Hepatitis E virus infection of transplanted kidneys.

Immunocompromised patients are at risk of chronic hepatitis E (HEV) infection. Recurrent T cell and borderline rejections in a pediatric patient with high HEV copy numbers led us to study HEV infection within renal transplants. To investigate the frequency of renal HEV infection in transplanted patients, 15 samples from patients with contemporaneous diagnoses of HEV infection were identified at our center. Ten samples had sufficient residual paraffin tissue for immunofluorescence (IF) and RNA-fluorescence-in-situ-hybridization (RNA-FISH). The biopsy of the pediatric index patient was additionally sufficient for tissue polymerase chain reaction and electron microscopy. HEV RNA was detected in paraffin tissue of the index patient by tissue polymerase chain reaction. Subsequently, HEV infection was localized in tubular epithelial cells by IF, RNA-FISH, and electron microscopy. One additional biopsy from an adult was positive for HEV by RNA-FISH and IF. Focal IF positivity for HEV peptide was observed in 7 additional allografts. Ribavirin therapy was not successful in the pediatric index patient; after relapse, ribavirin is still administered. In the second patient, successful elimination of HEV was achieved after short-course ribavirin therapy. HEV infection is an important differential diagnosis for T cell rejection within transplanted kidneys. Immunostaining of HEV peptide does not necessarily prove acute infection. RNA-FISH seems to be a reliable method to localize HEV.

Acute Hepatitis E Infection during Chemotherapy for Lung Cancer: A Case Report.

Acute hepatitis E, one of the causes of acute liver injury, has been increasingly diagnosed in developed countries in recent years. Misdiagnosis of acute hepatitis E virus (HEV) infection as drug-induced liver injury (DILI) may lead to discontinuation of effective chemotherapy. Thus, viral hepatitis, including hepatitis E, must be ruled out in the diagnosis of DILI. A 78-year-old woman with lung adenocarcinoma and multiple bone metastases received maintenance therapy with pemetrexed + pembrolizumab for a year. Increased aspartate aminotransferase and alanine aminotransferase levels, indicating acute liver injury, were observed. Initially, DILI was suspected, and she was given medications to lower the levels of hepatic enzymes. She was later admitted to the hospital with the chief complaint of general malaise and anorexia. Serum aspartate aminotransferase and alanine aminotransferase levels were markedly elevated (381 and 854 U/L, respectively). Acute HEV infection was diagnosed based on the detection of serum HEV immunoglobulin A antibodies. The patient received liver support therapy, and the serum hepatic enzymes recovered to normal levels. Chemotherapy was resumed without any subsequent relapse of hepatic enzyme elevation. When DILI is suspected during chemotherapy, exclusion of viral hepatitis is mandatory, which can be achieved by measuring markers of hepatitis viruses, including HEV, and examining the patient's detailed medical history.

Risk factors associated with Hepatitis E virus infection in kidney transplant recipients in a single tertiary Center in the United States.

BACKGROUND: Hepatitis E virus (HEV), the causative agent of hepatitis E, is a common but self-limiting disease. However, in immunosuppressed kidney transplant 47 recipients (KTRs), HEV infection can become chronic. We investigated risk factors associated with HEV infection among 271 KTRs at the Johns Hopkins Hospital transplanted between 1988 and 2012. METHODS: HEV infection was defined as having positive anti-HEV IgM, anti-HEV IgG, or HEV RNA. The risk factors included: age at transplant, sex, hemodialysis/peritoneal dialysis, plasmapheresis, transfusions, community urbanization, and other socioeconomic factors. Logistic regression was used to determine independent risk factors associated with HEV infection. RESULTS: Out of 271 KTRs, 43 (16%) had HEV infection though not active disease. HEV infection in KTRs was associated with older age (≥45 years; OR = 4.04; 95% CI = 1.81-57 10.03; p = 0.001) and living in communities with low proportions of minorities (OR = 0.22; 95% 58 CI = 0.04-0.90; p = 0.046). CONCLUSION: KTRs who had HEV infection may be at an increased risk of developing chronic HEV.

Hepatitis E Virus Seroprevalence Among Liver Transplant Recipients with Persistent Elevation of Liver Enzymes: A Single Center Report.

