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.
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 .