Incidence and risk factors of de novo hepatitis E virus infection after receiving liver transplantation.

Organ transplant recipients with hepatitis E virus (HEV) infection bears high risk to develop chronic hepatitis, which is generally associated with immunosuppressive therapies. This study aimed to identify the incidence and predictors of de novo HEV infection in patients after receiving transplantation. We performed a large retrospective study to investigate the prevalence of anti-HEV at baseline, incidence of de novo HEV infection after transplantation, and the risk factors of HEV infection among patients with liver transplant in China. A total of 407 liver transplant recipients were examined for the presence of anti-HEV immunoglobulin G, IgM antibodies, and HEV RNA in serum. Basal indexes in individuals with evidence of post-transplant HEV infection were compared with those without evidence of that, and risk factors associated with HEV infection were assessed. The prevalence of anti-HEV at pretransplant in liver transplant recipients was 25.8% (105/407). Serum-negative conversion occurred in 34 (32.38%) of 105 liver transplant patients. Sixty-five out of 302 patients had de novo HEV infection after transplantation, with a cumulative incidence of 42.74% during follow-up. After transplantation, HEV infection was associated with liver failure (p = 0.012), hypoproteinemia (p = 0.030) and higher level of r-glutamyl transferase (GGT) (p = 0.022) before transplantation. Graft rejection (OR = 0.075; p = 0.045) was negatively associated with serum-negative conversion in patients who had positive anti-HEV antibody before transplantation. The incidence of de novo HEV infection after transplantation were higher in China. Liver failure, hypoproteinemia, and GGT elevation may be associated with HEV infection after liver transplantation. This study suggests that prevention and control of HEV infection after liver transplantation should be paid attention in patients bearing these risk factors.

Detection of Hepatitis E Virus (HEV) Among Ruminant Animals.

BACKGROUND: HEV is endemic in several Middle Eastern countries including Saudi Arabia, which hosts the annual pilgrimage for Muslims from around the world. One of the Hajj rituals is the sacrifice of animals, including camels, cows, goats, and sheep. HEV Zoonosis is established in swine and other suspected species, including deer, rabbits, dromedary, and Bactrian camels. HEV was identified in small, domesticized animals like goats, cows, sheep, and horses. We previously investigated HEV seroprevalence in Camels. This study aimed to evaluate HEV seroprevalence in other highly consumed ruminants in Saudi Arabia, namely cows, sheep, and goats. METHODS: Sera from cows (n = 47), goats (n = 56), and sheep (n = 67) were analyzed for the presence of HEV-IgG by using in-house developed ELISA assays. RESULTS: The highest seroprevalence was found in sheep (62.7%), followed by cows (38.3%), and then goats (14.3%), with a p-value of < 0.001. No other demographic characteristics of the animals were significantly correlated with the HEV seroprevalence. CONCLUSIONS: This study provides baseline data as the first study on the seroprevalence of HEV in ruminant animals in Saudi Arabia. The high seroprevalence found in sheep and cows must be further investigated for the potential zoonotic HEV transmission to humans. Further studies are needed to investigate the active viremia in these animal species through nucleic acid detection and sequencing to provide data on the circulating HEV genotypes among the targeted animal species. The detection of HEV in different animal products, such as milk, liver, and others, also remains an important study area to consider.

Hepatitis E virus immunosuppressed animal models.

Hepatitis E virus (HEV) is an important emerging pathogen producing significant morbidity in immunosuppressed patients. HEV has been detrimental to solid organ transplant (SOT) patients, cancer patients, and HIV-positive patients, where chronic HEV infections occur. Blood-borne transfusions and multiple cases of chronic HEV infection in transplant patients have been reported in the past few decades, necessitating research on HEV pathogenesis using immunosuppressed animal models. Numerous animal species with unique naturally occurring HEV strains have been found, several of which have the potential to spread to humans and to serve as pathogenesis models. Host immunosuppression leads to viral persistence and chronic HEV infection allows for genetic adaptation to the human host creating new strains with worse disease outcomes. Procedures necessary for SOT often entail blood transfusions placing immunosuppressive patients into a "high risk group" for HEV infection. This scenario requires an appropriate immunosuppressive animal model to understand disease patterns in these patients. Hence, this article reviews the recent advances in the immunosuppressed animal models for chronic HEV infection with emphasis on pathogenesis, immune correlates, and the liver pathology associated with the chronic HEV infections.

