Neurologic Disorders in Immunocompetent Patients with Autochthonous Acute Hepatitis E

Neurologic disorders, mainly Guillain-Barré syndrome and Parsonage–Turner syndrome (PTS), have been described in patients with hepatitis E virus (HEV) infection in industrialized and developing countries. We report a wider range of neurologic disorders in nonimmunocompromised patients with acute HEV infection. Data from 15 French immunocompetent patients with acute HEV infection and neurologic disorders were retrospectively recorded from January 2006 through June 2013. The disorders could be divided into 4 main entities: mononeuritis multiplex, PTS, meningoradiculitis, and acute demyelinating neuropathy. HEV infection was treated with ribavirin in 3 patients (for PTS or mononeuritis multiplex). One patient was treated with corticosteroids (for mononeuropathy multiplex), and 5 others received intravenous immunoglobulin (for PTS, meningoradiculitis, Guillain-Barré syndrome, or Miller Fisher syndrome). We conclude that pleiotropic neurologic disorders are seen in HEV-infected immunocompetent patients. Patients with acute neurologic manifestations and aminotransferase abnormalities should be screened for HEV infection.     

Effect of Hepatitis E Virus RNA Universal Blood Donor Screening,Catalonia, Spain, 2017‒2020

Hepatitis E virus (HEV) is the major cause of acute viral hepatitis in several countries in Europe. HEV is acquired mainly by consumption of contaminated pork but can also be transmitted through blood transfusion. HEV infection is usually self-limited but can become persistent in immunocompromised persons. During the first 30 months of HEV RNA universal screening of blood donations in Catalonia, Spain, we identified 151 HEV RNA–positive donations (1/4,341 blood donations). Most infected donors reported consumption of pates and sausages, and 58% were negative for HEV IgM and IgG. All HEV isolates belonged to genotype 3. All infected donors spontaneously resolved the infection, and no neurologic symptoms and reinfections were observed after 1 year of follow-up. Since the implementation of HEV RNA universal screening, no new cases of transfusion-transmitted HEV infection were reported. Our data indicate HEV screening of blood donations provides safer blood for all recipients, especially for immunosuppressed persons.     

Genotype Distribution and Sequence Variation of Hepatitis E Virus, Hong Kong

Most acute cases of infection with hepatitis E virus (HEV) in Hong Kong were autochthonous, sporadic, and occurred in older adults. All except 1 isolate belonged to genotype 4; most were phylogenetically related to swine isolates. The epidemiology is similar to that in industrialized countries, where zoonosis is the major source of HEV infection in humans.     

Virulent Strain of Hepatitis E Virus Genotype 3, Japan

Hepatitis E virus (HEV) genotype 3, which usually causes asymptomatic infection in Japan, induced severe hepatitis in 8 patients. To better understand genetic features of HEV associated with increased virulence, we determined the complete or near-complete nucleotide sequences of HEV from these 8 patients and from 5 swine infected with genotype 3 strain swJ19. Phylogenetic analysis showed that the isolates from the 8 patients and the 5 swine grouped separately from the other genotype 3 isolates to create a unique cluster, designated JIO. The human JIO-related viruses encoded 18 amino acids different from those of the other HEV genotype 3 strains. One substitution common to almost all human HEV strains in the JIO cluster was located in the helicase domain (V239A) and may be associated with increased virulence. A zoonotic origin of JIO-related viruses is suspected because the isolates from the 5 swine also possessed the signature V239A substitution in helicase.     

