Viral hepatitis E represents an important global health problem caused by the hepatitis E virus (HEV). Cases of HEV infection are increasingly associated with food-borne transmissions after the consumption of raw or undercooked food products from infected animals in high-income regions. Although most cases of infection are asymptomatic, severe courses of infection have been reported in specific groups of people, predominantly among pregnant women and immunocompromised patients. The viral nucleic acid of HEV is increasingly being reported in food-producing animals and different products of an animal origin. Even though the incubation period for HEV infection is long, several direct epidemiological links between human cases and the consumption of HEV-contaminated meat and meat products have been described. In this article, we review the current knowledge on human HEV infections, HEV in different food-producing animals and products of an animal origin, as well as the accumulation and resistance to HEV in farm and slaughterhouse environments. We also provide preventive measures to help eliminate HEV from animals, the human population, and the environment.

Hepatitis E Virus (HEV) has gained public health attention as one of the causative agents of viral hepatitis. Our study aimed to provide data about HEV seropositivity in the Israeli general population, including its seroprevalence geographical distribution, and to identify variables as possible risk factors for HEV exposure. A seroprevalence cross-sectional study was conducted: HEV serological status was determined in 716 blood samples collected from the routine check-up blood samples. Demographic information was available for all samples. The overall prevalence of HEV IgG in an apparently healthy population in the north of Israel was 10.5%, with no evidence of positive HEV IgM. There was a significant association between HEV seropositivity and elderly age and low socioeconomic status (SES). The age-adjusted seroprevalence was significantly lower among Jews compared to Arabs with a rate ratio of 2.02. We identified clusters (hot spots) of HEV infection in three regions under study. Our results confirmed a high prevalence of anti-HEV in the country where clinical hepatitis E is not endemic. For the first time, this study showed that a hot spot analysis was able to provide new knowledge about actual exposure zones. As HEV infection is not a notifiable disease, it is probably underdiagnosed. Thus, better awareness among physicians is warranted.

Introduction: Hepatitis E virus (HEV) infection is caused by viruses belonging to the Hepeviridae family. HEV infection can be self-limiting; however, extrahepatic manifestations may be present. The purpose of the current study was to establish the seroprevalence of HEV among Bulgarian liver transplant recipients (LTRs) and to identify associated risk factors. Materials & Methods: The present study was conducted between April 1, 2023, and October 30, 2023, at the Military Medical Academy, Sofia, Bulgaria. All serum samples were tested for anti-HEV IgG/IgM using HEV IgG/IgM enzyme-linked immunosorbent assay on Dia.Pro (Milan, Italy). Each participating LTR completed a detailed paper-based closed-ended questionnaire regarding the associated risk factors for HEV infection. Results: The study included 73 LTRs with a mean age of 47.0 ± 14.0 years. Anti-HEV IgG antibodies were detected in 25 LTRs (34.2%), including 20 males (37.7%) and 5 females (25%). All participants were HEV-IgM negative. HEV seropositivity rates were higher but not statistically significant in LTRs aged >60 years than in those aged <60 years (40% vs. 32.7%). A significant factor by logistic regression was "high level of education" (odds ratio [OR] = 2.917; p = 0.038). Conclusion: To the best of our knowledge, this is the first seroepidemiological HEV study among LTRs from Bulgaria that found a high seroprevalence (34.2%).

Hepatitis E virus (HEV) is a major cause of acute hepatitis. HEV genotypes 1 and 2 are associated with oro-faecal epidemics and fulminant hepatitis in pregnant women. HEV genotypes 3 and 4 are a zoonosis transmitted by uncooked pork. Infection is usually spontaneously resolutive. Chronic hepatitis may occur in immunocompromised patients. Extrahepatic disease is also possible. Prevention is based on hygiene, especially in high-risk patients, and access to safe drinking water for all. A recombinant vaccine against HEV has been developed and is currently being validated by the WHO.

