In December 2009, a 32-year-old Caucasian woman was diagnosed with acute myeloid leukemia [t(11;19)]. She had no history of recent travel, contact with animals, or consumption of venison, liver sausage, or offal. She received a blood transfusion prior to undergoing consecutive cycles of chemotherapy. In February 2010, she underwent hematopoietic stem cell transplantation with cells obtained from her brother. A standard screening protocol performed prior to the transplantation showed she was seropositive for HSV, CMV, varicella zoster virus (VZV), EBV, and T. gondii. Further virologic investigation revealed vaccine-derived immunity to HBV, but no evidence of HAV, HCV, or HIV. One month post-transplantation, in March 2010, CMV reactivated and was treated with consecutive antiviral agents (valacyclovir, foscavir, ganciclovir, and cidofovir). In May 2010, pathologic laboratory values were obtained for alanine aminotransferase (ALT; 544 IU/L), aspartate aminotransferase (259 IU/L), and gamma-glutamyltransferase (GGT; 92 IU/L). Findings from an abdominal ultrasound were negative. She underwent a liver biopsy, with histologic findings compatible with acute viral hepatitis. In September 2010, she developed CMV-ventriculitis, which was confirmed by magnetic resonance imaging and presence of viral DNA in cerebrospinal fluid, and was successfully treated with ganciclovir plus cidofovir.\nLiver function tests remained abnormal, and in November 2010, a serum test for HEV RNA was conducted, revealing a high viral load (>5×106 copies/mL). Thus, a diagnosis of HEV infection (genotype 3f) was made, and the patient was treated with ribavirin monotherapy. Serologic HEV testing (RecomWell Hepatitis IgG/IgM; Mikrogen GmbH, Neuried, Germany) remained negative. Although no serum samples were available to evaluate pretransplant serostatus, the hematopoietic stem cell donor was HEV-seronegative. The HEV viraemia remained stable (5×106 copies/mL) for several months. In February 2011, Aspergillus pneumonia with pleural effusion appeared, without hepatic involvement, which was treated with caspofungin plus amphotericin B. One week later, the patient became extremely confused and suffered from dizziness and reduced consciousness. Examination of a plasma sample showed 2,565 copies/mL of adenovirus in addition to the persistent, high HEV viral load (5×106 copies/mL), and a sample of cerebral spinal fluid was positive for HEV RNA (3,700 copies/mL); CMV, adenovirus, EBV, and Toxoplasma were excluded.\nThe patient died in March 2011 due to multiple organ failure. Based on the chronic (>3 months), high-level detection of HEV RNA and no reported recent travel to endemic areas, an autochthonous, chronic HEV infection was most likely. An alternative origin of infection, such as the ingestion of contaminated food during the post-transplant period or transplantation of contaminated cells or blood products could not fully be excluded. Furthermore, no remaining stem cell preparation (prepared in an external laboratory) could be tested for the presence of HEV RNA.
A 69-year old male received seven cycles of R-CHOP plus two cycles of RTX in 2008 and 2009 for non-Hodgkin’s, lymphoma leading to long-term remission. A regular follow-up examination in July 2016 revealed elevated aminotransferases indicating hepatitis. An extended laboratory examination including HEV serology without HEV RNA testing failed to unravel the underlying cause. A liver biopsy obtained in September 2016 exhibited histological features of viral hepatitis, but laboratory results remained negative for hepatotropic viruses. The patient remained undiagnosed until HEV RNA quantitation was performed in March 2018, revealing a HEV load of 4.15 E6 copies/mL despite persistent HEV seronegativity until present (recomWell HEV IgG/IgM and for confirmation recomLine HEV IgG/IgM, both Mikrogen Neuried, Germany). Weight-based RBV was administered at a dose of 1000 mg/day for three months and the patient cleared HEV, which led to the termination of therapy. HEV relapsed after 4 weeks and RBV treatment was re-induced at a dose of 1000 mg/d for 4 additional months without achieving viral clearance. After a treatment pause of two months RBV was continued at a reduced dose of 800 mg/d due to increasing fatigue and insomnia of the patient, who shows persisting HEV replication and constantly elevated aminotransferases until present.