Hepatitis E Virus Infection Epidemiology in Recipients of Allogeneic Hematopoietic Cell Transplant

Abstract

Among 292 recipients of allogeneic hematopoietic cell transplant (2018-2022), 64 (21.9%) tested positive for anti-hepatitis E virus (HEV) immunoglobulin G. Among 208 recipients tested by plasma/serum HEV polymerase chain reaction (2012-2022), 3 (1.4%) primary HEV infections were diagnosed; in 1 patient, plasma HEV polymerase chain reaction relapsed positive for 100 days. HEV infection remains rare albeit associated with persistent viral replication.

Keywords: acute hepatitis E; allogeneic hematopoietic cell transplantation; hepatitis E virus; immunosuppression; seroprevalance.

Figure 1.

Characteristics of 3 recipients of an allogeneic HCT with acute HEV infection posttransplant, with evolution of liver function tests and Ct levels of HEV RT-PCR depicted with GvHD and ribavirin treatment periods. For each time point represented on graphs by days before and after transplant, a plasma HEV RT-PCR was performed. ALT, alanine aminotransferase; AST, aspartate aminotransferase; Ct, cycle threshold; GvHD, graft-vs-host disease; HCT, hematopoietic cell transplant; HEV, hepatitis E virus; RT-PCR, reverse transcriptase polymerase chain reaction. Patient 1 was a 34-year-old allogeneic HCT recipient with extranodal NK/T-cell lymphoma previously treated with an autologous HCT. He was diagnosed with HEV infection based on elevated liver enzymes (AST, 240 UI/L; ALT, 184 UI/L; γ-glutamyltransferase, 13 UI/L; total bilirubin, 31 μmol/L) without any clinical symptoms 12 days before the allogeneic HCT procedure. Consumption of raw sea food within several weeks before diagnosis was identified as the major risk factor. HEV RNA was detected in plasma and stools upon diagnosis, with Ct values of 24 and 34, respectively. Treatment with ribavirin was initiated orally at a dose of 600 mg/d 34 days after diagnosis. The first negative plasma RT-PCR result was recorded after 55 days of treatment initiation, 89 days after diagnosis. Treatment was continued for 918 days, until death occurred because of septic shock with lymphoma relapse. Under treatment, HEV RNA in plasma was not detected between 75 and 201 days posttransplant. A transient viral rebound was observed between 243 and 343 days posttransplant in the context of newly diagnosed GvHD (oral, genital, and skin) treated with high-dose corticosteroids. HEV RNA was again undetectable after 427 days posttransplant and remained negative until death. Patient 2 was 60 years old with multiple myeloma previously treated with an autologous HCT. The patient was diagnosed with liver GvHD 8 months posttransplant, 1 year prior to the diagnosis of HEV infection. HEV RNA was not detected in plasma at the time of liver GvHD diagnosis. The patient developed elevated liver enzymes (AST, 105 UI/L; ALT, 143 UI/L; γ-glutamyltransferase, 4351 UI/L; total bilirubin, 6 μmol/L) without symptoms, which prompted a test for HEV RNA in plasma 20 months after allogeneic HCT. The RT-PCR test result was positive with a Ct value of 18.3. HEV RNA was also detected in stools upon diagnosis (Ct, 22.6). No specific exposure could be identified. Treatment with oral ribavirin at a dose of 400 mg/d was initiated 12 days after the diagnosis. Sixty-six days later, no HEV RNA could be detected in plasma. HEV RNA was again positive with high Ct values (33.5-37.7) until death, 143 days after treatment initiation. The patient died of multiorgan failure with adenovirus systemic infection, norovirus enteritis, and polymicrobial bacteremia in the context of skin, intestinal, and hepatic GvHD. Patient 3 was a 23-year-old allogenic HCT recipient with anaplastic large cell lymphoma previously treated with an autologous HCT. The patient was diagnosed with steroid-refractory GvHD of the gastrointestinal tract 1 month posttransplant and disseminated aspergillosis 574 days posttransplant. After antifungal initiation, he developed elevated liver enzymes (AST, 130 UI/L; ALT, 149 UI/L; γ-glutamyltransferase, 610 UI/L; total bilirubin, 11 μmol/L). Drug-induced liver injury was considered, but HEV RNA was also detected in plasma with a Ct value of 13, 602 days posttransplant. Treatment with oral ribavirin at a dose of 600 mg/d was initiated 7 days after the diagnosis and stopped 5 days later because of pancreatitis. He died 697 days posttransplant because of an invasive fungal infection. Notably, HEV RT-PCR tests were retrospectively performed, and HEV RNA could be detected up to 247 days before HEV infection diagnosis without elevated liver enzymes at this time.