Acute Hepatitis E Virus Infection Research Articles

The prevalence of HEV among non-A-C hepatitis in Qatar and efficiency of serological markers for the diagnosis of hepatitis E

BackgroundThe rapid growth of Qatar in the last two decades has attracted a large influx of immigrant workers who mostly come from HEV-hyperendemic countries. Thus, we aim to investigate the prevalence of HEV among acute non-A-C hepatitis patients in Qatar; and to evaluate the performance of four dominant commercial serological assays for HEV diagnosis.Methods259 patients with non-A-C hepatitis were tested using the Wantai HEV-IgM, HEV-IgG, HEV-Ag ELISA kits, and the MP Biomedical HEV-Total Ab ELISA kit. ALT levels were tested and HEV RNA (viral loads) was performed using Taqman AmpliCube HEV RT-PCR kit (Mikrogen, Neuried, Germany). The performance of each kit was assessed according to the RT-PCR results.ResultsHEV-RNA was detected in 23.1% of the samples. Most of these HEV-RNA-positive cases belonged to non-Qatari residents from the Indian subcontinent; India, Pakistan, etc. HEV-Ag, HEV-IgM, HEV-IgG, HEV-Total Ab were detected in 5.56%, 8.65%, 32.1%, and 34.2% of all tested samples, respectively. Elevated ALT levels were highly correlated with the HEV-Ag, HEV-IgM, HEV-RNA but not with the HEV-IgG and HEV-Total Ab. Although HEV-Ag was very specific (100%), yet its sensitivity was poor (36.7%). HEV-IgM demonstrated the best second marker for diagnosis of acute HEV after RT-PCR as jugged by the overall performance parameters: specificity (96.2%), sensitivity (71.4%), PPV (83.3%), NPP (92.7%), agreement with RT-PCR (91.0%), and Kappa-value (0.71).ConclusionOur study demonstrated a high prevalence of HEV virus in Qatar, mostly among immigrants from the Indian subcontinent. The HEV-IgM represents the best marker for detecting the acute HEV infection, where RT-PCR cannot be performed.

Evaluation of hepatitis E antigen kinetics and its diagnostic utility for prediction of the outcomes of hepatitis E virus genotype 1 infection

ABSTRACT HEV-Ag ELISA assay is a reliable diagnostic test in resource-limited areas. HEV genotype 1 (HEV-1) infections are either self-limited or progress to fulminant hepatic failure (FHF) and death if anti-HEV therapy is delayed. Limited data is available about the diagnostic utility of HEV Ag on HEV-1 infections. Herein we aimed to study the kinetics of HEV Ag during HEV-1 infections at different stages, i.e., acute HEV infection, recovery, and progression to FHF. Also, we evaluated the diagnostic utility of this marker to predict the outcomes of HEV-1 infections. Plasma of acute hepatitis E (AHE) patients were assessed for HEV RNA by RT-qPCR, HEV Ag, and anti-HEV IgM by ELISA. The kinetics of HEV Ag was monitored at different time points; acute phase of infection, recovery, FHF stage, and post-recovery. Our results showed that the level of HEV Ag was elevated in AHE patients with a significantly higher level in FHF patients than recovered patients. We identified a plasma HEV Ag threshold that can differentiate between self-limiting infection and FHF progression with 100% sensitivity and 88.89% specificity. HEV Ag and HEV RNA have similar kinetics during the acute phase and self-limiting infection. In the FHF stage, HEV Ag and anti-HEV IgM have similar patterns of kinetics which could be the cause of liver damage. In conclusion, the HEV Ag assay can be used as a biomarker for predicting the consequences of HEV-1 infections which could be diagnostically useful for taking the appropriate measures to reduce the complications, especially for high-risk groups.