Porphyria cutanea tarda triggered by hepatitis-E virus.

Porphyria cutanea tarda (PCT) is the most common chronic porphyria, with approximate prevalence of 1:10,000. PCT is frequently associated with hepatitis C virus (HCV), malignant lymphoma and iron overload. Here, we present a case of PCT onset subsequent to hepatitis E virus infection (HEV), characterised by symptoms including skin fragility, haemorrhagic bullous skin exanthema, and onycholysis. The patient was successfully treated by erythrocytapheresis and hydroxychloroquine. After exclusion of other possible causes of PCT, HEV infection was identified as the likely trigger of the disease in this genetically predisposed individual, representing the first reported instance of such an association. Erythrocytapheresis emerged as a viable alternative to phlebotomy for PCT treatment. This case underscores the significance of considering HEV infection in the aetiology of PCT and highlights erythrocytapheresis as a promising therapeutic approach (Ref. 8). Text in PDF www.elis.sk Keywords: hepatitis E, porphyria cutanea tarda, erythrocytapheresis, hydroxychloroquine.

Production and Characterization of Self-Assembled Virus-like Particles Comprising Capsid Proteins from Genotypes 3 and 4 Hepatitis E Virus (HEV) and Rabbit HEV Expressed in Escherichia coli.

The zoonotic transmission of hepatitis E virus (HEV) genotypes 3 (HEV-3) and 4 (HEV-4), and rabbit HEV (HEV-3ra) has been documented. Vaccination against HEV infection depends on the capsid (open reading frame 2, ORF2) protein, which is highly immunogenic and elicits effective virus-neutralizing antibodies. Escherichia coli (E. coli) is utilized as an effective system for producing HEV-like particles (VLPs). However, research on the production of ORF2 proteins from these HEV genotypes in E. coli to form VLPs has been modest. In this study, we constructed 21 recombinant plasmids expressing various N-terminally and C-terminally truncated HEV ORF2 proteins for HEV-3, HEV-3ra, and HEV-4 in E. coli. We successfully obtained nine HEV-3, two HEV-3ra, and ten HEV-4 ORF2 proteins, which were primarily localized in inclusion bodies. These proteins were solubilized in 4 M urea, filtered, and subjected to gel filtration. Results revealed that six HEV-3, one HEV-3ra, and two HEV-4 truncated proteins could assemble into VLPs. The purified VLPs displayed molecular weights ranging from 27.1 to 63.4 kDa and demonstrated high purity (74.7-95.3%), as assessed by bioanalyzer, with yields of 13.9-89.6 mg per 100 mL of TB medium. Immunoelectron microscopy confirmed the origin of these VLPs from HEV ORF2. Antigenicity testing indicated that these VLPs possess characteristic HEV antigenicity. Evaluation of immunogenicity in Balb/cAJcl mice revealed robust anti-HEV IgG responses, highlighting the potential of these VLPs as immunogens. These findings suggest that the generated HEV VLPs of different genotypes could serve as valuable tools for HEV research and vaccine development.

The 2023 South Sudanese outbreak of Hepatitis E emphasizes ongoing circulation of genotype 1 in North, Central, and East Africa.