Genotype analysis of hepatitis E virus from sporadic hepatitis E cases in northern China

Hepatitis E is an important public health problem in many countries. However, there is no definite conclusion about the zoonotic reservoir, transmission patterns and risk factors of hepatitis E in the human population. The aim of this study was to analyze the epidemiological and viral genotype characteristics of hepatitis E cases in northern China. Surveillance was conducted in two hospitals in Liaoning and Hebei province from July 2010 to June 2012. Out of a total of 116 diagnosed patients, 88 (75.9%) were male and 28 (24.1%) were female and most (73%) were in the age group 40–70 years. In both hospitals, cases were diagnosed more frequently in March than in other months. HEV RNA was amplified from 41 patients and characterized by nucleotide sequencing and phylogenetic analysis. Most of the isolates (37 strains, 90.3%) were genotype 4, including subgenotypes 4a, 4b, 4d, 4h, 4i and a new subgenotype. One subgenotype 3a strain was isolated from Baoding, Hebei province. Three genotype 1b strains were found from patients in Jinzhou, Liaoning province. Most of the genotype 4 strains and the genotype 3 strains were phylogenetically related to known swine isolates. In conclusion, the finding that HEV infects mostly middle-aged and elderly men and that the incidence spiked in March may reflect the zoonotic transmission characteristics of HEV infection. Pigs, but not rabbits, were the important reservoirs in this area, because genotype 4 HEV was found to be responsible for the majority hepatitis E cases. However, genotype 1 is still present in northern China. Also, the first isolation of genotype 3 HEV in this area indicates that alternative routes of HEV transmission might exist.     

IFN-γ+874基因多态性与慢HBV和/或HCV感染及不同临床转归的关系

目的 研究HBV和/或HCV感染及其不同临床转归者干扰素-γ(IFN-γ)+874基因多态性(SNP),探讨其免疫遗传机制.方法 对河北省赵县某农村HBV和/或HCV感染者及对照共277人采集空腹静脉血,用ELISA检测抗-HBV、抗-HCV生物标志物,筛选出HBV重叠HCV感染79例、单纯HBV感染69例、HCV感染55例和对照74例.用RT-nPCR检测HCV RNA,Beckman LX-20全自动生化仪检测肝功能丙氨酸氨基转移酶(ALT),用PCR-SSP检测IFN-γ+874 T/A SNP,分析IFN-γ+874 T/A SNP与HBV和/或HCV感染、不同临床转归、ALT和HCVRNA表达的关系.结果 (1)不同感染类型即单纯HBV、HCV感染和重叠感染者+874 AA频率明显高于对照,+874 TA频率明显低于对照(X~2=16.15,P=0.01),OR值及95%CI分别是3.22(1.43～7.25)、2.70(1.24～5.92)、4.02(1.88～8.55),各感染类型间差异无统计学意义(X~2=1.97,P=0.73);+874 T/A等位基因频率在各组间差异无统计学意义(X~2=4.87,P=0.18);(2)不同临床转归即轻型、中重型肝炎和肝硬化组+874 AA频率明显高于对照组、+874 TA 频率明显低于对照组(X~2=14.17,P=0.03),OR值(95%CI)分别是3.09(1.51～6.33)、3.85(1.70～8.70)、3.14(1.08～9.17).+874 T/A等位基因频率与不同临床转归无统计关联(X~2=6.07,P=0.11);(3)IFN-γ+874SNP与HCV病毒复制无统计学关联(X~2=2.36,P=0.31),与ALT水平无统计学关联(X~2=0.15,P=0.93).结论 IFN-γ+874 T/A SNP与HBV和/或HCV感染者慢性化及不同临床转归有一定关联,IFN-γ+874 AA能增加HBV和/或HCV感染及其临床转归的危险,+874 TA则减低其感染和临床转归风险.     