BACKGROUND: Chronic hepatitis E infection has been reported in solid organ transplant recipients following acute hepatitis due to the compromised immune status. Almost all reports are from areas where hepatitis E virus (HEV) genotypes 3 and 4 are the dominant genotypes. This study was conducted to investigate the role of hepatitis E infection as an etiology for liver enzymes elevation in liver transplant recipients from the largest liver transplant program in Iran. METHODS: In a prospective study from June to December 2015, in a single liver transplantation center in Iran, all adult liver recipients who were investigated for the etiology of persistent elevation of liver enzymes were tested for HEV serology status. RESULTS: Of 122 patients included in the study, 19 (15.6%) were positive for HEV serology. Seropositive patients were significantly older than seronegative ones (mean age 43.79 vs. 31.58, P < 0.001); however, they were not different in other characteristics including sex distribution and mean of liver enzymes in each occasion. Liver biopsies were done in 16 HEV seropositive patients and none of the biopsies showed evidence for acute or chronic viral hepatitis. CONCLUSION: In this study, with 15.6% rate of HEV seropositivity in liver recipients with persistent elevation of liver enzymes, we were not able to confirm any clinical evidence for active acute or chronic hepatitis E infection. This could theoretically be attributed to the fact that the dominant prevalent HEV genotype in our endemic area is not associated with a chronic form of infection.

Hepatitis E virus: Efficacy of pasteurization of plasma-derived VWF/FVIII concentrate determined by pig bioassay.

BACKGROUND: Hepatitis E virus (HEV) is the leading cause of acute hepatitis throughout the world. Increasing blood component transfusion-associated HEV infections highlight the need for reliable virus inactivation procedures for plasma derivatives from pooled plasma donations. STUDY DESIGN AND METHODS: An animal infection study was conducted to evaluate the efficiency of HEV inactivation by pasteurization during the manufacturing process of the von Willebrand Factor/Factor VIII (VWF/FVIII) concentrate Haemate P/Humate-P (CSL Behring, Marburg, Germany). For this purpose, groups of pigs were inoculated with stabilized VWF/FVIII intermediate spiked with HEV-positive liver homogenate and exposed to increasing incubation times of 0, 3, 6, and 10 h at 60°C. Animals were evaluated for virus replication over 27 days and in a subsequent trial over 92 days. RESULTS: Virus replication was detected in animals up to the 6-h pasteurization group. In contrast, pasteurization for 10 h did not reveal virus detection when the observation period was 27 days. In an additional experiment using the 10-h pasteurized material, two individuals started virus excretion and seroconverted when the observation period was extended to 92 days. Based on the total infection rate (2 of 12) of the animals inoculated with the sample pasteurized for 10 h, a virus reduction factor of at least 4.7 log10 is calculated. CONCLUSION: This study demonstrates that pasteurization at 60°C for 10 h of an HEV-positive plasma derivative leads to the effective reduction of infectivity, resulting in a VWF/FVIII product with an appropriate margin of safety for HEV.

Blood transfusion is unlikely to be a source for hepatitis E virus transmission in India.

INTRODUCTION: Transmission of hepatitis E virus (HEV) through transfusion has been reported from countries where genotype 3 virus is predominant. Data from countries with predominantly genotype 1 HEV, such as India, are limited. We studied the risk of HEV transmission following transfusion of blood or blood components in India. METHODS: Adult patients undergoing cardiac surgery who received transfusion of blood or blood products in the peri-operative period and who lacked history of any transfusion or surgery in the preceding 1 year were studied. A pre-transfusion blood specimen was collected for IgG anti-HEV antibody test. For the participants who were seronegative for anti-HEV, follow up specimens were collected at every 2-3-month intervals for up to 6 months after surgery and were tested for IgM and IgG anti-HEV antibodies. RESULTS: Of the 335 participants originally enrolled, 191 (57%) could be followed up. Of them, 103 (53.9%) were seropositive for HEV IgG at baseline and were excluded. Of the remaining 88 participants (age 42 ± 14.1 years; 55 [63%] male), none reported hepatitis-like illness during the follow up period of 81 ± 23 days. Also, none of these 88 participants was found to have seroconversion to anti-HEV IgM or IgG positivity in the follow up specimens. CONCLUSION: Transfusion-mediated transmission of HEV was not observed in our cohort and may be infrequent in the Indian population, where genotype 1 is the predominant HEV type.

Hepatitis E Virus Infection in an Italian Cohort of Hematopoietic Stem Cell Transplantation Recipients: Seroprevalence and Infection.

