Acute Hepatitis E Virus Infection Research Articles

Detection of hepatitis E virus RNA in saliva for diagnosis of acute infection.

Diagnosis of acute hepatitis E virus (HEV) infection is established by detection of anti-HEV IgM antibodies by ELISA or by amplification of serum viral RNA. Here, we evaluate the diagnostic value of testing HEV RNA in saliva to identify patients with acute HEV infection. Prospective proof-of-concept study including patients with acute hepatitis. Whole blood and neat saliva samples were obtained from all patients. Saliva samples were processed and analysed for HEV RNA by RT-PCR within 2hr after collection. A total of 34 patients with acute hepatitis and 12 healthy donors were included in the study. HEV RNA in serum was confirmed by RT-PCR in eight of these patients (23.5%; 95% CI: 12.2%-40.2%). HEV was isolated in the saliva of eight of 34 patients (23.5%; 95% CI: 12.2%-40.2%). All patients with HEV RNA amplified in saliva had detectable HEV RNA in serum. HEV was isolated neither in the saliva of any of the 26 patients without detectable HEV RNA in serum nor in healthy donors. Our study suggests that acute HEV infection could be diagnosed by assessing viral load in saliva.

Pathological Cerebrospinal Fluid Findings in Patients With Neuralgic Amyotrophy and Acute Hepatitis E Virus Infection.

There is growing evidence that hepatitis E virus (HEV) infection can present with extrahepatic manifestations including neurological disorders. Among these, neuralgic amyotrophy (NA) has been reported to occur in some industrialized countries. We investigated 35 patients with NA and a control group for markers of HEV infection. Acute HEV infection was found in NA patients only and was associated with an inflammatory response in the central nervous system. Shedding of HEV RNA into the cerebrospinal fluid and intrathecal production of anti-HEV immunoglobulin M occurred in 1 patient, suggesting that HEV is neurotropic.

Guillain-Barre syndrome caused by hepatitis E infection: case report and literature review

BackgroundHepatitis E infection is a global disorder that causes substantial morbidity. Numerous neurologic illnesses, including Guillain–Barre syndrome (GBS), have occurred in patients with hepatitis E virus (HEV) infection.Case presentationWe report a 58 year-old non-immunocompromised man who presented with progressive muscle weakness in all extremities during an episode of acute HEV infection, which was confirmed by measuring the anti-HEV IgM antibodies in the serum. Both cerebrospinal fluid examination and electrophysiological study were in agreement with the diagnosis of HEV-associated GBS. Following the treatment with intravenous immunoglobulin, the patient’s neurological condition improved rapidly.ConclusionsHEV infection should be strongly considered in patients with neurological symptoms, especially those with elevated levels of liver enzymes.

Hepatitis E Virus Infection in Acute Non-Traumatic Neuropathy: A Large Prospective Case-Control Study in China

Neurological manifestations are potently associated with hepatitis E virus (HEV) infection in Europe, mainly attributed to genotype (G) 3 HEV infection. We determined the frequency and causal relationship of HEV in patients with non-traumatic neurological disorders in China, where G4 HEV is prevalent. Consecutive patients diagnosed with neurological illnesses and individuals visiting the physical examination center in a hospital of eastern China were tested for HEV by serology and molecular method. 1117 patients and 1475 healthy controls were enrolled. Anti-HEV IgM antibodies were detectable in 6 (0.54%) of the patients and 10 (0.68%) of the healthy controls (P = 0.651). Serum HEV RNA was detected in all of the 16 individuals. The six patients with positive anti-HEV IgM included two viral encephalitis, two posterior circulation ischemia, one peripheral neuropathy and one Guillian-Barre syndrome. They had no symptoms of acute viral hepatitis except two patients of viral encephalitis had mildly transaminitis. Additional, 39.51% patients and 35.63% controls without acute HEV infection were anti-HEV IgG positive (P = 0.144). Anti-HEV IgG positivity was more frequent in male and elderly in both the patients and control groups, but unrelated to the incidence of any non-traumatic neurological illness, hospital stay or treatment outcome, except linking to better outcome of hemorrhagic stroke disease. These data demonstrate that HEV appears not to contribute to acute neurological disorders in China. Nevertheless, we cannot exclude a possible causative role, suggesting that testing for HEV in this population, especially in situations of unexplained deregulated liver function would be warranted. Funding Statement: This study was supported by National Natural Science Foundation of China (No. 31770186) (to Y. Wang) Declaration of Interests: The authors have declared that no competing interests exist. Ethics Approval Statement: The standard protocol, ethical approvals and registrations of this study were approved by an ethical standards committee of The First People's Hospital of Yancheng City and all patients gave informed consent that allowed future testing of archived bio-samples.

