Universal nucleic acid donor screening revealed epidemiological features of hepatitis E and prevented transfusion-transmitted infection in Japan.

BACKGROUND: More than 45 cases of transfusion-transmitted hepatitis E virus infection (TT-HEV) have been reported in Japan. Therefore, in 2020, universal individual donation nucleic acid amplification testing (ID-NAT) was implemented for HEV. STUDY DESIGN AND METHODS: We characterized HEV NAT-positive blood donors. The number of new HEV infections and the asymptomatic infection rate were estimated using the HEV NAT-positive rate. HEV RNA quantitation, phylogenetic analysis, and antibody tests were performed, and the residual risk of TT-HEV was assessed based on the lookback study results. RESULTS: A total of 5,075,100 blood donations were screened with ID-NAT during the first year of implementation, among which 2804 (0.055%; males: 0.060%, females: 0.043%) were NAT-positive with regional differences. Approximately 270,000 new HEV infection cases were estimated to occur annually in Japan, with an asymptomatic infection rate of 99.9%. The median HEV RNA concentration, excluding cases below the limit of quantification, was 205 IU/mL. Among the 1113 cases where the genotype could be determined, HEV-3 and HEV-4 accounted for 98.8% (1100) and 1.2% (13), respectively. The maximum duration of HEV viremia, including the pre- and post-ID-NAT window periods, was estimated to be 88.2 days. Within the 3 years since ID-NAT implementation, no confirmed cases of breakthrough TT-HEV were observed. DISCUSSION: Multiple indigenous HEV strains are prevalent in Japan, infecting a significant number of individuals. However, since the implementation of ID-NAT, TT-HEV has been prevented due to the test's high sensitivity.

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

BACKGROUND: Hepatitis 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. AIM: To demonstrate the prevalence of HEV infection in solid organ transplant (SOT) recipients. METHODS: We 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. RESULTS: Of 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). CONCLUSION: HEV 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.

Incidence and prevalence of acute hepatitis E virus infection in patients with suspected Drug-Induced Liver Injury in the Spanish DILI Registry.

BACKGROUND AND AIMS: Drug-induced liver injury (DILI) presents with a wide phenotypic spectrum requiring an extensive differential diagnosis. Hepatitis E virus (HEV) is not systematically ruled out during acute hepatitis assessment in Spain. The aims of this study were to establish the role of HEV infection and its phenotypic presentation in patients initially suspected of DILI and to determine the anti-HEV seroprevalence rate. METHODS: An analysis of 265 patients with suspected DILI and considered for enrolment in the Spanish DILI Registry and 108 controls with normal liver profiles was undertaken. Anti-HEV Immunoglobulin (Ig) G antibodies were analysed in serum from all subjects. In those with serum samples extracted within 6 months from liver damage onset (n = 144), HEV antigen (Ag) and anti-HEV IgM antibodies were tested in duplicate by ELISA. In addition, RT-PCR was performed externally in eight patients. RESULTS: Out of 144 patients, 12 (8%) were positive for anti-HEV IgM, mean age was 61 years. Underlying hepatic diseases (OR = 23.4, P < .001) and AST peak >20 fold upper limit of normal (OR = 10.9, P = .002) were associated with the diagnosis of acute hepatitis E. The overall anti-HEV IgG seroprevalence rate was 35%, evenly distributed between patients with suspected DILI (34%), and controls (39%). CONCLUSIONS: HEV seroprevalence and acute hepatitis E rates are relatively high in Spain. A search for active HEV infection is therefore advised in patients assessed for suspicion of DILI, particularly in patients with underlying liver diseases and high transaminase levels.

Multiphasic presentation of neuralgic amyotrophy associated with hepatitis E virus infection.

BACKGROUND: The aim of this study was to further characterize the clinical phenotype of hepatitis E virus (HEV)-associated neuralgic amyotrophy (NA). METHODS: Three patients with HEV-associated NA underwent clinical, electrodiagnostic, and ultrasound assessment. RESULTS: In all patients, symptoms developed in several phases within a time span of 4-6 weeks, with three or more nerves involved. Symptoms were bilateral in two. In two patients, nerves of the trunk and the lower limb were affected as well. In one patient, three bouts occurred, each heralded by an increase in pain. In the other two, pain subsided quickly and nerve damage developed in two phases. Segmental enlargement with or without hourglass-like constrictions of the nerves was demonstrated by ultrasound in all. CONCLUSIONS: The multiphasic presentation, together with the extensive multi-nerve involvement, may reflect a severe and protracted inflammation of the nerves in HEV-associated NA.

