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.
A 31-year old male patient underwent kidney transplantation due to hypoplastic kidneys in 1997. He developed a severe post-transplant lymphoma (PTLD) requiring chemotherapy (five cycles of RTX and high-dose cytarabine followed by another cycle of RTX monotherapy) in April 2013. In 2015, he experienced terminal renal graft failure leading to the discontinuation of post-transplant immunosuppression consisting of corticosteroids and mycophenolate mofetil. He suffered from immunoglobin deficiency treated with intravenous immunoglobin G substitutions. In May 2019, an abdominal ultrasound revealed a compensated liver cirrhosis. Extended laboratory testing revealed HEV infection which was also detectable in retained blood samples, confirming the diagnosis of a chronic hepatitis E. RBV treatment was initiated (dose of 200 mg/d), but had to be discontinued shortly after due to severe thrombocytopenia and the reduced general condition of the patient.\nsummarizes the underlying disease, immunosuppressive medication, time from last administration of RTX to HEV diagnosis, laboratory results, and HEV serology at the time of HEV diagnosis of the present patient cohort.\nshows the clinical course of HEV infection in our five patients, depicting the HEV load under the respective RBV treatment regimens and the development of HEV mutations associated with RBV resistance determined by Sanger sequencing. As depicted in , patient #1 exhibited hypogammaglobulinemia with decreased levels of IgG, IgA, and IgM. While expressing normal levels of CD19+ cells, class-switched memory B cells (CD19+ IgD-IgM-CD27+) were clearly diminished (0.2% of CD19+). In addition, patient #1 showed a profound T- and CD4-lymphopenia (190/µL absolute counts) and a low percentage of naïve CD4+ cells. In patient #2, no CD19+ B cells were detectable more than 12 months after the last RTX treatment. In agreement with the diagnosis of Waldenstrom’s disease, IgM levels were increased, while levels of IgG and IgA were reduced. Expressing only a mild T-lymphopenia, patient #2 also showed a relevant reduction in CD4+ cells (180/µL absolute cell count) and low naïve CD4+ cells. Patient #3 exhibited lower IgG trough levels and a complete reduction of IgA and IgM under immunoglobulin replacement therapy. No CD19+ B cells were detectable. Moreover, patient #3 also showed CD4-lymphopenia (100/µL absolute cell count) with low naïve CD4 cells. Patient #4 revealed hypogammaglobulinemia with reduced levels of IgG, IgA, and IgM with completely diminished CD19+ cells. In addition, patient #4 showed profound T- and CD4-lymphopenia (180/µL absolute counts) including a low percentage of naïve CD4+ cells (1%). According to his clinical files, patient #5 had normal immunoglobulin levels after kidney transplantation and before the initiation of PTLD chemotherapy. After chemotherapy the patient expressed constant hypogammaglobulinemia with IgG levels as low as 0.75 g/L, IgA levels of 0.2 and no detectable IgM levels. Finally, patient #5 also showed complete B-lymphopenia, NK-lymphopenia, and a severe T-lymphopenia with an absolute CD4 count of 50/µL.\nIn summary, all patients exhibited relevant hypogammaglobulinemia and T-lymphopenia following RTX-containing treatment regimens in the past.\nHEV subgenotypes and potential RBV treatment failure-associated mutations are listed in .