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Li M, Wang Y, Wan W, Song Z, Wang P, Zhou H. Hepatitis E virus infection during pregnancy: Advances in animal models. Res Vet Sci 2024; 180:105429. [PMID: 39378754 DOI: 10.1016/j.rvsc.2024.105429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 09/30/2024] [Accepted: 10/01/2024] [Indexed: 10/10/2024]
Abstract
Hepatitis E virus (HEV) is one of the major pathogens causing acute viral hepatitis worldwide, which usually causes acute self-limited diseases in general individuals. However, it can lead to high mortality and adverse pregnancy outcomes in pregnant women. Due to the lack of effective and stable cell culture models for HEV, the establishment of suitable animal models for HEV infection during pregnancy is necessary. An electronic search of the relevant database was conducted to identify eligible articles. Main animal models for the study of HEV infection during pregnancy include rabbits, swine, nonhuman primates and Mongolian gerbils. These animal models have been used to study the prevention, treatment and possible mechanisms of HEV infection during pregnancy. Studies using these animal models have investigated the potential pathogenesis of HEV infection during pregnancy. It has been found that immune mechanism (changes in the CD4/CD8 ratio and cytokines), hormonal changes (increase in pregnancy-related hormones) and viral factors (different genotypes and genome structures) can lead to HEV-related adverse pregnancy outcomes in animal models. In this review, we aimed to comprehensively present the characteristics of different animal models and the pathogenesis of HEV-related adverse pregnancy outcomes.
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Affiliation(s)
- Manyu Li
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, Beijing 100050, China; NMPA Key Laboratory for Quality Research and Evaluation of Medical Devices, Beijing, China; NMPA Key Laboratory for Quality Research and Evaluation of In Vitro Diagnostics, Beijing, China.
| | - Yan Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital/First Clinical College of Shanxi Medical University, No. 85, Jiefangnan Road, Yingze District, Taiyuan 030001, Shanxi, China
| | - Wenjun Wan
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, Beijing 100050, China; NMPA Key Laboratory for Quality Research and Evaluation of Medical Devices, Beijing, China; NMPA Key Laboratory for Quality Research and Evaluation of In Vitro Diagnostics, Beijing, China
| | - Zeyu Song
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, Beijing 100050, China; NMPA Key Laboratory for Quality Research and Evaluation of Medical Devices, Beijing, China; NMPA Key Laboratory for Quality Research and Evaluation of In Vitro Diagnostics, Beijing, China
| | - Peilong Wang
- Heji Hospital Affiliated to Changzhi Medical College, Gastroenterology Center Endoscopy Department, Changzhi 046000, Shanxi, China.
| | - Haiwei Zhou
- Division I of In Vitro Diagnostics for Infectious Diseases, Institute for In Vitro Diagnostics Control, National Institutes for Food and Drug Control, Beijing 100050, China; NMPA Key Laboratory for Quality Research and Evaluation of Medical Devices, Beijing, China; NMPA Key Laboratory for Quality Research and Evaluation of In Vitro Diagnostics, Beijing, China.
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2
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Kanda T, Li TC, Takahashi M, Nagashima S, Primadharsini PP, Kunita S, Sasaki-Tanaka R, Inoue J, Tsuchiya A, Nakamoto S, Abe R, Fujiwara K, Yokosuka O, Suzuki R, Ishii K, Yotsuyanagi H, Okamoto H. Recent advances in hepatitis E virus research and the Japanese clinical practice guidelines for hepatitis E virus infection. Hepatol Res 2024; 54:1-30. [PMID: 38874115 DOI: 10.1111/hepr.14062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/22/2024] [Accepted: 05/09/2024] [Indexed: 06/15/2024]
Abstract
Acute hepatitis E was considered rare until reports emerged affirming the existence of hepatitis E virus (HEV) genotypes 3 and 4 infections in Japan in the early 2000s. Extensive studies by Japanese researchers have highlighted the pivotal role of pigs and wild animals, such as wild boars and deer, as reservoirs for HEV, linking them to zoonotic infections in Japan. Currently, when hepatitis occurs subsequent to the consumption of undercooked or grilled pork, wild boar meat, or offal (including pig liver and intestines), HEV infection should be considered. Following the approval of anti-HEV immunoglobulin A antibody as a diagnostic tool for hepatitis E by Japan's Health Insurance System in 2011, the annual number of diagnosed cases of HEV infection has surged. Notably, the occurrence of post-transfusion hepatitis E promoted nationwide screening of blood products for HEV using nucleic acid amplification tests since 2020. Furthermore, chronic hepatitis E has been observed in immunosuppressed individuals. Considering the significance of hepatitis E, heightened preventive measures are essential. The Japan Agency for Medical Research and Development Hepatitis A and E viruses (HAV and HEV) Study Group, which includes special virologists and hepatologists, held a virtual meeting on February 17, 2024. Discussions encompassed pathogenesis, transmission routes, diagnosis, complications, severity factors, and ongoing and prospective vaccination or treatments for hepatitis E. Rigorous assessment of referenced studies culminated in the formulation of recommendations, which are detailed within this review. This comprehensive review presents recent advancements in HEV research and Japanese clinical practice guidelines for HEV infection.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Satoshi Kunita
- Center for Experimental Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryuzo Abe
- Department of Emergency Medicine, Oita University, Oita, Japan
| | - Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koji Ishii
- Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
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Orosz L, Sárvári KP, Dernovics Á, Rosztóczy A, Megyeri K. Pathogenesis and clinical features of severe hepatitis E virus infection. World J Virol 2024; 13:91580. [PMID: 38984076 PMCID: PMC11229844 DOI: 10.5501/wjv.v13.i2.91580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/08/2024] [Accepted: 04/15/2024] [Indexed: 06/24/2024] Open
Abstract
The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.
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Affiliation(s)
- László Orosz
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Károly Péter Sárvári
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - Áron Dernovics
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
| | - András Rosztóczy
- Department of Internal Medicine, Division of Gastroenterology, University of Szeged, Szeged 6725, Csongrád-Csanád, Hungary
| | - Klára Megyeri
- Department of Medical Microbiology, University of Szeged, Szeged 6720, Csongrád-Csanád, Hungary
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Sayed IM, El-Shamy A, Abdelwahab SF. Emerging Pathogens Causing Acute Hepatitis. Microorganisms 2023; 11:2952. [PMID: 38138096 PMCID: PMC10745594 DOI: 10.3390/microorganisms11122952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Acute hepatitis is defined as an inflammation or injury in the hepatocytes that continues for a short period of time (less than 6 months) [...].
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Affiliation(s)
- Ibrahim M Sayed
- Department of Biomedical & Nutritional Sciences, University of Massachusetts Lowell, Lowell, MA 01854, USA
| | - Ahmed El-Shamy
- Master of Pharmaceutical Sciences Program, College of Graduate Studies, California Northstate University, Elk Grove, CA 95757, USA
| | - Sayed F Abdelwahab
- Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
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Yang Y, Liu B, Tian J, Teng X, Liu T. Vital role of autophagy flux inhibition of placental trophoblast cells in pregnancy disorders induced by HEV infection. Emerg Microbes Infect 2023; 12:2276336. [PMID: 37882369 PMCID: PMC10796124 DOI: 10.1080/22221751.2023.2276336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Accepted: 10/23/2023] [Indexed: 10/27/2023]
Abstract
Hepatitis E virus (HEV) has become one of the important pathogens that threaten the global public health. Type 3 and 4 HEV are zoonotic, which can spread vertically and cause placental damage. At the same time, autophagy plays an important role in the process of embryo development and pregnancy maintenance. However, the relationship between HEV and autophagy, especially in the placenta tissue, has not been clarified. We found lower litter rates in HEV-infected female mice, with significant intrauterine abortion of the embryo (24.19%). To explore the effects of HEV infection on placenta autophagy, chorionic cells (JEG-3) and mice placenta have been employed as research objects, while the expression of autophagy-related proteins (ATGs) has been detected in JEG-3 cells with different times of HEV inoculation. The results demonstrated that the expression of protein LC3 decreased and p62 accumulated, meanwhile ATGs such as ATG4B, ATG5, and ATG9A in JEG-3 cells have decreased significantly. In addition, the maturation of autophagosomes, which referred to the process of the combination of autophagosomes and lysosomes was prevented by HEV infection as well. All processes of autophagic flux, which include the initiation, development, and maturation three stages, were suppressed in JEG-3 cells after HEV infection. Similarly, the protein and gene expression of LC3 were significantly decreased in the placenta of pregnant mice with HEV infection. In summary, our results suggested that HEV inhibited autophagy in JEG-3 cells and placenta of pregnant mice, which might be the important pathogenic mechanisms of HEV infection leading to embryo abortion.