Prevalence of active hepatitis E virus infection and efficacy of ribavirin treatment in renal allograft recipients.

BACKGROUND: Hepatitis E virus (HEV) genotype 3 infection frequently progresses to chronic disease with persisting HEV viremia in immunocompromised patients. Here, we evaluated the prevalence of HEV infection in renal allograft recipients and investigated the efficacy and tolerability of ribavirin monotherapy. METHODS: A total of 947 recipients on average 8.7 years post transplant were screened for anti-HEV IgG, IgM and HEV-RNA. Sixteen HEV-viremic renal allograft recipients were treated with ribavirin for 12 weeks. HEV-RNA concentration, laboratory and clinical parameters were assessed at baseline, during therapy and 12 weeks after treatment cessation. HEV-genotyping was performed in all HEV-viremic patients. RESULTS: Past HEV infection was detected serologically in 18% of the renal allograft recipients. Ongoing HEV replication was found in 16 recipients (all genotype 3). Unanimously, distinct HEV sequences were revealed in all HEV-viremic patients. At the start of ribavirin treatment, median HEV-RNA viral load was 4.3 × 106 (8000-5.0 × 106 ) IU/mL. Ninety-four percentage of HEV-infected allograft recipients showed a sustained virological response 12 weeks after treatment cessation. Ribavirin treatment was associated with rapid decrease in liver enzymes and rare occurrence of anemia. CONCLUSIONS: Prevalence of active HEV infection is important in renal transplant patients without signs of nosocomial infection. Ribavirin treatment was safe and effective.

Evaluation of an antigen assay for diagnosing acute and chronic hepatitis E genotype 4 infection.

BACKGROUND AND AIM: Results obtained from different hepatitis E virus (HEV) tests are usually inconsistent. The detection of serum HEV antigen (Ag) has been suggested to be more sensitive for the diagnosis of genotypes 1 and 3 HEV. METHODS: We compared the diagnostic accuracies of serum HEV Ag and HEV RNA by using 202 serum samples from patients suspected acute viral hepatitis. RESULTS: The HEV Ag assay was 100% specific. The lower detected levels of viremia ranged from 102 to 103  copies/mL. The sensitivity of the HEV Ag test was 90.5%. One of the 42 cases was negative for anti-HEV IgM, but HEV Ag was still detectable. The detectable period of HEV Ag was in concordance with the detectable period of HEV RNA. Serum HEV Ag was persistently detected in two cases of chronic hepatitis E, confirmed by the persistent presence of HEV RNA despite being negative for anti-HEV IgM. HEV Ag demonstrated good consistency with positive HEV RNA (k = 0.938, P < 0.001). Receiver operating characteristic analysis of HEV Ag suggested a second cut-off value of >0.095 to predict HEV patients with 95.24% sensitivity and 98.75% specificity, and the area under the curve was 0.9887, which was higher than that of three commercial anti-HEV IgM ELISA tests. CONCLUSIONS: The presence of HEV Ag has good consistency with HEV RNA in both acute and chronic genotype 4 hepatitis E. HEV Ag is a more promising serum marker to identify active genotype 4 HEV infection than anti-HEV IgM and HEV RNA.

Course of HEV viremia and anti-HEV IgM/IgG response in asymptomatic blood donors.

BACKGROUND: Globally, an estimated 20 million Hepatitis E infections occur every year. The course of viremia and antibody response has been investigated in patients with symptomatic hepatitis E. However, the majority of HEV infections in industrialized countries take a subclinical course. OBJECTIVES: To investigate the course of HEV viremia and epitope specific anti-HEV IgM/IgG response in asymptomatic blood donors in order to understand the immune response and viral clearance in asymptomatic blood donors with HEV infections. METHODS: In this study 27 HEV viremic donors were identified by HEV-PCR during routine screening of blood donors and the course of anti-HEV IgM/IgG and HEV-RNA was retrospectively studied using RT-PCR and a commercial immunoblot (Mikrogen®) allowing classification of the antibody response according to HEV epitopes. RESULTS: At time of donation, serological testing failed to identify viremic donors as 70.4% had no detectable antibody response. Anti-HEV IgM could be detected in 22.2% of viremic donors while anti-HEV IgG could be found in 7.4%. At least three donors experienced prolonged viremia beyond 100 days. Spontaneous HEV-RNA clearance within a median time span of 57 days was observed in all 27 donors. In all donors anti-HEV IgG specific for the immunogenic viral epitope O2C could be detected in close temporal association with viral clearance. CONCLUSION: Serological testing is inappropriate for identifying HEV-viremic blood donors. Acute HEV infection in asymptomatic blood donors can persist for more than 100 days. HEV-RNA clearance coincided with the appearance of anti-HEV IgM/IgG confirming the importance of a B-cell mediated response in clearing acute infections. Anti-HEV IgM and IgG specific for the epitope O2C are associated with the clearance of HEV-viremia.

