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 March 2013, a 62-year-old Bulgarian man was admitted with a provisional diagnosis of acute hepatitis based on a preexisting chronic HBV infection (inactive HBV carrier state: positive for HB surface antigen, core antibody, and envelope antibody; negative for HB envelope antigen and surface antibody with existing cirrhosis and ascites). One day prior to admission, the patient suffered from an acute onset of progressive, worsening upper abdominal discomfort, frequent episodes of diarrhea (2–3 times/day), loss of appetite, and fulminant jaundice without systemic symptoms. Laboratory results revealed elevated levels of aspartate aminotransferase (2,452 IU/L), ALT (1,161 IU/L), and GGT (301 IU/L), with high total bilirubin (392 μmol/L; direct bilirubin level: 345 μmol/L), and thrombocytopenia (119×106/L); C-reactive protein was markedly elevated (41.6 mg/L). HAV, HCV, and HIV were excluded. Serologic markers of previous CMV, EBV, and T. gondii infections were positive. Abdominal ultrasound showed known macronodular liver cirrhosis with manifest splenorenal shunting and splenomegaly. Anti-HEV IgM (165.9 IU/mL) and IgG (212.6 IU/mL) antibodies were positive. To exclude acute HBV-associated liver failure, polymerase chain reaction testing was performed using a commercially available kit (Abbott Laboratories, USA) to detect HBV-DNA (<12.5 IU/mL). HEV RNA was detected (9.76×105 copies/mL), and sequencing revealed HEV genotype 3f. Due to the severity of his condition, the patient was immediately transferred and underwent a high-urgency liver transplantation (CMV-positive transplant). The patient experienced the following complications: an ischemic cerebrovascular accident, acute renal failure, corticoid-induced diabetes mellitus, and CMV reactivation one month post-transplant (plasma viral load: 1,493 IU/L).\nIn September 2013, the patient died as a result of cardiac deterioration. A possible route of transmission could not be proven. However, there was a history of recent consumption of insufficiently heated pork sausage. Furthermore, the patient was at increased risk of developing severe complications due to the preexisting chronic liver disease.