|
1
|
Castagna F, Liguori G, Lombardi R, Bava R, Costagliola A, Giordano A, Quintiliani M, Giacomini D, Albergo F, Gigliotti A, Lupia C, Ceniti C, Tilocca B, Palma E, Roncada P, Britti D. Hepatitis E and Potential Public Health Implications from a One-Health Perspective: Special Focus on the European Wild Boar ( Sus scrofa). Pathogens 2024; 13:840. [PMID: 39452712 PMCID: PMC11510200 DOI: 10.3390/pathogens13100840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/26/2024] Open
Abstract
The hepatitis E virus (HEV) has become increasingly important in recent years in terms of risk for public health, as the main causative agent of acute viral hepatitis. It is a foodborne disease transmitted to humans through the consumption of contaminated water or contaminated food. Human-to-human transmission is sporadic and is linked to transfusions or transplants. The main reservoirs of the hepatitis E virus are domestic pigs and wild boars, although, compared to pigs, wild boars represent a lesser source of risk since their population is smaller and the consumption of derived products is more limited. These peculiarities often make the role of the wild boar reservoir in the spread of the disease underestimated. As a public health problem that involves several animal species and humans, the management of the disease requires an interdisciplinary approach, and the concept of "One Health" must be addressed. In this direction, the present review intends to analyze viral hepatitis E, with a particular focus on wild boar. For this purpose, literature data have been collected from different scientific search engines: PubMed, MEDLINE, and Google scholar, and several keywords such as "HEV epidemiology", "Extrahepatic manifestations of Hepatitis E", and "HEV infection control measures", among others, have been used. In the first part, the manuscript provides general information on the disease, such as epidemiology, transmission methods, clinical manifestations and implications on public health. In the second part, it addresses in more detail the role of wild boar as a reservoir and the implications related to the virus epidemiology. The document will be useful to all those who intend to analyze this infectious disease from a "One-Health" perspective.
Collapse
Affiliation(s)
- Fabio Castagna
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
- Mediterranean Ethnobotanical Conservatory, 88054 Catanzaro, Italy;
| | - Giovanna Liguori
- Local Health Authority, ASL, 71121 Foggia, Italy; (G.L.); (R.L.)
| | - Renato Lombardi
- Local Health Authority, ASL, 71121 Foggia, Italy; (G.L.); (R.L.)
| | - Roberto Bava
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| | - Anna Costagliola
- Department of Veterinary Medicine and Animal Productions, University of Napoli Federico II, 80100 Naples, Italy;
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Department of Biology, College of Science and Technology, Temple University, 1900 N 12th Street, Philadelphia, PA 19122, USA;
- Department of Medical Biotechnology, University of Siena, 10100 Siena, Italy
| | | | | | - Francesco Albergo
- Department of Management, Finance and Technology, University LUM Giuseppe Degennaro, 70100 Casamassima, Italy;
| | - Andrea Gigliotti
- Interregional Park of Sasso Simone and Simoncello, 61021 Carpegna, Italy;
| | - Carmine Lupia
- Mediterranean Ethnobotanical Conservatory, 88054 Catanzaro, Italy;
| | - Carlotta Ceniti
- ASL Napoli 3 SUD, Department of Prevention, 80053 Castellammare di Stabia, Italy;
| | - Bruno Tilocca
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| | - Ernesto Palma
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| | - Paola Roncada
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| | - Domenico Britti
- Department of Health Sciences, University of Catanzaro Magna Græcia, 88100 Catanzaro, Italy; (F.C.); (B.T.); (E.P.); (P.R.); (D.B.)
| |
Collapse
|
|
2
|
Li X, Sun X, Pinpin J, Zhao Q, Sun Y. Multifunctional ORF3 protein of hepatitis E virus. J Med Virol 2024; 96:e29691. [PMID: 38783788 DOI: 10.1002/jmv.29691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/23/2024] [Accepted: 05/14/2024] [Indexed: 05/25/2024]
Abstract
Hepatitis E virus (HEV) is an emerging zoonotic pathogen that is transmitted primarily through the fecal-oral route and can cause acute hepatitis in humans. Since HEV was identified as a zoonotic pathogen, different species of HEV strains have been globally identified from various hosts, leading to an expanding range of hosts. The HEV genome consists of a 5' noncoding region, three open reading frames (ORFs), and a 3' noncoding region. The ORF3 protein is the smallest but has many functions in HEV release and pathogenesis. In this review, we systematically summarize recent progress in understanding the functions of the HEV ORF3 protein in virion release, biogenesis of quasi-enveloped viruses, antigenicity, and host environmental regulation. This review will help us to understand HEV replication and pathogenesis mechanisms better.
Collapse
Affiliation(s)
- Xiaoxuan Li
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| | - Xuwen Sun
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| | - Ji Pinpin
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| | - Qin Zhao
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| | - Yani Sun
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, Shaanxi, China
| |
Collapse
|
|
3
|
Subramaniam S, Fares-Gusmao R, McGivern DR. Quantification of Hepatitis E Virus ORF2 Protein by a Novel Sandwich ELISA. Viruses 2024; 16:393. [PMID: 38543759 PMCID: PMC10974087 DOI: 10.3390/v16030393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/21/2024] [Accepted: 02/28/2024] [Indexed: 05/23/2024] Open
Abstract
Hepatitis E virus (HEV) causes acute hepatitis in humans, which can progress to chronicity in immunosuppressed individuals. Almost all reported HEV infections are caused by Paslahepevirus balayani genotypes 1-4. The structural ORF2 protein is the major antigen detected in the blood of HEV-infected individuals. ELISA assays to detect IgM antibodies to HEV are the first-line diagnostic tests; however, they showed variable performance with frequently discordant results. A qualitative HEV antigen (ORF2) ELISA is currently available for research use. Here, we report a novel quantitative sandwich ELISA to measure HEV ORF2 protein in 3 matrix types. An optimal pair of capture and detection antibodies was selected among 12 unique combinations tested. A sandwich ELISA protocol was developed using these mAbs and biotin-streptavidin technology. The protocol was further optimized to quantify ORF2 antigen in different matrices by interpolating from a standard curve with a linear range of 3.17 to 50.8 femtomoles/mL. Using this method, ORF2 protein was detected in the cell culture medium of Huh7 cells as early as 2-3 days after transfection with HEV genome RNA and in a medium of human hepatocytes infected with HEV. ORF2 antigen was readily detected in the first 2 weeks post-HEV infection in gerbil sera. In immunosuppressed gerbils, ORF2 was detected up to 6 weeks, and the levels were significantly higher between 3 and 6 weeks post-infection. HEV ORF2 antigen levels showed a strong positive correlation with HEV RNA levels in both cell culture medium and gerbil sera. Our novel sandwich ELISA detected at least 7.3 femtomoles/mL ORF2 protein in human plasma spiked with cell culture propagated HEV and detected ORF2 protein in human plasma samples that tested positive for HEV RNA but negative for anti-HEV antibodies. Further, the assay was nonreactive, with negative human plasma, and HBV or HCV-positive human plasma demonstrating specificity. Overall, our ORF2 antigen ELISA will be useful for quantifying ORF2 antigen in cell culture medium, gerbil serum, and human plasma. Further studies are warranted to evaluate its utility in HEV clinical diagnosis.
Collapse
Affiliation(s)
| | | | - David R. McGivern
- Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA; (S.S.); (R.F.-G.)
| |
Collapse
|
|
4
|
Chen Z, Li G, Situ J, Li Z, Guo S, Huang Y, Wu S, Tang Z, Wen G, Wang S, Fang M, Wang Y, Yu H, Sridhar S, Zheng Z, Xia N. Redeveloping antigen detection kits for the diagnosis of rat hepatitis E virus. J Clin Microbiol 2023; 61:e0071023. [PMID: 38038482 PMCID: PMC10729709 DOI: 10.1128/jcm.00710-23] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 10/07/2023] [Indexed: 12/02/2023] Open
Abstract
The emergence of Rocahepevirus ratti [species HEV ratti (r HEV)] as a causative agent of hepatitis E in humans presents a new potential threat to global public health. The R. ratti genotype 1 (r-1 HEV) variant only shares 50%-60% genomic identity with Paslahepevirus balayani [species HEV balayani (b HEV)] variants, which are the main causes of hepatitis E infection in humans. Here, we report antigen diagnoses for r-1 HEV and b HEV using an enzymatic immunoassay (EIA) method. We detected recombinant virus-like particles protein (HEV 239) of r HEV and b HEV using a collection of hepatitis E virus (HEV)-specific monoclonal antibodies. Two optimal candidates, the capture antibody P#1-H4 and the detection antibodies C145 (P#1-H4*/C145#) and C158 (P#1-H4*/C158#), were selected to detect antigen in infected rat samples and r-1 HEV- or b HEV-infected human clinical samples. The two candidates showed similar diagnostic efficacy to the Wantai HEV antigen kit in b HEV-infected clinical samples. Genomic divergence resulted in low diagnostic efficacy of the Wantai HEV antigen kit (0%, 0 of 10) for detecting r-1 HEV infection. Compared with the P#1-H4*/C145# candidate (80%, 8 of 10), the P#1-H4*/C158# candidate had excellent diagnostic efficacy in r-1 HEV-infected clinical samples (100%, 10 of 10). The two candidates bind to a discrete antigenic site that is highly conserved across r HEV and b HEV. P#1-H4*/C145# and P#1-H4*/C158# are efficacious candidate antibody combinations for rat HEV antigen detection.
Collapse
Affiliation(s)
- Zihao Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Guanghui Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Jianwen Situ
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Zhiyong Li
- The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Shaoqi Guo
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Yang Huang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Shusheng Wu
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Zimin Tang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Guiping Wen
- United Diagnostic and Research Center for Clinical Genetics, Women and Children’s Hospital, School of Medicine & School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Siling Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Mujin Fang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Yingbin Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Hai Yu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Siddharth Sridhar
- Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong, China
- Carol Yu Centre for Infection, The University of Hong Kong, Hong Kong, China
| | - Zizheng Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, Fujian, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
- Research Unit of Frontier Technology of Structural Vaccinology, Chinese Academy of Medical Sciences, Xiamen, Fujian, China
| |
Collapse
|
|
5
|
Tang ZM, Wen GP, Ying D, Wang SL, Liu C, Tian WK, Wang YB, Fang MJ, Zhou YL, Ge YS, Wu T, Zhang J, Huang SJ, Zheng ZZ, Xia NS. Profile of clinical characteristics and serologic markers of sporadic hepatitis E in a community cohort study. Emerg Microbes Infect 2023; 12:2140613. [PMID: 36314245 PMCID: PMC9769141 DOI: 10.1080/22221751.2022.2140613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatitis E virus (HEV) is a pathogen of global significance, but the value of HEV-related markers in the diagnosis of hepatitis E remains controversial. Previous studies on hepatitis E profiles have been mainly cross-sectional and conducted among inpatients in large hospitals, and hepatitis E cases have been primarily defined by limited partial markers. In this community-based study, 4,110 active hepatitis cases from a population of nearly 600,000 were followed over 48 months and serial serum samples were collected. Both HEV pathogen (HEV RNA and antigen) and anti-HEV antibody markers were used to determine HEV infection status and the relationship between hepatitis and HEV infection. In total, 98 hepatitis E patients were identified and all available isolates from 58 patients belonged to HEV genotype 4. The mean age of the patients was 58.14 years, with an overwhelming proportion of males (70.4%). Hepatitis E accounted for 22.86% of active hepatitis cases with alanine aminotransferase levels ≥15.0-fold the upper limit of normal, suggesting the need to include HEV in routine testing for these patients. Ninety-two hepatitis E patients were positive for at least 2 of HEV antigen, anti-HEV IgM, and HEV RNA markers at presentation, and 90.22% of them were positive for HEV antigen and anti-HEV IgM. HEV antigen, HEV RNA, and anti-HEV IgM positivity were observed in 89.80%, 82.65%, and 93.88% of hepatitis E patients at presentation, respectively. However, only 57.14% of anti-HEV IgM positivity occurred in hepatitis E patients. These findings will advance our understanding of hepatitis E and improve diagnosis.