HEV-positive blood donations represent a relevant infection risk for immunosuppressed recipients.

BACKGROUND & AIMS: Routine HEV testing of blood products has recently been implemented in Great Britain and the Netherlands. The relevance of transfusion-transmitted HEV infections is still controversially discussed in Europe. METHODS: All blood donations at the University Medical Center Hamburg-Eppendorf were prospectively tested for HEV RNA by pooled PCR from October 2016 to May 2017. Reactive samples were individually retested. Additionally, stored samples from previous donations of positive donors were tested to determine the duration of HEV viraemia. HEV RNA-positive donors and a control cohort were asked to answer a questionnaire. RESULTS: Twenty-three out of 18,737 HEV RNA-positive donors were identified (0.12%). Only two of the positive donors (8.7%) presented with elevated aminotransferases at time of donation (alanine aminotransferase: 192 and 101 U/L). The retrospective analysis of all positive donors revealed that four asymptomatic donors had been HEV viraemic for up to three months with the longest duration of HEV viraemia exceeding four months. Despite the HEV-testing efforts, 14 HEV RNA-positive blood products were transfused into 12 immunocompromised and two immunocompetent patients. One recipient of these products developed fatal acute-on-chronic liver failure complicated by Pseudomonas septicemia. The questionnaire revealed that HEV RNA-positive donors significantly more often consumed raw pork meat (12 out of 18; 67%) than controls (89 out of 256; 35%; p = 0.01). In two donors, undercooked pork liver dishes were identified as the source of infection. HEV genotyping was possible in 7 out of 23 of HEV viraemic donors and six out of seven isolates belonged to HEV Genotype 3, Group 2. CONCLUSIONS: Prolonged HEV viraemia can be detected at a relatively high rate in Northern German blood donors, leading to transfusion-transmitted HEV infections in several patients with the risk of severe and fatal complications. Eating raw pork tartare represented a relevant risk for the acquisition of HEV infection. LAY SUMMARY: The relevance of transfusion-transmitted hepatitis E virus infections has been discussed controversially. Herein, we present the first report on routine hepatitis E virus screening of blood donations at a tertiary care centre in Germany. Hepatitis E viraemia was found at a relatively high rate of 0.12% among blood donors, which represents a relevant transfusion-related risk for vulnerable patient populations.

[Hepatitis E virus infection]. / Hépatite E.

Hepatitis E virus infection. Hepatitis E virus (HEV) infection is currently recognized as an endemic pathogen in developed countries, especially in Western Europe. In these regions, HEV is a zoonotic agent and is mainly transmitted by the consumption of under cooked pig or game meat. HEV infection is generally a self-limiting illness in immunocompetent subjects. Conversely, in immunocompromised patients, i.e., solid-organ-transplant recipients, human immunodeficiency virus-infected patients with a low CD4 cell count, hematological patients receiving chemotherapy, and patients given immune suppressive therapy, HEV can lead to chronic hepatitis and cirrhosis. In this case, if viral replication persists despite immunosuppressive regimen decrease, ribavirin therapy has to be initiated to allow viral clearance. Recently, some extra-hepatic manifestations associated with HEV infection have been observed, suggesting a broader tropism than initially considered.

Hépatite E. Après avoir été longtemps considéré comme un pathogène d'importation au retour de zones à faible niveau d'hygiène, le virus de l'hépatite E (VHE) est désormais reconnu comme endémique dans de nombreux pays développés. Sa transmission y est alors zoonotique à partir d'un réservoir animalier domestique et sauvage. Le VHE est ainsi la principale cause d'hépatite aiguë d'origine virale en France et en Europe de l'Ouest. Bien que l'infection soit généralement asymptomatique chez les sujets immunocompétents, les patients immunodéprimés, à savoir les transplantés d'organes solides, les patients infestés par le virus de l'immunodéficience humaine avec un taux de lymphocytes CD4 bas, les patients d'oncohématologie traités par chimiothérapie ou les patients recevant une biothérapie immunosuppressive, peuvent développer une infection chronique, avec un risque élevé d'évolution vers la cirrhose. Si la réplication virale persiste malgré la réduction de l'immunosuppression, un traitement par ribavirine doit être instauré. Récemment, des manifestations extrahépatiques associées aux infections par le VHE ont été caractérisées, laissant envisager un tropisme non restreint au compartiment hépatique.

