver injury, and mortality. Severe disease is also encountered in persons with preexisting chronic liver disease. Some cases have associated extrahepatic features, particularly acute pancreatitis and neurological manifestations. Chronic infection appears to be extremely infrequent with these HEV genotypes. The exact pathogenesis of liver injury remains unknown, although the host immune response appears to be important for viral clearance as well as for induction of liver injury. Hormonal and immune factors appear to be responsible for the severe disease during pregnancy.
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Affiliation(s)
- Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Amit Goel
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Lhomme S, Legrand-Abravanel F, Kamar N, Izopet J. Screening, diagnosis and risks associated with Hepatitis E virus infection. Expert Rev Anti Infect Ther 2019; 17:403-418. [DOI: 10.1080/14787210.2019.1613889] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Sébastien Lhomme
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Florence Legrand-Abravanel
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Nassim Kamar
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
- Department of Nephrology and Organs Transplantation, CHU Rangueil, Toulouse, France
| | - Jacques Izopet
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
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Abstract
Donor-derived infections are defined as any infection present in the donor that is transmitted to 1 or more recipients. Donor-derived infections can be categorized into 2 groups: "expected" and "unexpected" infections. Expected transmissions occur when the donor is known to have an infection, such as positive serology for cytomegalovirus, Epstein Barr virus, or hepatitis B core antibody, at the time of donation. Unexpected transmissions occur when a donor has no known infection before donation, but 1 or more transplant recipients develop an infection derived from the common donor. Unexpected infections are estimated to occur in far less than 1% of solid organ transplant recipients. We will review the epidemiology, risk factors, and approaches to prevention and management of donor-derived viral infectious disease transmission in liver transplantation.
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43
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Performance characteristics of the VIDAS® ANTI-HEV IgM and IgG assays. J Clin Virol 2019; 112:10-14. [DOI: 10.1016/j.jcv.2019.01.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 01/08/2019] [Accepted: 01/10/2019] [Indexed: 12/27/2022]
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Abravanel F, Lacipière A, Lhomme S, Dubois M, Minier L, Peron JM, Alric L, Kamar N, Izopet J. Performance of a commercial assay for detecting and quantifying HEV RNA in faeces. J Clin Virol 2018; 109:1-5. [PMID: 30336371 PMCID: PMC7106495 DOI: 10.1016/j.jcv.2018.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 10/05/2018] [Accepted: 10/09/2018] [Indexed: 01/11/2023]
Abstract
No commercial HEV RNA assay is validated for use in faecal samples. Monitoring HEV faecal excretion is recommended for managing chronic HEV infection in solid-organ transplant recipients. We evaluated the Altona assay by testing patients on ribavirin therapy. Background Detecting hepatitis E virus (HEV) RNA in faeces is useful for diagnosing and monitoring HEV infections, particularly in immunocompromised patients requiring ribavirin therapy. Objectives This study evaluated the performance of the Altona RealStar HEV RNA kit for detecting and quantifying HEV in faeces. Study design RNA was extracted from 94 stool samples by two methods: QIAamp Viral RNA Mini kit and MagNA Pure 96 automate. The Altona results were compared to a reference laboratory-developed accredited ISO15189 RT-PCR assay. Results The Altona and reference assays detect HEV RNA in 77/93 (82.8%) and 83/93 (89.2%) of the QIAamp extracted samples, respectively, after exclusion of invalid result; they detected HEV RNA in 67/92 (72.8%) and 66/92 (71.7%) of the MagNA Pure extracted samples, respectively, which emphasizes the importance of the RNA extraction method. The HEV RNA concentrations obtained with Altona RT-PCR and the reference RT-PCR were well correlated whatever the extraction method, and Bland Altman analyses indicated that the Altona values were higher than the reference assay values. The Altona values for QIAamp-extracted and MagNA Pure-extracted HEV RNA were very similar. Conclusions The Altona RealStar assay is suitable for quantifying HEV RNA in the faeces and monitoring HEV RNA shedding during ribavirin therapy. Extraction is critical for detecting faecal HEV with high performance RT-PCR assays.
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Affiliation(s)
- Florence Abravanel
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France; CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, F-31300, France.