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Affiliation(s)
- Yifei Yang
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Bo Liu
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Jijing Tian
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
| | - Xuepeng Teng
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People’s Republic of China
| | - Tianlong Liu
- National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China
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Wen GP, Wang MM, Tang ZM, Liu C, Yu ZH, Wang Z, Zheng ZZ, Zhou YL, Ge YS. Prevalence of Hepatitis E Virus and Its Associated Outcomes among Pregnant Women in China. Pathogens 2023; 12:1072. [PMID: 37764880 PMCID: PMC10536528 DOI: 10.3390/pathogens12091072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/18/2023] [Accepted: 08/19/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatitis E virus (HEV) is a significant public health concern worldwide. Pregnant women are at high risk of severe HEV infection. Various adverse outcomes in pregnant women related to HEV infection have been well documented in low-income and middle-income countries with poor sanitation. However, previous studies have provided inconsistent conclusions regarding the effects of HEV infection on the health of pregnant women and their infants in developed countries and contemporary China. In China, previous studies on HEV in pregnant women mainly focused on anti-HEV IgM and/or anti-HEV IgG. In this study, 4244 pregnant women were retrospectively analyzed for HEV-related markers. The positive rates of HEV antigen, HEV RNA, anti-HEV IgM, and anti-HEV IgG were 0.28%, 0.54%, 0.35%, and 10.49%, respectively. Among the 467 pregnant women who tested positive for at least one HEV-related marker, 92.93% (434) were positive for anti-HEV IgG only and 0.21% (1) were positive for HEV antigen, anti-HEV IgM, and anti-HEV IgG. Although the prevalence of anti-HEV IgG significantly increased with age, the prevalence of anti-HEV IgM, HEV RNA, and HEV antigen did not differ among pregnant women of different ages. Thirty-three pregnant women were positive for at least one of anti-HEV IgM, HEV antigen, and HEV RNA, and these individuals were recently or currently infected with HEV. None of the 33 pregnant women exhibited obvious clinical symptoms. Of the 33 pregnant women, 39.39% (13) experienced adverse fetal outcomes, including preterm birth, fetal distress, and low birth weight, the incidence of which was significantly higher than in pregnant women who were not recently or currently infected with HEV. These findings suggest that maternal HEV infection may impact the health of fetuses; thus, these results may contribute to the development of appropriate public health interventions for this population.
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Affiliation(s)
- Gui-Ping Wen
- Department of Central Laboratory, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Min-Ming Wang
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zi-Min Tang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, China
- NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Chang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zi-Hao Yu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zheng Wang
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen 361102, China
- School of Pharmacy, Xiamen University, Xiamen 361102, China
| | - Zi-Zheng Zheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yu-Lin Zhou
- Department of Central Laboratory, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen 361102, China
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yun-Sheng Ge
- Department of Central Laboratory, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen 361102, China
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Khuroo MS. Discovery of Hepatitis E and Its Impact on Global Health: A Journey of 44 Years about an Incredible Human-Interest Story. Viruses 2023; 15:1745. [PMID: 37632090 PMCID: PMC10459142 DOI: 10.3390/v15081745] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
The story of the discovery of hepatitis E originated in the late 1970s with my extreme belief that there was a hidden saga in the relationship between jaundice and pregnancy in developing countries and the opportunity for a massive epidemic of viral hepatitis, which hit the Gulmarg Kashmir region in November 1978. Based on data collected from a door-to-door survey, the existence of a new disease, epidemic non-A, non-B hepatitis, caused by a hitherto unknown hepatitis virus, was announced. This news was received by the world community with hype and skepticism. In the early 1980s, the world watched in awe as an extreme example of human self-experimentation led to the identification of VLP. In 1990, a cDNA clone from the virus responsible for epidemic non-A, non-B hepatitis was isolated. Over the years, we traversed three eras of ambiguity, hope, and hype of hepatitis E research and conducted several seminal studies to understand the biology of HEV and manifestations of hepatitis E. Many milestones have been reached on the long and winding road of hepatitis E research to understand the structure, biology, and diversity of the agent, changing the behavior of the pathogen in developed countries, and the discovery of a highly effective vaccine.
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Affiliation(s)
- Mohammad Sultan Khuroo
- Digestive Diseases Centre, Dr. Khuroo's Medical Clinic, Srinagar, Jammu & Kashmir 190010, India
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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: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 07/16/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) is a major cause of viral hepatitis globally. There is growing concern about transfusion-transmitted HEV (TT-HEV) as an emerging global health problem. HEV can potentially result in chronic infection in immunocompromised patients, leading to a higher risk of liver cirrhosis and even death. Between 0.0013% and 0.281% of asymptomatic blood donors around the world have HEV viremia, and 0.27% to 60.5% have anti-HEV immunoglobulin G. HEV is infectious even at very low blood concentrations of the virus. Immunosuppressed patients who develop persistent hepatitis E infection should have their immunosuppressant regimen reduced; ribavirin may be considered as treatment. Pegylated interferon can be considered in those who are refractory or intolerant to ribavirin. Sofosbuvir, a nucleotide analog, showed modest antiviral activity in some clinical studies but sustained viral response was not achieved. Therefore, rescue treatment remains an unmet need. The need for HEV screening of all blood donations remains controversial. Universal screening has been adopted in some countries after consideration of risk and resource availability. Various pathogen reduction methods have also been proposed to reduce the risk of TT-HEV. Future studies are needed to define the incidence of transmission through transfusion, their clinical features, outcomes and prognosis.
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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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Khuroo MS. Hepatitis E and Pregnancy: An Unholy Alliance Unmasked from Kashmir, India. Viruses 2021; 13:1329. [PMID: 34372535 PMCID: PMC8310059 DOI: 10.3390/v13071329] [Citation(s) in RCA: 4] [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: 06/04/2021] [Revised: 06/22/2021] [Accepted: 07/05/2021] [Indexed: 12/23/2022] Open
Abstract
The adverse relationship between viral hepatitis and pregnancy in developing countries had been interpreted as a reflection of retrospectively biased hospital-based data collection by the West. However, the discovery of hepatitis E virus (HEV) as the etiological agent of an epidemic of non-A, non-B hepatitis in Kashmir, and the documenting of the increased incidence and severity of hepatitis E in pregnancy via a house-to-house survey, unmasked this unholy alliance. In the Hepeviridae family, HEV-genotype (gt)1 from genus Orthohepevirus A has a unique open reading frame (ORF)4-encoded protein which enhances viral polymerase activity and viral replication. The epidemics caused by HEV-gt1, but not any other Orthohepevirus A genotype, show an adverse relationship with pregnancy in humans. The pathogenesis of the association is complex and at present not well understood. Possibly multiple factors play a role in causing severe liver disease in the pregnant women including infection and damage to the maternal-fetal interface by HEV-gt1; vertical transmission of HEV to fetus causing severe fetal/neonatal hepatitis; and combined viral and hormone related immune dysfunction of diverse nature in the pregnant women, promoting viral replication. Management is multidisciplinary and needs a close watch for the development and management of acute liver failure. (ALF). Preliminary data suggest beneficial maternal outcomes by early termination of pregnancy in patients with lower grades of encephalopathy.
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Affiliation(s)
- Mohammad Sultan Khuroo
- Digestive Diseases Centre, Dr. Khuroo's Medical Clinic, Srinagar, Jammu and Kashmir 190010, India
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Velavan TP, Pallerla SR, Johne R, Todt D, Steinmann E, Schemmerer M, Wenzel JJ, Hofmann J, Shih JWK, Wedemeyer H, Bock CT. Hepatitis E: An update on One Health and clinical medicine. Liver Int 2021; 41:1462-1473. [PMID: 33960603 DOI: 10.1111/liv.14912] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 03/09/2021] [Accepted: 04/08/2021] [Indexed: 12/12/2022]
Abstract
The hepatitis E virus (HEV) is one of the main causes of acute hepatitis and the de facto global burden is underestimated. HEV-related clinical complications are often undetected and are not considered in the differential diagnosis. Convincing findings from studies suggest that HEV is clinically relevant not only in developing countries but also in industrialized countries. Eight HEV genotypes (HEV-1 to HEV-8) with different human and animal hosts and other HEV-related viruses are in circulation. Transmission routes vary by genotype and location, with large waterborne outbreaks in developing countries and zoonotic food-borne infections in developed countries. An acute infection can be aggravated in pregnant women, organ transplant recipients, patients with pre-existing liver disease and immunosuppressed patients. HEV during pregnancy affects the fetus and newborn with an increased risk of vertical transmission, preterm and stillbirth, neonatal jaundice and miscarriage. Hepatitis E is associated with extrahepatic manifestations that include neurological disorders such as neuralgic amyotrophy, Guillain-Barré syndrome and encephalitis, renal injury and haematological disorders. The risk of transfusion-transmitted HEV is increasingly recognized in Western countries where the risk may be because of a zoonosis. RNA testing of blood components is essential to determine the risk of transfusion-transmitted HEV. There are currently no approved drugs or vaccines for HEV infections. This review focuses on updating the latest developments in zoonoses, screening and diagnostics, drugs in use and under development, and vaccines.
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Affiliation(s)
- Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research, VG-CARE, Hanoi, Vietnam.,Faculty of Medicine, Duy Tan University, Da Nang, Vietnam
| | - Srinivas R Pallerla
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Vietnamese-German Center for Medical Research, VG-CARE, Hanoi, Vietnam
| | - Reimar Johne
- German Federal Institute for Risk Assessment, Berlin, Germany
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.,European Virus Bioinformatics Center (EVBC), Jena, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mathias Schemmerer
- Institute of Clinical Microbiology and Hygiene, National Consultant Laboratory for HAV and HEV, University Medical Center Regensburg, Regensburg, Germany
| | - Jürgen J Wenzel
- Institute of Clinical Microbiology and Hygiene, National Consultant Laboratory for HAV and HEV, University Medical Center Regensburg, Regensburg, Germany
| | - Jörg Hofmann
- Institute of Virology, Charité Universitätsmedizin Berlin, Labor Berlin-Charité-Vivantes GmbH, Berlin, Germany
| | | | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research, Partner Hannover-Braunschweig, Braunschweig, Germany
| | - Claus-Thomas Bock
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.,Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
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Abstract
Progesterone is crucial for the maintenance of pregnancy. During pregnancy hepatitis E virus (HEV) infection is associated with increased fulminant hepatic failure and mortality rates. In this study, we determined whether progesterone modulates HEV replication and HEV-induced innate cytokine response in Huh7-S10-3 human liver cells. We first demonstrated that Huh7-S10-3 liver cells expressed SH3-domain-containing progesterone receptor membrane component (PGRMC)1/2 receptors involved in the progesterone nonclassical signaling pathway, while the classical progesterone receptor isoforms progesterone receptor-A and -B protein levels were undetectable. We showed that the genotype 3 HEV (strain P6) induced mRNA expression of type III interferon (IFN-λ1), but not other innate cytokines in Huh7-S10-3 cells. Pretreatment with progesterone at concentrations of 80 nM, 160 nM, or 480 nM, which are the physiological concentrations typically seen in the first- to third-trimester during pregnancy, significantly increased HEV replication in Huh7-S10-3 cells. However, pretreatment of cells with progesterone (80 nM) did not affect the level of HEV-induced IFN-λ1 mRNA expression. We further showed that loss of PGRMC1/2 receptors by small interfering RNA (siRNA) knockdown leads to an increase in HEV-induced IFN-λ1 expression levels at early time points via the extracellular signal-regulated kinase pathway and thus resulted in a reduced level of HEV replication. Collectively, the results indicated that progesterone-mediated modulation of HEV replication in human liver cells is plausibly through SH3-domain containing proteins such as PGRMC1/2, but not likely through immunomodulation of HEV-induced interferon response in liver cells. The results have important implications in understanding the underlying mechanisms of high mortality and fulminant hepatitis in HEV-infected pregnant women.
