Sven Pischke

Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants

BACKGROUND & AIMS Hepatitis E virus (HEV) infection can cause chronic hepatitis in recipients of solid organ transplants. However, the factors that contribute to chronic infection and the outcomes of these patients are incompletely understood. We performed a retrospective analysis of data from 17 centers from Europe and the United States that described the progression, outcomes, and factors associated with development of chronic HEV infection in recipients of transplanted solid organs. METHODS We studied data from 85 recipients of solid organ transplants who were infected with HEV. Chronic HEV infection was defined by the persistent increases in levels of liver enzymes and polymerase chain reaction evidence of HEV in the serum and/or stool for at least 6 months. RESULTS Fifty-six patients (65.9%) developed chronic hepatitis. Univariate analysis associated liver transplant, shorter times since transplant, lower levels of liver enzymes and serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive therapy (rather than cyclosporin A) with chronic hepatitis. On multivariate analysis, the independent predictive factors associated with chronic HEV infection were the use of tacrolimus rather than cyclosporin A (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.49-1.97; P = .004) and a low platelet count at the time of diagnosis with HEV infection (OR, 1.02; 95% CI, 1.001-1.1; P = .04). Of patients with chronic hepatitis, 18 (32.1%) achieved viral clearance after the dose of immunosuppressive therapy was reduced. No HEV reactivation was observed after HEV clearance. CONCLUSIONS HEV infection causes chronic hepatitis in more than 60% of recipients of solid organ transplants. Tacrolimus therapy is the main predictive factor for chronic hepatitis. Dose reductions of immunosuppressive therapy resulted in viral clearance in more than 30% of patients.

Pathogenesis and treatment of hepatitis e virus infection.

Hepatitis E has been considered to be a travel-associated, acute, self-limiting liver disease that causes fulminant hepatic failure in specific high-risk groups only. However, hepatitis E virus (HEV) infection can also be acquired in industrialized countries-HEV genotype 3 infection is a zoonosis, with pigs and rodents serving as animal reservoirs. In recent years, cases of chronic HEV infection that were associated with progressive liver disease have been described in several cohorts of immunocompromised individuals, including recipients of organ transplants. The topic of hepatitis E is therefore re-emerging and has raised the following important questions: what is the risk for HEV infection in Western countries (eg, from eating uncooked meat)? How frequently does chronic hepatitis E develop among human immunodeficiency virus-infected patients and recipients of organ transplants? What are the treatment options? What is the current status of vaccine development? What do we know about the pathogenesis of HEV infection, and why does it have a more severe course in pregnant women? This review summarizes the current knowledge on the pathogenesis and treatment of HEV infection.

Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients

Hepatitis E virus (HEV) infection induces self‐limiting liver disease in immunocompetent individuals. Cases of chronic hepatitis E have recently been identified in organ transplant recipients. We questioned if chronic hepatitis E plays a role in graft hepatitis after liver transplantation in a low endemic area. Two hundred twenty‐six liver transplant recipients, 129 nontransplanted patients with chronic liver disease, and 108 healthy controls were tested for HEV antibodies. HEV RNA was investigated in all sera from transplanted patients. HEV antibodies were detected in 1 healthy control (1%), 4 patients with chronic liver disease (3%), and 10 liver transplant recipients (4%). Three liver transplant patients also tested positive for HEV RNA. Two of them developed persistent viremia with HEV genotype 3. The patients were anti‐HEV immunoglobulin G–negative and HEV RNA–negative before transplantation and had an episode of acute hepatitis 5 or 7 months after transplantation, which led to advanced liver fibrosis after 22 months in 1 patient. Seroconversion to anti‐HEV occurred not before 4 months after the first detection of HEV RNA. The possibility of reverse zoonotic transmission was experimentally confirmed by the infection of 5 pigs with a patients serum. The pigs showed histological inflammation in the liver, and HEV RNA was detectable in different organs, including muscle. In conclusion, the prevalence of HEV infection in Central European liver transplant recipients is low; however, chronic hepatitis E may occur and needs to be considered in the differential diagnosis of graft hepatitis. The diagnosis of HEV infection should be based on HEV RNA determination in immunosuppressed patients. We suggest that immunocompromised individuals should avoid eating uncooked meat and contact with possibly HEV‐infected animals. Liver Transpl 16:74–82, 2010.

