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Background: Norovirus (NoV) infection frequently progresses to chronic disease after kidney transplant (KTx). This study aims to assess potential risk factors helping to determine patients at risk of chronic NoV infection and to analyze the effect of NoV on allograft outcome. Additionally, we assessed the effectiveness of intravenous immunoglobulin (IVIg) therapy for chronic NoV infection., Methods: The study enrolled 60 KTx patients requiring hospitalization because of NoV infection. Clinical parameters, severity of NoV infection and potential risk factors were evaluated. Outcome parameters were clinical symptoms, rehospitalizations, persistent shedding of virus, and effects on allograft function., Results: Patients were divided into 2 groups: 29 had acute NoV infection only, 31 progressed to chronic NoV infection. Chronic NoV infection was defined as a recurrence of clinical symptoms plus redetection of NoV in stool. Lymphocyte-depleting induction therapy and diabetes mellitus were independent risk factors for chronic infection. For patients with chronic NoV infection, length of stay in hospital was significantly prolonged (P = 0.024). Allograft function remained impaired in the chronic NoV group 6 and 12 mo after initial admission. IVIg was administered to 18 patients with chronic NoV infection. No further clinical symptoms of NoV infection occurred in 13 (72%) of these patients. However, NoV was still detectable in stool specimens from 10 (77%) of these patients., Conclusions: Chronic NoV infection is associated with reduced allograft function. Administration of IVIg to patients with chronic NoV infection seems beneficial in achieving freedom from clinical symptoms, despite limited effects on shedding of virus., Competing Interests: A.G. has received honoraria from Ablynx/Sanofi, Alexion, and Novartis. O.W. has received research grants for clinical studies, speakers’ fees, honoraria, and travel expenses from Amgen, Alexion, Astellas, Basilea, Biotest, Bristol-Myers Squibb, Correvio, Chiesi, Gilead, Hexal, Janssen, Dr F. Köhler Chemie, MSD, Novartis, Roche, Pfizer, Sanofi, TEVA, and UCB. A.K. has received research grants for clinical studies, speakers’ fees, honoraria and travel expenses from Alexion, Amicus, Amgen, Astellas, Bayer Vital, Binding-Site, Bristol-Myers Squibb, CytoSorbents, Chiesi, Fresenius, GlaxoSmithKline, Hexal, Janssen, Kyowa Kirin, MSD, Novartis, Roche, Peripal, Pfizer, Stada Pharma, Shire, Sanofi, Teva, Vifor Fresenius Medical Care, and Otsuka. The other authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Liver transplantation is often the ultimate option of therapy for chronically hepatitis B virus (HBV) infected patients. Prevention of reinfection is therapy intensive and cost-effective. Adoptive transfer of HBV-specific immunity with the liver from an immune living liver donor (LLD) could be a new approach to prevent reinfection., Methods: Forty-six potential LLDs were vaccinated against HBV. Humoral (antibodies to hepatitis B virus surface antigen [anti-HBs]-titer) and cellular (IFN-gamma-ELISpot and proliferation-assay) immune responses were examined in donors after immunization and in recipients before and after transplantation., Results: Anti-HBs-titers of up to 50,000 IU/L were detected in LLDs. Fourteen recipients received livers from these donors. We detected humoral immunity in one HBV-naïve recipient and in one chronically HBV-infected recipient after transplantation. A transfer of cellular immunity (SI>3) was seen in three recipients. These patients received livers from donors with high anti-HBs-titers of more than 9000 IU/L. Cellular immunity was also detected in the corresponding donors (SI >3 and spots >22)., Conclusions: Our study demonstrates that HBV-specific humoral and cellular immunity can be transferred by liver transplantation after vaccination of the donors. The transfer of B-cell and T-cell immunity correlates with the magnitude of immune responses in the donor.

Background: Previous data indicate that a transfer of specific humoral and cellular immunity by way of allogeneic hematopoietic cell transplantation (HCT) should, in principle, be possible., Methods: In the HCT setting with a follow-up of up to 55 months, we studied the transfer of hepatitis B virus (HBV) specific immunity from electively immunized donors into HLA compatible recipients suffering from chronic myeloid leukemia (CML). After excluding preexisting HBV specific immunity in donor-recipient pairs, 27 prospective donors were vaccinated against HBV. In addition, on an average of 22 months postHCT, 8 of the 19 recipients were immunized once for HBV., Results: Donor vaccination resulted in detectable hepatitis B surface (HBs) antibodies in 85% of donors and specific cellular in vitro responses in 77%. Two weeks postHCT, 86 and 67% of the recipients displayed positive humoral and cellular HBV reactions, respectively, which then decreased. Afterwards, HBV immunity reappeared in 83% of the recipients without revaccination. Following a single vaccination in recipients, seven of eight displayed a typical memory response. An HBV specific response was already detectable 1 week after vaccination, approximately 1,300-fold (humoral) and 60-fold (cellular) higher than observed in the corresponding donors after a single immunization., Conclusions: The "spontaneous" recurrence of HBV immunity and the memory response in recipients give evidence for an elective immune transfer (e.g., for viral antigens) by way of allogeneic HCT.

Background: Reinfection of liver grafts with hepatitis B virus (HBV) is a pertinent problem in clinical liver transplantation, requiring the development of new treatment strategies. However, no animal model is currently available to study the course and mechanism of hepatitis B reinfection. This was the reason to establish the technique of liver transplantation in the woodchuck, which is a widely used animal model for HBV infection., Material and Methods: For the reinfection study, woodchuck hepatitis virus (WHV)-negative animals were selected as donors, whereas chronic carriers served as recipients (n=3). Immunosuppression consisted of cyclosporine in a daily dose of 5 mg/kg. Blood and liver samples were obtained before and 8 hr, 3 weeks, and 10 weeks after transplantation. Virological markers included serological testing for WHV DNA, WHV surface antigen (WHsAg), core antigen (WHcAg), and their antibodies (anti-WHs and anti-WHc). WHV DNA replication intermediates and viral RNA were detected by Southern blot hybridization and Northern blot, respectively. Viral proteins in the liver were visualized by immunohistochemistry for WHsAg and WHcAg., Results: Early after transplantation membranous but no intracytoplasmic staining for WHsAg was detected in the liver graft, which was negative for WHcAg as well as WHV-DNA and RNA. Nearly all hepatocytes in the liver grafts of animals killed at 3 weeks and 10 weeks posttransplant showed strong membranous (WHsAg) and intracytoplasmic (WHsAg and WHcAg) staining, which was higher in frequency and intensity than in carriers before transplantation. The apparently reduced level of WHV replication intermediates and viral RNA in the reinfected liver grafts compared with the carrier animals was caused by the severe morphological changes leading to a replacement of hepatocytes by extended portal infiltrates., Conclusion: The woodchuck proved to be a suitable model to study WHV reinfection after liver transplantation, because the operative procedure was well tolerated. The first sign of viral presence in the graft was WHsAg detected exclusively in the sinusoids. Reinfection was proven by heavy intracytoplasmic staining for WHsAg and WHcAg in the majority of hepatocytes and detection of viral DNA and RNA in the graft.