Collapse
Affiliation(s)
- 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, PR People’s Republic of China,NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Gui-Ping Wen
- 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, PR People’s Republic of 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, PR People’s Republic of China
| | - Dong Ying
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China,School of Life Sciences, Xiamen University, Xiamen, PR People’s Republic of China
| | - Si-Ling Wang
- 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, PR People’s Republic of 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, PR People’s Republic of China
| | - Wei-Kun Tian
- 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, PR People’s Republic of China
| | - Ying-Bin Wang
- 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, PR People’s Republic of China
| | - Mu-Jin Fang
- 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, PR People’s Republic of China,NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Yu-Lin Zhou
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Yun-Sheng Ge
- United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China
| | - Ting Wu
- 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, PR People’s Republic of China
| | - Jun Zhang
- 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, PR People’s Republic of China
| | - Shou-Jie Huang
- 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, PR People’s Republic of China, Shou-Jie Huang ; Zi-Zheng Zheng ; Ning-Shao Xia National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiangan South Road, Xiamen, Fujian, 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, PR People’s Republic of China, Shou-Jie Huang ; Zi-Zheng Zheng ; Ning-Shao Xia National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiangan South Road, Xiamen, Fujian, 361102, China
| | - Ning-Shao Xia
- 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, PR People’s Republic of China,NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, School of Public Health, Xiamen University, Xiamen, PR People’s Republic of China,School of Life Sciences, Xiamen University, Xiamen, PR People’s Republic of China, Shou-Jie Huang ; Zi-Zheng Zheng ; Ning-Shao Xia National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiangan South Road, Xiamen, Fujian, 361102, China
| |
Collapse
|
|
6
|
Younes N, Yassine HM, Nizamuddin PB, Kourentzi K, Tang P, Ayoub HH, Khalili M, Coyle PV, Litvinov D, Willson RC, Abu-Raddad LJ, Nasrallah GK. Seroprevalence of hepatitis E virus (HEV) among male craft and manual workers in Qatar (2020-2021). Heliyon 2023; 9:e21404. [PMID: 38027884 PMCID: PMC10660033 DOI: 10.1016/j.heliyon.2023.e21404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 10/19/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Background The rapid growth of Qatar in the last two decades has attracted a large influx of immigrant craft and manual workers (CMWs) seeking employment in jobs associated with food handling, domestic service, and construction. Nearly 60 % of Qatar's population are expatriates CMWs, including many from hyperendemic countries for HEV. Thus, estimating the seroprevalence of HEV in Qatar and understanding its epidemiology is essential for public health efforts to control HEV transmission in Qatar. Methods Blood samples from 2670 CMWs were collected between 2020 and 2021. All samples were tested for HEV-IgG antibodies. Positive HEV-IgG samples were tested for HEV-IgM antibodies, and those positives were also tested for viral antigens using an HEV-Ag ELISA kit and HEV-RNA by RT-PCR to confirm current HEV infections. Results The seroprevalence of HEV-IgG was 27.3 % (729/2670; 95 % CI: 25.6-29.0). Of those HEV-IgG positive, 8.23 % (60/729; 95 % CI: 6.30-10.5) were HEV-IgM positive. Of the IgM-positive samples, 2 were HEV-RNA positive (3.39 %; 95 % CI: 0.40-11.7), and 1 was HEV-Ag positive (1.69 %; 95 % CI: 0.04-9.09). In addition, HEV-IgG seroprevalence was associated with age and nationality, with the highest seroprevalence in participants from Egypt (IgG 60.0 %; IgM 5.56 %), Pakistan (IgG 59.0 %; IgM 2.24 %), Nepal (IgG 29.3 %; IgM 2.70 %), Bangladesh (IgG 27.8 %; IgM 2.45 %), and India (IgG 23.9 %; IgM 2.43 %). Conclusion In this study, we showed that the seroprevalence of HEV among CMWs was slightly higher than what was previously reported among the urban population in Qatar (2013-2016).
Collapse
Affiliation(s)
- Nadin Younes
- Biomedical Research Center, Qatar University, Doha, 2713, Qatar
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Doha, 2713, Qatar
| | - Hadi M. Yassine
- Biomedical Research Center, Qatar University, Doha, 2713, Qatar
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Doha, 2713, Qatar
| | | | - Katerina Kourentzi
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
| | - Patrick Tang
- Division of Microbiology, Sidra Medicine, Doha, 26999, Qatar
| | - Houssein H. Ayoub
- Mathematics Program, Department of Mathematics, Statistics, and Physics, College of Arts and Sciences, Qatar University, Doha, 2713, Qatar
| | - Makiyeh Khalili
- Department of Laboratory Medicine, Hamad Medical Corporation, Doha, 3050, Qatar
| | - Peter V. Coyle
- Department of Pediatrics, Women's Wellness and Research Center, Hamad Medical Corporation, Doha, 3050, Qatar
| | - Dmitri Litvinov
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
- Center for Integrated Bio & Nano Systems, University of Houston, Houston, TX 77204, USA
| | - Richard C. Willson
- William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA
- Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA
| | - Laith J. Abu-Raddad
- Infectious Disease Epidemiology Group, Weill Cornell Medicine-Qatar, Cornell University, Doha, Qatar
- World Health Organization Collaborating Centre for Disease Epidemiology Analytics on HIV/AIDS, Sexually Transmitted Infections, and Viral Hepatitis, Weill Cornell Medicine-Qatar, Cornell University, Doha, Qatar
- Department of Population Health Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - Gheyath K. Nasrallah
- Biomedical Research Center, Qatar University, Doha, 2713, Qatar
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Doha, 2713, Qatar
| |
Collapse
|
|
7
|
Songtanin B, Molehin AJ, Brittan K, Manatsathit W, Nugent K. Hepatitis E Virus Infections: Epidemiology, Genetic Diversity, and Clinical Considerations. Viruses 2023; 15:1389. [PMID: 37376687 DOI: 10.3390/v15061389] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
According to the World Health Organization, approximately 20 million people worldwide are infected annually with the hepatitis E virus (HEV). There are four main genotypes of HEV. Genotype 1 and genotype 2 are common in developing countries and are transmitted by contaminated water from a fecal-oral route. Genotype 3 and genotype 4 are common in developed countries and can lead to occasional transmission to humans via undercooked meat. Hepatitis E virus 1 and HEV3 can lead to fulminant hepatitis, and HEV3 can lead to chronic hepatitis and cirrhosis in immunocompromised patients. The majority of patients with HEV infection are asymptomatic and usually have spontaneous viral clearance without treatment. However, infection in immunocompromised individuals can lead to chronic HEV infection. Both acute and chronic HEV infections can have extrahepatic manifestations. No specific treatment is required for acute HEV infection, no treatment has been approved in chronic infection, and no HEV vaccine has been approved by the (United States) Food and Drug Administration. This review focuses on the molecular virology (HEV life cycle, genotypes, model systems, zoonosis), pathogenesis, clinical manifestation, and treatment of chronic HEV infection, especially in immunocompromised patients, to provide clinicians a better understanding of the global distribution of these infections and the significant effect they can have on immunocompromised patients.
Collapse
Affiliation(s)
- Busara Songtanin
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Adebayo J Molehin
- Department of Microbiology & Immunology, College of Graduate Studies, Midwestern University, Glendale, AZ 85308, USA
| | - Kevin Brittan
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Wuttiporn Manatsathit
- Department of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| |
Collapse
|
|
8
|
Prpić J, Kunić A, Keros T, Lojkić I, Brnić D, Jemeršić L. Absence of Hepatitis E Virus (HEV) Circulation in the Most Widespread Wild Croatian Canine Species, the Red Fox ( Vulpes vulpes) and Jackal ( Canis aureus moreoticus). Microorganisms 2023; 11:microorganisms11040834. [PMID: 37110256 PMCID: PMC10145003 DOI: 10.3390/microorganisms11040834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/11/2023] [Accepted: 03/22/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatitis E virus (HEV) can infect a wide range of domestic and wild animals, and the identification of new host species is reported successively worldwide. Nevertheless, its zoonotic potential and natural transmission, especially in wildlife remains unclear, primarily due to the discrete nature of HEV infections. Since the red fox (Vulpus vulpus) is the most widespread carnivore worldwide, and has been recognized as a potential HEV reservoir, its role as a potent host species is of increasing interest. Another wild canine species, the jackal （Canis aureus moreoticus）, is becoming more important within the same habitat as that of the red fox since its number and geographical distribution have been rapidly growing. Therefore, we have chosen these wild species to determine their potential role in the epidemiology and persistence of HEV in the wilderness. The main reason for this is the finding of HEV and a rather high HEV seroprevalence in wild boars sharing the same ecological niche as the wild canine species, as well as the risk of the spread of HEV through red foxes into the outskirts of cities, where possible indirect and even direct contact with people are not excluded. Therefore, our study aimed to investigate the possibility of natural HEV infection of free-living wild canines, by testing samples for the presence of HEV RNA and anti-HEV antibodies to gain better epidemiological knowledge of the disease. For this purpose, 692 red fox and 171 jackal muscle extracts and feces samples were tested. Neither HEV RNA nor anti-HEV antibodies were detected. Although HEV circulation was not detected in the tested samples, to our knowledge, these are the first results that include jackals as a growing and important omnivore wildlife species for the presence of HEV infection in Europe.
Collapse
Affiliation(s)
- Jelena Prpić
- Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| | - Ana Kunić
- Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| | - Tomislav Keros
- Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| | - Ivana Lojkić
- Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| | - Dragan Brnić
- Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| | - Lorena Jemeršić
- Croatian Veterinary Institute, Savska cesta 143, 10000 Zagreb, Croatia
| |
Collapse
|
|
9
|
Zhao C, Wang Y. Laboratory Diagnosis of HEV Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:199-213. [PMID: 37223868 DOI: 10.1007/978-981-99-1304-6_14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Serological and nucleic acid tests for detecting hepatitis E virus (HEV) have been developed for both epidemiologic and diagnostic purposes. The laboratory diagnosis of HEV infection depends on the detection of HEV antigen or HEV RNA in the blood, stool, and other body fluids, and serum antibodies against HEV (immunoglobulin [Ig]A, IgM, and IgG). Anti-HEV IgM antibodies and low avidity IgG can be detected during the acute phase of the illness and can last approximately 12 months, representing primary infection, whereas anti-HEV IgG antibodies can last more than several years, representing remote exposure. Thus, the diagnosis of acute infection is based on the presence of anti-HEV IgM, low avidity IgG, HEV antigen, and HEV RNA, while epidemiological investigations are mainly based on anti-HEV IgG. Although significant progress has been made in developing and optimizing different formats of HEV assays, improving their sensitivity and specificity, there are many shortcomings and challenges in inter-assay concordance, validation, and standardization. This article reviews the current knowledge on the diagnosis of HEV infection, including the most common available laboratory diagnostic techniques.