In April 2023, an outbreak of acute hepatitis was reported amongst internally displaced persons in the Nazareth community of South Sudan. IgM serology-based screening suggested the likely etiologic agent to be Hepatitis E virus (HEV). In this study, plasma specimens collected from anti-HEV IgM-positive cases were subjected to additional RT-qPCR testing and sequencing of extracted nucleic acids, resulting in the recovery of five full and eight partial HEV genomes. Maximum likelihood phylogenetic reconstruction confirmed the genomes belong to HEV genotype 1. Using distance-based methods, we show that genotype 1 is best split into three sub-genotypes instead of the previously proposed seven, and that these sub-genotypes are geographically restricted. The South Sudanese sequences confidently cluster within sub-genotype 1e, endemic to northeast, central, and east Africa. Bayesian Inference of phylogeny incorporating sampling dates shows that this new outbreak is not directly descended from other recent local outbreaks for which sequence data is available. However, the analysis suggests that sub-genotype 1e has been consistently and cryptically circulating locally for at least the past half century and that the known outbreaks are often not directly descended from one another. The ongoing presence of HEV, combined with poor sanitation and hygiene in the conflict-affected areas in the region, place vulnerable populations at risk for infection and its more serious effects, including progression to fulminant hepatitis.

Combining RNA Interference and RIG-I Activation to Inhibit Hepatitis E Virus Replication.

Hepatitis E virus (HEV) poses a significant global health threat, with an estimated 20 million infections occurring annually. Despite being a self-limiting illness, in most cases, HEV infection can lead to severe outcomes, particularly in pregnant women and individuals with pre-existing liver disease. In the absence of specific antiviral treatments, the exploration of RNAi interference (RNAi) as a targeted strategy provides valuable insights for urgently needed therapeutic interventions against Hepatitis E. We designed small interfering RNAs (siRNAs) against HEV, which target the helicase domain and the open reading frame 3 (ORF3). These target regions will reduce the risk of viral escape through mutations, as they belong to the most conserved regions in the HEV genome. The siRNAs targeting the ORF3 efficiently inhibited viral replication in A549 cells after HEV infection. Importantly, the siRNA was also highly effective at inhibiting HEV in the persistently infected A549 cell line, which provides a suitable model for chronic infection in patients. Furthermore, we showed that a 5' triphosphate modification on the siRNA sense strand activates the RIG-I receptor, a cytoplasmic pattern recognition receptor that recognizes viral RNA. Upon activation, RIG-I triggers a signaling cascade, effectively suppressing HEV replication. This dual-action strategy, combining the activation of the adaptive immune response and the inherent RNAi pathway, inhibits HEV replication successfully and may lead to the development of new therapies.

Chronic hepatitis E virus-induced spinal cord atrophy in a patient with chronic lymphatic leukemia: a case report and interdisciplinary management proposal.

Background: The hepatitis E virus (HEV) can cause acute viral hepatitis with or without neurological manifestations, and occasionally progresses to chronic infection in immunocompromised individuals. The management of chronic HEV infection in cancer patients may be challenging due to the complex immunological constellation. Furthermore, the diagnostic workflow and the impact on quality of life of neurological HEV manifestations in immunocompromised patients have not been sufficiently delineated previously. Case description: A 61-year-old male with systemically treated chronic lymphocytic leukemia (CLL) experienced a slowly progressive atrophy of the spinal cord due to a chronic HEV infection. Despite continuous antiviral treatment with ribavirin, the patient's neurological condition continued to deteriorate, particularly following subsequent attempts to treat CLL. Treatment with obinutuzumab resulted in acute bowel and urinary retention and a further deterioration of motor skills, prompting the discontinuation of obinutuzumab. The patient's neurological status improved after the administration of intravenous immunoglobulins. Conclusion: This case study provides a comprehensive long-term follow-up of a cancer patient with chronic HEV infection and associated CNS involvement, which resulted in progressive neurological disability over several years. The challenges faced in diagnosing new neurological symptoms in patients undergoing immunosuppressive cancer treatment underscore the need for an interdisciplinary diagnostic approach that includes HEV testing. We propose a diagnostic pathway for future validation in immunocompromised cohorts presenting with neurological symptoms, emphasizing its potential to enhance clinical outcomes.

Serological indication of chronic inflammatory demyelinating polyneuropathy as an extrahepatic manifestation of hepatitis E virus infection.