Hepatitis E virus is prevalent in the pig population of Lao People's Democratic Republic and evidence exists for homogeneity with Chinese Genotype 4 human isolates

The objective of this study was to determine the prevalence and genotypic range of Hepatitis E virus (HEV) in the pig population of northern Lao People's Democratic Republic (PDR). We collected 181 faecal samples from indigenous-breed pigs ≤6 months of age and the faeces was stored in RNA stabilisation buffer due to cold-chain and transport limitations. Twenty-one (11.6%) pigs had detectable HEV RNA and 43.5% of village pig herds were infected. Based on a 240 base pair-nucleotide sequence flanking the junction of open reading frames 1, 2 and 3 (ORF1, ORF2 and ORF3) the isolates were phylogenetically classified within genotype 4. Phylogenetic analyses revealed distinct genetic groupings of the Lao HEV isolates and two groups clustered with human and pig HEV isolates from China. This was the first study to demonstrate genotype 4 HEV in Lao PDR and indicates pigs are a potential reservoir for human HEV infection.     

北京铁路部分人群散发性急性非甲非乙非丙型肝炎病原学分析

对北京铁路地区部分人群５８例散发性急性非甲非乙非丙型肝炎进行了ＨＥＶ和ＨＧＶ血清学调查。结果如下,抗－ＨＥＶ阳性２２例（３７．９３％）,抗－ＨＧＶ和ＨＧＶＲＮＡ阳性共１２例（２０．６８％）,其中３例为戊型和庚型肝炎病毒混合感染。戊肝、庚肝病毒感染均以３１～４０岁发病最多,且男多于女;戊肝主要发生在冬春季,多有肠道暴露史;庚型肝炎病毒感染无明显季节性,有肠道外暴露史。ＨＧＶ可单独感染,提示它可能有一定的致病性。     

Neurologic disorders and hepatitis E, France, 2010

We report meningitis with diffuse neuralgic pain or polyradiculoneuropathy associated with PCR-documented acute hepatitis E in 2 adults. These observations suggest that diagnostic testing for hepatitis E virus should be conducted for patients who have neurologic symptoms and liver cytolysis.     

上海市部分地区散发性戊型肝炎病毒基因型别和发病危险因素研究

目的探讨上海市部分地区急性散发性戊型肝炎（戊肝）病毒（HEV）型别和发病危险因素.方法用巢式RT-PCR方法检测HEV序列,并进行序列的同源性比较分析;同时采取1：2病例对照研究的方法,选取上海市3个区2003-2004年急性散发性确诊戊肝86例住院病例,分别配以本区和其他区健康人群对照组,用单因素和多因素logistlc回归模型进行分析.结果病毒序列分析表明戊肝病例中的HEV病毒序列属于Ⅳ型;单因素分析结果显示居住条件、外出就餐、有海鲜河鲜食用史等均为戊肝发病的危险因素;多因素分析结果显示海鲜（生、炝）食用史（OR=7.048）是戊肝感染 的危险因素.结论上海市部分地区散发性HEV流行株以Ⅳ型病毒株为主,海鲜（生、炝）食用史等是戊肝发病的危险因素.     

Evaluation of the protective effects of a nanogel-based vaccine against rabbit hepatitis E virus

Infection with hepatitis E virus (HEV) has raised serious public health concerns worldwide. In this study, a nanogel-based vaccine encapsulating the capsid protein of rabbit HEV was developed and its protective efficacy was compared with a subunit vaccine. A total of 23 rabbits were divided into 5 groups: (1) negative control (n = 4), (2) positive control (n = 4), (3) nanogel control (n = 5), (4) nanogel vaccine (n = 5), and (5) subunit vaccine (n = 5). Rabbits were vaccinated two times, at weeks 0 and 1, with nanogel and subunit vaccines, respectively, and challenged with rabbit HEV at week 4. By week 11, rabbits vaccinated with the nanogel vaccine produced higher antibodies than those vaccinated with the subunit vaccine. Fecal viral shedding and viremia were identified in rabbits of the positive and nanogel control groups at weeks 6–10. However, there was no viral shedding and viremia in rabbits immunized with both the nanogel and subunit vaccines. Alanine aminotransferase and aspartate aminotransferase levels were not elevated in any rabbit. However, histopathological examination revealed much less hepatic inflammation in rabbits of the nanogel vaccine group compared to the positive and nanogel control groups. Significant increases in IL-12 and IFN–γlevels were identified from rabbits immunized with the nanogel vaccine. Collectively, these results indicate that the newly developed nanogel vaccine induced sufficient immunity leading to complete protection from HEV infection in rabbits. Application of this vaccine should be considered as a preventive measure against HEV infection in other animal species and humans.     