Hepatitis E virus (HEV) infection can become chronic in immunocompromised patients, like solid organ transplant recipients (SOTRs). We evaluated HEV prevalence, risk factors, and outcomes among SOTRs in a hyperendemic HEV area. Three hundred SOTRs were enrolled from April to July 2019 and tested for anti-HEV IgM and IgG and HEV RNA. Sixty-three recipients (21%) were positive for any HEV marker. HEV infection was independently associated with older age and pork liver sausage consumption. Three viremic recipients harbored genotype 3e and 3f according to HEV RNA sequencing and phylogenetic analysis. Overall, 10 recipients had markers of active/recent infection (HEV RNA and/or anti-HEV IgM) and were followed up prospectively. Five of them spontaneously resolved their HEV infection. In two recipients, HEV clearance was achieved only through immunosuppression reduction, while three needed ribavirin therapy to achieve virologic resolution. We observed a chronic course in 30% of SOTRs with active/recent HEV infection. No association was found between tacrolimus assumption and chronicization. In conclusion, we found a high prevalence of infection among SOTRs attending a transplant center in a hyperendemic Italian HEV region. Systematic screening for all HEV markers and dietary education for infection control are needed for transplant recipients.

Hepatitis E virus (HEV) is one of the leading causes of acute hepatitis, with immunosuppressed individuals, such as oncology patients, being particularly vulnerable to chronic infections that may progress to liver disease or fatal outcomes. Assay variability complicates HEV prevalence assessment in at-risk groups. This study aimed to compare the reliability and concordance of three HEV antibody assays-Wantai, Euroimmun, and Elecsys®-in immunosuppressed oncology patients.

In this prospective pilot study, serum samples were obtained from oncology patients between September 2020 and October 2021. Samples were collected both at baseline (treatment-naive) and during ongoing treatment. A healthy control group was retrospectively included for comparative analysis. Anti-HEV IgM and IgG antibodies were tested in all samples using enzyme-linked immunosorbent assays (Wantai, Euroimmun) and an electrochemiluminescence immunoassay (Elecsys®). Demographic and clinical data, along with information on HEV risk factors, were extracted from medical records and patient questionnaires.

HEV IgM prevalence ranged from 0% (Wantai) to 6% (Elecsys®), while IgG prevalence was 12% (Euroimmun), 38% (Wantai), and 53% (Elecsys®). Concordance was poor, with Cohen's Kappa values indicating slight to moderate agreement (κ = 0.000-0.553). Patients with hematological malignancies exhibited the highest IgG seroprevalence. Risk factor analysis revealed the highest association between HEV exposure and the consumption of undercooked pork or crop-based agriculture.

Significant variability among HEV serological assays highlights the challenges of reliable HEV diagnostics in immunosuppressed oncology patients. Assay selection and improved testing strategies are critical for this high-risk group.

Chronic infections with hepatitis E virus (HEV), especially those of genotype 3 (G3), frequently lead to liver fibrosis and cirrhosis in patients. However, the causation and mechanism of liver fibrosis triggered by chronic HEV infection remain poorly understood. Here, we found that the viral multiple-domain replicase (ORF1) undergoes unique ubiquitin-proteasomal processing leading to formation of the HEV-Derived SMAD Activator (HDSA), a viral polypeptide lacking putative helicase and RNA polymerase domains. The HDSA is stable, non-HSP90-bound, localizes to the nucleus, and is abundant in G3 HEV-infected hepatocytes of various origins. Markedly, the HDSA in hepatocytes potentiates the fibrogenic TGF-β/SMAD pathway by forming compact complexes with SMAD3 to facilitate its promoter binding and coactivator recruitment, leading to significant fibrosis in HEV-susceptible gerbils. Virus infection-induced liver fibrosis in HEV-susceptible gerbils could be prevented by mutating the residues P989C, A990C, and A991C (PAA-3C) within ORF1, which are required for proteasomal processing. Thus, we have identified a viral protein derived from host proteasomal processing, defined its notable role in liver fibrosis and highlighted the nature of an unanticipated host-HEV interaction that facilitates hepatitis E pathogenesis.