Multiple remissions of extracavitary primary effusion lymphoma treated with a single cycle of liposomal doxorubicin in a patient infected with HIV.

Primary effusion lymphoma (pel) is a rare human herpesvirus 8 (hhv8)-related large B cell lymphoma with plasmablastic, immunoblastic, or anaplastic features that often carries a poor prognosis. This lymphoma occurs mainly in patients with hiv infection, most often with Epstein-Barr virus (ebv) co-infection, and usually presents as body cavity effusions or, less commonly, as extracavitary lesions without effusion (ec-pel). Chemotherapeutic treatment options are limited and require concurrent antiretroviral therapy (art). Here, we report the case of an adult patient with hiv infection and chronic hepatitis E virus (hev) co-infection who had low CD4 T cell recovery after years of art. The patient then developed a cutaneous ec-pel which rapidly regressed after 1 cycle of liposomal doxorubicin (ld) for his Kaposi sarcoma (ks) before treatment with chop chemotherapy. He had previously received numerous cycles of ld for cutaneous ks over 2 years. Because of the patient's low CD4 T cell count, hev co-infection, and earlier unexpected remission of ec-pel before chop, the patient opted for a single trial of ld before other options. Surprisingly, he experienced a complete remission lasting 18 months. Subsequently, his ec-pel relapsed twice at 31 and at 41 months after the initial diagnosis. Upon recurrence, a similar single cycle of ld was given, which again induced remission. The patient today is in complete remission after a total of 4 ld infusions over 54 months. This patient represents a unique case of hiv-with-hhv8-related, ebv-negative ec-pel with chronic hev coinfection, in which rapid remission was achieved after a single cycle of ld, suggesting an antiviral response in addition to the chemotherapeutic effect.

Low prevalence of IgG antibodies against antigens of HEV genotypes 1 and 3 in women with a high-risk pregnancy.

The aim of the study was to assess whether high-risk pregnant women have a higher prevalence of HEV during the perinatal period. This was a cross-sectional study of 428 patients: Group 1, 127 women with a high-risk pregnancy; Group 2, 97 asymptomatic people with reactivity to HCV or HBV; Group 3, 94 patients with clinical symptoms suggestive of HEV infection; and Group 4, 110 healthy blood donors from an urban area of Mexico City. ELISA was used to measure antibody to HEV genotypes 1 and 3. The prevalence rates of anti-HEV IgG antibodies were 0.79% in Group 1, 2.1% in Group 2, 7.4% in Group 3, and 0% in Group 4. Women with a high-risk pregnancy did not have a higher prevalence of HEV infection in this clinical setting.

Clinical and virological features of acute hepatitis E in Gunma prefecture, Japan between 2004 and 2015.

AIM: To evaluate the clinical and virological features of acute hepatitis E (AH-E) in Gunma prefecture and focus on the hepatitis E virus (HEV) infection in immunocompromised patients. METHODS: A total of 30 patients with AH-E diagnosed at our Gunma University Hospital, and located in 3-39-15 Showa-machi, Maebashi, Gunma 371-8511 Japan, and its affiliated hospitals from 2004 to 2015, were studied. We evaluated the detailed medical histories, laboratory examinations and virological features of these participants. RESULTS: Of the 30 patients, 21 patients were men, with a median age of 61 years. Three of these patients had a history of recent oversea travel. A total of 14 patients had eaten raw or undercooked meat/viscera from animals, and two patients had contracted transfusion-transmitted AH-E. Eight patients were immunocompromised, including those with hematological disease, cancer receiving systemic chemotherapy and kidney transplant or connective tissue disease undergoing immunosuppressive medications. The alanine aminotransferase and total bilirubin levels were more significantly reduced in these immunocompromised patients than in the non-immunocompromised patients. Severe thrombocytopenia, an extra-hepatic manifestation of AH-E, occurred in one case. Among the 22 HEV strains whose subgenotype was determined, two were imported strains (1a and 1f), and 11 strains formed four distinct phylogenetic clusters within subgenotype 3b. The remaining nine strains differed from each other by 9.8-22.4%, and were classified into four subgenotypes (3a, 3b, 3e and 3f). CONCLUSION: Markedly divergent HEV strains (3a, 3b, 3e and 3f) were found to circulate in Gunma. Although immunosuppression appears to play a crucial role in establishing chronic sequels, AH-E in eight immunocompromised patients, including transfusion-transmitted HEV infection in two patients, did not become chronic.