Collapse
Affiliation(s)
- Chenyan Zhao
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Youchun Wang
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming, China.
| |
Collapse
|
|
10
|
Sayed IM, Karam-Allah Ramadan H, Hafez MHR, Elkhawaga AA, El-Mokhtar MA. Hepatitis E virus (HEV) open reading frame 2: Role in pathogenesis and diagnosis in HEV infections. Rev Med Virol 2022; 32:e2401. [PMID: 36209386 DOI: 10.1002/rmv.2401] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/12/2022]
Abstract
Hepatitis E virus (HEV) infection occurs worldwide. The HEV genome includes three to four open reading frames (ORF1-4). ORF1 proteins are essential for viral replication, while the ORF3 protein is an ion channel involved in the exit of HEV from the infected cells. ORF2 proteins form the viral capsid required for HEV invasion and assembly. They also suppress interferon production and inhibit antibody-mediated neutralisation of HEV, allowing the virus to hijack the host immune response. ORF2 is the only detectable viral protein in the human liver during HEV infection and it is secreted in the plasma, stool, and urine of HEV-infected patients, making it a reliable diagnostic marker. The plasma HEV ORF2 antigen level can predict the outcome of HEV infections. Hence, monitoring HEV ORF2 antigen levels may be useful in assessing the efficacy of anti-HEV therapy. The ORF2 antigen is immunogenic and includes epitopes that can induce neutralising antibodies; therefore, it is a potential HEV vaccine candidate. In this review, we highlighted the different forms of HEV ORF2 protein and their roles in HEV pathogenesis, diagnosis, monitoring the therapeutic efficacy, and vaccine development.
Collapse
Affiliation(s)
- Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Haidi Karam-Allah Ramadan
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud H R Hafez
- International Scholar, African Leadership Academy, Johannesburg, South Africa
| | - Amal A Elkhawaga
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Microbiology and Immunology Department, Faculty of Pharmacy, Sphinx University, Assiut, Egypt
| |
Collapse
|
|
11
|
Shata MTM, Hetta HF, Sharma Y, Sherman KE. Viral hepatitis in pregnancy. J Viral Hepat 2022; 29:844-861. [PMID: 35748741 PMCID: PMC9541692 DOI: 10.1111/jvh.13725] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/17/2021] [Accepted: 06/13/2022] [Indexed: 12/09/2022]
Abstract
Viral hepatitis is caused by a heterogenous group of viral agents representing a wide range of phylogenetic groups. Many viruses can involve the liver and cause liver injury but only a subset are delineated as 'hepatitis viruses' based upon their primary site of replication and tropism for hepatocytes which make up the bulk of the liver cell population. Since their discovery, beginning with the agent that caused serum hepatitis in the 1960s, the alphabetic designations have been utilized. To date, we have five hepatitis viruses, A through E, though it is postulated that others may exist. This chapter will focus on those viruses. Note that hepatitis D is included as a subset of hepatitis B, as it cannot exist without concurrent hepatitis B infection. Pregnancy has the potential to affect all aspects of these viral agents due to the unique immunologic and physiologic changes that occur during and after the gestational period. In this review, we will discuss the most common viral hepatitis and their effects during pregnancy.
Collapse
Affiliation(s)
- Mohamed Tarek M. Shata
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
| | - Helal F. Hetta
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA,Department of Medical Microbiology and Immunology, Faculty of MedicineAssiut UniversityAssiutEgypt
| | - Yeshika Sharma
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
| | - Kenneth E. Sherman
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
| |
Collapse
|
|
12
|
A Secreted Form of the Hepatitis E Virus ORF2 Protein: Design Strategy, Antigenicity and Immunogenicity. Viruses 2022; 14:v14102122. [PMID: 36298677 PMCID: PMC9610824 DOI: 10.3390/v14102122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/10/2022] [Accepted: 09/17/2022] [Indexed: 11/17/2022] Open
Abstract
Hepatitis E virus (HEV) is an important public health burden worldwide, causing approximately 20 million infections and 70,000 deaths annually. The viral capsid protein is encoded by open reading frame 2 (ORF2) of the HEV genome. Most ORF2 protein present in body fluids is the glycosylated secreted form of the protein (ORF2S). A recent study suggested that ORF2S is not necessary for the HEV life cycle. A previously reported efficient HEV cell culture system can be used to understand the origin and life cycle of ORF2S but is not sufficient for functional research. A more rapid and productive method for yielding ORF2S could help to study its antigenicity and immunogenicity. In this study, the ORF2S (tPA) expression construct was designed as a candidate tool. A set of representative anti-HEV monoclonal antibodies was further used to map the functional antigenic sites in the candidates. ORF2S (tPA) was used to study antigenicity and immunogenicity. Indirect ELISA revealed that ORF2S (tPA) was not antigenically identical to HEV 239 antigen (p239). The ORF2S-specific antibodies were successfully induced in one-dose-vaccinated BALB/c mice. The ORF2S-specific antibody response was detected in plasma from HEV-infected patients. Recombinant ORF2S (tPA) can act as a decoy to against B cells. Altogether, our study presents a design strategy for ORF2S expression and indicates that ORF2S (tPA) can be used for functional and structural studies of the HEV life cycle.
Collapse
|
|
13
|
Velavan TP, Pallerla SR, Johne R, Todt D, Steinmann E, Schemmerer M, Wenzel JJ, Hofmann J, Shih JWK, Wedemeyer H, Bock CT. Hepatitis E: An update on One Health and clinical medicine. Liver Int 2021; 41:1462-1473. [PMID: 33960603 DOI: 10.1111/liv.14912] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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.
Collapse
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
| |
Collapse
|
|
14
|
Sanabria-Cabrera J, Sanjuán-Jiménez R, Clavijo E, Medina-Cáliz I, González-Jiménez A, García-Cortés M, Ortega-Alonso A, Jiménez-Pérez M, González-Grande R, Stephens C, Robles-Díaz M, Lucena MI, Andrade RJ. Incidence and prevalence of acute hepatitis E virus infection in patients with suspected Drug-Induced Liver Injury in the Spanish DILI Registry. Liver Int 2021; 41:1523-1531. [PMID: 33107176 DOI: 10.1111/liv.14713] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 09/23/2020] [Accepted: 10/16/2020] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS Drug-induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti-HEV seroprevalence rate. METHODS An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti-HEV Immunoglobulin (Ig) G antibodies were analysed in serum from all subjects. In those with serum samples extracted within 6 months from liver damage onset (n = 144), HEV antigen (Ag) and anti-HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT-PCR was performed externally in eight patients. RESULTS Out of 144 patients, 12 (8%) were positive for anti-HEV IgM, mean age was 61 years. Underlying hepatic diseases (OR = 23.4, P < .001) and AST peak >20 fold upper limit of normal (OR = 10.9, P = .002) were associated with the diagnosis of acute hepatitis E. The overall anti-HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%). CONCLUSIONS HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels.
Collapse
Affiliation(s)
- Judith Sanabria-Cabrera
- UICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Universidad de Malaga, Málaga, Spain
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Rocío Sanjuán-Jiménez
- UICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Universidad de Malaga, Málaga, Spain
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Encarnación Clavijo
- Servicio de Microbiología, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Inmaculada Medina-Cáliz
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Andrés González-Jiménez
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Miren García-Cortés
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
- CIBERehd (Centro de Investigación Biomédica en Red de enfermedades Hepáticas y Digestivas), Madrid, Spain
| | - Aida Ortega-Alonso
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
| | - Miguel Jiménez-Pérez
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Regional de Málaga, Málaga, Spain
| | - Rocío González-Grande
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Regional de Málaga, Málaga, Spain
| | - Camilla Stephens
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
- CIBERehd (Centro de Investigación Biomédica en Red de enfermedades Hepáticas y Digestivas), Madrid, Spain
| | - Mercedes Robles-Díaz
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
- CIBERehd (Centro de Investigación Biomédica en Red de enfermedades Hepáticas y Digestivas), Madrid, Spain
| | - M Isabel Lucena
- UICEC IBIMA, Plataforma SCReN (Spanish Clinical Research Network), Servicio de Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Universidad de Malaga, Málaga, Spain
- CIBERehd (Centro de Investigación Biomédica en Red de enfermedades Hepáticas y Digestivas), Madrid, Spain
| | - Raúl J Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain
- CIBERehd (Centro de Investigación Biomédica en Red de enfermedades Hepáticas y Digestivas), Madrid, Spain
| |
Collapse
|
|
15
|
Al Absi ES, Al-Sadeq DW, Khalili M, Younes N, Al-Dewik N, Abdelghany SK, Abouzid SS, Al Thani AA, Yassine HM, Coyle PV, Nasrallah GK. The prevalence of HEV among non-A-C hepatitis in Qatar and efficiency of serological markers for the diagnosis of hepatitis E. BMC Gastroenterol 2021; 21:266. [PMID: 34130641 PMCID: PMC8207580 DOI: 10.1186/s12876-021-01841-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 06/08/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The rapid growth of Qatar in the last two decades has attracted a large influx of immigrant workers who mostly come from HEV-hyperendemic countries. Thus, we aim to investigate the prevalence of HEV among acute non-A-C hepatitis patients in Qatar; and to evaluate the performance of four dominant commercial serological assays for HEV diagnosis. METHODS 259 patients with non-A-C hepatitis were tested using the Wantai HEV-IgM, HEV-IgG, HEV-Ag ELISA kits, and the MP Biomedical HEV-Total Ab ELISA kit. ALT levels were tested and HEV RNA (viral loads) was performed using Taqman AmpliCube HEV RT-PCR kit (Mikrogen, Neuried, Germany). The performance of each kit was assessed according to the RT-PCR results. RESULTS HEV-RNA was detected in 23.1% of the samples. Most of these HEV-RNA-positive cases belonged to non-Qatari residents from the Indian subcontinent; India, Pakistan, etc. HEV-Ag, HEV-IgM, HEV-IgG, HEV-Total Ab were detected in 5.56%, 8.65%, 32.1%, and 34.2% of all tested samples, respectively. Elevated ALT levels were highly correlated with the HEV-Ag, HEV-IgM, HEV-RNA but not with the HEV-IgG and HEV-Total Ab. Although HEV-Ag was very specific (100%), yet its sensitivity was poor (36.7%). HEV-IgM demonstrated the best second marker for diagnosis of acute HEV after RT-PCR as jugged by the overall performance parameters: specificity (96.2%), sensitivity (71.4%), PPV (83.3%), NPP (92.7%), agreement with RT-PCR (91.0%), and Kappa-value (0.71). CONCLUSION Our study demonstrated a high prevalence of HEV virus in Qatar, mostly among immigrants from the Indian subcontinent. The HEV-IgM represents the best marker for detecting the acute HEV infection, where RT-PCR cannot be performed.
Collapse
Affiliation(s)
- Enas S Al Absi
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Duaa W Al-Sadeq
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar
- College of Medicine, Member of QU Health, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Makiyeh Khalili
- Department of Laboratory Medicine, Hamad Medical Corporation, Doha, Qatar
| | - Nadin Younes
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar
| | - Nader Al-Dewik
- Clinical and Metabolic Genetics Section, Pediatrics Department, Hamad General Hospital, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
- Qatar Medical Genetic Center and Interim Translational Research Institute, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
- College of Health and Life Science, Hamad Bin Khalifa University, P.O. Box 34110, Doha, Qatar
- Department of Pediatrics, Women's Wellness and Research Center, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Sara K Abdelghany
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Women's Science Building, C01, P.O. Box 2713, Doha, Qatar
| | - Somaia S Abouzid
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Women's Science Building, C01, P.O. Box 2713, Doha, Qatar
| | - Asma A Al Thani
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Women's Science Building, C01, P.O. Box 2713, Doha, Qatar
| | - Hadi M Yassine
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Women's Science Building, C01, P.O. Box 2713, Doha, Qatar
| | - Peter V Coyle
- Virology Laboratory, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Gheyath K Nasrallah
- Biomedical Research Center, Qatar University, P.O. Box 2713, Doha, Qatar.