Detection of HEV-specific antibodies in four non-human primate species, including great apes, from different zoos in Germany.

The hepatitis E virus (HEV) has been described in humans and various animal species in different regions of the world. However, the knowledge on natural HEV infection in non-human primates and the corresponding risk of zoonotic transmission is scarce. To determine whether primates in captivity are affected by HEV infection, we investigated 259 individual sera of clinically healthy non-human primates of 14 species from nine German zoos. Using a commercial double-antigen-sandwich ELISA and a commercial IgG ELISA, 10 animals (3·9%) reacted positive in at least one assay. Three ape species and one Old World monkey species were among the seropositive animals: bonobo (Pan paniscus), gorilla (Gorilla gorilla gorilla), lar gibbon (Hylobates lar) and drill (Mandrillus leucophaeus). Testing for anti-HEV-IgM antibodies by commercial ELISA and for viral RNA by reverse-transcription real-time polymerase chain reaction resulted in negative results for all animals indicating the absence of acute HEV infections. In the past, no clinical signs of hepatitis were recorded for the seropositive animals. The results suggest that non-human primates in zoos can get naturally and subclinically infected with HEV or related hepeviruses. Future studies should evaluate potential sources and transmission routes of these infections and their impact on human health.

Acute-on-Chronic Liver Failure with Complicating Pancreatitis After Autochthonous Hepatitis E Infection

: Hepatitis E virus infection (HEV) is the most common cause of acute viral hepatitis in the world. Genotypes 1 and 2 are responsible for large outbreaks and sporadic cases in the developing countries, whereas genotypes 3 and 4 are zoonotic infections and cause sporadic autochthonous disease with usually mild course in the immunocompetent host without preexisting liver damage. Acute pancreatitis is acknowledged as an extrahepatic complication of acute viral hepatitis, most often related to acute hepatitis A to C. More than 50 cases of HEV-associated acute pancreatitis are reported from South Asia where HEV genotype 1 prevails. The current study reports the case of an 85-year-old male with autochthonous acute HEV infection, which progressed into acute-on-chronic liver failure (ACLF) and was complicated by severe acute pancreatitis. This case underlines autochthonous HEV infection as a cause of multiple organ failure in patients with pre-existing liver disease and suggests an association with acute pancreatitis. Clinicians should be aware of life-threatening complications of autochthonous HEV infection, especially in patients with cirrhosis.

Research advances in chronicity of hepatitis E virus infection

Hepatitis E virus (HEV) infection usually causes acute hepatitis and has a self-limiting progression. The patients often recover within 6 months with good prognosis. Recent studies have found that HEV infection may become chronic in special situations, which manifests as persistent liver function abnormalities for at least 6 months after acute HEV infection and the presence of viral nucleic acid in serum, feces, and/or liver tissue. Chronicity of HEV infection mainly occurs in immunocompromised patients, and it is rare but very dangerous in clinical practice. An understanding of the pathogenesis, clinical manifestations, treatment methods, and preventive measures of chronicity of HEV infection helps clinical physicians develop an effective management regimen and improve patient prognosis. This article introduces related issues, in order to raise the awareness of this disease among clinical physicians.

Is Acute Hepatitis E Virus (HEV) Infection a Steroid-Responsive Disease?