Paslahepevirus balayani (hepatitis E virus) is a zoonotic pathogen, with rabbit Paslahepevirus balayani (HEV-3ra) being widely distributed among global rabbit populations. Notably, in China, rabbits constitute a significant HEV host, second only to swine. Emerging evidence suggests that HEV-3ra possesses the capability to cross species barriers and infect humans. Against this backdrop, our investigation aimed to delineate the HEV infection status and epidemiological patterns in the commercial rabbits of Hebei Province, China. We collected 386 liver and 100 fecal samples across four regions in Hebei Province. Detection of HEV RNA in these specimens was achieved by employing reverse transcription quantitative polymerase chain reaction (RT-qPCR) and reverse transcription nested PCR (RT-Nested PCR), focusing on the amplification of a segment of the open reading frame 2 (ORF2) and the complete genome. Among the 486 samples, 73 were tested positive for HEV RNA, resulting in an overall positive rate of 15.0%. The positive rates for liver and fecal samples were 11.7% (45/386) and 28.0% (28/100), respectively. The study successfully obtained 38 partial ORF2 sequences and 5 complete genome sequences. Sequence analysis revealed that the complete genome sequences shared 86.0-94.5% nucleotide identity with HEV-3ra sequences in GenBank. Phylogenetic analysis confirmed that all strains belonged to HEV-3ra and were closely related to previously reported sequences from China. This study provides the first comprehensive genomic overview of circulating HEV-3ra strains in Hebei, offering valuable insights into the infection dynamics and prevalence of HEV-3ra among commercial rabbits, which can inform public health strategies.

Cancer patients with haematological malignancies are at risk for chronic hepatitis E virus infection following chimeric antigen receptor (CAR) T-cell therapy. Strong clinical suspicion is essential for the early diagnosis and prompt treatment of this difficult-to-treat type of viral hepatitis. Commentary on: Schwarz et al. Chronic hepatitis E in a patient after CAR-T cell treatment for diffuse large B-cell lymphoma and rapid progression towards decompensated liver cirrhosis. Br J Haematol 2025; 206:977-980.

Hepatitis E virus (HEV) causes 3.3 million symptomatic cases and 44,000 deaths per year. Chronic infections can arise in immunocompromised individuals, and pregnant women may suffer from fulminant disease as a consequence of HEV infection. Despite these important implications for public health, no specific antiviral treatment has been approved to date. Here, we report combined functional, biochemical, and X-ray crystallographic studies that characterize the human antibody response in convalescent HEV patients. We identified a class of potent and broadly neutralizing human antibodies (bnAbs), targeting a quaternary epitope located at the tip of the HEV capsid protein pORF2 that contains an N-glycosylation motif and is conserved across members of the Hepeviridae. These glycan-sensitive bnAbs specifically recognize the non-glycosylated pORF2 present in infectious particles but not the secreted glycosylated form acting as antibody decoy. Our most potent bnAb protects human liver-chimeric mice from intraperitoneal HEV challenge and co-housing exposure. These results provide insights into the bnAb response to this important emerging pathogen and support the development of glycan-sensitive antibodies to combat HEV infection.

Infection with one or several of the five known hepatitis viruses is a leading cause of liver disease and poses a high risk of developing hepatocellular carcinoma upon chronic infection. Chronicity is primarily caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) and poses a significant health burden worldwide. Co-infection of chronic HBV infected patients with hepatitis D virus (HDV) is less common but is marked as the most severe form of chronic viral hepatitis. Hepatitis A virus (HAV) and hepatitis E virus (HEV) primarily cause self-limiting acute hepatitis. However, studies have also reported chronic progression of HEV disease in immunocompromised patients. While considerable progress has been made in the treatment of HCV and HBV through the development of direct-acting antivirals (DAAs), challenges including drug resistance, incomplete viral suppression resulting in failure to achieve clearance and the lack of effective treatment options for HDV and HEV remain. Host-targeting antivirals (HTAs) have emerged as a promising alternative approach to DAAs and aim to disrupt virus-host interactions by modulating host cell pathways that are hijacked during the viral replication cycle. The aim of this review is to provide a comprehensive overview about the major milestones in research and development of HTAs for chronic HBV/HDV and HCV infections. It also summarizes the current state of knowledge on promising host-targeting therapeutic options against HEV infection.

Hepatitis E virus (HEV) is a major cause of acute and chronic hepatitis in humans. The HEV open reading frames (ORF1) encodes a large non-structural protein essential for viral replication, which contains several functional domains, including helicase and RNA-dependent RNA polymerase. A confusing aspect is that, while RNA viruses typically encode large polyproteins that rely on their enzymatic activity for processing into functional units, the processing of the ORF1 protein and the mechanisms involved remain unclear. The ORF1 plays a pivotal role in the viral life cycle, thus mutations in this region, especially those occurring under environmental pressures such as during antiviral drug treatment, could significantly affect viral replication and survival. Here, we summarize the recent advances in the functional domains, processing, and mutations of ORF1. Gaining a deeper understanding of HEV biology, particularly focusing on ORF1, could facilitate the development of new strategies to control HEV infections.