Resolution of hepatitis E virus infection in CD8+ T cell-depleted rhesus macaques

HEV is a significant cause of acute hepatitis globally. Some genotypes establish persistent infection when immunity is impaired. Adaptive immune mechanisms that mediate resolution of infection have not been identified. Herein, the requirement for CD8+ T cells to control HEV infection was assessed in rhesus macaques, a model of acute and persistent HEV infection in humans. Rhesus macaques were untreated or treated with depleting anti-CD8α monoclonal antibodies before challenge with an HEV genotype (gt)3 isolate derived from a chronically infected human patient. HEV replication, alanine aminotransferase, anti-capsid antibody and HEV-specific CD4+ and CD8+ T cell responses were assessed after infection. HEV control in untreated macaques coincided with the onset of a neutralizing IgG response against the ORF2 capsid and liver infiltration of functional HEV-specific CD4+ and CD8+ T cells. Virus control was delayed by 1 week in CD8+ T cell-depleted macaques. Infection resolved with onset of a neutralizing IgG antibody response and a much more robust expansion of CD4+ T cells with antiviral effector function. Liver infiltration of functional CD8+ T cells coincident with HEV clearance in untreated rhesus macaques, and a 1-week delay in HEV clearance in CD8+ T cell-depleted rhesus macaques, support a role for this subset in timely control of virus replication. Resolution of infection in the absence of CD8+ T cells nonetheless indicates that neutralizing antibodies and/or CD4+ T cells may act autonomously to inhibit HEV replication. HEV susceptibility to multiple adaptive effector mechanisms may explain why persistence occurs only with generalized immune suppression. The findings also suggest that neutralizing antibodies and/or CD4+ T cells should be considered as a component of immunotherapy for chronic infection. The hepatitis E virus (HEV) is a major cause of liver disease globally. Some genetic types (genotypes) of HEV persist in the body if immunity is impaired. Our objective was to identify immune responses that promote clearance of HEV. Findings indicate that HEV may be susceptible to multiple arms of the immune response that can act independently to terminate infection. They also provide a pathway to assess immune therapies for chronic HEV infection.

Contribution of soluble ORF2 viral protein to viral replication and host immune response during acute Hepatitis E virus infection

Abstract The hepatitis E virus (HEV) is a small, positive-stranded RNA virus that is a major cause of acute viral hepatitis globally. Acute HEV infection is typically asymptomatic and resolves within 8–10 weeks. HEV encodes 2 forms of capsid protein. A cytoplasmic form (ORF2c) is essential for virion structure. A secreted glycosylated form (ORF2s) accumulates at high titer in serum and can mask anti-ORF2 neutralizing antibodies. Here, we explored the contribution of ORF2s to HEV replicative fitness in vivo, and its role in generating anti-ORF2 antibodies (Abs). Rhesus Macaques (RM) were challenged by direct hepatic injection of infectious ORF2s+ and ORF2s− RNA. The replication of an HEV mutant lacking ORF2s expression was delayed by ~2 weeks when compared with wildtype virus and peak titers were nearly 10-fold lower for ORF2s−. No reversion of the 3 ORF2s silencing mutations was detected in the ORF2s− genomes, indicating genetic stability. The delay in replication and lower peak titer was unexpected as the viruses replicate similarly in cell culture. In addition, our data demonstrated that ORF2s has a significant and unexpected impact on generation of antibodies. Specifically, serum anti-ORF2 antibodies were only transiently detected in ORF2s− infected RM. As expected, anti-ORF2 titers were high and sustained in ORF2s+ infected RM. Furthermore, anti-ORF2 Ab response primed by ORF2s− infection differed in protection against reinfection when compared to ORF2s+. The ORF2s− challenged animals were re-infected upon second exposure to HEV infection. These findings indicate ORF2s may be dispensable for viral replication in vivo but is required for long-lived antibody response to mediate protection against re-exposure.

