*Purpose: Post-transplant lymphoproliferative disorder (PTLD) remains a serious problem in the pediatric transplant population. The Clinical Trials of Organ Transplantation in Children (CTOT-C)-06 is an ongoing, prospective NIAID-sponsored multi-institutional study intended to identify viral and immune biomarkers of Epstein-Barr virus (EBV)-associated PTLD.

*Methods: Enrollment for the study ended in August, 2018 while sample collection and follow up will continue until August, 2019. 865 pediatric transplant recipients (218 kidney, 418 liver, 177 heart, 52 small intestine) were enrolled at seven centers in the US. The mean age at transplant was 6.7 yrs (range <1-21 yr); 54% male and 46% female. Immunosuppression and anti-viral therapy were per each center's standard protocol. EBV serostatus was collected at the time of transplant. EBV PCR data was collected during each 3 months period up to 24 months post transplant and every 6 months thereafter.

*Results: There were 30 documented cases of biopsy proven EBV+ PTLD (overall incidence=3.5%). The prospectively observed incidence was 13.5% in small intestine, 3.9% in heart, 2.8% in kidney and 2.4% in liver. Subjects were grouped according to EBV serostatus (+ or -) of donor (D) and recipient (R). The mean time (days) from transplant to diagnosis of EBV+ PTLD was similar for the D^–R^– group (317.0±45.2, range=285-349) and the D^–R⁺ group (325.7± 193.4, range 162-539) followed by the D⁺R^– group (451±410.0, range 51-1308) with the longest interval in the D⁺R⁺ group (768±726.4, range 112-2303). Patients who were EBV seronegative at the time of transplant had an increased incidence of EBV+ PTLD (R^– = 4.7% vs R⁺ = 2.7%). Further, seronegative recipients whose donors were seropositive also had an increased incidence of EBV+ PTLD (D⁺R^– = 5.4% vs. D^–R⁺ = 3.3%; D⁺R⁺= 2.5%; D^–R^– = 2.7%). Patients with a positive EBV PCR (DNAemia) at any time post-transplant, had a markedly increased incidence of PTLD, however this differed by organ: 37.5% in small intestine, 19.4% in heart, 10.3% in kidney and 7.5% in liver. Of the 30 cases of PTLD, 29 (96.7%) had an EBV+ PCR at any time compared to 27% of patients without PTLD.

*Conclusions: These results delineate the burden of pediatric PTLD in the modern era of immunosuppression, further quantifying the increased risk for seronegative patients, especially with a seropositive donor, and highlight the markedly increased risk of EBV+ PTLD among heavily immunosuppressed patients who develop EBV DNAemia any time post transplant.

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