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University, Women's Science Building, C01, P.O. Box 2713, Doha, Qatar.
| |
Collapse
|
|
16
|
El-Mokhtar MA, Karam-Allah Ramadan H, Abdel Hameed MR, M Kamel A, A Mandour S, Ali M, Abdel-Malek MAY, M Abd El-Kareem D, Adel S, H Salama E, Khalaf KAB, Sayed IM. Evaluation of hepatitis E antigen kinetics and its diagnostic utility for prediction of the outcomes of hepatitis E virus genotype 1 infection. Virulence 2021; 12:1334-1344. [PMID: 34002677 PMCID: PMC8143225 DOI: 10.1080/21505594.2021.1922027] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
HEV-Ag ELISA assay is a reliable diagnostic test in resource-limited areas. HEV genotype 1 (HEV-1) infections are either self-limited or progress to fulminant hepatic failure (FHF) and death if anti-HEV therapy is delayed. Limited data is available about the diagnostic utility of HEV Ag on HEV-1 infections. Herein wWe aimed to study the kinetics of HEV Ag during HEV-1 infections at different stages, i.e., acute HEV infection, recovery, and progression to FHF. Also, we evaluated the diagnostic utility of this marker to predict the outcomes of HEV-1 infections. Plasma of acute hepatitis E (AHE) patients were assessed for HEV RNA by RT-qPCR, HEV Ag, and anti-HEV IgM by ELISA. The kinetics of HEV Ag was monitored at different time points; acute phase of infection, recovery, FHF stage, and post-recovery. Our results showed that the level of HEV Ag was elevated in AHE patients with a significantly higher level in FHF patients than recovered patients. We identified a plasma HEV Ag threshold that can differentiate between self-limiting infection and FHF progression with 100% sensitivity and 88.89% specificity. HEV Ag and HEV RNA have similar kinetics during the acute phase and self-limiting infection. In the FHF stage, HEV Ag and anti-HEV IgM have similar patterns of kinetics which could be the cause of liver damage. In conclusion, the HEV Ag assay can be used as a biomarker for predicting the consequences of HEV-1 infections which could be diagnostically useful for taking the appropriate measures to reduce the complications, especially for high-risk groups.
Collapse
Affiliation(s)
- Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Microbiology and Immunology Department, Faculty of Pharmacy, Sphinx University, Assiut, Egypt
| | - Haidi Karam-Allah Ramadan
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Muhamad R Abdel Hameed
- Department of Internal Medicine and Hematology Unit, Assiut University Hospitals, Assiut University, Assiut, Egypt
| | - Ayat M Kamel
- Microbiology and Immunology Department, Faculty of Pharmacy, Assiut University, Assiut Egypt
| | - Sahar A Mandour
- Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, Minia, Egypt
| | - Maha Ali
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Egypt
| | | | | | - Sara Adel
- Department of Clinical Pathology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt
| | - Eman H Salama
- Department of Clinical Pathology, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Khaled Abo Bakr Khalaf
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA
| |
Collapse
|
|
17
|
Anti-HEV IgG Avidity Testing: Utility for Diagnosing Acute and Resolved Genotype 3 Infections. Viruses 2021; 13:v13020236. [PMID: 33546482 PMCID: PMC7913725 DOI: 10.3390/v13020236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 01/27/2021] [Accepted: 01/29/2021] [Indexed: 11/24/2022] Open
Abstract
European Association of the Study of the Liver (EASL) guidelines specify HEV RNA, as well as anti-HEV IgG and IgM as positive markers for acute HEV infection. HEV RNA assay sensitivity limitations may lead to false negative test results in patients with low levels of viremia. Moreover, anti-HEV IgM positivity is not a reliable indicator for distinguishing between acute and resolved infections given the ability of this antibody to persist several months after a resolved infection. Our study aims were to assess HEV IgG avidity for diagnosing acute and resolved infections, regardless of the anti-HEV IgM serostatus, and examine assay reliability when evaluating different genotype 3 (GT3) HEV subtypes. Patient serum samples (n = 104) were tested for HEV IgG avidity by utilizing the DIA.PRO kit on a DSX automated instrument. Among patients identified with acute HEV infections, 32 were infected with GT3: GT3c (n = 5), GT3e (n = 8), 3f (n = 17) and GT3-unsubtyped (n = 2). Avidity sensitivity was 91.2% and specificity was 100%. For patients with long-lasting anti-HEV IgM persistence, an Avidity Index >70% was observed. Thus, the DIA.PRO avidity assay may be utilized to distinguish between recently acquired and resolved HEV GT3 infections. However, for equivocal results (Avidity Index > 40–70%), HEV RNA molecular testing will be required to confirm a recent infection.
Collapse
|
|
18
|
Development and Clinical Validation of a Pangenotypic PCR-Based Assay for the Detection and Quantification of Hepatitis E Virus ( Orthohepevirus A Genus). J Clin Microbiol 2021; 59:JCM.02075-20. [PMID: 33148702 DOI: 10.1128/jcm.02075-20] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/22/2020] [Indexed: 01/01/2023] Open
Abstract
The objective of this study was to design a pangenotypic PCR-based assay for the detection and quantification of hepatitis E virus (HEV) RNA from across the entire spectrum of described genotypes belonging to the Orthohepevirus A genus. The optimal conditions and the performance of the assay were determined by testing the WHO standard strain (6219/10) and the WHO HEV panel (8578/13). Similarly, performance comparisons were made with two commercial assays (Real Star HEV RT-PCR 2.0 and ampliCube HEV 2.0 Quant) to detect HEV RNA at concentrations below 1,000 IU/ml with viral strains from the WHO and to test samples from 54 patients with acute hepatitis. The assay presented in this study was able to detect the entire spectrum of described genotypes belonging to the Orthohepevirus A genus, demonstrating better performance than both commercial kits. This procedure may represent a significant improvement in the molecular diagnosis of HEV infection.
Collapse
|
|
19
|
Dynamics of Hepatitis E Virus (HEV) Antibodies and Development of a Multifactorial Model To Improve the Diagnosis of HEV Infection in Resource-Limited Settings. J Clin Microbiol 2021; 59:JCM.02321-20. [PMID: 33239375 DOI: 10.1128/jcm.02321-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 11/19/2020] [Indexed: 02/06/2023] Open
Abstract
Serological markers are important for the diagnosis of hepatitis E virus (HEV) infection. This study aims to compare the diagnostic performance of the anti-HEV IgM and the HEV antigen (Ag) assays and establish a multifactorial model to improve the diagnosis of current HEV infection when HEV RNA detection is not available. A total of 809 serum samples, including 325 anti-HEV IgM-positive and 484 anti-HEV IgM-negative samples, were tested for HEV RNA. The anti-HEV IgM assay had very high sensitivity (99.4%) but moderate accuracy (79.2%) and specificity (74.3%). By retrospective follow-up of 58 patients with sequential samples (n = 143) tested for anti-HEV antibodies, we found anti-HEV IgM remained positive for more than 10 months in some HEV-infected patients, when HEV RNA was already undetectable; thus, decision solely based on anti-HEV IgM may lead to misdiagnosis. In contrast, the HEV Ag assay had very high specificity (100%). However, the detection efficiency of HEV Ag greatly diminished when the HEV RNA level was low or the anti-HEV IgG level was high. By logistic regression, a model integrating anti-HEV IgM, alanine aminotransferase, and HEV Ag was proposed, and the cutoff value was determined based on the testing results of the 143 sequential samples. The model was further evaluated with 67 randomly selected IgM-positive samples from single-visit patients. Overall, the model outperformed the anti-HEV IgM or the HEV Ag assay in the diagnosis of current HEV infection (sensitivity/specificity/accuracy, 89.5%/95.2%/91.9%). The area under the receiver operating characteristics curve of the model was greater than 0.97.
Collapse
|
|
20
|
Aslan AT, Balaban HY. Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment. World J Gastroenterol 2020; 26:5543-5560. [PMID: 33071523 PMCID: PMC7545399 DOI: 10.3748/wjg.v26.i37.5543] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 08/11/2020] [Accepted: 09/09/2020] [Indexed: 02/06/2023] Open
Abstract
The hepatitis E virus (HEV) is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s. Globally, it is one of the most frequent causes of acute viral hepatitis. The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus. Among the eight different genotypes identified to date, HEV genotype 1 (HEV1), HEV2, HEV3, and HEV4 are the most frequent genotypes causing infections in humans. HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies. They are also responsible for severe hepatitis in pregnant patients and infants. In contrast, HEV3 and HEV4 are zoonotic, and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals. Their main reservoir is the pig, and they are mostly encountered in developed countries. The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women, infants, older people, immunocompromised individuals, patients with underlying chronic liver diseases, and workers that come into close contact with HEV-infected animals. In the clinical perspective, HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis, acute-on-chronic liver disease, chronic hepatitis, cirrhosis, and liver failure. Although HEV mainly results in acute self-limiting infection, chronic HEV infection may occur among immunocompromised patients (e.g., solid-organ transplant recipients). Additionally, HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade, although the causal link for many of them still needs to be proven. Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. However, ribavirin is contraindicated in pregnant patients, and interferon-alpha cannot be used in most transplant recipients. Therefore, there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirin-resistant HEV. In this review article, a literature search using PubMed and MEDLINE databases was performed, up to March 2020. Only the articles published in English were reviewed.
Collapse
Affiliation(s)
| | - Hatice Yasemin Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
| |
Collapse
|
|
21
|
Li K, Dong F, Gao F, Bian L, Sun S, Du R, Hu Y, Mao Q, Zheng H, Wu X, Liang Z. Effect of freezing on recombinant hepatitis E vaccine. Hum Vaccin Immunother 2020; 16:1545-1553. [PMID: 31809644 PMCID: PMC7482780 DOI: 10.1080/21645515.2019.1694327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 11/13/2019] [Indexed: 12/19/2022] Open
Abstract
Studies have revealed that vaccines are more often exposed to sub-zero temperatures during cold chain transportation than what was previously known. Such exposure might be detrimental to the potency of temperature-sensitive vaccines. The aim of this study was to evaluate the impact of exposure to freezing on the physicochemical properties and biological activities of recombinant hepatitis E (rHE) vaccine. Changes in rHE vaccine due to freezing temperatures were analyzed with regard to sedimentation rate, antigenicity, and antibody affinity and potency. The freezing temperature of rHE was measured, then rHE vaccine was exposed to freezing temperatures below -10°C.Significant increase of sedimentation rate was noted, according to shake test and massed precipitates. In addition, the binding affinity of rHE vaccine to six specific monoclonal antibodies was significantly reduced and the in vivo potency for eliciting a protective IgG response was also partially lost, especially for anti-HEV neutralizing antibodies. Altogether, our work indicates that exposure of rHE vaccine to a temperature below -10°C results in the loss of structural integrity and biological potency of rHE vaccine.