Hepatitis E virus infection in high-risk populations in Osun State, Nigeria

Hepatitis E virus (HEV) infection is an emerging infection that is of major public health concern, especially in some vulnerable groups like immunosuppressed individuals, pregnant women and HBV-coinfected individuals. HEV is transmitted faecal/oral or zoonotically depending on the HEV-genotype. This study aimed at investigating HEV infections among different at-risk populations in Osun State, Southwestern Nigeria. A total of 720 serum samples were collected from animal handlers, pregnant women, people living with HIV/AIDS, and Hepatitis B virus (HBV) infected individuals. Commercially available Enzyme-Linked Immunosorbent Assays (ELISA) were used for the detection of anti-HEV total and IgM antibodies. Polymerase chain reaction (PCR) was carried out in the HEV seropositive samples and all the samples from individuals infected with HBV. Descriptive analysis and chi-square test of association were performed.The anti-HEV total antibody seroprevalence in HIV-positive individuals, animal handlers and pregnant women was 11.4% (n = 47/411), 7.9% (n = 7/89), and 6.3% (n = 10/160), respectively. Markers of acute HEV infection (anti-HEV IgM) were detected in 2.2% of HIV-positive individuals (n = 9/411) and 1.8% of animal handlers (n = 2/89), respectively, and in 0.6% of pregnant women (n = 1/160). However, all samples were HEV RNA negative.This study analysed the presence of markers of HEV infection among different at-risk populations without clinical symptoms of HEV infection. Our results showed that HEV is an underestimated threat to public health in Nigeria and underlines the need of an HEV surveillance system to understand the distribution and transmission of HEV infection in animals and/to humans.

Hepatitis E in solid organ transplant recipients: A systematic review and meta-analysis.

BACKGROUNDHepatitis E virus (HEV) infection is underdiagnosed due to the use of serological assays with low sensitivity. Although most patients with HEV recover completely, HEV infection among patients with pre-existing chronic liver disease and organ-transplant recipients on immunosuppressive therapy can result in decompensated liver disease and death.AIMTo demonstrate the prevalence of HEV infection in solid organ transplant (SOT) recipients. METHODSWe searched Ovid MEDLINE, EMBASE, and the Cochrane Library for eligible articles through October 2020. The inclusion criteria consisted of adult patients with history of SOT. HEV infection is confirmed by either HEV-immunoglobulin G, HEV-immunoglobulin M, or HEV RNA assay.RESULTSOf 563 citations, a total of 22 studies (n = 4557) were included in this meta-analysis. The pooled estimated prevalence of HEV infection in SOT patients was 20.2% [95% confidence interval (CI): 14.9-26.8]. The pooled estimated prevalence of HEV infection for each organ transplant was as follows: liver (27.2%; 95%CI: 20.0-35.8), kidney (12.8%; 95%CI: 9.3-17.3), heart (12.8%; 95%CI: 9.3-17.3), and lung (5.6%; 95%CI: 1.6-17.9). Comparison across organ transplants demonstrated statistical significance (Q = 16.721, P = 0.002). The subgroup analyses showed that the prevalence of HEV infection among SOT recipients was significantly higher in middle-income countries compared to high-income countries. The pooled estimated prevalence of de novo HEV infection was 5.1% (95%CI: 2.6-9.6) and the pooled estimated prevalence of acute HEV infection was 4.3% (95%CI: 1.9-9.4).CONCLUSIONHEV infection is common in SOT recipients, particularly in middle-income countries. The prevalence of HEV infection in lung transplant recipients is considerably less common than other organ transplants. More studies examining the clinical impacts of HEV infection in SOT recipients, such as graft failure, rejection, and mortality are warranted.

Acute CNS infections – Expanding the spectrum of neurological manifestations of hepatitis E virus?

BackgroundCentral nervous system (CNS) infections can be caused by a variety of viruses, but in a significant number of patients no viral or other pathogen can be identified using routine diagnostic work-up. Interestingly, several case reports and series described Hepatitis E virus (HEV) as a potential pathogen. However, systematic studies have not been conducted so far. MethodsWe identified 243 patients from Southwestern Germany with acute CNS infections of unknown cause treated in our clinic between 2008 and 2018, of which serum and/or cerebrospinal fluid (CSF) samples were available. These patients were retrospectively tested for anti-HEV IgM and IgG antibodies. In addition, HEV PCR was performed in the majority of cases including IgM-negative patients with symptom onset <8 days. 263 healthy individuals served as controls. ResultsEvidence of an acute HEV infection was found in four patients (1.7%). Three had recent HEV infection defined as positive anti-HEV IgM and IgG antibodies, one had current HEV infection defined as (additional) detection of HEV RNA in serum. However, anti-HEV IgM and IgG seroprevalence did not differ significantly from controls, though these had considerably lower IgM levels. Interestingly, anti-HEV IgG seroprevalence was unexpectedly high (30.7%) and revealed an age-dependent increase to more than 50% in patients older than 60 years. ConclusionThis study supports previous findings that HEV could play a role in acute CNS infections. Therefore, we encourage testing for acute HEV infection if no other pathogen can be identified. However, further studies are necessary to prove a causal role.