Introduction: While HEV infection often is self-limited, prolonged infection can put the patient at significant risk for liver injury, and treatment with Ribavirin can have mixed success. The following case represents an occasion in which lab result delay and clinical decision-making led to the improved outcome of a patient with acute HEV infection. Case Report: A 50 Year old South Asian female presented to her primary care physician (PCP) with complaints of diarrhea and fever after returning from a recent trip to Pakistan. This was treated by her PCP with Rifaximin, but the diarrhea continued. Lab results showed ALT and AST levels at 985 and 679, respectively. The patient was started on a course of ciprofloxacin and azithromycin, but her condition did not significantly improve. She was then referred to the hepatology clinic for workup. Labs were repeated, and tests for Hepatitis E and autoantibody titers were ordered. The patient followed up two days later and lab results showed elevated immunoglobulin G levels and a positive anti-Smith autoantibody titer (1:80). Autoimmune hepatitis was suspected and a liver biopsy was ordered. The liver biopsy results showed signs of nonspecific lobular inflammatory infiltration, and an order for Prednisone 60 mg by mouth once daily was added to the management plan while awaiting results of other serologies. The patient was then hospitalized for exacerbation of her condition and arthralgia in her extremities. However, she quickly responded to the course of steroids with marked improvement of her liver enzymes. Upon her next follow-up, steroids were being tapered, and the previously ordered pending lab results had come back positive for HEV IgG and IgM. HEV viral load was 145,000 IU/mL, and her ALT and AST had dropped to 164 and 25, respectively. She was started on Ribavirin 600mg daily as per HEV protocol. Within 2 weeks, viral HEV RNA was undetectable and her liver enzymes returned to within normal limits. Discussion: This patient had undiagnosed Hepatitis E, most likely contracted on a recent trip abroad. The inadvertent use of and response to prednisone suggests that steroids may be an efficacious adjunct to ribavirin in the management of acute Hepatitis E.

Donʼt Ask, Donʼt Tell: A Lesson on Evaluating Acute Hepatitis

Acute hepatitis A virus (HAV) infection is common in developing countries. It can range from asymptomatic to fulminant hepatitis. The mean peak of total bilirubin in acute HAV infection is usually less than 10 mg/dL with mean jaundice lasting about 4 weeks. Cases of prolonged or relapsing cholestatic HAV were reported at a global incidence of 5-10%. Acute HAV infection with prolonged cholestatic jaundice (PCJ) is rare. We present a severe prolonged cholestatic HAV infection likely complicated by concurrent Chikungunya virus infection and drug induced liver injury. A 39 year old female, born in India, presented to our hospital with subjective fevers, malaise, and myalgias for 3 weeks. She returned from a trip to India 1 month ago. On admission she had a temperature of 100.1°F. Her physical exam was within normal limits with no documented hepatomegaly. Her initial blood work showed elevated transaminases (aspartate aminotransferase (AST u/L) 122, alanine aminotransferase (ALT u/L) 143)with normal alkaline phosphatase (ALP) and total bilirubin (TB). Three days into her admission she showed some clinical improvement but with worsening of AST to 1958 and ALT to 1605 reaching a peak of AST 3804 and ALT 3335; ALP remained normal and TB increased to 4.0 mg/dL. US of abdomen showed hepatic steatosis. Viral markers were positive for HAV IgM but negative for acute EBV, CMV, HBV, HCV and HEV infection. Her autoimmune panel was negative. She was discharged 1 week later with clinical improvement; AST 556 and ALT 1418, ALP 77 and INR 1.58. Her TB remained elevated to 7.6. She was readmitted to the hospital 2 weeks later with pruritus and worsening fatigue. Her AST was 88 and ALT 59, with ALP of 148 and a TB of 23.4. Her INR was 2.09. A repeat US showed no biliary ductal dilation or stones. She tested positive for Chikungunya IgM. She admitted to ingesting multiple herbal products. Her liver tests normalized at 4 months with positive HAV and Chikungunya IgG.FigureFigureFigureWe present a severe prolonged cholestatic HAV infection likely complicated by concurrent Chikungunya infection and drug induced liver injury. Acute HAV infection with prolonged cholestatic jaundice (PCJ) is rare. Acute Chikungunya has been documented as a cause of acute cholestatic hepatitis. A thorough history of drug exposure is essential in the evaluation of cholestatic liver injury. Furthermore, CDC recommendation for HAV vaccination for travelers should be reinforced even on immigrants from endemic countries.