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Belei O, Ancusa O, Mara A, Olariu L, Amaricai E, Folescu R, Zamfir CL, Gurgus D, Motoc AG, Stânga LC, Strat L, Marginean O. Current Paradigm of Hepatitis E Virus Among Pediatric and Adult Patients. Front Pediatr 2021; 9:721918. [PMID: 34660485 PMCID: PMC8515027 DOI: 10.3389/fped.2021.721918] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2021] [Accepted: 08/31/2021] [Indexed: 12/26/2022] Open
Abstract
Hepatitis E virus (HEV) infection is a polymorphic condition, present throughout the world and involving children and adults. Multiple studies over the last decade have contributed to a better understanding of the natural evolution of this infection in various population groups, several reservoirs and transmission routes being identified. To date, acute or chronic HEV-induced hepatitis has in some cases remained underdiagnosed due to the lower accuracy of serological tests and due to the evolutionary possibility with extrahepatic manifestations. Implementation of diagnostic tests based on nucleic acid analysis has increased the detection rate of this disease. The epidemiological and clinical features of HEV hepatitis differ depending on the geographical areas studied. HEV infection is usually a self-limiting condition in immunocompetent patients, but in certain categories of vulnerable patients it can induce a sudden evolution toward acute liver failure (pregnant women) or chronicity (immunosuppressed patients, post-transplant, hematological, or malignant diseases). In acute HEV infections in most cases supportive treatment is sufficient. In patients who develop chronic hepatitis with HEV, dose reduction of immunosuppressive medication should be the first therapeutic step, especially in patients with transplant. In case of unfavorable response, the initiation of antiviral therapy is recommended. In this review, the authors summarized the essential published data related to the epidemiological, clinical, paraclinical, and therapeutic aspects of HEV infection in adult and pediatric patients.
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Affiliation(s)
- Oana Belei
- First Pediatric Clinic, Disturbance of Growth and Development on Children Research Center, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Oana Ancusa
- Fifth Department of Internal Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Adelina Mara
- Department of Internal Medicine, Emergency City Hospital, Timisoara, Romania
| | - Laura Olariu
- First Pediatric Clinic, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Elena Amaricai
- Department of Rehabilitation Physical Medicine and Rheumatology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Roxana Folescu
- Department of Balneology, Medical Recovery and Rheumatology, Family Discipline, Center for Preventive Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Carmen Lacramioara Zamfir
- Department of Morpho-Functional Sciences I, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania
| | - Daniela Gurgus
- Department of Balneology, Medical Recovery and Rheumatology, Family Discipline, Center for Preventive Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Andrei G Motoc
- Department of Anatomy and Embriology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Livia Claudia Stânga
- Department of Microbiology, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Liliana Strat
- Department of Mother and Child Medicine, "Grigore T. Popa" University of Medicine and Pharmacy, Iasi, Romania
| | - Otilia Marginean
- First Pediatric Clinic, Disturbance of Growth and Development on Children Research Center, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
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Hoffmann P, Behnisch R, Gsenger J, Schnitzler P, Gauss A. Hepatitis E seroprevalence in a German cohort of patients with inflammatory bowel diseases. PLoS One 2020; 15:e0239825. [PMID: 33027305 PMCID: PMC7540852 DOI: 10.1371/journal.pone.0239825] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS The incidence of hepatitis E virus (HEV)-infections in industrialized nations has been increasing over the past years. Patients suffering from inflammatory bowel diseases (IBD) may be more prone to transmission. Data on HEV seroprevalence in IBD patients is scarce and has not been reported in German IBD patients. The German Health Examination Survey for Adults 2008-2011, which included 4.422 samples, found a HEV seroprevalence of 16.8%, increasing with age. The aim of the present study was to determine the seroprevalence of anti-HEV IgG in a German cohort of IBD patients, and to explore which parameters have an impact on HEV seroprevalence. MATERIAL AND METHODS This is an uncontrolled, cross-sectional, retrospective monocentric study. Among the patients visiting the IBD outpatient clinic between 25 January, 2019 and 24 September, 2019, 328 patients with Crohn's disease (CD) and 150 patients with ulcerative colitis (UC) were included in the study. IgG antibodies against HEV were determined by enzyme-linked immunosorbent assay. Positive antibody titers were verified using immunoblot analysis. Medical records were reviewed for demographic and clinical parameters to identify potential risk factors for HEV infection. RESULTS The prevalence of anti-HEV IgG antibodies was 17.4% in CD patients and 24.7% in UC patients. No patient with positive HEV PCR was detected. Greater age of CD und UC patients and longer duration of anti-interleukin 12/23 treatment in CD patients were associated with higher anti-HEV IgG antibody rates. CONCLUSIONS In summary, we conclude that patients with UC have a higher anti-HEV IgG antibody prevalence than the general population in Germany, and that immunosuppressive therapy may carry no higher risk for HEV infection.
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Affiliation(s)
- Peter Hoffmann
- Department of Gastroenterology and Hepatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Rouven Behnisch
- Department of Medical Biometry, Institute of Medical Biometry and Informatics, Heidelberg University Hospital, Heidelberg, Germany
| | - Julia Gsenger
- Center for Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany
| | - Paul Schnitzler
- Center for Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany
| | - Annika Gauss
- Department of Gastroenterology and Hepatology, Heidelberg University Hospital, Heidelberg, Germany
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14
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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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15
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Abstract
BACKGROUND Hepatitis E virus (HEV) generally causes self-limiting viral hepatitis. However, in pregnant women, HEV infection can be severe and has been associated with up to 30% mortality in the third trimester. Additionally, HEV infection in pregnancy is also associated with high rates of preterm labor and vertical transmission. MAIN BODY HEV is now recognized as a global health problem in both developing and industrialized countries. HEV can be transmitted via the fecal-oral route, zoonotic route, and blood transfusion route. An altered immune status, hormonal levels, and viral factors may be related to the severity of the disease. Currently, no established treatment is available for HEV in pregnant women. A Chinese vaccine has been demonstrated to be protective against HEV in the general population and seems to be safe in pregnancy; however, its safety and efficacy in a large population of pregnant women remain to be determined. CONCLUSION This review summarizes the current knowledge about HEV infection during pregnancy and focuses on the epidemiology, clinical manifestations, mechanisms underlying severe liver injury, and management and prevention of HEV infection during pregnancy. Considering that HEV infection during pregnancy may result in poor outcomes, screening for and monitoring HEV infection early in pregnancy should be taken into account. In addition, a better understanding of the pathogenesis will help to develop potential treatment strategies targeting HEV infection in pregnancy.
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Affiliation(s)
- Chunchen Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China
| | - Xiaoxue Wu
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China
| | - Jianbo Xia
- Department of Laboratory Medicine, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430070, People's Republic of China.
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16
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Beyer S, Szewzyk R, Gnirss R, Johne R, Selinka HC. Detection and Characterization of Hepatitis E Virus Genotype 3 in Wastewater and Urban Surface Waters in Germany. FOOD AND ENVIRONMENTAL VIROLOGY 2020; 12:137-147. [PMID: 32172512 PMCID: PMC7225198 DOI: 10.1007/s12560-020-09424-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 03/04/2020] [Indexed: 05/18/2023]
Abstract
In highly populated areas, environmental surveillance of wastewater and surface waters is a key factor to control the circulation of viruses and risks for public health. Hepatitis E virus (HEV) genotype 3 is considered as an emerging pathogen in industrialized countries. Therefore, this study was carried out to determine the prevalence of HEV in environmental waters in urban and suburban regions in Germany. HEV was monitored in water samples using quantitative RT-PCR (RT-qPCR) and nested RT-PCR without or with virus concentration via polyethylene glycol precipitation or ultracentrifugation. By RT-qPCR, 84-100% of influent samples of wastewater treatment plants were positive for HEV RNA. Genotypes HEV-3c and 3f were identified in wastewater, with HEV-3c being the most prevalent genotype. These data correlate with subtypes identified earlier in patients from the same area. Comparison of wastewater influent and effluent samples revealed a reduction of HEV RNA of about 1 log10 during passage through wastewater treatment plants. In addition, combined sewer overflows (CSOs) after heavy rainfalls were shown to release HEV RNA into surface waters. About 75% of urban river samples taken during these CSO events were positive for HEV RNA by RT-qPCR. In contrast, under normal weather conditions, only around 30% of river samples and 15% of samples from a bathing water located at an urban river were positive for HEV. Median concentrations of HEV RNA of all tested samples at this bathing water were below the limit of detection.