Anti-HEV IgG Avidity Testing: Utility for Diagnosing Acute and Resolved Genotype 3 Infections.

European Association of the Study of the Liver (EASL) guidelines specify HEV RNA, as well as anti-HEV IgG and IgM as positive markers for acute HEV infection. HEV RNA assay sensitivity limitations may lead to false negative test results in patients with low levels of viremia. Moreover, anti-HEV IgM positivity is not a reliable indicator for distinguishing between acute and resolved infections given the ability of this antibody to persist several months after a resolved infection. Our study aims were to assess HEV IgG avidity for diagnosing acute and resolved infections, regardless of the anti-HEV IgM serostatus, and examine assay reliability when evaluating different genotype 3 (GT3) HEV subtypes. Patient serum samples (n = 104) were tested for HEV IgG avidity by utilizing the DIA.PRO kit on a DSX automated instrument. Among patients identified with acute HEV infections, 32 were infected with GT3: GT3c (n = 5), GT3e (n = 8), 3f (n = 17) and GT3-unsubtyped (n = 2). Avidity sensitivity was 91.2% and specificity was 100%. For patients with long-lasting anti-HEV IgM persistence, an Avidity Index >70% was observed. Thus, the DIA.PRO avidity assay may be utilized to distinguish between recently acquired and resolved HEV GT3 infections. However, for equivocal results (Avidity Index > 40–70%), HEV RNA molecular testing will be required to confirm a recent infection.

Autoimmune liver disease-associated serologic profiling in Chinese patients with acute hepatitis E virus infection

The association between hepatitis E virus (HEV) and autoimmune liver diseases has been well-researched; however, the focus has been on autoimmune hepatitis (AIH) and not primary biliary cholangitis (PBC). Therefore, we aimed to investigate the prevalence and evolution of AIH- and PBC-related autoantibodies in Chinese patients with HEV infection. In this retrospective study, 164 patients with acute HEV were included, specifically those whose liver autoantibody results were available and who had no pre-existing liver disease at the time of HEV diagnosis. Positive liver autoimmune serology was present in 69 (42.1%) patients and 21 (12.8%) had at least two autoantibodies at diagnosis. Greater age and alkaline phosphatase levels were independent risk factors for autoantibody positivity. Follow-up serologic tests, which were available for 27 of the 69 autoantibody-positive patients, showed that although antinuclear antibodies disappeared in 11/20 (55.0%) and antimitochondrial antibodies disappeared in 4/5 (80%) patients, 16 still remained positive for autoantibodies and two of them even developed new PBC-related antibodies, as described below. One patient developed a rim-like ANA pattern, accompanied by an enhancement of anti-gp210 positivity; and the other was diagnosed as PBC, based on chronic elevation of cholestatic enzymes and presentation with de novo AMA-M2, 18 months after HEV clearance. In conclusion, AIH- and PBC-related autoantibodies are frequently present during acute HEV infection, indicating that HEV should be excluded before diagnosing AIH and/or PBC. Importantly, some cases maintained or developed autoantibodies after viral clearance, and one patient subsequently developed PBC, highlighting that these individuals warrant long-term follow-up.