The occurrence of hepatitis E virus (HEV) in patients with Schistosomiasis mansoni (SM) is still poorly understood in Brazil. The objective of this study was to estimate the seroprevalence of anti-HEV IgG in patients with SM and its association with the periportal fibrosis (PPF), assessed by serum markers and ultrasound criteria. This cross-sectional study was carried out in an endemic area in Pernambuco, Brazil, with schistosomal patients who underwent coproscopic survey. Anti-HEV antibody IgG were evaluated by using ELISA (Euroimmun®, Lübeck, Germmany). In positive cases, HEV-RNA was tested by using real-time PCR. Among the 286 patients (60.8% women; 56% 18-44 years), 116 (40.6%) had advanced PPF (Niamey pattern D/E/F). Anti-HEV IgG was positive in 15 (5.24%), and all were HEV-RNA negative. Anti-HEV IgG was more frequent in patients with an advanced PPF (D/E/F) pattern (p = 0.034) and those with the largest spleen diameter (p = 0.039). In this study, the occurrence of anti-HEV IgG in patients with SM was higher than described in the same region and more frequent among patients with evidence of advanced liver fibrosis.

Hepatitis E virus (HEV) exists in two distinct forms: a non-enveloped form (neHEV), which is present in feces and bile, and a quasi-enveloped form (eHEV), found in circulating blood and culture supernatants. This study aimed to elucidate the roles of Ras-associated binding 13 (Rab13) and protein kinase A (PKA) in the entry mechanisms of both eHEV and neHEV, utilizing small interfering RNA (siRNA) and chemical inhibitors. The results demonstrated that the entry of both viral forms is dependent on Rab13 and PKA. Further investigation into the involvement of tight junction (TJ) proteins revealed that the targeted knockdown of zonula occludens-1 (ZO-1) significantly impaired the entry of both eHEV and neHEV. In addition, in ZO-1 knockout (KO) cells inoculated with either viral form, HEV RNA levels in culture supernatants did not increase, even up to 16 days post-inoculation. Notably, the absence of ZO-1 did not affect the adsorption efficiency of eHEV or neHEV, nor did it influence HEV RNA replication. In cell-to-cell spread assays, ZO-1 KO cells inoculated with eHEV showed a lack of expression of HEV ORF2 and ORF3 proteins. In contrast, neHEV-infected ZO-1 KO cells showed markedly reduced ORF2 and ORF3 protein expression within virus-infected foci, compared to non-targeting knockout (NC KO) cells. These findings underscore the crucial role of ZO-1 in facilitating eHEV entry and mediating the cell-to-cell spread of neHEV in infected cells.

Hepatitis E virus (HEV) infection is a major cause of acute viral hepatitis worldwide. The efficacy and safety of the HEV239 vaccine have been validated, with protection lasting at least 10 years. This study extended the phase 3 trial of HEV239 (NCT01014845), presenting data on the durability of the anti-HEV IgG response elicited by one or two doses in the participants with different baseline serostatus. Over half of baseline seronegative individuals retained detectable antibodies at month 91 after two doses, with geometric mean concentration levels above the detection limit at month 67 (no available data for month 91). Seropositive individuals exhibited more prolonged and higher anti-HEV IgG response. After a single dose, individuals with pre-existing immunity achieved high and sustained antibody levels for over 103 months, comparable to the two-dose regimen. Both single-dose and two-dose HEV239 regimens demonstrated notable immunogenicity and persistence, potentially offering substantial protective benefits.

The 2nd International Hepatitis E Virus Symposium was held on April 28 and 29, 2023, in London, UK. The conference was hosted by the International Vaccine Institute and brought together key clinicians, researchers, and private and public stakeholders for a dedicated forum on hepatitis E virus (HEV). The scientific program spanned multiple facets of HEV, from updates on clinical research and diagnostic advances to vaccine development. The conference highlighted presentations on several critical HEV vaccine studies that will greatly impact the field, including the largest effectiveness study of Hecolin vaccine outside of China and the first reactive mass-vaccination campaign in South Sudan. This report summarizes information shared at the convening and offers perspectives on the steps forward for hepatitis E.

