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      Unexpected high seroprevalence of hepatitis E virus in patients with alcohol-related cirrhosis

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          Abstract

          Introduction

          Little is known about hepatitis E virus (HEV) infection in patients with cirrhosis. The aim of the present study was to describe the frequency of HEV infection and associated risk factors in patients with cirrhosis from Argentina.

          Materials and methods

          We evaluated HEV seroprevalence (IgG anti-HEV) and acute infections (IgM and RNA) in patients with cirrhosis (n = 140) vs. healthy controls (n = 300). Additionally, we compared the same outcomes in individuals with alcohol-related cirrhosis (n = 43) vs. patients with alcohol use disorder (without cirrhosis, n = 72).

          Results

          The overall HEV seroprevalence in the cohort of subjects with cirrhosis was 25% (35/140), compared to 4% in the healthy control group [12/300; OR = 8; (95% CI = 4–15.99); p<0.05]. HEV seropositivity was significantly higher in alcohol-related cirrhosis compared to other causes of cirrhosis [39.5% vs. 12.4%; OR = 4.71; (95% CI = 1.9–11.6); p<0.05] and to healthy controls [OR = 15.7; (95% CI = 6.8–36.4); p = 0.0001]. The HEV seroprevalence in alcoholic-related cirrhosis vs. with alcohol use disorder was 39.5% vs. 12.5% [OR = 4.58; (95% CI = 1.81–11.58); p<0.001].

          Conclusion

          We found a high seroprevalence of HEV in patients with cirrhosis and in individuals with alcohol use disorder. The simultaneous presence of both factors (cirrhosis + alcohol) showed more association to HEV infection. Larger studies with prospective follow up are needed to further clarify this interaction.

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          Most cited references23

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          Proposed reference sequences for hepatitis E virus subtypes

          The nomenclature of hepatitis E virus (HEV) subtypes is inconsistent and makes comparison of different studies problematic. We have provided a table of proposed complete genome reference sequences for each subtype. The criteria for subtype assignment vary between different genotypes and methodologies, and so a conservative pragmatic approach has been favoured. Updates to this table will be posted on the International Committee on Taxonomy of Viruses website (http://talk.ictvonline.org/r.ashx?C). The use of common reference sequences will facilitate communication between researchers and help clarify the epidemiology of this important human pathogen. This subtyping procedure might be adopted for other taxa of the genus Orthohepevirus.
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            Alcohol’s Effect on Host Defense

            Alcohol affects many organs, including the immune system, with even moderate amounts of alcohol influencing immune responses. Although alcohol can alter the actions of all cell populations involved in the innate and adaptive immune responses, the effect in many cases is a subclinical immunosuppression that becomes clinically relevant only after a secondary insult (e.g., bacterial or viral infection or other tissue damage). Alcohol’s specific effects on the innate immune system depend on the pattern of alcohol exposure, with acute alcohol inhibiting and chronic alcohol accelerating inflammatory responses. The proinflammatory effects of chronic alcohol play a major role in the pathogenesis of alcoholic liver disease and pancreatitis, but also affect numerous other organs and tissues. In addition to promoting proinflammatory immune responses, alcohol also impairs anti-inflammatory cytokines. Chronic alcohol exposure also interferes with the normal functioning of all aspects of the adaptive immune response, including both cell-mediated and humoral responses. All of these effects enhance the susceptibility of chronic alcoholics to viral and bacterial infections and to sterile inflammation.
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              Detection by reverse transcription-PCR and genetic characterization of field isolates of swine hepatitis E virus from pigs in different geographic regions of the United States.