Collapse
Affiliation(s)
- Kelei Li
- Division of Hepatitis Virus Vaccines, National Institute for Food and Drug Control, Beijing, China
- Research and Development Center, Minhai Biotechnology Co. Ltd, Beijing, China
| | - Fangyu Dong
- The Second Department of Research, Lanzhou Institute of Biological Products Co. Ltd, Lanzhou, China
| | - Fan Gao
- Division of Hepatitis Virus Vaccines, National Institute for Food and Drug Control, Beijing, China
| | - Lianlian Bian
- Division of Hepatitis Virus Vaccines, National Institute for Food and Drug Control, Beijing, China
| | - Shiyang Sun
- Division of Hepatitis Virus Vaccines, National Institute for Food and Drug Control, Beijing, China
| | - Ruixiao Du
- Division of Hepatitis Virus Vaccines, National Institute for Food and Drug Control, Beijing, China
| | - Yalin Hu
- Quality Assurance Department, Hualan Biological Engineering Inc, Xinxiang, China
| | - Qunying Mao
- Division of Hepatitis Virus Vaccines, National Institute for Food and Drug Control, Beijing, China
| | - Haifa Zheng
- Research and Development Center, Minhai Biotechnology Co. Ltd, Beijing, China
| | - Xing Wu
- Division of Hepatitis Virus Vaccines, National Institute for Food and Drug Control, Beijing, China
| | - Zhenglun Liang
- Division of Hepatitis Virus Vaccines, National Institute for Food and Drug Control, Beijing, China
| |
Collapse
|
|
22
|
Riveiro-Barciela M, Rando-Segura A, Barreira-Díaz A, Bes M, P Ruzo S, Piron M, Quer J, Sauleda S, Rodríguez-Frías F, Esteban R, Buti M. Unexpected long-lasting anti-HEV IgM positivity: Is HEV antigen a better serological marker for hepatitis E infection diagnosis? J Viral Hepat 2020; 27:747-753. [PMID: 32106351 DOI: 10.1111/jvh.13285] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/28/2020] [Accepted: 02/10/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis E virus (HEV) is the leading cause of acute hepatitis worldwide. The minimum criterion for diagnosis of acute infection is detection of anti-HEV antibodies, although there are scant data on IgM duration. Our aim was to assess the persistence of HEV markers after acute self-limited hepatitis E. HEV serological tests (IgM by Mikrogen and Wantai and HEV-Ag) and HEV RNA were carried out in two cohorts: (a) patients with prior acute hepatitis E (ALT >10 x ULN plus positive IgM ± HEV RNA) currently self-limited and (b) 50 blood donors with positive HEV RNA. Among 25 cases of prior acute hepatitis E, after a median follow-up of 34 months, all presented undetectable HEV RNA. However, anti-HEV IgM remained detectable in 14 (56%) by Mikrogen, 6 (24%) by Wantai and none for HEV-Ag. Anti-HEV IgM tested positive in 80%-100% within the second year and 17%-42% over 3 years later, by Wantai and Mikrogen, respectively. Among HEV RNA-positive donors, 12 (25%) tested positive for either IgM by Mikrogen or Wantai, 9 (18%) for both and 18 (36%) for HEV-Ag. HEV-Ag positivity was more likely as HEV RNA was higher (14% if <2.2 log IU/mL; 64% if RNA ≥ 3.7). Overall, HEV-Ag performed best, with a positive predictive value of 100% and diagnostic accuracy of 57%. Anti-HEV IgM exhibited unexpectedly long persistence after a self-limited acute hepatitis E. HEV-Ag had the best performance and could be especially useful in settings where HEV RNA is not available.
Collapse
Affiliation(s)
- Mar Riveiro-Barciela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autonoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | | | - Ana Barreira-Díaz
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Marta Bes
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
| | - Sofía P Ruzo
- Lab. Malalties Hepàtiques-Hepatitis Virals, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Barcelona, Spain
| | - Maria Piron
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
| | - Josep Quer
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Lab. Malalties Hepàtiques-Hepatitis Virals, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Barcelona, Spain
| | - Silvia Sauleda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
| | - Francisco Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Liver Pathology Unit (Biochemistry and Microbiology departments, Clinical Laboratories), Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Rafael Esteban
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autonoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - María Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autonoma de Barcelona, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
23
|
Zhang Q, Zong X, Li D, Lin J, Li L. Performance Evaluation of Different Commercial Serological Kits for Diagnosis of Acute Hepatitis E Viral Infection. Pol J Microbiol 2020; 69:217-222. [PMID: 32548990 PMCID: PMC7324857 DOI: 10.33073/pjm-2020-025] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Revised: 05/04/2020] [Accepted: 05/09/2020] [Indexed: 12/24/2022] Open
Abstract
Clinical diagnosis of hepatitis E viral (HEV) infection mainly relies on serological assays, and the current status of misdiagnoses regarding HEV infection is uncertain. In this study, patients with acute HEV infection were tested for anti-HEV IgM and IgG, a HEV antigen (Ag), and viral loads (HEV RNA). Serology was performed using four commercial HEV ELISA kits: Wantai, Kehua, Lizhu, and Genelabs IgM and IgG. The HEV RNA was detected using RT-PCR assays. The sensitivities of different kits for anti-HEV IgM ranged from 82.6% to 86%. Each kit for anti-HEV IgM was highly specific (97.8–100%). The sensitivities of all kits to detect anti-HEV IgG with (87.2–91.9%) had a substantial agreement, but the Kehua and Genelabs tests were more specific than the Wantai and Lizhu tests. The Wantai tests for the HEV Ag and HEV RNA were also important for acute HEV infections (Kappa = 0.787). Furthermore, a total of 6.98% of HEV infections were positive for HEV RNA but negative for both the HEV Ag and anti-HEV antibodies of IgM and IgG classes. Our findings demonstrate that the diagnosis of hepatitis E may be missed if only serological assays are used. Thus, a combination of serological and nucleic acid testing provides the optimal sensitivity and specificity to the diagnostic process.
Collapse
Affiliation(s)
- Qiang Zhang
- Department of Clinical Laboratory , Branch of Tianjin Third Central Hospital , Tianjin , China
| | - Xiaolong Zong
- Department of Clinical Laboratory , The Second Hospital of Tianjin Medical University , Tianjin , China
| | - Dongming Li
- Department of Clinical Laboratory , Tianjin Third Central Hospital , Tianjin , China
| | - Jing Lin
- Department of Clinical Laboratory , Branch of Tianjin Third Central Hospital , Tianjin , China
| | - Lihua Li
- Department of Clinical Laboratory , Branch of Tianjin Third Central Hospital , Tianjin , China
| |
Collapse
|
|
24
|
Sayed IM, Verhoye L, Montpellier C, Abravanel F, Izopet J, Cocquerel L, Meuleman P. Hepatitis E Virus (HEV) Open Reading Frame 2 Antigen Kinetics in Human-Liver Chimeric Mice and Its Impact on HEV Diagnosis. J Infect Dis 2020; 220:811-819. [PMID: 31001628 DOI: 10.1093/infdis/jiz171] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 04/09/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Hepatitis E virus infection (HEV) is an emerging problem in developed countries. Diagnosis of HEV infection is based on the detection of HEV-specific antibodies, viral RNA, and/or antigen (Ag). Humanized mice were previously reported as a model for the study of HEV infection, but published data were focused on the quantification of viral RNA. However, the kinetics of HEV Ag expression during infection remains poorly understood. METHODS Plasma specimens and suspensions of fecal specimens from HEV-infected and ribavirin-treated humanized mice were analyzed using HEV antigen-specific enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction analysis, density gradient analysis, and Western blotting. RESULT Open reading frame 2 (ORF2) Ag was detected in both plasma and stool from HEV-infected mice, and levels increased over time. Contrary to HEV RNA, ORF2 Ag levels were higher in mouse plasma than in stool. Interestingly, ORF2 was detected in plasma from mice that tested negative for HEV RNA in plasma but positive for HEV RNA in stool and was detected after viral clearance in mice that were treated with ribavirin. Plasma density gradient analysis revealed the presence of the noninfectious glycosylated form of ORF2. CONCLUSION ORF2 Ag can be used as a marker of active HEV infection and for assessment of the effect of antiviral therapy, especially when fecal samples are not available or molecular diagnostic tests are not accessible.
Collapse
Affiliation(s)
- Ibrahim M Sayed
- Laboratory of Liver Infectious Diseases, Faculty of Medicine and Health Sciences, Ghent University, Belgium.,Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Egypt
| | - Lieven Verhoye
- Laboratory of Liver Infectious Diseases, Faculty of Medicine and Health Sciences, Ghent University, Belgium
| | - Claire Montpellier
- Center for Infection and Immunity of Lille, Institut Pasteur de Lille, INSERM (U1019), CNRS (UMR 8204), Lille University, Toulouse, France.,CHU Lille, Lille, Toulouse, France
| | - Florence Abravanel
- INSERM (U1043), IFR-BMT, Toulouse, France.,Laboratory of Virology, CHU Purpan, Toulouse, France.,Université Paul-Sabatier, Toulouse, France
| | - Jacques Izopet
- INSERM (U1043), IFR-BMT, Toulouse, France.,Laboratory of Virology, CHU Purpan, Toulouse, France.,Université Paul-Sabatier, Toulouse, France
| | - Laurence Cocquerel
- Center for Infection and Immunity of Lille, Institut Pasteur de Lille, INSERM (U1019), CNRS (UMR 8204), Lille University, Toulouse, France.,CHU Lille, Lille, Toulouse, France
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Faculty of Medicine and Health Sciences, Ghent University, Belgium
| |
Collapse
|
|
25
|
Sayed IM, Meuleman P. Updates in Hepatitis E virus (HEV) field; lessons learned from human liver chimeric mice. Rev Med Virol 2019; 30:e2086. [PMID: 31835277 DOI: 10.1002/rmv.2086] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 09/09/2019] [Accepted: 09/11/2019] [Indexed: 12/14/2022]
Abstract
Hepatitis E virus (HEV) is the most common cause of viral hepatitis globally, and it is an emerging pathogen in developed countries. In vivo studies of HEV have long been hindered due to the lack of an efficient small animal model. Recently, human liver chimeric mice were described as an elegant model to study chronic HEV infection. HEV infection was established in mice with humanized liver that were challenged with stool preparations containing HEV genotype (gt)1 and/or gt3. An increase in viral load and the level of HEV Ag in mouse samples were markers of active infection. Plasma-derived HEV preparations were less infectious. The kinetics of HEV ORF2 Ag during HEV infection and its impact on HEV diagnosis were described in this model. In addition, the nature of HEV particles and HEV ORF2 Ag were characterized. Moreover, humanized mice were used to study the impact of HEV infection on the hepatic innate transcriptome and evaluation of anti-HEV therapies. This review highlights recent advances in the HEV field gathered from well-established experimental mouse models, with an emphasis on this model as a tool for elucidating the course of HEV infection, the study of the HEV life cycle, the interaction of the virus with the host, and the evaluation of new anti-HEV therapies.