Ribavirin treatment of acute and chronic hepatitis E: a single-centre experience.

The role of ribavirin for treatment of severe acute or chronic hepatitis E virus (HEV) infection is not well defined.

Chronic Hepatitis E in Heart Transplant Recipients

Chronic courses of hepatitis E virus (HEV) infections have been described in immunosuppressed patients. We aimed to study the role of HEV infections in heart transplant recipients (HTR). 274 HTR were prospectively screened for HEV infection using an anti‐HEV‐IgG ELISA and HEV‐PCR. In addition, 137 patients undergoing cardiac surgery (non‐HTR) and 537 healthy subjects were studied cross‐sectionally. The anti‐HEV‐IgG seroprevalence was 11% in HTR, 7% in non‐HTR and 2% in healthy controls (HTR vs. healthy controls p<0.0001; non‐HTR vs. healthy controls p<0.01). Anti‐HEV tested positive in 4.0% in control cohorts of other immunocompromised patients (n = 474). Four HTR (1.5%) were chronically infected with HEV as shown by HEV‐PCR and all four patients had liver transaminases of >200 IU/L and histological or clinical evidence of advanced liver disease. In three patients ribavirin treatment was successful with a sustained biochemical and virological response while treatment failed in one cirrhotic patient after ribavirin dose reduction. Heart transplant recipients and patients undergoing cardiac surgery have an increased risk for HEV infections. Chronic hepatitis E may explain elevated liver enzymes in heart transplant recipients. Treatment of HEV infection with ribavirin is effective but the optimal dose and duration of ribavirin therapy remains to be determined.

Hepatitis E virus (HEV)‐specific T‐cell responses are associated with control of HEV infection

Hepatitis E virus (HEV) infection is usually self‐limited but may lead to acute hepatitis and rarely to fulminant hepatic failure. Persistent HEV infections have recently been described in organ transplant recipients receiving immunosuppressive medications, suggesting that HEV is controlled by adaptive immune responses. However, only few studies have investigated HEV‐specific T‐cell responses and immune correlates for the failure to clear HEV infection have not been established so far. We investigated T‐cell responses against HEV in 38 subjects including anti‐HEV‐positive (exposed, n = 9) and anti‐HEV‐negative (n = 10) healthy controls, 12 anti‐HEV‐positive but HEV RNA‐negative organ transplant recipients, and seven transplant recipients with chronic hepatitis E. Proliferation as well as cytokine production of CD4+ and CD8+ T cells was studied after stimulation with overlapping peptides spanning all proteins encoded by HEV‐open reading frame (ORF)2 and HEV‐ORF3. We show that (1) strong and multispecific HEV‐specific T‐cell responses are present in exposed healthy controls, and to a lesser extent also in recovered patients after transplantation; (2) that these responses are absent in patients with chronic hepatitis E but become detectable after viral clearance; and (3) that HEV‐specific T‐cell responses can be restored in vitro by blocking the PD‐1 or CTLA‐4 pathways. However, a combination of PD‐1 and CTLA‐4 blockade had no synergistic effects. We conclude that chronic hepatitis E is associated with impaired HEV‐specific T‐cell responses and suggest that enhancing adaptive cellular immunity against HEV might prevent persistent HEV infections. (HEPATOLOGY 2012)

Hepatitis E Seroprevalence in Europe: A Meta-Analysis

There have been large numbers of studies on anti-HEV IgG seroprevalence in Europe, however, the results of these studies have produced high variability of seroprevalence rates, making interpretation increasingly problematic. Therefore, the aim of this study was to develop a clearer understanding of anti-HEV IgG seroprevalence in Europe and identify risk groups for HEV exposure by a meta-analysis of published studies. Methods: All European HEV-seroprevalence studies from 2003 to 2015 were reviewed. Data were stratified by assay, geographical location, and patient cohort (general population, patients with HIV, solid-organ transplant recipients, chronic liver disease patients, and individuals in contact with swine/wild animals). Data were pooled using a mixed-effects model. Results: Four hundred thirty-two studies were initially identified, of which 73 studies were included in the analysis. Seroprevalence estimates ranged from 0.6% to 52.5%, increased with age, but were unrelated to gender. General population seroprevalence varied depending on assays: Wantai (WT): 17%, Mikrogen (MG): 10%, MP-diagnostics (MP): 7%, DiaPro: 4%, Abbott 2%. The WT assay reported significantly higher seroprevalence rates across all cohorts (p < 0.001). Individuals in contact with swine/wild animals had significantly higher seroprevalence rates than the general population, irrespective of assay (p < 0.0001). There was no difference between any other cohorts. The highest seroprevalence was observed in France (WT: 32%, MP: 16%) the lowest in Italy (WT: 7.5%, MP 0.9%). Seroprevalence varied between and within countries. The observed heterogeneity was attributed to geographical region (23%), assay employed (23%) and study cohort (7%). Conclusion: Seroprevalcence rates primarily depend on the seroassy that is used, followed by the geographical region and study cohort. Seroprevalence is higher in individuals exposed to swine and/or wild animals, and increases with age.