Hepatitis E: Still Waters Run Deep.

Hepatitis E is an infectious inflammatory disease of the liver caused by the hepatitis E virus (HEV), a single-stranded RNA virus. Today, it is estimated that there are more than 20 million HEV infections every year, leading to 3.3 million symptomatic cases and more than 56,000 deaths. For a long time it was believed that HEV was a travel-associated disease, endemic in developing countries with poor hygienic standards and unsafe water supply. However, over the past years, publications have demonstrated that autochthonous HEV infections in industrialized countries are far more common than previously thought. Awareness for HEV amongst health care practitioners in industrialized countries is still limited. This relatively rare disease is of great importance, especially in immunocompromised patients where it can cause chronic liver disease. This article comprehensively reviews current literature to give an overview on clinically important topics. It will focus on epidemiological aspects, acute and chronic HEV infection as well as extra-hepatic manifestations, diagnostic approach and treatment options. Furthermore, the article is concluded with a brief outlook on perspectives and urgent problems to be addressed in the future.

Persistent Hepatitis E Infection in a Patient with Tuberous Sclerosis Complex Treated with Everolimus: A Case Report.

IntroductionThe incidence of hepatitis E (HEV) genotype 3 is rising in developed countries. HEV infections are usually self-limiting, but can become chronic in immunocompromised patients. This might lead to rapid fibrosis development even resulting in cirrhosis. Chronic HEV is mainly described in patients after solid-organ or hematological transplantations. We present the first case of HEV infection in a patient with tuberous sclerosis complex (TSC) treated with everolimus, a mammalian target of rapamycin (mTOR) inhibitor.CaseA 46-year-old male with TSC was referred to the infectious diseases department with an acute rise of liver enzymes during routine laboratory check-up. He was diagnosed with an acute HEV infection. His current treatment for TSC was everolimus. After awaiting a spontaneous clearance for 3 months, everolimus was discontinued. Hereafter, the infection was cleared within another 3 months.DiscussionDue to a favorable side-effect profile, everolimus is gaining popularity as an immunosuppressive therapy. However, in vitro experiments suggest that inhibition of mTOR leads to a significant increase in HEV replication. Thus far, there have been no clinical reports of HEV infections in patients treated with everolimus.ConclusionDue to higher dosing of everolimus in TSC patients, they are more vulnerable to the development of chronic HEV infection. Periodic assessment of transaminases in these patients is advised.

Transmission of hepatitis E virus infection to human-liver chimeric FRG mice using patient plasma

Hepatitis E virus (HEV) is considered as an important pathogen in developing countries but there is growing evidence of its increasing significance and prevalence in the Western world. Although most acute HEV infections resolve spontaneously, chronicity has been observed in immunocompromised patients. The study of HEV has been hampered by the absence of practical animal models. Because the in vivo study of HEV was essentially limited to primates and pigs we recently established the human-liver chimeric uPA-SCID mouse model as a useful tool to study HEV infection. Because the humanized FRG mouse model, another type of mouse with humanized liver, is more easily accessible to the scientific community, we investigated its susceptibility to HEV infection. FRG mice were transplanted with human hepatocytes and challenged with different HEV genotypes using different routes of exposure. Our data clearly shows that the humanized FRG mouse is an alternative animal model for the study HEV infection. As observed in the uPA-SCID model, controlled oral inoculation did not lead to active infection. However, intrasplenic injection of genotype 3-infected patient plasma did result into persistent infection. Although the efficiency of transmission was low, this observation corroborates previously published case reports of blood transfusion-associated HEV transmission.