              Hepatitis E virus (HEV) is an important public health concern in many developing countries. HEV is also endemic in some industrialized counties, including the United States. With our recent discovery of swine HEV in pigs that is genetically closely related to human HEV, hepatitis E is now considered a zoonotic disease. Human strains of HEV are genetically heterogenic. So far in the United States, only one strain of swine HEV has been identified and characterized from a pig. To determine the extent of genetic variations and the nature of swine HEV infections in U.S. pigs, we developed a universal reverse transcription-PCR (RT-PCR) assay that is capable of detecting genetically divergent strains of HEV. By using this universal RT-PCR assay, we tested fecal and serum samples of pigs of 2 to 4 months of age from 37 different U.S. swine farms for the presence of swine HEV RNA. Thirty-four of the 96 pigs (35%) and 20 of the 37 swine herds (54%) tested were positive for swine HEV RNA. The sequences of a 348-bp region within the ORF2 gene of 27 swine HEV isolates from different geographic regions were determined. Sequence analyses revealed that the 27 U.S. swine HEV isolates shared 88 to 100% nucleotide sequence identities with each other and 89 to 98% identities with the prototype U.S. strain of swine HEV. These U.S. swine HEV isolates are only distantly related to the Taiwanese strains of swine HEV, with about 74 to 78% nucleotide sequence identities; to most known human strains of HEV worldwide, with <79% sequence identities; and to avian HEV, with 54 to 56% sequence identities. Phylogenetic analysis showed that all the U.S. swine HEV isolates identified in this study clustered in the same genotype with the prototype U.S. swine HEV and the two U.S. strains of human HEV. The data from this study indicated that swine HEV is widespread and enzoonotic in U.S. swine herds and that, as is with human HEV, swine HEV isolates from different geographic regions of the world are also genetically heterogenic. These data further raise potential concerns for zoonosis, xenozoonosis, and food safety.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: MethodologyRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                24 October 2019
                2019
                : 14
                : 10
                : e0224404
                Affiliations
                [1 ] Instituto de Virología “Dr. J. M. Vanella”, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
                [2 ] Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
                [3 ] Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB)—CONICET—Instituto Universitario del Hospital Italiano (IUHI)—Hospital Italiano (HIBA), Buenos Aires, Argentina
                [4 ] Sección de Hepatología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
                [5 ] Departamento de Investigación, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
                [6 ] Hospital Córdoba, Córdoba, Argentina
                [7 ] Departamento de Gastroenterología, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba, Argentina
                [8 ] LACE Laboratorios, Córdoba, Argentina
                [9 ] Department of Medicine, Division of Infectious Diseases and International Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America
                Medizinische Fakultat der RWTH Aachen, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-0742-4116
                Article
                PONE-D-19-20415
                10.1371/journal.pone.0224404
                6812777
                31648288
                dd3d4e59-87b3-4531-b2c9-200ec92d348a
                © 2019 Fantilli et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 July 2019
                : 12 October 2019
                Page count
                Figures: 1, Tables: 1, Pages: 9
                Funding
                This work was supported by the Agencia Nacional de Promoción de Ciencia y Técnica de Argentina, ANPCyT, Foncyt, grant number PICT-2016-0143 ( https://www.argentina.gob.ar/ciencia/agencia/fondo-para-la-investigacion-cientifica-y-tecnologica-foncyt) to VR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Cirrhosis
                Biology and life sciences
                Microbiology
                Medical microbiology
                Microbial pathogens
                Viral pathogens
                Hepatitis viruses
                Hepatitis E virus
                Medicine and health sciences
                Pathology and laboratory medicine
                Pathogens
                Microbial pathogens
                Viral pathogens
                Hepatitis viruses
                Hepatitis E virus
                Biology and life sciences
                Organisms
                Viruses
                Viral pathogens
                Hepatitis viruses
                Hepatitis E virus
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                Epidemiology
                Medical Risk Factors
                Biology and Life Sciences
                Nutrition
                Diet
                Alcohol Consumption
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                Alcohol Consumption
                Physical Sciences
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                Organic Compounds
                Alcohols
                Physical Sciences
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                People and places
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                South America
                Argentina
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Chronic Liver Disease
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Immunology
                Autoimmune Diseases
                Primary Biliary Cirrhosis
                Biology and Life Sciences
                Immunology
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                Medicine and Health Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
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                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Biliary Disorders
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