Understanding the Immune Response Changes to Clinical Interventions for Epstein–Barr Virus Infection Prior to Lymphoma Development in Children After Organ Transplants ( UNEARTH )

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLD) remain a major complication of solid organ transplants (SOT), occurring in 1%-10% of patients, but in greater proportions in children. About 50%-80% of cases are Epstein-Barr Virus (EBV) associated, through partially known and still unknown mechanisms. Even in EBV seronaive SOT recipients, transplant of an SOT from an EBV seropositive donor does not always lead to peripheral blood EBV replication. Longitudinal peripheral blood EBV DNA nucleic acid testing (NAT) after SOT has not improved the individual prediction of PTLD occurrence, likely due to variable SOT recipient immune responses. METHODS: This prospective study is designed to assess longitudinal and comprehensive T and NK cell phenotyping and responses to peripheral blood EBV replication via multispectral flow cytometry and other assays. We will also compare local to central EBV NAT values and test whether torquetenovirus NAT can act as a simpler assay to predict EBV clearance. We will collect 1390 blood samples across 5 time points in the first year after 347 enrolled (278 completed) SOTs (kidney, liver, heart, lung or intestine) from three major pediatric SOT centers in the U.S.A. RESULTS: As of June 30, 2025, our study has enrolled 133 participants, of whom 110 have received an organ transplant (27% Hispanic ethnicity, 16% black race, median age 8 years, across all 4 major SOT types). CONCLUSIONS: By study end, we will know the global immune responses to EBV replication across a spectrum of clinical pediatric SOT situations. We expect to find key immune mechanisms that will predict poor or delayed EBV clearance despite clinical interventions. These findings may lead to new translational immunotherapy approaches to treat EBV DNaemia or prevent PTLD. We expect that our findings will also inform EBV oncogenesis in other immunocompromised or immunocompetent populations.