De-Novo Autoimmune Hepatitis with Consecutive Acute Liver Failure Induced by Hepatitis E Infection: A Case Report

: A 49-year-old male patient was referred to our institution for acute liver failure (ALV). Apart from cholestasis, coagulopathy, and hepatic encephalopathy (HE) I°, laboratory studies revealed a significant increase in liver enzymes with an alanine aminotransferase (ALT) level of 4’108 U/L and an aspartate aminotransferase (AST) level of 3’878 U/l (normal < 50 U/L), a constellation essentially compatible with autoimmune hepatitis (AIH). Work-up of serological markers for hepatitis E (HEV-IgM and PCR) was at the same time positive. Furthermore, the patient was strongly positive for antinuclear autoantibodies (ANA) with a titer of 1:1’280 (normal upper limit 1:80), and also presented hypergammaglobulinemia (immunoglobulin IgG-level of 21.3 g/L; normal 7, 0 - 16, 0 g/L). Liver histology demonstrated massive hepatitis and necrosis with the presence of plasma cells. Due to the diagnosis of de-novo autoimmune hepatitis, therapy with steroids was performed despite the evidence of acute HEV-infection. It was of great importance that the patient recovered completely while neither antiviral therapy with ribavirin nor liver transplantation (LT) was necessary in the further course.

Investigation of underlying comorbidities as risk factors for symptomatic human hepatitis E virus infection.

Symptomatic Hepatitis E virus (HEV) infection occurs in few infected subjects, and the risk factors are not completely known. To explore the risk factors for adverse clinical outcomes in acute HEV infections. A large retrospective study was conducted. The baseline characteristics, clinical outcomes, and laboratory data of 512 acute HEV infection cases were analysed using logistic regression models. All patients exhibited autochthonous sporadic HEV infections, and most were elderly. Their symptoms varied from asymptomatic to severe liver diseases. In all, 215 patients (42.0%) had liver failure and/or decompensation, and 45 (8.2%) patients died within 3 months. Nearly 60% of patients had underlying chronic liver diseases (CLDs), 20% were cirrhotic, and various extrahepatic underlying comorbidities were common. The logistic regression analysis revealed that underlying CLDs, especially cirrhosis, were closely associated with disease severity (OR = 8.78, P < 0.001) but not with mortality in patients with severe liver diseases. In addition to the known factors, including an old age, the male gender and CLDs, we identified pre-existing extrahepatic tumours, diabetes, and chronic respiratory and renal diseases as novel independent predictors for adverse clinical outcomes. Importantly, patients without these four extrahepatic comorbidities showed a much lower mortality rate (4.2%, P < 0.001) than patients with one (18.5%) or more comorbidities (34.5%). Previous comorbidities, including tumours, diabetes, and chronic liver, lung and kidney diseases, were independent risk factors for adverse outcomes, especially mortality, in acute HEV infections. This study provides valuable data for improving the prevention and control of HEV infection.

Acute Hepatitis E Virus Infection in Two Geographical Regions of Nigeria.

Hepatitis E virus (HEV) remains a major public health concern in resource limited regions of the world. Yet data reporting is suboptimal and surveillance system is inadequate. In Nigeria, there is dearth of information on prevalence of acute HEV infection. This study was therefore designed to describe acute HEV infection among antenatal clinic attendees and community dwellers from two geographical regions in Nigeria. Seven hundred and fifty plasma samples were tested for HEV IgM by Enzyme Linked Immunosorbent Assay (ELISA) technique. The tested samples were randomly selected from a pool of 1,115 blood specimens previously collected for viral hepatitis studies among selected populations (pregnant women, 272; Oyo community dwellers, 438; Anambra community dwellers, 405) between September 2012 and August 2013. One (0.4%) pregnant woman in her 3rd trimester had detectable HEV IgM, while community dwellers from the two study locations had zero prevalence rates of HEV IgM. Detection of HEV IgM in a pregnant woman, especially in her 3rd trimester, is of clinical and epidemiological significance. The need therefore exists for establishment of a robust HEV surveillance system in Nigeria and especially amidst the pregnant population in a bid to improve maternal and child health.

