In June 2014, a 66-year-old Caucasian man was admitted for investigation of bilateral shoulder pain associated with remarkably dark urine. He revealed a ten-day history of general malaise, loss of appetite, anorexia, and an influenza-like syndrome with diffuse myalgia. The shoulder pain was evolutive, followed by progressive neurologic complaints, including muscular weakness and loss of force in the left hand accompanied by paresthesia of the fingers and dysesthesia of the palm of the hand. The patient reported a recent trip to Southeast Asia. Magnetic resonance imaging of the head and cervical spine showed no abnormalities, as did computed tomography of the thorax and abdomen. Liver function tests showed elevated ALT (188 IU/L), alkaline phosphatase (159 IU/L), total bilirubin (29.1 μmol/L), and GGT (814 IU/L). Serology was negative for CMV, EBV, HIV, HSV, VZV, T. gondii, parvovirus B19, and Coxiella burnetii. Serology for HBV was weakly positive for the core antibody (signal-to-cutoff ratio: 9.19), and negative for surface and envelope antigens and antibodies. Polymerase chain reaction for HBV was negative. Anti-HEV IgG (174 IU/mL) and IgM (137 IU/mL) were positive, although no serum HEV RNA could be detected at the time of diagnosis. Immunoblot analysis (RecomLine Hepatitis E IgG/IgM; Mikrogen GmbH) confirmed the presence of the antibody with high suspicion of a genotype 3 infection (no bands for genotype 1 visible). It is likely that cross-reactivity with acute HEV infection lead to a false-positive HB core antibody reactivity, which became undetectable during the convalescent phase of HEV infection. Electromyography confirmed bilateral (idiopathic) brachial plexopathy suggestive of Parsonage–Turner syndrome. Therefore, the patient was diagnosed with an acute HEV infection triggering a bilateral Parsonage–Turner syndrome.\nThe patient was managed conservatively with physical therapy and nonsteroidal anti-inflammatory drugs and opiates for pain relief, without any antiviral therapy. Neurologic signs and symptoms improved within two months, and laboratory parameters returned to values within the physiologic reference range within one month. The patient recovered completely after eight months of intensive revalidation exercise.
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 .