A 63-year-old Swedish white man underwent orthotopic heart transplantation in July 2012 secondary to dilated cardiomyopathy. Preoperative liver enzymes and bilirubin were within normal ranges with the exception of a slightly elevated aspartate aminotransferase (AST; 1.3 times the upper limit of normal). He had an elevated prothrombin time-international normalized ratio (PT-INR) consistent with his warfarin treatment for atrial fibrillation. Virus serology was negative for hepatitis C virus and hepatitis B virus and he was immune against hepatitis A virus. In addition, he had antibodies against cytomegalovirus (CMV) and Epstein–Barr virus.\nThe surgery was complicated by excessive bleeding, which required administration of clotting factors, plasma and thrombocytes. Postoperatively, he developed a moderate worsening of a pre-existing renal insufficiency and thrombocytopenia. Also, a transient rise in bilirubin and liver enzymes was noted. The maintenance immunosuppressive therapy consisted of tacrolimus (target 6 to 8μg/L), everolimus (target 3 to 6μg/L), mycophenolate mofetil 1g twice a day and prednisolone 15mg daily. One month after surgery he was discharged with normal transaminases.\nAt 6-month follow-up, a marked elevation of liver enzymes was noted and, retrospectively, a borderline enzyme elevation was observed 2 months post-surgery (Fig. ). An abdominal ultrasound showed a suspected liver hemangioma, but was otherwise normal. Echocardiography revealed moderate pericardial effusion without hemodynamic compromise, and normal cardiac function. An endomyocardial biopsy showed no signs of significant rejection. Drug-induced hepatotoxicity was initially suspected because of a temporally related increase in simvastatin dosing, but discontinuation of this drug had no effect on his liver enzymes. Autoantibodies, antinuclear antibodies (ANA), smooth muscle antibodies (SMA) and antimitochondrial antibodies (AMA) for autoimmune hepatitis were all negative. He had not seroconverted in markers for hepatitis B or C infection. He had a low titer of CMV DNA in sera consistent with minor reactivation, which was absent at follow-up a week later.\nSerology for HEV was reactive for both anti-HEV-IgM and IgG-antibodies (recomWell HEV IgG/IgM enzyme-linked immunosorbent assay, Mikrogen Diagnostik, Germany), and HEV RNA (1.6×107 copies per mL) was detected in serum by quantitative polymerase chain reaction (PCR) [] at the 6-month follow-up. A retrospective investigation revealed that the patient was negative for anti-HEV and HEV RNA 2 months prior to surgery and at the day of surgery, but HEV RNA was detected 3 weeks post-surgery in the first available serum sample post-transplantation (Fig. ). At that time point, the serology for HEV was negative and remained negative for the next 9 weeks despite detectable HEV RNA. Both anti-HEV IgM and IgG were detectable in the next available serum sample, which was obtained 26 weeks post-surgery (Fig. ).\nSix months after surgery, the immunosuppressive therapy had been reduced, and consisted of tacrolimus (target 3 to 6μg/L), everolimus, (target 3 to 6μg/L), mycophenolate mofetil 0.5g twice a day, and prednisolone 7.5mg daily. After diagnosis of HEV infection, the dose of mycophenolate mofetil was reduced further to 0.25g twice a day and treatment with ribavirin initiated at a dosing of 800mg daily. Ribavirin therapy resulted in a rapid decline of liver enzymes and after 2 months of treatment, the level of HEV RNA in his serum dropped from 1.6×107 to 63 copies per mL (Fig. ). He then experienced an exacerbation of gout, which was treated by increasing prednisolone dosing to 20mg daily for 3 days followed by 10mg for another 3 days. During this period and up to 9 weeks afterwards HEV replication reactivated and the serum viral load increased to 2.3×104 copies per mL.\nRibavirin treatment was complicated by anemia with a decline in hemoglobin concentration from 13.6 to 10.7g/dL, and thus an increase in dosing to 1200mg daily had to be postponed for 1 month. On this treatment dosing, he cleared the HEV infection in 1.5 months and treatment with ribavirin continued for an additional 3 months (i.e. total treatment duration: 800mg/day for 4.5 months and 1200mg/day for 4.5 months), and a sustained virological response (SVR) was achieved. A liver biopsy 1 year later revealed lack of fibrosis and only minor, non-significant inflammation (grade 0 to 1 according to Batts–Ludwig classification).\nHE is a notifiable disease in Sweden, and possible routes of infection should be investigated. The patient lived and worked in Gothenburg and had not travelled outside Sweden during the last years. He reported no close contact with pigs or other animals, except for birds. No additional cases of HEV infection were diagnosed at the ward during his hospitalization. Sera from the heart donor was retrospectively investigated and found negative for both HEV RNA and anti-HEV IgG and IgM. During surgery and shortly thereafter, the patient received considerable amounts of blood-derived products including thrombocytes, clotting factors and plasma. The clotting factors were produced from a pharmaceutical company assuring that all blood products were tested and negative for HEV RNA in pooled samples. In total thrombocytes, erythrocytes and plasma from 17 different donors were administered to the patient. One year after the transplantation, all 17 donors were asked to provide a serum sample for serological investigation of HEV markers. Of the donors, 12 accepted, and among them, one had detectable anti-HEV IgG. This donor had anti-HEV IgG at a high titer, but had undetectable anti-HEV IgM and HEV RNA in serum. Despite repeated efforts, the remaining five donors did not provide serum samples.\nTo obtain the gt and an indication of the origin of the infecting strain, the viral genome was amplified, sequenced and phylogenetically analyzed in the polymerase region of ORF1 as previously described []. A phylogenetic tree based on the sequences obtained and the corresponding genomic region in 120 HEV strains obtained from GenBank showed that the infecting virus from the transplanted patient was a HEV strain belonging to gt 3. This strain was found on a branch in the phylogenetic tree formed by a HEV strain from German wild boar and from individuals with clinical manifestation of HEV infection during the last 4 years in the Netherlands, Sweden, Germany, and Bulgaria (Fig. ).
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.