Comparing the Clinical Features and Outcomes of Acute Hepatitis E Viral Infections with Those of Acute Hepatitis A, B, and C Infections in Korea

Objectives: This study investigated the etiology of acute viral hepatitis and compared the clinical features of hepatitis E virus (HEV) infections with those of other acute viral hepatitis infections in Korea. Methods: This study included 2,357 consecutive patients who were diagnosed with acute hepatitis, based on acute illness with jaundice or elevated alanine aminotransferase levels (>100 IU/L), between January 2007 and January 2016. Acute viral infections were observed in 23 (19.8%) patients with HEV, 49 (42.2%) patients with hepatitis A virus, 28 (24.1%) patients with hepatitis B virus, and 16 (13.8%) patients with hepatitis C virus. Results: The incidence of acute HEV infection was higher among older patients (median age: 49 years) and male patients (69.6%), and was associated with the consumption of undercooked or uncooked meat (43.5%). Half of the acute HEV infections involved underlying liver disease, such as alcoholic liver disease, chronic hepatitis B, common bile duct stones, and autoimmune hepatitis. Two HEV-infected patients were diagnosed with Guillain-Barré syndrome, although no patients developed fulminant hepatitis. Conclusion: Our findings indicate that HEV infection in Korea is frequently transmitted through the consumption of raw meat and may cause acute or chronic liver disease.

Diagnostic Challenges and Clinical Characteristics of Hepatitis E Virus–Associated Guillain-Barré Syndrome

ImportanceHepatitis E virus (HEV) recently has been shown to be an antecedent infection in Guillain-Barré syndrome (GBS), but the clinical spectrum of HEV-associated GBS is not yet documented, and diagnosing acute HEV infection can be a challenge.ObjectivesTo determine the prevalence of HEV-associated GBS in a Belgian cohort, study the clinical spectrum of HEV-associated GBS, and discuss difficulties in diagnosing acute HEV infection.Design, Setting, and ParticipantsThis single-center, retrospective cohort study was conducted between January 1, 2007, and November 1, 2015. All patients with GBS or a GBS variant who presented to the adult neurology department of the University Hospital Leuven were identified via a search of the electronic medical records. Hepatitis E virus IgM and IgG reactivity was determined. In a subgroup, polymerase chain reaction for HEV was performed.Main Outcomes and MeasuresHepatitis E virus IgM and IgG reactivity.ResultsOf 73 eligible patients (mean [SD] age, 52 [18] years; 29 females and 44 males), 6 (8%) showed positive reactivity on IgM assays for HEV, indicating a possible acute HEV infection. Four of the 6 patients (67%) had increased alanine aminotransferase levels of more than 1.5 times the upper limit of normal, while 4 of 22 patients (18%) with increased alanine aminotransferase levels showed positive reactivity on HEV IgM assays. Serum samples of 2 of 6 patients with positive reactivity on HEV IgM assays also revealed positive test results for cytomegalovirus or Epstein-Barr virus, indicating possible cross-reactivity. Thus, 4 patients (6%) in our cohort had probable acute HEV infection. Two of these patients presented with an infrequent GBS variant.Conclusions and RelevanceAcute HEV infection was frequently associated with GBS in our cohort. Abnormal alanine aminotransferase levels at admission can indicate the presence of an associated HEV infection. When HEV testing is considered, it is important to test for other infectious agents in parallel, as cross-reactivity can occur. Further studies are required to guide neurologists in their workup of underlying triggers of GBS.

Acute Hepatitis E: Two Sides of the Same Coin.

The relevance of acute hepatitis E virus (HEV) infections has been underestimated for a long time. In the past, HEV infection had been interpreted falsely as a disease limited to the tropics until the relevance of autochthonous HEV infections in the Western world became overt. Due to increased awareness, the incidence of diagnosed autochthonous HEV infections (predominantly genotype 3) in industrialized countries has risen within the last decade. The main source of infections in industrialized countries seems to be infected swine meat, while infections with the tropical HEV genotypes 1 and 2 usually are mainly transmitted fecal-orally by contaminated drinking water. In the vast majority of healthy individuals, acute HEV infection is either clinically silent or takes a benign self-limited course. In patients who develop a symptomatic HEV infection, a short prodromal phase with unspecific symptoms is followed by liver specific symptoms like jaundice, itching, uncoloured stool and darkened urine. Importantly, tropical HEV infections may lead to acute liver failure, especially in pregnant women, while autochthonous HEV infections may lead to acute-on-chronic liver failure in patients with underlying liver diseases. Immunosuppressed individuals, such as transplant recipients or human immunodeficiency virus (HIV)-infected patients, are at risk for developing chronic hepatitis E, which may lead to liver fibrosis and cirrhosis in the long term. Importantly, specific treatment options for hepatitis E are not approved by the regulation authorities, but off-label ribavirin treatment seems to be effective in the treatment of chronic HEV-infection and may reduce the disease severity in patients suffering from acute liver failure.