Immunization with recombinant ORF2 p551 protein protects common marmosets (Callithrix jacchus) against homologous and heterologous hepatitis E virus challenge

BackgroundHepatitis E virus (HEV) is a major causative agent of acute hepatitis worldwide, prompting continuous HEV vaccine efforts. Vaccine development is hampered by the lack of convenient animal models susceptible to infection with different HEV genotypes. We produced recombinant open reading frame 2 protein (pORF2; p551) of HEV genotype (GT) 3 and assessed its immunogenicity and protectivity against HEV challenge in common marmosets (Callithrix jacchus, CM).Methodsp551 with consensus sequence corresponding to amino acid residues 110–660 of HEV GT3 pORF2 was expressed in E. coli and purified by affinity chromatography. CMs were immunized intramuscularly with 20 μg of p551 VLPs with alum adjuvant (n = 4) or adjuvant alone (n = 2) at weeks 0, 3, 7 and 19. At week 27, p551-immunized and control animals were challenged with HEV GT1 or GT3 and thereafter longitudinally screened for markers of liver function, anti-HEV IgG and HEV RNA in feces and sera.ResultsPurified p551 formed VLPs with particle size of 27.71 ± 2.42 nm. Two immunizations with p551 induced anti-HEV IgG mean titer of 1:1810. Immunized CMs challenged with homologous and heterologous HEV genotype did not develop HEV infection during the follow-up. Control CMs infected with both HEV GT1 and GT3 demonstrated signs of HEV infection with virus shedding and elevation of the levels of liver enzymes. High levels of anti-HEV IgG persisted in vaccinated CMs and control CMs that resolved HEV infection, for up to two years post challenge.ConclusionsCMs are shown to be a convenient laboratory animal model susceptible to infection with HEV GT1 and GT3. Immunization with HEV GT3 ORF2/p551 triggers potent anti-HEV antibody response protecting CMs from homologous and heterologous HEV challenge. This advances p551 in VLPs as a prototype vaccine against HEV.     

Hepatitis E Virus seroprevalence and chronic infections in patients with HIV, Switzerland

We screened 735 HIV-infected patients in Switzerland with unexplained alanine aminotransferase elevation for hepatitis E virus (HEV) immunoglobulin G. Although HEV seroprevalence in this population is low (2.6%), HEV RNA can persist in patients with low CD4 cell counts. Findings suggest chronic HEV infection should be considered as a cause of persistent alanine aminotransferase elevation.     

A truncated ORF2 protein contains the most immunogenic site on ORF2: antibody responses to non-vaccine sequences following challenge of vaccinated and non-vaccinated macaques with hepatitis E virus

A candidate hepatitis E vaccine is composed of amino acids (aa) 112-607 of the 660-aa protein encoded by open reading frame 2 (ORF2) of hepatitis E virus (HEV). We have studied the antibody response to vaccine-associated epitopes and to epitopes excluded from the vaccine to determine if important epitopes were omitted from the vaccine and if antibody responses to these regions could be used to differentiate between infection and vaccination. ELISAs were developed based on genotype 1 ORF2 peptides, containing aa 112-607 (vaccine), 458-607 (minimum neutralization site), 1-111 (N-terminus) and 607-660 (C-terminus), as well as on ORF3 peptides, containing aa 1-123 (complete) and 91-123 (C-terminus). All naive macaques infected with HEV genotype 1, 2, 3 or 4 produced antibodies to all ORF2 peptides. Anti-ORF3 was detected in both monkeys infected with genotype 1 virus and in one of two infected with genotype 2 virus. These antibody responses were considerably weaker than those directed against the neutralization site. In contrast, vaccinated animals that were challenged with HEV had a diminished or absent immune response to the peptides not included in the vaccine. Thus, only minor epitopes were excluded from the vaccine; they had limited utility for distinguishing between vaccination and infection.     