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Affiliation(s)
- Sophia Beyer
- Section II 1.4 Microbiological Risks, German Environment Agency (UBA), Corrensplatz 1, 14195, Berlin, Germany
| | - Regine Szewzyk
- Section II 1.4 Microbiological Risks, German Environment Agency (UBA), Corrensplatz 1, 14195, Berlin, Germany
| | - Regina Gnirss
- Berliner Wasserbetriebe (BWB), Cicerostr. 24, 10709, Berlin, Germany
| | - Reimar Johne
- German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Straße 8-10, 10589, Berlin, Germany
| | - Hans-Christoph Selinka
- Section II 1.4 Microbiological Risks, German Environment Agency (UBA), Corrensplatz 1, 14195, Berlin, Germany.
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17
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El-Mokhtar MA, Othman ER, Khashbah MY, Ismael A, Ghaliony MAA, Seddik MI, Sayed IM. Evidence of the Extrahepatic Replication of Hepatitis E Virus in Human Endometrial Stromal Cells. Pathogens 2020; 9:pathogens9040295. [PMID: 32316431 PMCID: PMC7238207 DOI: 10.3390/pathogens9040295] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/10/2020] [Accepted: 04/14/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatitis E virus (HEV) is the most common cause of acute viral hepatitis worldwide. The tropism of HEV is not restricted to the liver, and the virus replicates in other organs. Not all the extrahepatic targets for HEV are identified. Herein, we found that non-decidualized primary human endometrial stromal cells (PHESCs), which are precursors for the decidua and placenta, are susceptible to HEV infection. PHESCs, isolated from healthy non-pregnant women (n = 5), were challenged with stool-derived HEV-1 and HEV-3. HEV RNA was measured by qPCR, and HEV capsid protein was assessed by flow cytometry, immunofluorescence (IF), and ELISA. HEV infection was successfully established in PHESCs. Intracellular and extracellular HEV RNA loads were increased over time, indicating efficient replication in vitro. In addition, HEV capsid protein was detected intracellularly in the HEV-infected PHESCs and accumulated extracellularly over time, confirming the viral assembly and release from the infected cells. HEV-1 replicated more efficiently in PHESCs than HEV-3 and induced more inflammatory responses. Ribavirin (RBV) treatment abolished the replication of HEV in PHESCs. In conclusion, PHESCs are permissive to HEV infection and these cells could be an endogenous source of HEV infection during pregnancy and mediate HEV vertical transmission.
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Affiliation(s)
- Mohamed A. El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, 71515 Assiut, Egypt;
- Reproductive Science Research Center, Assiut University, 71515 Assiut, Egypt; (E.R.O.); (M.Y.K.)
| | - Essam R. Othman
- Reproductive Science Research Center, Assiut University, 71515 Assiut, Egypt; (E.R.O.); (M.Y.K.)
- Department of Obstetrics and Gynecology, Assiut University, 71515 Assiut, Egypt
- Department of Reproductive Medicine, Academic Endometriosis Center, Amsterdam University Medical Center, Postbus 22660, 1100 DD Amsterdam, The Netherlands
| | - Maha Y. Khashbah
- Reproductive Science Research Center, Assiut University, 71515 Assiut, Egypt; (E.R.O.); (M.Y.K.)
- Department of Obstetrics and Gynecology, Assiut University, 71515 Assiut, Egypt
| | - Ali Ismael
- Department of Internal Medicine, Faculty of Medicine, Zagazig University, 44519 Zagazig, Egypt;
| | - Mohamed AA Ghaliony
- Department of Tropical Medicine and Gastroenterology Department, Assiut University, 71515 Assiut, Egypt;
| | - Mohamed Ismail Seddik
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, 71515 Assiut, Egypt;
| | - Ibrahim M. Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, 71515 Assiut, Egypt;
- Reproductive Science Research Center, Assiut University, 71515 Assiut, Egypt; (E.R.O.); (M.Y.K.)
- Department of Pathology, School of Medicine, University of California, San Diego, CA 92093, USA
- Correspondence: or
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18
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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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19
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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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20
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Horvatits T, Schulze Zur Wiesch J, Lütgehetmann M, Lohse AW, Pischke S. The Clinical Perspective on Hepatitis E. Viruses 2019; 11:E617. [PMID: 31284447 PMCID: PMC6669652 DOI: 10.3390/v11070617] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/26/2019] [Accepted: 07/03/2019] [Indexed: 12/17/2022] Open
Abstract
Every year, there are an estimated 20 million hepatitis E virus (HEV) infections worldwide, leading to an estimated 3.3 million symptomatic cases of hepatitis E. HEV is largely circulating in the west and is associated with several hepatic and extrahepatic diseases. HEV Genotype 1 and 2 infections are waterborne and causative for epidemics in the tropics, while genotype 3 and 4 infections are zoonotic diseases and are mainly transmitted by ingestion of undercooked pork in industrialized nations. The clinical course of these infections differs: genotype 1 and 2 infection can cause acute illness and can lead to acute liver failure (ALF) or acute on chronic liver failure (ACLF) with a high mortality rate of 20% in pregnant women. In contrast, the majority of HEV GT-3 and -4 infections have a clinically asymptomatic course and only rarely lead to acute on chronic liver failure in elderly or patients with underlying liver disease. Immunosuppressed individuals infected with genotype 3 or 4 may develop chronic hepatitis E, which then can lead to life-threatening cirrhosis. Furthermore, several extra-hepatic manifestations affecting various organs have been associated with ongoing or previous HEV infections but the causal link for many of them still needs to be proven. There is no approved specific therapy for the treatment of acute or chronic HEV GT-3 or -4 infections but off-label use of ribavirin has been demonstrated to be safe and effective in the majority of patients. However, in approximately 15% of chronically HEV infected patients, cure is not possible.
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Affiliation(s)
- Thomas Horvatits
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Julian Schulze Zur Wiesch
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Marc Lütgehetmann
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
- Institute of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany
| | - Sven Pischke
- Department of Medicine, University Medical Center Hamburg-Eppendorf, 22527 Hamburg, Germany.
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel and Heidelberg Partner sites, 22527 Hamburg, Germany.
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21
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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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22
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Primadharsini PP, Nagashima S, Okamoto H. Genetic Variability and Evolution of Hepatitis E Virus. Viruses 2019; 11:E456. [PMID: 31109076 PMCID: PMC6563261 DOI: 10.3390/v11050456] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/15/2019] [Accepted: 05/16/2019] [Indexed: 12/16/2022] Open
Abstract
Hepatitis E virus (HEV) is a single-stranded positive-sense RNA virus. HEV can cause both acute and chronic hepatitis, with the latter usually occurring in immunocompromised patients. Modes of transmission range from the classic fecal-oral route or zoonotic route, to relatively recently recognized but increasingly common routes, such as via the transfusion of blood products or organ transplantation. Extrahepatic manifestations, such as neurological, kidney and hematological abnormalities, have been documented in some limited cases, typically in patients with immune suppression. HEV has demonstrated extensive genomic diversity and a variety of HEV strains have been identified worldwide from human populations as well as growing numbers of animal species. The genetic variability and constant evolution of HEV contribute to its physiopathogenesis and adaptation to new hosts. This review describes the recent classification of the Hepeviridae family, global genotype distribution, clinical significance of HEV genotype and genomic variability and evolution of HEV.
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Affiliation(s)
- Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan.
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan.
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Tochigi 329-0498, Japan.
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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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24
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Bouthry E, Benachi A, Vivanti AJ, Letamendia E, Vauloup-Fellous C, Roque-Afonso AM. Autochthonous Hepatitis E during Pregnancy, France. Emerg Infect Dis 2019; 24:1586-1587. [PMID: 30016249 PMCID: PMC6056134 DOI: 10.3201/eid2408.180105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Acute hepatitis E virus infections occurred during the third trimester in 2 pregnant women in France who sought treatment with nonspecific symptoms or asymptomatic elevation of liver enzymes. Infection cleared quickly in both women. We detected no hepatitis E RNA in 1 newborn’s feces at 3 weeks of age.
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25
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Horvatits T, Pischke S. HEV in pregnancy: Understanding the crucial role of steroid hormones. Liver Int 2019; 39:621-622. [PMID: 30916863 DOI: 10.1111/liv.13942] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Thomas Horvatits
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
| | - Sven Pischke
- Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
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26
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Abstract
Hepatitis E virus (HEV) infection has distinct features, depending upon the genotype and geographical area. HEV genotypes 1 and 2 are endemic to various developing countries causing epidemics of acute viral hepatitis with human to human transmission. On the other hand, HEV genotypes 3 and 4 prevalent in developed countries commonly lead to subclinical infection and are transmitted zoonotically. HEV infection typically causes acute self-limiting illness associated with low morbidity and mortality. Infection with HEV genotype 1 or 2 in pregnancy, especially in the third trimester may lead to severe illness and fulminant liver failure. Poor maternal and fetal outcomes have been reported. Areas covered: This review highlights the various aspects of HEV infection in pregnancy including diagnosis, management, and prevention. Expert commentary: Treatment is mainly supportive with diligent monitoring and intensive care. Therapeutic termination of pregnancy cannot be recommended based to the available literature. Early liver transplantation (LT) should be considered in these patients although the indications and timing of LT are still controversial. Prevention of HEV infection or illness by improved sanitation and active/passive immunization needs further research.