Characterization of the Specificity, Functionality, and Durability of Host T-Cell Responses Against the Full-Length Hepatitis E Virus.

The interplay between host antiviral immunity and immunopathology during hepatitis E virus (HEV) infection determines important clinical outcomes. We characterized the specificity, functionality, and durability of host T‐cell responses against the full‐length HEV virus and assessed a novel “Quantiferon” assay for the rapid diagnosis of HEV infection. Eighty‐nine volunteers were recruited from Oxford, Truro (UK), and Toulouse (France), including 44 immune‐competent patients with acute HEV infection, 18 HEV‐exposed immunosuppressed organ‐transplant recipients (8 with chronic HEV), and 27 healthy volunteers. A genotype 3a peptide library (616 overlapping peptides spanning open reading frames [ORFs] 1‐3) was used in interferon‐gamma (IFN‐γ) T‐cell ELISpot assays. CD4+/CD8+ T‐cell subsets and polyfunctionality were defined using ICCS and SPICE analysis. Quantification of IFN‐γ used whole‐blood stimulation with recombinant HEV‐capsid protein in the QuantiFERON kit. HEV‐specific T‐cell responses were detected in 41/44 immune‐competent HEV exposed volunteers (median magnitude: 397 spot‐forming units/106 peripheral blood mononuclear cells), most frequently targeting ORF2. High‐magnitude, polyfunctional CD4 and CD8+ T cells were detected during acute disease and maintained to 12 years, but these declined over time, with CD8+ responses becoming more monofunctional. Low‐level responses were detectable in immunosuppressed patients. Twenty‐three novel HEV CD4+ and CD8+ T‐cell targets were mapped predominantly to conserved genomic regions. QuantiFERON testing demonstrated an inverse correlation between IFN‐γ production and the time from clinical presentation, providing 100% specificity, and 71% sensitivity (area under the receiver operator characteristic curve of 0.86) for HEV exposure at 0.3 IU/mL. Conclusion: Robust HEV‐specific T‐cell responses generated during acute disease predominantly target ORF2, but decline in magnitude and polyfunctionality over time. Defining HEV T‐cell targets will be important for the investigation of HEV‐associated autoimmune disease. (Hepatology 2016;64:1934‐1950).

Acute, Recent and Past HEV Infection among Voluntary Blood Donors in China: A Systematic Review and Meta-Analysis.

IntroductionHepatitis E virus is one of new threats to blood safety which was usually considered to be transmitted via fecal-oral route. China is one of the hyperendemic regions where frequent outbreaks of hepatitis E are noted. However, the overall prevalence of HEV infection among mainland Chinese blood donors is not clear until now.MethodThe peer-reviewed literatures reporting the prevalence of HEV in Chinese blood donors were identified by systematic searching of five electronic databases. The systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement issued in 2009. Data manipulation and statistical analyses were performed by Stata 12.0.ResultsFourteen eligible articles involving 22 independent studies were included. Pooled prevalence of HEV infection biomarkers (anti-HEV IgG, anti-HEV IgM, RNA and antigen) among mainland Chinese blood donors were 29.2%, 1.1%, 0.1% and 0.1%, respectively which were higher than the data reported in other countries. The analysis of HEV genotypes indicated that the most prevalent strains in Chinese blood donors were genotype 1 and 4.ConclusionsMainland China is indicated with a relatively higher risk of transmission of hepatitis E through transfusion and the screening of blood donors for HEV RNA, especially in HEV-endemic areas, might reduce the potential risk of HEV infection via transfusion.