Guillain-Barré syndrome and neuralgic amyotrophy have been associated with hepatitis E virus (HEV) genotype 3 infections, while myasthenia gravis (MG) has been associated with HEV genotype 4 infections. However, whether chronic inflammatory demyelinating polyneuropathy (CIDP) is associated with HEV infections has not been conclusively clarified yet. 102 CIDP patients, 102 age- and sex-matched blood donors, 61 peripheral neuropathy patients (non-CIDP patients), and 26 MG patients were tested for HEV and anti-HEV IgM and IgG. Sixty-five of the 102 (64%) CIDP patients tested positive for anti-HEV IgG and one (1%) for anti-HEV IgM. No other patient tested positive for ati-HEV IgM. In the subgroup of CIDP patients with initial diagnosis (without previous IVIG treatment), 30/54 (56%) tested positive for anti-HEV IgG. Anti-HEV rates were significantly lower in blood donors (28%), non-CIDP peripheral neuropathy patients (20%), and MG patients (12%). No subject tested positive for HEV viremia. CSF tested negative for in 61 CIDP patients (54 patients with primary diagnosis). The development of CIDP but not non-CIDP polyneuropathy may be triggered by HEV exposure in an HEV genotype 3 endemic region. The increased anti-HEV seroprevalence in CIDP patients is not a consequence of IVIG therapy.

Global temporal trends and projections of acute hepatitis E incidence among women of childbearing age: Age-period-cohort analysis 2021.

BACKGROUND & AIMS: Acute hepatitis E (AHE) poses a significant threat to global public health, particularly among women of childbearing age (WCBA), who are at heightened risk for severe pregnancy-related complications. This study aimed to delineate the temporal trends and project future incidence of AHE in WCBA, providing insights crucial for targeted prevention and control strategies. METHODS: Data on AHE incidence from the Global Health data 2021. The age-period-cohort (APC) model was applied to analyze trends across different age groups, periods, and birth cohorts, and the Bayesian APC model was utilized for forecasting future epidemiological trajectories. RESULTS: Globally, AHE incidence numbers among WCBA rose from 2,831,075 in 1992 to 3,420,786 in 2021, while the age-standardized incidence rate (ASIR) declined from 194.66 to 179.54 per 100,000 with a global net drift of -0.28%. However, high SDI regions showed a contrasting trend with a positive net drift of 0.02%. The age effect was consistent across SDI regions and globally, showing a decrease with advancing age, while unfavorable period and cohort effects were exhibited in high-SDI region. At the national level, locations exhibited varying trends of change. The BAPC model predicted a total of 3,759,384 AHE global cases in WCBA by 2030, with an expected mild increase in the ASIR. The outlook for the management and containment of AHE is grim in certain countries, including India. CONCLUSIONS: The study revealed a complex epidemiological landscape of AHE in WCBA, with increasing global incidence numbers juxtaposed against a declining ASIR. The AHE burden by 2030 remain severe among WCBA. Young WCBA and high SDI region merit particular attention. The findings underscore the need for region-specific strategies to curb the projected rise in AHE incidence and align with the 2030 WHO goals.

From discovery to treatment: tracing the path of hepatitis E virus.

The hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. HEV is classified into eight genotypes, labeled HEV-1 through HEV-8. Genotypes 1 and 2 exclusively infect humans, while genotypes 3, 4, and 7 can infect both humans and animals. In contrast, genotypes 5, 6, and 8 are restricted to infecting animals. While most individuals with a strong immune system experience a self-limiting infection, those who are immunosuppressed may develop chronic hepatitis. Pregnant women are particularly vulnerable to severe illness and mortality due to HEV infection. In addition to liver-related complications, HEV can also cause extrahepatic manifestations, including neurological disorders. The immune response is vital in determining the outcome of HEV infection. Deficiencies in T cells, NK cells, and antibody responses are linked to poor prognosis. Interestingly, HEV itself contains microRNAs that regulate its replication and modify the host's antiviral response. Diagnosis of HEV infection involves the detection of HEV RNA and anti-HEV IgM/IgG antibodies. Supportive care is the mainstay of treatment for acute infection, while chronic HEV infection may be cleared with the use of ribavirin and pegylated interferon. Prevention remains the best approach against HEV, focusing on sanitation infrastructure improvements and vaccination, with one vaccine already licensed in China. This comprehensive review provides insights into the spread, genotypes, prevalence, and clinical effects of HEV. Furthermore, it emphasizes the need for further research and attention to HEV, particularly in cases of acute hepatitis, especially among solid-organ transplant recipients.