Hepatitis E virus (HEV) variants infecting humans belong to two species: Paslahepevirus balayani (bHEV) and Rocahepevirus ratti (rat hepatitis E virus; rHEV). R. ratti is a ubiquitous rodent pathogen that has recently been recognized to cause hepatitis in humans. Transmission routes of rHEV from rats to humans are currently unknown. In this study, we examined rHEV exposure in cats and dogs to determine if they are potential reservoirs of this emerging human pathogen. Virus-like particle-based IgG enzymatic immunoassays (EIAs) capable of differentiating rHEV & bHEV antibody profiles and rHEV-specific real-time RT-PCR assays were used for this purpose. The EIAs could detect bHEV and rHEV patient-derived IgG spiked in dog and cat sera. Sera from 751 companion dogs and 130 companion cats in Hong Kong were tested with these IgG enzymatic immunoassays (EIAs). Overall, 13/751 (1.7%) dogs and 5/130 (3.8%) cats were sero-reactive to HEV. 9/751 (1.2%) dogs and 2/130 (1.5%) cats tested positive for rHEV IgG, which was further confirmed by rHEV immunoblots. Most rHEV-seropositive animals were from areas in or adjacent to districts reporting human rHEV infection. Neither 881 companion animals nor 652 stray animals carried rHEV RNA in serum or rectal swabs. Therefore, we could not confirm a role for cats and dogs in transmitting rHEV to humans. Further work is required to understand the reasons for low-level seropositivity in these animals.

Patients undergoing solid-organ transplantation (SOT) face a tumultuous journey. Prior to transplant, their medical course is characterized by organ dysfunction, diminished quality of life, and reliance on organ support, all of which are endured in hopes of reaching the haven of organ transplantation. Peritransplant altered mental status may indicate neurologic insults acquired during transplant and may have long-lasting consequences. Even years after transplant, these patients are at heightened risk for neurologic dysfunction from a myriad of metabolic, toxic, and infectious causes. This review provides a comprehensive examination of causes, diagnostic approaches, neuroimaging findings, and management strategies for altered mental status in SOT recipients. Given their complexity and the numerous etiologies for neurologic dysfunction, liver transplant patients are a chief focus in this review; however, we also review lesser-known contributors to neurological injury across various transplant types. From hepatic encephalopathy to cerebral edema, seizures, and infections, this review highlights the importance of recognizing and managing pre- and posttransplant neurological complications to optimize patient outcomes.

Establishing the safety and immunogenicity of a hepatitis E virus vaccine in multiple populations could facilitate broader access and prevent maternal and infant mortality.

We conducted a phase 1, randomized, double-blinded, placebo-controlled (4:1 vaccine to placebo) trial of 30 µg HEV-239 (Hecolin, Xiamen Innovax Biotech Company Limited, China) administered intramuscularly in healthy US adults aged 18-45 years. Participants were vaccinated on days 1, 29, and 180. Participants reported solicited local and systemic reactions for 7 days following vaccination and were followed through 12 months after enrollment for safety and immunogenicity (IgG, IgM).

Solicited local and systemic reactions between treatment and placebo group were similar and overall mild. No participants experienced serious adverse events related to HEV-239. All participants receiving HEV-239 seroconverted at 1 month following the first dose and remained seropositive throughout the study. HEV-239 elicited a robust hepatitis E IgG response that peaked 1 month following the second dose (geometric mean concentration [GMC], 6.16; 95% confidence interval [CI], 4.40-8.63), was boosted with the third dose (GMC, 11.50; 95% CI, 7.90-16.75) and persisted through 6 months.

HEV-239 is safe and elicits a durable immune response through at least 6 months after the third dose in healthy US adults.

NCT03827395.