Hepatitis E virus persists in the ejaculate of chronically infected men

Hepatitis E virus (HEV) infections are prevalent worldwide. Various viruses have been detected in the ejaculate and can outlast the duration of viremia, indicating replication beyond the blood-testis barrier. HEV replication in diverse organs, however, is still widely misunderstood. We aimed to determine the occurrence, features and morphology of HEV in the ejaculate. The presence of HEV in testis was assessed in 12 experimentally HEV-genotype 3-infected pigs. We further tested ejaculate, urine, stool and blood from 3 chronically HEV genotype 3-infected patients and 6 immunocompetent patients with acute HEV infection by HEV-PCR. Morphology and genomic characterization of HEV particles from various human compartments were determined by HEV-PCR, density gradient measurement, immune-electron microscopy and genomic sequencing. In 2 of the 3 chronically HEV-infected patients, we observed HEV-RNA (genotype 3c) in seminal plasma and semen with viral loads >2 logs higher than in the serum. Genomic sequencing showed significant differences between viral strains in the ejaculate compared to stool. Under ribavirin-treatment, HEV shedding in the ejaculate continued for >9 months following the end of viremia. Density gradient measurement and immune-electron microscopy characterized (enveloped) HEV particles in the ejaculate as intact. The male reproductive system was shown to be a niche of HEV persistence in chronic HEV infection. Surprisingly, sequence analysis revealed distinct genetic HEV variants in the stool and serum, originating from the liver, compared to variants in the ejaculate originating from the male reproductive system. Enveloped HEV particles in the ejaculate did not morphologically differ from serum-derived HEV particles. Enveloped hepatitis E virus particles could be identified by PCR and electron microscopy in the ejaculate of immunosuppressed chronically infected patients, but not in immunocompetent experimentally infected pigs or in patients with acute self-limiting hepatitis E.

Prognostic Significance of End-Stage Liver Diseases, Respiratory Tract Infection, and Chronic Kidney Diseases in Symptomatic Acute Hepatitis E.

Symptomatic hepatitis E virus (HEV) infection is sporadic, and usually occurs in a limited number of infected patients, which hinders the investigation of risk factors for clinical outcomes in patients with acute HEV infection. A retrospective cohort study enrolling 1913 patients with symptomatic acute hepatitis E in Beijing 302 Hospital from January 1, 2001 to December 31, 2018 was conducted. The baseline characteristics, clinical features and laboratory data of these HEV infection cases were analyzed. Albumin (ALB), platelet (PLT), alanine aminotransferase (ALT), total bilirubin (T-BiL), international normalized ratio (INR) and serum creatinine (SCR) levels, along with the model for end-stage liver disease (MELD) score, hospitalization days, co-morbidity number and mortality were taken as major parameters for comparing the clinical manifestations in our study. We found that not all pre-existing chronic liver diseases exacerbate clinical manifestations of acute hepatitis E. Alcoholic hepatitis, fatty liver hepatitis, hepatic cyst, drug-induced hepatitis and hepatocellular carcinoma were not significantly associated with mortality of HEV patients. Among all of the comorbidities, end-stage liver diseases (ESLDs, including ascites, cirrhosis, hepatic coma and hepatorenal syndrome), respiratory tract infection and chronic kidney diseases (CKDs, including renal insufficiency and renal failure) were found to remarkably increase the mortality of patients with symptomatic HEV infection. Furthermore, the severity evaluation indexes (SEI), such as MELD score, duration of hospital stay, and co-morbidity number in HEV patients with underlying comorbidities were much worse than that of their counterparts without relevant comorbidities.

Role of Hepatitis E Virus Infection in North American Patients With Severe Acute Liver Injury.

INTRODUCTION:The aim of this study was to determine the role of hepatitis E virus (HEV) infection in a large cohort of prospectively enrolled patients with severe acute liver injury (ALI).METHODS:Serum samples from 594 consecutive adults enrolled between 2008 and 2018 in the US Acute Liver Failure Study Group ALI registry were tested for anti-HEV IgM and anti-HEV IgG levels. Those with detectable anti-HEV IgM underwent further testing for HEV RNA using real-time polymerase chain reaction.RESULTS:The median age of patients was 38 years; 41% were men and 72% Caucasian. Etiologies of ALI included acetaminophen hepatotoxicity (50%), autoimmune hepatitis (8.9%), hepatitis B virus (8.9%), and idiosyncratic drug-induced liver injury (7.9%). Overall, 62 patients (10.4%) were negative for anti-HEV IgM but positive for IgG, whereas only 3 men (0.5%) were positive for both anti-HEV IgM and IgG. These 3 cases were initially diagnosed as having indeterminate, HEV, and hepatitis B virus-related ALI. One of these patients had detectable HEV RNA genotype 3, and another anti-HEV IgM+ patient had detectable HEV antigens by immunohistochemistry on liver biopsy. On multivariate modeling, older (odds ratio: 1.99) and non-Caucasian subjects (odds ratio: 2.92) were significantly more likely to have detectable anti-HEV IgG (P < 0.0001).DISCUSSION:Acute HEV infection is an infrequent cause of ALI in hospitalized North American adults. The anti-HEV IgG+ patients were significantly older and more likely to be non-Caucasian. These data are consistent with other population-based studies that indicate exposure to HEV in the general US population is declining over time and might reflect a cohort effect.