Chronic hepatitis E virus (HEV) infection in hematopoietic stem cell transplantation (HSCT) recipients is an emerging threat. The aim of this study was to provide data on the HEV burden in an Italian cohort of HSCT recipients and analyze risk factors for HEV seropositivity. This retrospective study reports data from 596 HSCT recipients compiled between 2010 and 2019. It included patients who underwent transplantation between 2010 and 2015 for whom pretransplantation (n = 419) and post-transplantation (n = 161) serum samples were available and tested retrospectively, as well as patients in whom prospective HEV testing was performed during the standard care: pre-HSCT IgG screening in 144, pre-HSCT HEV-RNA screening in addition to IgG screening in 60, and HEV-RNA testing in case of clinical suspicion of HEV infection in 59 (26 of whom were also included in the IgG screening cohorts). The rate of pre-HSCT HEV-IgG positivity was 6.0% (34 of 563). Older age was an independent risk factor for seropositivity (P = .039). None of the 34 HEV-IgG-positive patients had detectable HEV-RNA. One case of transient HEV-RNA positivity pre-HSCT was identified through screening. Two patients were diagnosed with chronic HEV hepatitis, and 1 patient was successfully treated with ribavirin. The burden of HEV infection in HSCT recipients in Italy is limited, and pre-HSCT screening appears to be of no benefit. Timely diagnosis of HEV infection with HEV-RNA is mandatory in cases of clinical suspicion.

The challenge of chronic hepatitis E in liver transplant recipients: Failure of sofosbuvir plus ribavirin therapy / Problema de la hepatitis E crónica en los receptores de trasplante de hígado: fracaso del tratamiento con sofosbuvir más ribavirina

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Hepatitis E virus is an infrequent but potentially serious infection in allogeneic hematopoietic stem cell transplant recipients.

Hepatitis E virus (HEV) can cause chronic infection and liver cirrhosis in immunocompromised individuals. The frequency and clinical importance of HEV was studied retrospectively in a cohort of 236 Swedish allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In blood samples collected at 6 months after HSCT, HEV RNA was identified in 8/236 (3.4%) patients, and 11/236 (4.7%) patients had detectable anti-HEV IgG and/or IgM, eight of whom were HEV RNA negative. Two of the patients with positive HEV RNA died with ongoing signs of hepatitis: one of acute liver and multiple organ failure, the other of unrelated causes. The remaining six patients with HEV RNA had cleared the infection at 7-24 (median 8.5) months after HSCT. HEV infection was associated with elevated alanine aminotransferase at 6 months after HSCT (OR 15, 1.3-174, p = 0.03). Active graft-versus-host disease of the liver at 6 months after HSCT was present in 3/8 (38%) patients with HEV RNA, but was not significantly associated with HEV infection. In conclusion, HEV infection is an important differential diagnosis in patients with elevated liver enzymes after HSCT. Although spontaneous clearance was common, the clinical course may be severe.

Exposure to hepatitis E virus in hemodialysis patients from west-central Poland.

Hepatitis E virus (HEV) causes travel-related but also locally acquired infections in industrialized parts of the world, including European countries. Food and blood transfusions are possible sources of transmission. Infections caused by zoonotic variants of the virus (particularly HEV-3) may progress to chronic liver disease in a nonnegligible proportion of immunocompromised people. The aim of this study was to assess the prevalence of serological markers of HEV infection in 189 patients on renal replacement therapy (RRT, currently on hemodialysis, HD) living in west-central Poland and to determine the factors related to HEV exposure in this group. Testing was carried out using commonly used commercial assays (Wantai Biological Pharmacy Enterprise Co, Beijing, China). Anti-HEV IgG was detected in 94 patients (49.7%); none of the participants had anti-HEV IgM or HEV Ag. Patients on RRT (HD) for less than 6 months were significantly more likely to be anti-HEV IgG-positive than dependent of RRT (HD) for more than half a year (80% vs 47%; P = .014). Exposure to HEV in patients from west-central Poland is frequent, but no clear sources of this infection have been identified. There were no serological features of ongoing liver disease caused by HEV in the study subjects.

Study of a hepatitis E virus outbreak involving drinking water and sewage contamination in Shimla, India, 2015-2016.