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Affiliation(s)
- Premashis Kar
- a Department of Gastroenterology and Hepatology , Max Super Speciality Hospital , Ghaziabad , India
| | - Anando Sengupta
- a Department of Gastroenterology and Hepatology , Max Super Speciality Hospital , Ghaziabad , India
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27
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Charre C, Ramière C, Dumortier J, Abravanel F, Lhomme S, Gincul R, Scholtès C. Chronic Genotype 3 Hepatitis E in Pregnant Woman Receiving Infliximab and Azathioprine. Emerg Infect Dis 2019; 24:941-943. [PMID: 29664396 PMCID: PMC5938778 DOI: 10.3201/eid2405.171845] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Acute hepatitis E virus infection during pregnancy has a high fatality rate in developing countries. Little data are available on chronic infection in pregnant women. We report a case of chronic hepatitis E during treatment with infliximab and azathioprine, without adverse event during pregnancy and with spontaneous resolution after delivery.
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28
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Hepatitis E virus: reasons for emergence in humans. Curr Opin Virol 2018; 34:10-17. [PMID: 30497051 DOI: 10.1016/j.coviro.2018.11.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 11/08/2018] [Accepted: 11/13/2018] [Indexed: 12/11/2022]
Abstract
Hepatitis E virus (HEV) infects both humans and other animal species. Recently, we have seen a steady increase in autochthonous cases of human HEV infection in certain areas especially in Europe, and large outbreaks in several African countries among the displaced population. This mini-review critically analyzes potential host, environmental, and viral factors that may be associated with the emergence of hepatitis E in humans. The existence of numerous HEV reservoir animals such as pig, deer and rabbit results in human exposure to infected animals via direct contact or through animal meat consumption. Contamination of drinking, irrigation and coastal water by animal and human wastes lead to emergence of endemic cases in industrialized countries and outbreaks in displaced communities especially in war-torn countries.
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29
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Gouilly J, Chen Q, Siewiera J, Cartron G, Levy C, Dubois M, Al-Daccak R, Izopet J, Jabrane-Ferrat N, El Costa H. Genotype specific pathogenicity of hepatitis E virus at the human maternal-fetal interface. Nat Commun 2018; 9:4748. [PMID: 30420629 PMCID: PMC6232144 DOI: 10.1038/s41467-018-07200-2] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 10/03/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis E virus (HEV) infection, particularly HEV genotype 1 (HEV-1), can result in fulminant hepatic failure and severe placental diseases, but mechanisms underlying genotype-specific pathogenicity are unclear and appropriate models are lacking. Here, we model HEV-1 infection ex vivo at the maternal-fetal interface using the decidua basalis and fetal placenta, and compare its effects to the less-pathogenic genotype 3 (HEV-3). We demonstrate that HEV-1 replicates more efficiently than HEV-3 both in tissue explants and stromal cells, produces more infectious progeny virions and causes severe tissue alterations. HEV-1 infection dysregulates the secretion of several soluble factors. These alterations to the cytokine microenvironment correlate with viral load and contribute to the tissue damage. Collectively, this study characterizes an ex vivo model for HEV infection and provides insights into HEV-1 pathogenesis during pregnancy that are linked to high viral replication, alteration of the local secretome and induction of tissue injuries.
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Affiliation(s)
- Jordi Gouilly
- Centre of Pathophysiology Toulouse Purpan, INSERM U1043, CNRS UMR5282, Toulouse III University, 31024, Toulouse, France
| | - Qian Chen
- Centre of Pathophysiology Toulouse Purpan, INSERM U1043, CNRS UMR5282, Toulouse III University, 31024, Toulouse, France
| | - Johan Siewiera
- University of California San Francisco, School of Medicine, Laboratory of Medicine, San Francisco, CA, USA
| | - Géraldine Cartron
- Service de Gynécologie-Obstétrique, Hôpital Paule de Viguier, Centre Hospitalier Universitaire, 31059, Toulouse, France
| | - Claude Levy
- Service de Gynécologie-Obstétrique, Clinique Sarrus-Teinturiers, 31300, Toulouse, France
| | - Martine Dubois
- Laboratoire de Virologie, Institute of Federative Biology, Centre Hospitalier Universitaire, 31059, Toulouse, France
| | - Reem Al-Daccak
- INSERM UMRS976, Université Paris Diderot, Hôpital Saint-Louis, 75010, Paris, France
| | - Jacques Izopet
- Centre of Pathophysiology Toulouse Purpan, INSERM U1043, CNRS UMR5282, Toulouse III University, 31024, Toulouse, France
- Laboratoire de Virologie, Institute of Federative Biology, Centre Hospitalier Universitaire, 31059, Toulouse, France
| | - Nabila Jabrane-Ferrat
- Centre of Pathophysiology Toulouse Purpan, INSERM U1043, CNRS UMR5282, Toulouse III University, 31024, Toulouse, France.
| | - Hicham El Costa
- Centre of Pathophysiology Toulouse Purpan, INSERM U1043, CNRS UMR5282, Toulouse III University, 31024, Toulouse, France.
- Laboratoire de Virologie, Institute of Federative Biology, Centre Hospitalier Universitaire, 31059, Toulouse, France.
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30
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Dalton HR, Izopet J. Transmission and Epidemiology of Hepatitis E Virus Genotype 3 and 4 Infections. Cold Spring Harb Perspect Med 2018. [PMID: 29530946 DOI: 10.1101/cshperspect.a032144] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Following the introduction of robust serological and molecular tools, our understanding of the epidemiology of zoonotic hepatitis E virus (HEV) has improved considerably in recent years. Current thinking suggests that consumption of pork meat products is the key route of infection in humans, but it is certainly not the only one. Other routes of infection include environmental spread, contaminated water, and via the human blood supply. The epidemiology of HEV genotype (gt)3 and gt4 is complex, as there are several sources and routes of infection, and it is likely that these vary between and within countries and over time.
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Affiliation(s)
- Harry R Dalton
- Royal Cornwall Hospital, Truro TR1 3LJ, United Kingdom.,European Centre for Environment and Human Health, University of Exeter, Truro TR1 3LJ, United Kingdom
| | - Jacques Izopet
- Department of Virology, Hepatitis E Virus National Reference Centre, Toulouse University Hospital, 31059 Toulouse, France.,Toulouse-Purpan Centre for Pathophysiology, INSERM UMR1043/CNRS UMR 5282, CPTP, Toulouse University Paul Sabatier, 31024 Toulouse, France
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31
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Smith DB, Simmonds P. Classification and Genomic Diversity of Enterically Transmitted Hepatitis Viruses. Cold Spring Harb Perspect Med 2018; 8:a031880. [PMID: 29530950 PMCID: PMC6120691 DOI: 10.1101/cshperspect.a031880] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hepatitis A virus (HAV) and hepatitis E virus (HEV) are significant human pathogens and are responsible for a substantial proportion of cases of severe acute hepatitis worldwide. Genetically, both viruses are heterogeneous and are classified into several genotypes that differ in their geographical distribution and risk group association. There is, however, little evidence that variants of HAV or HEV differ antigenically or in their propensity to cause severe disease. Genetically more divergent but primarily hepatotropic variants of both HAV and HEV have been found in several mammalian species, those of HAV being classified into eight species within the genus Hepatovirus in the virus family Picornaviridae. HEV is classified as a member of the species Orthohepevirus A in the virus family Hepeviridae, a species that additionally contains viruses infecting pigs, rabbits, and a variety of other mammalian species. Other species (Orthohepevirus B-D) infect a wide range of other mammalian species including rodents and bats.
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Affiliation(s)
- Donald B Smith
- Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom
| | - Peter Simmonds
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom
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32
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Prevalence, morbidity, and therapy of hepatitis E virus infection in pediatric renal allograft recipients. Pediatr Nephrol 2018; 33:1215-1225. [PMID: 29500631 DOI: 10.1007/s00467-018-3905-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/24/2018] [Accepted: 01/25/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV) infection in immunocompromised patients such as solid organ transplant recipients may bear a high risk of becoming a chronic infection with progression to liver cirrhosis. So far, data on HEV infection in pediatric renal transplant recipients are limited. METHODS This single-center cohort study investigated period prevalence, morbidity, and treatment of HEV infection in 90 pediatric renal allograft recipients aged 9.9 ± 5.6 years at transplantation (58.9% males). HEV serology was determined by enzyme-linked immunosorbent assay and immunoblot, HEV replication by quantitative nucleic acid testing. RESULTS Twelve of 90 (13.3%) patients were HEV seropositive, and 4/90 (4.4%) recipients showed active HEV replication (103-108 copies/mL, corresponding to 0.5 × 103 and 0.5 × 108 WHO IU/mL) in serum and stool. In all patients with HEV replication, genotype 3 was identified by partial sequencing of HEV ORF1 and ORF2 and phylogenetic analysis. All patients with HEV replication developed chronic infection associated with moderately elevated liver enzymes. HEV replication was unresponsive to reduction of immunosuppression, whereas ribavirin monotherapy (mean dosage 9.7 ± 3.6 mg/kg per day over 85 ± 11 days) was associated with sustained viral clearance and normalization of liver enzymes in all patients. Ribavirin therapy was associated with reversible, hyporegenerative anemia. CONCLUSIONS Given an HEV seroprevalence of 13.3% in pediatric renal transplant recipients and an HEV viremia of 4.4%, HEV infection should be considered in patients with otherwise unexplained elevation of liver enzymes. HEV infection does not necessarily respond to reduction of immunosuppressive therapy, but can be effectively and safely treated with ribavirin.