Hepatitis E in Germany—an Under-Reported Infectious Disease

BACKGROUND At least 17% of the population in Germany has been infected with the hepatitis E virus (HEV); thus, HEV infections are more frequent than was previously assumed. However, fewer than 500 HEV infections were reported to the Robert Koch Institute in 2013. METHOD Review of pertinent literature retrieved by a selective search in PubMed. RESULTS Persons living in Germany generally acquire hepatitis E infection within the country by consuming infected and undercooked pork; in rare cases, hepatitis E infections are imported from the tropics. HEV can be transmitted via blood products, blood transfusions, and organ transplantation. More than 99% of HEV infections are asymptomatic and self-limiting, but there are also severe cases with acute liver failure. Immunosuppressed persons can develop chronic HEV infection, potentially leading, within a few years, to liver cirrhosis with life-threatening sequelae. Moreover, HEV infection may be associated with extrahepatic manifestations such as Guillain-Barré syndrome. In two retrospectively evaluated case series, ribavirin was found to be active against HEV and can be used to treat either acute or chronic HEV infection. CONCLUSION Hepatitis E must be considered in the differential diagnosis of elevated hepatic enzyme levels and of systemic and neurological conditions of uncertain origin. The infection is usually self-limiting but can take a severe course in immunosuppressed persons. In such cases, ribavirin can be used as an antiviral treatment.

HEV-associated cryoglobulinaemia and extrahepatic manifestations of hepatitis E

Hepatitis E virus infection might cause various extrahepatic manifestations including rheumato logical symptoms, arthralgia, and rash as suggested by a recent study by Al-Shukri and colleagues. Possible pathomechanisms of how the hepatitis E virus might cause extrahepatic manifestations are 1 Kirby T. Record highs of sexually transmitted infections in UK’s MSM. Lancet Infect Dis 2014; 14: 16–17. 2 Colson P, Gouriet F, Badiaga S, Tamalet C, Stein A, Raoult D. Real-time laboratory surveillance of sexually-transmissible infections in Marseille University hospitals reveals rise of gonorrhoea, syphilis and human immunodefi ciency virus seroconversions in 2012. Euro Surveill 2013; 18: 4. 3 Mercer CH, Tanton C, Prah P, Erens B, Sonnenberg P, Clifton S et al. Changes in sexual attitudes and lifestyles in Britain through the life course and over time: fi ndings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet 2013; 382: 1781–94. age was 38 years old (range 14–81) with a peak in the 18–35 age group (57·3%). HIV status was not available for 85 patients. For those for whom status was available, 40% were HIV positive. In summary, in our laboratory sexually transmitted infections other than syphilis reached record levels in 2013, suggesting a change in sexual practices. We recommend that specifi c precautions and possibly prophylaxis should be proposed by the associations for the next Europride.