Disseminated inflammation of the central nervous system associated with acute hepatitis E: a case report

BackgroundHepatitis E infection affects over 20 million people worldwide. Reports of neurological manifestations are largely limited to the peripheral nervous system. We report a middle-aged genotype 3c male patient with acute hepatitis E virus (HEV) infection and severe neurological deficits with evidence of multiple disseminated inflammatory lesions of the central nervous system.Case presentationA 42-year-old male patient presented to our emergency department with musculoskeletal weakness, bladder and bowel retention, blurred vision and ascending hypoesthesia up to the level of T8. Serology showed elevated liver enzymes and positive IgM-titers of hepatitis E. Analysis of cerebrospinal fluid (CSF) showed mild pleocytosis and normal levels of glucose, lactate and protein. HEV-RNA-copies were detected in the CSF and stool. Within 3 days after admission the patient became paraplegic, had complete visual loss and absent pupillary reflexes. MRI showed inflammatory demyelination of the optic nerve sheaths, multiple subcortical brain regions and the spinal cord. Electrophysiology revealed axonal damage of the peroneal nerve on both sides with absent F-waves. Treatment was performed with methylprednisolone, two cycles of plasma exchange (PLEX), one cycle of intravenous immunoglobulins (IVIG) and ribavirin which was used off-label. Liver enzymes normalized after 1 week and serology was negative for HEV-RNA after 3 weeks. Follow-up MRI showed progressive demyelination and new leptomeningeal enhancement at the thoracic spine and cauda equina 4 weeks after admission. Four months later, after rehabilitation was completed, repeated MRI showed gliotic transformation of the spinal cord without signs of an active inflammation. Treatment with rituximab was initiated. The patient remained paraplegic and hypoesthesia had ascended up to T5. Nevertheless, he regained full vision.ConclusionsOur case indicates a possible association of acute HEV infection with widespread disseminated central nervous system inflammation. Up to now, no specific drugs have been approved for the treatment of acute HEV infection. We treated our patient off-label with ribavirin and escalated immunomodulatory therapy considering clinical progression and the possibility of an autoimmune response targeting nerve cell structures.While response to treatment was rather limited in our case, detection of HEV in patients with acute neurological deficits might help optimize individual treatment strategies.

An outbreak of hepatitis E in Yavatmal, India, 2019.

Hepatitis E, a public health concern in developing countries, frequently presents in epidemic, as well as in sporadic forms. This study investigated an outbreak of viral hepatitis at Yavatmal, Maharashtra, India in March 2019. Blood samples from 10 patients were received at Indian Council of Medical Research-National Institute of Virology, Pune to test for the presence of enterically transmitted hepatitis viruses. Subsequently, 49 suspected cases were screened for anti-hepatitis E virus (HEV)/hepatitis A virus (HAV) immunoglobulin M and immunoglobulin G (IgG) antibodies, alanine amino-transferase levels and HEV RNA. Water samples were screened for HEV and HAV RNA followed by phylogenetic analysis. Overall 32 of 49 (65.3%) suspected cases had recent acute HEV infection, while dual infection with HAV was noted in one case (2.04%). Forty-eight of 49 suspected cases were positive for anti-HAV IgG antibodies indicative of previously acquired immunity against HAV. Water samples had evidence of HEV contamination as detected by reverse transcription-polymerase chain reaction. Sequencing of HEV RNA from both patients (n = 2) and water samples (n = 5) indicated HEV genotype 1 to be the etiological agent of this outbreak. Serological and molecular evidence confirmed HEV as the etiology. Mixing of contaminated drain water with the domestic water supply may have triggered this outbreak. Subsequent changing of the defaulted water pipelines and its segregation from drain pipelines by the health authorities resulted in progressive decline of this outbreak. Despite the limitations, periodic surveillance of HEV exposure pattern and reporting of small outbreaks would supplement to the global disease burden data of hepatitis E.