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33
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Hepatitis E in High-Income Countries: What Do We Know? And What Are the Knowledge Gaps? Viruses 2018; 10:v10060285. [PMID: 29799485 PMCID: PMC6024799 DOI: 10.3390/v10060285] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 05/16/2018] [Accepted: 05/23/2018] [Indexed: 12/11/2022] Open
Abstract
Hepatitis E virus (HEV) is a positive-strand RNA virus transmitted by the fecal–oral route. HEV genotypes 1 and 2 infect only humans and cause mainly waterborne outbreaks. HEV genotypes 3 and 4 are widely represented in the animal kingdom, and are mainly transmitted as a zoonosis. For the past 20 years, HEV infection has been considered an imported disease in developed countries, but now there is evidence that HEV is an underrecognized pathogen in high-income countries, and that the incidence of confirmed cases has been steadily increasing over the last decade. In this review, we describe current knowledge about the molecular biology of HEV, its clinical features, its main routes of transmission, and possible therapeutic strategies in developed countries.
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34
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Izopet J. [HEV and transfusion-recipient risk]. ANNALES PHARMACEUTIQUES FRANÇAISES 2018; 76:89-96. [PMID: 29395014 DOI: 10.1016/j.pharma.2017.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 12/18/2017] [Indexed: 02/06/2023]
Abstract
HEV infections are mainly food- and water-borne but transfusion-transmission has occurred in both developing and developed countries. The infection is usually asymptomatic but it can lead to fulminant hepatitis in patients with underlying liver disease and pregnant women living in developing countries. It also causes chronic hepatitis E, with progressive fibrosis and cirrhosis, in approximately 60 % of immunocompromised patients infected with HEV genotype 3. Extra-hepatic manifestations such as neurological and renal manifestations have been reported. The risk of a transfusion-transmitted HEV infection is linked to the frequency of viremia in blood donors, the donor virus load and the volume of plasma in the final transfused blood component. Several developed countries have adopted measures to improve blood safety based on the epidemiology of HEV.
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Affiliation(s)
- J Izopet
- Laboratoire de virologie, centre national de référence virus des hépatites à transmission entérique (hépatites A et E), institut fédératif de biologie, CHU de Purpan, 330, avenue de Grande-Bretagne, TSA 40031, 31059 Toulouse, France; Inserm U1043/CNRS 5282, université Paul-Sabatier, centre de physiopathologie de Toulouse-Purpan, 31024 Toulouse cedex 03, France.
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35
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Knegendorf L, Drave SA, Dao Thi VL, Debing Y, Brown RJP, Vondran FWR, Resner K, Friesland M, Khera T, Engelmann M, Bremer B, Wedemeyer H, Behrendt P, Neyts J, Pietschmann T, Todt D, Steinmann E. Hepatitis E virus replication and interferon responses in human placental cells. Hepatol Commun 2018; 2:173-187. [PMID: 29404525 PMCID: PMC5796324 DOI: 10.1002/hep4.1138] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 11/17/2017] [Accepted: 12/03/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis E virus (HEV) is a member of the genus Orthohepevirus in the family Hepeviridae and the causative agent of hepatitis E in humans. HEV is a major health problem in developing countries, causing mortality rates up to 25% in pregnant women. However, these cases are mainly reported for HEV genotype (gt)1, while gt3 infections are usually associated with subclinical courses of disease. The pathogenic mechanisms of adverse maternal and fetal outcome during pregnancy in HEV-infected pregnant women remain elusive. In this study, we observed that HEV is capable of completing the full viral life cycle in placental-derived cells (JEG-3). Following transfection of JEG-3 cells, HEV replication of both HEV gts could be observed. Furthermore, determination of extracellular and intracellular viral capsid levels, infectivity, and biophysical properties revealed production of HEV infectious particles with similar characteristics as in liver-derived cells. Viral entry was analyzed by infection of target cells and detection of either viral RNA or staining for viral capsid protein by immunofluorescence. HEV gt1 and gt3 were efficiently inhibited by ribavirin in placental as well as in human hepatoma cells. In contrast, interferon-α sensitivity was lower in the placental cells compared to liver cells for gt1 but not gt3 HEV. Simultaneous determination of interferon-stimulated gene expression levels demonstrated an efficient HEV-dependent restriction in JEG-3. Conclusion: We showed differential tissue-specific host responses to HEV genotypes, adding to our understanding of the mechanisms contributing to fatal outcomes of HEV infections during pregnancy. Using this cell-culture system, new therapeutic options for HEV during pregnancy can be identified and evaluated. (Hepatology Communications 2018;2:173-187).
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Affiliation(s)
- Leonard Knegendorf
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
| | - Svenja A. Drave
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
| | - Viet Loan Dao Thi
- Laboratory of Virology and Infectious DiseaseRockefeller UniversityNew YorkNY
| | - Yannick Debing
- Rega Institute for Medical Research, Department of Microbiology and ImmunologyKatholieke Universiteit LeuvenLeuvenBelgium
| | - Richard J. P. Brown
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
| | - Florian W. R. Vondran
- ReMediES, Department of General, Visceral, and Transplantation Surgery, Hannover Medical SchoolHannoverGermany
- German Center for Infection Research, partner site Hannover‐BraunschweigHannoverGermany
| | - Kathrin Resner
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
| | - Martina Friesland
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
| | - Tanvi Khera
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
| | - Michael Engelmann
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology, and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Heiner Wedemeyer
- German Center for Infection Research, partner site Hannover‐BraunschweigHannoverGermany
- Department of Gastroenterology, Hepatology, and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Patrick Behrendt
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
- German Center for Infection Research, partner site Hannover‐BraunschweigHannoverGermany
- Department of Gastroenterology, Hepatology, and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Johan Neyts
- Rega Institute for Medical Research, Department of Microbiology and ImmunologyKatholieke Universiteit LeuvenLeuvenBelgium
| | - Thomas Pietschmann
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
- German Center for Infection Research, partner site Hannover‐BraunschweigHannoverGermany
| | - Daniel Todt
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
| | - Eike Steinmann
- Institute for Experimental Virology, TWINCORE, Center for Experimental and Clinical Infection ResearchHannoverGermany
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36
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Vercouter A, Meuleman P. Elucidating the differences in pathogenicity between hepatitis E virus genotypes: The quest continues. Hepatol Commun 2018; 2:128-130. [PMID: 29404519 PMCID: PMC5796321 DOI: 10.1002/hep4.1152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 01/10/2018] [Indexed: 12/16/2022] Open
Affiliation(s)
| | - Philip Meuleman
- Laboratory of Liver Infectious DiseasesGhent UniversityGhentBelgium
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37
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Nan Y, Wu C, Zhao Q, Zhou EM. Zoonotic Hepatitis E Virus: An Ignored Risk for Public Health. Front Microbiol 2017; 8:2396. [PMID: 29255453 PMCID: PMC5723051 DOI: 10.3389/fmicb.2017.02396] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 11/20/2017] [Indexed: 12/27/2022] Open
Abstract
Hepatitis E virus (HEV) is a quasi-enveloped, single-stranded positive-sense RNA virus. HEV belongs to the family Hepeviridae, a family comprised of highly diverse viruses originating from various species. Since confirmation of HEV's zoonosis, HEV-induced hepatitis has been a public health concern both for developing and developed countries. Meanwhile, the demonstration of a broad host range for zoonotic HEV suggests the existence of a variety of transmission routes that could lead to human infection. Moreover, anti-HEV antibody serosurveillance worldwide demonstrates a higher than expected HEV prevalence rate that conflicts with the rarity and sporadic nature of reported acute hepatitis E cases. In recent years, chronic HEV infection, HEV-related acute hepatic failure, and extrahepatic manifestations caused by HEV infection have been frequently reported. These observations suggest a significant underestimation of the number and complexity of transmission routes previously predicted to cause HEV-related disease, with special emphasis on zoonotic HEV as a public health concern. Significant research has revealed details regarding the virology and infectivity of zoonotic HEV in both humans and animals. In this review, the discovery of HEV zoonosis, recent progress in our understanding of the zoonotic HEV host range, and classification of diverse HEV or HEV-like isolates from various hosts are reviewed in a historic context. Ultimately, this review focuses on current understanding of viral pathogenesis and cross-species transmission of zoonotic HEV. Moreover, host factors and viral determinants influencing HEV host tropism are discussed to provide new insights into HEV transmission and prevalence mechanisms.
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Affiliation(s)
- Yuchen Nan
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
- Scientific Observing and Experimental Station of Veterinary Pharmacology and Diagnostic Technology, Ministry of Agriculture, Xianyang, China
| | - Chunyan Wu
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
- Scientific Observing and Experimental Station of Veterinary Pharmacology and Diagnostic Technology, Ministry of Agriculture, Xianyang, China
| | - Qin Zhao
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
- Scientific Observing and Experimental Station of Veterinary Pharmacology and Diagnostic Technology, Ministry of Agriculture, Xianyang, China
| | - En-Min Zhou
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Xianyang, China
- Scientific Observing and Experimental Station of Veterinary Pharmacology and Diagnostic Technology, Ministry of Agriculture, Xianyang, China
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38
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Ankcorn MJ, Tedder RS. Hepatitis E: the current state of play. Transfus Med 2017; 27:84-95. [PMID: 28382704 DOI: 10.1111/tme.12405] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 11/08/2016] [Accepted: 02/22/2017] [Indexed: 12/16/2022]
Abstract
The hepatitis E virus (HEV) is a major cause of acute hepatitis globally. Genotypes 1 and 2 (G1 and G2) are obligate human pathogens transmitted faeco-orally, leading to epidemics in developing countries. In contrast, genotypes 3 and 4 (G3 and G4) have a wider host range, including humans, but are primarily porcine viruses and are transmitted from animals to humans as a food-borne zoonosis when meat from an infected animal is consumed. HEV is increasingly recognised as a problem in developed countries, including countries in Europe. G3 HEV is now the most common cause of acute viral hepatitis in the UK and cases continue to rise. The majority of these infections are acquired within the UK and thought to be from insufficiently cooked meat, predominantly processed pork meat. Previously thought to only cause self-limiting disease, HEV infection can persist in immunosuppressed patients, which may lead to chronic hepatitis and the rapid development of cirrhosis. Of particular interest to the transfusion community has been the possibility of transfusion-transmitted HEV, which has been reported from countries classically considered HEV-endemic but also non-endemic countries in Europe and Japan. This has prompted some countries to introduce screening for HEV in blood donations.