Hepatitis E in HIV‐positive patients in a low‐endemic country

To the Editor: Hepatitis E virus (HEV) infection has emerged as a special topic of interest in recent years as cases of chronic hepatitis E have been described in organ transplant recipients [1,2]. We therefore read with great interest the recent article by Madejon et al. [3] published in the April 2009 issue of the Journal of Viral Hepatitis describing a lack of evidence for chronic hepatitis E in HIV-infected Spanish patients. The authors tested a cohort of 93 HIV-positive patients for the presence of HEV RNA, and none were found to be positive for this marker in serum. However, the study was not able to answer the important question if HEV infection may take more frequently a chronic course in HIV-infected patients, as IgG anti-HEV antibodies were not tested for and no information was given on the overall seroprevalence of anti-HEV in Spanish HIV-infected patients. We therefore first determined the prevalence of HEV infection in German HIVinfected patients and secondly attempted to establish whether HIV-infected patients who acquire HEV are able to clear the virus or have a higher risk of developing chronic infection. We tested 123 HIV-positive patients [30 men; mean age 44 years (range 19–75)] recruited at the HIV-outpatient clinic of Hannover Medical School for anti-HEV IgG by a commercial ELISA kit (Abbott laboratories, Chicago, IL, USA). HIV viral load was determined by COBAS Taqman (Roche Diagnostics, Grenzach-Wyhlen, Germany) which has a lower limit of quantification of 47 copies per mL. Liver enzymes were normal in 83 patients whilst 40 patients had elevated ALT levels including 10 individuals who also had elevated bilirubin levels. The mean CD4+ T cell count was 392/lL (range 2–1602); 17% of patients had a CD4+ T cell count below 200/ll. HIV-RNA was not detectable by COBAS Taqman (<47 copies per mL) in 85 patients. The mean viral load for HIV in the remaining 38 patients was 94.594 copies per mL (50–26 200 000 copies per mL). The majority of patients were born in Germany (n = 82) whilst 31 had migrated to Germany from various other countries from Asia, Africa and Eastern Europe. Six patients had chronic hepatitis B virus (HBV) and 11 had chronic hepatitis C virus (HCV) infection, whilst one patient was co-infected with HBV and HCV. Anti-HEV-IgG-positive samples were tested for HEV RNA by RT-PCR [4]. IgG-antibodies against HEV were detected by the Abbott-ELISA kit in six HIV-infected patients (5%). All six patients were Germans, but one was born in Africa (three men, three women), and none of these patients was HBV-DNA or HCV-RNA positive. Two of the female patients acquired HIV infection by heterosexual contact, and the third through drug abuse. The three male patients were homosexual. The age of the anti-HEV-positive patients ranged between 39 and 51 years and CD4+ counts between 417 and 923 cells per lL. HIV-RNA was negative in five patients. Importantly, all six anti-HEV-positive patients tested negative for HEV RNA by nested RT-PCR. Five of the six patients had normal ALT levels, and one patient had a moderately elevated ALT level of 94 U/L. Previous studies from Russia and Belarus examining the frequency of anti-HEV IgG in HIV-infected patients demonstrated a significantly increased prevalence of anti-HEV IgG (11%) when compared to the general population (<2%). The anti-HEV prevalence among AIDS patients was even higher at 40% [5]. In addition, a study from Argentina also showed a raised HEV-IgG-seroprevalence in HIV-patients (6.6%) when compared to healthy controls (1.8%) [6]. In this study, we found a seroprevalence of 5% which seemed to be slightly higher than our experience with healthy employees and blood donors where anti-HEV IgG antibodies were found in one of 108 subjects studied [7]. The reason for the slightly higher anti-HEV seroprevalence in HIV-infected patients is unknown. HEV is usually transmitted by the faecal–oral route. However, there have been isolated reports on HEV transmission by blood transfusions [8,9]. The risk of HEV transmission by sexual exposure or by IV drug abuse is still not known. Importantly, HEV infection can also be acquired as a zoonosis because HEV genotype 3 is present in various animal species including swine, rats and cats [10,11]. We recently described two cases of chronic hepatitis E in liver transplant recipients; both patients were infected with HEV genotype 3 [7]. One may speculate that viral factors could contribute to the course of HEV infection, i.e. if an infection becomes chronic. However, no serotyping assays are available yet distinguishing between past HEV genotype 1 infections and exposure to genotype 3. Thus, we do not know if our six HIV-infected patients who were anti-HEV positive were actually infected with HEV genotype 1 or 3. In conclusion, HEV infection is a rather rare event in HIVinfected German patients. In line with the Madrid experience, we did not find evidence for chronic hepatitis E in our cohort. Unfortunately, we are not able to determine the exact time point when the six patients had been infected with HEV. It is indeed possible that the individuals may have been already anti-HEV positive when they acquired HIV infection and thus, our data do not exclude the possibility of chronic HEV infections in HIV-positive patients. Nevertheless, general screening for anti-HEV may not be necessary in countries of low endemicity. However, HEV infection should be considered in the differential diagnosis of otherwise unexplained hepatitis particularly in immunocompromised patients. Journal of Viral Hepatitis, 2010, 17, 598–599 doi:10.1111/j.1365-2893.2009.01219.x