S2664 Acute HEV Infection Causing Elevated Liver Enzymes in a Kidney Transplant Recipient

S2664 Acute HEV Infection Causing Elevated Liver Enzymes in a Kidney Transplant Recipient

Parsonage-Turner syndrome associated with hepatitis E infection in immunocompetent patients

Introduction The hepatitis E virus (HEV) is the leading cause of acute hepatitis around the world. In recent years, knowledge has increased concerning extrahepatic manifestations caused by HEV, including neurological manifestations such as Parsonage-Turner syndrome (PTS). PTS is characterized by severe shoulder or arm pain and patchy paresis with muscle weakness. The aim of the present study was to assess the association between HEV and PTS. Materials and Methods We reported two cases of PTS associated with HEV, which were diagnosed in a short period of time in the same village. PTS was diagnosed by physical examination and electrophysiological studies, and serology testing for IgM, low-avidity IgG, and RNA of HEV established the diagnosis of acute HEV infection. Results A 44-year-old man who presented cervicobrachial pain accompanied by paresthesia, dyspnea, and isolated derangement of liver enzymes and 57-year-old women with cervical pain radiated to upper limbs, paresthesia, and liver cytolysis, although, this patient was initially diagnosed as having drug-induced hepatitis. Finally, the diagnosis was Parsonage- Turner syndrome associated with hepatitis e virus. In both patients, symptoms were bilateral and they required hospital admission. Both consumed vegetables are grown in a local patch and the phylogenetic analysis showed genotype 3f. Then, we reviewed the literature on PTS and HEV and we found 62 previously described cases that were more likely to be men (86.20 %) with more frequent bilateral symptoms (85.71 %). Genotype 3 is the most commonly associated. Three of those cases were diagnosed in Spain. Conclusions According to our findings, HEV should be considered in patients with neuralgic amyotrophy, including those with the absence of liver cytolysis.

Significance of Anti-Nuclear Antibodies and Cryoglobulins in Patients with Acute and Chronic HEV Infection.

Background: Hepatitis E virus (HEV) has been associated with immunological phenomena. Their clinical significance, however, still needs to be clarified, that is, whether cryoglobulins or autoantibodies impact overt disease in HEV-infected individuals. To better understand, we analyzed these different immune phenomena in three cohorts, each representing different types of HEV infection. Methods: The cohorts included: (i) immunocompetent patients with acute hepatitis E, (ii) immunosuppressed patients with chronic hepatitis E, and (iii) individuals with asymptomatic HEV infection. Together, they consisted of 57 individuals and were studied retrospectively for the presence of anti-nuclear antibodies (ANAs), cryoglobulins, and serum total IgG. They were then compared with a control cohort of 17 untreated patients with chronic hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection. Results: Thirteen (23%) were immunocompetent patients with acute hepatitis E (median alanine aminotransferase (ALT) = 872 U/L), 15 (26%) were immunosuppressed patients with chronic hepatitis E (median ALT = 137 U/L), and 29 (51%) were blood donors with asymptomatic HEV infection (median ALT = 35 U/L). Overall, 24% tested positive for elevated ANA titers of >1:160, and 11% presented with a specific ANA pattern. ANA detection was not associated with the type of HEV infection, IgG levels, sex, or age. All individuals tested negative for anti-mitochondrial antibodies, anti-neutrophil cytoplasmic antibodies, liver-kidney microsomal antibodies, anti-myeloperoxidase-, and anti-proteinase-3 antibodies. Five patients (9%) tested positive for cryoglobulins. Notably, cryoglobulinemia was present in overt hepatitis E (Groups (i) and (ii); one acute and four chronic HEV infections), but was not present in any of the asymptomatic blood donors (p = 0.02). The frequency of cryoglobulins and elevated ANAs did not differ significantly between HEV and HBV/HCV patients. Conclusion: In line with findings on HBV and HCV infections, we frequently observed detection of ANAs (24%) and cryoglobulins (9%) in association with HEV infections. The presence of cryoglobulins was limited to patients with overt hepatitis E. We add to the findings on the immune phenomena of hepatitis E.