Hepatitis E virus (HEV) is distinct from other hepatotropic viruses because it is zoonotic. HEV-1 and HEV-2 exclusively infect humans, whereas HEV-3 and HEV-4 are zoonotic. However, the viral and/or host factors responsible for cross-species HEV transmission remain elusive. The hypervariable region (HVR) in HEV is extremely heterogenetic and is implicated in HEV adaptation. Here, we investigated the potential role of Serine phosphorylation in the HVR in HEV replication. We first analyzed HVR sequences across different HEV genotypes and identified a unique region at the N-terminus of the HVR, which is variable in the human-exclusive HEV genotypes but relatively conserved in zoonotic HEV genotypes. Using predictive tools, we identified four potential phosphorylation sites that are highly conserved in zoonotic HEV-3 and HEV-4 genomes but absent in human-exclusive HEV-1 strains. To explore the functional significance of these putative phosphorylation sites, we introduced mutations into the HEV-3 infectious clone and indicator replicon, replacing each Serine residue individually with alanine or aspartic acid, and assessed the impact of these substitutions on HEV-3 replication. We found that the phospho-blatant S711A mutant significantly reduced virus replication, whereas the phospho-mimetic S711D mutant modestly reduced virus replication. Conversely, mutations in the other three Serine residues did not significantly affect HEV-3 replication. Furthermore, we demonstrated that Ser711 phosphorylation did not alter host cell tropism of zoonotic HEV-3. In conclusion, our results showed that potential phosphorylation of the Ser711 residue significantly affects HEV-3 replication in vitro, providing new insights into the potential mechanisms of zoonotic HEV transmission.IMPORTANCEHEV is an important zoonotic pathogen, causing both acute and chronic hepatitis E and extrahepatic manifestation of diseases, such as neurological sequelae. The zoonotic HEV-3 is linked to chronic infection and neurological diseases. The specific viral and/or host factors facilitating cross-species HEV infection are unknown. The intrinsically disordered HVR in ORF1 is crucial for viral fitness and adaptation, both in vitro and in vivo. We hypothesized that phosphorylation of Serine residues in the HVR of zoonotic HEV by unknown host cellular kinases is associated with cross-species HEV transmission. In this study, we identified a conserved region within the HVR of zoonotic HEV strains but absent in the human-exclusive HEV-1 and HEV-2. We elucidated the important role of phosphorylation at the Ser711 residue in zoonotic HEV-3 replication, without altering the host cell tropism. These findings contribute to our understanding the mechanisms of cross-species HEV transmission.

Often, organ transplantation is the only option to improve the life expectancy and quality of life of patients with terminal organ failure. Despite improved donor and organ assessment, a residual risk remains for transmitting infection, tumor, or other disease from the donor to recipients. Analysis, reporting, and managing of donor-derived diseases through a vigilance and surveillance system (V&S) is mandatory in many countries. We report on suspected and proven/probable donor-derived infections (DDI) in Germany over a period of 8 years (2016-2023).

All incoming serious-adverse-event and serious-adverse-reaction (SAE/SAR) reports from 01.01.2016 to 31.12.2023 were evaluated for suspected DDI. Analysis of imputability followed the definition of the US Disease Transmission Advisory Committee (DTAC). Only probable and proven cases according to DTAC classification were defined as DDI.

During the study period, 9771 donors in Germany donated post-mortem organs to 27 919 recipients. In that period 612 SAE/SAR cases were reported, 377 (62%) involved infections. 41 cases were proven/probable DDI affecting 58 recipients (seven recipients died, 12%). Suspected infections were bacterial (182/377, 48%), fungal (135/377, 36%), viral (55/377, 15%), and parasitic (5/377, 1%). In case of bacterial DDI, no recipient died, but organ loss occurred in six recipients. In case of fungal or viral DDI, 19% (3/16) and 21% (3/14) of the recipients died, respectively.

DDI are rare in solid organ transplantation (58/27 919, 0.21%), but when they occur, they are associated with high morbidity and mortality in affected recipients. Careful and detailed donor evaluation and a reliable V&S help improve recipient safety.

HEV infection has become a global health concern. The study of HEV pathogenicity has been hindered by the lack of a suitable in vitro culture system. In the present research, we systematic demonstration of efficient replication of swine GT4 HEV in A549 cells, Huh-7 cells, and HepG2/C3A cell lines. The results of the immunofluorescence assay and immunofluorescence confocal assay showed that swine GT4 HEV is efficiently replicated in three cell lines at 72 h postinoculation. Meanwhile, we also detected the virus titer quantified were increased at 2-, 6,- and 11-days postinoculation. Moreover, we successfully observed HEV virus particles in the cell suspension at 6 days postinoculation. This finding holds significance for advancing in vitro HEV studies.