BACKGROUND: Hepatitis E, caused by hepatitis E virus (HEV), accounts for 50% of acute hepatitis cases in India. We report an outbreak of hepatitis E in Shimla, India, in 2015-2016. METHODS: ICMR-National Institute of Virology (NIV), Pune, received two batches of water samples from Shimla in January 2016 to test for the presence of enterically transmitted hepatitis viruses. Subsequently, 57 icterus patients were tested for various markers of hepatotropic viruses, i.e. anti-HEV IgM/IgG, anti-hepatitis A virus (anti-HAV) IgM/IgG antibodies and HEV RNA. Water samples were screened for HEV and HAV RNA followed by phylogenetic analysis. RESULTS: Overall, 48/57 patients availing municipal water had evidence of HEV infection, detected by serology and RT-PCR. All the water samples tested positive for HEV and HAV RNA, while the patients were negative for anti-HAV IgM antibody, indicating no recent HAV infection. Phylogenetic analysis confirmed the aetiological agent of the current outbreak to be HEV genotype 1. CONCLUSIONS: Serology and RT-PCR confirmed HEV as the aetiology of the outbreak. The absence of new cases of hepatitis A, despite the presence of HAV in the water supply, could be due to previously acquired immunity. Sewage contamination of water leading to faecal-oral transmission of HEV still remains a concern, thus emphasising the need for a vaccination/control strategy.

Chronic hepatitis E after kidney transplantation with an antibody response suggestive of reinfection: a case report.

BACKGROUND: Hepatitis E virus (HEV) infection is now recognized as a major cause of acute hepatitis worldwide. HEV specific antibodies develop shortly after infection and are thought to confer protection. CASE PRESENTATION: We report an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies. HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes. Upon retrospective analysis of stored serum samples we found that the patient was HEV RNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin. CONCLUSIONS: In conclusion, the patient suffered from a chronic course of HEV infection, which was successfully treated with ribavirin. Our case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressed patients and supports the notion that HEV antibodies do not confer universal protection. Counseling patients at risk for chronic HEV infection seems advisable. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.

Hepatitis E outbreak in a mechanical factory in Qingdao City, China.

OBJECTIVE: In July 2018, recurrent hepatitis E cases were reported from a factory in Qingdao City, China. The aim of this study was to identify additional cases, and help prevent future incidents by identifying possible risk factors for infection. METHODS: Participants were asked to provide blood samples for hepatitis E virus (HEV) IgM and IgG antibodies screening, as well as liver function test. A questionnaire that assessed demographics, potential risk factors, and clinical symptoms was completed by participants. HEV RNA genotyping was performed using a nested Reverse Transcriptional Polymerase Chain Reaction (RT-PCR) method. Adjusted Poisson regression model for participant characteristics and risk factors was constructed for multivariate analysis. RESULTS: Overall, 41(14.5%, 41/283) participants had recent acute infection (21 of these were symptomatic). The result of multivariate analysis demonstrated a significant association of acute HEV infection with consumption of pig liver within the past two months (Relative Risk 2.61, 95% confidence interval (CI) 1.10-6.17, p=0.0294). Sequencing of HEV RNA from seventeen acute cases indicated three HEV isolates of genotype 4 induced this outbreak. CONCLUSIONS: This was probably a common-source foodborne hepatitis E outbreak, related to the consumption of undercooked pig liver.

Locally Acquired Chronic Hepatitis E Followed by Epstein-Barr Virus Reactivation and Burkitt Lymphoma as a Suspected Extrahepatic Manifestation in a Liver Transplant Recipient.

BACKGROUND Hepatitis E virus (HEV) is a common cause of acute hepatitis in developing regions. In high-income countries, hepatitis E is an emergent zoonotic disease of increasing concern. Clinically, the infection is usually acute and self-limited in immunocompetent individuals, although rare chronic cases in immunocompromised patients have been reported. Both acute and chronic infections have been recently associated with several extrahepatic manifestations, including neurological and hematological disorders. CASE REPORT A case of autochthonous chronic HEV infection in a liver-transplanted man from a non-endemic country is presented. Phylogenetic analysis revealed a swine origin of the HEV human infection. Chronic hepatitis E was treated with a 9-week course of ribavirin, after which viral clearance was achieved. Subsequently, the patient developed a post-transplant lymphoproliferative disorder (PTLD) in the form of Burkitt lymphoma. At the time of lymphoma diagnosis, the patient had shown a strong reactivation of Epstein-Barr virus (EBV) infection. After additional antiviral ganciclovir therapy and chemotherapy, the patient had a complete recovery with no sequelae. CONCLUSIONS The differential diagnosis of persistently elevated transaminases in transplanted and/or immunocompromised patients should include testing for HEV by appropriate nucleic acid techniques (NATs). Cases of HEV infection with an atypical clinical outcome, such as the one presented herein, highlights the need for increased awareness of chronic hepatitis E and its association with a wide range of extrahepatic manifestations.