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Affiliation(s)
- M J Ankcorn
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK.,Transfusion Microbiology, National Health Service Blood and Transplant, London, UK
| | - R S Tedder
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, London, UK.,Transfusion Microbiology, National Health Service Blood and Transplant, London, UK
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Ricci A, Allende A, Bolton D, Chemaly M, Davies R, Fernandez Escamez PS, Herman L, Koutsoumanis K, Lindqvist R, Nørrung B, Robertson L, Ru G, Sanaa M, Simmons M, Skandamis P, Snary E, Speybroeck N, Ter Kuile B, Threlfall J, Wahlström H, Di Bartolo I, Johne R, Pavio N, Rutjes S, van der Poel W, Vasickova P, Hempen M, Messens W, Rizzi V, Latronico F, Girones R. Public health risks associated with hepatitis E virus (HEV) as a food-borne pathogen. EFSA J 2017; 15:e04886. [PMID: 32625551 PMCID: PMC7010180 DOI: 10.2903/j.efsa.2017.4886] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatitis E virus (HEV) is an important infection in humans in EU/EEA countries, and over the last 10 years more than 21,000 acute clinical cases with 28 fatalities have been notified with an overall 10-fold increase in reported HEV cases; the majority (80%) of cases were reported from France, Germany and the UK. However, as infection in humans is not notifiable in all Member States, and surveillance differs between countries, the number of reported cases is not comparable and the true number of cases would probably be higher. Food-borne transmission of HEV appears to be a major route in Europe; pigs and wild boars are the main source of HEV. Outbreaks and sporadic cases have been identified in immune-competent persons as well as in recognised risk groups such as those with pre-existing liver damage, immunosuppressive illness or receiving immunosuppressive treatments. The opinion reviews current methods for the detection, identification, characterisation and tracing of HEV in food-producing animals and foods, reviews literature on HEV reservoirs and food-borne pathways, examines information on the epidemiology of HEV and its occurrence and persistence in foods, and investigates possible control measures along the food chain. Presently, the only efficient control option for HEV infection from consumption of meat, liver and products derived from animal reservoirs is sufficient heat treatment. The development of validated quantitative and qualitative detection methods, including infectivity assays and consensus molecular typing protocols, is required for the development of quantitative microbial risk assessments and efficient control measures. More research on the epidemiology and control of HEV in pig herds is required in order to minimise the proportion of pigs that remain viraemic or carry high levels of virus in intestinal contents at the time of slaughter. Consumption of raw pig, wild boar and deer meat products should be avoided.
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Kumar N, Das V, Agarwal A, Pandey A, Agrawal S. Fetomaternal outcomes in pregnant women with hepatitis E infection; still an important fetomaternal killer with an unresolved mystery of increased virulence in pregnancy. Turk J Obstet Gynecol 2017; 14:106-113. [PMID: 28913146 PMCID: PMC5558410 DOI: 10.4274/tjod.15045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 04/10/2017] [Indexed: 01/25/2023] Open
Abstract
Objective: Hepatitis is a prevalent infection in developing countries. While hepatitis B and C are deepening their roots in the developed world, hepatitis A and E are common in the developing world. The uniqueness of hepatitis is in its transformation from a relatively self-limiting disease in the non-pregnant state, to a highly virulent disease during pregnancy. Materials and Methods: This retrospective observational study was conducted in the Department of Obstetrics and Gynecology, King George’s Medical University, Lucknow, for a period of six months from June 2016 to November 2016 [probably during an endemic peak of hepatitis E virus (HEV)] to observe the clinical outcomes in HEV-infected pregnant women. Results: A total of 32 anti-HEV immunoglobulin M-positive pregnant women were included, and fetomaternal outcomes were analyzed. Hepatitis E positivity was significantly associated with maternal mortality, intrauterine demise with prematurity, and premature rupture of membranes was the most common fetal complication noted. Conclusion: The difference in extent of virulence of infection and variations in maternal morbidity, mortality, and rates of intrauterine demise, signify the presence of some factors that play a role and need to be further studied and evaluated.
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Affiliation(s)
- Namrata Kumar
- King George's Medical University, Department of Obstetrics and Gynecology, Lucknow, India
| | - Vinita Das
- King George's Medical University, Department of Obstetrics and Gynecology, Lucknow, India
| | - Anjoo Agarwal
- King George's Medical University, Department of Obstetrics and Gynecology, Lucknow, India
| | - Amita Pandey
- King George's Medical University, Department of Obstetrics and Gynecology, Lucknow, India
| | - Smriti Agrawal
- King George's Medical University, Department of Obstetrics and Gynecology, Lucknow, India
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Pérez-Gracia MT, Suay-García B, Mateos-Lindemann ML. Hepatitis E and pregnancy: current state. Rev Med Virol 2017; 27:e1929. [PMID: 28318080 DOI: 10.1002/rmv.1929] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 02/23/2017] [Accepted: 02/24/2017] [Indexed: 12/17/2022]
Abstract
Hepatitis E virus (HEV) is responsible for more than 50% of acute viral hepatitis cases in endemic countries. Approximately 2 billion individuals live in hepatitis E-endemic areas and, therefore, are at risk of infection. According to World Health Organization, HEV causes about 20.1 million infections and 70 000 deaths every year. In developing countries with poor sanitation, this disease is transmitted through contaminated water and is associated with large outbreaks, affecting hundreds or thousands of people. In developed countries, autochthonous cases of HEV have been increasingly recognized in the past several years. Hepatitis E virus typically causes an acute, self-limiting illness similar to other acute viral hepatitis, such as hepatitis A or B, with about 0.2% to 1% mortality rate in the general population. However, the course of hepatitis E in pregnancy is different than the mild self-constraining infection described in other populations. During pregnancy, HEV infection can take a fulminant course, resulting in fulminant hepatic failure, membrane rupture, spontaneous abortions, and stillbirths. Studies from various developing countries have shown a high incidence of HEV infection in pregnancy with a significant proportion of pregnant women progressing to fulminant hepatitis with a fatality rate of up to 30%. The present review will highlight new aspects of the HEV infection and pregnancy.
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Affiliation(s)
- María Teresa Pérez-Gracia
- Área de Microbiología, Departamento de Farmacia, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad CEU Cardenal Herrera, Moncada, Spain
| | - Beatriz Suay-García
- Área de Microbiología, Departamento de Farmacia, Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad CEU Cardenal Herrera, Moncada, Spain
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Hepatitis E Virus in Industrialized Countries: The Silent Threat. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9838041. [PMID: 28070522 PMCID: PMC5192302 DOI: 10.1155/2016/9838041] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 11/07/2016] [Accepted: 11/15/2016] [Indexed: 12/11/2022]
Abstract
Hepatitis E virus (HEV) is the main cause of acute viral hepatitis worldwide. Its presence in developing countries has been documented for decades. Developed countries were supposed to be virus-free and initially only imported cases were detected in those areas. However, sporadic and autochthonous cases of HEV infection have been identified and studies reveal that the virus is worldwide spread. Chronic hepatitis and multiple extrahepatic manifestations have also been associated with HEV. We review the data from European countries, where human, animal, and environmental data have been collected since the 90s. In Europe, autochthonous HEV strains were first detected in the late 90s and early 2000s. Since then, serological data have shown that the virus infects quite frequently the European population and that some species, such as pigs, wild boars, and deer, are reservoirs. HEV strains can be isolated from environmental samples and reach the food chain, as shown by the detection of the virus in mussels and in contaminated pork products as sausages or meat. All these data highlight the need of studies directed to control the sources of HEV to protect immunocompromised individuals that seem the weakest link of the HEV epidemiology in industrialized regions.
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Lhomme S, Marion O, Abravanel F, Chapuy-Regaud S, Kamar N, Izopet J. Hepatitis E Pathogenesis. Viruses 2016; 8:E212. [PMID: 27527210 PMCID: PMC4997574 DOI: 10.3390/v8080212] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 07/22/2016] [Accepted: 07/27/2016] [Indexed: 02/08/2023] Open
Abstract
Although most hepatitis E virus (HEV) infections are asymptomatic, some can be severe, causing fulminant hepatitis and extra-hepatic manifestations, including neurological and kidney injuries. Chronic HEV infections may also occur in immunocompromised patients. This review describes how our understanding of the pathogenesis of HEV infection has progressed in recent years.