Seroprevalence of anti-hepatitis E antibodies and antigens among HIV-infected patients in Fars Province, southern Iran

ObjectiveHIV-infected patients have immunological and clinical features that might affect the pathogenesis, as well as the outcome of the HIV/HEV co-infection. The current study aimed to determine the seroprevalence of anti-HEV antibodies and HEV antigens among HIV-infected patients in Fars Province, Southwest Iran.MethodsBlood samples (5 mL) were collected from 251 HIV-confirmed patients. Respective data, including patients’ demographic information, were obtained for each patient. The presence of HEV antigens and anti-HEV antibodies (IgG) were assessed by commercial ELISA kits, based on the manufacturers’ instructions.ResultsOut of 251 cases, 158 (62.9%) were male and 91 (36.3%) were female. Patients’ age varied from 14 to 83 (mean: 40 ± 9.7) years. Out of 251 HIV positive cases, 26 (10.4%) were positive for anti-HEV IgG antibodies and 6 (2.4%) were positive for HEV-antigens. Also, 2 (0.8%) of the patients were positive for both anti-HEV IgG antibodies and antigens. Statistical analysis revealed no significant association between sex and seropositivity to either HEV antigen or antibodies. Moreover, no significant association was seen between age and seropositivity to HEV antigen or antibody (P = 0.622 and 0.945, respectively).ConclusionOur results showed a relatively low prevalence of HEV-antibodies in HIV-infected patients, indicating that HIV positive patients may not be at greater risk of HEV infection than the general population. Moreover, HEV-antigen was detected in a few cases of HIV-infected individuals which indicate an acute or chronic HEV infection in these patients.

HEV and HBV Dual Infection: A Review.

Hepatitis E virus (HEV) is a global health problem, affecting about 20 million people worldwide. There is significant overlap of hepatitis B virus (HBV) and HEV endemicity in many Asian countries where dual infections with HEV and HBV can occur. Though the clinical course of HEV is largely self-limited, HEV superinfection in patients with chronic hepatitis B (CHB) can result in acute exacerbation of underlying CHB. HEV superinfection in patients with CHB-related cirrhosis has been identified as a risk factor for decompensated cirrhosis and an independent predictor of mortality. Whereas acute HEV infection in pregnancy can cause fulminant liver failure, the few studies on pregnant patients with dual HBV and HEV infection have shown a subclinical course. Immunosuppression is a risk factor for the development of chronic HEV infection, which can be managed by decreasing the dose of immune-suppressants and administering ribavirin. Vaccination for HEV has been developed and is in use in China but its efficacy in patients with CHB has yet to be established in the USA. In this review, we appraise studies on dual infection with HEV and HBV, including the effect of HEV superinfection and coinfection in CHB, management strategies used and the role of active vaccination in the prevention of HEV.

BALB/c Mouse Is a Potential Animal Model System for Studying Acute and Chronic Genotype 4 Hepatitis E Virus Infection.

Hepatitis E virus (HEV) is the main pathogen of hepatitis worldwide. However, its infection biology and pathogenesis remain largely unknown. Suitable small-animal models are required to advance the study of HEV infection. Although an efficient model of genotype 1 (gt1) and gt3 HEV infection has been established in human liver chimeric mice, the infectivity of gt4 HEV infection in mice has not been comprehensively characterized. In this study, immunocompromised BALB/c nude, immunocompetent BALB/c, and C57BL/6 mice were inoculated with either gt3 or gt4 HEV (19 HEV strains, including human, swine, macaque-adapted, and cow HEV strains). Infectivity was identified by viral RNA and antigen detection, inflammation, and histopathological analysis. Then, HEV-infected BALB/c mice were treated with antiviral drugs. Acute HEV infection was established in BALB/c mice inoculated with eight gt4 HEV strains. However, gt3 HEV strains failed to achieve active HEV infection. HEV infection was established in BALB/c nude and regular mice inoculated with gt4 HEV but not in C57BL/6 mice. Gt4 HEV infection resulted in rapid viremia and high titers in feces, sera, and replication sites. HEV infection in mice showed no gender preference. Furthermore, chronic gt4 HEV infection was well imitated in BALB/c mice for 32 weeks and caused liver fibrosis.ConclusionBALB/c mice have a great potential for reproducing the process of gt4 HEV infection. The successful establishment of a gt4 HEV small-animal model provides an opportunity to further understand HEV infection biology and zoonotic transmission and develop anti-HEV vaccine.