Serological and molecular survey of rat hepatitis E virus (Rocahepevirus ratti) in drug users.

ABSTRACTRat hepatitis E virus (ratHEV) is an emerging cause of acute hepatitis of zoonotic origin. Since seroprevalence studies are scarce, at-risk groups are almost unknown. Because blood-borne infections frequently occur in people with drug use, who are particularly vulnerable to infection due to lack of housing and homelessness, this population constitutes a priority in which ratHEV infection should be evaluated. Therefore, the aim of this study was to evaluate the ratHEV seroprevalence and RNA detection rate in drug users as a potential at-risk population. We designed a retrospective study involving individuals that attended drug rehabilitation centres. Exposure to ratHEV was assessed by specific antibody detection using ELISA and dot blot (DB) assay and the presence of active infection by ratHEV RNA detection using RT-qPCR. Three-hundred and forty-one individuals were included, the most of them being men (67.7%) with an average age of 45 years. A total of 17 individuals showed specific IgG antibodies against ratHEV (4.6%; 95% CI; 3.1%-7.9%). One case of active ratHEV infection was identified (0.3%; 95% CI: 0.1%-1.8%). This was a 57-year-old homeless woman with limited financial resources, who had active cocaine and heroin use via parenteral route. In conclusion, we identified a potential exposure to ratHEV among drug users. Targeted studies in drug users with proper control groups are necessary to evaluate high-risk populations and transmission routes more accurately.

The AP-1 adaptor complex is essential for intracellular trafficking of the ORF2 capsid protein and assembly of Hepatitis E virus.

Although the Hepatitis E virus (HEV) is an emerging global health burden, little is known about its interaction with the host cell. HEV genome encodes three proteins including the ORF2 capsid protein that is produced in different forms, the ORF2i protein which is the structural component of viral particles, and the ORF2g/c proteins which are massively secreted but are not associated with infectious material. We recently demonstrated that the endocytic recycling compartment (ERC) is hijacked by HEV to serve as a viral factory. However, host determinants involved in the subcellular shuttling of viral proteins to viral factories are unknown. Here, we demonstrate that the AP-1 adaptor complex plays a pivotal role in the targeting of ORF2i protein to viral factories. This complex belongs to the family of adaptor proteins that are involved in vesicular transport between the trans-Golgi network and early/recycling endosomes. An interplay between the AP-1 complex and viral protein(s) has been described for several viral lifecycles. In the present study, we demonstrated that the ORF2i protein colocalizes and interacts with the AP-1 adaptor complex in HEV-producing or infected cells. We showed that silencing or drug-inhibition of the AP-1 complex prevents ORF2i protein localization in viral factories and reduces viral production in hepatocytes. Modeling of the ORF2i/AP-1 complex also revealed that the S domain of ORF2i likely interacts with the σ1 subunit of AP-1 complex. Hence, our study identified for the first time a host factor involved in addressing HEV proteins (i.e. ORF2i protein) to viral factories.

Misdiagnosed Antibiotic-Induced Liver Injury: Unveiling Acute Hepatitis E in a 65-Year-Old Patient.