Hepatitis e virus detection in liver tissue from patients with suspected drug-induced liver injury.

Hepatitis E virus (HEV) infection is increasingly recognized as a cause of acute hepatitis in the industrialized world. We aimed to determine the frequency of acute HEV infection in cases of suspected drug-induced liver injury (DILI), mainly a diagnosis of exclusion. To this aim, formalin-fixed paraffin-embedded (FFPE) liver tissues of all cases routinely processed in our institute during a 2 1/2 years period in which DILI was among the differential diagnoses (157 liver biopsies, 1 liver explant) were subjected to semi-nested RT-PCR for the detection of HEV RNA. Histopathology was re-evaluated on all cases tested positive. HEV RNA was detectable in 3 of 158 cases (2%) tested, comprising autochthonic as well as travel-related infections with genotypes 1, 3, and 4 each found once, respectively. Histopathologic findings comprised one case with subtotal hepatic necrosis and two cases of acute (cholestatic) hepatitis not distinguishable from acute hepatitis of other etiology. Thus, the overall frequency of acute HEV infection as determined by detection of HEV RNA in liver tissue is substantially increased in patients with suspected DILI compared to the healthy population, emphasizing the need to actively look for HEV infection in cases of suspected DILI. Molecular testing for HEV RNA in routinely processed FFPE liver tissues can be applied to cases with undetermined HEV status.

Hepatitis E in hemodialysis and kidney transplant patients in south-east Italy.

AIM: To investigate the serovirological prevalence and clinical features of hepatitis E virus (HEV) infection in end-stage renal failure patients and in the healthy population. METHODS: HEV infection is a viral disease that can cause sporadic and epidemic hepatitis. Previous studies unexpectedly showed a high prevalence of HEV antibodies in immunosuppressed subjects, including hemodialysis (HD) patients and patients who had undergone kidney transplant. A cohort/case-control study was carried out from January 2012 to August 2013 in two hospitals in southern Italy (Foggia and S. Giovanni Rotondo, Apulia). The seroprevalence of HEV was determined in 801 subjects; 231 HD patients, 120 renal transplant recipients, and 450 health individuals. All HD patients and the recipients of renal transplants were attending the Departments of Nephrology and Dialysis at two hospitals located in Southern Italy, and were included progressively in this study. Serum samples were tested for HEV antibodies (IgG/IgM); in the case of positivity they were confirmed by a Western blot assay and were also tested for HEV-RNA, and the HEV genotypes were determined. RESULTS: A total of 30/801 (3.7%) patients were positive for anti-HEV Ig (IgG and/or IgM) and by Western blot. The healthy population presented with a prevalence of 2.7%, HD patients had a prevalence of 6.0%, and transplant recipients had a prevalence of 3.3%. The overall combined HEV-positive prevalence in the two groups with chronic renal failure was 5.1%. The rates of exposure to HEV (positivity of HEV-IgG/M in the early samples) were lower in the healthy controls, but the difference among the three groups was not statistically significant (P > 0.05). Positivity for anti-HEV/IgM was detected in 4/30 (13.33%) anti-HEV Ig positive individuals, in 2/14 HD patients, in 1/4 transplant individuals, and in 1/12 of the healthy population. The relative risk of being HEV-IgM-positive was significantly higher among transplant recipients compared to the other two groups (OR = 65.4, 95%CI: 7.2-592.7, P < 0.001), but the subjects with HEV-IgM positivity were numerically too few to calculate a significant difference. No patient presented with chronic hepatitis from HEV infection alone. CONCLUSION: This study indicated a higher, but not significant, circulation of HEV in hemodialysis patients vs the healthy population. Chronic hepatitis due to the HEV virus was not observed.

Association of Bell's Palsy with Hepatitis E Virus Infection: A Rare Entity.

Hepatitis E virus (HEV) infection is a common cause of acute hepatitis in India and other developing countries. The data regarding the neurologic manifestation of HEV infection are limited. The neurologic disorders including Guillain-Barré syndrome, polyradiculopathy, neuralgic amyotrophy, encephalitis, bilateral brachial neuritis, ataxia/proximal myopathy, and acute transverse myelitis have been described. Bell's palsy and other cranial nerve involvement in hepatitis A virus (HAV) and HEV infection are rare. We present the second case of Bell's palsy associated with HEV.