| | - Audrey Lacipière
- CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, F-31300, France
| | - Sébastien Lhomme
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France; CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, F-31300, France
| | - Martine Dubois
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France; CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, F-31300, France
| | - Luce Minier
- CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, F-31300, France
| | - Jean-Marie Peron
- CHU Toulouse, Hôpital Purpan, Département de Gastroentérologie, F-31300, France
| | - Laurent Alric
- CHU Toulouse, Hôpital Purpan, Service de médecine interne, F-31300, France
| | - Nassim Kamar
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France; CHU Toulouse, Hôpital Rangueil, Département de Néphrologie, Dialyse et Transplantation multi-organe, F-31300 France
| | - Jacques Izopet
- INSERM, U1043, Centre de Physiopathologie de Toulouse Purpan, Toulouse, F-31300, France; CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, F-31300, France
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Ankcorn M, Moreira F, Ijaz S, Symes A, Buckland MS, Workman S, Warburton F, Tedder RS, Lowe DM. Absence of Persistent Hepatitis E Virus Infection in Antibody-Deficient Patients Is Associated With Transfer of Antigen-Neutralizing Antibodies From Immunoglobulin Products. J Infect Dis 2018; 219:245-253. [DOI: 10.1093/infdis/jiy504] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/16/2018] [Indexed: 02/07/2023] Open
Affiliation(s)
- Mike Ankcorn
- Blood Borne Virus Unit, Virus Reference Department, Public Health England
- Transfusion Microbiology, National Health Service Blood and Transplant
| | - Fernando Moreira
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
| | - Samreen Ijaz
- Blood Borne Virus Unit, Virus Reference Department, Public Health England
| | - Andrew Symes
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
| | - Matthew S Buckland
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
- Institute of Immunity and Transplantation, University College London, Royal Free Campus
| | - Sarita Workman
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
| | - Fiona Warburton
- Statistics, Modelling, and Economics Department, Public Health England
| | - Richard S Tedder
- Blood Borne Virus Unit, Virus Reference Department, Public Health England
- Transfusion Microbiology, National Health Service Blood and Transplant
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - David M Lowe
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
- Institute of Immunity and Transplantation, University College London, Royal Free Campus
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Hepatitis E during Tocilizumab Therapy in a Patient with Rheumatoid Arthritis: Case Report and Literature Review. Case Rep Rheumatol 2018; 2018:6873276. [PMID: 30147981 PMCID: PMC6083553 DOI: 10.1155/2018/6873276] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 06/27/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatitis E is an acute self-limiting disease caused by hepatitis E virus (HEV). Recent reports show that HEV can induce chronic hepatitis or be reactivated in immunocompromised hosts. We report a 63-year-old woman with rheumatoid arthritis (RA) who developed hepatitis E during treatment with tocilizumab. Analysis of serially stocked serum samples confirmed that hepatitis was caused by primary infection with HEV and not by viral reactivation. Her liver function improved after discontinuing tocilizumab and remained within the normal range without reactivation of HEV for >5 years after restarting tocilizumab. We also reviewed the published cases of hepatitis E that developed during RA treatment.
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An Update on the Clinicopathologic Features and Pathologic Diagnosis of Hepatitis E in Liver Specimens. Adv Anat Pathol 2018; 25:273-281. [PMID: 29697415 DOI: 10.1097/pap.0000000000000195] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Infection with the hepatitis E virus (HEV) is globally seen a leading cause of hepatitis. Now increasingly recognized also in industrialized countries, hepatitis E constitutes a significant health problem worldwide. The patient's immune status determines the clinical course and histopathology of hepatitis E. In immunocompetent patients, hepatitis E usually follows an asymptomatic or subclinical course, but may also present with acute hepatitis. In contrast, immunocompromised patients may develop chronic hepatitis, and patients with preexisting liver diseases are at risk for liver decompensation with potentially fatal outcome. Whereas pathologists only occasionally encounter liver biopsies from immunocompetent individuals with hepatitis E, they are more likely exposed to biopsies from patients with preexisting liver disease or immunocompromised individuals. Histopathologic hallmarks of hepatitis E in immunocompetent patients comprise lobular disarray, lobular, and portal inflammation, as well as hepatocyte necrosis of varying extend and regeneration. Thus, it is similar to acute non-E viral hepatitis, yet further differential diagnoses include autoimmune hepatitis and drug-induced liver injury. Histopathologic findings of hepatitis E in preexisting liver disease are determined by the underlying pathology, but may be more severe. Histopathologic presentation of hepatitis E in immunocompromised patients is highly variable, ranging from minimal active hepatitis to chronic hepatitis with severe activity and progressive fibrosis. Taken together, the variability of the histologic features depending on the clinical context and the overlap with other liver diseases make the histopathologic diagnosis of hepatitis E challenging. Immunohistochemistry for HEV open reading frame 2 protein and molecular testing for HEV RNA are useful tissue-based ancillary tools.
