A 22-year old male patient had been treated with eculizumab from 2013 to 2015 for two years followed by RTX due to an atypical hemolytic-uremic syndrome and immune thrombocytopenia. RTX was administered from May to June 2015 (three cycles). In the following years, the patient suffered from recurrent infections including several episodes of bacterial bloodstream infections. A severe immunoglobulin deficiency was diagnosed and the patient was treated with intravenous immunoglobulin G substitutions. The patient also received long-term treatment with corticosteroids. Elevated aminotransferases were noticed from the end of 2015. In September 2017, he was admitted to our intensive care unit with a septic shock caused by an abscess in the left axilla. During recovery from the sepsis, jaundice was noticed and HEV RNA was detected in his blood (413 mio copies/mL) and feces. RBV therapy was initiated at a reduced dose of 200 mg/d due to his impaired renal function and was subsequently reduced to 200 mg three times per week. In the further course, RBV treatment was increased to a dose of 200–400 mg/d but had to be terminated after 4.5 months due to severe anemia and leukopenia. HEV replication remained continuously detectable throughout the complete RBV treatment period, confirming non-response in this patient.
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.