Collapse
Affiliation(s)
- Ibrahim M Sayed
- Department of Pathology, School of Medicine, University of California, San Diego, San Diego, California, USA.,Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| |
Collapse
|
|
26
|
Lhomme S, Legrand-Abravanel F, Kamar N, Izopet J. Screening, diagnosis and risks associated with Hepatitis E virus infection. Expert Rev Anti Infect Ther 2019; 17:403-418. [DOI: 10.1080/14787210.2019.1613889] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Sébastien Lhomme
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Florence Legrand-Abravanel
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| | - Nassim Kamar
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
- Department of Nephrology and Organs Transplantation, CHU Rangueil, Toulouse, France
| | - Jacques Izopet
- Department of Virology, National reference center for Hepatitis E Virus, CHU Purpan, Toulouse, France
- Inserm UMR1043, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France
- Université de Toulouse, Toulouse III, Toulouse, France
| |
Collapse
|
|
27
|
Geng Y, Zhao C, Guo T, Xu Y, Wang X, Huang W, Liu H, Wang Y. Detection of Hepatitis E Virus in Raw Pork and Pig Viscera As Food in Hebei Province of China. Foodborne Pathog Dis 2019; 16:325-330. [DOI: 10.1089/fpd.2018.2572] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Affiliation(s)
- Yansheng Geng
- Health Science Center, Hebei University, Baoding, China
| | - Chenyan Zhao
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Tingyu Guo
- Health Science Center, Hebei University, Baoding, China
| | - Ying Xu
- Health Science Center, Hebei University, Baoding, China
| | - Xuanpu Wang
- Health Science Center, Hebei University, Baoding, China
| | - Weijin Huang
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Huan Liu
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Youchun Wang
- Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| |
Collapse
|
|
28
|
Zhang H, Rao H, Wang Y, Wang J, Kong X, Ji Y, Zhu L, Liu Y, Fang J, Yang M, Luo B, Wang Z, Shi Y, Wang Y, Wang H, Zhao J, Wei L. Evaluation of an antigen assay for diagnosing acute and chronic hepatitis E genotype 4 infection. J Gastroenterol Hepatol 2019; 34:458-465. [PMID: 30069920 DOI: 10.1111/jgh.14405] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 06/14/2018] [Accepted: 07/09/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Results obtained from different hepatitis E virus (HEV) tests are usually inconsistent. The detection of serum HEV antigen (Ag) has been suggested to be more sensitive for the diagnosis of genotypes 1 and 3 HEV. METHODS We compared the diagnostic accuracies of serum HEV Ag and HEV RNA by using 202 serum samples from patients suspected acute viral hepatitis. RESULTS The HEV Ag assay was 100% specific. The lower detected levels of viremia ranged from 102 to 103 copies/mL. The sensitivity of the HEV Ag test was 90.5%. One of the 42 cases was negative for anti-HEV IgM, but HEV Ag was still detectable. The detectable period of HEV Ag was in concordance with the detectable period of HEV RNA. Serum HEV Ag was persistently detected in two cases of chronic hepatitis E, confirmed by the persistent presence of HEV RNA despite being negative for anti-HEV IgM. HEV Ag demonstrated good consistency with positive HEV RNA (k = 0.938, P < 0.001). Receiver operating characteristic analysis of HEV Ag suggested a second cut-off value of >0.095 to predict HEV patients with 95.24% sensitivity and 98.75% specificity, and the area under the curve was 0.9887, which was higher than that of three commercial anti-HEV IgM ELISA tests. CONCLUSIONS The presence of HEV Ag has good consistency with HEV RNA in both acute and chronic genotype 4 hepatitis E. HEV Ag is a more promising serum marker to identify active genotype 4 HEV infection than anti-HEV IgM and HEV RNA.
Collapse
Affiliation(s)
- Haiying Zhang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Huiying Rao
- Department of Hepatology, Peking University People's Hospital, Beijing, China
| | - Yijin Wang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Jianghua Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Xiangsha Kong
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Ying Ji
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Ling Zhu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Yan Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Jilian Fang
- Department of Hepatology, Peking University People's Hospital, Beijing, China
| | - Ming Yang
- Department of Hepatology, Peking University People's Hospital, Beijing, China
| | - Bifen Luo
- Department of Hepatology, Peking University People's Hospital, Beijing, China
| | - Zhenyu Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Yijun Shi
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China
| | - Hao Wang
- Department of Hepatology, Peking University People's Hospital, Beijing, China
| | - Jingmin Zhao
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing, China
| |
Collapse
|
|
29
|
Hepatitis E virus was not detected in feces and milk of cows in Hebei province of China: No evidence for HEV prevalence in cows. Int J Food Microbiol 2019; 291:5-9. [DOI: 10.1016/j.ijfoodmicro.2018.11.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Revised: 10/03/2018] [Accepted: 11/04/2018] [Indexed: 01/10/2023]
|
|
30
|
Tang FF, Mo XD, Wang Y, Yan CH, Chen YH, Chen H, Han W, Chang YJ, Zhang HY, Xie YD, Ma H, Wei L, Xu LP, Huang XJ, Zhang XH. Hepatitis E virus infection after haploidentical haematopoietic stem cell transplantation: incidence and clinical course. Br J Haematol 2018; 184:788-796. [PMID: 30426480 DOI: 10.1111/bjh.15672] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 10/01/2018] [Indexed: 01/05/2023]
Affiliation(s)
- Fei-Fei Tang
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Xiao-Dong Mo
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Yu Wang
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Chen-Hua Yan
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Yu-Hong Chen
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Huan Chen
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Wei Han
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Ying-Jun Chang
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Hai-Ying Zhang
- Peking University People's Hospital; Peking University Institute of Hepatology; Beijing China
| | - Yan-Di Xie
- Peking University People's Hospital; Peking University Institute of Hepatology; Beijing China
| | - Hui Ma
- Peking University People's Hospital; Peking University Institute of Hepatology; Beijing China
| | - Lai Wei
- Peking University People's Hospital; Peking University Institute of Hepatology; Beijing China
| | - Lan-Ping Xu
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| | - Xiao-Jun Huang
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
- Peking-Tsinghua Centre for Life Sciences; Beijing China
| | - Xiao-Hui Zhang
- Beijing Key Laboratory of Haematopoietic Stem Cell Transplantation; Peking University People's Hospital; Peking University Institute of Haematology; Beijing China
| |
Collapse
|
|
31
|
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: 72] [Impact Index Per Article: 10.3] [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.
Collapse
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
| |
Collapse
|
|
32
|
Wang Y, Wang S, Wu J, Jiang Y, Zhang H, Li S, Liu H, Yang C, Tang H, Guo N, Peppelenbosch MP, Wei L, Pan Q, Zhao J. Hepatitis E virus infection in acute non-traumatic neuropathy: A large prospective case-control study in China. EBioMedicine 2018; 36:122-130. [PMID: 30190208 PMCID: PMC6197649 DOI: 10.1016/j.ebiom.2018.08.053] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 08/27/2018] [Accepted: 08/27/2018] [Indexed: 01/12/2023] Open
Abstract
Neurological manifestations are potentially associated with hepatitis E virus (HEV) infection in Europe, mainly attributed to genotype (GT) 3 HEV infection. In this study, we determined the frequency and causal relationship of HEV in patients with non-traumatic neurological disorders in China, where GT4 HEV is prevalent. 1117 consecutive patients diagnosed with neurological illnesses in a hospital of eastern China and 1475 healthy controls who took routine examination in the same hospital were tested for HEV by serology and molecular methods. Anti-HEV IgM antibodies were detectable in 6 (0.54%) of the patients and 10 (0.68%) of the healthy controls (P = 0.651). Serum HEV RNA was detected in all of the 16 individuals with positive anti-HEV IgM. The six patients with HEV infection included two viral encephalitis, two posterior circulation ischemia, one peripheral neuropathy and one Guillian-Barré syndrome. They had no symptoms of acute viral hepatitis except two patients of viral encephalitis that showed mildly transaminitis. Additional, 39.51% patients and 35.63% controls without acute HEV infection were positive for anti-HEV IgG (P = 0.144). Anti-HEV IgG positivity was more frequent in male and elderly in both the patients and control groups, but unrelated to the incidence of any non-traumatic neurological illness, hospital stay or treatment outcome, except linking to better outcome of hemorrhagic stroke disease. These data demonstrated that HEV appears not to contribute to acute neurological disorders in China. Nevertheless, we cannot exclude a possible causative role, suggesting that testing HEV in this population, especially in situations of unexplained deregulated liver function would be warranted.
HEV infection is identified in 0.54% patients with acute neurological injury in this study, where GT4 HEV is prevalent. The incidence of HEV infection is not significantly different between neurological patients and healthy controls. A potential causal relationship between GT4 HEV infection and viral encephalitis has been indicated. Patients with viral encephalitis are prone to have deranged liver function following HEV infection. The prevalence of GT4 HEV is higher in male and elderly in both neurological patients and healthy controls. Neurological injury is the most common extra-hepatic manifestation in patients with hepatitis E virus (HEV) infection. HEV associated neurological syndromes have been widely reported in Europe, mainly attributed to genotype 3 HEV infection. We determined the frequency and causal relationship of HEV in patients with non-traumatic neurological disorders in China, where genotype 4 HEV is prevalent. We have demonstrated that 0.54% patients with acute non-traumatic neurological injury have evidence of HEV infection. The overall incidence of HEV infection is not significantly different between patients and healthy controls. Nevertheless, we cannot exclude a possible causative role, suggesting that testing HEV in this population, especially in situations of unexplained deregulated liver function would be warranted.
Collapse
Affiliation(s)
- Yijin Wang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
| | - Shan Wang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Jian Wu
- Department of Laboratory Medicine, The First People's Hospital of Yancheng City, Yancheng, Jiangsu, China; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Yiyun Jiang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Haiying Zhang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Beijing, China
| | - Shujuan Li
- Department of Nephrology, The First People's Hospital of Yancheng City, Yancheng, Jiangsu, China
| | - Hongyang Liu
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China; Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Changshuang Yang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Haijun Tang
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China
| | - Naizhou Guo
- Department of Laboratory Medicine, The First People's Hospital of Yancheng City, Yancheng, Jiangsu, China
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Beijing, China
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
| | - Jingmin Zhao
- Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
| |
Collapse
|
|
33
|
Dalton HR, Kamar N, Baylis SA, Moradpour D, Wedemeyer H, Negro F. EASL Clinical Practice Guidelines on hepatitis E virus infection. J Hepatol 2018; 68:1256-1271. [PMID: 29609832 DOI: 10.1016/j.jhep.2018.03.005] [Citation(s) in RCA: 434] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 03/09/2018] [Indexed: 02/08/2023]
Abstract
Infection with hepatitis E virus (HEV) is a significant cause of morbidity and mortality, representing an important global health problem. Our understanding of HEV has changed completely over the past decade. Previously, HEV was thought to be limited to certain developing countries. We now know that HEV is endemic in most high-income countries and is largely a zoonotic infection. Given the paradigm shift in our understanding of zoonotic HEV and that locally acquired HEV is now the commonest cause of acute viral hepatitis in many European countries, the focus of these Clinical Practice Guidelines will be on HEV genotype 3 (and 4).
Collapse
|
|
34
|
Origin, antigenicity, and function of a secreted form of ORF2 in hepatitis E virus infection. Proc Natl Acad Sci U S A 2018; 115:4773-4778. [PMID: 29669922 DOI: 10.1073/pnas.1721345115] [Citation(s) in RCA: 134] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The enterically transmitted hepatitis E virus (HEV) adopts a unique strategy to exit cells by cloaking its capsid (encoded by the viral ORF2 gene) and circulating in the blood as "quasi-enveloped" particles. However, recent evidence suggests that the majority of the ORF2 protein present in the patient serum and supernatants of HEV-infected cell culture exists in a free form and is not associated with virus particles. The origin and biological functions of this secreted form of ORF2 (ORF2S) are unknown. Here we show that production of ORF2S results from translation initiated at the previously presumed AUG start codon for the capsid protein, whereas translation of the actual capsid protein (ORF2C) is initiated at a previously unrecognized internal AUG codon (15 codons downstream of the first AUG). The addition of 15 amino acids to the N terminus of the capsid protein creates a signal sequence that drives ORF2S secretion via the secretory pathway. Unlike ORF2C, ORF2S is glycosylated and exists as a dimer. Nonetheless, ORF2S exhibits substantial antigenic overlap with the capsid, but the epitopes predicted to bind the putative cell receptor are lost. Consistent with this, ORF2S does not block HEV cell entry but inhibits antibody-mediated neutralization. These results reveal a previously unrecognized aspect in HEV biology and shed new light on the immune evasion mechanisms and pathogenesis of this virus.
