Hepatitis E Virus: A Novel Opportunistic Pathogen in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Versluis Jurjen , Pas Suzan D , Agteresch Erik , de Man Rob A , Osterhaus Albert , van der Eijk Annemiek A , Cornelissen Jan 
Published: October 2019

Abstract
Abstract 4137
Hepatitis E virus (HEV) is an emerging pathogen in developed countries. It may cause an acute, most times self-limiting viral hepatitis in healthy individuals. However, persistent chronic infection and cirrhosis in immunocompromised patients, such as recipients of solid organ transplantation, have recently been reported. Sofar, the incidence and sequela of hepatitis due to HEV is unknown in recipients of allogenic stem cell transplantation (alloHSCT). Following two recent cases, we set out to evaluate the point prevalence and clinical sequela of HEV infection in a recent cohort of alloHSCT recipients. 328 patients who received an alloHSCT between January 2006 and July 2011 were included. Recent follow-up plasma samples taken after transplantation were screened for the presence of HEV RNA by real-time PCR. In addition, available plasma samples from all episodes with CTC grade 2–4 liver function abnormalities were retrospectively screened for HEV RNA. Chronic HEV infection was defined as having HEV RNA in serum or plasma lasting for more than 6 months. Furthermore, phylogenetic analysis was performed to determine genotype and to exclude a common source of infection and to examine potential HEV reactivation.
The cohort included 178 male and 150 female patients with a median age at transplantation of 50 (range: 17–66) years. Stem cell sources and donors included sibling donors (n=149), unrelated donors (n=141), and 48 umbilical cord blood (UCB) grafts. 207 episodes of liver function abnormalities were evaluated in addition to the cross-sectional RT-PCR analysis. In total, eight cases (2.4%) of HEV were found, of which six were found in cross-sectional RT-PCR analysis and two by evaluation of abnormal liver functions. Furthermore, HEV specific IgG could be detected prior to alloHSCT in 12.9% of the patients. Two patients (0.6%) were IgM positive, though HEV viremia could not be detected by PCR. Phylogenetic analyses did not reveal a common viral strain in these patients. The median age of HEV infected patients was 56 (range 39–66) months, with 5 males and 3 females. All eight patients were transplanted with grafts from an alternative donor, including MUD (n=5) and UCB (n=3). The median time from alloHSCT to infection was 4.6 (range: 2–18) months and the median duration of HEV infection was 6.4 (range: 2–42) months. The median of maximum PT (ALAT) values at infection was 289 (range: 138–1507) U/l, and median of maximum ferritin levels prior to infection was 1842 (range: 104–5049) ug/l. At the time of infection, six patients were receiving intensive immunosuppression, prescribed for prevention of GVHD (n=2) or for GVHD treatment (n=4). HEV infected patients were mistakenly diagnosed before as hepatic graft-versus-host disease (GVHD) (n=5), or drug-toxicity (n=3). Remarkably, one patient presented with two episodes of viremia with negative HEV PCR in between, characterized as viral reactivation by identical HEV ORF2 sequences, while no HEV specific IgG or IgM antibodies were developed. Five patients failed to rapidly clear HEV and developed chronic HEV infection. Four patients died with HEV viremia and signs of ongoing hepatitis, whereas four other patients cleared HEV within a median period of 8.8 (range: 2–42) months, containing two patients with chronic hepatitis and fibrosis diagnosed with liver biopsy.
In conclusion, although HEV is a relatively infrequent opportunistic pathogen after alloHSCT, HEV may be associated with persistent viremia and the development of chronic active hepatitis, especially in recipients of alternative donor alloHSCT. In addition, recipients of alloHSCT with positive serology for hepatitis E prior transplantation may develop viral reactivation leading to hepatitis. Given the relative frequent diagnosis of hepatic GVHD and/or drug associated liver toxicity, a differential diagnosis including hepatitis E is mandatory. Future alloHSCT recipients from endemic area's should be screened for hepatitis E prior to transplantation and may be monitored during episodes of intensive immunnosuppressive therapy.

Disclosures:
No relevant conflicts of interest to declare.