The hepatitis E virus (HEV) is an emerging infectious disease with zoonotic potential, causing acute hepatitis in humans. Infections in healthy individuals are often acute, self-limiting and asymptomatic, thus leading to the underdiagnosis of HEV infections. Asymptomatic HEV infections pose a problem for blood transfusion safety by increasing the risk for transfusion-transmitted HEV infections. Here, we describe the journey from determining the HEV seroprevalence among blood donors to the implementation of routine HEV RNA testing of all blood products in Switzerland in 2018 and summarise the HEV cases detected since. In total, 290 HEV-positive blood donations were detected by mini-pool nucleic acid testing (NAT) in Switzerland in the period of October 2018-December 2023, equal to an incidence of 20.7 per 100,000 donations. Thanks to the implemented scheme, no transfusion-transmitted infections occurred in this period. Furthermore, blood donation monitoring has proven to be an effective means of detecting HEV outbreaks in the general population. HEV cases in Swiss blood donors are caused by two major genotypes, the Swiss-endemic subtypes 3h3 and 3c. Interestingly, 11 HEV cases (5%) were of genotype 3ra, a variant found in wild and farmed rabbits. Our results indicate that mini-pool NAT is an efficient method to reduce the risk of transfusion-transmitted HEV infections.

Hepatitis E virus (HEV) infection, one of the most common forms of hepatitis worldwide, is often associated with extrahepatic, particularly renal, manifestations. However, the underlying mechanisms are incompletely understood. Here, we report the development of a de novo immune complex-mediated glomerulonephritis (GN) in a kidney transplant recipient with chronic hepatitis E. Applying immunostaining, electron microscopy, and mass spectrometry after laser-capture microdissection, we show that GN develops in parallel with increasing glomerular deposition of a non-infectious, genome-free and non-glycosylated HEV open reading frame 2 (ORF2) capsid protein. No productive HEV infection of kidney cells is detected. Patients with acute hepatitis E display similar but less pronounced deposits. Our results establish a link between the production of HEV ORF2 protein and the development of hepatitis E-associated GN in the immunocompromised state. The formation of glomerular IgG-HEV ORF2 immune complexes discovered here provides a potential mechanistic explanation of how the hepatotropic HEV can cause variable renal manifestations. These findings directly provide a tool for etiology-based diagnosis of hepatitis E-associated GN as a distinct entity and suggest therapeutic implications.

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis. Since the coronavirus disease 2019 (COVID-19) pandemic, immunocompromised individuals face an increased risk of HEV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) co-infection, posing a threat of liver failure and prolonged illness. A 69-year-old male, with a history of chronic lymphocytic leukemia, was co-infected with HEV and SARS-CoV-2. Given the progressive decline in liver function post-admission, steroid therapy was initiated, which led to treatment-related complications. Additionally, the patient experienced an aggravation of COVID-19 symptoms due to persistent SARS-CoV-2 infection, effectively managed through a combination of antiviral medications and corticosteroids. This case describes the intricate clinical trajectory and therapeutic approach for managing HEV and SARS-CoV-2 co-infection, underscoring the potential efficacy of short-term corticosteroid intervention alongside comprehensive antiviral treatment.

Hepatitis E virus (HEV) infections are a major cause of acute viral hepatitis in humans worldwide. In immunocompetent individuals, the majority of HEV infections remain asymptomatic and lead to spontaneous clearance of the virus, and only a minority of individuals with infection (5-16%) experience symptoms of acute viral hepatitis. However, HEV infections can cause up to 30% mortality in pregnant women, become chronic in immunocompromised patients and cause extrahepatic manifestations. A growing body of evidence suggests that the host immune response to infection with different HEV genotypes is a critical determinant of distinct HEV infection outcomes. In this Review, we summarize key components of the innate and adaptive immune responses to HEV, including the underlying immunological mechanisms of HEV associated with acute and chronic liver failure and interactions between T cell and B cell responses. In addition, we discuss the current status of vaccines against HEV and raise outstanding questions regarding the immune responses induced by HEV and treatment of the disease, highlighting areas for future investigation.

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.

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.