Collapse
|
|
35
|
Zhou S, Ren L, Xia X, Miao Z, Huang F, Li Y, Zhu M, Xie Z, Xu Y, Qian Y, Pan Q, Wang K. Hepatitis E virus infection in HIV-infected patients: A large cohort study in Yunnan province, China. J Med Virol 2018; 90:1121-1127. [PMID: 29457639 DOI: 10.1002/jmv.25060] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 02/07/2018] [Indexed: 12/23/2022]
Abstract
Hepatitis E virus (HEV) infection in immunocompromised patients often results in distinct outcome, compared to the infection in general population. This study aimed to investigate the prevalence, potential risk factors, and clinical features of HEV infection among HIV patients treated with antiretroviral therapy (ART) in Yunnan province, China. A total of 770 HIV-infected patients between May 2015 and February 2016 were enrolled in Yunnan, China. All patients received ART. All plasma samples were tested for anti-HEV IgG, anti-HEV IgM antibodies using ELISA kits, and HEV RNA by real-time qRT-PCR. Association between anti-HEV antibody positivity and demographic, clinical and laboratory measures was assessed in univariate and multivariate logistic regression models. Of the 770 HIV-infected patients, 342 patients (44.42%) were anti-HEV IgG antibody positive, and six patients (0.78%) were anti-HEV IgM antibody positive. None of the patients was HEV RNA positive, as tested in our assays. We found that age, gender, CD4 cell count, WHO stage, marital status, and total cholesterol levels were associated with HEV infection. We report a high seroprevalence rate and several potential risk factors of HEV infection in a large HIV cohort from Yunnan province in China. Further research on identification of the circulating HEV strains and the clinical outcome of this patient population is required.
Collapse
Affiliation(s)
- Shiyi Zhou
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China.,Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rooterdam, The Netherlands
| | - Li Ren
- The First People's Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Xueshan Xia
- Faculty of Life Science and Technology, Center for Molecular Medicine in Yunnan province, Kunming University of Science and Technology, Kunming, Yunnan Province, China
| | - Zhijiang Miao
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rooterdam, The Netherlands.,Faculty of Life Science and Technology, Center for Molecular Medicine in Yunnan province, Kunming University of Science and Technology, Kunming, Yunnan Province, China
| | - Fen Huang
- Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Yunlong Li
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rooterdam, The Netherlands.,Medical Faculty, Kunming University of Science and Technology, Kunming, China
| | - Mei Zhu
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Zhenrong Xie
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Yu Xu
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Yuan Qian
- The First People's Hospital of Zhaotong City, Zhaotong,, Yunnan Province, China
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rooterdam, The Netherlands
| | - Kunhua Wang
- Yunnan Institute of Digestive Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| |
Collapse
|
|
36
|
Ying D, Hong C, Wen G, Tang Z, Wang S, Zhang X, Liu C, Ge S, Zheng Z, Xia N. Development and evaluation of a rapid point-of-care test for detecting the hepatitis E virus antigen. Clin Biochem 2018. [PMID: 29518382 DOI: 10.1016/j.clinbiochem.2018.03.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV)-caused acute viral hepatitis is a major threat to public health worldwide. Recently, an enzyme linked immunosorbent assay (ELISA) kit detecting the HEV antigen was reported to have good concordance with the HEV RNA load and showed good clinical performance. But the ELISA kits can barely satisfy the needs of community clinics. In this study, a fluorescent microbead-based immunoassay (FMIA) for detecting the HEV antigen was developed and evaluated. METHODS A mouse anti-HEV monoclonal antibody (mAb) conjugated with fluorescent microbeads was used as capturing antibody and another mouse mAb was used as detection antibody. Overall, 150 serum samples were collected from HEV-infected patients (n = 50) and non-HEV cases (n = 100) to evaluate the performance of the FMIA. RESULTS The FMIA results showed a strong linear correlation with the viral RNA load. The diagnostic sensitivity and specificity of the HEV antigen FMIA were 92.0% (46/50) and 100.0% (100/100), respectively, and the test was consistent (kappa = 0.937, p = 0.627) with the commercial HEV antigen ELISA. The FMIA also showed good consistency with the PCR results (kappa = 0.939, p = 0.134). CONCLUSIONS As a rapid point-of-care (POC) test, a FMIA that is developed with acceptable performance is suitable for acute hepatitis E diagnosis, especially in developing countries and regions, because of its reduced time and simplified operation.
Collapse
Affiliation(s)
- Dong Ying
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, PR China
| | - Congming Hong
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China
| | - Guiping Wen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China
| | - Zimin Tang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China
| | - Siling Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China
| | - Xu Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China
| | - Chang Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China
| | - Shengxiang Ge
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China.
| | - Zizheng Zheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China.
| | - Ningshao Xia
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, PR China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China
| |
Collapse
|
|
37
|
Montpellier C, Wychowski C, Sayed IM, Meunier JC, Saliou JM, Ankavay M, Bull A, Pillez A, Abravanel F, Helle F, Brochot E, Drobecq H, Farhat R, Aliouat-Denis CM, Haddad JG, Izopet J, Meuleman P, Goffard A, Dubuisson J, Cocquerel L. Hepatitis E Virus Lifecycle and Identification of 3 Forms of the ORF2 Capsid Protein. Gastroenterology 2018; 154:211-223.e8. [PMID: 28958858 DOI: 10.1053/j.gastro.2017.09.020] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 09/08/2017] [Accepted: 09/14/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Hepatitis E virus (HEV) infection is a major cause of acute hepatitis worldwide. Approximately 2 billion people live in areas endemic for HEV and are at risk of infection. The HEV genome encodes 3 proteins, including the ORF2 capsid protein. Detailed analyses of the HEV life cycle has been hampered by the lack of an efficient viral culture system. METHODS We performed studies with gt3 HEV cell culture-produced particles and patient blood and stool samples. Samples were fractionated on iodixanol gradients and cushions. Infectivity assays were performed in vitro and in human liver chimeric mice. Proteins were analyzed by biochemical and proteomic approaches. Infectious particles were analyzed by transmission electron microscopy. HEV antigen levels were measured with the Wantaï enzyme-linked immunosorbent assay. RESULTS We developed an efficient cell culture system and isolated HEV particles that were infectious in vitro and in vivo. Using transmission electron microscopy, we defined the ultrastructure of HEV cell culture-produced particles and particles from patient sera and stool samples. We also identified the precise sequence of the infectious particle-associated ORF2 capsid protein. In cultured cells and in samples from patients, HEV produced 3 forms of the ORF2 capsid protein: infectious/intracellular ORF2 (ORF2i), glycosylated ORF2 (ORF2g), and cleaved ORF2 (ORF2c). The ORF2i protein associated with infectious particles, whereas the ORF2g and ORF2c proteins were massively secreted glycoproteins not associated with infectious particles. ORF2g and ORF2c were the most abundant antigens detected in sera from patients. CONCLUSIONS We developed a cell culture system and characterized HEV particles; we identified 3 ORF2 capsid proteins (ORF2i, ORF2g, and ORFc). These findings will advance our understanding of the HEV life cycle and improve diagnosis.
Collapse
Affiliation(s)
- Claire Montpellier
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Czeslaw Wychowski
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France.
| | - Ibrahim M Sayed
- Laboratory of Liver Infectious Diseases, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium; Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Jean-Michel Saliou
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Maliki Ankavay
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Anne Bull
- Inserm-U966, University F. Rabelais, Tours, France
| | - André Pillez
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Florence Abravanel
- CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France
| | - François Helle
- EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France
| | - Etienne Brochot
- EA4294, Laboratoire de Virologie, Centre Universitaire de Recherche en Santé, Centre Hospitalier Universitaire et Université de Picardie Jules Verne, Amiens, France
| | - Hervé Drobecq
- University of Lille, CNRS, Institut Pasteur de Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Target Therapies, Lille, France
| | - Rayan Farhat
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Cécile-Marie Aliouat-Denis
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Juliano G Haddad
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Jacques Izopet
- CHU Toulouse, Hôpital Purpan, Laboratoire de virologie, National Reference Center for Hepatitis E, Toulouse, France
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium
| | - Anne Goffard
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Jean Dubuisson
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France
| | - Laurence Cocquerel
- University of Lille, CNRS, INSERM, CHU Lille, Pasteur Institute of Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, Lille, France.
| |
Collapse
|
|
38
|
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.
Collapse
|
|
39
|
Denner J. Xenotransplantation - A special case of One Health. One Health 2017; 3:17-22. [PMID: 28616498 PMCID: PMC5454160 DOI: 10.1016/j.onehlt.2017.02.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 01/25/2017] [Accepted: 02/07/2017] [Indexed: 12/20/2022] Open
Abstract
The chronic shortage of human transplants to treat tissue and organ failure has led to the development of xenotransplantation, the transplantation of cells, tissues and organs from another species to human recipients. For a number of reasons, pigs are best suited as donor animals. Successful, routine xenotransplantation would have an enormous impact on the health of the human population, including the young, who sometimes require a replacement organ or islet cells, but especially the elderly, who more often suffer the consequences of organ failure. The first form of xenotransplantation applied to humans is the use of pig islet cells to treat insulin-dependent diabetes, a procedure that will have a significant economic impact. However, although xenotransplantation using pig cells, tissues and organs may save and prolong the lives of patients, it may also be associated with the transmission of porcine microorganisms to the recipient, eventually resulting in emerging infectious diseases. For this reason, the health of both the donor animals and the human recipients represents a special and sensitive case of the One Health concept. Basic research leading to strategies how to prevent transmission of porcine microorganisms by selection of virus-free animals, treatment of donor pigs by antiviral drugs, vaccines, colostrum deprivation, early weaning, Caesarean delivery, embryo transfer and/or gene editing should be undertaken to supply an increasing number of potential recipients with urgently required transplants. The methods developed for the detection and elimination of porcine microorganisms in the context of xenotransplantation will also contribute to an improvement in the health of pig populations in general and an increase in the quality of meat products. At present, there is evidence for transmission of porcine viruses to humans eating pork and having contact with pigs, however the impact of these viruses on public health is still unknown.