BACKGROUND Common causes of severely elevated transaminases, especially alanine transaminase, due to liver diseases include drug-induced liver injury and acute viral hepatitis, especially hepatitis E, which can present similarly in clinical practice. Broad differential diagnostic workup in patients with elevated transaminases is required to not overlook the possibility of hepatitis E infection. CASE REPORT We report on a 65-year-old asymptomatic man who was referred to the Emergency Department from the rehabilitation center due to markedly elevated liver transaminases. Physical examination revealed no jaundice or abdominal pain. Laboratory findings included severely elevated aspartate transaminase, alanine transaminase, and bilirubin levels. He was previously treated with imipenem/cilastatin and clindamycin for a surgical site infection of his jaw after the removal of a squamous cell carcinoma 2 weeks earlier. An ultrasound of the liver was unremarkable. Drug-induced liver injury was suspected, and all potentially hepatotoxic drugs, including antibiotics, were stopped. Due to the rapid and marked increase in liver transaminases, further tests were performed, including testing for hepatitis E. Serum anti-hepatitis E virus immunoglobulin M, immunoglobulin G antibodies, and hepatitis E virus-ribonucleic acid-polymerase chain reaction turned positive, and the diagnosis of hepatitis E was confirmed. Supportive care was applied. Liver transaminases decreased spontaneously. CONCLUSIONS The diagnostic workup in patients with markedly elevated liver transaminases and suspected drug-induced liver injury should include the screening for hepatitis E. Making the correct diagnosis is crucial given the differing treatment approaches, the implications on further therapy, and the risk of contagion of hepatitis E.

Prevalence of hepatitis A and E viruses in wastewater in Asian countries.

Hepatitis A and E viruses (HAV and HEV, respectively) remain a significant global health concern despite advancements in healthcare and vaccination programs. Regular monitoring and vaccine efficacy of HAV are still lacking in different countries. This study aimed to investigate HAV and HEV prevalence in developed, developing, and least-developed Asian countries using wastewater as a surveillance tool. A total of 232 untreated wastewater samples were collected from six wastewater treatment plants, a sewage treatment plant, or an open drainage in six countries [Nepal (n = 51), Indonesia (n = 37), Thailand (n = 30), Vietnam (n = 27), the Philippines (n = 17), and Japan (n = 70)] between April and October 2022. Viruses in wastewater were concentrated by simple centrifugation or polyethylene glycol precipitation method, followed by viral RNA extraction and reverse transcription-quantitative polymerase chain reaction. HAV and HEV RNA were detected in the samples from Nepal (51 % for HAV and 2 % for HEV), Thailand (3 % for both viruses), and Japan (1 % for HAV and 24 % for HEV). Only HAV RNA was found in 11 % of the samples in Indonesia, whereas only HEV RNA was detected in Vietnam and the Philippines, with a positive ratio of 15 % and 12 %, respectively. These results highlighted the geographic variability in HAV and HEV prevalence, underscoring the need for localized public health strategies to address specific viral hepatitis challenges in each country.

Understanding hepatitis E vaccination intention among women of childbearing-age: A theory-based cross-sectional study.

OBJECTIVES: The purpose of this study was to investigate the HEV vaccination intention, its determinants, and overall influence mechanisms among childbearing-age women. METHOD: The current study was cross-sectional and conducted online from June 25, 2023 to September 25, 2023 in Nanjing, China. Logistic regression models were constructed to identify the intention-associated background factors. Technology Acceptance Model (TAM) and Theory of Planned Behavior (TPB) were integrated and expanded as TAM-TPB model to further investigate the determinants and overall influence mechanism of HEV vaccination intention among this population using structural equation modeling. RESULTS: A total of 423 eligible participants were included in this study. High general HEV knowledge was independently associated with an increased intention to get HEV vaccination (OR = 1.97, 95 % CI: 1.11-3.58, P = 0.023). All the hypotheses proposed in the theoretical TAM-TPB model were supported, with perceived ease of use, perceived usefulness, attitude, subjective norm, and perceived behavioral control positively affecting the intention of HEV vaccination (all P values <0.05), while perceived risk (P = 0.003) exhibited an inverse association with HEV vaccination intention. The model achieved an acceptable fit, and the total explained variance of HEV vaccination intention was as high as 86.20 %. Moreover, no significant common method bias was observed. CONCLUSION: This is the first theory-based study that explored the HEV vaccination intention, its determinants, and overall influence mechanism among childbearing-age women. The results of the current study are of great importance for improving the understanding of the HEV vaccination intention among females of childbearing age.