Monitoring of EBV-specific immunity and humoral milieu factors as early markers for PTLD development in EBV positive high risk pediatric SOT patients - first results of the EB-VISI study
Rebecca Schultze-Florey1, Lioudmila Marra Kotchenkova1, Sabine Tischer-Zimmermann2, Agnes Bonifacius2, Julia Carlens3, Urte Grosser4, Edzard zu Knyphausen5, Nona Mazhari6, Thilo Fleck7, Rainer Blasczyk2, Martin Zimmermann1, Britta Eiz-Vesper2, Britta Maecker-Kolhoff1.
1Pediatric Hematology and Oncology, Hannover Medical school, Hannover, Germany; 2Institute for Transfusion Medicine, Hannover Medical school, Hannover, Germany; 3Pediatric Pneumology, Allergology and Neonatology, Hannover Medical school, Hannover, Germany; 4Pediatric Cardiology, Hannover Medical school, Hannover, Germany; 5Pediatric Cardiology, Heart and Diabetes Center NRW , Bad Oeynhausen, Germany; 6Pediatric Cardiology , University of Gießen, Gießen, Germany; 7Pediatric Cardiology , University of Freiburg, Freiburg, Germany
EB-VISI study.
Introduction: Post-transplant lymphoproliferative disorders (PTLD) represent a severe complication in pediatric solid organ transplant (SOT) recipients. In particular, following heart and lung transplantation in children there is a 20-30% risk of PTLD development within the first 5 years. No standard monitoring for early detection or prediction of PTLD has been established to date. EBV reactivation in EBV-negative patients is a major risk factor for PTLD development; however, monitoring of EBV load in peripheral blood alone is not sufficient to identify patients at high risk. We aim at establishing a set of cellular and / or serologic markers with potential value in predicting development of EBV+ PTLD in high risk SOT patients.
Methods: We set up a prospective pilot study to identify markers that would be informative to be examined in further transplanted patients. The follow-up study was extended to establish a cohort of 100 pediatric heart and lung transplant patients. Blood samples were taken in a 2-4-month interval from asymptomatic EBV+ participants. Samples were analyzed for 1) phenotype of immune cells by flow cytometry, 2) frequency of EBV-specific T cells by interferon-y ELISPOT assay using various EBV antigens, and 3) for humoral factors. Data were analyzed for mean, standard deviation and 95% confidence interval and compared to patients with EBV+ PTLD.
Results: So far 103 EBV+ patients have been included and 13 patients with EBV+ PTLD. Sex ratio is balanced. Median follow up after transplantation is 8.3 years. All patients received their SOT during childhood; 20 patients are now >20 years old, while the remaining are children and adolescents. PTLD patients were between at median 6 years old and 1.2 years after SOT. We started to analyze the intra- and inter-individual consistency of absolute immune cell counts and generated reference values for this patient cohort. The cellular immune response to several EBV antigens analyzed by interferon-y ELISPOT was highly variable.
Conclusion: This ongoing study aims at elucidating factors for early diagnosis of high PTLD risk in EBV+ SOT recipients. Early results demonstrate the feasibility of complex cellular analysis and first insights into the immune system under immunosuppression. Updated results will be presented during the meeting.
[1] Martinez O. Biomarkers for PTLD diagnosis and therapies. Pediatric Nephrology. 2020 Jul;35(7):1173-1181.
[2] Allen U. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13652