Collapse
Affiliation(s)
- Joachim Denner
- Corresponding author at: Robert Koch Institute, Nordufer 20, D-13353 Berlin, Germany.Robert Koch InstituteNordufer 20BerlinD-13353Germany
| |
Collapse
|
|
40
|
Nouhin J, Prak S, Madec Y, Barennes H, Weissel R, Hok K, Pavio N, Rouet F. Hepatitis E virus antibody prevalence, RNA frequency, and genotype among blood donors in Cambodia (Southeast Asia). Transfusion 2016; 56:2597-2601. [PMID: 27480100 DOI: 10.1111/trf.13731] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2016] [Revised: 05/02/2016] [Accepted: 06/06/2016] [Indexed: 12/31/2022]
Abstract
BACKGROUND Recent studies conducted in developed countries described hepatitis E virus (HEV) as an emerging infectious threat to blood safety. However, data on HEV among blood donors from southeast Asia are lacking. STUDY DESIGN AND METHODS Between July and August 2014, we assessed the presence of HEV immunoglobulin (Ig)G and IgM in 301 Cambodian blood donors. All samples were further tested for the presence of HEV RNA using an in-house reverse transcription-polymerase chain reaction. ORF2/ORF3 phylogenetic analysis was performed on positive HEV RNA specimens. RESULTS We found HEV IgG in 28.2% of blood donors from Cambodia. Three blood donors tested positive for HEV IgM with three distinct patterns: IgM(+)/IgG(-)/RNA(-) (n = 1), IgM(+)/IgG(+)/RNA(-) (n = 1), and IgM(+)/IgG(+)/RNA(+) (n = 1). Thus, the prevalence rates of HEV IgM and HEV RNA were 1.0 and 0.3%. Interestingly, the viremic blood donor harbored a HEV strain that belonged to Genotype 3 (HEV-3) and clustered with a Cambodian riverine HEV-3 isolate. CONCLUSION Due to the high frequency of Cambodian blood donors with positive HEV IgG, we conclude that HEV is endemic in this country. Large-scale studies must be considered to determine whether Cambodian blood donation screening is warranted to enhance blood safety in regard to HEV. In addition, our findings suggest that river water may be a significant source of exposure to HEV-3.
Collapse
Affiliation(s)
- Janin Nouhin
- HIV/Hepatitis Unit, Pasteur Institute in Cambodia, Phnom Penh, Cambodia.,Université Paris Diderot-Paris 7
| | - Sophearot Prak
- HIV/Hepatitis Unit, Pasteur Institute in Cambodia, Phnom Penh, Cambodia
| | - Yoann Madec
- Unité d'Epidémiologie des Maladies Emergentes, Institut Pasteur, Paris, France
| | - Hubert Barennes
- Epidemiology and Public Health Unit, Pasteur Institute in Cambodia, Phnom Penh, Cambodia.,Epidemiologie-Biostatistique, ISPED, Centre INSERM U897, Bordeaux, France
| | | | - Kimcheng Hok
- National Blood Transfusion Center, Phnom Penh, Cambodia
| | - Nicole Pavio
- UMR 1161 Virologie, Anses Laboratoire de Santé Animale, Maisons-Alfort, France
| | - François Rouet
- HIV/Hepatitis Unit, Pasteur Institute in Cambodia, Phnom Penh, Cambodia.
| |
Collapse
|
|
41
|
Mishra S, Borkakoti J, Kumar S, Kar P. Role of HEV antigen detection in HEV-related acute viral hepatitis and acute liver failure. J Med Virol 2016; 88:2179-2185. [PMID: 27153108 DOI: 10.1002/jmv.24567] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2016] [Indexed: 01/10/2023]
Abstract
Detection of HEV antigen presents as an interesting low cost, novel, and rapid diagnostic technique to ascertain HEV viremia where facilities for reverse transcriptase polymerase chain reaction (RT PCR) are sparse. This study was undertaken to assess the relative efficacy of HEV antigen detection by ELISA with currently available diagnostic tests in patients of HEV-related acute viral hepatitis (AVH) and acute liver failure (ALF). This study included 36 ALF and 64 AVH cases. HEV RNA and HEV viral load were determined by RT PCR and real time PCR, respectively. Evidence of recent HEV infection was detected in 45/64 AVH cases and 22/36 ALF cases. IgM anti-HEV antibody, HEV RNA, and HEV antigen were positive in 34/45 (75.56%), 26/45 (57.77%), and 21/45 (46.66%), in the AVH group, and 16/22 (72.72%), 14/22 (63.63%), 12/22 (54.54%) in ALF group, respectively. The concordance between HEV RNA and HEV antigen was 75.56% (P < 0.01) with κ-coefficient of 0.516 and 75.27% (P = 0.07) with κ-coefficient of 0.441 (P = 0.07) in the AVH and ALF patients, respectively, indicating moderate concordance. It was established that HEV antigen detection can be used as a valuable marker of active viremia and a cheaper surrogate to HEV RT PCR, particularly in window period, pregnant and immunocompromised patients, however, it did not correlate with severity of disease or influence the final outcome of illness in any of the study groups. J. Med. Virol 88:2179-2185, 2016. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Saurabh Mishra
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Jayanta Borkakoti
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Suresh Kumar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Premashis Kar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India.
| |
Collapse
|
|
42
|
Trémeaux P, Lhomme S, Chapuy-Regaud S, Peron JM, Alric L, Kamar N, Izopet J, Abravanel F. Performance of an antigen assay for diagnosing acute hepatitis E virus genotype 3 infection. J Clin Virol 2016; 79:1-5. [DOI: 10.1016/j.jcv.2016.03.019] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 03/11/2016] [Accepted: 03/20/2016] [Indexed: 12/17/2022]
|
|
43
|
Behrendt P, Bremer B, Todt D, Brown RJP, Heim A, Manns MP, Steinmann E, Wedemeyer H. Hepatitis E Virus (HEV) ORF2 Antigen Levels Differentiate Between Acute and Chronic HEV Infection. J Infect Dis 2016; 214:361-8. [PMID: 27234418 DOI: 10.1093/infdis/jiw161] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2015] [Accepted: 04/07/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Hepatitis E virus (HEV) genotype 3 infections are frequent in Europe and North America, with acute and chronic courses described in the literature. HEV RNA detection by real-time polymerase chain reaction (PCR) is the gold standard for diagnosis. Recently, an anti-HEV antigen (Ag)-specific enzyme-linked immunosorbent assay (ELISA) directed against the HEV capsid became commercially available. The effectiveness of anti-HEV Ag-specific ELISA at detecting HEV genotype 3 infections remains undefined. METHODS The performance of anti-HEV Ag-ELISA was compared with that of real-time PCR, using sera from a cohort of acutely infected individuals, in addition to a cohort of chronically infected patients undergoing ribavirin therapy. Furthermore, virion properties were evaluated by density fractionation. RESULTS Anti-HEV Ag-specific ELISA was less sensitive than real-time PCR at detection of HEV infection. Anti-HEV Ag-specific ELISA revealed significantly higher HEV Ag in chronically infected individuals as compared to acutely infected patients, with high sensitivity and specificity to distinguish acute from chronic HEV infection. Of note, HEV Ag remained detectable for >100 days after HEV RNA clearance in ribavirin-treated patients with chronic HEV. Density gradients revealed the presence of membrane-associated virions in the sera, with a different distribution as compared to HEV RNA. CONCLUSIONS The anti-HEV Ag-specific ELISA is less sensitive than HEV RNA real-time PCR but represents a useful tool to discriminate chronic from acute infection.
Collapse
Affiliation(s)
- Patrick Behrendt
- TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Infection Research German Center for Infection Research Department for Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover
| | - Birgit Bremer
- Department for Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover
| | - Daniel Todt
- TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Infection Research
| | - Richard J P Brown
- TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Infection Research
| | - Albert Heim
- Institute of Virology Hannover Medical School, Germany
| | - Michael P Manns
- German Center for Infection Research Department for Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover
| | - Eike Steinmann
- TWINCORE, Center for Experimental and Clinical Infection Research, Institute for Experimental Infection Research
| | - Heiner Wedemeyer
- German Center for Infection Research Department for Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover
| |
Collapse
|
|
44
|
Singh MP, Majumdar M, Goyal K, Lakshmi P, Bhatia D, Ratho R. Investigation of suspected viral hepatitis outbreaks in North West India. Diagn Microbiol Infect Dis 2016; 84:309-14. [PMID: 26853491 DOI: 10.1016/j.diagmicrobio.2015.12.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Revised: 12/08/2015] [Accepted: 12/09/2015] [Indexed: 11/15/2022]
|
|
45
|
Geng Y, Zhao C, Huang W, Harrison TJ, Zhang H, Geng K, Wang Y. Detection and assessment of infectivity of hepatitis E virus in urine. J Hepatol 2016; 64:37-43. [PMID: 26362822 DOI: 10.1016/j.jhep.2015.08.034] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Revised: 08/27/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Hepatitis E virus (HEV) is known to be excreted in the stool but there has been no report of its presence in urine. This study investigated the presence of HEV RNA and antigen (HEV-Ag) in urine and its possible transmission. METHODS Serum and urine samples from patients with chronic or acute HEV infection and HEV infected monkeys were tested for viral and biochemical markers. Liver and kidney biopsies from the infected monkeys were analyzed by histopathology and immunohistochemistry. The infectivity of HEV from urine was assessed by inoculation into monkeys. RESULTS HEV RNA and HEV-Ag were detected persistently in the urine of a patient with chronic HEV infection. Subsequently, HEV RNA was detected in the urine of three of the eight (37.5%) acute patients, all of whom had detectable HEV-Ag in their urine. HEV RNA and HEV-Ag were also detectable in the urine of HEV infected monkeys. The ratio of HEV-Ag to RNA in the urine of the infected monkeys was significantly higher than in their sera and feces. The parameters of routine urinalysis remained within the normal ranges in the hepatitis E patients and infected monkeys, however, pathological changes and HEV-Ag were observed in the kidneys of the infected monkeys. Furthermore, one of two monkeys became infected with HEV after inoculation with urine from another infected monkey. CONCLUSIONS HEV infection may result in kidney injury and the urine may pose a risk of transmission. HEV-Ag detection in urine may be valuable for diagnosis of ongoing HEV infection.
Collapse
Affiliation(s)
- Yansheng Geng
- Health Science Center, Hebei University, No. 342 Yuhuadonglu, Baoding 071000, China
| | - Chenyan Zhao
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China
| | - Weijin Huang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China
| | - Tim J Harrison
- Division of Medicine, University College London Medical School, Cruciform Building, 90 Gower Street, London WC1E 6BT, UK
| | - Hongxin Zhang
- Health Science Center, Hebei University, No. 342 Yuhuadonglu, Baoding 071000, China
| | - Kunjing Geng
- Baoding Hospital for Infectious Disease, Baoding, China
| | - Youchun Wang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Beijing 100050, China.
| |
Collapse
|
|
46
|
Abstract
Serological and nucleic acid tests for detecting hepatitis E virus (HEV) have been developed for both epidemiologic and diagnostic purposes. The laboratory diagnosis of HEV infection depends on the detection of HEV antigen, HEV RNA, and serum antibodies against HEV (immunoglobulin [Ig]A, IgM, and IgG). Anti-HEV IgM antibodies can be detected during the acute phase of the illness and can last approximately 4 or 5 months, representing recent exposure, whereas anti-HEV IgG antibodies can last more than 10 years, representing remote exposure. Thus, the diagnosis of acute infection is based on the presence of anti-HEV IgM, HEV antigen, and HEV RNA, while epidemiological investigations are mainly based on anti-HEV IgG. Although significant progress has been made in developing and optimizing different formats of HEV assays, improving their sensitivity and specificity, there are many shortcomings and challenges in inter-assay concordance, validation, and standardization. This article reviews the current knowledge on the diagnosis of HEV infection, including the most common available laboratory diagnostic techniques.
Collapse
Affiliation(s)
- Chenyan Zhao
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Dongcheng District, Beijing, 100050, China
| | - Youchun Wang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Dongcheng District, Beijing, 100050, China.
| |
Collapse
|