HEV antibody detection constitutes the main screening test for HEV infection. The aim of this study is to compare the sensitivity and specificity of four techniques: LIAISON® MUREX DiaSorin anti-HEV IgG and anti-HEV IgM assays, Hepatitis E VIRCLIA® IgM and IgG monotests, WANTAI HEV-IgM and IgG ELISA and VIDAS® anti-HEV IgM and IgG tests in five panels of samples configurated according to the immunoblot (RecomLine, Mikrogen, Neuss, Germany). Anti-HEV IgM sensitivity in the acute phase was 100% in all techniques, while sensitivity, including the immediate convalescence phase, was 96.74% for LIAISON®, 83.14% for VIRCLIA®, 84.78% for WANTAI and 88.04% for VIDAS®. Anti-HEV IgM specificity was 100% for both LIAISON® and VIRCLIA®. Anti-HEV IgM WANTAI agreed with VIRCLIA® with a good Kappa coefficient (κ = 0.71). Anti-HEV IgG post-infection sensitivity was 100% for LIAISON®, VIDAS® and VIRCLIA® and 99% for WANTAI. Anti-HEV IgG specificity reached 97.17% for LIAISON and 88.68% for VIRCLIA®. Our results demonstrated a better capacity of LIAISON® MUREX anti-HEV IgM than that of competitors for detecting acute infections as well as accurate anti-HEV IgG results and in how to resolve them.

In high-income countries hepatitis E virus (HEV) is an uncommonly diagnosed porcine-derived zoonoses. After identifying disproportionate chronic HEV infections in persons with cystic fibrosis (pwCF) postlung transplant, we sought to understand its epidemiology and potential drivers.

All pwCF post-transplant attending our regional CF centre were screened for HEV. HEV prevalence was compared against non-transplanted pwCF and with all persons screened for suspected HEV infection from 2016 to 2022 in Alberta, Canada. Those with chronic HEV infection underwent genomic sequencing and phylogenetic analysis. Owing to their swine derivation, independently sourced pancreatic enzyme replacement therapy (PERT) capsules were screened for HEV.

HEV seropositivity was similar between transplanted and non-transplanted pwCF (6/29 (21%) vs 16/83 (19%); p=0.89). Relative to all other Albertans investigated for HEV as a cause of hepatitis (n=115/1079, 10.7%), pwCF had a twofold higher seropositivity relative risk and this was four times higher than the Canadian average. Only three chronic HEV infection cases were identified in all of Alberta, all in CF lung transplant recipients (n=3/29, 10.3%). Phylogenetics confirmed cases were unrelated porcine-derived HEV genotype 3a. Ninety-one per cent of pwCF were taking PERT (median 8760 capsules/person/year). HEV RNA was detected by RT-qPCR in 44% (47/107) of PERT capsules, and sequences clustered with chronic HEV cases.

PwCF had disproportionate rates of HEV seropositivity, regardless of transplant status. Chronic HEV infection was evident only in CF transplant recipients. HEV may represent a significant risk for pwCF, particularly post-transplant. Studies to assess HEV incidence and prevalence in pwCF, and potential role of PERT are required.

Viral hepatitis is a major cause of liver illness worldwide. Despite advances in the understanding of these infections, the pathogenesis of hepatitis remains a complex process driven by intricate interactions between hepatitis viruses and host cells at the molecular level. This paper will examine in detail the dynamics of these host-pathogen interactions, highlighting the key mechanisms that regulate virus entry into the hepatocyte, their replication, evasion of immune responses, and induction of hepatocellular damage. The unique strategies employed by different hepatitis viruses, such as hepatitis B, C, D, and E viruses, to exploit metabolic and cell signaling pathways to their advantage will be discussed. At the same time, the innate and adaptive immune responses put in place by the host to counter viral infection will be analyzed. Special attention will be paid to genetic, epigenetic, and environmental factors that modulate individual susceptibility to different forms of viral hepatitis. In addition, this work will highlight the latest findings on the mechanisms of viral persistence leading to the chronic hepatitis state and the potential implications for the development of new therapeutic strategies. Fully understanding the complex host-pathogen interactions in viral hepatitis is crucial to identifying new therapeutic targets, developing more effective approaches for treatment, and shedding light on the mechanisms underlying progression to more advanced stages of liver damage.