New Hepatitis E Virus Genotype in Camels,the Middle East

In a molecular epidemiology study of hepatitis E virus (HEV) in dromedaries in Dubai, United Arab Emirates, HEV was detected in fecal samples from 3 camels. Complete genome sequencing of 2 strains showed >20% overall nucleotide difference to known HEVs. Comparative genomic and phylogenetic analyses revealed a previously unrecognized HEV genotype.Hepatitis E virus (HEV) belongs to the family Hepeviridae and genus Hepevirus. Among humans worldwide, HEV is the most common cause of acute viral hepatitis. The disease is generally self-limiting, but mortality rates are high among pregnant women and young infants. Chronic HEV infection is a problem for immunocompromised patients, such as those who have received a solid organ transplant and those with HIV infection. In addition to humans, HEV has been found in the other mammals: pigs, boar, deer, rodents, ferrets, rabbits, mongoose, bats, cattle, sheep, foxes, minks, and horses (1–3). Among the 4 known HEV genotypes, HEV1 and HEV2 infect only humans; whereas, HEV3 and HEV4 can infect humans, pigs, and other mammals. Human infections with HEV3 and HEV4 have been associated with consumption of raw or undercooked pork or game meat (4). Traditionally, HEV infection is mainly transmitted through water contaminated with infected feces. Since water supplies and sanitary infrastructures have been improved, animals have become a major source of human HEV infection. We detected HEV in fecal samples from dromedary camels in the Middle East.     

戊型肝炎病毒感染动物模型应用于抗-HEV试剂评价的初步研究

目的应用实验室戊型肝炎病毒（HEV）感染恒河猴动物模型对抗-HEV诊断试剂进行初步的评价。方法用1和4基因型的HEV静脉注射分别感染4只恒河猴，检测实验猴的丙氨酸氨基转移酶（ALT）水平，逆转录聚合酶链反应（RT-PCR）方法检测粪便标本中HEVRNA，抗-HEVIgG试剂（GL-IgG，wT-IgG）分别检测实验猴系列血清抗体水平。结果HEV感染的8只实验猴均出现粪便排毒，1和4基因型HEV感染的实验猴分别有1只和2只出现ALT升高，GL-IgG试剂检测1型HEV实验感染猴有2只抗体阳转，4型HEV实验感染猴有1只抗体阳转；而wT-IgG试剂检测1、4型HEV实验感染猴的抗体均阳转。两种试剂检测感染猴窗口期抗体阳转时间相近，GL-IgG试剂抗体阳性持续到12周，wrT-IgG试剂在16周观察期内均阳性。结论两种试剂均可检测出感染实验猴的抗体，但wT-IgG试剂具有检测灵敏度较高的特点。     

广西地区猪、鼠、狗戊型肝炎病毒感染血清学分析

目的了解广西地区猪、鼠和狗血清中抗．戊型肝炎病毒（HEV）IgG抗体流行情况。方法应用HEV基因1型开放读码框（ORF）2和ORF3多肽包被酶标板，辣根过氧化物酶（HRP）标记的羊抗猪、羊抗鼠和羊抗狗建立的酶联免疫吸附试验（ELISA）法检测猪、鼠和狗血清中抗．HEV IgG。结果总抗．HEV IgG阳性率为31．84％（170／534），其中猪血清抗．HEV IgG阳性率为26．40％（66／250），鼠血清抗．HEV IgG阳性率为43．02％（77／179），狗血清抗．HEV IgG阳性率为25．71％（27／105）。结论猪、鼠和狗血清中存在HEV感染，鼠抗．HEV IgG阳性率最高。