Prevalence of hepatitis E virus infection in multiple transfused Brazilian patients with thalassemia and sickle cell disease.

Hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. The virus is acquired by fecal-oral route; however, it can also be transmitted by blood transfusion. The objective of the study was to examine anti-HEV immunoglobulin G and HEV RNA prevalence in multiple transfused patients with thalassemia and sickle cell disease (SCD), and in blood donors. The HEV seroprevalence in the patients was 13% (20% in thalassemics; 7.7% in SCD), and 11% in blood donors. No positive result for HEV RNA was obtained. This is a pioneer study examining HEV circulation in Brazilian patients with hemoglobinopathies.

Chronic Hepatitis E in Rheumatology and Internal Medicine Patients: A Retrospective Multicenter European Cohort Study.

Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis (n = 5), psoriatic arthritis (n = 4), other variants of chronic arthritis (n = 4), primary immunodeficiency (n = 3), systemic granulomatosis (n = 2), lupus erythematosus (n = 1), Erdheim⁻Chester disease (n = 1), and retroperitoneal fibrosis (n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids (n = 2), mycophenolate mofetil/prednisone (n = 1), and sirolimus/prednisone (n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection.

Rat Hepatitis E Virus as Cause of Persistent Hepatitis after Liver Transplant.

All hepatitis E virus (HEV) variants reported to infect humans belong to the species Orthohepevirus A (HEV-A). The zoonotic potential of the species Orthohepevirus C (HEV-C), which circulates in rats and is highly divergent from HEV-A, is unknown. We report a liver transplant recipient with hepatitis caused by HEV-C infection. We detected HEV-C RNA in multiple clinical samples and HEV-C antigen in the liver. The complete genome of the HEV-C isolate had 93.7% nt similarity to an HEV-C strain from Vietnam. The patient had preexisting HEV antibodies, which were not protective against HEV-C infection. Ribavirin was an effective treatment, resulting in resolution of hepatitis and clearance of HEV-C viremia. Testing for this zoonotic virus should be performed for immunocompromised and immunocompetent patients with unexplained hepatitis because routine hepatitis E diagnostic tests may miss HEV-C infection. HEV-C is also a potential threat to the blood product supply.

Hepatitis E virus genotype 3 is a common finding in liver-transplanted patients undergoing liver biopsy for elevated liver enzymes with a low De Ritis ratio and suspected acute rejection: A real-world cohort.

BACKGROUND: Hepatitis E virus (HEV) infection is a potential reason for elevated liver enzymes after liver transplantation (LT). Our aim was to analyze a real-world cohort of LT patients, who underwent liver biopsy for elevated transaminases and suspected acute rejection, to evaluate frequency of post-transplant HEV infection. PATIENTS: Data from 160 liver biopsies were analyzed. Seventy-one patients were biopsied on schedule after LT without elevated liver enzymes. A subgroup of 25 patients with elevated liver enzymes and suspected rejection was chosen for further analysis. Patient demographics and data were retrieved from a clinical database, patients' charts, and reports. RESULTS: Hepatitis E virus infection was diagnosed in five of 25 patients with suspected acute rejection (20%). HEV genotype 3 was detected in three of the five HEV-infected patients. Patients with HEV infection showed higher ALT levels (P = 0.014), lower De Ritis ratio (P = 0.021), and more frequent glucocorticoid therapy (P = 0.012) compared to HEV-negative patients. CONCLUSION: We found a rate of 20% HEV infections in LT patients undergoing liver biopsy for elevated liver enzymes and suspected acute rejection. These data indicate the necessity for HEV testing in all LT patients with elevated liver enzymes and suspected acute rejection.

Ribavirin therapy of hepatitis E infection may cause hyporegenerative anemia in pediatric renal transplant patients.

HEV infection can lead to chronic hepatitis in immunosuppressed patients; extrahepatic manifestations are rarely seen. Here, we report a 13-year-old renal transplant patient with chronic hepatitis E and renal involvement. Ribavirin therapy led to temporary virus clearance and amelioration of kidney function. However, ribavirin therapy caused severe hyporegenerative anemia, which has so far only been reported in patients treated with a combination of ribavirin and interferon alpha.