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Characterization of Three Novel Linear Neutralizing B-Cell Epitopes in the Capsid Protein of Swine Hepatitis E Virus. J Virol 2018; 92:JVI.00251-18. [PMID: 29669835 DOI: 10.1128/jvi.00251-18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 04/10/2018] [Indexed: 01/13/2023] Open
Abstract
Hepatitis E virus (HEV) causes liver disease in humans and is thought to be a zoonotic infection, with domestic animals, including swine and rabbits, being a reservoir. One of the proteins encoded by the virus is the capsid protein. This is likely the major immune-dominant protein and a target for vaccination. Four monoclonal antibodies (MAbs), three novel, 1E4, 2C7, and 2G9, and one previously characterized, 1B5, were evaluated for binding to the capsid protein from genotype 4 swine HEV. The results indicated that 625DFCP628, 458PSRPF462, and 407EPTV410 peptides on the capsid protein comprised minimal amino acid sequence motifs recognized by 1E4, 2C7, and 2G9, respectively. The data suggested that 2C7 and 2G9 epitopes were partially exposed on the surface of the capsid protein. Truncated genotype 4 swine HEV capsid protein (sp239, amino acids 368 to 606) can exist in multimeric forms. Preincubation of swine HEV with 2C7, 2G9, or 1B5 before addition to HepG2 cells partially blocked sp239 cell binding and inhibited swine HEV infection. The study indicated that 2C7, 2G9, and 1B5 partially blocked swine HEV infection of rabbits better than 1E4 or normal mouse IgG. The cross-reactivity of antibodies suggested that capsid epitopes recognized by 2C7 and 2G9 are common to HEV strains infecting most host species. Collectively, MAbs 2C7, 2G9, and 1B5 were shown to recognize three novel linear neutralizing B-cell epitopes of genotype 4 HEV capsid protein. These results enhance understanding of HEV capsid protein structure to guide vaccine and antiviral design.IMPORTANCE Genotype 3 and 4 HEVs are zoonotic viruses. Here, genotype 4 HEV was studied due to its prevalence in human populations and pig herds in China. To improve HEV disease diagnosis and prevention, a better understanding of the antigenic structure and neutralizing epitopes of HEV capsid protein are needed. In this study, the locations of three novel linear B-cell recognition epitopes within genotype 4 swine HEV capsid protein were characterized. Moreover, the neutralizing abilities of three MAbs specific for this protein, 2C7, 2G9, and 1B5, were studied in vitro and in vivo Collectively, these findings reveal structural details of genotype 4 HEV capsid protein and should facilitate development of applications for the design of vaccines and antiviral drugs for broader prevention, detection, and treatment of HEV infection of diverse human and animal hosts.
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De Winter BCM, Hesselink DA, Kamar N. Dosing ribavirin in hepatitis E-infected solid organ transplant recipients. Pharmacol Res 2018; 130:308-315. [PMID: 29499270 DOI: 10.1016/j.phrs.2018.02.030] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 02/06/2018] [Accepted: 02/26/2018] [Indexed: 12/22/2022]
Abstract
Hepatitis E virus (HEV) is the most common cause of viral hepatitis worldwide. Genotypes 1 and 2 (GT1 and GT2) are mainly present in developing countries, while GT3 and GT4 are prevalent in developed and high-income countries. In the majority of cases, HEV causes a self-limiting hepatitis. GT3 and GT4 can be responsible for a chronic hepatitis that can lead to cirrhosis in immunocompromized patients, i.e. solid-organ- and stem-cell-transplant-patients, human immunodeficiency virus-infected patients, and patients receiving chemotherapy or immunotherapy. HEV has also been associated with extra-hepatic manifestations such as neurologic disorders (Guillain-Barré Syndrome and neuralgic amyotrophy) and kidney disease. In patients with chronic hepatitis, reduction of immunosuppression, when possible, is the first therapeutic option. In the remaining patients, ribavirin therapy has been shown to very efficient for treating HEV infection leading to a sustained virological response in nearly 80-85% of patients. However, the mechanism of action of ribavirin in this setting is still unknown, as is the impact of HEV RNA polymerase mutations. There are unmet needs with regard to the treatment of chronic HEV with ribavirin. These include the optimal dosing and duration of treatment, and the potential beneficial effects of therapeutic drug monitoring on the virological response and the incidence of side effects. In the present review, we will provide an overview of HEV epidemiology, its mode of transmission and clinical manifestations, as well as its treatment by ribavirin with a focus on the drug's pharmacokinetics and dosing.
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Affiliation(s)
- Brenda C M De Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Rotterdam Transplant Group, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Internal Medicine, Division of Nephrology and Organ Transplantation, CHU Rangueil, INSERM U1043, IFR-BMT, Université Paul Sabatier, Toulouse, France.
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50
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O'Gorman J, Burke Á, O'Flaherty N. Hepatitis E virus - key points for the clinical haematologist. Br J Haematol 2018; 181:579-589. [PMID: 29468650 DOI: 10.1111/bjh.15133] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 01/06/2018] [Indexed: 12/13/2022]
Abstract
In recent years there has been a paradigm shift in our understanding of the epidemiology and clinical features of hepatitis E virus (HEV) infection. Once classically described as an acute hepatitis associated with waterborne outbreaks in areas of poor sanitation, HEV is now recognised to be endemic in Europe and is probably zoonotic in origin. Evidence for transfusion-transmitted HEV has prompted the introduction of blood donor screening in a number of countries, but the risk to the haematology patient from food sources remains. The aim of this review therefore, is to equip the clinical haematologist with the knowledge required to diagnose HEV infection and to aid decision-making in patient management. The article also provides information on addressing patient concerns about their risk of acquiring hepatitis E and how this risk can be mitigated.
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Affiliation(s)
- Joanne O'Gorman
- Consultant Clinical Microbiologist, National Virus Reference Laboratory, University College Dublin, Dublin, Ireland
| | - Áine Burke
- Consultant Haematologist, Sligo University Hospital, Sligo, Ireland
| | - Niamh O'Flaherty
- Consultant Clinical Microbiologist, National Virus Reference Laboratory, University College Dublin, Dublin, Ireland.,Consultant Clinical Microbiologist, Irish Blood Transfusion Service, Dublin 8, Ireland
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