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Affiliation(s)
- Sébastien Lhomme
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
| | - Olivier Marion
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
- INSERM, UMR1043, Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, 31000 Toulouse, France.
| | - Florence Abravanel
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
| | - Sabine Chapuy-Regaud
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
| | - Nassim Kamar
- INSERM, UMR1043, Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, 31000 Toulouse, France.
| | - Jacques Izopet
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
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De Paschale M, Ceriani C, Romanò L, Cerulli T, Cagnin D, Cavallari S, Ndayake J, Zaongo D, Diombo K, Priuli G, Viganò P, Clerici P. Epidemiology of hepatitis E virus infection during pregnancy in Benin. Trop Med Int Health 2015; 21:108-113. [PMID: 26523476 DOI: 10.1111/tmi.12632] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
OBJECTIVES Hepatitis E virus (HEV) is the cause of enterically transmitted non-A, non-C hepatitis (an infection that is particularly severe during pregnancy) in tropical and subtropical countries. As there are no published data concerning the prevalence of HEV antibodies in Benin, their presence was investigated in pregnant women undergoing routine HIV screening in a rural area in northern Benin and in pregnant women with acute non-A, non-C hepatitis. METHODS A total of 278 serum samples were collected from asymptomatic pregnant women in 2011 were tested for HEV and hepatitis A virus (HAV) antibodies, and the HEV IgM-positive samples were further tested for HEV-RNA. A further seven samples of pregnant women with acute non-A, non-C hepatitis collected during episodes of acute hepatitis in 2005 were also analysed. RESULTS Of the 278 samples collected in 2011, 16.19% were positive for HEV IgG and 1.44% for HEV IgM (none positive for HEV-RNA), and 99.64% were positive for total HAV antibodies (none positive for HAV IgM). Six of the seven samples collected in 2005 were positive for HEV IgG and IgM, and two were also positive for HEV-RNA. CONCLUSIONS The circulation of HEV infection is significant among pregnant women in Benin, in whom the consequences may be fatal.
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Affiliation(s)
| | | | - Luisa Romanò
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | | | - Debora Cagnin
- Microbiology Unit, Hospital of Legnano, Milan, Italy
| | | | | | | | | | | | - Paolo Viganò
- Infectious Diseases Department, Hospital of Legnano, Milan, Italy
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Lapa D, Capobianchi MR, Garbuglia AR. Epidemiology of Hepatitis E Virus in European Countries. Int J Mol Sci 2015; 16:25711-43. [PMID: 26516843 PMCID: PMC4632823 DOI: 10.3390/ijms161025711] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 09/12/2015] [Accepted: 10/16/2015] [Indexed: 12/22/2022] Open
Abstract
Over the last decade the seroprevalence of immunoglobulin (IgG) anti hepatitis E virus (HEV) has been increasing in European countries and shows significant variability among different geographical areas. In this review, we describe the serological data concerning the general population and risk groups in different European countries. Anti-HEV antibody prevalence ranged from 1.3% (blood donors in Italy) to 52% (blood donors in France). Various studies performed on risk groups in Denmark, Moldova and Sweden revealed that swine farmers have a high seroprevalence of HEV IgG (range 13%-51.1%), confirming that pigs represent an important risk factor in HEV infection in humans. Subtypes 3e,f are the main genotypes detected in the European population. Sporadic cases of autochthonous genotype 4 have been described in Spain, France, and Italy. Although most HEV infections are subclinical, in immune-suppressed and transplant patients they could provoke chronic infection. Fulminant hepatitis has rarely been observed and it was related to genotype 3. Interferon and ribavirin treatment was seen to represent the most promising therapy.
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Affiliation(s)
- Daniele Lapa
- Laboratory of Virology, "Lazzaro Spallanzani" National Institute for Infectious Diseases, Via Portuense 292, Rome 00149, Italy.
| | - Maria Rosaria Capobianchi
- Laboratory of Virology, "Lazzaro Spallanzani" National Institute for Infectious Diseases, Via Portuense 292, Rome 00149, Italy.
| | - Anna Rosa Garbuglia
- Laboratory of Virology, "Lazzaro Spallanzani" National Institute for Infectious Diseases, Via Portuense 292, Rome 00149, Italy.
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Lachish T, Erez O, Daudi N, Shouval D, Schwartz E. Acute hepatitis E virus in pregnant women in Israel and in other industrialized countries. J Clin Virol 2015; 73:20-24. [PMID: 26521225 DOI: 10.1016/j.jcv.2015.10.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 10/10/2015] [Accepted: 10/16/2015] [Indexed: 10/22/2022]
Abstract
BACKGROUND AND OBJECTIVES Acute hepatitis E virus (HEV) is the most common etiology of viral hepatitis in adults in developing countries. HEV is rare in industrialized countries but its incidence is rising both in returning travelers and through autochthonous infection. In developing countries HEV is associated with a high rate of fulminant hepatitis and mortality during pregnancy and contributes to poor obstetric and fetal outcomes. There are no reliable data on the outcome of HEV during pregnancy in industrialized countries. STUDY DESIGN A retrospective analysis of acute HEV cases diagnosed in Israel were examined. The clinical course of the disease among pregnant women was retrieved. A systematic review of the literature was performed for cases of HEV and pregnancy, originating or treated in industrialized countries RESULTS Between the years 1993-2013, 68 cases of acute HEV were diagnosed in Israel, including 9 pregnant women (13%). An additional 6 reported cases were found from a literature search. From the 15 women (10 autochthonous cases and 5 imported cases), the outcome was favorable in 10 cases, however, 5 cases (33%) resulted in fulminant hepatitis and two women underwent an urgent liver transplantation. No fatality occurred in the mothers and all babies were born alive and healthy. DISCUSSION This is the first case series of acute HEV infection in pregnant women in industrialized countries. Acute HEV infection poses a significant risk in pregnancy, irrespective of patients' country of origin. In contrast to reports from developing countries, all babies and mothers survived.
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Affiliation(s)
- Tamar Lachish
- The Infectious Diseases Unit, Shaare-Zedek Medical Center, Jerusalem, Israel.
| | - Ortal Erez
- The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
| | - Nili Daudi
- The Liver Unit, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
| | - Daniel Shouval
- The Liver Unit, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
| | - Eli Schwartz
- The Center for Geographic Medicine and Department of Medicine C, Sheba Medical Center, Tel Hashomer and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
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47
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[Hepatitis E virus: opinions of the Working Group of the Federal Ministry of Health Blood]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2015; 58:198-218. [PMID: 25608627 DOI: 10.1007/s00103-014-2103-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Zhang Y, Zeng H, Liu P, Liu L, Xia J, Wang L, Zou Q, Wang L, Zhuang H. Hepatitis E vaccine immunization for rabbits to prevent animal HEV infection and zoonotic transmission. Vaccine 2015. [PMID: 26212003 DOI: 10.1016/j.vaccine.2015.07.040] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Hepatitis E virus (HEV) infection has become a significant global public health concern as increasing cases of acute and chronic hepatitis E are reported. HEV of animal origin was proved to be a possible source of human infection and a previous study showed that the recent licensed HEV 239 vaccine can serve as a candidate vaccine to manage animal sources of HEV infection. However, previous immunization strategy for rabbits was the same as that for human, which is too costly to conduct large-scale animal vaccination. In an effort to reduce the costs, three vaccination schemes were assessed in the present study. Forty specific pathogen-free (SPF) rabbits were divided randomly into five groups with eight animals for each and inoculated intramuscularly with different doses of HEV 239 and placebo, respectively. All animals were challenged intravenously with swine HEV-4 and rabbit HEV of different titers 7 weeks after the initial immunization and then fecal virus excretion was monitored for 10 weeks. The results indicated that immunizing rabbits with two 10μg doses of the vaccine is superior to vaccination with two 20μg doses or a single 30μg dose, which can protect rabbits against homologous and heterologous HEV infection. These findings could enable implementation of large-scale animal vaccination to prevent rabbit HEV infection and zoonotic transmission.
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Affiliation(s)
- Yulin Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Hang Zeng
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Peng Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Liu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Junke Xia
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Lin Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Qinghua Zou
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Ling Wang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
| | - Hui Zhuang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
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Pauli G, Aepfelbacher M, Bauerfeind U, Blümel J, Burger R, Gärtner B, Gröner A, Gürtler L, Heiden M, Hildebrandt M, Jansen B, Offergeld R, Schlenkrich U, Schottstedt V, Seitz R, Strobel J, Willkommen H, Baylis SA. Hepatitis E Virus. Transfus Med Hemother 2015; 42:247-65. [PMID: 26557817 DOI: 10.1159/000431191] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 02/10/2015] [Indexed: 12/12/2022] Open
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50
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Sayed IM, Vercauteren K, Abdelwahab SF, Meuleman P. The emergence of hepatitis E virus in Europe. Future Virol 2015. [DOI: 10.2217/fvl.15.29] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
ABSTRACT Hepatitis E virus (HEV) infections appear to be an emerging problem in Europe. Infections are mainly caused by viruses of genotype 3. Pigs and wild boar are the main reservoirs of HEV in Europe and most autochthonous infections are probably caused by the consumption of uncooked or undercooked infected meat. Nevertheless, transfusion-associated transmission has been described in different European countries but the efficiency of this route of transmission need to be further investigated. Most acute infections are asymptomatic or the induced symptoms are rather nonspecific. Although people that are otherwise completely healthy can spontaneously clear an HEV infection, people with underlying liver disease and/or suffering from immune deficiencies may require treatment to avoid chronicity and exacerbation of liver disease. In this review, we give an epidemiological overview of HEV in Europe and the potential complications.
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Affiliation(s)
- Ibrahim M Sayed
- Center for Vaccinology, Ghent University, Ghent University Hospital, B-9000 Gent, Belgium
- Microbiology & Immunology Department, Faculty of Medicine, Assuit University, Assuit 71515, Egypt
| | - Koen Vercauteren
- Center for Vaccinology, Ghent University, Ghent University Hospital, B-9000 Gent, Belgium
| | - Sayed F Abdelwahab
- Microbiology and Immunology Department, Faculty of Medicine, Minia University, Minia 61511, Egypt
| | - Philip Meuleman
- Center for Vaccinology, Ghent University, Ghent University Hospital, B-9000 Gent, Belgium
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